ACS Publications. Most Trusted. Most Cited. Most Read
Quick View

OR SEARCH CITATIONS

My Activity
Publications
CONTENT TYPES

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Am. Chem. Soc. 2021, 143, 40, 16370-16376
RETURN TO ISSUEPREVCommunicationNEXT

Palladium-Catalyzed Nondirected Late-Stage C–H Deuteration of Arenes

  • Mirxan Farizyan
    Mirxan Farizyan
    Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 36, 48149 Münster, Germany
    More by Mirxan Farizyan
  • , 
  • Arup Mondal
    Arup Mondal
    Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 36, 48149 Münster, Germany
    More by Arup Mondal
  • , 
  • Sourjya Mal
    Sourjya Mal
    Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 36, 48149 Münster, Germany
    More by Sourjya Mal
  • , 
  • Fritz Deufel
    Fritz Deufel
    Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 36, 48149 Münster, Germany
    More by Fritz Deufel
  • , and 
  • Manuel van Gemmeren*
    Manuel van Gemmeren
    Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 36, 48149 Münster, Germany
    *[email protected]
    More by Manuel van Gemmeren
    Orcidhttps://orcid.org/0000-0003-3080-3579
Cite this: J. Am. Chem. Soc. 2021, 143, 40, 16370–16376
Publication Date (Web):September 28, 2021
https://doi.org/10.1021/jacs.1c08233

Copyright © 2022 The Authors. Published by American Chemical Society. This publication is licensed under

CC-BY-NC-ND 4.0.
  • Open Access

Article Views

14422

Altmetric

-

Citations

31
LEARN ABOUT THESE METRICS
PDF (2 MB)
Get e-Alerts
Supporting Info (1)»
SUBJECTS:

Abstract

High Resolution Image
Download MS PowerPoint Slide

We describe a palladium-catalyzed nondirected late-stage deuteration of arenes. Key aspects include the use of D2O as a convenient and easily available deuterium source and the discovery of highly active N,N-bidentate ligands containing an N-acylsulfonamide group. The reported protocol enables high degrees of deuterium incorporation via a reversible C–H activation step and features extraordinary functional group tolerance, allowing for the deuteration of complex substrates. This is exemplified by the late-stage isotopic labeling of various pharmaceutically relevant motifs and related scaffolds. We expect that this method, among other applications, will prove useful as a tool in drug development processes and for mechanistic studies.

This publication is licensed under

CC-BY-NC-ND 4.0.
  • cc licence
  • by licence
  • nc licence
  • nd licence

Over the last decades the incorporation of hydrogen atom isotopes into organic molecules has received considerable attention and remains a key research goal in both academic and industrial research. (1) Isotopically labeled compounds feature a broad range of applications, starting from their use in the elucidation of reaction mechanisms (2) or as internal standards in mass spectrometry studies. (3) Isotopically labeled analogues of bioactive molecules play a critical role in drug discovery processes, for example in absorption, distribution, metabolism, and excretion (ADME) studies to gain insights into their metabolic profile and toxicity. (4) In an increasing number of cases, deuterated molecules are marketed as new pharmaceuticals, (5) often characterized by improved pharmacokinetic and pharmacodynamic properties. These diverse applications have spurred continued interest in the development of convenient and robust synthetic methods to incorporate deuterium into complex aromatic scaffolds, which occur in many bioactive molecules and related compounds. (1d,e)

Methods such as the de novo synthesis of complex deuterated analogues and the introduction of D/T in prefunctionalized positions often prove to be time-consuming and cost-intensive. (6) Efforts have thus been made to establish methods for direct hydrogen isotope exchange (HIE) of aromatic C–H bonds that could in principle enable efficient postsynthetic incorporation of hydrogen isotopes into bioactive molecules. (1d,e,7)

Traditional methods for direct H/D exchange of arenes include pH-dependent methods (Scheme 1A), where the incorporation of deuterium is achieved by the use of Brønsted/Lewis acids, mostly via an SEAr-type mechanism. (8) Examples of base-mediated HIE reactions of arenes are also known. (9) Owing to the typically harsh reaction conditions, these methods are usually employed for simple arenes. Heterogenous methods for HIE of arenes are well-developed, and high activity can be achieved with many transition metals. (3e,10) This approach offers technical advantages like simple purification (11) but faces challenges such as undesired side reactions. (12)

Scheme 1

Scheme 1. Approaches toward the Deuteration of Arenes
High Resolution Image
Download MS PowerPoint Slide

The potential to achieve high selectivities for HIE under comparably mild conditions, thus enabling a broader functional group tolerance, has spurred research toward homogeneously catalyzed methods. (1b,d,e,13) In this context, the use of directing groups (DGs) has proven to be highly useful. (14) Methods based on various transition metals have been established and feature high efficiencies and broad functional group tolerances (Scheme 1B). (15) While DGs usually lead to selective deuteration at the ortho position, specialized DGs to achieve meta deuteration have also been described. (16)

Recent studies have focused on the use of native functional groups rather than designed DGs to enable directed late-stage C–H deuteration. (17)

These directed protocols are complemented by nondirected approaches, (18) which offer the possibility to address unbiased C–H bonds without requiring a DG on the substrate, thus potentially enabling H/D exchange on a substantially broader range of substrates. Nondirected methods for the deuteration of simple arenes are well-established, (19) but catalysts that enable nondirected HIE of drug molecules and other similarly complex scaffolds have only recently been described (Scheme 1C). (20) Chirik and co-workers introduced an iron catalyst capable of inducing HIE with a variety of pharmaceuticals using D2 as the deuterium source. (20a) The same group later described a Ni-based catalyst that delivered deuterated and tritiated drug molecules efficiently using D2 and T2 as the sources of deuterium and tritium, respectively. (20c) Recently, de Ruiter et al. described an Fe–PCP-pincer complex that proved to be highly active for the nondirected H/D exchange of arenes using C6D6 as the deuterium source and tolerated a considerable range of functional groups. (20e) These catalysts provided substantial progress toward the mild and efficient HIE of complex molecules and raised interest in the development of complementary methods. (1e,20f)

Our group has recently developed Pd-catalysts for nondirected late-stage functionalization of complex (hetero)arenes. (21,22) An extensive mechanistic investigation of our dual-ligand-based catalyst system (23) showed that the C–H activation step is reversible (Scheme 1D). We envisioned that a highly active catalyst for the reversible C–H activation of arenes using our dual ligand design could enable a homogeneous nondirected method for Pd-catalyzed late-stage HIE with the potential to complement existing methods based on 3d metals with regard to the substrate scope and/or deuterium source used.

On the basis of these considerations, we engaged in detailed optimization studies. (24)Table 1 shows the deuteration of model substrate 1 using different bidentate ligands in 1,1,1,3,3,3-hexafluoropropan-2-ol-d1 (d1-HFIP). N-Acetylglycine (L1) as the ligand resulted in moderate H/D-exchange (entry 1). Building upon our recent finding that bulky arylamides as concerted metalation–deprotonation (CMD)-promoting groups in ethylenediamine ligands show superior activity in HIE, (24) we synthesized the analogous glycine derivatives L2 and L3 (entries 2 and 3). These α-amino acid-derived ligands lead to a significant improvement in deuterium incorporation. An extensive search for novel ligand classes with improved properties regarding activity and regioselectivity led us to discover N,N-bidentate ligands that feature N-acylsulfonamide groups. Interestingly, introducing this motif instead of the carboxylic acid moiety offers additional potential for ligand diversification by introducing further variable positions. Using mesityl-substituted ligand L4 gave similar results as L1, albeit with less deuteration at the ortho position, whereas L5 led to decreased values (entries 4 and 5). A significant improvement resulted when the two structural variations were combined in L6 and L7 (entries 6 and 7).

Table 1. Optimization of the Ligand Structurea,b
   D content (%) 
entryligandyield (%)orthometaparatotal D content
1L1991150231.66
2L2952273412.42
3L39724.579472.65
4L498446231.27
5L598735211.05
6L697572462.08
7L7971790742.87
8cL7953995843.51
9c,dL7993460322.15
10cno L7980000
11c,eL7946295954.05
a

Reactions were performed on a 0.1 mmol scale.

b

Yields and degrees of deuteration were determined by 1H NMR spectroscopy using mesitylene as an internal standard. The total deuterium content was determined by mass spectrometry.

c

The reaction was performed with D2O/HFIP (7:3) as the solvent. Since D2O is used as part of the solvent system, this corresponds to an excess of approximately 390 equiv.

d

No 3-trifluoromethylquinoline.

e

The reaction was performed with a reaction time of 48 h.

An investigation of alternative, more convenient deuterium sources showed that improved results are obtained with a 7:3 D2O/HFIP mixture as the solvent (Table 1, entry 8). This is particularly attractive since d1-HFIP, which is comparably costly or needs to be synthesized, can be replaced by a cheap and convenient deuterium source. Control experiments at this stage revealed that both ligands are indeed required to obtain optimal results (entries 9 and 10). Finally, nearly complete deuteration of the meta and para positions was observed when L7 was used with an increased reaction time (entry 11).

Interestingly, the seemingly sterically most hindered ligand enables the highest deuteration at the ortho position. This can be explained by two factors. First, the steric bulk does not point toward the substrate in the key C–H activation step, (23) and second, the ligand enables the highest overall activities, such that even the least reactive site on the substrate is deuterated. However, it remains substantially slower than the other positions (entries 8 and 11). Since the conditions developed in Table 1 (conditions B in Scheme 2) were found using a particularly challenging electron-poor substrate, we hypothesized that more electron-rich substrates might be deuterated under milder conditions. A reoptimization (see the Supporting Information (SI) for details) delivered a second set of reaction conditions using L3 with AgF as an additive at lower temperatures (conditions A in Scheme 2)

Scheme 2

Scheme 2. Reaction Scopea,b
High Resolution Image
Download MS PowerPoint Slide

aReactions were performed on a 0.2 mmol scale.

bPositions with less than 10% D incorporation are typically not depicted explicitly but are reflected in the DTotal value (for experimental details, see the SI).

cThe reaction was performed at 40 °C for 72 h.

dDetermined by 1H NMR spectroscopy.

Having established two sets of conditions, we evaluated the scope of our method (Scheme 2). We initiated our investigation by using simple arenes to assess the general functional group tolerance when applying our catalyst systems. The yields of the reisolated substrates were in general good to excellent. The use of alkylated arene 2 under very mild conditions resulted in high H/D exchange in the arene moiety (DTotal = 4.22). Excellent degrees of deuteration were also observed for anisole derivative 3. Notably, our protocol tolerates ketones (4), a functional group that occurs in a wide range of bioactive molecules, but is challenging for many literature methods. Using conditions B, in addition to the deuteration on the arene core, butyrophenone 4 underwent little but measurable isotope exchange in the relatively acidic α-position, presumably via an acid–base mechanism. The electron-poor arenes 1, 5, and 6 were likewise subjected to conditions B, leading to very high degrees of deuteration, especially at the meta and para positions. Dialkyl-substituted substrate 7 smoothly underwent H/D exchange in the arene moiety. Interestingly, halogenated arene 8 was well-tolerated under conditions A, giving the reisolated substrate in good yield with a high overall degree of deuteration. Further disubstituted arenes containing ester, amide, and ether, as well as free hydroxy and acid groups (9–13) gave high levels of deuterium incorporation (up to DTotal = 3.97). Aniline derivatives (14) as well as aldehydes and extended π systems (15) are likewise tolerated under the reaction conditions. Finally, we probed whether our protocol can be used for heterocycles. The comparably electron-rich heteroarenes pyrrole 16, oxazole 17, and thiazole 18 could be deuterated in moderate to good yields with appreciable levels of deuterium incorporation. The deuteration of pyridine derivative 19 confirmed that this substrate class is in principle amenable if the N atom is sufficiently shielded to avoid catalyst poisoning.

We proceeded to evaluate the suitability of our method for the late-stage deuteration of bioactive molecules and related scaffolds. Subjecting estrone derivative 20 to conditions A delivered the deuterated compound [D]20 in very good yield with a high degree of deuteration on the arene moiety. Interestingly, the sterically most congested position underwent H/D exchange to a reduced extent. Similarly, with tyrosine derivative 21 the deuterium incorporation at the sterically more hindered position was lower than at the position ortho to the methoxy group. Furthermore, nateglinide methyl ester 22, the Evans-type reagent 23, guaifenesin derivative 24, watermelon ketone (25), and carbofuran (26) were subjected to conditions A, leading to almost complete deuterium incorporation into the respective arene moieties, thereby demonstrating functional group tolerance toward amides, esters, ethers, and carbamates.

Representatives of the fibrate class such as cipofibrate methyl ester (27), clofibrate (28), bezafibrate methyl ester (29), and fenofibrate (30) were efficiently deuterated. Because of the presence of an electron-poor and a rather electron-rich arene moiety, substrates 29 and 30 were subjected to both conditions A and B. With the milder reaction conditions A, a good degree of deuteration on the electron-rich arene was observed, while with conditions B both arene moieties were efficiently deuterated.

Fluorescein derivative 31 was also subjected to both catalyst systems. With conditions A, the electron-rich positions underwent efficient H/D exchange (DTotal = 2.49) exclusively, whereas conditions B led to substantially increased overall deuterium incorporation (DTotal = 4.57). Nearly complete deuteration of the arene moieties occurred with sonidegib precursor 32. Etodolac methyl ester (33), which contains an indole substructure, likewise underwent efficient H/D exchange using conditions A.

Methyl ester derivatives of naproxen (34), ketoprofen (35), and flurbiprofen (36), as representatives of the profen class of medications, were almost completely deuterated at the arene position (up to DTotal = 7.57). Fenbufen derivative 37 could likewise be deuterated. It should be noted that besides the aromatic core, the α-keto position underwent almost complete deuteration, presumably via an acid/base-type mechanism.

Derivatives of diflunisal (38) and isoxepac (39) gave high degrees of deuteration under conditions B. (−)-Menthol esters of 3-thiophenecarboxylic acid (40) and benzoic acid (41) could both be deuterated efficiently. Finally, subjecting benalaxyl (42), palonosetron precursor 43, praziquantel (44), and camphor derivative 45 to our catalyst led to nearly complete deuterium incorporation in the arene moieties as well as the olefinic position of 45.

Finally, Scheme 2 depicts a number of substrates that could not be deuterated using our method because of either substrate decomposition (46–50) or an absence of reactivity that presumably originates from catalyst poisoning by the substrate (51–53).

As evidenced by the above scope studies, we have developed a broadly applicable protocol for the nondirected late-stage deuteration of arenes using dual ligand-based palladium catalysts. Enabled by the development of a novel ligand class, a variety of bioactive molecules and related structures could be isotopically labeled using D2O as a cheap and convenient deuterium source. This method is applicable to both electron-rich and electron-poor arenes and tolerates a wide range of functional groups, rendering it complementary to established protocols. We expect that our catalysts will prove useful for isotopic labeling in various fields, with potential applications ranging from mechanistic studies to drug development.

Supporting Information

ARTICLE SECTIONS
Jump To

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.1c08233.

  • Optimization of the reaction conditions, preparative procedures, and analytical data for the compounds (PDF)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

ARTICLE SECTIONS
Jump To
  • Corresponding Author
  • Authors
    • Mirxan Farizyan - Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 36, 48149 Münster, Germany
    • Arup Mondal - Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 36, 48149 Münster, Germany
    • Sourjya Mal - Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 36, 48149 Münster, Germany
    • Fritz Deufel - Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 36, 48149 Münster, Germany
  • Author Contributions

    M.F. and A.M. contributed equally.

    Author Contributions

    S.M. and F.D. contributed equally.

  • Funding

    We acknowledge generous financial support by the DFG (Emmy Noether Programme) and WWU Münster. Additionally, this project received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (Grant Agreement 946044).

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

ARTICLE SECTIONS
Jump To

We thank all of the members of our MS and NMR department for their excellent service, A. Uttry for helpful scientific discussions, and Prof. Dr. Frank Glorius for his generous support.

References

ARTICLE SECTIONS
Jump To

This article references 24 other publications.

  1. 1
    (a) Junk, T.; Catallo, W. J. Hydrogen isotope exchange reactions involving C–H (D, T) bonds. Chem. Soc. Rev. 1997, 26, 401– 406,  DOI: 10.1039/CS9972600401
    [Crossref], [CAS], Google Scholar
    1a
    Hydrogen isotope exchange reactions involving C-H (D, T) bonds
    Junk, Thomas; Catallo, W. James
    Chemical Society Reviews (1997), 26 (5), 401-406CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    Exchange reactions involving the displacement of hydrogen bonded to carbon by its heavier isotopes are of interest for both mechanistic and product-oriented research. This review surveys practical strategies for the prepn. of isotopically labeled compds., discusses recent progress made in developing mild and regioselective exchange protocols, and summarizes the mechanistic aspects of C-H bond activation under homogeneous and heterogeneous exchange conditions; 32 refs.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXnvFajtLY%253D&md5=dc8eb0cae2f11917727dd411c2b8ee7d
    .
    (b) Atzrodt, J.; Derdau, V.; Fey, T.; Zimmermann, J. The renaissance of H/D exchange. Angew. Chem., Int. Ed. 2007, 46, 7744– 7765,  DOI: 10.1002/anie.200700039
    [Crossref], [PubMed], [CAS], Google Scholar
    1b
    The renaissance of H/D exchange
    Atzrodt, Jens; Derdau, Volker; Fey, Thorsten; Zimmermann, Jochen
    Angewandte Chemie, International Edition (2007), 46 (41), 7744-7765CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. The increasing demand for stable isotopically labeled compds. has led to an increased interest in H/D-exchange reactions at carbon centers. Today deuterium-labeled compds. are used as internal stds. in mass spectrometry or to help elucidate mechanistic theories. Access to these deuterated compds. takes place significantly more efficiently and more cost effectively by exchange of hydrogen by deuterium in the target mol. than by classical synthesis. This review will conc. on the preparative application of the H/D-exchange reaction in the prepn. of deuterium-labeled compds. Advances over the last ten years are brought together and critically evaluated.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1alsL3M&md5=d4c01740a03e307d6e89ab954bd11809
    .
    (c) Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid, M. Deuterium- and Tritium-Labelled Compounds: Applications in the Life Sciences. Angew. Chem., Int. Ed. 2018, 57, 1758– 1784,  DOI: 10.1002/anie.201704146
    [Crossref], [CAS], Google Scholar
    1c
    Deuterium- and Tritium-Labelled Compounds: Applications in the Life Sciences
    Atzrodt, Jens; Derdau, Volker; Kerr, William J.; Reid, Marc
    Angewandte Chemie, International Edition (2018), 57 (7), 1758-1784CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Hydrogen isotopes are unique tools for identifying and understanding biol. and chem. processes. Hydrogen isotope labeling allows for the traceless and direct incorporation of an addnl. mass or radioactive tag into an org. mol. with almost no changes in its chem. structure, phys. properties, or biol. activity. Using deuterium-labeled isotopologues to study the unique mass-spectrometric patterns generated from mixts. of biol. relevant mols. drastically simplifies anal. Such methods are now providing unprecedented levels of insight in a wide and continuously growing range of applications in the life sciences and beyond. Tritium (3H), in particular, has seen an increase in utilization, esp. in pharmaceutical drug discovery. The efforts and costs assocd. with the synthesis of labeled compds. are more than compensated for by the enhanced mol. sensitivity during anal. and the high reliability of the data obtained. In this Review, advances in the application of hydrogen isotopes in the life sciences are described.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjs1Cgtw%253D%253D&md5=4d6ee858335dbe9f59601428a56415bd
    .
    (d) Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid, M. C-H. Functionalisation for Hydrogen Isotope Exchange. Angew. Chem., Int. Ed. 2018, 57, 3022– 3047,  DOI: 10.1002/anie.201708903
    [Crossref], [CAS], Google Scholar
    1d
    C-H Functionalisation for Hydrogen Isotope Exchange
    Atzrodt, Jens; Derdau, Volker; Kerr, William J.; Reid, Marc
    Angewandte Chemie, International Edition (2018), 57 (12), 3022-3047CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. The various applications of hydrogen isotopes (deuterium, D, and tritium, T) in the phys. and life sciences demand a range of methods for their installation in an array of mol. architectures. In this Review, we describe recent advances in synthetic C-H functionalization for hydrogen isotope exchange.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1Wns7Y%253D&md5=b5fbc8a8f484dd90dd05c098db7fcae6
    .
    (e) Kang, Q.-K.; Shi, H. Catalytic Hydrogen Isotope Exchange Reactions in Late-Stage Functionalization. Synlett 2021,  DOI: 10.1055/a-1354-0367
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  2. 2
    Simmons, E. M.; Hartwig, J. F. On the interpretation of deuterium kinetic isotope effects in C–H bond functionalizations by transition-metal complexes. Angew. Chem., Int. Ed. 2012, 51, 3066– 3072,  DOI: 10.1002/anie.201107334
    [Crossref], [PubMed], [CAS], Google Scholar
    2
    On the Interpretation of Deuterium Kinetic Isotope Effects in C-H Bond Functionalizations by Transition-Metal Complexes
    Simmons, Eric M.; Hartwig, John F.
    Angewandte Chemie, International Edition (2012), 51 (13), 3066-3072CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. We have presented in this essay a reminder of the limitations of some of the expts. used most commonly to measure kinetic isotope effects for processes involving C-H bond functionalization. Specifically, we have shown that the KIE expt. that allows one to conclude that C-H bond cleavage occurs during the rate-detg. step of a reaction is the measurement of the rates or rate consts. of two independent reactions with two substrates, one contg. a C-H bond and one contg. a C-D bond. We hope that this presentation will assist in the selection of expts. to conduct when seeking information on whether C-H bond cleavage occurs during the "rate-detg." or "turnover-limiting" step of a metal-mediated C-H bond functionalization process.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjtFOrsb8%253D&md5=354e995f450827f2028567b5f2849017
  3. 3
    (a) Wehmeyer, K. R.; Knight, P. M.; Parry, R. C. Evaluation of a benchtop ion trap gas chromatographic-tandem mass spectrometric instrument for the analysis of a model drug, tebufelone, in plasma using a stable-isotope internal standard. J. Chromatogr., Biomed. Appl. 1996, 676, 53– 59,  DOI: 10.1016/0378-4347(95)00417-3
    [Crossref], [PubMed], [CAS], Google Scholar
    3a
    Evaluation of a benchtop ion trap gas chromatographic-tandem mass spectrometric instrument for the analysis of a model drug, tebufelone, in plasma using a stable-isotope internal standard
    Wehmeyer, Kenneth R.; Knight, Paula M.; Parry, Ritchard C.
    Journal of Chromatography B: Biomedical Sciences and Applications (1996), 676 (1), 53-9CODEN: JCBBEP; ISSN:0378-4347. (Elsevier)
    The performance of a benchtop GC-ion trap MS-MS instrument, the Varian Saturn 4D, was evaluated for the anal. of a model drug, tebufelone, in plasma. The sample prepn. scheme was designed to provide a highly complex ext. with matrix-derived interferences eluting near and at the retention time of tebufelone and its stable-isotope-labeled analog. The performance of the ion trap in the selected-reaction-monitoring mode was evaluated and also compared with results obtained on a benchtop GC-MS linear quadrupole instrument operated in the selected-ion-monitoring mode. The ion trap, operated in the selected-reaction-monitoring mode, was found to provide a higher degree of selectivity for the anal. of tebufelone. The increased selectivity obtained on the ion trap operated in the selected-reaction-monitoring mode resulted in superior accuracy and precision, as well as a lower limit of quantitation relative to that obtained by the GC-MS anal. A linear std. curve was obtained over three orders of magnitude and the limit of quantitation for tebufelone in plasma was 100 pg/mL using the GC-ion trap MS-MS instrument.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XhvV2nsLk%253D&md5=6fa1f375f31e418dd91afaf4d314dd5b
    .
    (b) Kao, C.-Y.; Giese, R. W. Measurement of N7-(2’-hydroxyethyl)guanine in human DNA by gas chromatography electron capture mass spectrometry. Chem. Res. Toxicol. 2005, 18, 70– 75,  DOI: 10.1021/tx049854d
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    3b
    Measurement of N7-(2'-Hydroxyethyl)guanine in Human DNA by Gas Chromatography Electron Capture Mass Spectrometry
    Kao, Chi-Yu; Giese, Roger W.
    Chemical Research in Toxicology (2005), 18 (1), 70-75CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
    An improved method is presented, based on gas chromatog.-electron capture mass spectrometry (GC-EC-MS), for measuring N7-(2'-hydroxyethyl)guanine (N7-HEG) in DNA from an in vivo sample. The method was used to detect this adduct in amts. of human DNA ranging from 0.07 to 11.5 μg isolated from granulocytes. In this method, the DNA is spiked with a stable isotope internal std. (N7-HEG-d4) and heated in water to release the adduct in a nucleobase form. After the adduct is extd. into 1-butanol, it is purified by reverse phase HPLC and derivatized with HONO, pentafluorobenzyl bromide, and pivalic anhydride. Further purifn. by silica solid phase extn. and reverse phase HPLC is done prior to injection into a GC-EC-MS. Relatively clean GC-EC-MS chromatograms result, contributing to the high sensitivity that is obsd. In the samples tested, from 1.6 to 240 N7-HEG adducts in 107 nucleotides were obsd., a 150-fold range.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVyhsrbI&md5=ad9a3b632556925af9f999d3a8ebdcf8
    .
    (c) Stokvis, E.; Rosing, H.; Beijnen, J. H. Stable isotopically labeled internal standards in quantitative bioanalysis using liquid chromatography/mass spectrometry: necessity or not?. Rapid Commun. Mass Spectrom. 2005, 19, 401– 407,  DOI: 10.1002/rcm.1790
    [Crossref], [PubMed], [CAS], Google Scholar
    3c
    Stable isotopically labeled internal standards in quantitative bioanalysis using liquid chromatography/mass spectrometry: necessity or not?
    Stokvis, Ellen; Rosing, Hilde; Beijnen, Jos H.
    Rapid Communications in Mass Spectrometry (2005), 19 (3), 401-407CODEN: RCMSEF; ISSN:0951-4198. (John Wiley & Sons Ltd.)
    It appears to be a general belief that stable isotopically labeled (SIL) internal stds. yield better assay performance results for quant. bioanal. liq. chromatog./mass spectrometry (LC/MS) assays than does any other internal std. In this article we describe our experiences with structural analogs and SIL internal stds. and their merits and demerits. SIL internal stds. are the first choice, but deuterium-labeled compds. may demonstrate unexpected behavior, such as different retention times or recoveries, than the analyte. In addn., a SIL internal std. with identical chem. properties as the analyte may cover up assay problems with stability, recovery, and ion suppression. Since SIL internal stds. are not always available or are very expensive, structural analogs can be used, however, with consideration of several issues, which are usually displayed during method validation.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhsVCjsbw%253D&md5=39bf96f7b335e919972f4eba38af30bc
    .
    (d) Mutlib, A. E. Application of stable isotope-labeled compounds in metabolism and in metabolism-mediated toxicity studies. Chem. Res. Toxicol. 2008, 21, 1672– 1689,  DOI: 10.1021/tx800139z
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    3d
    Application of Stable Isotope-Labeled Compounds in Metabolism and in Metabolism-Mediated Toxicity Studies
    Daniels, Scott; Espina, Robert; Kao, Kevin; Yuan, Haodan; Lin, Jianrong; Diamond, Sharon; Johnson, Barry; Rodgers, James; Prakash, Shimoga; Unger, Steve; Christ, David; Miwa, Gerald; Gan, Liang-Shang; Mutlib, Abdul E.
    Chemical Research in Toxicology (2008), 21 (9), 1672-1689CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
    A review. Stable isotope-labeled compds. have been synthesized and utilized by scientists from various areas of biomedical research during the last several decades. Compds. labeled with stable isotopes, such as deuterium and carbon-13, have been used effectively by drug metab. scientists and toxicologists to gain better understanding of drugs' disposition and their potential role in target organ toxicities. The combination of stable isotope-labeling techniques with mass spectrometry and NMR spectroscopy, which allows rapid acquisition and interpretation of data, has promoted greater use of these stable isotope-labeled compds. in absorption, distribution, metab., and excretion (ADME) studies. Examples of the use of stable isotope-labeled compds. in elucidating structures of metabolites and delineating complex metabolic pathways are presented in this review. The application of labeled compds. in mechanistic toxicity studies will be discussed by providing an example of how strategic placement of a deuterium atom in a drug mol. mitigated specific-specific renal toxicity. Other examples from the literature demonstrating the application of stable isotope-labeled compds. in understanding metab.-mediated toxicities are presented. Furthermore, an example of how a stable isotope-labeled compd. was utilized to better understand some of the gene changes in toxicogenomic studies is discussed. The interpretation of large sets of data produced from toxicogenomics studies can be a challenge. One approach that could be used to simplify interpretation of the data, esp. from studies designed to link gene changes with the formation of reactive metabolites thought to be responsible for toxicities, is through the use of stable isotope-labeled compds. This is a relatively unexplored territory and needs to be further investigated. The employment of anal. techniques, esp. mass spectrometry and NMR, used in conjunction with stable isotope-labeled compds. to establish and understand mechanistic link between reactive metabolite formation, genomic, and proteomic changes and onset of toxicity is proposed. The use of stable isotope-labeled compds. in early human ADME studies as a way of identifying and possibly quantifying all drug-related components present in systemic circulation is suggested.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXpvVyjuro%253D&md5=0718486f07b08b673ef45eb3b88e57de
    .
    (e) Atzrodt, J.; Derdau, V. Pd- and Pt-catalyzed H/D exchange methods and their application for internal MS standard preparation from a Sanofi-Aventis perspective. J. Labelled Compd. Radiopharm. 2010, 53, 674– 685,  DOI: 10.1002/jlcr.1818
    [Crossref], [CAS], Google Scholar
    3e
    Pd- and Pt-catalyzed H/D exchange methods and their application for internal MS standard preparation from a Sanofi-Aventis perspective
    Atzrodt, Jens; Derdau, Volker
    Journal of Labelled Compounds and Radiopharmaceuticals (2010), 53 (11-12), 674-685CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
    This review addresses method developments both homogeneous and heterogeneous Pd- and Pt-catalyzed exchange, including catalyst activation principles and recent practical applications together with example procedures. Specific requirements for isotopically labeled internal MS std. prepn. are discussed from a Sanofi-Aventis perspective on recent examples.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXis1SjsA%253D%253D&md5=7cb25562f3949122991f6b6aa776e73f
  4. 4
    (a) Marathe, P. H.; Shyu, W. C.; Humphreys, W. G. The use of radiolabeled compounds for ADME studies in discovery and exploratory development. Curr. Pharm. Des. 2004, 10, 2991– 3008,  DOI: 10.2174/1381612043383494
    [Crossref], [PubMed], [CAS], Google Scholar
    4a
    The use of radiolabeled compounds for ADME studies in discovery and exploratory development
    Marathe, P. H.; Shyu, W. C.; Humphreys, W. G.
    Current Pharmaceutical Design (2004), 10 (24), 2991-3008CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
    A review. Radiolabeled compds. are excellent investigative tools and widely used to carry out ADME studies during drug discovery and development stages. The most commonly used radioisotopes are 14C and 3H. 3H materials are generally easier to synthesize than 14C materials. Therefore, a variety of probes and substrates used in in vitro assays are labeled with 3H. Since synthesis of 14C material requires intensive resources, it is usually not available until after a mol. is considered for potential development or after the mol. enters the development phase. Improvement in the technol. in radiochem. has enabled the use of radiolabeled compds. earlier in pre-clin. and clin. development to address mechanistic issues. For in vitro studies, radiolabeled probes are utilized to test affinity with various transporters, to perform metab. comparison among species and to assess possible formation of reactive metabolites. For in vivo studies, radiolabeled compds. are employed to identify and elucidate metabolites formed, to investigate the extent of absorption, bioavailability, tissue distribution, mass balance, routes of excretion, and pre-systemic metab. Due to the significant impact of radiolabeled studies on drug development, these studies will be performed earlier than have been in the past and will continue to be an integral part of drug discovery and development.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXntFOgtrw%253D&md5=b0b323bcbe208f215038a22c7c517db0
    .
    (b) Harbeson, S. L.; Tung, R. D. Deuterium in Drug Discovery and Development. Annu. Rep. Med. Chem. 2011, 46, 403– 417,  DOI: 10.1016/B978-0-12-386009-5.00003-5
    [Crossref], [CAS], Google Scholar
    4b
    Deuterium in drug discovery and development
    Harbeson, Scott L.; Tung, Roger D.
    Annual Reports in Medicinal Chemistry (2011), 46 (), 403-417CODEN: ARMCBI; ISSN:0065-7743. (Elsevier)
    A review presents the use of deuterium to alter the metabolic properties of compds. and discusses past and current development of potential deuterium-contg. drugs.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVCks7fL&md5=48188b3d60119f12cad9ae7ebe877ef5
    .
    (c) Isin, E. M.; Elmore, C. S.; Nilsson, G. N.; Thompson, R. A.; Weidolf, L. Use of radiolabeled compounds in drug metabolism and pharmacokinetic studies. Chem. Res. Toxicol. 2012, 25, 532– 542,  DOI: 10.1021/tx2005212
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    4c
    Use of Radiolabeled Compounds in Drug Metabolism and Pharmacokinetic Studies
    Isin, Emre M.; Elmore, Charles S.; Nilsson, Goran N.; Thompson, Richard A.; Weidolf, Lars
    Chemical Research in Toxicology (2012), 25 (3), 532-542CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
    A review. As part of the drug discovery and development process, it is important to understand the fate of the drug candidate in humans and the relevance of the animal species used for preclin. toxicity and pharmacodynamic studies. Therefore, various in vitro and in vivo studies are conducted during the different stages of the drug development process to elucidate the absorption, distribution, metab., and excretion properties of the drug candidate. Although state-of-the-art LC/MS techniques are commonly employed for these studies, radiolabeled mols. are still frequently required for the quantification of metabolites and to assess the retention and excretion of all drug related material without relying on structural information and MS ionization properties. In this perspective, we describe the activities of Isotope Chem. at AstraZeneca and give a brief overview of different commonly used approaches for the prepn. of 14C- and 3H-labeled drug candidates. Also various drug metab. and pharmacokinetic studies utilizing radiolabeled drug candidates are presented with inhouse examples where relevant. Finally, we outline strategic changes to our use of radiolabeled compds. in drug metab. and pharmacokinetic studies, with an emphasis on delaying of in vivo studies employing radiolabeled drug mols.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivFWns7w%253D&md5=9511e0850d2966ba6b0832fb10bcdab3
    .
    (d) Gant, T. G. Using deuterium in drug discovery: leaving the label in the drug. J. Med. Chem. 2014, 57, 3595– 3611,  DOI: 10.1021/jm4007998
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    4d
    Using Deuterium in Drug Discovery: Leaving the Label in the Drug
    Gant, Thomas G.
    Journal of Medicinal Chemistry (2014), 57 (9), 3595-3611CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A review. Deuterium, the stable isotope of hydrogen, is known to medicinal chemists for its utility in mechanistic, spectroscopic, and tracer studies. In fact, well-known applications utilizing deuterium exist within every subdiscipline in pharmaceutical discovery and development. Recent emphasis on incorporation of deuterium into the active pharmaceutical ingredient has come about as a result of inquiries into the potential for substantial benefits of the deuterium kinetic isotope effect on the safety and disposition of the drug substance. This Perspective traces the author's experience in reviving and expanding this potential utility, first suggested many decades prior by the discoverer of this, the simplest of all isotopes.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFegsrvJ&md5=3818a1dba9be431098ad9dd941dababc
    .
    (e) Elmore, C. S.; Bragg, R. A. Isotope chemistry; a useful tool in the drug discovery arsenal. Bioorg. Med. Chem. Lett. 2015, 25, 167– 171,  DOI: 10.1016/j.bmcl.2014.11.051
    [Crossref], [PubMed], [CAS], Google Scholar
    4e
    Isotope chemistry; a useful tool in the drug discovery arsenal
    Elmore, Charles S.; Bragg, Ryan A.
    Bioorganic & Medicinal Chemistry Letters (2015), 25 (2), 167-171CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    A review. As Medicinal Chemists are responsible for the synthesis and optimization of compds., they often provide intermediates for use by isotope chem. Nevertheless, there is generally an incomplete understanding of the crit. factors involved in the labeling of compds. The remit of an Isotope Chem. group varies from company to company, but often includes the synthesis of compds. labeled with radioisotopes, esp. H-3 and C-14 and occasionally I-125, and stable isotopes, esp. H-2, C-13, and N-15. Often the remit will also include the synthesis of drug metabolites. The methods used to prep. radiolabeled compds. by Isotope Chemists have been reviewed relatively recently. However, the organization and utilization of Isotope Chem. has not been discussed recently and will be reviewed herein.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVWhsL3I&md5=3df9e36e8505b2255c7b8ef652ff96c9
  5. 5
    (a) Mullard, A. FDA approves first deuterated drug. Nat. Rev. Drug Discovery 2017, 16, 305,  DOI: 10.1038/nrd.2017.89
    [Crossref], [CAS], Google Scholar
    5a
    FDA approves dupilumab for severe eczema
    Mullard, Asher
    Nature Reviews Drug Discovery (2017), 16 (5), 305CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
    There is no expanded citation for this reference.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvVCjtbo%253D&md5=361e2f015369489f80b032336b38d849
    .
    (b) Pirali, T.; Serafini, M.; Cargnin, S.; Genazzani, A. A. Applications of Deuterium in Medicinal Chemistry. J. Med. Chem. 2019, 62, 5276– 5297,  DOI: 10.1021/acs.jmedchem.8b01808
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    5b
    Applications of deuterium in medicinal chemistry
    Pirali, Tracey; Serafini, Marta; Cargnin, Sarah; Genazzani, Armando A.
    Journal of Medicinal Chemistry (2019), 62 (11), 5276-5297CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A review. The use of deuteration in medicinal chem. has exploded in the past years, and the FDA has recently approved the first deuterium-labeled drug. Precision deuteration goes beyond the pure and simple amelioration of the pharmacokinetic parameters of a drug and might provide an opportunity when facing problems in terms of metab.-mediated toxicity, drug interactions, and low bioactivation. The use of deuterium is even broader, offering the opportunity to lower the degree of epimerization, reduce the dose of coadministered boosters, and discover compds. where deuterium is the basis for the mechanism of action. Nevertheless, designing, synthesizing, and developing a successful deuterated drug is far from straightforward, and the translation from concept to practice is often unpredictable. This Perspective provides an overview of the recent developments of deuteration, with a focus on deuterated clin. candidates, and highlights both opportunities and challenges of this strategy.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXpvFKjtw%253D%253D&md5=1ce58dbff268894dc319bfc00a1ae01f
  6. 6
    (a) Thomas, A. F. Deuterium Labeling in Organic Chemistry; Appleton-Century-Crofts, 1971.
    Google Scholar
    There is no corresponding record for this reference.
    (b) Chapelle, M. R.; Kent, B. B.; Jones, J. R.; Lu, S.-Y.; Morgan, A. D. Development of combined microwave-enhanced labelling procedures for maximising deuterium incorporation. Tetrahedron Lett. 2002, 43, 5117– 5118,  DOI: 10.1016/S0040-4039(02)00986-3
    [Crossref], [CAS], Google Scholar
    6b
    Development of combined microwave-enhanced labelling procedures for maximizing deuterium incorporation
    Chapelle, Michael R.; Kent, Barry B.; Jones, John R.; Lu, Shui-Yu; Morgan, Alan D.
    Tetrahedron Letters (2002), 43 (29), 5117-5118CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)
    Combined hydrogenation/arom. dehalogenation under microwave-enhanced conditions provides a rapid route to deuterium labeled compds. with enhanced isotopic incorporation.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XkvVent7k%253D&md5=5a57bfc0af2563dd38196c18afbcf858
    .
    (c) Alonso, F.; Beletskaya, I. P.; Yus, M. Metal-mediated reductive hydrodehalogenation of organic halides. Chem. Rev. 2002, 102, 4009– 4091,  DOI: 10.1021/cr0102967
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    6c
    Metal-Mediated Reductive Hydrodehalogenation of Organic Halides
    Alonso, Francisco; Beletskaya, Irina P.; Yus, Miguel
    Chemical Reviews (Washington, DC, United States) (2002), 102 (11), 4009-4091CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review discusses the use of a variety of metals to hydrodehalogenate org. halides. The use of compds. of alkali and alk. earth metals such as lithium, sodium, potassium, magnesium, and calcium, main group metals and metalloids such as boron, aluminum, gallium, and indium, silicon, germanium, and tin, antimony, selenium, and tellurium, transition metals such as titanium and zirconium, vanadium, chromium, molybdenum and tungsten, manganese and rhenium, iron, cobalt, and nickel, ruthenium, rhodium, and palladium, osmium, iridium, and platinum, and copper and silver, and lanthanide and actinide metals as hydrodehalogenating agents is discussed.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xns1Ghsro%253D&md5=17d566566c648e132e2bc926c0bac0c4
    .
    (d) Guaragna, A.; Pedatella, S.; Pinto, V.; Palumbo, G. Synthesis of C-Protected 2,2-Dideutero β 3 -Amino Acids. Synthesis 2006, 2006, 4013– 4016,  DOI: 10.1055/s-2006-950314
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
    .
    (e) Fontana, E.; Venegoni, S. Syntheses of (R,S)-naproxen and its 6-O-desmethylated metabolite labelled with 2H. J. Labelled Compd. Radiopharm. 2008, 51, 239– 241,  DOI: 10.1002/jlcr.1511
    [Crossref], [CAS], Google Scholar
    6e
    Syntheses of (R,S)-naproxen and its 6-O-desmethylated metabolite labeled with 2H
    Fontana, E.; Venegoni, S.
    Journal of Labelled Compounds and Radiopharmaceuticals (2008), 51 (5), 239-241CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
    Naproxen, a well-known non-steroidal anti-inflammatory drug, and its 6-O-desmethylated metabolite were labeled with 2H. (R,S)-Naproxen labeled with 2H (I) was obtained in five steps using the com. available [2H3]iodomethane as the stable labeled reagent. The demethylation of I using 48% HBr in 1-butyl-3-methylimidazolium tetrafluoroborate gave the corresponding 2H-labeled 6-O-desmethylated metabolite.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXot1egsb0%253D&md5=08345ebb234cec921633f38d6ed4e451
    .
    (f) Kallepalli, V. A.; Gore, K. A.; Shi, F.; Sanchez, L.; Chotana, G. A.; Miller, S. L.; Maleczka, R. E.; Smith, M. R. Harnessing C-H Borylation/Deborylation for Selective Deuteration, Synthesis of Boronate Esters, and Late Stage Functionalization. J. Org. Chem. 2015, 80, 8341– 8353,  DOI: 10.1021/acs.joc.5b01588
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    6f
    Harnessing C-H Borylation/Deborylation for Selective Deuteration, Synthesis of Boronate Esters, and Late Stage Functionalization
    Kallepalli, Venkata A.; Gore, Kristin A.; Shi, Feng; Sanchez, Luis; Chotana, Ghayoor A.; Miller, Susanne L.; Maleczka, Robert E.; Smith, Milton R.
    Journal of Organic Chemistry (2015), 80 (16), 8341-8353CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    In the presence of iridium catalysts such as [Ir(cod)OMe]2, aryl and heteroaryl mono- and di(pinacolboronates) underwent regioselective deborylation; reaction of aryl- and heteroaryl mono(pinacolboronates) using D2O yielded regioselectively deuterated arenes, while deborylation of di(pinacolboronates) yielded mono(pinacolboronates) with different and complementary regioselectivity from a direct monoborylation. Di(pinacolboronates) were prepd. using iridium-catalyzed borylation; diborylation and chemoselective deborylation reactions were performed in one pot in some instances. The iridium-catalyzed borylations were compared to palladium-catalyzed deborylations of diborylated indoles described by Movassaghi; for a 3-methylindole-derived diboronate and for three thiophenediboronates, the iridium-catalyzed conditions were more effective. Nonracemic clopidogrel was regioselectively deuterated and monoborylated using iridium-catalyzed mono- and diborylation and deborylation reactions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1KitLzM&md5=5f6906f5e3c8c03a8156a29c959fe195
    .
    (g) Upshur, M. A.; Chase, H. M.; Strick, B. F.; Ebben, C. J.; Fu, L.; Wang, H.; Thomson, R. J.; Geiger, F. M. Vibrational Mode Assignment of α-Pinene by Isotope Editing: One Down, Seventy-One To Go. J. Phys. Chem. A 2016, 120, 2684– 2690,  DOI: 10.1021/acs.jpca.6b01995
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    6g
    Vibrational Mode Assignment of α-Pinene by Isotope Editing: One Down, Seventy-One To Go
    Upshur, Mary Alice; Chase, Hilary M.; Strick, Benjamin F.; Ebben, Carlena J.; Fu, Li; Wang, Hongfei; Thomson, Regan J.; Geiger, Franz M.
    Journal of Physical Chemistry A (2016), 120 (17), 2684-2690CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
    This study aims to reliably assign the vibrational sum frequency generation (SFG) spectrum of α-pinene at the vapor/solid interface using a method involving deuteration of various Me groups. The synthesis of five deuterated isotopologues of α-pinene is presented to det. the impact that removing contributions from Me group C-H oscillators has on its SFG response. 0.6 cm-1 resoln. SFG spectra of these isotopologues show varying degrees of differences in the C-H stretching region when compared to the SFG response of unlabeled α-pinene. The largest spectral changes were obsd. for the isotopologue contg. a fully deuterated vinyl Me group. Noticeable losses in signal intensities allow us to reliably assign the 2860 cm-1 peak to the vinyl Me sym. stretch. Furthermore, upon removing the vinyl Me group entirely by synthesizing apopinene, the steric influence of the unlabeled C9H14 fragment on the SFG response of α-pinene SFG can be readily obsd. The work presented here brings us one step closer to understanding the vibrational spectroscopy of α-pinene.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xls1Kit7c%253D&md5=bc8f3892aab9fb4b073c4a1146dd9352
    .
    (h) Neumann, K. T.; Lindhardt, A. T.; Bang-Andersen, B.; Skrydstrup, T. Synthesis and selective 2 H-, 13 C-, and 15 N-labeling of the Tau protein binder THK-523. J. Labelled Compd. Radiopharm. 2017, 60, 30– 35,  DOI: 10.1002/jlcr.3470
    [Crossref], [PubMed], [CAS], Google Scholar
    6h
    Synthesis and selective 2H-, 13C-, and 15N-labeling of the Tau protein binder THK-523
    Neumann, Karoline T.; Lindhardt, Anders T.; Bang-Andersen, Benny; Skrydstrup, Troels
    Journal of Labelled Compounds and Radiopharmaceuticals (2017), 60 (1), 30-35CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
    Isotopically labeled versions of the (fluoroethoxy)quinolinylaniline THK-523 I (X = N, 15N; Y = C, 13C; R, R1 = H, D), which binds to tau protein, were prepd. using carbonylative Sonogashira and Buchwald-Hartwig coupling, hydrogenative cyclization, and isotopic exchange reactions. Using a two-chamber reactor and sources for in-situ generation of hydrogen and carbon monoxide, stoichiometric amts. of labeled carbon monoxide and hydrogen equiv. were used. Iridium-catalyzed deuteration of I (X = N; Y = C, 13C; R = H, D; R1 = H) yielded further deuterated analogs. Using Buchwald-Hartwig coupling of ammonium sulfate or 15N-labeled ammonium sulfate, the 15N-THK-523 analog I (X = 15N; Y = C; R = R1 = H) was prepd.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvVGisrfO&md5=93cba77143822d8c08548af90e689d57
  7. 7
    Voges, R.; Heys, J. R.; Moenius, T. Preparation of Compounds Labeled with Tritium and Carbon-14; Wiley, 2009.
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  8. 8
    (a) Garnett, J. L.; Long, M. A.; Vining, R. F. W.; Mole, T. New simple method for rapid, selective aromatic deuteration using organoaluminum dihalide catalysts. J. Am. Chem. Soc. 1972, 94, 5913– 5914,  DOI: 10.1021/ja00771a073
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    8a
    New simple method for rapid, selective aromatic deuteration using organoaluminum dihalide catalysts
    Garnett, J. L.; Long, M. A.; Vining, R. F. W.; Mole, T.
    Journal of the American Chemical Society (1972), 94 (16), 5913-14CODEN: JACSAT; ISSN:0002-7863.
    Organoaluminum dihalides catalyze isotopic H exchange between deuterated aromatic compds. (e.g. perdeuterobenzene) and non-deuterated aromatic nuclei. Equil. is reached within minutes at room temp. for most aromatics and is highly specific for the aromatic protons. This procedure constitutes a new simple labeling technique for compds. such as toluene and bromobenzene.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE38XltVSqtL4%253D&md5=6fc52a9972472cacf5cb4d13aad09346
    .
    (b) Long, M. A.; Garnett, J. L.; Vining, R. F. W. Rapid deuteriation and tritiation of organic compounds using organometallic and elemental halides as catalysts. J. Chem. Soc., Perkin Trans. 2 1975, 1298,  DOI: 10.1039/p29750001298
    [Crossref], [CAS], Google Scholar
    8b
    Rapid deuteration and tritiation of organic compounds using organometallic and elemental halides as catalysts
    Long, Mervyn A.; Garnett, John L.; Vining, Ross F. W.
    Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1975), (12), 1298-303CODEN: JCPKBH; ISSN:0300-9580.
    RAlCl2 (R = Me, Et, Ph) and elemental halides, e.g. NbCl5, WCl6, SbCl5, and BBr3, were used as catalysts for the deuteration and tritiation of org. compds. For D labeling of arom. compds. C6D6 was used as D source and EtAlCl2 as catalyst with traces of H2O serving as cocatalysts, although for max. reproducibility very dry conditions with MeAlCl2 catalyst and HCl cocatalyst were used. The tritiation procedure, which was used for arom. compds., cycloalkenes, and O-contg. compds., involved the use of high sp. activity tritiated water to hydrolyze a complex of EtAlCl2 with the substrate, T labeling accompanying the hydrolysis. The labeling of PhMe using the elemental halides as catalysts was examd.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2MXmtVGrt74%253D&md5=fca7526b2340aeeccafcd8248bee594e
    .
    (c) Seibles, J. C.; Bollinger, D. M.; Orchin, M. Synthesis of Perdeuteriobenzo[a] pyrene. Angew. Chem., Int. Ed. Engl. 1977, 16, 656– 657,  DOI: 10.1002/anie.197706561
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
    .
    (d) Branch, C. S.; Barron, A. R. Arene-mercury complexes stabilized by gallium chloride: relative rates of H/D and arene exchange. J. Am. Chem. Soc. 2002, 124, 14156– 14161,  DOI: 10.1021/ja0206590
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    8d
    Arene-Mercury Complexes Stabilized by Gallium Chloride: Relative Rates of H/D and Arene Exchange
    Branch, Catherine S.; Barron, Andrew R.
    Journal of the American Chemical Society (2002), 124 (47), 14156-14161CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The Hg(arene)2(GaCl4)2 catalyzed H/D exchange reaction of C6D6 with arenes occurs via an electrophilic arom. substitution reaction in which the coordinated arene protonates the C6D6. To investigate this mechanism, the kinetics of the Hg(C6H5Me)2(GaCl4)2 catalyzed H/D exchange reaction of C6D6 with naphthalene were studied. Sep. second-order rate consts. were detd. for the 1- and 2-positions on naphthalene; i.e., the initial rate of H/D exchange = k1i[Hg][C-H1] + k2i[Hg][C-H2]. The ratio of k1i/k2i ranges from 11 to 2.5 over the temp. range studied, commensurate with the proposed electrophilic arom. substitution reaction. Observation of the reactions over an extended time period shows that the rates change with time, until they again reach a new and const. second-order kinetics regime. The overall form of the rate equation is unchanged: final rate = k1f[Hg][C-H1] + k2f[Hg][C-H2]. This change in the H/D exchange is accompanied by ligand exchange between Hg(C6D6)2(GaCl4)2 and naphthalene to give Hg(C10H8)2(GaCl4)2, that was characterized by 13C CPMAS NMR and UV-visible spectroscopy. The activation parameters for the ligand exchange may be detd. and are indicative of a dissociative reaction and are consistent with our previously calcd. bond dissocn. for Hg(C6H6)2(AlCl4)2. The initial Hg(arene)2(GaCl4)2 catalyzed reaction of naphthalene with C6D6 involves the deuteration of naphthalene by coordinated C6D6; however, as ligand exchange progresses, the pathway for H/D exchange changes to where the protonation of C6D6 by coordinated naphthalene dominates. The site selectivity for the H/D exchange is initially due to the electrophilic arom. substitution of naphthalene. As ligand exchange occurs, this selectivity is controlled by the activation of the naphthalene C-H bonds by mercury.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XotlSrsLk%253D&md5=cb3797fca9e418261a6fb5f11b22bda3
    .
    (e) Hakala, U.; Wähälä, K. Expedient deuterolabeling of polyphenols in ionic liquids-DCl/D2O under microwave irradiation. J. Org. Chem. 2007, 72, 5817– 5819,  DOI: 10.1021/jo070231p
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    8e
    Expedient Deuterolabeling of Polyphenols in Ionic Liquids-DCl/D2O under Microwave Irradiation
    Hakala, Ullastiina; Waehaelae, Kristiina
    Journal of Organic Chemistry (2007), 72 (15), 5817-5819CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Postsynthetic regioselective arom. ring H/D exchanges in polyphenolic compds. are rapidly performed in high yields and isotopic purities in ionic liq.-DCl/D2O under microwave irradn. Other C-H bonds, including benzylic and lactone α-carbonyl sites, are not affected.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmslyrtrw%253D&md5=ee14aa74377af93e548541173cef3846
    .
    (f) Martins, A.; Lautens, M. A simple, cost-effective method for the regioselective deuteration of anilines Org. Org. Lett. 2008, 10, 4351– 4353,  DOI: 10.1021/ol801763j
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    8f
    A Simple, Cost-Effective Method for the Regioselective Deuteration of Anilines
    Martins, Andrew; Lautens, Mark
    Organic Letters (2008), 10 (19), 4351-4353CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
    A highly effective and operationally simple method for the regioselective deuteration of anilines is presented. A variety of electron-rich and electron-deficient anilines are efficiently deuterated at the ortho and/or para position with respect to the nitrogen in the presence of 1 equiv of conc HCl in D2O. Under the present conditions, arom. methoxy groups do not facilitate deuteration, enabling a chemo- and regioselective deuteration of p-anisidine.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVOqt7fP&md5=e1f682cc99aa7cdf701475a3fa630c53
    .
    (g) Mačková, M.; Himl, M.; Minářová, L.; Lang, J.; Lhoták, P. Regioselective deuteration of 25,27-dialkoxycalix[4]arenes. Tetrahedron Lett. 2011, 52, 2543– 2546,  DOI: 10.1016/j.tetlet.2011.03.030
    [Crossref], [CAS], Google Scholar
    8g
    Regioselective deuteration of 25,27-dialkoxycalix[4]arenes
    Mackova, Michaela; Himl, Michal; Minarova, Lenka; Lang, Jan; Lhotak, Pavel
    Tetrahedron Letters (2011), 52 (20), 2543-2546CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
    A direct deuteration of the upper rim of calix[4]arene has been carried out. 25,27-Dialkoxy derivs. of calix[4]arene (R = Me, Et, Pr, Bu) were regioselectively deuterated at the para positions of unsubstituted phenolic rings using DCl/D2O in tetrachloroethane. Interestingly, identical reaction conditions do not lead to deuteration of mono- or tri-substituted derivs. where only simple cleavage of alkyl substituents was obsd.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXkvVKgsLY%253D&md5=2c11885fe9807da2efa6ee582c547417
    .
    (h) Zhou, L.; Bian, X.; Yang, S.; Mu, B. A two-step synthesis of deuterium labeled 8, 8, 9, 9-d4-hexadecane from nonanoic acid. J. Labelled Compd. Radiopharm. 2012, 55, 158– 160,  DOI: 10.1002/jlcr.1962
    [Crossref], [CAS], Google Scholar
    8h
    A two-step synthesis of deuterium labeled 8, 8, 9, 9-d4-hexadecane from nonanoic acid
    Zhou, Lei; Bian, Xinyu; Yang, Shizhong; Mu, Bozhong
    Journal of Labelled Compounds and Radiopharmaceuticals (2012), 55 (4), 158-160CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
    Labeled compds. are essential in elucidating metabolic mechanisms and reaction pathways. A two-step synthesis of deuterium-labeled 8, 8, 9, 9-d4-hexadecane from nonanoic acid is described here. The synthesis procedures involved hydrogen-deuterium exchange of nonanoic acid with 3.00 M DCl-D2O and then Kolbe electrolysis of the deuterated nonanoic acid to achieve the desired n-alkane that was confirmed by gas chromatog.-mass spectrometry and 1H NMR. This method might provide an alternative route for the prepn. of specifically deuterated alkanes of different chain lengths (C > 4) in which deuterium atoms are located at two adjacent carbons of the alkane's carbon chain. Copyright © 2012 John Wiley & Sons, Ltd.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitVCmtrc%253D&md5=e582af6a74c60b17413d1c24e660a581
    .
    (i) Murai, Y.; Wang, L.; Masuda, K.; Sakihama, Y.; Hashidoko, Y.; Hatanaka, Y.; Hashimoto, M. Rapid and Controllable Hydrogen/Deuterium Exchange on Aromatic Rings of α-Amino Acids and Peptides. Eur. J. Org. Chem. 2013, 2013, 5111– 5116,  DOI: 10.1002/ejoc.201300405
    [Crossref], [CAS], Google Scholar
    8i
    Rapid and controllable hydrogen/deuterium exchange on aromatic rings of α-amino acids and peptides
    Murai, Yuta; Wang, Lei; Masuda, Katsuyoshi; Sakihama, Yasuko; Hashidoko, Yasuyuki; Hatanaka, Yasumaru; Hashimoto, Makoto
    European Journal of Organic Chemistry (2013), 2013 (23), 5111-5116CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Novel hydrogen/deuterium exchange for arom. α-amino acids and their corresponding peptides were performed through the use of deuterated trifluoromethanesulfonic acid (TfOD). Detailed anal. of the exchange revealed that equal hydrogen/deuterium exchange was obsd. for phenylalanine, and specific exchange at the ortho-positions of phenol for tyrosine was also detected. The stereochem. of the arom. α-amino acids was retained under the exchange conditions. The hydrogen/deuterium exchange properties for these arom. α-amino acids are identical for peptides that contain several arom. α-amino acids. The exchange proceeded significantly faster than previous methods. Detailed anal. of the exchange revealed that the method could be controlled by temp., time, and the amt. of reagent.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVKrtbfF&md5=e61270d9a873e4979fc815529ed4dd50
    .
    (j) Müller, K.; Seubert, A. Synthesis of deuterium-labelled fluorobenzoic acids to be used as internal standards in isotope dilution mass spectrometry. Isot. Environ. Health Stud. 2014, 50, 88– 93,  DOI: 10.1080/10256016.2013.830612
    [Crossref], [PubMed], [CAS], Google Scholar
    8j
    Synthesis of deuterium-labelled fluorobenzoic acids to be used as internal standards in isotope dilution mass spectrometry
    Mueller, Karsten; Seubert, Andreas
    Isotopes in Environmental and Health Studies (2014), 50 (1), 88-93CODEN: IEHSF8; ISSN:1025-6016. (Taylor & Francis Ltd.)
    A method for the deuterium labeling of fluorobenzoic acids (FBAs) via acidic H/D exchange of the arom. hydrogen atoms in concd. D2SO4 is described. The synthesis is shown to be easy, fast, low-priced and without the use of catalysts or further purifn. The use of at least double-deuterated FBAs as internal stds. in org. isotope diln. mass spectrometry allows the detn. of FBAs in complex matrixes with highest possible accuracy in combination with a simplified anal. evaluation.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitF2jsLk%253D&md5=1edfbbf2834b40c879a082c8c266aa6e
    .
    (k) Wang, L.; Murai, Y.; Yoshida, T.; Okamoto, M.; Masuda, K.; Sakihama, Y.; Hashidoko, Y.; Hatanaka, Y.; Hashimoto, M. Hydrogen/deuterium exchange of cross-linkable α-amino acid derivatives in deuterated triflic acid Biosci. Biosci., Biotechnol., Biochem. 2014, 78, 1129– 1134,  DOI: 10.1080/09168451.2014.917267
    [Crossref], [PubMed], [CAS], Google Scholar
    8k
    Hydrogen/deuterium exchange of cross-linkable α-amino acid derivatives in deuterated triflic acid
    Wang, Lei; Murai, Yuta; Yoshida, Takuma; Okamoto, Masashi; Masuda, Katsuyoshi; Sakihama, Yasuko; Hashidoko, Yasuyuki; Hatanaka, Yasumaru; Hashimoto, Makoto
    Bioscience, Biotechnology, and Biochemistry (2014), 78 (7), 1129-1134CODEN: BBBIEJ; ISSN:1347-6947. (Taylor & Francis Ltd.)
    In this paper we report here a hydrogen/deuterium exchange (H/D exchange) of cross-linkable α-amino acid derivs. with deuterated trifluoromethanesulfonic acid (TfOD). H/D exchange with TfOD was easily applied to o-catechol contg. phenylalanine (DOPA) within an hour. A partial H/D exchange was obsd. for trifluoromethyldiazirinyl (TFMD) phenylalanine derivs. N-Acetyl-protected natural arom. α-amino acids (Tyr and Trp) were more effective in H/D exchange than unprotected ones. The N-acetylated TFMD phenylalanine deriv. afforded slightly higher H/D exchange than unprotected derivs. An effective post-deuteration method for cross-linkable α-amino acid derivs. will be useful for the anal. of biol. functions of bioactive peptides and proteins by mass spectrometry.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1OrsrjI&md5=ebf9bb44b18e5f906dfe85ca886b486e
    .
    (l) Munz, D.; Webster-Gardiner, M.; Fu, R.; Strassner, T.; Goddard, W. A.; Gunnoe, T. B. Proton or Metal? The H/D Exchange of Arenes in Acidic Solvents. ACS Catal. 2015, 5, 769– 775,  DOI: 10.1021/cs501620f
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    8l
    Proton or metal? The H/D exchange of arenes in acidic solvents
    Munz, Dominik; Webster-Gardiner, Michael; Fu, Ross; Strassner, Thomas; Goddard, William A., III; Gunnoe, T. Brent
    ACS Catalysis (2015), 5 (2), 769-775CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    The H/D exchange of arenes in acidic media by transition-metal and main-group-metal complexes and common inorg. salts was studied. The influence of Lewis acidity, anions, charge, and ligands was evaluated. The results indicate that the detn. of H/D exchange activity in acidic media is not related to the formation of metal-carbon bonds (i.e., C-H activation). The combined exptl. data (regioselectivity, activation energy, kinetics, isotope effects, solvent effects) and DFT calcns. point toward a proton catalysis mechanism. Thus, highly Lewis acidic metal compds., such as aluminum(III) triflate, were extraordinarily active for the H/D exchange reactions. Indeed, the degree of H/D exchange reactivity allows for a comparative measurement of Lewis acidities.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFKjuw%253D%253D&md5=fd7d5dfacfc64dd094c4b0b888ac1478
    .
    (m) Fischer, O.; Hubert, A.; Heinrich, M. R. Shifted Selectivity in Protonation Enables the Mild Deuteration of Arenes Through Catalytic Amounts of Bronsted Acids in Deuterated Methanol. J. Org. Chem. 2020, 85, 11856– 11866,  DOI: 10.1021/acs.joc.0c01604
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    8m
    Shifted Selectivity in Protonation Enables the Mild Deuteration of Arenes Through Catalytic Amounts of Bronsted Acids in Deuterated Methanol
    Fischer, Oliver; Hubert, Anja; Heinrich, Markus R.
    Journal of Organic Chemistry (2020), 85 (18), 11856-11866CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Taking advantage of the "differentiating effect" of the solvent methanol, deuterations of electron-rich arom. systems can be carried out under mild acid catalysis and thus under far milder conditions than known so far. The exceptional functional group tolerance obsd. under the optimized conditions, which even includes highly acid-labile groups, results from a hitherto unexploited shifted selectivity in protonation, and enabled simple and straightforward access to complex deuterium-labeled compds.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsF2rtbrM&md5=8cc8141abc4a644222476d6255e11812
  9. 9
    (a) Beak, P.; Brown, R. A. The tertiary amide as an effective director of ortho lithiation. J. Org. Chem. 1982, 47, 34– 46,  DOI: 10.1021/jo00340a008
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    9a
    The tertiary amide as an effective director of ortho lithiation
    Beak, Peter; Brown, Roger A.
    Journal of Organic Chemistry (1982), 47 (1), 34-46CODEN: JOCEAH; ISSN:0022-3263.
    The tertiary amides BzNR2 (R = Et, Me2CH) give ortho-lithiated species on treatment with EtCHMeLi or BuLi-TMEDA, resp., at -78°. Lithiation of BzNEt2, followed by reaction with MeI, EtI, PhCOMe, Me2CO, BzH or (MeO)3B-H2O2, gives the expected ortho substituted product. Intramol. competition between the diethylamido and chloro, methoxyl, sulfonamido, (dimethylamino)methyl, or oxazolino functions in ortho- and para-substituted benzamides establishes the tertiary amido group to be more effective in directing metalation than any noncarboxamide functional group. The secondary amide has a directing ability comparable to the tertiary amide although the yields are low. A labeling study suggests that lithiation of the ortho position of BzN(CHMe2)2 is direct and not the result of rearrangement of an initially formed α-aza anion. Control of metalation at the ortho or benzylic position by proper selection of the organolithium base is illustrated for p-MeC6H4CON(CHMe2)2. The value of the tertiary amide for control of ortho lithiations and regiospecific arom. substitutions is noted.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL38XjsFemtQ%253D%253D&md5=ea9df59d44986ba8e2e84159740833ea
    .
    (b) Clayden, J.; Pink, J. H.; Westlund, N.; Wilson, F. X. Controlling the regioselectivity of lithiation using kinetic isotope effects: Deuterium as a protecting group for carbon. Tetrahedron Lett. 1998, 39, 8377– 8380,  DOI: 10.1016/S0040-4039(98)01930-3
    [Crossref], [CAS], Google Scholar
    9b
    Controlling the regioselectivity of lithiation using kinetic isotope effects: deuterium as a protecting group for carbon
    Clayden, Jonathan; Pink, Jennifer H.; Westlund, Neil; Wilson, Francis X.
    Tetrahedron Letters (1998), 39 (46), 8377-8380CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)
    By substituting deuterium for hydrogen at positions of high kinetic acidity in amides and carbamates, the usual regiochem. course of their reactions with alkyllithiums (ortho-lithiation vs. lateral lithiation vs. nucleophilic addn.) can be altered or overturned by the kinetic isotope effect. The deuterium substituent functions in these reactions as a protecting group for carbon.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXntFejs7g%253D&md5=d12b195cc20f90bb31c86b90e2b641f7
    .
    (c) Ahmed, A.; Clayden, J.; Rowley, M. Anion translocation in organolithiums: A mechanism for the lithiation and cyclisation of tertiary naphthamides. Tetrahedron Lett. 1998, 39, 6103– 6106,  DOI: 10.1016/S0040-4039(98)01291-X
    [Crossref], [CAS], Google Scholar
    9c
    Anion translocation in organolithiums: a mechanism for the lithiation and cyclization of tertiary naphthamides
    Ahmed, Anjum; Clayden, Jonathan; Rowley, Michael
    Tetrahedron Letters (1998), 39 (34), 6103-6106CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)
    Deuterium labeling shows that an intramol. proton transfer ("anion translocation") is a key step in the mechanism leading to an α-lithiated tertiary naphthamide and thence to the products of anionic cyclization. The kinetic isotope effect means that proton transfer from the ortho position can become the sole mechanism for α-lithiation, though for undeuterated amides a parallel mechanism also operates in which lithiation occurs directly at the position α to nitrogen.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXlt1Snurw%253D&md5=2a79577ff7c14da83ea86212cb5aa9f3
    .
    (d) Zhan, M.; Xu, R.; Tian, Y.; Jiang, H.; Zhao, L.; Xie, Y.; Chen, Y. A Simple and Cost-Effective Method for the Regioselective Deuteration of Phenols. Eur. J. Org. Chem. 2015, 2015, 3370– 3373,  DOI: 10.1002/ejoc.201500192
    [Crossref], [CAS], Google Scholar
    9d
    A Simple and Cost-Effective Method for the Regioselective Deuteration of Phenols
    Zhan, Miao; Xu, Ruixue; Tian, Ye; Jiang, Hongxia; Zhao, Lifeng; Xie, Yongmei; Chen, Yuanwei
    European Journal of Organic Chemistry (2015), 2015 (15), 3370-3373CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A highly effective and operationally simple method for the deuteration of phenols using NaOH as a catalyst and D2O as the deuterium source was presented. A high regioselectivity for the ortho and/or para hydrogens relative to the oxygen atom was achieved, as well as a high degree of deuterium incorporation. The method also had a high functional-group tolerance, and allowed the deuteration of complex pharmaceutically interesting substrates.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmsF2muro%253D&md5=07d3723fd909e8792574dde894b756d5
    .
    (e) Salamanca, V.; Albéniz, A. C. Deuterium Exchange between Arenes and Deuterated Solvents in the Absence of a Transition Metal: Synthesis of D-Labeled Fluoroarenes. Eur. J. Org. Chem. 2020, 3206– 3212,  DOI: 10.1002/ejoc.202000284
    [Crossref], [CAS], Google Scholar
    9e
    Deuterium Exchange between Arenes and Deuterated Solvents in the Absence of a Transition Metal: Synthesis of D-Labeled Fluoroarenes
    Salamanca, Vanesa; Albeniz, Ana C.
    European Journal of Organic Chemistry (2020), 2020 (22), 3206-3212CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Fluoroarenes can be selectively deuterated by H/D exchange with common deuterated solvents in the presence of a catalytic amt. of an alkali metal carbonate or, for the less acidic arenes, stoichiometric quantities of potassium phosphate. This is a sustainable method that does not need transition metal catalysis or the multistep synthesis of a main-group organometallics. This exchange needs to be taken into account when using H/D scrambling as a mechanistic probe in reactions involving fluoroarenes.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlvFKisL4%253D&md5=c977d87e70714b2fc8b61264fdf72ff5
  10. 10
    (a) Fraser, R. R.; Renaud, R. N. The Steric Effect in the Platinum-Catalyzed Exchange Reaction between Aromatic Ring Protons and Deuterium Oxide. J. Am. Chem. Soc. 1966, 88, 4365– 4370,  DOI: 10.1021/ja00971a011
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    10a
    The steric effect in the platinum-catalyzed exchange reaction between aromatic ring protons and deuterium oxide
    Fraser, Robert R.; Renaud, Roger N.
    Journal of the American Chemical Society (1966), 88 (19), 4365-70CODEN: JACSAT; ISSN:0002-7863.
    The relative rates of the platinum-catalyzed exchange of heavy water with the o-, m-, and ρ-protons in several monosubstituted benzenes were detd. A very large steric effect but no detectable electronic effect was observed. These results are interpreted as support for the dissociative mechanism of exchange. 32 references.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF28XkvV2qurs%253D&md5=f55096088a49edda57da5ed8ecd9c85d
    .
    (b) Matsubara, S.; Yokota, Y.; Oshima, K. Palladium-catalyzed decarboxylation and decarbonylation under hydrothermal conditions: decarboxylative deuteration. Org. Lett. 2004, 6, 2071– 2073,  DOI: 10.1021/ol0492602
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    10b
    Palladium-catalyzed decarboxylation and decarbonylation under hydrothermal conditions: decarboxylative deuteration
    Matsubara, Seijiro; Yokota, Yutaka; Oshima, Koichiro
    Organic Letters (2004), 6 (12), 2071-2073CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
    Decarboxylation of free carboxylic acid was performed by Pd/C catalyst under hydrothermal water (250 °C/4 MPa). Under the hydrothermal conditions of deuterium oxide, decarbonylative deuteration was obsd. to give fully deuterated hydrocarbons from carboxylic acids or aldehydes. For example, the decarboxylation of 4-hydroxybenzenepropanoic acid (I) under hydrothermal conditions in the presence of water-d2 gave 4-(ethyl-d5)phen-2,3,5,6-d4-ol-d (II).
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjvFSnsr8%253D&md5=ae279145774b9aa3ce7f5b0ee40fa3c0
    .
    (c) Yamamoto, M.; Yokota, Y.; Oshima, K.; Matsubara, S. H-D exchange reaction on benzene ring of polystyrene in hydrothermal deuterium oxide with platinum(IV) oxide catalyst. Chem. Commun. 2004, 1714– 1715,  DOI: 10.1039/B405063K
    [Crossref], [PubMed], [CAS], Google Scholar
    10c
    H-D exchange reaction on benzene ring of polystyrene in hydrothermal deuterium oxide with platinum(IV) oxide catalyst
    Yamamoto, Mitsuru; Yokota, Yutaka; Oshima, Koichiro; Matsubara, Seijiro
    Chemical Communications (Cambridge, United Kingdom) (2004), (15), 1714-1715CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    Benzene rings of polystyrene samples are labeled with deuterium oxide and catalytic amt. of platinum(IV) oxide under hydrothermal conditions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmtVWgsbw%253D&md5=5ac0b7e5838747bf41c75aafa3950995
    .
    (d) Yamamoto, M.; Oshima, K.; Matsubara, S. Platinum(IV) oxide catalyzed H-D exchange reactions in arylsilanes. Org. Lett. 2004, 6, 5015– 5017,  DOI: 10.1021/ol047738w
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    10d
    Platinum(IV) Oxide Catalyzed H-D Exchange Reactions in Arylsilanes
    Yamamoto, Mitsuru; Oshima, Koichiro; Matsubara, Seijiro
    Organic Letters (2004), 6 (26), 5015-5017CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
    Triphenyl(alkyl)silanes and triphenylsilanols were regioselectively deuterated at 3,4,5-positions of the benzene ring by treatment with D2O in the presence of platinum(IV) oxide under hydrothermal conditions. In some cases, ortho-deuteration also was obsd. to the extent about 26%. The reaction mechanism is discussed.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVCru7vL&md5=2b66b3b02960ebf93596a8cfc4a95955
    .
    (e) Derdau, V.; Atzrodt, J.; Zimmermann, J.; Kroll, C.; Brückner, F. Hydrogen-deuterium exchange reactions of aromatic compounds and heterocycles by NaBD4-activated rhodium, platinum and palladium catalysts. Chem. - Eur. J. 2009, 15, 10397– 10404,  DOI: 10.1002/chem.200901107
    [Crossref], [PubMed], [CAS], Google Scholar
    10e
    Hydrogen-Deuterium Exchange Reactions of Aromatic Compounds and Heterocycles by NaBD4-Activated Rhodium, Platinum and Palladium Catalysts
    Derdau, Volker; Atzrodt, Jens; Zimmermann, Jochen; Kroll, Carsten; Brueckner, Francois
    Chemistry - A European Journal (2009), 15 (40), 10397-10404, S10397/1-S10397/8CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Conventional thermal and microwave conditions were compared for hydrogen-deuterium (H/D) exchange reactions of aminobenzoic acids catalyzed by NaBD4-activated Pd/C or RhCl3 with D2O as the deuterium source. We also investigated different NaBD4-activated metal catalysts (including Pd/C, RhCl3 and Pt/C) under microwave conditions for an efficient H/D exchange of arom. and heterocyclic compds. Even higher deuterium incorporations were obtained for Pd/C and Pt/C catalyst mixts. due to the previously obsd. synergistic effect. Finally, we have applied these optimized conditions for one-step syntheses of the MS stds. of several pharmaceutically active compds.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1KisL%252FN&md5=c8274ea63c0033118faf5cceb3ca193e
    .
    (f) Sajiki, H. Development of deuterium labeling method based on the heterogeneous platinum group metal-catalyzed C-H activation. Yakugaku Zasshi 2013, 133, 1177– 1193,  DOI: 10.1248/yakushi.13-00218
    [Crossref], [PubMed], [CAS], Google Scholar
    10f
    Development of deuterium labeling method based on the heterogeneous platinum group metal-catalyzed C-H activation
    Sajiki, Hironao
    Yakugaku Zasshi (2013), 133 (11), 1177-1193CODEN: YKKZAJ; ISSN:0031-6903. (Pharmaceutical Society of Japan)
    A review. Deuterium (D)labeled compds. are utilized in various scientific fields such as mechanistic elucidation of reactions, prepn. of new functional materials, tracers for microanal., deuterium labeled heavy drugs and so on. Although the H-D exchange reaction is a straightforward method to produce deuterated org. compds., many precedent methods require expensive deuterium gas and/or harsh reaction conditions. A part of our leading research agendas is intended to the development of novel and functional heterogeneous platinum-group catalysts and the reclamation of unknown functionalities of existing heterogeneous platinum-group catalysts. During the course of the study, benzylic positions of substrates were site-selectively deuterated under mild and palladium-on-carbon (Pd/C)-catalyzed hydrogenation conditions in heavy water (D2O). Heat conditions promoted the H-D exchange reactivity and facilitated the H-D exchange reaction at not only the benzylic sites but also inactive C-H bonds and heterocyclic nuclei. It is noteworthy that platinum-on-carbon (Pt/C) indicated a quite high affinity toward arom. nuclei, and the H-D exchange reaction was strongly enhanced by the use of Pt/C as a catalyst under milder conditions. The mixed use of Pd/C and Pt/C was found to be more efficient in the H-D exchange reaction compared to the independent use of Pd/C or Pt/C. Furthermore, simple alkanes could also be efficiently deuterated under rhodium-on-carbon (Rh/C)-catalyzed conditions. The use of ruthenium-on-carbon (Ru/C) enabled the regiospecific and efficient deuterium incorporation at α-positions of alcs. and results were applied as a regio- and stereoselective multi-deuteration method of sugar derivs.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXltlKgsw%253D%253D&md5=b38d85aeba66ae9a5bef2270da341cea
    .
    (g) Pieters, G.; Taglang, C.; Bonnefille, E.; Gutmann, T.; Puente, C.; Berthet, J.-C.; Dugave, C.; Chaudret, B.; Rousseau, B. Regioselective and stereospecific deuteration of bioactive aza compounds by the use of ruthenium nanoparticles. Angew. Chem., Int. Ed. 2014, 53, 230– 234,  DOI: 10.1002/anie.201307930
    [Crossref], [CAS], Google Scholar
    10g
    Regioselective and Stereospecific Deuteration of Bioactive Aza Compounds by the Use of Ruthenium Nanoparticles
    Pieters, Gregory; Taglang, Celine; Bonnefille, Eric; Gutmann, Torsten; Puente, Celine; Berthet, Jean-Claude; Dugave, Christophe; Chaudret, Bruno; Rousseau, Bernard
    Angewandte Chemie, International Edition (2014), 53 (1), 230-234CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    An efficient H/D exchange method allowing the deuteration of pyridines, quinolines, indoles and alkyl amines with D2 in the presence of PVP-supported ruthenium (Ru@PVP) nanoparticles is described. By a general and simple procedure involving mild reaction conditions and simple filtration to recover the labeled product, the isotopic labeling of 22 compds. proceeded in good yield with high chemoselectivity and regioselectivity. The viability of this procedure was demonstrated by the labeling of eight biol. active compds. Remarkably, enantiomeric purity was conserved in the labeled compds., even though labeling took place in the vicinity of the stereogenic center. The level of isotopic enrichment obsd. is suitable for metabolomic studies in most cases. This approach is also perfectly adapted to tritium labeling because it uses a gas as an isotopic source. Besides these applications to mols. of biol. interest, this study reveals a rich and underestimated chem. on the surface of ruthenium nanoparticles. The title compds. thus formed included 3-methylpyridine-2,6-d2, 4-(1-pyrrolidinyl)pyridine-2,6-d2, 6-(phenyl-2,6-d2)pyridine-2-d, 1H-indole-2,3-d2, deuterated nicotine, deuterated paroxetine, piperidine-2,2,6,6-d4 and related substances. The synthesis of the target compds. was achieved using piperidine, morpholine, benzenepropanamine, 1-hexanamine, anabasine, papaverine, melatonin, (9α,13α,14α)-3-methoxy-17-methylmorphinanone (dextromethorphan), protriptyline, paroxetine as starting materials.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVSgsL3I&md5=ae01ca07bfa41f36a91c44264835d30a
    .
    (h) Bresó-Femenia, E.; Godard, C.; Claver, C.; Chaudret, B.; Castillón, S. Selective catalytic deuteration of phosphorus ligands using ruthenium nanoparticles: a new approach to gain information on ligand coordination. Chem. Commun. 2015, 51, 16342– 16345,  DOI: 10.1039/C5CC06984J
    [Crossref], [PubMed], [CAS], Google Scholar
    10h
    Selective catalytic deuteration of phosphorus ligands using ruthenium nanoparticles: a new approach to gain information on ligand coordination
    Breso-Femenia, Emma; Godard, Cyril; Claver, Carmen; Chaudret, Bruno; Castillon, Sergio
    Chemical Communications (Cambridge, United Kingdom) (2015), 51 (91), 16342-16345CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    Ph rings in phenyl- or phenyl-alkylphosphines are selectively deuterated at the ortho position using Ru/PVP nanoparticles, while are fully reduced in the case of arylphosphine oxide derivs. and do not react in the case of arylphosphite. This different behavior provides information about the coordination mode of each ligand.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsV2nsLrI&md5=4c6b25c04dfc5ad2b5c944b9350f2b2a
    .
    (i) Sawama, Y.; Nakano, A.; Matsuda, T.; Kawajiri, T.; Yamada, T.; Sajiki, H. H. –D Exchange Deuteration of Arenes at Room Temperature. Org. Process Res. Dev. 2019, 23, 648– 653,  DOI: 10.1021/acs.oprd.8b00383
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    10i
    H-D Exchange Deuteration of Arenes at Room Temperature
    Sawama, Yoshinari; Nakano, Akihiro; Matsuda, Takumi; Kawajiri, Takahiro; Yamada, Tsuyoshi; Sajiki, Hironao
    Organic Process Research & Development (2019), 23 (4), 648-653CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    Arenes underwent C-H deuteration reactions with D2O in the presence of Pt/C, Ir/C, or combinations of both catalysts in isopropanol/D2O under argon at ambient temp. to yield arenes deuterated at the arene C-H bonds.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlGntLs%253D&md5=ae39643d643ff7cde575d9f64e126809
    .
    (j) Park, K.; Ito, N.; Yamada, T.; Sajiki, H. Efficient Continuous-Flow H–D Exchange Reaction of Aromatic Nuclei in D2O/2-PrOH Mixed Solvent in a Catalyst Cartridge Packed with Platinum on Carbon Beads. Bull. Chem. Soc. Jpn. 2021, 94, 600– 605,  DOI: 10.1246/bcsj.20200325
    [Crossref], [CAS], Google Scholar
    10j
    Efficient continuous-flow H-D exchange reaction of aromatic nuclei in D2O/2-PrOH mixed solvent in a catalyst cartridge packed with platinum on carbon beads
    Park, Kwihwan; Ito, Naoya; Yamada, Tsuyoshi; Sajiki, Hironao
    Bulletin of the Chemical Society of Japan (2021), 94 (2), 600-605CODEN: BCSJA8; ISSN:0009-2673. (Chemical Society of Japan)
    Herein, a continuous-flow deuteration methodol. for various arom. compds. is developed based on heterogeneous platinum-catalyzed hydrogen-deuterium exchange. The reaction entails the transfer of a substrate dissolved in a mixed solvent of 2-propanol and deuterium oxide into a catalyst cartridge packed with platinum on carbon beads (Pt/CB). Pt/CB could be continuously used without significant deterioration of catalyst activity for at least 24 h. Deuteration proceeded within 60 s of the substrate solns. being passed through the Pt/CB layer in the Pt/CB-packed cartridge.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXlvVGltbg%253D&md5=35cae148db1d5c74f7c61670fcdd3baa
  11. 11
    Smith, G. V.; Notheisz, F. Heterogeneous Catalysis in Organic Chemistry; Academic Press, 1999.
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  12. 12
    Beller, M.; Bolm, C. Transition Metals for Organic Synthesis: Building Blocks and Fine Chemicals, 2nd rev. enl. ed.; Wiley-VCH, 2004.
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  13. 13
    (a) Feng, Y.; Lail, M.; Foley, N. A.; Gunnoe, T. B.; Barakat, K. A.; Cundari, T. R.; Petersen, J. L. Hydrogen-deuterium exchange between TpRu(PMe3)(L)X (L = PMe3 and X = OH, OPh, Me, Ph, or NHPh; L = NCMe and X = Ph) and deuterated arene solvents: evidence for metal-mediated processes. J. Am. Chem. Soc. 2006, 128, 7982– 7994,  DOI: 10.1021/ja0615775
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    13a
    Hydrogen-Deuterium Exchange between TpRu(PMe3)(L)X (L = PMe3 and X = OH, OPh, Me, Ph, or NHPh; L = NCMe and X = Ph) and Deuterated Arene Solvents: Evidence for Metal-Mediated Processes
    Feng, Yuee; Lail, Marty; Foley, Nicholas A.; Gunnoe, T. Brent; Barakat, Khaldoon A.; Cundari, Thomas R.; Petersen, Jeffrey L.
    Journal of the American Chemical Society (2006), 128 (24), 7982-7994CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Pyrazolylborato-ruthenium complexes undergo isotopic exchange with deuterated arene solvents. Regioselective isotopic exchange of TpRu(PMe3)2X [X = OH, OPh, Me, Ph, or NHPh; Tp = hydridotris(pyrazolyl)borate] with C6D6 and C6D5CD3 proceeds at 90-130° giving complexes deuterated in X or Tp positions. For X = OH or NHPh, H/D exchange occurs at hydroxide and anilido ligands, resp. For X = OH, OPh, Me, Ph, or NHPh, isotopic exchange occurs at the Tp 4-positions with only minimal deuterium incorporation at the Tp 3- or 5-positions or PMe3 ligands. For TpRu(PMe3)(NCMe)Ph, the H/D exchange occurs at 60° at all three Tp positions and the Ph ring. TpRu(PMe3)2Cl, TpRu(PMe3)2OTf (OTf = trifluoromethanesulfonate), and TpRu(PMe3)2SH do not initiate H/D exchange in C6D6 after extended periods of time at elevated temps. Mechanistic studies indicate that the likely pathway for the H/D exchange involves ligand dissocn. (PMe3 or NCMe), Ru-mediated activation of an arom. C-D bond, and deuteration of basic nondative ligand (hydroxide or anilido) or Tp positions via net D+ transfer.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XkvVehtbc%253D&md5=7ea9f349f622aedd1b7870bbdf390e37
    .
    (b) Allen, P. H.; Hickey, M. J.; Kingston, L. P.; Wilkinson, D. J. Metal-catalysed isotopic exchange labelling: 30 years of experience in pharmaceutical R&D. J. Labelled Compd. Radiopharm. 2010, 53, 731– 738,  DOI: 10.1002/jlcr.1825
    [Crossref], [CAS], Google Scholar
    13b
    Metal-catalyzed isotopic exchange labeling: 30 years of experience in pharmaceutical R&D
    Allen, Paul H.; Hickey, Michael J.; Kingston, Lee P.; Wilkinson, David J.
    Journal of Labelled Compounds and Radiopharmaceuticals (2010), 53 (11-12), 731-738CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
    A review. Metal-catalyzed exchange has been used extensively in the labs. of AstraZeneca plc at R&D Charnwood to label a variety of mols. of pharmaceutical interest with the isotopes of deuterium and tritium. Despite early prejudices against the use of tritiated compds., particularly in ADME studies, the development of directed isotopic exchange techniques has enabled timely and economic support for many pharmaceutical projects.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXis1Sjug%253D%253D&md5=b6ad9bbdd8f2802cc4b3a3e0c9fb1af1
    .
    (c) Lockley, W. J. S.; Heys, J. R. Metal-catalysed hydrogen isotope exchange labelling: a brief overview. J. Labelled Compd. Radiopharm. 2010, 53, 635– 644,  DOI: 10.1002/jlcr.1851
    [Crossref], [CAS], Google Scholar
    13c
    Metal-catalysed hydrogen isotope exchange labelling: a brief overview
    Lockley, William J. S.; Heys, J. Richard
    Journal of Labelled Compounds and Radiopharmaceuticals (2010), 53 (11-12), 635-644CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
    An overview is given of this Special Issue of the Journal of Labeled Compds. and Radiopharmaceuticals dealing with the subject of metal-catalyzed hydrogen isotope exchange labeling. In addn. to summarizing the areas covered by the contributed papers, the overview also adds some historical information and gives short reviews of those areas and metals, not specifically covered by the contributed papers.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXisF2qtQ%253D%253D&md5=5c80171c3472da38e545cdc64a19f7e4
    .
    (d) Di Giuseppe, A.; Castarlenas, R.; Oro, L. A. Mechanistic considerations on catalytic H/D exchange mediated by organometallic transition metal complexes. C. R. Chim. 2015, 18, 713– 741,  DOI: 10.1016/j.crci.2015.02.006
    [Crossref], [CAS], Google Scholar
    13d
    Mechanistic considerations on catalytic H/D exchange mediated by organometallic transition metal complexes
    Di Giuseppe, Andrea; Castarlenas, Ricardo; Oro, Luis A.
    Comptes Rendus Chimie (2015), 18 (7), 713-741CODEN: CRCOCR; ISSN:1631-0748. (Elsevier Masson SAS)
    A review. The purpose of this review is to analyze the different reaction mechanisms of the H/D exchange on org. substrates catalyzed by transition metal complexes in homogeneous phase. The metal-catalyzed H/D exchange is a multifaceted reaction whose mechanism depends strongly on the reaction conditions and on the metal complex used as a catalyst. It is possible to group the different mechanisms into three main families depending on the "role" and behavior of the catalyst: (i) Lewis acid-base catalysis; (ii) C-H activation (iii) insertion/β-elimination. For each macro-group, several representative examples are discussed and critically evaluated in order to provide the reader with keys to the understanding of how the different catalytic systems act and how their modification may affect their performance in terms of activity and selectivity. This knowledge is fundamental for designing improved organometallic H/D catalysts for labeling org. products in greener conditions with more cost-effective processes.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXptFGhurY%253D&md5=bf0a04fadc22033ad4665692faf80456
  14. 14
    (a) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Beyond thermodynamic acidity: a perspective on the complex-induced proximity effect (CIPE) in deprotonation reactions. Angew. Chem., Int. Ed. 2004, 43, 2206– 2225,  DOI: 10.1002/anie.200300590
    [Crossref], [CAS], Google Scholar
    14a
    Beyond thermodynamic acidity: A perspective on the complex-induced proximity effect (CIPE) in deprotonation reactions
    Whisler, Marna C.; MacNeil, Stephen; Snieckus, Victor; Beak, Peter
    Angewandte Chemie, International Edition (2004), 43 (17), 2206-2225CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. The concept of the complex-induced proximity effect (CIPE) in deprotonations is helpful in elucidating the mechanisms involved in carbanion chem. and in planning org. syntheses. In this review, the consequences of complexation of organolithium bases to functional groups of the substrates before the proton-transfer step are discussed. Exptl. data from kinetic measurements and isotope-labeling expts. as well as the results of calcns. in many cases point to a prelithiation complex as a reaction intermediate. Some examples from natural products synthesis illustrate how this concept can be used to obtain intermediates in a regio- or stereoselective manner. Of particular interest is the functionalization of positions that are remote from the coordination group.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjslOgtbs%253D&md5=3b679a38b4503d52c57681d32a71ba96
    .
    (b) Sambiagio, C.; Schönbauer, D.; Blieck, R.; Dao-Huy, T.; Pototschnig, G.; Schaaf, P.; Wiesinger, T.; Zia, M. F.; Wencel-Delord, J.; Besset, T.; Maes, B. U. W.; Schnürch, M. A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry. Chem. Soc. Rev. 2018, 47, 6603– 6743,  DOI: 10.1039/C8CS00201K
    [Crossref], [PubMed], [CAS], Google Scholar
    14b
    A comprehensive overview of directing groups applied in metal-catalyzed C-H functionalization chemistry
    Sambiagio, Carlo; Schonbauer, David; Blieck, Remi; Dao-Huy, Toan; Pototschnig, Gerit; Schaaf, Patricia; Wiesinger, Thomas; Zia, Muhammad Farooq; Wencel-Delord, Joanna; Besset, Tatiana; Maes, Bert U. W.; Schnurch, Michael
    Chemical Society Reviews (2018), 47 (17), 6603-6743CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. In this review, the recent advances in the field of metal-catalyzed group-directed C-H functionalization reactions were summarized.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlOgsr7N&md5=77d3e0e3466b7dc98740cae4cc962a03
  15. 15
    (a) Nilsson, G. N.; Kerr, W. J. The development and use of novel iridium complexes as catalysts for ortho-directed hydrogen isotope exchange reactions. J. Labelled Compd. Radiopharm. 2010, 53, 662– 667,  DOI: 10.1002/jlcr.1817
    [Crossref], [CAS], Google Scholar
    15a
    The development and use of novel iridium complexes as catalysts for ortho-directed hydrogen isotope exchange reactions
    Nilsson, Goeran N.; Kerr, William J.
    Journal of Labelled Compounds and Radiopharmaceuticals (2010), 53 (11-12), 662-667CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
    The prepn. and application of groups of new Ir complexes are described. In particular, Ir complexes possessing phosphine ligands and a bulky N-heterocyclic carbene are robust and readily handled species and were applied in a range of directed H-D and -tritium exchange processes and, in particular, with drug-like substrates or within ADMET-related studies. Overall, these new Ir(I) complexes are highly active catalysts and display catalytic activity far in excess of the industry std., Crabtree's catalyst, with excellent levels of labeling being achieved over short reaction times and at low metal complex loadings, while tolerating a wide range of functional moieties. Also and again in contrast to systems employing Crabtree's catalyst, the low catalyst loadings and short reaction times made possible by these emerging Ir carbene complexes have delivered tritiated products with very good levels of labeling and without any appreciable byproduct waste prodn.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXis1Sjsg%253D%253D&md5=ccd19ca7691c49c4f8b84199e0229a28
    .
    (b) Brown, J. A.; Cochrane, A. R.; Irvine, S.; Kerr, W. J.; Mondal, B.; Parkinson, J. A.; Paterson, L. C.; Reid, M.; Tuttle, T.; Andersson, S.; Nilsson, G. N. The Synthesis of Highly Active Iridium(I) Complexes and their Application in Catalytic Hydrogen Isotope Exchange. Adv. Synth. Catal. 2014, 356, 3551– 3562,  DOI: 10.1002/adsc.201400730
    [Crossref], [CAS], Google Scholar
    15b
    The Synthesis of Highly Active Iridium(I) Complexes and their Application in Catalytic Hydrogen Isotope Exchange
    Brown, Jack A.; Cochrane, Alison R.; Irvine, Stephanie; Kerr, William J.; Mondal, Bhaskar; Parkinson, John A.; Paterson, Laura C.; Reid, Marc; Tuttle, Tell; Andersson, Shalini; Nilsson, Goeran N.
    Advanced Synthesis & Catalysis (2014), 356 (17), 3551-3562CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Robust iridium(I) complexes bearing a sterically encumbered N-heterocyclic carbene ligand, alongside a phosphine ligand, were synthesized and studied in hydrogen isotope exchange processes. These complexes have allowed isotope incorporation over a range of substrates using practically convenient deuterium and tritium gas. Also, these active catalysts are capable of isotope incorporation to particularly high levels, while employing low catalyst loadings and in short reaction times. In addn. to this, these new catalyst species showed flexible levels of chemoselectivity, which can be altered by simple manipulation of preparative approaches. Also, a no. of industrially-relevant drug mols. also was labeled, including the sulfonamide contg. drug, Celecoxib. Alongside detailed NMR expts., initial mechanistic studies also were performed, providing insight into both substrate binding energies, and, more importantly, relative energies of key steps in the mechanistic cycle as part of the overall exchange process.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVGkurjF&md5=60694614df3600e544066dbda1e877e9
    .
    (c) Ma, S.; Villa, G.; Thuy-Boun, P. S.; Homs, A.; Yu, J.-Q. Palladium-catalyzed ortho-selective C–H deuteration of arenes: evidence for superior reactivity of weakly coordinated palladacycles. Angew. Chem., Int. Ed. 2014, 53, 734– 737,  DOI: 10.1002/anie.201305388
    [Crossref], [CAS], Google Scholar
    15c
    Palladium-Catalyzed ortho-Selective C-H Deuteration of Arenes: Evidence for Superior Reactivity of Weakly Coordinated Palladacycles
    Ma, Sandy; Villa, Giorgio; Thuy-Boun, Peter S.; Homs, Anna; Yu, Jin-Quan
    Angewandte Chemie, International Edition (2014), 53 (3), 734-737CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    We disclose a protocol for the palladium-catalyzed ortho-selective C-H deuteration of arenes. Phenylacetic acids and benzoic acids are suitable substrates for this reaction. This reaction offers a catalytic route to ortho-deuterated phenylacetic acids and benzoic acids and demonstrates the sharp difference in reactivity of palladacycle intermediates held together by weak and strong coordination.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVOhsLbK&md5=a2a7f70d33b75a62b79a8161f81245ad
    .
    (d) Giles, R.; Ahn, G.; Jung, K. W. H–D exchange in deuterated trifluoroacetic acid via ligand-directed NHC-palladium catalysis: a powerful method for deuteration of aromatic ketones, amides, and amino acids. Tetrahedron Lett. 2015, 56, 6231– 6235,  DOI: 10.1016/j.tetlet.2015.09.100
    [Crossref], [PubMed], [CAS], Google Scholar
    15d
    H-D exchange in deuterated trifluoroacetic acid via ligand-directed NHC-palladium catalysis: a powerful method for deuteration of aromatic ketones, amides, and amino acids
    Giles, Richard; Ahn, Green; Jung, Kyung Woon
    Tetrahedron Letters (2015), 56 (45), 6231-6235CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
    A method has been developed for one-step ortho-selective ligand-directed H-D exchange, accompanied in some cases by concurrent acid-catalyzed electrophilic deuteration. This method is effective for deuteration of arom. substrates ranging from ketones to amides and amino acids, including compds. of biol. and pharmaceutical interest such as acetaminophen and edaravone. Use of a palladium catalyst featuring an NHC ligand is crit. for the obsd. reactivity. Exptl. evidence strongly suggests that palladium facilitates C-H activation of the arom. substrates, a mechanism seldom obsd. under strongly acidic conditions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1Sqt77L&md5=a2bfc3ba3c7327bb6617180c88d52bb1
    .
    (e) Kerr, W. J.; Lindsay, D. M.; Reid, M.; Atzrodt, J.; Derdau, V.; Rojahn, P.; Weck, R. Iridium-catalysed ortho-H/D and -H/T exchange under basic conditions: C–H activation of unprotected tetrazoles. Chem. Commun. 2016, 52, 6669– 6672,  DOI: 10.1039/C6CC02137A
    [Crossref], [PubMed], [CAS], Google Scholar
    15e
    Iridium-catalysed ortho-H/D and -H/T exchange under basic conditions: C-H activation of unprotected tetrazoles
    Kerr, William J.; Lindsay, David M.; Reid, Marc; Atzrodt, Jens; Derdau, Volker; Rojahn, Patrick; Weck, Remo
    Chemical Communications (Cambridge, United Kingdom) (2016), 52 (40), 6669-6672CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    The first examples of selective ortho-directed C-H activation with unprotected 2-aryltetrazoles I (X = 4-MeO, 2-Me, 3-Cl, etc.) are described. A new base-assisted protocol for iridium(I) hydrogen isotope exchange catalysis allows access to ortho-deuterated and tritiated tetrazoles, e.g., II, including the tetrazole-contg. pharmaceutical, Valsartan. Preliminary mechanistic studies are also presented.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmsF2gs74%253D&md5=9908e32861f87aeba57c3fbebc868dcc
    .
    (f) Valero, M.; Kruissink, T.; Blass, J.; Weck, R.; Güssregen, S.; Plowright, A. T.; Derdau, V. C–H Functionalization-Prediction of Selectivity in Iridium(I)-Catalyzed Hydrogen Isotope Exchange Competition Reactions. Angew. Chem., Int. Ed. 2020, 59, 5626– 5631,  DOI: 10.1002/anie.201914220
    [Crossref], [CAS], Google Scholar
    15f
    C-H Functionalization - Prediction of Selectivity in Iridium(I)-Catalyzed Hydrogen Isotope Exchange Competition Reactions
    Valero, Megane; Kruissink, Thomas; Blass, Jennifer; Weck, Remo; Guessregen, Stefan; Plowright, Alleyn T.; Derdau, Volker
    Angewandte Chemie, International Edition (2020), 59 (14), 5626-5631CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    An assessment of the C-H activation catalyst [(COD)Ir(IMes)(PPh3)]PF6 (COD = 1,5-cyclooctadiene, IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) in the deuteration of Ph rings contg. different functional directing groups is divulged. Competition expts. have revealed a clear order of the directing groups in the hydrogen isotope exchange (HIE) with an iridium(I) catalyst. Through DFT calcns. the iridium-substrate coordination complex has been identified to be the main trigger for reactivity and selectivity in the competition situation with two or more directing groups. We postulate that the competition concept found in this HIE reaction can be used to explain regioselectivities in other transition-metal-catalyzed functionalization reactions of complex drug-type mols. as long as a C-H activation mechanism is involved.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitFChsrk%253D&md5=b59404a1dac4781fdd999c7bd937e596
    .
    (g) Hu, G.-Q.; Li, E.-C.; Zhang, H.-H.; Huang, W. Ag(i)-Mediated hydrogen isotope exchange of mono-fluorinated (hetero)arenes. Org. Biomol. Chem. 2020, 18, 6627– 6633,  DOI: 10.1039/D0OB01273D
    [Crossref], [PubMed], [CAS], Google Scholar
    15g
    Ag(I)-Mediated hydrogen isotope exchange of mono-fluorinated (hetero)arenes
    Hu, Guang-Qi; Li, En-Ci; Zhang, Hong-Hai; Huang, Wei
    Organic & Biomolecular Chemistry (2020), 18 (34), 6627-6633CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
    An efficient approach to install deuterium into mono-fluorinated (hetero)arenes by a Ag2CO3/Sphos-mediated HIE protocol with D2O as the deuterium source has been disclosed. This method showed a specific site selectivity of deuteration at the α-position of the fluorine atom, which is complementary to the existing transition metal-catalyzed HIE process.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFygsr7K&md5=ab40300c850d858c63556540cdc5f9cd
    .
    (h) Kerr, W. J.; Knox, G. J.; Paterson, L. C. Recent advances in iridium(I) catalysis towards directed hydrogen isotope exchange. J. Labelled Compd. Radiopharm. 2020, 63, 281– 295,  DOI: 10.1002/jlcr.3812
    [Crossref], [PubMed], [CAS], Google Scholar
    15h
    Recent advances in iridium(I) catalysis towards directed hydrogen isotope exchange
    Kerr, William J.; Knox, Gary J.; Paterson, Laura C.
    Journal of Labelled Compounds and Radiopharmaceuticals (2020), 63 (6), 281-295CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
    A review. A broadened array of new iridium catalysts and assocd. protocols for direct and selective C-H activation and hydrogen isotope insertion within a no. of new chem. entities of direct relevance to the pharmaceutical industry was described.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisFOlsLg%253D&md5=5b4e341c980b6d0fe7a11907168a3aa9
  16. 16
    (a) Bag, S.; Petzold, M.; Sur, A.; Bhowmick, S.; Werz, D. B.; Maiti, D. Palladium-Catalyzed Selective meta-C–H Deuteration of Arenes: Reaction Design and Applications. Chem. - Eur. J. 2019, 25, 9433– 9437,  DOI: 10.1002/chem.201901317
    [Crossref], [PubMed], [CAS], Google Scholar
    16a
    Palladium-Catalyzed Selective meta-C-H Deuteration of Arenes: Reaction Design and Applications
    Bag, Sukdev; Petzold, Martin; Sur, Aishanee; Bhowmick, Suman; Werz, Daniel B.; Maiti, Debabrata
    Chemistry - A European Journal (2019), 25 (40), 9433-9437CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    An easily removable pyrimidine-based auxiliary was employed for the meta-C-H deuteration of arenes. The scope of this Pd-catalyzed deuteration using com. available [D1]- and [D4]-acetic acid was demonstrated by its application in phenylacetic acid and phenylmethanesulfonate derivs. A detailed mechanistic study led to explore the reversibility of the non-rate detg. C-H activation step. The of meta-deuterium incorporation illustrated the template morphol. in terms of selectivity. The applicability of this method was demonstrated by the selective deuterium incorporation into various pharmaceuticals.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXptFWnsLk%253D&md5=6acdafea0b292d63d5d37e7f1bfe3e25
    .
    (b) Xu, H.; Liu, M.; Li, L.-J.; Cao, Y.-F.; Yu, J.-Q.; Dai, H.-X. Palladium-Catalyzed Remote meta-C–H Bond Deuteration of Arenes Using a Pyridine Template. Org. Lett. 2019, 21, 4887– 4891,  DOI: 10.1021/acs.orglett.9b01784
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    16b
    Palladium-Catalyzed Remote meta-C-H Bond Deuteration of Arenes Using a Pyridine Template
    Xu, Hui; Liu, Min; Li, Ling-Jun; Cao, Ya-Fang; Yu, Jin-Quan; Dai, Hui-Xiong
    Organic Letters (2019), 21 (12), 4887-4891CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    In the presence of Pd(OAc)2, arylacetates and benzylphosphonate esters and benzylic and arylethyl ethers of a fluoropyridinylphenol such as I (R = H) underwent chemoselective and regioselective directed meta-deuteration in perdeuteroacetic acid to yield aryl-deuterated esters and ethers such as I (R = D) with ≥84% deuteration at the meta positions and ≤10% deuteration at other positions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFGqsLbO&md5=6083204eb397c4a3073876c0a0f8d315
  17. 17
    (a) Burhop, A.; Weck, R.; Atzrodt, J.; Derdau, V. Hydrogen-Isotope Exchange (HIE) Reactions of Secondary and Tertiary Sulfonamides and Sulfonylureas with Iridium(I) Catalysts. Eur. J. Org. Chem. 2017, 2017, 1418– 1424,  DOI: 10.1002/ejoc.201601599
    [Crossref], [CAS], Google Scholar
    17a
    Hydrogen-Isotope Exchange (HIE) Reactions of Secondary and Tertiary Sulfonamides and Sulfonylureas with Iridium(I) Catalysts
    Burhop, Annina; Weck, Remo; Atzrodt, Jens; Derdau, Volker
    European Journal of Organic Chemistry (2017), 2017 (11), 1418-1424CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
    For the first time we report the optimized hydrogen-isotope exchange (HIE) conditions for the selective arom. deuteration of various sulfonylureas and tertiary sulfonamides, as well as for a broad range of secondary sulfonamides. Based on a comprehensive screening of readily available Ir catalysts, the Kerr-type NHC catalyst 5 [(cod)Ir(IMes)Cl] proved to be most efficient in the HIE reaction of secondary sulfonamides and sulfonylureas [e.g., N,4-dimethylbenzenesulfonamide → o,o-d2-N,4-dimethylbenzenesulfonamide (up to 85% D incorporation, 97% yield) with catalyst 5]. However, for tertiary sulfonamides, the com. available Burgess catalyst (I.BArF-), not yet utilized in HIE reactions, resulted in a much higher incorporation of deuterium. Finally, we tested the new HIE protocol for the labeling of a series of sulfa drugs and adapted the conditions to allow for selective tritium labeling.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXltVWgtrg%253D&md5=f9234ab97508c2c248824f89fb3ab1ea
    .
    (b) Jess, K.; Derdau, V.; Weck, R.; Atzrodt, J.; Freytag, M.; Jones, P. G.; Tamm, M. Hydrogen Isotope Exchange with Iridium(I) Complexes Supported by Phosphine-Imidazolin-2-imine P,N Ligands. Adv. Synth. Catal. 2017, 359, 629– 638,  DOI: 10.1002/adsc.201601291
    [Crossref], [CAS], Google Scholar
    17b
    Hydrogen Isotope Exchange with Iridium(I) Complexes Supported by Phosphine-Imidazolin-2-imine P,N Ligands
    Jess, Kristof; Derdau, Volker; Weck, Remo; Atzrodt, Jens; Freytag, Matthias; Jones, Peter G.; Tamm, Matthias
    Advanced Synthesis & Catalysis (2017), 359 (4), 629-638CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Phenylene-bridged hybrid phosphine-imidazolin-2-imine RP,NR' ligands (R = Ph, Cy, i-Pr, t-Bu; R' = Me, i-Pr) were prepd. from 1,2-dibromobenzene by Pd-catalyzed C-N coupling with 1,3,4,5-tetramethylimidazolin-2-imine or 1,3-diisopropyl-4,5-dimethylimidazolin-2-imine, followed by lithiation with tert-butyllithium and reaction with the chlorophosphines (R2PCl). Their reaction with the dimeric Ir complex [Ir(cod)Cl]2 (cod = 1,5-cyclooctadiene) and subsequent anion exchange with Na tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBArF24) or KPF6 (KPF6) afforded Ir complexes [(RP,NR')Ir(cod)]BArF24 or [(RP,NR')Ir(cod)]PF6, resp. The latter PF6 salts were structurally characterized, revealing short Ir-N bonds as an indication of electron-rich N donor atoms. The former complexes were tested for their applicability in catalytic H/D exchange. In particular, the complex with the ligand t-BuP,NMe showed remarkable performance in H/D exchange with a broad range of arom. substrates, including ketones, amides, esters, heterocycles and nitro compds., and also promoted H/D exchange at arom. Boc-protected amines, benzylamines and methoxy derivs.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Oitrc%253D&md5=cd6c4f720b2223a53882c2e62665194b
    .
    (c) Valero, M.; Becker, D.; Jess, K.; Weck, R.; Atzrodt, J.; Bannenberg, T.; Derdau, V.; Tamm, M. Directed Iridium-Catalyzed Hydrogen Isotope Exchange Reactions of Phenylacetic Acid Esters and Amides. Chem. - Eur. J. 2019, 25, 6517– 6522,  DOI: 10.1002/chem.201901449
    [Crossref], [PubMed], [CAS], Google Scholar
    17c
    Directed Iridium-Catalyzed Hydrogen Isotope Exchange Reactions of Phenylacetic Acid Esters and Amides
    Valero, Megane; Becker, Daniel; Jess, Kristof; Weck, Remo; Atzrodt, Jens; Bannenberg, Thomas; Derdau, Volker; Tamm, Matthias
    Chemistry - A European Journal (2019), 25 (26), 6517-6522CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    For the first time, a catalytic protocol for a highly selective hydrogen isotope exchange (HIE) of phenylacetic acid esters and amides under very mild reaction conditions is reported. Using a homogeneous iridium catalyst supported by a bidentate phosphine-imidazolin-2-imine P,N ligand, the HIE reaction on a series of phenylacetic acid derivs. proceeds with high yields, high selectivity, and with deuterium incorporation up to 99 %. The method is fully adaptable to the specific requirements of tritium chem., and its effectiveness was demonstrated by direct tritium labeling of the fungicide benalaxyl and the drug camylofine. Further insights into the mechanism of the HIE reaction with catalyst, [IrL(COD)][BArF24] (1, [2071645-61-7], L = N-(2-(bis(tert-butyl)phosphino)phenyl)-1,3,4,5-tetramethylimidazolin-2-imine, COD = cyclooctadiene, BArF34- = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate), have been provided utilizing DFT calcns., NMR studies, and X-ray diffraction anal.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXot1WjtL0%253D&md5=b8e24e12e74bbf8d9b5043632bb67e9a
    .
    (d) Müller, V.; Weck, R.; Derdau, V.; Ackermann, L. Ruthenium(II)-Catalyzed Hydrogen Isotope Exchange of Pharmaceutical Drugs by C–H Deuteration and C–H Tritiation. ChemCatChem 2020, 12, 100– 104,  DOI: 10.1002/cctc.201902051
    [Crossref], [CAS], Google Scholar
    17d
    Ruthenium(II)-Catalyzed Hydrogen Isotope Exchange of Pharmaceutical Drugs by C-H Deuteration and C-H Tritiation
    Mueller, Valentin; Weck, Remo; Derdau, Volker; Ackermann, Lutz
    ChemCatChem (2020), 12 (1), 100-104CODEN: CHEMK3; ISSN:1867-3880. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Well-defined ruthenium(II) biscarboxylate complexes enabled selective ortho-deuteration with weakly-coordinating, synthetically useful carboxylic acid with outstanding levels of isotopic labeling. The robust nature of the catalytic system was reflected by a broad functional group tolerance in an operationally-simple manner, allowing the isotope labeling of challenging pharmaceuticals and bioactive heterocyclic motifs. The synthetic power of our method was highlighted by the selective tritium-labeling of repaglinide, an antidiabetic drug, providing access to defined tritium labeled therapeutics.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlejt7%252FP&md5=cafca5b68265e784d6f47c060ffb0701
    .
    (e) Valero, M.; Bouzouita, D.; Palazzolo, A.; Atzrodt, J.; Dugave, C.; Tricard, S.; Feuillastre, S.; Pieters, G.; Chaudret, B.; Derdau, V. NHC-Stabilized Iridium Nanoparticles as Catalysts in Hydrogen Isotope Exchange Reactions of Anilines. Angew. Chem., Int. Ed. 2020, 59, 3517– 3522,  DOI: 10.1002/anie.201914369
    [Crossref], [CAS], Google Scholar
    17e
    NHC-Stabilized Iridium Nanoparticles as Catalysts in Hydrogen Isotope Exchange Reactions of Anilines
    Valero, Megane; Bouzouita, Donia; Palazzolo, Alberto; Atzrodt, Jens; Dugave, Christophe; Tricard, Simon; Feuillastre, Sophie; Pieters, Gregory; Chaudret, Bruno; Derdau, Volker
    Angewandte Chemie, International Edition (2020), 59 (9), 3517-3522CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Air-stable iridium nanoparticles stabilized with the N-heterocyclic carbene 1,3-dicyclohexyl-2-imidazolylidene were prepd. from [(η4-1,5-cyclooctadiene)Ir(OMe)]2 and the dicyclohexylimidazolidinium chloride. In the presence of the stabilized iridium nanoparticles, anilines underwent regioselective ortho-deuteration with D2 and D2O in THF to yield deuterated anilines. An aniline contg. the volixibat pharmacophore underwent tritiation with T2 in THF to yield the monotritiated aniline.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitFeisLY%253D&md5=028c4bdfb3225075a6a613c29313fb8c
    .
    (f) Daniel-Bertrand, M.; Garcia-Argote, S.; Palazzolo, A.; Mustieles Marin, I.; Fazzini, P.-F.; Tricard, S.; Chaudret, B.; Derdau, V.; Feuillastre, S.; Pieters, G. Multiple Site Hydrogen Isotope Labelling of Pharmaceuticals. Angew. Chem., Int. Ed. 2020, 59, 21114– 21120,  DOI: 10.1002/anie.202008519
    [Crossref], [CAS], Google Scholar
    17f
    Multiple Site Hydrogen Isotope Labeling of Pharmaceuticals
    Daniel-Bertrand, Marion; Garcia-Argote, Sebastien; Palazzolo, Alberto; Mustieles Marin, Irene; Fazzini, Pier-Francesco; Tricard, Simon; Chaudret, Bruno; Derdau, Volker; Feuillastre, Sophie; Pieters, Gregory
    Angewandte Chemie, International Edition (2020), 59 (47), 21114-21120CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Radiolabeling is fundamental in drug discovery and development as it is mandatory for preclin. ADME studies and late-stage human clin. trials. Herein, a general, effective, and easy to implement method for the multiple site incorporation of deuterium and tritium atoms using the com. available and air-stable iridium precatalyst [Ir(COD)(OMe)]2 is described. A large scope of pharmaceutically relevant substructures can be labeled using this method including pyridine, pyrazine, indole, carbazole, aniline, oxazoles/thiazoles, thiophene, but also electron-rich Ph groups. The high functional group tolerance of the reaction is highlighted by the labeling of a wide range of complex pharmaceuticals, contg. notably halogen or sulfur atoms and nitrile groups. The multiple site hydrogen isotope incorporation has been explained by the in situ formation of complementary catalytically active species: monometallic iridium complexes and iridium nanoparticles.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvVCjsbbJ&md5=77dc22d342ada10985806f8f7aaefa88
  18. 18
    (a) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Beyond directing groups: transition-metal-catalyzed C–H activation of simple arenes. Angew. Chem., Int. Ed. 2012, 51, 10236– 10254,  DOI: 10.1002/anie.201203269
    [Crossref], [CAS], Google Scholar
    18a
    Beyond Directing Groups: Transition-Metal-Catalyzed C-H Activation of Simple Arenes
    Kuhl, Nadine; Hopkinson, Matthew N.; Wencel-Delord, Joanna; Glorius, Frank
    Angewandte Chemie, International Edition (2012), 51 (41), 10236-10254CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. The use of coordinating moieties as directing groups for the functionalization of arom. C-H bonds has become an established tool to enhance reactivity and induce regioselectivity. Nevertheless, with regard to the synthetic applicability of C-H activation, there is a growing interest in transformations in which the directing group can be fully abandoned, thus allowing the direct functionalization of simple benzene derivs. However, this approach requires the disclosure of new strategies to achieve reactivity and to control selectivity. In this review, recent advances in the emerging field of non-chelate-assisted C-H activation are discussed, highlighting some of the most intriguing and inspiring examples of induction of reactivity and selectivity.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlylsL3J&md5=88a6f0d7a65bc848644a07b3f898f0a9
    .
    (b) Hartwig, J. F.; Larsen, M. A. Undirected, Homogeneous C–H Bond Functionalization: Challenges and Opportunities. ACS Cent. Sci. 2016, 2, 281– 292,  DOI: 10.1021/acscentsci.6b00032
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    18b
    Undirected, Homogeneous C-H Bond Functionalization: Challenges and Opportunities
    Hartwig, John F.; Larsen, Matthew A.
    ACS Central Science (2016), 2 (5), 281-292CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
    The functionalization of C-H bonds has created new approaches to prepg. org. mols. by enabling new strategic "disconnections" during the planning of a synthetic route. Such functionalizations also have created the ability to derivatize complex mols. by modifying one or more of the many C-H bonds. For these reasons, researchers are developing new types of functionalization reactions of C-H bonds and new applications of these processes. These C-H bond functionalization reactions can be divided into two general classes: those directed by coordination to an existing functional group prior to the cleavage of the C-H bond (directed) and those occurring without coordination prior to cleavage of the C-H bond (undirected). The undirected functionalizations of C-H bonds are much less common and more challenging to develop than the directed reactions. This outlook will focus on undirected C-H bond functionalization, as well as related reactions that occur by a noncovalent assocn. of the catalyst prior to C-H bond cleavage. The inherent challenges of conducting undirected functionalizations of C-H bonds and the methods for undirected functionalization that are being developed will be presented, along with the factors that govern selectivity in these reactions. Finally, this outlook discusses future directions for research on undirected C-H functionalization, with an emphasis on the limitations that must be overcome if this type of methodol. is to become widely used in academia and in industry.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmvFGjsr8%253D&md5=d8c467b3025de6302478a3751940aac0
    .
    (c) Wedi, P.; van Gemmeren, M. Arene-Limited Nondirected C-H Activation of Arenes. Angew. Chem., Int. Ed. 2018, 57, 13016– 13027,  DOI: 10.1002/anie.201804727
    [Crossref], [CAS], Google Scholar
    18c
    Arene-Limited Nondirected C-H Activation of Arenes
    Wedi, Philipp; van Gemmeren, Manuel
    Angewandte Chemie, International Edition (2018), 57 (40), 13016-13027CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. The nondirected C(sp2)-H activation of simple arenes has advanced significantly in recent years through the discovery of new catalyst systems that are able to perform transformations with the arene as the limiting reagent. Important developments in catalyst and ligand design that have improved reactivity and selectivity are reviewed.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1Olt7%252FN&md5=a5b65fd777f200c5b3adc7c6d7d6f2c9
    .
    (d) Mondal, A.; Wedi, P.; van Gemmeren, M. The Non-directed Distal C(sp2)–H Functionalization of Arenes. In Remote C–H Bond Functionalizations; Maiti, D., Guin, S., Eds.; Wiley-VCH, 2021; pp 191– 219.
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  19. 19
    (a) Kański, R.; Kańska, M. Deuteriation of hydroxybenzoic acids in the presence of homogeneous platinum catalyst. J. Radioanal. Nucl. Chem. 2003, 257, 385– 390,  DOI: 10.1023/A:1024752300898
    [Crossref], [CAS], Google Scholar
    19a
    Deuteriation of hydroxybenzoic acids in the presence of homogeneous platinum catalyst
    Kanski, R.; Kanska, M.
    Journal of Radioanalytical and Nuclear Chemistry (2003), 257 (2), 385-390CODEN: JRNCDM; ISSN:0236-5731. (Kluwer Academic Publishers)
    A one-step method has been elaborated for the deuteriation of hydroxybenzoic acids in the presence of homogeneous divalent platinum salt in a medium contg. soln. of deuteriated acetic acid in heavy water. The quasi-unimol. H/D exchange rate consts. have been detd. at 130°C for the particular position of proton on the arom. ring by 1H NMR integration signals. Different kinetic patterns of H/D exchange are shown for 2-hydroxy-, 3-hydroxy-, and 4-hydroxybenzoic acid.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXlsVCqsLo%253D&md5=4c954d053703617efc240d0906a7ae06
    .
    (b) Hanson, S. K.; Heinekey, D. M.; Goldberg, K. I. C–H Bond Activation by Rhodium(I) Phenoxide and Acetate Complexes: Mechanism of H–D Exchange between Arenes and Water. Organometallics 2008, 27, 1454– 1463,  DOI: 10.1021/om7012259
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    19b
    C-H Bond Activation by Rhodium(I) Phenoxide and Acetate Complexes: Mechanism of H-D Exchange between Arenes and Water
    Hanson, Susan Kloek; Heinekey, D. Michael; Goldberg, Karen I.
    Organometallics (2008), 27 (7), 1454-1463CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
    New rhodium(I) complexes (PNP)Rh(X) (PNP = 2,6-bis(di-tert-butylphosphinomethyl)pyridine) (X = OTf (1), OAc (3), OH (8), OCH2CF3 (9), OC6H5 (10), OC6H4NO2 (11)) have been prepd. Hydroxide complex 8 and trifluoroethoxide complex 9 undergo stoichiometric activation of benzene-d6 to form the Ph complex (PNP)Rh(C6D5). Acetate and aryloxide complexes 3, 10, and 11 are active catalysts for H-D exchange between arenes and water. Control expts. indicate that the rhodium complexes are the active catalysts and that the obsd. exchange is not catalyzed by adventitious acid. Mechanistic studies of the H-D exchange reaction support a pathway involving dissocn. of aryloxide or acetate ligand. The reaction is accelerated by added alc. and, for the acetate complex, inhibited by added sodium acetate.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXis1Kgtb0%253D&md5=31016fb9df8810e1c477cde997c3e6a8
    .
    (c) Hickman, A. J.; Villalobos, J. M.; Sanford, M. S. Quantitative Assay for the Direct Comparison of Platinum Catalysts in Benzene H/D Exchange. Organometallics 2009, 28, 5316– 5322,  DOI: 10.1021/om900495n
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    19c
    Quantitative assay for the direct comparison of platinum catalysts in benzene H/D exchange
    Hickman, Amanda J.; Villalobos, Janette M.; Sanford, Melanie S.
    Organometallics (2009), 28 (18), 5316-5322CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
    This paper describes a protocol for the direct comparison of diverse Pt catalysts in the H/D exchange between C6H6 and TFA-d1, CD3CO2D, and TFE-d3 using turnover no. (TON) as a std. metric. An initial survey of Pt complexes, including com. Pt salts (PtCl2, K2PtCl4) and Pt chloride complexes contg. bidentate and tridentate nitrogen donor ligands, has been conducted. These studies have established that the addn. of AgOAc (in TFA-d1) or AgBF4 (in CD3CO2D and TFE-d3) displaces the Cl ligands on the Pt precatalyst, which leads to dramatically increased turnover nos. In general, PtCl2 and K2PtCl4 provided the fewest turnovers, and species contg. bidentate ligands afforded higher turnover nos. than those with tridentate ligands. A diimine Pt complex was found to be a top performing catalyst for H/D exchange with all deuterium sources examd. Interestingly, the relative reactivity of many of the catalysts varied dramatically upon changing the deuterium source, highlighting the need to thoroughly assay potential catalysts under a variety of conditions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVejtbzM&md5=1e71cc6205c368112f3ed3c510d25228
    .
    (d) Emmert, M. H.; Gary, J. B.; Villalobos, J. M.; Sanford, M. S. Platinum and palladium complexes containing cationic ligands as catalysts for arene H/D exchange and oxidation. Angew. Chem., Int. Ed. 2010, 49, 5884– 5886,  DOI: 10.1002/anie.201002351
    [Crossref], [CAS], Google Scholar
    19d
    Platinum and Palladium Complexes Containing Cationic Ligands as Catalysts for Arene H/D Exchange and Oxidation
    Emmert, Marion H.; Gary, J. Brannon; Villalobos, Janette M.; Sanford, Melanie S.
    Angewandte Chemie, International Edition (2010), 49 (34), 5884-5886, S5884/1-S5884/46CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Palladium(II) and platinum(II) complexes of pyridinium-substituted bipyridine ligands I (R = Ph, 4-tBu-C6H4) are highly active and stable catalysts for H/D exchange and acetoxylation of arom. C-H bonds (TONs up to 3200, TOFs up to 0.1 s-1). The regioselectivity of the deuteration and acetoxylation is studied and compared to traditional catalysts.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpslCns7c%253D&md5=f488f98df16acc62330a1a9e3776ce92
    .
    (e) Rhinehart, J. L.; Manbeck, K. A.; Buzak, S. K.; Lippa, G. M.; Brennessel, W. W.; Goldberg, K. I.; Jones, W. D. Catalytic Arene H/D Exchange with Novel Rhodium and Iridium Complexes. Organometallics 2012, 31, 1943– 1952,  DOI: 10.1021/om2012419
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    19e
    Catalytic arene H/D exchange with novel rhodium and iridium complexes
    Rhinehart, Jennifer L.; Manbeck, Kimberly A.; Buzak, Sara K.; Lippa, Geoffrey M.; Brennessel, William W.; Goldberg, Karen I.; Jones, William D.
    Organometallics (2012), 31 (5), 1943-1952CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
    Rhodium(III) and iridium(III) scorpionate complexes with tridentate N,N,O-ligand, bis(3,5-dimethyl-1-pyrazolyl)acetate (bdmpza), fac-[M(bdmpza)Cl2L]n- (L = Cl, n = 1; L = py, n = 0) exhibit catalytic activity in arene deuteration, proceeding via C-H-activation and acidic deuterolysis. Three novel pendant acetate complexes, [Rh(bdmpza)Cl3]-M+, [Rh(bdmpza)Cl2(py)], and [Ir(bdmpza)Cl3]-Q+ (Q+ = Li+, Na+), were prepd. Abstraction of halide from these complexes with silver salts yielded species capable of C-H activation of arenes. The catalytic H/D exchange reaction between benzene and trifluoroacetic acid-d was optimized, and these conditions were used to evaluate H/D exchange in other arenes. Branched alkyl substituents in alkyl aroms. showed an affinity toward deuterium exchange in the β-alkyl position only. DFT calcns. were performed to det. the mechanism of H/D exchange.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XisVGht70%253D&md5=b8c1d19ba4f3351af09ec72ed1c3637d
    .
    (f) Iluc, V. M.; Fedorov, A.; Grubbs, R. H. H/D Exchange Processes Catalyzed by an Iridium-Pincer Complex. Organometallics 2012, 31, 39– 41,  DOI: 10.1021/om201049p
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    19f
    H/D Exchange Processes Catalyzed by an Iridium-Pincer Complex
    Iluc, Vlad M.; Fedorov, Alexey; Grubbs, Robert H.
    Organometallics (2012), 31 (1), 39-41CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
    PNP-pincer Ir dihydride (PNP)IrH2 (1; PNP = bis(2-(diisopropylphosphino)-4-methylphenyl)amide) performs the H/D exchange between arom. substrates and tertiary hydrosilanes and D2O or C6D6. Complete incorporation of D into sterically accessible Car-H and Si-H bonds was obsd. at a moderate temp. of 80°.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1ajsb7K&md5=9fc83e0643d4dd980d80b66ec281b83c
    .
    (g) Ibañez, S.; Poyatos, M.; Peris, E. Mono and dimetallic pyrene-imidazolylidene complexes of iridium(iii) for the deuteration of organic substrates and the C-C coupling of alcohols. Dalton. Trans. 2016, 45, 14154– 14159,  DOI: 10.1039/C6DT02942F
    [Crossref], [PubMed], [CAS], Google Scholar
    19g
    Mono and dimetallic pyrene-imidazolylidene complexes of iridium(III) for the deuteration of organic substrates and the C-C coupling of alcohols
    Ibanez, S.; Poyatos, M.; Peris, E.
    Dalton Transactions (2016), 45 (36), 14154-14159CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
    Three different Ir(III) complexes with pyrene-contg. N-heterocyclic carbenes have been prepd. and characterized. Two complexes contain a monodentate pyrene-imidazolylidene ligand, and have the formulas [IrCp*Cl2(pyrene-NHC)] and [IrCp*(CO3)(pyrene-NHC)]. The third complex is a dimetallic complex with a pyrene-di-imidazolylidene bridging ligand, with the formula [{IrCp*(CO3)}2(μ-pyrene-di-NHC)]. The catalytic activity of the three complexes was tested in the H/D exchange of org. substrates, and in the β-alkylation of 1-phenylethanol with primary alcs. In the deuteration of org. substrates, the carbonate complexes are active even in the absence of additives. The dimetallic complex is the most active one in the catalytic coupling of alcs., a result that may be interpreted as a consequence of the cooperativity between the two metal centers.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1yqtLrE&md5=e47ac57a93789821b574aa585e46e9df
    .
    (h) Li, E.-C.; Hu, G.-Q.; Zhu, Y.-X.; Zhang, H.-H.; Shen, K.; Hang, X.-C.; Zhang, C.; Huang, W. Ag2CO3-Catalyzed H/D Exchange of Five-Membered Heteroarenes at Ambient Temperature. Org. Lett. 2019, 21, 6745– 6749,  DOI: 10.1021/acs.orglett.9b02369
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    19h
    Ag2CO3-Catalyzed H/D Exchange of Five-Membered Heteroarenes at Ambient Temperature
    Li, En-Ci; Hu, Guang-Qi; Zhu, Yu-Xing; Zhang, Hong-Hai; Shen, Kang; Hang, Xiao-Chun; Zhang, Cong; Huang, Wei
    Organic Letters (2019), 21 (17), 6745-6749CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    Ag2CO3-catalyzed hydrogen isotope exchange of five-membered heteroarenes is disclosed. The reaction can be conducted in the open air, at ambient temp., and with D2O as deuterium source. Moreover, this protocol showed orthogonal site selectivity to existing technol., thereby greatly expanding the scope of substrates for HIE reaction. The mechanistic study indicated that the carbonate group plays a crucial role to achieve high levels of deuterium incorporation by lowering the activation energy of H/D exchange process.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFyktL3F&md5=afbb41b99e7294375e6f4d040abe7496
    .
    (i) Lassalle, S.; Jabbour, R.; Schiltz, P.; Berruyer, P.; Todorova, T. K.; Veyre, L.; Gajan, D.; Lesage, A.; Thieuleux, C.; Camp, C. Metal-Metal Synergy in Well-Defined Surface Tantalum-Iridium Heterobimetallic Catalysts for H/D Exchange Reactions. J. Am. Chem. Soc. 2019, 141, 19321– 19335,  DOI: 10.1021/jacs.9b08311
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    19i
    Metal-Metal Synergy in Well-Defined Surface Tantalum-Iridium Heterobimetallic Catalysts for H/D Exchange Reactions
    Lassalle, Sebastien; Jabbour, Ribal; Schiltz, Pauline; Berruyer, Pierrick; Todorova, Tanya K.; Veyre, Laurent; Gajan, David; Lesage, Anne; Thieuleux, Chloe; Camp, Clement
    Journal of the American Chemical Society (2019), 141 (49), 19321-19335CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A novel heterobimetallic Ta/Ir hydrido complex, [{Ta(CH2tBu)3}{IrH2(Cp*)}] 1, featuring a very short metal-metal bond, was isolated through an original alkane elimination route from Ta(CHtBu)(CH2tBu)3 and Cp*IrH4. This mol. precursor was used to synthesize well-defined SiO2-supported low-coordinate heterobimetallic hydrido species [≡SiOTa(CH2tBu)2{IrH2(Cp*)}], 5, and [≡SiOTa(CH2tBu)H{IrH2(Cp*)}], 6, using a surface organometallic chem. (SOMC) approach. The SOMC methodol. prevents undesired dimerization as encountered in soln. and leading to tetranuclear [{Ta(CH2tBu)2}(Cp*IrH)]2, 4. This approach therefore allows access to unique low-coordinate species not attainable in soln. These original supported Ta/Ir species exhibit drastically enhanced catalytic performances in H/D exchange reactions with respect to (i) monometallic analogs as well as (ii) homogeneous systems. In particular, material 6 promotes the H/D exchange between fluorobenzene and C6D6 or D2 as D sources with excellent productivity (TON up to 1422; TOF up to 23.3 h-1) under mild conditions (25°, sub-atm. D2 pressure) without any additives.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFehsLfJ&md5=26c6b037058e00c033231a509a60669e
    .
    (j) Smith, J. D.; Durrant, G.; Ess, D. H.; Gelfand, B. S.; Piers, W. E. H/D exchange under mild conditions in arenes and unactivated alkanes with C6D6 and D2O using rigid, electron-rich iridium PCP pincer complexes. Chem. Sci. 2020, 11, 10705– 10717,  DOI: 10.1039/D0SC02694H
    [Crossref], [PubMed], [CAS], Google Scholar
    19j
    H/D exchange under mild conditions in arenes and unactivated alkanes with C6D6 and D2O using rigid, electron-rich iridium PCP pincer complexes
    Smith, Joel D.; Durrant, George; Ess, Daniel H.; Gelfand, Benjamin S.; Piers, Warren E.
    Chemical Science (2020), 11 (39), 10705-10717CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    The synthesis and characterization of an iridium polyhydride complex (Ir-H4) supported by an electron-rich PCP framework is described. This complex readily loses mol. hydrogen allowing for rapid room temp. hydrogen isotope exchange (HIE) at the hydridic positions and the α-C-H site of the ligand with deuterated solvents such as benzene-d6, toluene-d8 and THF-d8. The removal of 1-2 equiv of mol. H2 forms unsatd. iridium carbene trihydride (Ir-H3) or monohydride (Ir-H) compds. that are able to create further unsatn. by reversibly transferring a hydride to the ligand carbene carbon. These species are highly active hydrogen isotope exchange (HIE) catalysts using C6D6 or D2O as deuterium sources for the deuteration of a variety of substrates. By modifying conditions to influence the Ir-Hn speciation, deuteration levels can range from near exhaustive to selective only for sterically accessible sites. Preparative level deuterations of select substrates were performed allowing for procurement of >95% deuterated compds. in excellent isolated yields; the catalyst can be regenerated by treatment of residues with H2 and is still active for further reactions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFKgt7rE&md5=5334feab94cd4fc8ace7a31576640101
    .
    (k) Martin, J.; Eyselein, J.; Grams, S.; Harder, S. Hydrogen Isotope Exchange with Superbulky Alkaline Earth Metal Amide Catalysts. ACS Catal. 2020, 10, 7792– 7799,  DOI: 10.1021/acscatal.0c01359
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    19k
    Hydrogen Isotope Exchange with Superbulky Alkaline Earth Metal Amide Catalysts
    Martin, Johannes; Eyselein, Jonathan; Grams, Samuel; Harder, Sjoerd
    ACS Catalysis (2020), 10 (14), 7792-7799CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    Heavier alk. earth (Ae) metal amide complexes Ae(NR2)2 (Ae = Ca, Sr, Ba) were found to be highly active catalysts for hydrogen isotope exchange (HIE). The activities for D/H exchange between C6D6 and H2 strongly increase with metal size (Ca < Sr < Ba) and with amide bulk: N(SiMe3)2 < N(DIPP)(SiiPr3)< N(SiiPr3)2, DIPP = 2,6-diisopropylphenyl. At 120°C and pressures of 10-50 bar, no hydrogenation side-products are produced, and TONs of 205 and TOFs of 268, competitive with those for precious metal catalysts, have been achieved. The reverse H/D exchange between C6H6 and D2 is even faster by a factor 1.5-2. Substrates also include a range of substituted arenes. Alkyl-substituted arom. rings are preferably deuterated in acidic benzylic positions, and this tendency increases with the no. of alkyl-substituents. Although unactivated (sp3)C-H units could not be deuterated, the (sp3)Si-H function in primary, secondary, and tertiary alkylsilanes could be converted. Two different pathways for C6H6/D2 isotope exchange have been evaluated by DFT calcns.: (A) a deprotonation/protonation mechanism and (B) direct nucleophilic arom. substitution. Although the exact nature of the catalyst(s) is unclear, the first step is the conversion of Ae(NR2)2 with D2 into R2NAeD which can aggregate to larger clusters. Energy profiles with model catalysts (iPr3Si)2NAeD and [(Me3Si)2NAeD]2 (Ae = Ca or Ba) show that the direct nucleophilic arom. substitution is the most likely mechanism for deuteration of arenes. The key to this unusual reaction is the initial formation of a π-arene···Ae complex which is followed by the generation of an intermediate with a Meisenheimer anion. Heavier Ae metal amide complexes are, despite the lack of partially filled d-orbitals for substrate activation, potent catalysts for HIE.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFGqu7vP&md5=8eb89d2242ffeb2387892bf7897e5e48
    .
    (l) Dong, B.; Cong, X.; Hao, N. Silver-catalyzed regioselective deuteration of (hetero)arenes and α-deuteration of 2-alkyl azaarenes. RSC Adv. 2020, 10, 25475– 25479,  DOI: 10.1039/D0RA02358B
    [Crossref], [CAS], Google Scholar
    19l
    Silver-catalyzed regioselective deuteration of (hetero)arenes and α-deuteration of 2-alkyl azaarenes
    Dong, Baobiao; Cong, Xuefeng; Hao, Na
    RSC Advances (2020), 10 (43), 25475-25479CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
    A simple silver-catalyzed regioselective deuteration of (hetero)arenes and α-deuteration of 2-alkyl azaarenes was described. This strategy provides an efficient and practical avenue to access various deuterated electron-rich arenes, azaarenes and α-deuterated 2-alkyl azaarenes with good to excellent deuterium incorporation utilizing D2O as the source of deuterium atoms.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlWktLrM&md5=b19d03be82031a4d48bf60e53a772475
    .
    (m) Tlahuext-Aca, A.; Hartwig, J. F. Site-Selective Silver-Catalyzed C–H Bond Deuteration of Five-Membered Aromatic Heterocycles and Pharmaceuticals. ACS Catal. 2021, 11, 1119– 1127,  DOI: 10.1021/acscatal.0c04917
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    19m
    Site-Selective Silver-Catalyzed C-H Bond Deuteration of Five-Membered Aromatic Heterocycles and Pharmaceuticals
    Tlahuext-Aca, Adrian; Hartwig, John F.
    ACS Catalysis (2021), 11 (3), 1119-1127CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    Catalytic methods for the direct introduction of hydrogen isotopes into org. mols. are essential to the development of improved pharmaceuticals and to the alteration of their absorption, distribution, metab., and excretion (ADME) properties. However, the development of homogeneous catalysts for selective incorporation of isotopes in the absence of directing groups under practical conditions remains a long-standing challenge. Herein, a phosphine-ligated, silver-carbonate complex catalyzes the site-selective deuteration of C-H bonds in five-membered arom. heterocycles and active pharmaceutical ingredients that have been resistant to catalytic H/D exchange. The reactions occur with CH3OD as a low-cost source of the isotope. The silver catalysts react with five-membered heteroarenes lacking directing groups, tolerate a wide range of functional groups, and react in both polar and nonpolar solvents. Mechanistic expts., including deuterium kinetic isotope effects, detn. of kinetic orders, and identification of the catalyst resting state, support C-H bond cleavage from a phosphine-ligated, silver-carbonate intermediate as the rate-detg. step of the catalytic cycle.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXpt1Gjtg%253D%253D&md5=dad0980c9928b34214b70a3da1516416
  20. 20
    (a) Pony Yu, R.; Hesk, D.; Rivera, N.; Pelczer, I.; Chirik, P. J. Iron-catalysed tritiation of pharmaceuticals. Nature 2016, 529, 195– 199,  DOI: 10.1038/nature16464
    [Crossref], [PubMed], [CAS], Google Scholar
    20a
    Iron-catalysed tritiation of pharmaceuticals
    Pony Yu, Renyuan; Hesk, David; Rivera, Nelo; Pelczer, Istvan; Chirik, Paul J.
    Nature (London, United Kingdom) (2016), 529 (7585), 195-199CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    A thorough understanding of the pharmacokinetic and pharmacodynamic properties of a drug in animal models is a crit. component of drug discovery and development. Such studies are performed in vivo and in vitro at various stages of the development process-ranging from preclin. absorption, distribution, metab. and excretion (ADME) studies to late-stage human clin. trials-to elucidate a drug mol.'s metabolic profile and to assess its toxicity. Radiolabeled compds., typically those that contain 14C or 3H isotopes, are one of the most powerful and widely deployed diagnostics for these studies. The introduction of radiolabels using synthetic chem. enables the direct tracing of the drug mol. without substantially altering its structure or function. The ubiquity of C-H bonds in drugs and the relative ease and low cost assocd. with tritium (3H) make it an ideal radioisotope with which to conduct ADME studies early in the drug development process. Here we describe an iron-catalyzed method for the direct 3H labeling of pharmaceuticals by hydrogen isotope exchange, using tritium gas as the source of the radioisotope. The site selectivity of the iron catalyst is orthogonal to currently used iridium catalysts and allows isotopic labeling of complementary positions in drug mols., providing a new diagnostic tool in drug development.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xns1KhtA%253D%253D&md5=427730f28e4453669f007a1c2fbd1872
    .
    (b) Yang, H.; Zarate, C.; Palmer, W. N.; Rivera, N.; Hesk, D.; Chirik, P. J. Site-Selective Nickel-Catalyzed Hydrogen Isotope Exchange in N -Heterocycles and Its Application to the Tritiation of Pharmaceuticals. ACS Catal. 2018, 8, 10210– 10218,  DOI: 10.1021/acscatal.8b03717
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    20b
    Site-Selective Nickel-Catalyzed Hydrogen Isotope Exchange in N-Heterocycles and Its Application to the Tritiation of Pharmaceuticals
    Yang, Haifeng; Zarate, Cayetana; Palmer, W. Neil; Rivera, Nelo; Hesk, David; Chirik, Paul J.
    ACS Catalysis (2018), 8 (11), 10210-10218CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    A nickel-catalyzed method for the site-selective hydrogen isotope exchange (HIE) of C(sp2)-H bonds in nitrogen heteroarenes is described and applied to the tritiation of pharmaceuticals. The α-diimine nickel hydride complex [(iPrDI)Ni(μ2-H)]2 (iPrDI = N,N'-bis(2,6-diisopropylphenyl)-2,3-butanediimine) mediates efficient HIE when employed as a single component precatalyst or generated in situ from readily available and air-stable metal and ligand precursors (iPrDI, [(NEt3)Ni(OPiv)2]2 (Piv = pivaloyl) and (EtO)3SiH). The nickel catalyst offers distinct advantages over existing methods, including: (i) high HIE activity at low D2 or T2 pressure; (ii) tolerance of functional groups, including aryl chlorides, alcs., secondary amides, and sulfones; (iii) activity with nitrogen-rich mols. such as the chemotherapeutic imatinib; and (iv) the ability to promote HIE in sterically hindered positions generally inaccessible with other transition metal catalysts. Representative active pharmaceutical ingredients were tritiated with specific activities in excess of the thresholds required for drug absorption, distribution, metab., and excretion studies (1 Ci/mmol) and for protein receptor-ligand binding assays (15 Ci/mmol). The activity and selectivity of the nickel-catalyzed method are demonstrated by comparison with the current state-of-the-art single-site (iridium and iron) and heterogeneous (Raney nickel and rhodium black) catalysts. A pathway involving C(sp2)-H activation by a α-diimine nickel hydride monomer is consistent with the exptl. measured relative rate consts. for HIE with electronically disparate pyridines, the pressure-dependence of activity, positional selectivity preferences, and kinetic isotope effects.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslKqt7rO&md5=85a656c4b8bad6c2484088d08246f907
    .
    (c) Zarate, C.; Yang, H.; Bezdek, M. J.; Hesk, D.; Chirik, P. J. Ni(I)-X Complexes Bearing a Bulky α-Diimine Ligand: Synthesis, Structure, and Superior Catalytic Performance in the Hydrogen Isotope Exchange in Pharmaceuticals. J. Am. Chem. Soc. 2019, 141, 5034– 5044,  DOI: 10.1021/jacs.9b00939
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    20c
    Ni(I)-X Complexes Bearing a Bulky α-Diimine Ligand: Synthesis, Structure, and Superior Catalytic Performance in the Hydrogen Isotope Exchange in Pharmaceuticals
    Zarate, Cayetana; Yang, Haifeng; Bezdek, Mate J.; Hesk, David; Chirik, Paul J.
    Journal of the American Chemical Society (2019), 141 (12), 5034-5044CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The synthesis and spectroscopic characterization of a family of Ni-X (X = Cl, Br, I, H) complexes supported by the bulky α-diimine chelate N,N'-bis(1R,2R,3R,5S)-(-)-isopinocampheyl-2,3-butanediimine (ipcADI) are described. Diimine-supported, three-coordinate Ni(I)-X complexes are proposed as key intermediates in a host of catalytic transformations such as C-C and C-heteroatom cross-coupling and C-H functionalization but have until now remained synthetically elusive. A combination of structural, spectroscopic, electrochem., and computational studies were used to establish the electronic structure of each monomeric [(ipcADI)NiX] (X = Cl, Br, I) complex as a Ni(I) deriv. supported by a redox-neutral α-diimine chelate. The dimeric Ni hydride, [(ipcADI)Ni(μ2-H)]2, was prepd. and characterized by x-ray diffraction; however, magnetic measurements and 1H NMR spectroscopy support monomer formation at ambient temp. in THF soln. This Ni hydride was used as a precatalyst for the H isotope exchange (HIE) of C-H bonds in arenes and pharmaceuticals. By virtue of the multisite reactivity and high efficiency, the new Ni precatalyst provided unprecedented high specific activities (50-99 Ci/mmol) in radiolabeling, meeting the threshold required for radioligand binding assays. Use of air-stable and readily synthesized Ni precursor, [(ipcADI)NiBr2], broad functional group tolerance, and compatibility with polar protic solvents are addnl. assets of the Ni-catalyzed HIE method.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXktV2mtLg%253D&md5=e61f2c33405102c0fa94501aec43e9a3
    .
    (d) Corpas, J.; Viereck, P.; Chirik, P. J. C(sp2)–H Activation with Pyridine Dicarbene Iron Dialkyl Complexes: Hydrogen Isotope Exchange of Arenes Using Benzene- d6 as a Deuterium Source. ACS Catal. 2020, 10, 8640– 8647,  DOI: 10.1021/acscatal.0c01714
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    20d
    C(sp2)-H Activation with Pyridine Dicarbene Iron Dialkyl Complexes: Hydrogen Isotope Exchange of Arenes Using Benzene-d6 as a Deuterium Source
    Corpas, Javier; Viereck, Peter; Chirik, Paul J.
    ACS Catalysis (2020), 10 (15), 8640-8647CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    Treatment of pyridine dicarbene iron dialkyl complexes with low («1 atm) pressures of H2 in a benzene-d6 soln. promoted rapid hydrogen isotope exchange (HIE) of the C(sp2)-H bonds in both electron-poor and -rich arom. and heteroarom. rings with benzene-d6 as the deuterium source. The iron-catalyzed reaction proceeded with predictable regioselectivity, engaging sterically accessible C-H bonds including ortho-to-fluorine sites. The site selectivity for the catalytic HIE reaction was studied to identify the kinetic preferences for C-H activation. Structure-activity relationship studies with a series of iron precatalysts established that introduction of substituents at the 3- and 5-positions of pyridine of the pincer significantly accelerated HIE. Mechanistic studies identified N2 as an inhibitor of C-H activation, while H2 served to generate the active catalyst.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlGnsbnN&md5=1f5ba81b99827a5ff77f1f90d930f7ad
    .
    (e) Garhwal, S.; Kaushansky, A.; Fridman, N.; Shimon, L. J. W.; Ruiter, G. de. Facile H/D Exchange at (Hetero)Aromatic Hydrocarbons Catalyzed by a Stable Trans-Dihydride N-Heterocyclic Carbene (NHC) Iron Complex. J. Am. Chem. Soc. 2020, 142, 17131– 17139,  DOI: 10.1021/jacs.0c07689
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    20e
    Facile H/D Exchange at (Hetero)Aromatic Hydrocarbons Catalyzed by a Stable Trans-Dihydride N-Heterocyclic Carbene (NHC) Iron Complex
    Garhwal, Subhash; Kaushansky, Alexander; Fridman, Natalia; Shimon, Linda J. W.; Ruiter, Graham de
    Journal of the American Chemical Society (2020), 142 (40), 17131-17139CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Earth-abundant metal pincer complexes have played an important role in homogeneous catalysis during the last ten years. Yet, despite intense research efforts, the synthesis of iron PCcarbeneP pincer complexes has so far remained elusive. Here we report the synthesis of the first PCNHCP functionalized iron complex [(PCNHCP)FeCl2] (1) and the reactivity of the corresponding trans-dihydride iron(II) dinitrogen complex [(PCNHCP)Fe(H)2N2] (2). Complex 2 is stable under an atm. of N2 and is highly active for hydrogen isotope exchange at (hetero)arom. hydrocarbons under mild conditions (50°C, N2). With benzene-d6 as the deuterium source, easily reducible functional groups such as esters and amides are well tolerated, contributing to the overall wide substrate scope (e.g., halides, ethers, and amines). DFT studies suggest a complex assisted σ-bond metathesis pathway for C(sp2)-H bond activation, which is further discussed in this study.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvVWhsLjM&md5=00ac282ea45b4c91c160d6cfc6fbfae7
    .
    (f) Yang, H.; Hesk, D. Base metal-catalyzed hydrogen isotope exchange. J. Labelled Compd. Radiopharm. 2020, 63, 296– 307,  DOI: 10.1002/jlcr.3826
    [Crossref], [PubMed], [CAS], Google Scholar
    20f
    Base metal-catalyzed hydrogen isotope exchange
    Yang, Haifeng; Hesk, David
    Journal of Labelled Compounds and Radiopharmaceuticals (2020), 63 (6), 296-307CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
    A review. In this review article, recent development of base metal catalysts for hydrogen isotope exchange (HIE) and their applications in isotopic labeling of pharmaceutical compds. was described. These research efforts have resulted in the development of labeling approaches that complement traditional methods in terms of activity and selectivity, thus diversifying the methodologies available for isotope chemists.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitFClsbk%253D&md5=cf90d3eceba15c7050c42e16f4a7b92a
  21. 21
    (a) Chen, H.; Wedi, P.; Meyer, T.; Tavakoli, G.; van Gemmeren, M. Dual Ligand-Enabled Nondirected C–H Olefination of Arenes. Angew. Chem., Int. Ed. 2018, 57, 2497– 2501,  DOI: 10.1002/anie.201712235
    [Crossref], [CAS], Google Scholar
    21a
    Dual Ligand-Enabled Nondirected C-H Olefination of Arenes
    Chen, Hao; Wedi, Philipp; Meyer, Tim; Tavakoli, Ghazal; van Gemmeren, Manuel
    Angewandte Chemie, International Edition (2018), 57 (9), 2497-2501CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The application of the Pd-catalyzed oxidative C-H olefination of arenes, also known as the Fujiwara-Moritani reaction, has traditionally been limited by the requirement for directing groups on the substrate or the need to use the arene in large excess, typically as a (co)solvent. Herein, the development of a catalytic system is described that, through the combined action of two complementary ligands, makes it possible to use directing-group-free arenes as limiting reagents for the first time. The reactions proceed under a combination of both steric and electronic control and enable the application of this powerful reaction to valuable arenes, which cannot be utilized in excess.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsl2ntLk%253D&md5=966a3aab705104d27ed1d207fa56c313
    .
    (b) Chen, H.; Mondal, A.; Wedi, P.; van Gemmeren, M. Dual Ligand-Enabled Nondirected C–H Cyanation of Arenes. ACS Catal. 2019, 9, 1979– 1984,  DOI: 10.1021/acscatal.8b04639
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    21b
    Dual Ligand-Enabled Nondirected C-H Cyanation of Arenes
    Chen, Hao; Mondal, Arup; Wedi, Philipp; van Gemmeren, Manuel
    ACS Catalysis (2019), 9 (3), 1979-1984CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    Arom. nitriles are key structural units in org. chem. and, therefore, highly attractive targets for C-H activation. Herein, the development of an arene-limited, nondirected C-H cyanation based on the use of two cooperatively acting com. available ligands is reported. The reaction enables the cyanation of arenes by C-H activation in the absence of directing groups and is therefore complementary to established approaches.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlChtbY%253D&md5=4c1c3123572388727dea895b967045cd
    .
    (c) Mondal, A.; Chen, H.; Flämig, L.; Wedi, P.; van Gemmeren, M. Sterically Controlled Late-Stage C–H Alkynylation of Arenes. J. Am. Chem. Soc. 2019, 141, 18662– 18667,  DOI: 10.1021/jacs.9b10868
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    21c
    Sterically Controlled Late-Stage C-H Alkynylation of Arenes
    Mondal, Arup; Chen, Hao; Flaemig, Lea; Wedi, Philipp; van Gemmeren, Manuel
    Journal of the American Chemical Society (2019), 141 (47), 18662-18667CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Herein, a complementary approach based on an arene-limited nondirected C-H activation is presented. The reaction is predominantly controlled by steric rather than electronic factors and thereby gives access to a complementary product spectrum with respect to traditional methods. A broad scope as well as the suitability of this protocol for late-stage functionalization are demonstrated.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFGjtL7M&md5=a0fb0441a7eda517bbafcd2a6d04e401
    .
    (d) Chen, H.; Farizyan, M.; Ghiringhelli, F.; van Gemmeren, M. Sterically Controlled C–H Olefination of Heteroarenes. Angew. Chem., Int. Ed. 2020, 59, 12213– 12220,  DOI: 10.1002/anie.202004521
    [Crossref], [CAS], Google Scholar
    21d
    Sterically Controlled C-H Olefination of Heteroarenes
    Chen, Hao; Farizyan, Mirxan; Ghiringhelli, Francesca; van Gemmeren, Manuel
    Angewandte Chemie, International Edition (2020), 59 (29), 12213-12220CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The regioselective functionalization of heteroarenes is a highly attractive synthetic target due to the prevalence of multiply substituted heteroarenes in nature and bioactive compds. Some substitution patterns remain challenging: While highly efficient methods for the C2-selective olefination of 3-substituted five-membered heteroarenes are reported, analogous methods to access the 5-olefinated products have remained limited by poor regioselectivities and/or the requirement to use an excess of the valuable heteroarene starting material. Herein the authors report a sterically controlled C-H olefination using heteroarenes as the limiting reagent. The method enables the highly C5-selective olefination of a wide range of heteroarenes and is useful in the context of late-stage functionalization.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpsFeqsb0%253D&md5=08ef07201918e838fa6328ccc04535d9
    .
    (e) Mondal, A.; van Gemmeren, M. Catalyst-Controlled Regiodivergent C–H Alkynylation of Thiophenes. Angew. Chem., Int. Ed. 2021, 60, 742– 746,  DOI: 10.1002/anie.202012103
    [Crossref], [CAS], Google Scholar
    21e
    Catalyst-Controlled Regiodivergent C-H Alkynylation of Thiophenes
    Mondal, Arup; van Gemmeren, Manuel
    Angewandte Chemie, International Edition (2021), 60 (2), 742-746CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Alkynes are highly attractive motifs in org. synthesis due to their presence in natural products and bioactive mols. as well as their versatility in a plethora of subsequent transformations. A common procedure to insert alkynes into (hetero)arenes, such as the thiophenes studied herein, consists of a halogenation followed by a Sonogashira cross-coupling. The regioselectivity of this approach depends entirely on the halogenation step. Similarly, direct alkynylations of thiophenes were described that follow the same regioselectivity patterns. Herein the authors report the development of a palladium catalyzed C-H activation/alkynylation of thiophenes. The method is applicable to a broad range of thiophene substrates. For 3-substituted substrates where controlling the regioselectivity between the C2 and C5 position is particularly challenging, two sets of reaction conditions enable a regiodivergent reaction, giving access to each regioisomer selectively. Both protocols use the thiophene as limiting reagent and show a broad scope, rendering the authors' method suitable for late-stage modification.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit12htLrM&md5=bb7cdf1279b1d70d6e59593962a6ddc5
    .
    (f) Santiago, C.; Chen, H.; Mondal, A.; van Gemmeren, M. Dual Ligand-Enabled Late-Stage Fujiwara–Moritani Reactions. Synlett 2021,  DOI: 10.1055/s-0040-1706014
    [Crossref], Google Scholar
    There is no corresponding record for this reference.
  22. 22

    For selected examples of arene-limited nondirected C–H activations with palladium catalysts, see:

    (a) Wang, P.; Verma, P.; Xia, G.; Shi, J.; Qiao, J. X.; Tao, S.; Cheng, P. T. W.; Poss, M. A.; Farmer, M. E.; Yeung, K.-S.; Yu, J.-Q. Ligand-accelerated non-directed C–H functionalization of arenes. Nature 2017, 551, 489– 493,  DOI: 10.1038/nature24632
    [Crossref], [PubMed], [CAS], Google Scholar
    22a
    Ligand-accelerated non-directed C-H functionalization of arenes
    Wang, Peng; Verma, Pritha; Xia, Guoqin; Shi, Jun; Qiao, Jennifer X.; Tao, Shiwei; Cheng, Peter T. W.; Poss, Michael A.; Farmer, Marcus E.; Yeung, Kap-Sun; Yu, Jin-Quan
    Nature (London, United Kingdom) (2017), 551 (7681), 489-493CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
    The directed activation of carbon-hydrogen bonds (C-H) is important in the development of synthetically useful reactions, owing to the proximity-induced reactivity and selectivity that is enabled by coordinating functional groups. Palladium-catalyzed non-directed C-H activation could potentially enable further useful reactions, because it can reach more distant sites and be applied to substrates that do not contain appropriate directing groups; however, its development has faced substantial challenges assocd. with the lack of sufficiently active palladium catalysts. Currently used palladium catalysts are reactive only with electron-rich arenes, unless an excess of arene is used, which limits synthetic applications. Here we report a 2-pyridone ligand that binds to palladium and accelerates non-directed C-H functionalization with arene as the limiting reagent. This protocol is compatible with a broad range of arom. substrates and we demonstrate direct functionalization of advanced synthetic intermediates, drug mols. and natural products that cannot be used in excessive quantities. We also developed C-H olefination and carboxylation protocols, demonstrating the applicability of our methodol. to other transformations. The site selectivity in these transformations is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C-H functionalization.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVKqtb%252FF&md5=0e2e4a01e016ca4fdee2dd3b82b2dcf9
    .
    (b) Naksomboon, K.; Valderas, C.; Gómez-Martínez, M.; Álvarez-Casao, Y.; Fernández-Ibáñez, M. Á. S. O-Ligand-Promoted Palladium-Catalyzed C–H Functionalization Reactions of Nondirected Arenes. ACS Catal. 2017, 7, 6342– 6346,  DOI: 10.1021/acscatal.7b02356
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    22b
    S,O-Ligand-Promoted Palladium-Catalyzed C-H Functionalization Reactions of Nondirected Arenes
    Naksomboon, Kananat; Valderas, Carolina; Gomez-Martinez, Melania; Alvarez-Casao, Yolanda; Fernandez-Ibanez, M. Angeles
    ACS Catalysis (2017), 7 (9), 6342-6346CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    Pd(II)-catalyzed C-H functionalization of nondirected arenes has been realized using an inexpensive and easily accessible type of bidentate S,O-ligand. The catalytic system shows high efficiency in the C-H olefination reaction of electron-rich and electron-poor arenes. This methodol. is operationally simple, scalable, and can be used in late-stage functionalization of complex mols. The broad applicability of this catalyst has been showcased in other transformations such as Pd(II)-catalyzed C-H acetoxylation and allylation reactions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlKhtbrE&md5=777190e5ff159903eeb9dce1ecff2486
    .
    (c) Naksomboon, K.; Poater, J.; Bickelhaupt, F. M.; Fernández-Ibáñez, M. Á. para-Selective C–H Olefination of Aniline Derivatives via Pd/S,O-Ligand Catalysis. J. Am. Chem. Soc. 2019, 141, 6719– 6725,  DOI: 10.1021/jacs.9b01908
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    22c
    para-Selective C-H Olefination of Aniline Derivatives via Pd/S,O-Ligand Catalysis
    Naksomboon, Kananat; Poater, Jordi; Bickelhaupt, F. Matthias; Fernandez-Ibanez, M. Angeles
    Journal of the American Chemical Society (2019), 141 (16), 6719-6725CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Herein we report a highly para-selective C-H olefination of aniline derivs. by a Pd/S,O-ligand-based catalyst. The reaction proceeds under mild reaction conditions with high efficiency and broad substrate scope, including mono-, di-, and trisubstituted tertiary, secondary, and primary anilines. The S,O-ligand is responsible for the dramatic improvements in substrate scope and the high para-selectivity obsd. This methodol. is operationally simple, scalable, and can be performed under aerobic conditions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmt1Olt78%253D&md5=fae7d273161877fa52525fe5973afd98
    .
    (d) Zhao, Da; Xu, P.; Ritter, T. Palladium-Catalyzed Late-Stage Direct Arene Cyanation. Chem. 2019, 5, 97– 107,  DOI: 10.1016/j.chempr.2018.09.027
    [Crossref], [CAS], Google Scholar
    22d
    Palladium-Catalyzed Late-Stage Direct Arene Cyanation
    Zhao, Da; Xu, Peng; Ritter, Tobias
    Chem (2019), 5 (1), 97-107CODEN: CHEMVE; ISSN:2451-9294. (Cell Press)
    The first general late-stage aryl C-H cyanation with broad substrate scope and functional-group tolerance was reported. The reaction was enabled by a dual-ligand combination of quinoxaline and an amino acid-derived ligand. The method was applicable to direct cyanation of several marketed small-mol. drugs, common pharmacophores and org. dyes.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFSgs7Y%253D&md5=e8fcabf4edda48542ae8619ea53d799f
    .
    (e) Liu, L.-Y.; Yeung, K.-S.; Yu, J.-Q. Ligand-Promoted Non-Directed C–H Cyanation of Arenes. Chem. - Eur. J. 2019, 25, 2199– 2202,  DOI: 10.1002/chem.201805772
    [Crossref], [PubMed], [CAS], Google Scholar
    22e
    Ligand-Promoted Non-Directed C-H Cyanation of Arenes
    Liu, Luo-Yan; Yeung, Kap-Sun; Yu, Jin-Quan
    Chemistry - A European Journal (2019), 25 (9), 2199-2202CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The first example of a 2-pyridone accelerated non-directed C-H cyanation with an arene as the limiting reagent was reported. This protocol was compatible with a broad scope of arenes, including advanced intermediates, drug mols. and natural products. A kinetic isotope expt. (kH/kD=4.40) indicated that the C-H bond cleavage is the rate-limiting step. Also, the reaction is readily scalable, further showcasing the synthetic utility of this method.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVKqtr0%253D&md5=48dc42d76a9bf2a181434f9446863e48
    .
    (f) Liu, L.-Y.; Qiao, J. X.; Yeung, K.-S.; Ewing, W. R.; Yu, J.-Q. meta-Selective C–H Arylation of Fluoroarenes and Simple Arenes. Angew. Chem., Int. Ed. 2020, 59, 13831– 13835,  DOI: 10.1002/anie.202002865
    [Crossref], [CAS], Google Scholar
    22f
    meta-Selective C-H Arylation of Fluoroarenes and Simple Arenes
    Liu, Luo-Yan; Qiao, Jennifer X.; Yeung, Kap-Sun; Ewing, William R.; Yu, Jin-Quan
    Angewandte Chemie, International Edition (2020), 59 (33), 13831-13835CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Fluorine is known to promote ortho-C-H metalation. Based upon this reactivity, we employed an activated norbornene that traps the ortho-palladation intermediate and is then relayed to the meta position, leading to meta-selective C-H arylation of fluoroarenes. Deuterium expt. suggests that this meta-arylation is initiated by ortho C-H activation and the catalytic cycle is terminated by C-2 protonation. A dual-ligand system is crucial for the obsd. high reactivity and site selectivity. Applying this approach to simple benzene or other arenes also affords arylation products with good yield and site selectivity.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlGmsLbE&md5=949197fc4ceec310bf56d8e9f0106f8c
    .
    (g) Dhankhar, J.; González-Fernández, E.; Dong, C.-C.; Mukhopadhyay, T. K.; Linden, A.; Čorić, I. Spatial Anion Control on Palladium for Mild C-H Arylation of Arenes. J. Am. Chem. Soc. 2020, 142, 19040– 19046,  DOI: 10.1021/jacs.0c09611
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    22g
    Spatial Anion Control on Palladium for Mild C-H Arylation of Arenes
    Dhankhar, Jyoti; Gonzalez-Fernandez, Elisa; Dong, Chao-Chen; Mukhopadhyay, Tufan K.; Linden, Anthony; Coric, Ilija
    Journal of the American Chemical Society (2020), 142 (45), 19040-19046CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    C-H arylation of arenes without the use of directing groups is a challenge, even for simple mols., such as benzene. We describe spatial anion control as a concept for the design of catalytic sites for C-H bond activation, thereby enabling nondirected C-H arylation of arenes at ambient temp. The mild conditions enable late-stage structural diversification of biol. relevant small mols., and site-selectivity complementary to that obtained with other methods of arene functionalization can be achieved. These results reveal the potential of spatial anion control in transition-metal catalysis for the functionalization of C-H bonds under mild conditions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitF2iu77I&md5=8d9b9d70e7300d188d0eee474cfa9c88
    .
    (h) Yin, B.; Fu, M.; Wang, L.; Liu, J.; Zhu, Q. Dual ligand-promoted palladium-catalyzed nondirected C–H alkenylation of aryl ethers. Chem. Commun. 2020, 56, 3293– 3296,  DOI: 10.1039/D0CC00940G
    [Crossref], [PubMed], [CAS], Google Scholar
    22h
    Dual ligand-promoted palladium-catalyzed nondirected C-H alkenylation of aryl ethers
    Yin, Biao; Fu, Manlin; Wang, Lei; Liu, Jiang; Zhu, Qing
    Chemical Communications (Cambridge, United Kingdom) (2020), 56 (22), 3293-3296CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    Herein, a novel strategy for nondirected C-H alkenylation of alkyl aryl ethers (anisole, phenetole, Pr Ph ether, Bu Ph ether and benzyl Ph ether), cyclic aryl ethers (1,4-benzodioxane, 2,3-dihydrobenzofuran, dibenzofuran), and di-Ph oxide promoted by a dual ligand catalyst was demonstrated. This catalytic system readily achieved the highly efficient alkenylation of aryl ethers. Moreover, the proposed methodol. was successfully employed for the late-stage modification of complex drugs contg. the aryl ether motif. Interestingly, the compds. developed herein displayed fluorescent properties, which would facilitate their biol. applications.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlt1SksL4%253D&md5=47bb743a05a6d570437d5422d60178bc
  23. 23
    Wedi, P.; Farizyan, M.; Bergander, K.; Mück-Lichtenfeld, C.; van Gemmeren, M. Mechanism of the Arene-Limited Nondirected C–H Activation of Arenes with Palladium. Angew. Chem., Int. Ed. 2021, 60, 15641– 15649,  DOI: 10.1002/anie.202105092
    [Crossref], [CAS], Google Scholar
    23
    Mechanism of the Arene-Limited Nondirected C-H Activation of Arenes with Palladium
    Wedi, Philipp; Farizyan, Mirxan; Bergander, Klaus; Mueck-Lichtenfeld, Christian; van Gemmeren, Manuel
    Angewandte Chemie, International Edition (2021), 60 (28), 15641-15649CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Recently palladium catalysts have been discovered that enable the directing-group-free C-H activation of arenes without requiring an excess of the arene substrate, thereby enabling methods for the late-stage modification of complex org. mols. The key to success has been the use of two complementary ligands, an N-acyl amino acid and an N-heterocycle. Detailed exptl. and computational mechanistic studies on the dual-ligand-enabled C-H activation of arenes have led us to identify the catalytically active species and a transition state model that explains the exceptional activity and selectivity of these catalysts. These findings are expected to be highly useful for further method development using this powerful class of catalysts.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsVKmtb7L&md5=97dec3ebe74490b094ef215167e6c4f0
  24. 24
    The initial optimization studies were conducted using the reverse dedeuteration with deuterated HFIP-benzoate [D]1 as a model substrate. See:Uttry, A.; Mal, S.; van Gemmeren, M. Late-Stage β-C(sp3)–H Deuteration of Carboxylic Acids. J. Am. Chem. Soc. 2021, 143, 10895– 10901,  DOI: 10.1021/jacs.1c06474
    [ACS Full Text ACS Full Text], [CAS], Google Scholar
    24
    Late-Stageβ-C(sp3)-H Deuteration of Carboxylic Acids
    Uttry, Alexander; Mal, Sourjya; van Gemmeren, Manuel
    Journal of the American Chemical Society (2021), 143 (29), 10895-10901CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    In this study, the late-stage β-C(sp3)-H deuteration of free carboxylic acids was described. On the basis of the finding that C-H activation with catalysts was reversible, the de-deuteration process was first optimized. The resulting method used ethylenediamine-based ligands and could be used to achieve the desired deuteration when using a deuterated solvent. The reported method allowed for the functionalization of a wide range of free carboxylic acids with diverse substitution patterns, as well as the late-stage deuteration of bioactive mols. and related frameworks and enables the functionalization of nonactivated methylene β-C(sp3)-H bonds for the first time.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhs1WmtbvL&md5=05d377aac5516de2d0abcb0a576a146b

    See the SI for details.

Cited By

This article is cited by 31 publications.

  1. Simon Kaltenberger, Manuel van Gemmeren. Controlling Reactivity and Selectivity in the Nondirected C–H Activation of Arenes with Palladium. Accounts of Chemical Research 2023, 56 (18) , 2459-2472. https://doi.org/10.1021/acs.accounts.3c00354
  2. Daniele Antermite, Andrew J. P. White, Luis Casarrubios, James A. Bull. On the Mechanism and Selectivity of Palladium-Catalyzed C(sp3)–H Arylation of Pyrrolidines and Piperidines at Unactivated C4 Positions: Discovery of an Improved Dimethylaminoquinoline Amide Directing Group. ACS Catalysis 2023, 13 (14) , 9597-9615. https://doi.org/10.1021/acscatal.3c01980
  3. Seo Jin Yun, Jisu Kim, Eunsu Kang, Hoimin Jung, Hyun Tae Kim, Minkyu Kim, Jung Min Joo. Nondirected Pd-Catalyzed C–H Perdeuteration and meta-Selective Alkenylation of Arenes Enabled by Pyrazolopyridone Ligands. ACS Catalysis 2023, 13 (7) , 4042-4052. https://doi.org/10.1021/acscatal.2c06303
  4. Heng Song, Wenjing Zhang, Hu Zhou, Jingjing Wei, Xingwei Cai, Fu Yang, Wei Li, Chen Xu. Remote Site-Selective C(sp3)–H Monodeuteration of Unactivated Alkenes via Chain-Walking Strategy. ACS Catalysis 2023, 13 (6) , 3644-3654. https://doi.org/10.1021/acscatal.3c00559
  5. Riley A. Roberts, Bryan E. Metze, Aleksandra Nilova, David R. Stuart. Synthesis of Arynes via Formal Dehydrogenation of Arenes. Journal of the American Chemical Society 2023, 145 (6) , 3306-3311. https://doi.org/10.1021/jacs.2c13007
  6. Jianbo Tang, Junhua Kong, Hui Xu, Zhi-Jiang Jiang, Yifan She, Jianfei Bai, Bencan Tang, Jia Chen, Zhanghua Gao, Kun Gao. Multideuteration of Nitroaromatics by Silver-Catalyzed Hydrogen-Isotope Exchange. The Journal of Organic Chemistry 2023, 88 (3) , 1560-1567. https://doi.org/10.1021/acs.joc.2c02618
  7. Ross D. Jansen-van Vuuren, Luka Jedlovčnik, Janez Košmrlj, Thomas E. Massey, Volker Derdau. Deuterated Drugs and Biomarkers in the COVID-19 Pandemic. ACS Omega 2022, 7 (46) , 41840-41858. https://doi.org/10.1021/acsomega.2c04160
  8. Jose B. Roque, Tyler P. Pabst, Paul J. Chirik. C(sp2)–H Activation with Bis(silylene)pyridine Cobalt(III) Complexes: Catalytic Hydrogen Isotope Exchange of Sterically Hindered C–H Bonds. ACS Catalysis 2022, 12 (15) , 8877-8885. https://doi.org/10.1021/acscatal.2c02429
  9. Jiajun Du, Haomin Wang, Lu Wei. Bringing Vibrational Imaging to Chemical Biology with Molecular Probes. ACS Chemical Biology 2022, 17 (7) , 1621-1637. https://doi.org/10.1021/acschembio.2c00200
  10. Soumya Kumar Sinha, Subir Panja, Jagrit Grover, Partha Sarathi Hazra, Saikat Pandit, Yogesh Bairagi, Xinglong Zhang, Debabrata Maiti. Dual Ligand Enabled Nondirected C–H Chalcogenation of Arenes and Heteroarenes. Journal of the American Chemical Society 2022, 144 (27) , 12032-12042. https://doi.org/10.1021/jacs.2c02126
  11. Xiang-Ting Min, Yong-Kang Mei, Bing-Zhi Chen, Li-Bowen He, Ting-Ting Song, Ding-Wei Ji, Yan-Cheng Hu, Boshun Wan, Qing-An Chen. Rhodium-Catalyzed Deuterated Tsuji–Wilkinson Decarbonylation of Aldehydes with Deuterium Oxide. Journal of the American Chemical Society 2022, 144 (25) , 11081-11087. https://doi.org/10.1021/jacs.2c04422
  12. Sara Kopf, Florian Bourriquen, Wu Li, Helfried Neumann, Kathrin Junge, Matthias Beller. Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules. Chemical Reviews 2022, 122 (6) , 6634-6718. https://doi.org/10.1021/acs.chemrev.1c00795
  13. Argha Saha, Srimanta Guin, Wajid Ali, Trisha Bhattacharya, Sheuli Sasmal, Nupur Goswami, Gaurav Prakash, Soumya Kumar Sinha, Hediyala B. Chandrashekar, Sanjib Panda, S. S. Anjana, Debabrata Maiti. Photoinduced Regioselective Olefination of Arenes at Proximal and Distal Sites. Journal of the American Chemical Society 2022, 144 (4) , 1929-1940. https://doi.org/10.1021/jacs.1c12311
  14. Hui‐Zhen Du, Jun‐Zhen Fan, Zhong‐Zhen Wang, Neil A. Strotman, Haifeng Yang, Bing‐Tao Guan. Cesium Amide‐Catalyzed Selective Deuteration of Benzylic C‐H Bonds with D 2 and Application for Tritiation of Pharmaceuticals. Angewandte Chemie 2023, 135 (8) https://doi.org/10.1002/ange.202214461
  15. Hui‐Zhen Du, Jun‐Zhen Fan, Zhong‐Zhen Wang, Neil A. Strotman, Haifeng Yang, Bing‐Tao Guan. Cesium Amide‐Catalyzed Selective Deuteration of Benzylic C‐H Bonds with D 2 and Application for Tritiation of Pharmaceuticals. Angewandte Chemie International Edition 2023, 62 (8) https://doi.org/10.1002/anie.202214461
  16. Akihiko Suzuki, Yuji Kamei, Masaaki Yamashita, Yusuke Seino, Yuto Yamaguchi, Tatsuhiko Yoshino, Masahiro Kojima, Shigeki Matsunaga. Photocatalytic Deuterium Atom Transfer Deuteration of Electron‐Deficient Alkenes with High Functional Group Tolerance. Angewandte Chemie 2023, 135 (3) https://doi.org/10.1002/ange.202214433
  17. Akihiko Suzuki, Yuji Kamei, Masaaki Yamashita, Yusuke Seino, Yuto Yamaguchi, Tatsuhiko Yoshino, Masahiro Kojima, Shigeki Matsunaga. Photocatalytic Deuterium Atom Transfer Deuteration of Electron‐Deficient Alkenes with High Functional Group Tolerance. Angewandte Chemie International Edition 2023, 62 (3) https://doi.org/10.1002/anie.202214433
  18. Sergio Barranco, Mónica H. Pérez-Temprano. Merging homogeneous transition metal catalysis and hydrogen isotope exchange. 2023, 157-193. https://doi.org/10.1016/bs.adomc.2022.12.003
  19. Zi-Mo Zhang, Shuai Liu, Hui Yang, Ning Wang, Yun-He Zou, Peng-Yu Zhuang, Xiao-Xia Wang, Hang Liu. Chemical constituents from Dendrobium chrysanthum and their chemotaxonomic significance. Biochemical Systematics and Ecology 2022, 105 , 104522. https://doi.org/10.1016/j.bse.2022.104522
  20. Yinggang Guo, Wankai An, Xinzhe Tian, Lixia Xie, Yun-Lai Ren. Coupling photocatalytic overall water splitting with hydrogenation of organic molecules: a strategy for using water as a hydrogen source and an electron donor to enable hydrogenation. Green Chemistry 2022, 24 (23) , 9211-9219. https://doi.org/10.1039/D2GC02427F
  21. Arup Mondal, Manuel van Gemmeren. Silberfreie C−H‐Aktivierung: Strategische Ansätze zur Erschließung des vollen Potenzials von C−H‐Aktivierungen in der nachhaltigen organischen Synthese. Angewandte Chemie 2022, 134 (48) https://doi.org/10.1002/ange.202210825
  22. Arup Mondal, Manuel van Gemmeren. Silver‐Free C−H Activation: Strategic Approaches towards Realizing the Full Potential of C−H Activation in Sustainable Organic Synthesis. Angewandte Chemie International Edition 2022, 61 (48) https://doi.org/10.1002/anie.202210825
  23. T. Tanaka, Y. Koga, Y. Honda, A. Tsuruta, N. Matsunaga, S. Koyanagi, S. Ohdo, R. Yazaki, T. Ohshima. Ternary catalytic α-deuteration of carboxylic acids. Nature Synthesis 2022, 1 (10) , 824-830. https://doi.org/10.1038/s44160-022-00139-9
  24. Luke Britton, Jamie H. Docherty, Jan Sklyaruk, Jessica Cooney, Gary S. Nichol, Andrew P. Dominey, Stephen P. Thomas. Iron-catalysed alkene and heteroarene H/D exchange by reversible protonation of iron-hydride intermediates. Chemical Science 2022, 13 (35) , 10291-10298. https://doi.org/10.1039/D2SC03802A
  25. Emeline Appert, Agnès Martin‐Mingot, Omar Karam, Fabien Zunino, Bastien Michelet, Fodil Bouazza, Sébastien Thibaudeau. Superacid‐Mediated Late‐Stage Aromatic Polydeuteration of Pharmaceuticals. Chemistry – A European Journal 2022, 28 (49) https://doi.org/10.1002/chem.202201583
  26. Moeko Itoga, Masako Yamanishi, Taro Udagawa, Ayane Kobayashi, Keiko Maekawa, Yoshiji Takemoto, Hiroshi Naka. Iridium-catalyzed α-selective deuteration of alcohols. Chemical Science 2022, 13 (30) , 8744-8751. https://doi.org/10.1039/D2SC01805E
  27. Florian Bourriquen, Nils Rockstroh, Stephan Bartling, Kathrin Junge, Matthias Beller. Manganese‐Catalysed Deuterium Labelling of Anilines and Electron‐Rich (Hetero)Arenes. Angewandte Chemie 2022, 134 (27) https://doi.org/10.1002/ange.202202423
  28. Florian Bourriquen, Nils Rockstroh, Stephan Bartling, Kathrin Junge, Matthias Beller. Manganese‐Catalysed Deuterium Labelling of Anilines and Electron‐Rich (Hetero)Arenes. Angewandte Chemie International Edition 2022, 61 (27) https://doi.org/10.1002/anie.202202423
  29. Patrick Morawietz, Remo Weck, Andrew A. Scholte, Jens Atzrodt, Stefan Güssregen, Volker Derdau. Significantly improved radiochemical yields in gaseous tritium reactions by iridium( i )-catalyzed hydrogen isotope exchange. Green Chemistry 2022, 24 (12) , 4824-4829. https://doi.org/10.1039/D2GC00534D
  30. Gaurav Prakash, Nilanjan Paul, Gwyndaf A. Oliver, Daniel B. Werz, Debabrata Maiti. C–H deuteration of organic compounds and potential drug candidates. Chemical Society Reviews 2022, 51 (8) , 3123-3163. https://doi.org/10.1039/D0CS01496F
  31. Kwihwan Park, Naoki Oka, Yoshinari Sawama, Takashi Ikawa, Tsuyoshi Yamada, Hironao Sajiki. Platinum on carbon-catalysed site-selective H–D exchange reaction of allylic alcohols using alkyl amines as a hydrogen source. Organic Chemistry Frontiers 2022, 9 (7) , 1986-1991. https://doi.org/10.1039/D2QO00177B
Download PDF

  • Abstract

    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 1

    Scheme 1. Approaches toward the Deuteration of Arenes
    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 2

    Scheme 2. Reaction Scopea,b
    High Resolution Image
    Download MS PowerPoint Slide

    aReactions were performed on a 0.2 mmol scale.

    bPositions with less than 10% D incorporation are typically not depicted explicitly but are reflected in the DTotal value (for experimental details, see the SI).

    cThe reaction was performed at 40 °C for 72 h.

    dDetermined by 1H NMR spectroscopy.

  • References

    ARTICLE SECTIONS
    Jump To

    This article references 24 other publications.

    1. 1
      (a) Junk, T.; Catallo, W. J. Hydrogen isotope exchange reactions involving C–H (D, T) bonds. Chem. Soc. Rev. 1997, 26, 401– 406,  DOI: 10.1039/CS9972600401
      [Crossref], [CAS], Google Scholar
      1a
      Hydrogen isotope exchange reactions involving C-H (D, T) bonds
      Junk, Thomas; Catallo, W. James
      Chemical Society Reviews (1997), 26 (5), 401-406CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      Exchange reactions involving the displacement of hydrogen bonded to carbon by its heavier isotopes are of interest for both mechanistic and product-oriented research. This review surveys practical strategies for the prepn. of isotopically labeled compds., discusses recent progress made in developing mild and regioselective exchange protocols, and summarizes the mechanistic aspects of C-H bond activation under homogeneous and heterogeneous exchange conditions; 32 refs.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXnvFajtLY%253D&md5=dc8eb0cae2f11917727dd411c2b8ee7d
      .
      (b) Atzrodt, J.; Derdau, V.; Fey, T.; Zimmermann, J. The renaissance of H/D exchange. Angew. Chem., Int. Ed. 2007, 46, 7744– 7765,  DOI: 10.1002/anie.200700039
      [Crossref], [PubMed], [CAS], Google Scholar
      1b
      The renaissance of H/D exchange
      Atzrodt, Jens; Derdau, Volker; Fey, Thorsten; Zimmermann, Jochen
      Angewandte Chemie, International Edition (2007), 46 (41), 7744-7765CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. The increasing demand for stable isotopically labeled compds. has led to an increased interest in H/D-exchange reactions at carbon centers. Today deuterium-labeled compds. are used as internal stds. in mass spectrometry or to help elucidate mechanistic theories. Access to these deuterated compds. takes place significantly more efficiently and more cost effectively by exchange of hydrogen by deuterium in the target mol. than by classical synthesis. This review will conc. on the preparative application of the H/D-exchange reaction in the prepn. of deuterium-labeled compds. Advances over the last ten years are brought together and critically evaluated.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1alsL3M&md5=d4c01740a03e307d6e89ab954bd11809
      .
      (c) Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid, M. Deuterium- and Tritium-Labelled Compounds: Applications in the Life Sciences. Angew. Chem., Int. Ed. 2018, 57, 1758– 1784,  DOI: 10.1002/anie.201704146
      [Crossref], [CAS], Google Scholar
      1c
      Deuterium- and Tritium-Labelled Compounds: Applications in the Life Sciences
      Atzrodt, Jens; Derdau, Volker; Kerr, William J.; Reid, Marc
      Angewandte Chemie, International Edition (2018), 57 (7), 1758-1784CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Hydrogen isotopes are unique tools for identifying and understanding biol. and chem. processes. Hydrogen isotope labeling allows for the traceless and direct incorporation of an addnl. mass or radioactive tag into an org. mol. with almost no changes in its chem. structure, phys. properties, or biol. activity. Using deuterium-labeled isotopologues to study the unique mass-spectrometric patterns generated from mixts. of biol. relevant mols. drastically simplifies anal. Such methods are now providing unprecedented levels of insight in a wide and continuously growing range of applications in the life sciences and beyond. Tritium (3H), in particular, has seen an increase in utilization, esp. in pharmaceutical drug discovery. The efforts and costs assocd. with the synthesis of labeled compds. are more than compensated for by the enhanced mol. sensitivity during anal. and the high reliability of the data obtained. In this Review, advances in the application of hydrogen isotopes in the life sciences are described.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjs1Cgtw%253D%253D&md5=4d6ee858335dbe9f59601428a56415bd
      .
      (d) Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid, M. C-H. Functionalisation for Hydrogen Isotope Exchange. Angew. Chem., Int. Ed. 2018, 57, 3022– 3047,  DOI: 10.1002/anie.201708903
      [Crossref], [CAS], Google Scholar
      1d
      C-H Functionalisation for Hydrogen Isotope Exchange
      Atzrodt, Jens; Derdau, Volker; Kerr, William J.; Reid, Marc
      Angewandte Chemie, International Edition (2018), 57 (12), 3022-3047CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. The various applications of hydrogen isotopes (deuterium, D, and tritium, T) in the phys. and life sciences demand a range of methods for their installation in an array of mol. architectures. In this Review, we describe recent advances in synthetic C-H functionalization for hydrogen isotope exchange.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1Wns7Y%253D&md5=b5fbc8a8f484dd90dd05c098db7fcae6
      .
      (e) Kang, Q.-K.; Shi, H. Catalytic Hydrogen Isotope Exchange Reactions in Late-Stage Functionalization. Synlett 2021,  DOI: 10.1055/a-1354-0367
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    2. 2
      Simmons, E. M.; Hartwig, J. F. On the interpretation of deuterium kinetic isotope effects in C–H bond functionalizations by transition-metal complexes. Angew. Chem., Int. Ed. 2012, 51, 3066– 3072,  DOI: 10.1002/anie.201107334
      [Crossref], [PubMed], [CAS], Google Scholar
      2
      On the Interpretation of Deuterium Kinetic Isotope Effects in C-H Bond Functionalizations by Transition-Metal Complexes
      Simmons, Eric M.; Hartwig, John F.
      Angewandte Chemie, International Edition (2012), 51 (13), 3066-3072CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. We have presented in this essay a reminder of the limitations of some of the expts. used most commonly to measure kinetic isotope effects for processes involving C-H bond functionalization. Specifically, we have shown that the KIE expt. that allows one to conclude that C-H bond cleavage occurs during the rate-detg. step of a reaction is the measurement of the rates or rate consts. of two independent reactions with two substrates, one contg. a C-H bond and one contg. a C-D bond. We hope that this presentation will assist in the selection of expts. to conduct when seeking information on whether C-H bond cleavage occurs during the "rate-detg." or "turnover-limiting" step of a metal-mediated C-H bond functionalization process.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjtFOrsb8%253D&md5=354e995f450827f2028567b5f2849017
    3. 3
      (a) Wehmeyer, K. R.; Knight, P. M.; Parry, R. C. Evaluation of a benchtop ion trap gas chromatographic-tandem mass spectrometric instrument for the analysis of a model drug, tebufelone, in plasma using a stable-isotope internal standard. J. Chromatogr., Biomed. Appl. 1996, 676, 53– 59,  DOI: 10.1016/0378-4347(95)00417-3
      [Crossref], [PubMed], [CAS], Google Scholar
      3a
      Evaluation of a benchtop ion trap gas chromatographic-tandem mass spectrometric instrument for the analysis of a model drug, tebufelone, in plasma using a stable-isotope internal standard
      Wehmeyer, Kenneth R.; Knight, Paula M.; Parry, Ritchard C.
      Journal of Chromatography B: Biomedical Sciences and Applications (1996), 676 (1), 53-9CODEN: JCBBEP; ISSN:0378-4347. (Elsevier)
      The performance of a benchtop GC-ion trap MS-MS instrument, the Varian Saturn 4D, was evaluated for the anal. of a model drug, tebufelone, in plasma. The sample prepn. scheme was designed to provide a highly complex ext. with matrix-derived interferences eluting near and at the retention time of tebufelone and its stable-isotope-labeled analog. The performance of the ion trap in the selected-reaction-monitoring mode was evaluated and also compared with results obtained on a benchtop GC-MS linear quadrupole instrument operated in the selected-ion-monitoring mode. The ion trap, operated in the selected-reaction-monitoring mode, was found to provide a higher degree of selectivity for the anal. of tebufelone. The increased selectivity obtained on the ion trap operated in the selected-reaction-monitoring mode resulted in superior accuracy and precision, as well as a lower limit of quantitation relative to that obtained by the GC-MS anal. A linear std. curve was obtained over three orders of magnitude and the limit of quantitation for tebufelone in plasma was 100 pg/mL using the GC-ion trap MS-MS instrument.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XhvV2nsLk%253D&md5=6fa1f375f31e418dd91afaf4d314dd5b
      .
      (b) Kao, C.-Y.; Giese, R. W. Measurement of N7-(2’-hydroxyethyl)guanine in human DNA by gas chromatography electron capture mass spectrometry. Chem. Res. Toxicol. 2005, 18, 70– 75,  DOI: 10.1021/tx049854d
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      3b
      Measurement of N7-(2'-Hydroxyethyl)guanine in Human DNA by Gas Chromatography Electron Capture Mass Spectrometry
      Kao, Chi-Yu; Giese, Roger W.
      Chemical Research in Toxicology (2005), 18 (1), 70-75CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
      An improved method is presented, based on gas chromatog.-electron capture mass spectrometry (GC-EC-MS), for measuring N7-(2'-hydroxyethyl)guanine (N7-HEG) in DNA from an in vivo sample. The method was used to detect this adduct in amts. of human DNA ranging from 0.07 to 11.5 μg isolated from granulocytes. In this method, the DNA is spiked with a stable isotope internal std. (N7-HEG-d4) and heated in water to release the adduct in a nucleobase form. After the adduct is extd. into 1-butanol, it is purified by reverse phase HPLC and derivatized with HONO, pentafluorobenzyl bromide, and pivalic anhydride. Further purifn. by silica solid phase extn. and reverse phase HPLC is done prior to injection into a GC-EC-MS. Relatively clean GC-EC-MS chromatograms result, contributing to the high sensitivity that is obsd. In the samples tested, from 1.6 to 240 N7-HEG adducts in 107 nucleotides were obsd., a 150-fold range.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVyhsrbI&md5=ad9a3b632556925af9f999d3a8ebdcf8
      .
      (c) Stokvis, E.; Rosing, H.; Beijnen, J. H. Stable isotopically labeled internal standards in quantitative bioanalysis using liquid chromatography/mass spectrometry: necessity or not?. Rapid Commun. Mass Spectrom. 2005, 19, 401– 407,  DOI: 10.1002/rcm.1790
      [Crossref], [PubMed], [CAS], Google Scholar
      3c
      Stable isotopically labeled internal standards in quantitative bioanalysis using liquid chromatography/mass spectrometry: necessity or not?
      Stokvis, Ellen; Rosing, Hilde; Beijnen, Jos H.
      Rapid Communications in Mass Spectrometry (2005), 19 (3), 401-407CODEN: RCMSEF; ISSN:0951-4198. (John Wiley & Sons Ltd.)
      It appears to be a general belief that stable isotopically labeled (SIL) internal stds. yield better assay performance results for quant. bioanal. liq. chromatog./mass spectrometry (LC/MS) assays than does any other internal std. In this article we describe our experiences with structural analogs and SIL internal stds. and their merits and demerits. SIL internal stds. are the first choice, but deuterium-labeled compds. may demonstrate unexpected behavior, such as different retention times or recoveries, than the analyte. In addn., a SIL internal std. with identical chem. properties as the analyte may cover up assay problems with stability, recovery, and ion suppression. Since SIL internal stds. are not always available or are very expensive, structural analogs can be used, however, with consideration of several issues, which are usually displayed during method validation.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhsVCjsbw%253D&md5=39bf96f7b335e919972f4eba38af30bc
      .
      (d) Mutlib, A. E. Application of stable isotope-labeled compounds in metabolism and in metabolism-mediated toxicity studies. Chem. Res. Toxicol. 2008, 21, 1672– 1689,  DOI: 10.1021/tx800139z
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      3d
      Application of Stable Isotope-Labeled Compounds in Metabolism and in Metabolism-Mediated Toxicity Studies
      Daniels, Scott; Espina, Robert; Kao, Kevin; Yuan, Haodan; Lin, Jianrong; Diamond, Sharon; Johnson, Barry; Rodgers, James; Prakash, Shimoga; Unger, Steve; Christ, David; Miwa, Gerald; Gan, Liang-Shang; Mutlib, Abdul E.
      Chemical Research in Toxicology (2008), 21 (9), 1672-1689CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
      A review. Stable isotope-labeled compds. have been synthesized and utilized by scientists from various areas of biomedical research during the last several decades. Compds. labeled with stable isotopes, such as deuterium and carbon-13, have been used effectively by drug metab. scientists and toxicologists to gain better understanding of drugs' disposition and their potential role in target organ toxicities. The combination of stable isotope-labeling techniques with mass spectrometry and NMR spectroscopy, which allows rapid acquisition and interpretation of data, has promoted greater use of these stable isotope-labeled compds. in absorption, distribution, metab., and excretion (ADME) studies. Examples of the use of stable isotope-labeled compds. in elucidating structures of metabolites and delineating complex metabolic pathways are presented in this review. The application of labeled compds. in mechanistic toxicity studies will be discussed by providing an example of how strategic placement of a deuterium atom in a drug mol. mitigated specific-specific renal toxicity. Other examples from the literature demonstrating the application of stable isotope-labeled compds. in understanding metab.-mediated toxicities are presented. Furthermore, an example of how a stable isotope-labeled compd. was utilized to better understand some of the gene changes in toxicogenomic studies is discussed. The interpretation of large sets of data produced from toxicogenomics studies can be a challenge. One approach that could be used to simplify interpretation of the data, esp. from studies designed to link gene changes with the formation of reactive metabolites thought to be responsible for toxicities, is through the use of stable isotope-labeled compds. This is a relatively unexplored territory and needs to be further investigated. The employment of anal. techniques, esp. mass spectrometry and NMR, used in conjunction with stable isotope-labeled compds. to establish and understand mechanistic link between reactive metabolite formation, genomic, and proteomic changes and onset of toxicity is proposed. The use of stable isotope-labeled compds. in early human ADME studies as a way of identifying and possibly quantifying all drug-related components present in systemic circulation is suggested.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXpvVyjuro%253D&md5=0718486f07b08b673ef45eb3b88e57de
      .
      (e) Atzrodt, J.; Derdau, V. Pd- and Pt-catalyzed H/D exchange methods and their application for internal MS standard preparation from a Sanofi-Aventis perspective. J. Labelled Compd. Radiopharm. 2010, 53, 674– 685,  DOI: 10.1002/jlcr.1818
      [Crossref], [CAS], Google Scholar
      3e
      Pd- and Pt-catalyzed H/D exchange methods and their application for internal MS standard preparation from a Sanofi-Aventis perspective
      Atzrodt, Jens; Derdau, Volker
      Journal of Labelled Compounds and Radiopharmaceuticals (2010), 53 (11-12), 674-685CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
      This review addresses method developments both homogeneous and heterogeneous Pd- and Pt-catalyzed exchange, including catalyst activation principles and recent practical applications together with example procedures. Specific requirements for isotopically labeled internal MS std. prepn. are discussed from a Sanofi-Aventis perspective on recent examples.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXis1SjsA%253D%253D&md5=7cb25562f3949122991f6b6aa776e73f
    4. 4
      (a) Marathe, P. H.; Shyu, W. C.; Humphreys, W. G. The use of radiolabeled compounds for ADME studies in discovery and exploratory development. Curr. Pharm. Des. 2004, 10, 2991– 3008,  DOI: 10.2174/1381612043383494
      [Crossref], [PubMed], [CAS], Google Scholar
      4a
      The use of radiolabeled compounds for ADME studies in discovery and exploratory development
      Marathe, P. H.; Shyu, W. C.; Humphreys, W. G.
      Current Pharmaceutical Design (2004), 10 (24), 2991-3008CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
      A review. Radiolabeled compds. are excellent investigative tools and widely used to carry out ADME studies during drug discovery and development stages. The most commonly used radioisotopes are 14C and 3H. 3H materials are generally easier to synthesize than 14C materials. Therefore, a variety of probes and substrates used in in vitro assays are labeled with 3H. Since synthesis of 14C material requires intensive resources, it is usually not available until after a mol. is considered for potential development or after the mol. enters the development phase. Improvement in the technol. in radiochem. has enabled the use of radiolabeled compds. earlier in pre-clin. and clin. development to address mechanistic issues. For in vitro studies, radiolabeled probes are utilized to test affinity with various transporters, to perform metab. comparison among species and to assess possible formation of reactive metabolites. For in vivo studies, radiolabeled compds. are employed to identify and elucidate metabolites formed, to investigate the extent of absorption, bioavailability, tissue distribution, mass balance, routes of excretion, and pre-systemic metab. Due to the significant impact of radiolabeled studies on drug development, these studies will be performed earlier than have been in the past and will continue to be an integral part of drug discovery and development.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXntFOgtrw%253D&md5=b0b323bcbe208f215038a22c7c517db0
      .
      (b) Harbeson, S. L.; Tung, R. D. Deuterium in Drug Discovery and Development. Annu. Rep. Med. Chem. 2011, 46, 403– 417,  DOI: 10.1016/B978-0-12-386009-5.00003-5
      [Crossref], [CAS], Google Scholar
      4b
      Deuterium in drug discovery and development
      Harbeson, Scott L.; Tung, Roger D.
      Annual Reports in Medicinal Chemistry (2011), 46 (), 403-417CODEN: ARMCBI; ISSN:0065-7743. (Elsevier)
      A review presents the use of deuterium to alter the metabolic properties of compds. and discusses past and current development of potential deuterium-contg. drugs.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVCks7fL&md5=48188b3d60119f12cad9ae7ebe877ef5
      .
      (c) Isin, E. M.; Elmore, C. S.; Nilsson, G. N.; Thompson, R. A.; Weidolf, L. Use of radiolabeled compounds in drug metabolism and pharmacokinetic studies. Chem. Res. Toxicol. 2012, 25, 532– 542,  DOI: 10.1021/tx2005212
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      4c
      Use of Radiolabeled Compounds in Drug Metabolism and Pharmacokinetic Studies
      Isin, Emre M.; Elmore, Charles S.; Nilsson, Goran N.; Thompson, Richard A.; Weidolf, Lars
      Chemical Research in Toxicology (2012), 25 (3), 532-542CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
      A review. As part of the drug discovery and development process, it is important to understand the fate of the drug candidate in humans and the relevance of the animal species used for preclin. toxicity and pharmacodynamic studies. Therefore, various in vitro and in vivo studies are conducted during the different stages of the drug development process to elucidate the absorption, distribution, metab., and excretion properties of the drug candidate. Although state-of-the-art LC/MS techniques are commonly employed for these studies, radiolabeled mols. are still frequently required for the quantification of metabolites and to assess the retention and excretion of all drug related material without relying on structural information and MS ionization properties. In this perspective, we describe the activities of Isotope Chem. at AstraZeneca and give a brief overview of different commonly used approaches for the prepn. of 14C- and 3H-labeled drug candidates. Also various drug metab. and pharmacokinetic studies utilizing radiolabeled drug candidates are presented with inhouse examples where relevant. Finally, we outline strategic changes to our use of radiolabeled compds. in drug metab. and pharmacokinetic studies, with an emphasis on delaying of in vivo studies employing radiolabeled drug mols.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivFWns7w%253D&md5=9511e0850d2966ba6b0832fb10bcdab3
      .
      (d) Gant, T. G. Using deuterium in drug discovery: leaving the label in the drug. J. Med. Chem. 2014, 57, 3595– 3611,  DOI: 10.1021/jm4007998
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      4d
      Using Deuterium in Drug Discovery: Leaving the Label in the Drug
      Gant, Thomas G.
      Journal of Medicinal Chemistry (2014), 57 (9), 3595-3611CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A review. Deuterium, the stable isotope of hydrogen, is known to medicinal chemists for its utility in mechanistic, spectroscopic, and tracer studies. In fact, well-known applications utilizing deuterium exist within every subdiscipline in pharmaceutical discovery and development. Recent emphasis on incorporation of deuterium into the active pharmaceutical ingredient has come about as a result of inquiries into the potential for substantial benefits of the deuterium kinetic isotope effect on the safety and disposition of the drug substance. This Perspective traces the author's experience in reviving and expanding this potential utility, first suggested many decades prior by the discoverer of this, the simplest of all isotopes.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFegsrvJ&md5=3818a1dba9be431098ad9dd941dababc
      .
      (e) Elmore, C. S.; Bragg, R. A. Isotope chemistry; a useful tool in the drug discovery arsenal. Bioorg. Med. Chem. Lett. 2015, 25, 167– 171,  DOI: 10.1016/j.bmcl.2014.11.051
      [Crossref], [PubMed], [CAS], Google Scholar
      4e
      Isotope chemistry; a useful tool in the drug discovery arsenal
      Elmore, Charles S.; Bragg, Ryan A.
      Bioorganic & Medicinal Chemistry Letters (2015), 25 (2), 167-171CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      A review. As Medicinal Chemists are responsible for the synthesis and optimization of compds., they often provide intermediates for use by isotope chem. Nevertheless, there is generally an incomplete understanding of the crit. factors involved in the labeling of compds. The remit of an Isotope Chem. group varies from company to company, but often includes the synthesis of compds. labeled with radioisotopes, esp. H-3 and C-14 and occasionally I-125, and stable isotopes, esp. H-2, C-13, and N-15. Often the remit will also include the synthesis of drug metabolites. The methods used to prep. radiolabeled compds. by Isotope Chemists have been reviewed relatively recently. However, the organization and utilization of Isotope Chem. has not been discussed recently and will be reviewed herein.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVWhsL3I&md5=3df9e36e8505b2255c7b8ef652ff96c9
    5. 5
      (a) Mullard, A. FDA approves first deuterated drug. Nat. Rev. Drug Discovery 2017, 16, 305,  DOI: 10.1038/nrd.2017.89
      [Crossref], [CAS], Google Scholar
      5a
      FDA approves dupilumab for severe eczema
      Mullard, Asher
      Nature Reviews Drug Discovery (2017), 16 (5), 305CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
      There is no expanded citation for this reference.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvVCjtbo%253D&md5=361e2f015369489f80b032336b38d849
      .
      (b) Pirali, T.; Serafini, M.; Cargnin, S.; Genazzani, A. A. Applications of Deuterium in Medicinal Chemistry. J. Med. Chem. 2019, 62, 5276– 5297,  DOI: 10.1021/acs.jmedchem.8b01808
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      5b
      Applications of deuterium in medicinal chemistry
      Pirali, Tracey; Serafini, Marta; Cargnin, Sarah; Genazzani, Armando A.
      Journal of Medicinal Chemistry (2019), 62 (11), 5276-5297CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A review. The use of deuteration in medicinal chem. has exploded in the past years, and the FDA has recently approved the first deuterium-labeled drug. Precision deuteration goes beyond the pure and simple amelioration of the pharmacokinetic parameters of a drug and might provide an opportunity when facing problems in terms of metab.-mediated toxicity, drug interactions, and low bioactivation. The use of deuterium is even broader, offering the opportunity to lower the degree of epimerization, reduce the dose of coadministered boosters, and discover compds. where deuterium is the basis for the mechanism of action. Nevertheless, designing, synthesizing, and developing a successful deuterated drug is far from straightforward, and the translation from concept to practice is often unpredictable. This Perspective provides an overview of the recent developments of deuteration, with a focus on deuterated clin. candidates, and highlights both opportunities and challenges of this strategy.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXpvFKjtw%253D%253D&md5=1ce58dbff268894dc319bfc00a1ae01f
    6. 6
      (a) Thomas, A. F. Deuterium Labeling in Organic Chemistry; Appleton-Century-Crofts, 1971.
      Google Scholar
      There is no corresponding record for this reference.
      (b) Chapelle, M. R.; Kent, B. B.; Jones, J. R.; Lu, S.-Y.; Morgan, A. D. Development of combined microwave-enhanced labelling procedures for maximising deuterium incorporation. Tetrahedron Lett. 2002, 43, 5117– 5118,  DOI: 10.1016/S0040-4039(02)00986-3
      [Crossref], [CAS], Google Scholar
      6b
      Development of combined microwave-enhanced labelling procedures for maximizing deuterium incorporation
      Chapelle, Michael R.; Kent, Barry B.; Jones, John R.; Lu, Shui-Yu; Morgan, Alan D.
      Tetrahedron Letters (2002), 43 (29), 5117-5118CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)
      Combined hydrogenation/arom. dehalogenation under microwave-enhanced conditions provides a rapid route to deuterium labeled compds. with enhanced isotopic incorporation.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XkvVent7k%253D&md5=5a57bfc0af2563dd38196c18afbcf858
      .
      (c) Alonso, F.; Beletskaya, I. P.; Yus, M. Metal-mediated reductive hydrodehalogenation of organic halides. Chem. Rev. 2002, 102, 4009– 4091,  DOI: 10.1021/cr0102967
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      6c
      Metal-Mediated Reductive Hydrodehalogenation of Organic Halides
      Alonso, Francisco; Beletskaya, Irina P.; Yus, Miguel
      Chemical Reviews (Washington, DC, United States) (2002), 102 (11), 4009-4091CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review discusses the use of a variety of metals to hydrodehalogenate org. halides. The use of compds. of alkali and alk. earth metals such as lithium, sodium, potassium, magnesium, and calcium, main group metals and metalloids such as boron, aluminum, gallium, and indium, silicon, germanium, and tin, antimony, selenium, and tellurium, transition metals such as titanium and zirconium, vanadium, chromium, molybdenum and tungsten, manganese and rhenium, iron, cobalt, and nickel, ruthenium, rhodium, and palladium, osmium, iridium, and platinum, and copper and silver, and lanthanide and actinide metals as hydrodehalogenating agents is discussed.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xns1Ghsro%253D&md5=17d566566c648e132e2bc926c0bac0c4
      .
      (d) Guaragna, A.; Pedatella, S.; Pinto, V.; Palumbo, G. Synthesis of C-Protected 2,2-Dideutero β 3 -Amino Acids. Synthesis 2006, 2006, 4013– 4016,  DOI: 10.1055/s-2006-950314
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
      .
      (e) Fontana, E.; Venegoni, S. Syntheses of (R,S)-naproxen and its 6-O-desmethylated metabolite labelled with 2H. J. Labelled Compd. Radiopharm. 2008, 51, 239– 241,  DOI: 10.1002/jlcr.1511
      [Crossref], [CAS], Google Scholar
      6e
      Syntheses of (R,S)-naproxen and its 6-O-desmethylated metabolite labeled with 2H
      Fontana, E.; Venegoni, S.
      Journal of Labelled Compounds and Radiopharmaceuticals (2008), 51 (5), 239-241CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
      Naproxen, a well-known non-steroidal anti-inflammatory drug, and its 6-O-desmethylated metabolite were labeled with 2H. (R,S)-Naproxen labeled with 2H (I) was obtained in five steps using the com. available [2H3]iodomethane as the stable labeled reagent. The demethylation of I using 48% HBr in 1-butyl-3-methylimidazolium tetrafluoroborate gave the corresponding 2H-labeled 6-O-desmethylated metabolite.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXot1egsb0%253D&md5=08345ebb234cec921633f38d6ed4e451
      .
      (f) Kallepalli, V. A.; Gore, K. A.; Shi, F.; Sanchez, L.; Chotana, G. A.; Miller, S. L.; Maleczka, R. E.; Smith, M. R. Harnessing C-H Borylation/Deborylation for Selective Deuteration, Synthesis of Boronate Esters, and Late Stage Functionalization. J. Org. Chem. 2015, 80, 8341– 8353,  DOI: 10.1021/acs.joc.5b01588
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      6f
      Harnessing C-H Borylation/Deborylation for Selective Deuteration, Synthesis of Boronate Esters, and Late Stage Functionalization
      Kallepalli, Venkata A.; Gore, Kristin A.; Shi, Feng; Sanchez, Luis; Chotana, Ghayoor A.; Miller, Susanne L.; Maleczka, Robert E.; Smith, Milton R.
      Journal of Organic Chemistry (2015), 80 (16), 8341-8353CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      In the presence of iridium catalysts such as [Ir(cod)OMe]2, aryl and heteroaryl mono- and di(pinacolboronates) underwent regioselective deborylation; reaction of aryl- and heteroaryl mono(pinacolboronates) using D2O yielded regioselectively deuterated arenes, while deborylation of di(pinacolboronates) yielded mono(pinacolboronates) with different and complementary regioselectivity from a direct monoborylation. Di(pinacolboronates) were prepd. using iridium-catalyzed borylation; diborylation and chemoselective deborylation reactions were performed in one pot in some instances. The iridium-catalyzed borylations were compared to palladium-catalyzed deborylations of diborylated indoles described by Movassaghi; for a 3-methylindole-derived diboronate and for three thiophenediboronates, the iridium-catalyzed conditions were more effective. Nonracemic clopidogrel was regioselectively deuterated and monoborylated using iridium-catalyzed mono- and diborylation and deborylation reactions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1KitLzM&md5=5f6906f5e3c8c03a8156a29c959fe195
      .
      (g) Upshur, M. A.; Chase, H. M.; Strick, B. F.; Ebben, C. J.; Fu, L.; Wang, H.; Thomson, R. J.; Geiger, F. M. Vibrational Mode Assignment of α-Pinene by Isotope Editing: One Down, Seventy-One To Go. J. Phys. Chem. A 2016, 120, 2684– 2690,  DOI: 10.1021/acs.jpca.6b01995
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      6g
      Vibrational Mode Assignment of α-Pinene by Isotope Editing: One Down, Seventy-One To Go
      Upshur, Mary Alice; Chase, Hilary M.; Strick, Benjamin F.; Ebben, Carlena J.; Fu, Li; Wang, Hongfei; Thomson, Regan J.; Geiger, Franz M.
      Journal of Physical Chemistry A (2016), 120 (17), 2684-2690CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
      This study aims to reliably assign the vibrational sum frequency generation (SFG) spectrum of α-pinene at the vapor/solid interface using a method involving deuteration of various Me groups. The synthesis of five deuterated isotopologues of α-pinene is presented to det. the impact that removing contributions from Me group C-H oscillators has on its SFG response. 0.6 cm-1 resoln. SFG spectra of these isotopologues show varying degrees of differences in the C-H stretching region when compared to the SFG response of unlabeled α-pinene. The largest spectral changes were obsd. for the isotopologue contg. a fully deuterated vinyl Me group. Noticeable losses in signal intensities allow us to reliably assign the 2860 cm-1 peak to the vinyl Me sym. stretch. Furthermore, upon removing the vinyl Me group entirely by synthesizing apopinene, the steric influence of the unlabeled C9H14 fragment on the SFG response of α-pinene SFG can be readily obsd. The work presented here brings us one step closer to understanding the vibrational spectroscopy of α-pinene.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xls1Kit7c%253D&md5=bc8f3892aab9fb4b073c4a1146dd9352
      .
      (h) Neumann, K. T.; Lindhardt, A. T.; Bang-Andersen, B.; Skrydstrup, T. Synthesis and selective 2 H-, 13 C-, and 15 N-labeling of the Tau protein binder THK-523. J. Labelled Compd. Radiopharm. 2017, 60, 30– 35,  DOI: 10.1002/jlcr.3470
      [Crossref], [PubMed], [CAS], Google Scholar
      6h
      Synthesis and selective 2H-, 13C-, and 15N-labeling of the Tau protein binder THK-523
      Neumann, Karoline T.; Lindhardt, Anders T.; Bang-Andersen, Benny; Skrydstrup, Troels
      Journal of Labelled Compounds and Radiopharmaceuticals (2017), 60 (1), 30-35CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
      Isotopically labeled versions of the (fluoroethoxy)quinolinylaniline THK-523 I (X = N, 15N; Y = C, 13C; R, R1 = H, D), which binds to tau protein, were prepd. using carbonylative Sonogashira and Buchwald-Hartwig coupling, hydrogenative cyclization, and isotopic exchange reactions. Using a two-chamber reactor and sources for in-situ generation of hydrogen and carbon monoxide, stoichiometric amts. of labeled carbon monoxide and hydrogen equiv. were used. Iridium-catalyzed deuteration of I (X = N; Y = C, 13C; R = H, D; R1 = H) yielded further deuterated analogs. Using Buchwald-Hartwig coupling of ammonium sulfate or 15N-labeled ammonium sulfate, the 15N-THK-523 analog I (X = 15N; Y = C; R = R1 = H) was prepd.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvVGisrfO&md5=93cba77143822d8c08548af90e689d57
    7. 7
      Voges, R.; Heys, J. R.; Moenius, T. Preparation of Compounds Labeled with Tritium and Carbon-14; Wiley, 2009.
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    8. 8
      (a) Garnett, J. L.; Long, M. A.; Vining, R. F. W.; Mole, T. New simple method for rapid, selective aromatic deuteration using organoaluminum dihalide catalysts. J. Am. Chem. Soc. 1972, 94, 5913– 5914,  DOI: 10.1021/ja00771a073
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      8a
      New simple method for rapid, selective aromatic deuteration using organoaluminum dihalide catalysts
      Garnett, J. L.; Long, M. A.; Vining, R. F. W.; Mole, T.
      Journal of the American Chemical Society (1972), 94 (16), 5913-14CODEN: JACSAT; ISSN:0002-7863.
      Organoaluminum dihalides catalyze isotopic H exchange between deuterated aromatic compds. (e.g. perdeuterobenzene) and non-deuterated aromatic nuclei. Equil. is reached within minutes at room temp. for most aromatics and is highly specific for the aromatic protons. This procedure constitutes a new simple labeling technique for compds. such as toluene and bromobenzene.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE38XltVSqtL4%253D&md5=6fc52a9972472cacf5cb4d13aad09346
      .
      (b) Long, M. A.; Garnett, J. L.; Vining, R. F. W. Rapid deuteriation and tritiation of organic compounds using organometallic and elemental halides as catalysts. J. Chem. Soc., Perkin Trans. 2 1975, 1298,  DOI: 10.1039/p29750001298
      [Crossref], [CAS], Google Scholar
      8b
      Rapid deuteration and tritiation of organic compounds using organometallic and elemental halides as catalysts
      Long, Mervyn A.; Garnett, John L.; Vining, Ross F. W.
      Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1975), (12), 1298-303CODEN: JCPKBH; ISSN:0300-9580.
      RAlCl2 (R = Me, Et, Ph) and elemental halides, e.g. NbCl5, WCl6, SbCl5, and BBr3, were used as catalysts for the deuteration and tritiation of org. compds. For D labeling of arom. compds. C6D6 was used as D source and EtAlCl2 as catalyst with traces of H2O serving as cocatalysts, although for max. reproducibility very dry conditions with MeAlCl2 catalyst and HCl cocatalyst were used. The tritiation procedure, which was used for arom. compds., cycloalkenes, and O-contg. compds., involved the use of high sp. activity tritiated water to hydrolyze a complex of EtAlCl2 with the substrate, T labeling accompanying the hydrolysis. The labeling of PhMe using the elemental halides as catalysts was examd.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2MXmtVGrt74%253D&md5=fca7526b2340aeeccafcd8248bee594e
      .
      (c) Seibles, J. C.; Bollinger, D. M.; Orchin, M. Synthesis of Perdeuteriobenzo[a] pyrene. Angew. Chem., Int. Ed. Engl. 1977, 16, 656– 657,  DOI: 10.1002/anie.197706561
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
      .
      (d) Branch, C. S.; Barron, A. R. Arene-mercury complexes stabilized by gallium chloride: relative rates of H/D and arene exchange. J. Am. Chem. Soc. 2002, 124, 14156– 14161,  DOI: 10.1021/ja0206590
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      8d
      Arene-Mercury Complexes Stabilized by Gallium Chloride: Relative Rates of H/D and Arene Exchange
      Branch, Catherine S.; Barron, Andrew R.
      Journal of the American Chemical Society (2002), 124 (47), 14156-14161CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The Hg(arene)2(GaCl4)2 catalyzed H/D exchange reaction of C6D6 with arenes occurs via an electrophilic arom. substitution reaction in which the coordinated arene protonates the C6D6. To investigate this mechanism, the kinetics of the Hg(C6H5Me)2(GaCl4)2 catalyzed H/D exchange reaction of C6D6 with naphthalene were studied. Sep. second-order rate consts. were detd. for the 1- and 2-positions on naphthalene; i.e., the initial rate of H/D exchange = k1i[Hg][C-H1] + k2i[Hg][C-H2]. The ratio of k1i/k2i ranges from 11 to 2.5 over the temp. range studied, commensurate with the proposed electrophilic arom. substitution reaction. Observation of the reactions over an extended time period shows that the rates change with time, until they again reach a new and const. second-order kinetics regime. The overall form of the rate equation is unchanged: final rate = k1f[Hg][C-H1] + k2f[Hg][C-H2]. This change in the H/D exchange is accompanied by ligand exchange between Hg(C6D6)2(GaCl4)2 and naphthalene to give Hg(C10H8)2(GaCl4)2, that was characterized by 13C CPMAS NMR and UV-visible spectroscopy. The activation parameters for the ligand exchange may be detd. and are indicative of a dissociative reaction and are consistent with our previously calcd. bond dissocn. for Hg(C6H6)2(AlCl4)2. The initial Hg(arene)2(GaCl4)2 catalyzed reaction of naphthalene with C6D6 involves the deuteration of naphthalene by coordinated C6D6; however, as ligand exchange progresses, the pathway for H/D exchange changes to where the protonation of C6D6 by coordinated naphthalene dominates. The site selectivity for the H/D exchange is initially due to the electrophilic arom. substitution of naphthalene. As ligand exchange occurs, this selectivity is controlled by the activation of the naphthalene C-H bonds by mercury.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XotlSrsLk%253D&md5=cb3797fca9e418261a6fb5f11b22bda3
      .
      (e) Hakala, U.; Wähälä, K. Expedient deuterolabeling of polyphenols in ionic liquids-DCl/D2O under microwave irradiation. J. Org. Chem. 2007, 72, 5817– 5819,  DOI: 10.1021/jo070231p
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      8e
      Expedient Deuterolabeling of Polyphenols in Ionic Liquids-DCl/D2O under Microwave Irradiation
      Hakala, Ullastiina; Waehaelae, Kristiina
      Journal of Organic Chemistry (2007), 72 (15), 5817-5819CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      Postsynthetic regioselective arom. ring H/D exchanges in polyphenolic compds. are rapidly performed in high yields and isotopic purities in ionic liq.-DCl/D2O under microwave irradn. Other C-H bonds, including benzylic and lactone α-carbonyl sites, are not affected.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmslyrtrw%253D&md5=ee14aa74377af93e548541173cef3846
      .
      (f) Martins, A.; Lautens, M. A simple, cost-effective method for the regioselective deuteration of anilines Org. Org. Lett. 2008, 10, 4351– 4353,  DOI: 10.1021/ol801763j
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      8f
      A Simple, Cost-Effective Method for the Regioselective Deuteration of Anilines
      Martins, Andrew; Lautens, Mark
      Organic Letters (2008), 10 (19), 4351-4353CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
      A highly effective and operationally simple method for the regioselective deuteration of anilines is presented. A variety of electron-rich and electron-deficient anilines are efficiently deuterated at the ortho and/or para position with respect to the nitrogen in the presence of 1 equiv of conc HCl in D2O. Under the present conditions, arom. methoxy groups do not facilitate deuteration, enabling a chemo- and regioselective deuteration of p-anisidine.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVOqt7fP&md5=e1f682cc99aa7cdf701475a3fa630c53
      .
      (g) Mačková, M.; Himl, M.; Minářová, L.; Lang, J.; Lhoták, P. Regioselective deuteration of 25,27-dialkoxycalix[4]arenes. Tetrahedron Lett. 2011, 52, 2543– 2546,  DOI: 10.1016/j.tetlet.2011.03.030
      [Crossref], [CAS], Google Scholar
      8g
      Regioselective deuteration of 25,27-dialkoxycalix[4]arenes
      Mackova, Michaela; Himl, Michal; Minarova, Lenka; Lang, Jan; Lhotak, Pavel
      Tetrahedron Letters (2011), 52 (20), 2543-2546CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
      A direct deuteration of the upper rim of calix[4]arene has been carried out. 25,27-Dialkoxy derivs. of calix[4]arene (R = Me, Et, Pr, Bu) were regioselectively deuterated at the para positions of unsubstituted phenolic rings using DCl/D2O in tetrachloroethane. Interestingly, identical reaction conditions do not lead to deuteration of mono- or tri-substituted derivs. where only simple cleavage of alkyl substituents was obsd.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXkvVKgsLY%253D&md5=2c11885fe9807da2efa6ee582c547417
      .
      (h) Zhou, L.; Bian, X.; Yang, S.; Mu, B. A two-step synthesis of deuterium labeled 8, 8, 9, 9-d4-hexadecane from nonanoic acid. J. Labelled Compd. Radiopharm. 2012, 55, 158– 160,  DOI: 10.1002/jlcr.1962
      [Crossref], [CAS], Google Scholar
      8h
      A two-step synthesis of deuterium labeled 8, 8, 9, 9-d4-hexadecane from nonanoic acid
      Zhou, Lei; Bian, Xinyu; Yang, Shizhong; Mu, Bozhong
      Journal of Labelled Compounds and Radiopharmaceuticals (2012), 55 (4), 158-160CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
      Labeled compds. are essential in elucidating metabolic mechanisms and reaction pathways. A two-step synthesis of deuterium-labeled 8, 8, 9, 9-d4-hexadecane from nonanoic acid is described here. The synthesis procedures involved hydrogen-deuterium exchange of nonanoic acid with 3.00 M DCl-D2O and then Kolbe electrolysis of the deuterated nonanoic acid to achieve the desired n-alkane that was confirmed by gas chromatog.-mass spectrometry and 1H NMR. This method might provide an alternative route for the prepn. of specifically deuterated alkanes of different chain lengths (C > 4) in which deuterium atoms are located at two adjacent carbons of the alkane's carbon chain. Copyright © 2012 John Wiley & Sons, Ltd.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitVCmtrc%253D&md5=e582af6a74c60b17413d1c24e660a581
      .
      (i) Murai, Y.; Wang, L.; Masuda, K.; Sakihama, Y.; Hashidoko, Y.; Hatanaka, Y.; Hashimoto, M. Rapid and Controllable Hydrogen/Deuterium Exchange on Aromatic Rings of α-Amino Acids and Peptides. Eur. J. Org. Chem. 2013, 2013, 5111– 5116,  DOI: 10.1002/ejoc.201300405
      [Crossref], [CAS], Google Scholar
      8i
      Rapid and controllable hydrogen/deuterium exchange on aromatic rings of α-amino acids and peptides
      Murai, Yuta; Wang, Lei; Masuda, Katsuyoshi; Sakihama, Yasuko; Hashidoko, Yasuyuki; Hatanaka, Yasumaru; Hashimoto, Makoto
      European Journal of Organic Chemistry (2013), 2013 (23), 5111-5116CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Novel hydrogen/deuterium exchange for arom. α-amino acids and their corresponding peptides were performed through the use of deuterated trifluoromethanesulfonic acid (TfOD). Detailed anal. of the exchange revealed that equal hydrogen/deuterium exchange was obsd. for phenylalanine, and specific exchange at the ortho-positions of phenol for tyrosine was also detected. The stereochem. of the arom. α-amino acids was retained under the exchange conditions. The hydrogen/deuterium exchange properties for these arom. α-amino acids are identical for peptides that contain several arom. α-amino acids. The exchange proceeded significantly faster than previous methods. Detailed anal. of the exchange revealed that the method could be controlled by temp., time, and the amt. of reagent.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVKrtbfF&md5=e61270d9a873e4979fc815529ed4dd50
      .
      (j) Müller, K.; Seubert, A. Synthesis of deuterium-labelled fluorobenzoic acids to be used as internal standards in isotope dilution mass spectrometry. Isot. Environ. Health Stud. 2014, 50, 88– 93,  DOI: 10.1080/10256016.2013.830612
      [Crossref], [PubMed], [CAS], Google Scholar
      8j
      Synthesis of deuterium-labelled fluorobenzoic acids to be used as internal standards in isotope dilution mass spectrometry
      Mueller, Karsten; Seubert, Andreas
      Isotopes in Environmental and Health Studies (2014), 50 (1), 88-93CODEN: IEHSF8; ISSN:1025-6016. (Taylor & Francis Ltd.)
      A method for the deuterium labeling of fluorobenzoic acids (FBAs) via acidic H/D exchange of the arom. hydrogen atoms in concd. D2SO4 is described. The synthesis is shown to be easy, fast, low-priced and without the use of catalysts or further purifn. The use of at least double-deuterated FBAs as internal stds. in org. isotope diln. mass spectrometry allows the detn. of FBAs in complex matrixes with highest possible accuracy in combination with a simplified anal. evaluation.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitF2jsLk%253D&md5=1edfbbf2834b40c879a082c8c266aa6e
      .
      (k) Wang, L.; Murai, Y.; Yoshida, T.; Okamoto, M.; Masuda, K.; Sakihama, Y.; Hashidoko, Y.; Hatanaka, Y.; Hashimoto, M. Hydrogen/deuterium exchange of cross-linkable α-amino acid derivatives in deuterated triflic acid Biosci. Biosci., Biotechnol., Biochem. 2014, 78, 1129– 1134,  DOI: 10.1080/09168451.2014.917267
      [Crossref], [PubMed], [CAS], Google Scholar
      8k
      Hydrogen/deuterium exchange of cross-linkable α-amino acid derivatives in deuterated triflic acid
      Wang, Lei; Murai, Yuta; Yoshida, Takuma; Okamoto, Masashi; Masuda, Katsuyoshi; Sakihama, Yasuko; Hashidoko, Yasuyuki; Hatanaka, Yasumaru; Hashimoto, Makoto
      Bioscience, Biotechnology, and Biochemistry (2014), 78 (7), 1129-1134CODEN: BBBIEJ; ISSN:1347-6947. (Taylor & Francis Ltd.)
      In this paper we report here a hydrogen/deuterium exchange (H/D exchange) of cross-linkable α-amino acid derivs. with deuterated trifluoromethanesulfonic acid (TfOD). H/D exchange with TfOD was easily applied to o-catechol contg. phenylalanine (DOPA) within an hour. A partial H/D exchange was obsd. for trifluoromethyldiazirinyl (TFMD) phenylalanine derivs. N-Acetyl-protected natural arom. α-amino acids (Tyr and Trp) were more effective in H/D exchange than unprotected ones. The N-acetylated TFMD phenylalanine deriv. afforded slightly higher H/D exchange than unprotected derivs. An effective post-deuteration method for cross-linkable α-amino acid derivs. will be useful for the anal. of biol. functions of bioactive peptides and proteins by mass spectrometry.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1OrsrjI&md5=ebf9bb44b18e5f906dfe85ca886b486e
      .
      (l) Munz, D.; Webster-Gardiner, M.; Fu, R.; Strassner, T.; Goddard, W. A.; Gunnoe, T. B. Proton or Metal? The H/D Exchange of Arenes in Acidic Solvents. ACS Catal. 2015, 5, 769– 775,  DOI: 10.1021/cs501620f
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      8l
      Proton or metal? The H/D exchange of arenes in acidic solvents
      Munz, Dominik; Webster-Gardiner, Michael; Fu, Ross; Strassner, Thomas; Goddard, William A., III; Gunnoe, T. Brent
      ACS Catalysis (2015), 5 (2), 769-775CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      The H/D exchange of arenes in acidic media by transition-metal and main-group-metal complexes and common inorg. salts was studied. The influence of Lewis acidity, anions, charge, and ligands was evaluated. The results indicate that the detn. of H/D exchange activity in acidic media is not related to the formation of metal-carbon bonds (i.e., C-H activation). The combined exptl. data (regioselectivity, activation energy, kinetics, isotope effects, solvent effects) and DFT calcns. point toward a proton catalysis mechanism. Thus, highly Lewis acidic metal compds., such as aluminum(III) triflate, were extraordinarily active for the H/D exchange reactions. Indeed, the degree of H/D exchange reactivity allows for a comparative measurement of Lewis acidities.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFKjuw%253D%253D&md5=fd7d5dfacfc64dd094c4b0b888ac1478
      .
      (m) Fischer, O.; Hubert, A.; Heinrich, M. R. Shifted Selectivity in Protonation Enables the Mild Deuteration of Arenes Through Catalytic Amounts of Bronsted Acids in Deuterated Methanol. J. Org. Chem. 2020, 85, 11856– 11866,  DOI: 10.1021/acs.joc.0c01604
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      8m
      Shifted Selectivity in Protonation Enables the Mild Deuteration of Arenes Through Catalytic Amounts of Bronsted Acids in Deuterated Methanol
      Fischer, Oliver; Hubert, Anja; Heinrich, Markus R.
      Journal of Organic Chemistry (2020), 85 (18), 11856-11866CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      Taking advantage of the "differentiating effect" of the solvent methanol, deuterations of electron-rich arom. systems can be carried out under mild acid catalysis and thus under far milder conditions than known so far. The exceptional functional group tolerance obsd. under the optimized conditions, which even includes highly acid-labile groups, results from a hitherto unexploited shifted selectivity in protonation, and enabled simple and straightforward access to complex deuterium-labeled compds.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsF2rtbrM&md5=8cc8141abc4a644222476d6255e11812
    9. 9
      (a) Beak, P.; Brown, R. A. The tertiary amide as an effective director of ortho lithiation. J. Org. Chem. 1982, 47, 34– 46,  DOI: 10.1021/jo00340a008
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      9a
      The tertiary amide as an effective director of ortho lithiation
      Beak, Peter; Brown, Roger A.
      Journal of Organic Chemistry (1982), 47 (1), 34-46CODEN: JOCEAH; ISSN:0022-3263.
      The tertiary amides BzNR2 (R = Et, Me2CH) give ortho-lithiated species on treatment with EtCHMeLi or BuLi-TMEDA, resp., at -78°. Lithiation of BzNEt2, followed by reaction with MeI, EtI, PhCOMe, Me2CO, BzH or (MeO)3B-H2O2, gives the expected ortho substituted product. Intramol. competition between the diethylamido and chloro, methoxyl, sulfonamido, (dimethylamino)methyl, or oxazolino functions in ortho- and para-substituted benzamides establishes the tertiary amido group to be more effective in directing metalation than any noncarboxamide functional group. The secondary amide has a directing ability comparable to the tertiary amide although the yields are low. A labeling study suggests that lithiation of the ortho position of BzN(CHMe2)2 is direct and not the result of rearrangement of an initially formed α-aza anion. Control of metalation at the ortho or benzylic position by proper selection of the organolithium base is illustrated for p-MeC6H4CON(CHMe2)2. The value of the tertiary amide for control of ortho lithiations and regiospecific arom. substitutions is noted.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL38XjsFemtQ%253D%253D&md5=ea9df59d44986ba8e2e84159740833ea
      .
      (b) Clayden, J.; Pink, J. H.; Westlund, N.; Wilson, F. X. Controlling the regioselectivity of lithiation using kinetic isotope effects: Deuterium as a protecting group for carbon. Tetrahedron Lett. 1998, 39, 8377– 8380,  DOI: 10.1016/S0040-4039(98)01930-3
      [Crossref], [CAS], Google Scholar
      9b
      Controlling the regioselectivity of lithiation using kinetic isotope effects: deuterium as a protecting group for carbon
      Clayden, Jonathan; Pink, Jennifer H.; Westlund, Neil; Wilson, Francis X.
      Tetrahedron Letters (1998), 39 (46), 8377-8380CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)
      By substituting deuterium for hydrogen at positions of high kinetic acidity in amides and carbamates, the usual regiochem. course of their reactions with alkyllithiums (ortho-lithiation vs. lateral lithiation vs. nucleophilic addn.) can be altered or overturned by the kinetic isotope effect. The deuterium substituent functions in these reactions as a protecting group for carbon.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXntFejs7g%253D&md5=d12b195cc20f90bb31c86b90e2b641f7
      .
      (c) Ahmed, A.; Clayden, J.; Rowley, M. Anion translocation in organolithiums: A mechanism for the lithiation and cyclisation of tertiary naphthamides. Tetrahedron Lett. 1998, 39, 6103– 6106,  DOI: 10.1016/S0040-4039(98)01291-X
      [Crossref], [CAS], Google Scholar
      9c
      Anion translocation in organolithiums: a mechanism for the lithiation and cyclization of tertiary naphthamides
      Ahmed, Anjum; Clayden, Jonathan; Rowley, Michael
      Tetrahedron Letters (1998), 39 (34), 6103-6106CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)
      Deuterium labeling shows that an intramol. proton transfer ("anion translocation") is a key step in the mechanism leading to an α-lithiated tertiary naphthamide and thence to the products of anionic cyclization. The kinetic isotope effect means that proton transfer from the ortho position can become the sole mechanism for α-lithiation, though for undeuterated amides a parallel mechanism also operates in which lithiation occurs directly at the position α to nitrogen.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXlt1Snurw%253D&md5=2a79577ff7c14da83ea86212cb5aa9f3
      .
      (d) Zhan, M.; Xu, R.; Tian, Y.; Jiang, H.; Zhao, L.; Xie, Y.; Chen, Y. A Simple and Cost-Effective Method for the Regioselective Deuteration of Phenols. Eur. J. Org. Chem. 2015, 2015, 3370– 3373,  DOI: 10.1002/ejoc.201500192
      [Crossref], [CAS], Google Scholar
      9d
      A Simple and Cost-Effective Method for the Regioselective Deuteration of Phenols
      Zhan, Miao; Xu, Ruixue; Tian, Ye; Jiang, Hongxia; Zhao, Lifeng; Xie, Yongmei; Chen, Yuanwei
      European Journal of Organic Chemistry (2015), 2015 (15), 3370-3373CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A highly effective and operationally simple method for the deuteration of phenols using NaOH as a catalyst and D2O as the deuterium source was presented. A high regioselectivity for the ortho and/or para hydrogens relative to the oxygen atom was achieved, as well as a high degree of deuterium incorporation. The method also had a high functional-group tolerance, and allowed the deuteration of complex pharmaceutically interesting substrates.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmsF2muro%253D&md5=07d3723fd909e8792574dde894b756d5
      .
      (e) Salamanca, V.; Albéniz, A. C. Deuterium Exchange between Arenes and Deuterated Solvents in the Absence of a Transition Metal: Synthesis of D-Labeled Fluoroarenes. Eur. J. Org. Chem. 2020, 3206– 3212,  DOI: 10.1002/ejoc.202000284
      [Crossref], [CAS], Google Scholar
      9e
      Deuterium Exchange between Arenes and Deuterated Solvents in the Absence of a Transition Metal: Synthesis of D-Labeled Fluoroarenes
      Salamanca, Vanesa; Albeniz, Ana C.
      European Journal of Organic Chemistry (2020), 2020 (22), 3206-3212CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Fluoroarenes can be selectively deuterated by H/D exchange with common deuterated solvents in the presence of a catalytic amt. of an alkali metal carbonate or, for the less acidic arenes, stoichiometric quantities of potassium phosphate. This is a sustainable method that does not need transition metal catalysis or the multistep synthesis of a main-group organometallics. This exchange needs to be taken into account when using H/D scrambling as a mechanistic probe in reactions involving fluoroarenes.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlvFKisL4%253D&md5=c977d87e70714b2fc8b61264fdf72ff5
    10. 10
      (a) Fraser, R. R.; Renaud, R. N. The Steric Effect in the Platinum-Catalyzed Exchange Reaction between Aromatic Ring Protons and Deuterium Oxide. J. Am. Chem. Soc. 1966, 88, 4365– 4370,  DOI: 10.1021/ja00971a011
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      10a
      The steric effect in the platinum-catalyzed exchange reaction between aromatic ring protons and deuterium oxide
      Fraser, Robert R.; Renaud, Roger N.
      Journal of the American Chemical Society (1966), 88 (19), 4365-70CODEN: JACSAT; ISSN:0002-7863.
      The relative rates of the platinum-catalyzed exchange of heavy water with the o-, m-, and ρ-protons in several monosubstituted benzenes were detd. A very large steric effect but no detectable electronic effect was observed. These results are interpreted as support for the dissociative mechanism of exchange. 32 references.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF28XkvV2qurs%253D&md5=f55096088a49edda57da5ed8ecd9c85d
      .
      (b) Matsubara, S.; Yokota, Y.; Oshima, K. Palladium-catalyzed decarboxylation and decarbonylation under hydrothermal conditions: decarboxylative deuteration. Org. Lett. 2004, 6, 2071– 2073,  DOI: 10.1021/ol0492602
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      10b
      Palladium-catalyzed decarboxylation and decarbonylation under hydrothermal conditions: decarboxylative deuteration
      Matsubara, Seijiro; Yokota, Yutaka; Oshima, Koichiro
      Organic Letters (2004), 6 (12), 2071-2073CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
      Decarboxylation of free carboxylic acid was performed by Pd/C catalyst under hydrothermal water (250 °C/4 MPa). Under the hydrothermal conditions of deuterium oxide, decarbonylative deuteration was obsd. to give fully deuterated hydrocarbons from carboxylic acids or aldehydes. For example, the decarboxylation of 4-hydroxybenzenepropanoic acid (I) under hydrothermal conditions in the presence of water-d2 gave 4-(ethyl-d5)phen-2,3,5,6-d4-ol-d (II).
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjvFSnsr8%253D&md5=ae279145774b9aa3ce7f5b0ee40fa3c0
      .
      (c) Yamamoto, M.; Yokota, Y.; Oshima, K.; Matsubara, S. H-D exchange reaction on benzene ring of polystyrene in hydrothermal deuterium oxide with platinum(IV) oxide catalyst. Chem. Commun. 2004, 1714– 1715,  DOI: 10.1039/B405063K
      [Crossref], [PubMed], [CAS], Google Scholar
      10c
      H-D exchange reaction on benzene ring of polystyrene in hydrothermal deuterium oxide with platinum(IV) oxide catalyst
      Yamamoto, Mitsuru; Yokota, Yutaka; Oshima, Koichiro; Matsubara, Seijiro
      Chemical Communications (Cambridge, United Kingdom) (2004), (15), 1714-1715CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      Benzene rings of polystyrene samples are labeled with deuterium oxide and catalytic amt. of platinum(IV) oxide under hydrothermal conditions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmtVWgsbw%253D&md5=5ac0b7e5838747bf41c75aafa3950995
      .
      (d) Yamamoto, M.; Oshima, K.; Matsubara, S. Platinum(IV) oxide catalyzed H-D exchange reactions in arylsilanes. Org. Lett. 2004, 6, 5015– 5017,  DOI: 10.1021/ol047738w
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      10d
      Platinum(IV) Oxide Catalyzed H-D Exchange Reactions in Arylsilanes
      Yamamoto, Mitsuru; Oshima, Koichiro; Matsubara, Seijiro
      Organic Letters (2004), 6 (26), 5015-5017CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
      Triphenyl(alkyl)silanes and triphenylsilanols were regioselectively deuterated at 3,4,5-positions of the benzene ring by treatment with D2O in the presence of platinum(IV) oxide under hydrothermal conditions. In some cases, ortho-deuteration also was obsd. to the extent about 26%. The reaction mechanism is discussed.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVCru7vL&md5=2b66b3b02960ebf93596a8cfc4a95955
      .
      (e) Derdau, V.; Atzrodt, J.; Zimmermann, J.; Kroll, C.; Brückner, F. Hydrogen-deuterium exchange reactions of aromatic compounds and heterocycles by NaBD4-activated rhodium, platinum and palladium catalysts. Chem. - Eur. J. 2009, 15, 10397– 10404,  DOI: 10.1002/chem.200901107
      [Crossref], [PubMed], [CAS], Google Scholar
      10e
      Hydrogen-Deuterium Exchange Reactions of Aromatic Compounds and Heterocycles by NaBD4-Activated Rhodium, Platinum and Palladium Catalysts
      Derdau, Volker; Atzrodt, Jens; Zimmermann, Jochen; Kroll, Carsten; Brueckner, Francois
      Chemistry - A European Journal (2009), 15 (40), 10397-10404, S10397/1-S10397/8CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Conventional thermal and microwave conditions were compared for hydrogen-deuterium (H/D) exchange reactions of aminobenzoic acids catalyzed by NaBD4-activated Pd/C or RhCl3 with D2O as the deuterium source. We also investigated different NaBD4-activated metal catalysts (including Pd/C, RhCl3 and Pt/C) under microwave conditions for an efficient H/D exchange of arom. and heterocyclic compds. Even higher deuterium incorporations were obtained for Pd/C and Pt/C catalyst mixts. due to the previously obsd. synergistic effect. Finally, we have applied these optimized conditions for one-step syntheses of the MS stds. of several pharmaceutically active compds.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1KisL%252FN&md5=c8274ea63c0033118faf5cceb3ca193e
      .
      (f) Sajiki, H. Development of deuterium labeling method based on the heterogeneous platinum group metal-catalyzed C-H activation. Yakugaku Zasshi 2013, 133, 1177– 1193,  DOI: 10.1248/yakushi.13-00218
      [Crossref], [PubMed], [CAS], Google Scholar
      10f
      Development of deuterium labeling method based on the heterogeneous platinum group metal-catalyzed C-H activation
      Sajiki, Hironao
      Yakugaku Zasshi (2013), 133 (11), 1177-1193CODEN: YKKZAJ; ISSN:0031-6903. (Pharmaceutical Society of Japan)
      A review. Deuterium (D)labeled compds. are utilized in various scientific fields such as mechanistic elucidation of reactions, prepn. of new functional materials, tracers for microanal., deuterium labeled heavy drugs and so on. Although the H-D exchange reaction is a straightforward method to produce deuterated org. compds., many precedent methods require expensive deuterium gas and/or harsh reaction conditions. A part of our leading research agendas is intended to the development of novel and functional heterogeneous platinum-group catalysts and the reclamation of unknown functionalities of existing heterogeneous platinum-group catalysts. During the course of the study, benzylic positions of substrates were site-selectively deuterated under mild and palladium-on-carbon (Pd/C)-catalyzed hydrogenation conditions in heavy water (D2O). Heat conditions promoted the H-D exchange reactivity and facilitated the H-D exchange reaction at not only the benzylic sites but also inactive C-H bonds and heterocyclic nuclei. It is noteworthy that platinum-on-carbon (Pt/C) indicated a quite high affinity toward arom. nuclei, and the H-D exchange reaction was strongly enhanced by the use of Pt/C as a catalyst under milder conditions. The mixed use of Pd/C and Pt/C was found to be more efficient in the H-D exchange reaction compared to the independent use of Pd/C or Pt/C. Furthermore, simple alkanes could also be efficiently deuterated under rhodium-on-carbon (Rh/C)-catalyzed conditions. The use of ruthenium-on-carbon (Ru/C) enabled the regiospecific and efficient deuterium incorporation at α-positions of alcs. and results were applied as a regio- and stereoselective multi-deuteration method of sugar derivs.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXltlKgsw%253D%253D&md5=b38d85aeba66ae9a5bef2270da341cea
      .
      (g) Pieters, G.; Taglang, C.; Bonnefille, E.; Gutmann, T.; Puente, C.; Berthet, J.-C.; Dugave, C.; Chaudret, B.; Rousseau, B. Regioselective and stereospecific deuteration of bioactive aza compounds by the use of ruthenium nanoparticles. Angew. Chem., Int. Ed. 2014, 53, 230– 234,  DOI: 10.1002/anie.201307930
      [Crossref], [CAS], Google Scholar
      10g
      Regioselective and Stereospecific Deuteration of Bioactive Aza Compounds by the Use of Ruthenium Nanoparticles
      Pieters, Gregory; Taglang, Celine; Bonnefille, Eric; Gutmann, Torsten; Puente, Celine; Berthet, Jean-Claude; Dugave, Christophe; Chaudret, Bruno; Rousseau, Bernard
      Angewandte Chemie, International Edition (2014), 53 (1), 230-234CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      An efficient H/D exchange method allowing the deuteration of pyridines, quinolines, indoles and alkyl amines with D2 in the presence of PVP-supported ruthenium (Ru@PVP) nanoparticles is described. By a general and simple procedure involving mild reaction conditions and simple filtration to recover the labeled product, the isotopic labeling of 22 compds. proceeded in good yield with high chemoselectivity and regioselectivity. The viability of this procedure was demonstrated by the labeling of eight biol. active compds. Remarkably, enantiomeric purity was conserved in the labeled compds., even though labeling took place in the vicinity of the stereogenic center. The level of isotopic enrichment obsd. is suitable for metabolomic studies in most cases. This approach is also perfectly adapted to tritium labeling because it uses a gas as an isotopic source. Besides these applications to mols. of biol. interest, this study reveals a rich and underestimated chem. on the surface of ruthenium nanoparticles. The title compds. thus formed included 3-methylpyridine-2,6-d2, 4-(1-pyrrolidinyl)pyridine-2,6-d2, 6-(phenyl-2,6-d2)pyridine-2-d, 1H-indole-2,3-d2, deuterated nicotine, deuterated paroxetine, piperidine-2,2,6,6-d4 and related substances. The synthesis of the target compds. was achieved using piperidine, morpholine, benzenepropanamine, 1-hexanamine, anabasine, papaverine, melatonin, (9α,13α,14α)-3-methoxy-17-methylmorphinanone (dextromethorphan), protriptyline, paroxetine as starting materials.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVSgsL3I&md5=ae01ca07bfa41f36a91c44264835d30a
      .
      (h) Bresó-Femenia, E.; Godard, C.; Claver, C.; Chaudret, B.; Castillón, S. Selective catalytic deuteration of phosphorus ligands using ruthenium nanoparticles: a new approach to gain information on ligand coordination. Chem. Commun. 2015, 51, 16342– 16345,  DOI: 10.1039/C5CC06984J
      [Crossref], [PubMed], [CAS], Google Scholar
      10h
      Selective catalytic deuteration of phosphorus ligands using ruthenium nanoparticles: a new approach to gain information on ligand coordination
      Breso-Femenia, Emma; Godard, Cyril; Claver, Carmen; Chaudret, Bruno; Castillon, Sergio
      Chemical Communications (Cambridge, United Kingdom) (2015), 51 (91), 16342-16345CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      Ph rings in phenyl- or phenyl-alkylphosphines are selectively deuterated at the ortho position using Ru/PVP nanoparticles, while are fully reduced in the case of arylphosphine oxide derivs. and do not react in the case of arylphosphite. This different behavior provides information about the coordination mode of each ligand.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsV2nsLrI&md5=4c6b25c04dfc5ad2b5c944b9350f2b2a
      .
      (i) Sawama, Y.; Nakano, A.; Matsuda, T.; Kawajiri, T.; Yamada, T.; Sajiki, H. H. –D Exchange Deuteration of Arenes at Room Temperature. Org. Process Res. Dev. 2019, 23, 648– 653,  DOI: 10.1021/acs.oprd.8b00383
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      10i
      H-D Exchange Deuteration of Arenes at Room Temperature
      Sawama, Yoshinari; Nakano, Akihiro; Matsuda, Takumi; Kawajiri, Takahiro; Yamada, Tsuyoshi; Sajiki, Hironao
      Organic Process Research & Development (2019), 23 (4), 648-653CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
      Arenes underwent C-H deuteration reactions with D2O in the presence of Pt/C, Ir/C, or combinations of both catalysts in isopropanol/D2O under argon at ambient temp. to yield arenes deuterated at the arene C-H bonds.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlGntLs%253D&md5=ae39643d643ff7cde575d9f64e126809
      .
      (j) Park, K.; Ito, N.; Yamada, T.; Sajiki, H. Efficient Continuous-Flow H–D Exchange Reaction of Aromatic Nuclei in D2O/2-PrOH Mixed Solvent in a Catalyst Cartridge Packed with Platinum on Carbon Beads. Bull. Chem. Soc. Jpn. 2021, 94, 600– 605,  DOI: 10.1246/bcsj.20200325
      [Crossref], [CAS], Google Scholar
      10j
      Efficient continuous-flow H-D exchange reaction of aromatic nuclei in D2O/2-PrOH mixed solvent in a catalyst cartridge packed with platinum on carbon beads
      Park, Kwihwan; Ito, Naoya; Yamada, Tsuyoshi; Sajiki, Hironao
      Bulletin of the Chemical Society of Japan (2021), 94 (2), 600-605CODEN: BCSJA8; ISSN:0009-2673. (Chemical Society of Japan)
      Herein, a continuous-flow deuteration methodol. for various arom. compds. is developed based on heterogeneous platinum-catalyzed hydrogen-deuterium exchange. The reaction entails the transfer of a substrate dissolved in a mixed solvent of 2-propanol and deuterium oxide into a catalyst cartridge packed with platinum on carbon beads (Pt/CB). Pt/CB could be continuously used without significant deterioration of catalyst activity for at least 24 h. Deuteration proceeded within 60 s of the substrate solns. being passed through the Pt/CB layer in the Pt/CB-packed cartridge.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXlvVGltbg%253D&md5=35cae148db1d5c74f7c61670fcdd3baa
    11. 11
      Smith, G. V.; Notheisz, F. Heterogeneous Catalysis in Organic Chemistry; Academic Press, 1999.
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    12. 12
      Beller, M.; Bolm, C. Transition Metals for Organic Synthesis: Building Blocks and Fine Chemicals, 2nd rev. enl. ed.; Wiley-VCH, 2004.
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    13. 13
      (a) Feng, Y.; Lail, M.; Foley, N. A.; Gunnoe, T. B.; Barakat, K. A.; Cundari, T. R.; Petersen, J. L. Hydrogen-deuterium exchange between TpRu(PMe3)(L)X (L = PMe3 and X = OH, OPh, Me, Ph, or NHPh; L = NCMe and X = Ph) and deuterated arene solvents: evidence for metal-mediated processes. J. Am. Chem. Soc. 2006, 128, 7982– 7994,  DOI: 10.1021/ja0615775
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      13a
      Hydrogen-Deuterium Exchange between TpRu(PMe3)(L)X (L = PMe3 and X = OH, OPh, Me, Ph, or NHPh; L = NCMe and X = Ph) and Deuterated Arene Solvents: Evidence for Metal-Mediated Processes
      Feng, Yuee; Lail, Marty; Foley, Nicholas A.; Gunnoe, T. Brent; Barakat, Khaldoon A.; Cundari, Thomas R.; Petersen, Jeffrey L.
      Journal of the American Chemical Society (2006), 128 (24), 7982-7994CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Pyrazolylborato-ruthenium complexes undergo isotopic exchange with deuterated arene solvents. Regioselective isotopic exchange of TpRu(PMe3)2X [X = OH, OPh, Me, Ph, or NHPh; Tp = hydridotris(pyrazolyl)borate] with C6D6 and C6D5CD3 proceeds at 90-130° giving complexes deuterated in X or Tp positions. For X = OH or NHPh, H/D exchange occurs at hydroxide and anilido ligands, resp. For X = OH, OPh, Me, Ph, or NHPh, isotopic exchange occurs at the Tp 4-positions with only minimal deuterium incorporation at the Tp 3- or 5-positions or PMe3 ligands. For TpRu(PMe3)(NCMe)Ph, the H/D exchange occurs at 60° at all three Tp positions and the Ph ring. TpRu(PMe3)2Cl, TpRu(PMe3)2OTf (OTf = trifluoromethanesulfonate), and TpRu(PMe3)2SH do not initiate H/D exchange in C6D6 after extended periods of time at elevated temps. Mechanistic studies indicate that the likely pathway for the H/D exchange involves ligand dissocn. (PMe3 or NCMe), Ru-mediated activation of an arom. C-D bond, and deuteration of basic nondative ligand (hydroxide or anilido) or Tp positions via net D+ transfer.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XkvVehtbc%253D&md5=7ea9f349f622aedd1b7870bbdf390e37
      .
      (b) Allen, P. H.; Hickey, M. J.; Kingston, L. P.; Wilkinson, D. J. Metal-catalysed isotopic exchange labelling: 30 years of experience in pharmaceutical R&D. J. Labelled Compd. Radiopharm. 2010, 53, 731– 738,  DOI: 10.1002/jlcr.1825
      [Crossref], [CAS], Google Scholar
      13b
      Metal-catalyzed isotopic exchange labeling: 30 years of experience in pharmaceutical R&D
      Allen, Paul H.; Hickey, Michael J.; Kingston, Lee P.; Wilkinson, David J.
      Journal of Labelled Compounds and Radiopharmaceuticals (2010), 53 (11-12), 731-738CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
      A review. Metal-catalyzed exchange has been used extensively in the labs. of AstraZeneca plc at R&D Charnwood to label a variety of mols. of pharmaceutical interest with the isotopes of deuterium and tritium. Despite early prejudices against the use of tritiated compds., particularly in ADME studies, the development of directed isotopic exchange techniques has enabled timely and economic support for many pharmaceutical projects.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXis1Sjug%253D%253D&md5=b6ad9bbdd8f2802cc4b3a3e0c9fb1af1
      .
      (c) Lockley, W. J. S.; Heys, J. R. Metal-catalysed hydrogen isotope exchange labelling: a brief overview. J. Labelled Compd. Radiopharm. 2010, 53, 635– 644,  DOI: 10.1002/jlcr.1851
      [Crossref], [CAS], Google Scholar
      13c
      Metal-catalysed hydrogen isotope exchange labelling: a brief overview
      Lockley, William J. S.; Heys, J. Richard
      Journal of Labelled Compounds and Radiopharmaceuticals (2010), 53 (11-12), 635-644CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
      An overview is given of this Special Issue of the Journal of Labeled Compds. and Radiopharmaceuticals dealing with the subject of metal-catalyzed hydrogen isotope exchange labeling. In addn. to summarizing the areas covered by the contributed papers, the overview also adds some historical information and gives short reviews of those areas and metals, not specifically covered by the contributed papers.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXisF2qtQ%253D%253D&md5=5c80171c3472da38e545cdc64a19f7e4
      .
      (d) Di Giuseppe, A.; Castarlenas, R.; Oro, L. A. Mechanistic considerations on catalytic H/D exchange mediated by organometallic transition metal complexes. C. R. Chim. 2015, 18, 713– 741,  DOI: 10.1016/j.crci.2015.02.006
      [Crossref], [CAS], Google Scholar
      13d
      Mechanistic considerations on catalytic H/D exchange mediated by organometallic transition metal complexes
      Di Giuseppe, Andrea; Castarlenas, Ricardo; Oro, Luis A.
      Comptes Rendus Chimie (2015), 18 (7), 713-741CODEN: CRCOCR; ISSN:1631-0748. (Elsevier Masson SAS)
      A review. The purpose of this review is to analyze the different reaction mechanisms of the H/D exchange on org. substrates catalyzed by transition metal complexes in homogeneous phase. The metal-catalyzed H/D exchange is a multifaceted reaction whose mechanism depends strongly on the reaction conditions and on the metal complex used as a catalyst. It is possible to group the different mechanisms into three main families depending on the "role" and behavior of the catalyst: (i) Lewis acid-base catalysis; (ii) C-H activation (iii) insertion/β-elimination. For each macro-group, several representative examples are discussed and critically evaluated in order to provide the reader with keys to the understanding of how the different catalytic systems act and how their modification may affect their performance in terms of activity and selectivity. This knowledge is fundamental for designing improved organometallic H/D catalysts for labeling org. products in greener conditions with more cost-effective processes.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXptFGhurY%253D&md5=bf0a04fadc22033ad4665692faf80456
    14. 14
      (a) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Beyond thermodynamic acidity: a perspective on the complex-induced proximity effect (CIPE) in deprotonation reactions. Angew. Chem., Int. Ed. 2004, 43, 2206– 2225,  DOI: 10.1002/anie.200300590
      [Crossref], [CAS], Google Scholar
      14a
      Beyond thermodynamic acidity: A perspective on the complex-induced proximity effect (CIPE) in deprotonation reactions
      Whisler, Marna C.; MacNeil, Stephen; Snieckus, Victor; Beak, Peter
      Angewandte Chemie, International Edition (2004), 43 (17), 2206-2225CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. The concept of the complex-induced proximity effect (CIPE) in deprotonations is helpful in elucidating the mechanisms involved in carbanion chem. and in planning org. syntheses. In this review, the consequences of complexation of organolithium bases to functional groups of the substrates before the proton-transfer step are discussed. Exptl. data from kinetic measurements and isotope-labeling expts. as well as the results of calcns. in many cases point to a prelithiation complex as a reaction intermediate. Some examples from natural products synthesis illustrate how this concept can be used to obtain intermediates in a regio- or stereoselective manner. Of particular interest is the functionalization of positions that are remote from the coordination group.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjslOgtbs%253D&md5=3b679a38b4503d52c57681d32a71ba96
      .
      (b) Sambiagio, C.; Schönbauer, D.; Blieck, R.; Dao-Huy, T.; Pototschnig, G.; Schaaf, P.; Wiesinger, T.; Zia, M. F.; Wencel-Delord, J.; Besset, T.; Maes, B. U. W.; Schnürch, M. A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry. Chem. Soc. Rev. 2018, 47, 6603– 6743,  DOI: 10.1039/C8CS00201K
      [Crossref], [PubMed], [CAS], Google Scholar
      14b
      A comprehensive overview of directing groups applied in metal-catalyzed C-H functionalization chemistry
      Sambiagio, Carlo; Schonbauer, David; Blieck, Remi; Dao-Huy, Toan; Pototschnig, Gerit; Schaaf, Patricia; Wiesinger, Thomas; Zia, Muhammad Farooq; Wencel-Delord, Joanna; Besset, Tatiana; Maes, Bert U. W.; Schnurch, Michael
      Chemical Society Reviews (2018), 47 (17), 6603-6743CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. In this review, the recent advances in the field of metal-catalyzed group-directed C-H functionalization reactions were summarized.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlOgsr7N&md5=77d3e0e3466b7dc98740cae4cc962a03
    15. 15
      (a) Nilsson, G. N.; Kerr, W. J. The development and use of novel iridium complexes as catalysts for ortho-directed hydrogen isotope exchange reactions. J. Labelled Compd. Radiopharm. 2010, 53, 662– 667,  DOI: 10.1002/jlcr.1817
      [Crossref], [CAS], Google Scholar
      15a
      The development and use of novel iridium complexes as catalysts for ortho-directed hydrogen isotope exchange reactions
      Nilsson, Goeran N.; Kerr, William J.
      Journal of Labelled Compounds and Radiopharmaceuticals (2010), 53 (11-12), 662-667CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
      The prepn. and application of groups of new Ir complexes are described. In particular, Ir complexes possessing phosphine ligands and a bulky N-heterocyclic carbene are robust and readily handled species and were applied in a range of directed H-D and -tritium exchange processes and, in particular, with drug-like substrates or within ADMET-related studies. Overall, these new Ir(I) complexes are highly active catalysts and display catalytic activity far in excess of the industry std., Crabtree's catalyst, with excellent levels of labeling being achieved over short reaction times and at low metal complex loadings, while tolerating a wide range of functional moieties. Also and again in contrast to systems employing Crabtree's catalyst, the low catalyst loadings and short reaction times made possible by these emerging Ir carbene complexes have delivered tritiated products with very good levels of labeling and without any appreciable byproduct waste prodn.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXis1Sjsg%253D%253D&md5=ccd19ca7691c49c4f8b84199e0229a28
      .
      (b) Brown, J. A.; Cochrane, A. R.; Irvine, S.; Kerr, W. J.; Mondal, B.; Parkinson, J. A.; Paterson, L. C.; Reid, M.; Tuttle, T.; Andersson, S.; Nilsson, G. N. The Synthesis of Highly Active Iridium(I) Complexes and their Application in Catalytic Hydrogen Isotope Exchange. Adv. Synth. Catal. 2014, 356, 3551– 3562,  DOI: 10.1002/adsc.201400730
      [Crossref], [CAS], Google Scholar
      15b
      The Synthesis of Highly Active Iridium(I) Complexes and their Application in Catalytic Hydrogen Isotope Exchange
      Brown, Jack A.; Cochrane, Alison R.; Irvine, Stephanie; Kerr, William J.; Mondal, Bhaskar; Parkinson, John A.; Paterson, Laura C.; Reid, Marc; Tuttle, Tell; Andersson, Shalini; Nilsson, Goeran N.
      Advanced Synthesis & Catalysis (2014), 356 (17), 3551-3562CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Robust iridium(I) complexes bearing a sterically encumbered N-heterocyclic carbene ligand, alongside a phosphine ligand, were synthesized and studied in hydrogen isotope exchange processes. These complexes have allowed isotope incorporation over a range of substrates using practically convenient deuterium and tritium gas. Also, these active catalysts are capable of isotope incorporation to particularly high levels, while employing low catalyst loadings and in short reaction times. In addn. to this, these new catalyst species showed flexible levels of chemoselectivity, which can be altered by simple manipulation of preparative approaches. Also, a no. of industrially-relevant drug mols. also was labeled, including the sulfonamide contg. drug, Celecoxib. Alongside detailed NMR expts., initial mechanistic studies also were performed, providing insight into both substrate binding energies, and, more importantly, relative energies of key steps in the mechanistic cycle as part of the overall exchange process.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVGkurjF&md5=60694614df3600e544066dbda1e877e9
      .
      (c) Ma, S.; Villa, G.; Thuy-Boun, P. S.; Homs, A.; Yu, J.-Q. Palladium-catalyzed ortho-selective C–H deuteration of arenes: evidence for superior reactivity of weakly coordinated palladacycles. Angew. Chem., Int. Ed. 2014, 53, 734– 737,  DOI: 10.1002/anie.201305388
      [Crossref], [CAS], Google Scholar
      15c
      Palladium-Catalyzed ortho-Selective C-H Deuteration of Arenes: Evidence for Superior Reactivity of Weakly Coordinated Palladacycles
      Ma, Sandy; Villa, Giorgio; Thuy-Boun, Peter S.; Homs, Anna; Yu, Jin-Quan
      Angewandte Chemie, International Edition (2014), 53 (3), 734-737CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      We disclose a protocol for the palladium-catalyzed ortho-selective C-H deuteration of arenes. Phenylacetic acids and benzoic acids are suitable substrates for this reaction. This reaction offers a catalytic route to ortho-deuterated phenylacetic acids and benzoic acids and demonstrates the sharp difference in reactivity of palladacycle intermediates held together by weak and strong coordination.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVOhsLbK&md5=a2a7f70d33b75a62b79a8161f81245ad
      .
      (d) Giles, R.; Ahn, G.; Jung, K. W. H–D exchange in deuterated trifluoroacetic acid via ligand-directed NHC-palladium catalysis: a powerful method for deuteration of aromatic ketones, amides, and amino acids. Tetrahedron Lett. 2015, 56, 6231– 6235,  DOI: 10.1016/j.tetlet.2015.09.100
      [Crossref], [PubMed], [CAS], Google Scholar
      15d
      H-D exchange in deuterated trifluoroacetic acid via ligand-directed NHC-palladium catalysis: a powerful method for deuteration of aromatic ketones, amides, and amino acids
      Giles, Richard; Ahn, Green; Jung, Kyung Woon
      Tetrahedron Letters (2015), 56 (45), 6231-6235CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
      A method has been developed for one-step ortho-selective ligand-directed H-D exchange, accompanied in some cases by concurrent acid-catalyzed electrophilic deuteration. This method is effective for deuteration of arom. substrates ranging from ketones to amides and amino acids, including compds. of biol. and pharmaceutical interest such as acetaminophen and edaravone. Use of a palladium catalyst featuring an NHC ligand is crit. for the obsd. reactivity. Exptl. evidence strongly suggests that palladium facilitates C-H activation of the arom. substrates, a mechanism seldom obsd. under strongly acidic conditions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1Sqt77L&md5=a2bfc3ba3c7327bb6617180c88d52bb1
      .
      (e) Kerr, W. J.; Lindsay, D. M.; Reid, M.; Atzrodt, J.; Derdau, V.; Rojahn, P.; Weck, R. Iridium-catalysed ortho-H/D and -H/T exchange under basic conditions: C–H activation of unprotected tetrazoles. Chem. Commun. 2016, 52, 6669– 6672,  DOI: 10.1039/C6CC02137A
      [Crossref], [PubMed], [CAS], Google Scholar
      15e
      Iridium-catalysed ortho-H/D and -H/T exchange under basic conditions: C-H activation of unprotected tetrazoles
      Kerr, William J.; Lindsay, David M.; Reid, Marc; Atzrodt, Jens; Derdau, Volker; Rojahn, Patrick; Weck, Remo
      Chemical Communications (Cambridge, United Kingdom) (2016), 52 (40), 6669-6672CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      The first examples of selective ortho-directed C-H activation with unprotected 2-aryltetrazoles I (X = 4-MeO, 2-Me, 3-Cl, etc.) are described. A new base-assisted protocol for iridium(I) hydrogen isotope exchange catalysis allows access to ortho-deuterated and tritiated tetrazoles, e.g., II, including the tetrazole-contg. pharmaceutical, Valsartan. Preliminary mechanistic studies are also presented.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmsF2gs74%253D&md5=9908e32861f87aeba57c3fbebc868dcc
      .
      (f) Valero, M.; Kruissink, T.; Blass, J.; Weck, R.; Güssregen, S.; Plowright, A. T.; Derdau, V. C–H Functionalization-Prediction of Selectivity in Iridium(I)-Catalyzed Hydrogen Isotope Exchange Competition Reactions. Angew. Chem., Int. Ed. 2020, 59, 5626– 5631,  DOI: 10.1002/anie.201914220
      [Crossref], [CAS], Google Scholar
      15f
      C-H Functionalization - Prediction of Selectivity in Iridium(I)-Catalyzed Hydrogen Isotope Exchange Competition Reactions
      Valero, Megane; Kruissink, Thomas; Blass, Jennifer; Weck, Remo; Guessregen, Stefan; Plowright, Alleyn T.; Derdau, Volker
      Angewandte Chemie, International Edition (2020), 59 (14), 5626-5631CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      An assessment of the C-H activation catalyst [(COD)Ir(IMes)(PPh3)]PF6 (COD = 1,5-cyclooctadiene, IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) in the deuteration of Ph rings contg. different functional directing groups is divulged. Competition expts. have revealed a clear order of the directing groups in the hydrogen isotope exchange (HIE) with an iridium(I) catalyst. Through DFT calcns. the iridium-substrate coordination complex has been identified to be the main trigger for reactivity and selectivity in the competition situation with two or more directing groups. We postulate that the competition concept found in this HIE reaction can be used to explain regioselectivities in other transition-metal-catalyzed functionalization reactions of complex drug-type mols. as long as a C-H activation mechanism is involved.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitFChsrk%253D&md5=b59404a1dac4781fdd999c7bd937e596
      .
      (g) Hu, G.-Q.; Li, E.-C.; Zhang, H.-H.; Huang, W. Ag(i)-Mediated hydrogen isotope exchange of mono-fluorinated (hetero)arenes. Org. Biomol. Chem. 2020, 18, 6627– 6633,  DOI: 10.1039/D0OB01273D
      [Crossref], [PubMed], [CAS], Google Scholar
      15g
      Ag(I)-Mediated hydrogen isotope exchange of mono-fluorinated (hetero)arenes
      Hu, Guang-Qi; Li, En-Ci; Zhang, Hong-Hai; Huang, Wei
      Organic & Biomolecular Chemistry (2020), 18 (34), 6627-6633CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
      An efficient approach to install deuterium into mono-fluorinated (hetero)arenes by a Ag2CO3/Sphos-mediated HIE protocol with D2O as the deuterium source has been disclosed. This method showed a specific site selectivity of deuteration at the α-position of the fluorine atom, which is complementary to the existing transition metal-catalyzed HIE process.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFygsr7K&md5=ab40300c850d858c63556540cdc5f9cd
      .
      (h) Kerr, W. J.; Knox, G. J.; Paterson, L. C. Recent advances in iridium(I) catalysis towards directed hydrogen isotope exchange. J. Labelled Compd. Radiopharm. 2020, 63, 281– 295,  DOI: 10.1002/jlcr.3812
      [Crossref], [PubMed], [CAS], Google Scholar
      15h
      Recent advances in iridium(I) catalysis towards directed hydrogen isotope exchange
      Kerr, William J.; Knox, Gary J.; Paterson, Laura C.
      Journal of Labelled Compounds and Radiopharmaceuticals (2020), 63 (6), 281-295CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
      A review. A broadened array of new iridium catalysts and assocd. protocols for direct and selective C-H activation and hydrogen isotope insertion within a no. of new chem. entities of direct relevance to the pharmaceutical industry was described.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisFOlsLg%253D&md5=5b4e341c980b6d0fe7a11907168a3aa9
    16. 16
      (a) Bag, S.; Petzold, M.; Sur, A.; Bhowmick, S.; Werz, D. B.; Maiti, D. Palladium-Catalyzed Selective meta-C–H Deuteration of Arenes: Reaction Design and Applications. Chem. - Eur. J. 2019, 25, 9433– 9437,  DOI: 10.1002/chem.201901317
      [Crossref], [PubMed], [CAS], Google Scholar
      16a
      Palladium-Catalyzed Selective meta-C-H Deuteration of Arenes: Reaction Design and Applications
      Bag, Sukdev; Petzold, Martin; Sur, Aishanee; Bhowmick, Suman; Werz, Daniel B.; Maiti, Debabrata
      Chemistry - A European Journal (2019), 25 (40), 9433-9437CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      An easily removable pyrimidine-based auxiliary was employed for the meta-C-H deuteration of arenes. The scope of this Pd-catalyzed deuteration using com. available [D1]- and [D4]-acetic acid was demonstrated by its application in phenylacetic acid and phenylmethanesulfonate derivs. A detailed mechanistic study led to explore the reversibility of the non-rate detg. C-H activation step. The of meta-deuterium incorporation illustrated the template morphol. in terms of selectivity. The applicability of this method was demonstrated by the selective deuterium incorporation into various pharmaceuticals.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXptFWnsLk%253D&md5=6acdafea0b292d63d5d37e7f1bfe3e25
      .
      (b) Xu, H.; Liu, M.; Li, L.-J.; Cao, Y.-F.; Yu, J.-Q.; Dai, H.-X. Palladium-Catalyzed Remote meta-C–H Bond Deuteration of Arenes Using a Pyridine Template. Org. Lett. 2019, 21, 4887– 4891,  DOI: 10.1021/acs.orglett.9b01784
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      16b
      Palladium-Catalyzed Remote meta-C-H Bond Deuteration of Arenes Using a Pyridine Template
      Xu, Hui; Liu, Min; Li, Ling-Jun; Cao, Ya-Fang; Yu, Jin-Quan; Dai, Hui-Xiong
      Organic Letters (2019), 21 (12), 4887-4891CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      In the presence of Pd(OAc)2, arylacetates and benzylphosphonate esters and benzylic and arylethyl ethers of a fluoropyridinylphenol such as I (R = H) underwent chemoselective and regioselective directed meta-deuteration in perdeuteroacetic acid to yield aryl-deuterated esters and ethers such as I (R = D) with ≥84% deuteration at the meta positions and ≤10% deuteration at other positions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFGqsLbO&md5=6083204eb397c4a3073876c0a0f8d315
    17. 17
      (a) Burhop, A.; Weck, R.; Atzrodt, J.; Derdau, V. Hydrogen-Isotope Exchange (HIE) Reactions of Secondary and Tertiary Sulfonamides and Sulfonylureas with Iridium(I) Catalysts. Eur. J. Org. Chem. 2017, 2017, 1418– 1424,  DOI: 10.1002/ejoc.201601599
      [Crossref], [CAS], Google Scholar
      17a
      Hydrogen-Isotope Exchange (HIE) Reactions of Secondary and Tertiary Sulfonamides and Sulfonylureas with Iridium(I) Catalysts
      Burhop, Annina; Weck, Remo; Atzrodt, Jens; Derdau, Volker
      European Journal of Organic Chemistry (2017), 2017 (11), 1418-1424CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
      For the first time we report the optimized hydrogen-isotope exchange (HIE) conditions for the selective arom. deuteration of various sulfonylureas and tertiary sulfonamides, as well as for a broad range of secondary sulfonamides. Based on a comprehensive screening of readily available Ir catalysts, the Kerr-type NHC catalyst 5 [(cod)Ir(IMes)Cl] proved to be most efficient in the HIE reaction of secondary sulfonamides and sulfonylureas [e.g., N,4-dimethylbenzenesulfonamide → o,o-d2-N,4-dimethylbenzenesulfonamide (up to 85% D incorporation, 97% yield) with catalyst 5]. However, for tertiary sulfonamides, the com. available Burgess catalyst (I.BArF-), not yet utilized in HIE reactions, resulted in a much higher incorporation of deuterium. Finally, we tested the new HIE protocol for the labeling of a series of sulfa drugs and adapted the conditions to allow for selective tritium labeling.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXltVWgtrg%253D&md5=f9234ab97508c2c248824f89fb3ab1ea
      .
      (b) Jess, K.; Derdau, V.; Weck, R.; Atzrodt, J.; Freytag, M.; Jones, P. G.; Tamm, M. Hydrogen Isotope Exchange with Iridium(I) Complexes Supported by Phosphine-Imidazolin-2-imine P,N Ligands. Adv. Synth. Catal. 2017, 359, 629– 638,  DOI: 10.1002/adsc.201601291
      [Crossref], [CAS], Google Scholar
      17b
      Hydrogen Isotope Exchange with Iridium(I) Complexes Supported by Phosphine-Imidazolin-2-imine P,N Ligands
      Jess, Kristof; Derdau, Volker; Weck, Remo; Atzrodt, Jens; Freytag, Matthias; Jones, Peter G.; Tamm, Matthias
      Advanced Synthesis & Catalysis (2017), 359 (4), 629-638CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Phenylene-bridged hybrid phosphine-imidazolin-2-imine RP,NR' ligands (R = Ph, Cy, i-Pr, t-Bu; R' = Me, i-Pr) were prepd. from 1,2-dibromobenzene by Pd-catalyzed C-N coupling with 1,3,4,5-tetramethylimidazolin-2-imine or 1,3-diisopropyl-4,5-dimethylimidazolin-2-imine, followed by lithiation with tert-butyllithium and reaction with the chlorophosphines (R2PCl). Their reaction with the dimeric Ir complex [Ir(cod)Cl]2 (cod = 1,5-cyclooctadiene) and subsequent anion exchange with Na tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBArF24) or KPF6 (KPF6) afforded Ir complexes [(RP,NR')Ir(cod)]BArF24 or [(RP,NR')Ir(cod)]PF6, resp. The latter PF6 salts were structurally characterized, revealing short Ir-N bonds as an indication of electron-rich N donor atoms. The former complexes were tested for their applicability in catalytic H/D exchange. In particular, the complex with the ligand t-BuP,NMe showed remarkable performance in H/D exchange with a broad range of arom. substrates, including ketones, amides, esters, heterocycles and nitro compds., and also promoted H/D exchange at arom. Boc-protected amines, benzylamines and methoxy derivs.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Oitrc%253D&md5=cd6c4f720b2223a53882c2e62665194b
      .
      (c) Valero, M.; Becker, D.; Jess, K.; Weck, R.; Atzrodt, J.; Bannenberg, T.; Derdau, V.; Tamm, M. Directed Iridium-Catalyzed Hydrogen Isotope Exchange Reactions of Phenylacetic Acid Esters and Amides. Chem. - Eur. J. 2019, 25, 6517– 6522,  DOI: 10.1002/chem.201901449
      [Crossref], [PubMed], [CAS], Google Scholar
      17c
      Directed Iridium-Catalyzed Hydrogen Isotope Exchange Reactions of Phenylacetic Acid Esters and Amides
      Valero, Megane; Becker, Daniel; Jess, Kristof; Weck, Remo; Atzrodt, Jens; Bannenberg, Thomas; Derdau, Volker; Tamm, Matthias
      Chemistry - A European Journal (2019), 25 (26), 6517-6522CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      For the first time, a catalytic protocol for a highly selective hydrogen isotope exchange (HIE) of phenylacetic acid esters and amides under very mild reaction conditions is reported. Using a homogeneous iridium catalyst supported by a bidentate phosphine-imidazolin-2-imine P,N ligand, the HIE reaction on a series of phenylacetic acid derivs. proceeds with high yields, high selectivity, and with deuterium incorporation up to 99 %. The method is fully adaptable to the specific requirements of tritium chem., and its effectiveness was demonstrated by direct tritium labeling of the fungicide benalaxyl and the drug camylofine. Further insights into the mechanism of the HIE reaction with catalyst, [IrL(COD)][BArF24] (1, [2071645-61-7], L = N-(2-(bis(tert-butyl)phosphino)phenyl)-1,3,4,5-tetramethylimidazolin-2-imine, COD = cyclooctadiene, BArF34- = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate), have been provided utilizing DFT calcns., NMR studies, and X-ray diffraction anal.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXot1WjtL0%253D&md5=b8e24e12e74bbf8d9b5043632bb67e9a
      .
      (d) Müller, V.; Weck, R.; Derdau, V.; Ackermann, L. Ruthenium(II)-Catalyzed Hydrogen Isotope Exchange of Pharmaceutical Drugs by C–H Deuteration and C–H Tritiation. ChemCatChem 2020, 12, 100– 104,  DOI: 10.1002/cctc.201902051
      [Crossref], [CAS], Google Scholar
      17d
      Ruthenium(II)-Catalyzed Hydrogen Isotope Exchange of Pharmaceutical Drugs by C-H Deuteration and C-H Tritiation
      Mueller, Valentin; Weck, Remo; Derdau, Volker; Ackermann, Lutz
      ChemCatChem (2020), 12 (1), 100-104CODEN: CHEMK3; ISSN:1867-3880. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Well-defined ruthenium(II) biscarboxylate complexes enabled selective ortho-deuteration with weakly-coordinating, synthetically useful carboxylic acid with outstanding levels of isotopic labeling. The robust nature of the catalytic system was reflected by a broad functional group tolerance in an operationally-simple manner, allowing the isotope labeling of challenging pharmaceuticals and bioactive heterocyclic motifs. The synthetic power of our method was highlighted by the selective tritium-labeling of repaglinide, an antidiabetic drug, providing access to defined tritium labeled therapeutics.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlejt7%252FP&md5=cafca5b68265e784d6f47c060ffb0701
      .
      (e) Valero, M.; Bouzouita, D.; Palazzolo, A.; Atzrodt, J.; Dugave, C.; Tricard, S.; Feuillastre, S.; Pieters, G.; Chaudret, B.; Derdau, V. NHC-Stabilized Iridium Nanoparticles as Catalysts in Hydrogen Isotope Exchange Reactions of Anilines. Angew. Chem., Int. Ed. 2020, 59, 3517– 3522,  DOI: 10.1002/anie.201914369
      [Crossref], [CAS], Google Scholar
      17e
      NHC-Stabilized Iridium Nanoparticles as Catalysts in Hydrogen Isotope Exchange Reactions of Anilines
      Valero, Megane; Bouzouita, Donia; Palazzolo, Alberto; Atzrodt, Jens; Dugave, Christophe; Tricard, Simon; Feuillastre, Sophie; Pieters, Gregory; Chaudret, Bruno; Derdau, Volker
      Angewandte Chemie, International Edition (2020), 59 (9), 3517-3522CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Air-stable iridium nanoparticles stabilized with the N-heterocyclic carbene 1,3-dicyclohexyl-2-imidazolylidene were prepd. from [(η4-1,5-cyclooctadiene)Ir(OMe)]2 and the dicyclohexylimidazolidinium chloride. In the presence of the stabilized iridium nanoparticles, anilines underwent regioselective ortho-deuteration with D2 and D2O in THF to yield deuterated anilines. An aniline contg. the volixibat pharmacophore underwent tritiation with T2 in THF to yield the monotritiated aniline.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitFeisLY%253D&md5=028c4bdfb3225075a6a613c29313fb8c
      .
      (f) Daniel-Bertrand, M.; Garcia-Argote, S.; Palazzolo, A.; Mustieles Marin, I.; Fazzini, P.-F.; Tricard, S.; Chaudret, B.; Derdau, V.; Feuillastre, S.; Pieters, G. Multiple Site Hydrogen Isotope Labelling of Pharmaceuticals. Angew. Chem., Int. Ed. 2020, 59, 21114– 21120,  DOI: 10.1002/anie.202008519
      [Crossref], [CAS], Google Scholar
      17f
      Multiple Site Hydrogen Isotope Labeling of Pharmaceuticals
      Daniel-Bertrand, Marion; Garcia-Argote, Sebastien; Palazzolo, Alberto; Mustieles Marin, Irene; Fazzini, Pier-Francesco; Tricard, Simon; Chaudret, Bruno; Derdau, Volker; Feuillastre, Sophie; Pieters, Gregory
      Angewandte Chemie, International Edition (2020), 59 (47), 21114-21120CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Radiolabeling is fundamental in drug discovery and development as it is mandatory for preclin. ADME studies and late-stage human clin. trials. Herein, a general, effective, and easy to implement method for the multiple site incorporation of deuterium and tritium atoms using the com. available and air-stable iridium precatalyst [Ir(COD)(OMe)]2 is described. A large scope of pharmaceutically relevant substructures can be labeled using this method including pyridine, pyrazine, indole, carbazole, aniline, oxazoles/thiazoles, thiophene, but also electron-rich Ph groups. The high functional group tolerance of the reaction is highlighted by the labeling of a wide range of complex pharmaceuticals, contg. notably halogen or sulfur atoms and nitrile groups. The multiple site hydrogen isotope incorporation has been explained by the in situ formation of complementary catalytically active species: monometallic iridium complexes and iridium nanoparticles.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvVCjsbbJ&md5=77dc22d342ada10985806f8f7aaefa88
    18. 18
      (a) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Beyond directing groups: transition-metal-catalyzed C–H activation of simple arenes. Angew. Chem., Int. Ed. 2012, 51, 10236– 10254,  DOI: 10.1002/anie.201203269
      [Crossref], [CAS], Google Scholar
      18a
      Beyond Directing Groups: Transition-Metal-Catalyzed C-H Activation of Simple Arenes
      Kuhl, Nadine; Hopkinson, Matthew N.; Wencel-Delord, Joanna; Glorius, Frank
      Angewandte Chemie, International Edition (2012), 51 (41), 10236-10254CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. The use of coordinating moieties as directing groups for the functionalization of arom. C-H bonds has become an established tool to enhance reactivity and induce regioselectivity. Nevertheless, with regard to the synthetic applicability of C-H activation, there is a growing interest in transformations in which the directing group can be fully abandoned, thus allowing the direct functionalization of simple benzene derivs. However, this approach requires the disclosure of new strategies to achieve reactivity and to control selectivity. In this review, recent advances in the emerging field of non-chelate-assisted C-H activation are discussed, highlighting some of the most intriguing and inspiring examples of induction of reactivity and selectivity.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlylsL3J&md5=88a6f0d7a65bc848644a07b3f898f0a9
      .
      (b) Hartwig, J. F.; Larsen, M. A. Undirected, Homogeneous C–H Bond Functionalization: Challenges and Opportunities. ACS Cent. Sci. 2016, 2, 281– 292,  DOI: 10.1021/acscentsci.6b00032
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      18b
      Undirected, Homogeneous C-H Bond Functionalization: Challenges and Opportunities
      Hartwig, John F.; Larsen, Matthew A.
      ACS Central Science (2016), 2 (5), 281-292CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
      The functionalization of C-H bonds has created new approaches to prepg. org. mols. by enabling new strategic "disconnections" during the planning of a synthetic route. Such functionalizations also have created the ability to derivatize complex mols. by modifying one or more of the many C-H bonds. For these reasons, researchers are developing new types of functionalization reactions of C-H bonds and new applications of these processes. These C-H bond functionalization reactions can be divided into two general classes: those directed by coordination to an existing functional group prior to the cleavage of the C-H bond (directed) and those occurring without coordination prior to cleavage of the C-H bond (undirected). The undirected functionalizations of C-H bonds are much less common and more challenging to develop than the directed reactions. This outlook will focus on undirected C-H bond functionalization, as well as related reactions that occur by a noncovalent assocn. of the catalyst prior to C-H bond cleavage. The inherent challenges of conducting undirected functionalizations of C-H bonds and the methods for undirected functionalization that are being developed will be presented, along with the factors that govern selectivity in these reactions. Finally, this outlook discusses future directions for research on undirected C-H functionalization, with an emphasis on the limitations that must be overcome if this type of methodol. is to become widely used in academia and in industry.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmvFGjsr8%253D&md5=d8c467b3025de6302478a3751940aac0
      .
      (c) Wedi, P.; van Gemmeren, M. Arene-Limited Nondirected C-H Activation of Arenes. Angew. Chem., Int. Ed. 2018, 57, 13016– 13027,  DOI: 10.1002/anie.201804727
      [Crossref], [CAS], Google Scholar
      18c
      Arene-Limited Nondirected C-H Activation of Arenes
      Wedi, Philipp; van Gemmeren, Manuel
      Angewandte Chemie, International Edition (2018), 57 (40), 13016-13027CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. The nondirected C(sp2)-H activation of simple arenes has advanced significantly in recent years through the discovery of new catalyst systems that are able to perform transformations with the arene as the limiting reagent. Important developments in catalyst and ligand design that have improved reactivity and selectivity are reviewed.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1Olt7%252FN&md5=a5b65fd777f200c5b3adc7c6d7d6f2c9
      .
      (d) Mondal, A.; Wedi, P.; van Gemmeren, M. The Non-directed Distal C(sp2)–H Functionalization of Arenes. In Remote C–H Bond Functionalizations; Maiti, D., Guin, S., Eds.; Wiley-VCH, 2021; pp 191– 219.
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    19. 19
      (a) Kański, R.; Kańska, M. Deuteriation of hydroxybenzoic acids in the presence of homogeneous platinum catalyst. J. Radioanal. Nucl. Chem. 2003, 257, 385– 390,  DOI: 10.1023/A:1024752300898
      [Crossref], [CAS], Google Scholar
      19a
      Deuteriation of hydroxybenzoic acids in the presence of homogeneous platinum catalyst
      Kanski, R.; Kanska, M.
      Journal of Radioanalytical and Nuclear Chemistry (2003), 257 (2), 385-390CODEN: JRNCDM; ISSN:0236-5731. (Kluwer Academic Publishers)
      A one-step method has been elaborated for the deuteriation of hydroxybenzoic acids in the presence of homogeneous divalent platinum salt in a medium contg. soln. of deuteriated acetic acid in heavy water. The quasi-unimol. H/D exchange rate consts. have been detd. at 130°C for the particular position of proton on the arom. ring by 1H NMR integration signals. Different kinetic patterns of H/D exchange are shown for 2-hydroxy-, 3-hydroxy-, and 4-hydroxybenzoic acid.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXlsVCqsLo%253D&md5=4c954d053703617efc240d0906a7ae06
      .
      (b) Hanson, S. K.; Heinekey, D. M.; Goldberg, K. I. C–H Bond Activation by Rhodium(I) Phenoxide and Acetate Complexes: Mechanism of H–D Exchange between Arenes and Water. Organometallics 2008, 27, 1454– 1463,  DOI: 10.1021/om7012259
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      19b
      C-H Bond Activation by Rhodium(I) Phenoxide and Acetate Complexes: Mechanism of H-D Exchange between Arenes and Water
      Hanson, Susan Kloek; Heinekey, D. Michael; Goldberg, Karen I.
      Organometallics (2008), 27 (7), 1454-1463CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
      New rhodium(I) complexes (PNP)Rh(X) (PNP = 2,6-bis(di-tert-butylphosphinomethyl)pyridine) (X = OTf (1), OAc (3), OH (8), OCH2CF3 (9), OC6H5 (10), OC6H4NO2 (11)) have been prepd. Hydroxide complex 8 and trifluoroethoxide complex 9 undergo stoichiometric activation of benzene-d6 to form the Ph complex (PNP)Rh(C6D5). Acetate and aryloxide complexes 3, 10, and 11 are active catalysts for H-D exchange between arenes and water. Control expts. indicate that the rhodium complexes are the active catalysts and that the obsd. exchange is not catalyzed by adventitious acid. Mechanistic studies of the H-D exchange reaction support a pathway involving dissocn. of aryloxide or acetate ligand. The reaction is accelerated by added alc. and, for the acetate complex, inhibited by added sodium acetate.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXis1Kgtb0%253D&md5=31016fb9df8810e1c477cde997c3e6a8
      .
      (c) Hickman, A. J.; Villalobos, J. M.; Sanford, M. S. Quantitative Assay for the Direct Comparison of Platinum Catalysts in Benzene H/D Exchange. Organometallics 2009, 28, 5316– 5322,  DOI: 10.1021/om900495n
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      19c
      Quantitative assay for the direct comparison of platinum catalysts in benzene H/D exchange
      Hickman, Amanda J.; Villalobos, Janette M.; Sanford, Melanie S.
      Organometallics (2009), 28 (18), 5316-5322CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
      This paper describes a protocol for the direct comparison of diverse Pt catalysts in the H/D exchange between C6H6 and TFA-d1, CD3CO2D, and TFE-d3 using turnover no. (TON) as a std. metric. An initial survey of Pt complexes, including com. Pt salts (PtCl2, K2PtCl4) and Pt chloride complexes contg. bidentate and tridentate nitrogen donor ligands, has been conducted. These studies have established that the addn. of AgOAc (in TFA-d1) or AgBF4 (in CD3CO2D and TFE-d3) displaces the Cl ligands on the Pt precatalyst, which leads to dramatically increased turnover nos. In general, PtCl2 and K2PtCl4 provided the fewest turnovers, and species contg. bidentate ligands afforded higher turnover nos. than those with tridentate ligands. A diimine Pt complex was found to be a top performing catalyst for H/D exchange with all deuterium sources examd. Interestingly, the relative reactivity of many of the catalysts varied dramatically upon changing the deuterium source, highlighting the need to thoroughly assay potential catalysts under a variety of conditions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVejtbzM&md5=1e71cc6205c368112f3ed3c510d25228
      .
      (d) Emmert, M. H.; Gary, J. B.; Villalobos, J. M.; Sanford, M. S. Platinum and palladium complexes containing cationic ligands as catalysts for arene H/D exchange and oxidation. Angew. Chem., Int. Ed. 2010, 49, 5884– 5886,  DOI: 10.1002/anie.201002351
      [Crossref], [CAS], Google Scholar
      19d
      Platinum and Palladium Complexes Containing Cationic Ligands as Catalysts for Arene H/D Exchange and Oxidation
      Emmert, Marion H.; Gary, J. Brannon; Villalobos, Janette M.; Sanford, Melanie S.
      Angewandte Chemie, International Edition (2010), 49 (34), 5884-5886, S5884/1-S5884/46CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Palladium(II) and platinum(II) complexes of pyridinium-substituted bipyridine ligands I (R = Ph, 4-tBu-C6H4) are highly active and stable catalysts for H/D exchange and acetoxylation of arom. C-H bonds (TONs up to 3200, TOFs up to 0.1 s-1). The regioselectivity of the deuteration and acetoxylation is studied and compared to traditional catalysts.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpslCns7c%253D&md5=f488f98df16acc62330a1a9e3776ce92
      .
      (e) Rhinehart, J. L.; Manbeck, K. A.; Buzak, S. K.; Lippa, G. M.; Brennessel, W. W.; Goldberg, K. I.; Jones, W. D. Catalytic Arene H/D Exchange with Novel Rhodium and Iridium Complexes. Organometallics 2012, 31, 1943– 1952,  DOI: 10.1021/om2012419
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      19e
      Catalytic arene H/D exchange with novel rhodium and iridium complexes
      Rhinehart, Jennifer L.; Manbeck, Kimberly A.; Buzak, Sara K.; Lippa, Geoffrey M.; Brennessel, William W.; Goldberg, Karen I.; Jones, William D.
      Organometallics (2012), 31 (5), 1943-1952CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
      Rhodium(III) and iridium(III) scorpionate complexes with tridentate N,N,O-ligand, bis(3,5-dimethyl-1-pyrazolyl)acetate (bdmpza), fac-[M(bdmpza)Cl2L]n- (L = Cl, n = 1; L = py, n = 0) exhibit catalytic activity in arene deuteration, proceeding via C-H-activation and acidic deuterolysis. Three novel pendant acetate complexes, [Rh(bdmpza)Cl3]-M+, [Rh(bdmpza)Cl2(py)], and [Ir(bdmpza)Cl3]-Q+ (Q+ = Li+, Na+), were prepd. Abstraction of halide from these complexes with silver salts yielded species capable of C-H activation of arenes. The catalytic H/D exchange reaction between benzene and trifluoroacetic acid-d was optimized, and these conditions were used to evaluate H/D exchange in other arenes. Branched alkyl substituents in alkyl aroms. showed an affinity toward deuterium exchange in the β-alkyl position only. DFT calcns. were performed to det. the mechanism of H/D exchange.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XisVGht70%253D&md5=b8c1d19ba4f3351af09ec72ed1c3637d
      .
      (f) Iluc, V. M.; Fedorov, A.; Grubbs, R. H. H/D Exchange Processes Catalyzed by an Iridium-Pincer Complex. Organometallics 2012, 31, 39– 41,  DOI: 10.1021/om201049p
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      19f
      H/D Exchange Processes Catalyzed by an Iridium-Pincer Complex
      Iluc, Vlad M.; Fedorov, Alexey; Grubbs, Robert H.
      Organometallics (2012), 31 (1), 39-41CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
      PNP-pincer Ir dihydride (PNP)IrH2 (1; PNP = bis(2-(diisopropylphosphino)-4-methylphenyl)amide) performs the H/D exchange between arom. substrates and tertiary hydrosilanes and D2O or C6D6. Complete incorporation of D into sterically accessible Car-H and Si-H bonds was obsd. at a moderate temp. of 80°.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1ajsb7K&md5=9fc83e0643d4dd980d80b66ec281b83c
      .
      (g) Ibañez, S.; Poyatos, M.; Peris, E. Mono and dimetallic pyrene-imidazolylidene complexes of iridium(iii) for the deuteration of organic substrates and the C-C coupling of alcohols. Dalton. Trans. 2016, 45, 14154– 14159,  DOI: 10.1039/C6DT02942F
      [Crossref], [PubMed], [CAS], Google Scholar
      19g
      Mono and dimetallic pyrene-imidazolylidene complexes of iridium(III) for the deuteration of organic substrates and the C-C coupling of alcohols
      Ibanez, S.; Poyatos, M.; Peris, E.
      Dalton Transactions (2016), 45 (36), 14154-14159CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
      Three different Ir(III) complexes with pyrene-contg. N-heterocyclic carbenes have been prepd. and characterized. Two complexes contain a monodentate pyrene-imidazolylidene ligand, and have the formulas [IrCp*Cl2(pyrene-NHC)] and [IrCp*(CO3)(pyrene-NHC)]. The third complex is a dimetallic complex with a pyrene-di-imidazolylidene bridging ligand, with the formula [{IrCp*(CO3)}2(μ-pyrene-di-NHC)]. The catalytic activity of the three complexes was tested in the H/D exchange of org. substrates, and in the β-alkylation of 1-phenylethanol with primary alcs. In the deuteration of org. substrates, the carbonate complexes are active even in the absence of additives. The dimetallic complex is the most active one in the catalytic coupling of alcs., a result that may be interpreted as a consequence of the cooperativity between the two metal centers.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1yqtLrE&md5=e47ac57a93789821b574aa585e46e9df
      .
      (h) Li, E.-C.; Hu, G.-Q.; Zhu, Y.-X.; Zhang, H.-H.; Shen, K.; Hang, X.-C.; Zhang, C.; Huang, W. Ag2CO3-Catalyzed H/D Exchange of Five-Membered Heteroarenes at Ambient Temperature. Org. Lett. 2019, 21, 6745– 6749,  DOI: 10.1021/acs.orglett.9b02369
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      19h
      Ag2CO3-Catalyzed H/D Exchange of Five-Membered Heteroarenes at Ambient Temperature
      Li, En-Ci; Hu, Guang-Qi; Zhu, Yu-Xing; Zhang, Hong-Hai; Shen, Kang; Hang, Xiao-Chun; Zhang, Cong; Huang, Wei
      Organic Letters (2019), 21 (17), 6745-6749CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      Ag2CO3-catalyzed hydrogen isotope exchange of five-membered heteroarenes is disclosed. The reaction can be conducted in the open air, at ambient temp., and with D2O as deuterium source. Moreover, this protocol showed orthogonal site selectivity to existing technol., thereby greatly expanding the scope of substrates for HIE reaction. The mechanistic study indicated that the carbonate group plays a crucial role to achieve high levels of deuterium incorporation by lowering the activation energy of H/D exchange process.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFyktL3F&md5=afbb41b99e7294375e6f4d040abe7496
      .
      (i) Lassalle, S.; Jabbour, R.; Schiltz, P.; Berruyer, P.; Todorova, T. K.; Veyre, L.; Gajan, D.; Lesage, A.; Thieuleux, C.; Camp, C. Metal-Metal Synergy in Well-Defined Surface Tantalum-Iridium Heterobimetallic Catalysts for H/D Exchange Reactions. J. Am. Chem. Soc. 2019, 141, 19321– 19335,  DOI: 10.1021/jacs.9b08311
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      19i
      Metal-Metal Synergy in Well-Defined Surface Tantalum-Iridium Heterobimetallic Catalysts for H/D Exchange Reactions
      Lassalle, Sebastien; Jabbour, Ribal; Schiltz, Pauline; Berruyer, Pierrick; Todorova, Tanya K.; Veyre, Laurent; Gajan, David; Lesage, Anne; Thieuleux, Chloe; Camp, Clement
      Journal of the American Chemical Society (2019), 141 (49), 19321-19335CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A novel heterobimetallic Ta/Ir hydrido complex, [{Ta(CH2tBu)3}{IrH2(Cp*)}] 1, featuring a very short metal-metal bond, was isolated through an original alkane elimination route from Ta(CHtBu)(CH2tBu)3 and Cp*IrH4. This mol. precursor was used to synthesize well-defined SiO2-supported low-coordinate heterobimetallic hydrido species [≡SiOTa(CH2tBu)2{IrH2(Cp*)}], 5, and [≡SiOTa(CH2tBu)H{IrH2(Cp*)}], 6, using a surface organometallic chem. (SOMC) approach. The SOMC methodol. prevents undesired dimerization as encountered in soln. and leading to tetranuclear [{Ta(CH2tBu)2}(Cp*IrH)]2, 4. This approach therefore allows access to unique low-coordinate species not attainable in soln. These original supported Ta/Ir species exhibit drastically enhanced catalytic performances in H/D exchange reactions with respect to (i) monometallic analogs as well as (ii) homogeneous systems. In particular, material 6 promotes the H/D exchange between fluorobenzene and C6D6 or D2 as D sources with excellent productivity (TON up to 1422; TOF up to 23.3 h-1) under mild conditions (25°, sub-atm. D2 pressure) without any additives.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFehsLfJ&md5=26c6b037058e00c033231a509a60669e
      .
      (j) Smith, J. D.; Durrant, G.; Ess, D. H.; Gelfand, B. S.; Piers, W. E. H/D exchange under mild conditions in arenes and unactivated alkanes with C6D6 and D2O using rigid, electron-rich iridium PCP pincer complexes. Chem. Sci. 2020, 11, 10705– 10717,  DOI: 10.1039/D0SC02694H
      [Crossref], [PubMed], [CAS], Google Scholar
      19j
      H/D exchange under mild conditions in arenes and unactivated alkanes with C6D6 and D2O using rigid, electron-rich iridium PCP pincer complexes
      Smith, Joel D.; Durrant, George; Ess, Daniel H.; Gelfand, Benjamin S.; Piers, Warren E.
      Chemical Science (2020), 11 (39), 10705-10717CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      The synthesis and characterization of an iridium polyhydride complex (Ir-H4) supported by an electron-rich PCP framework is described. This complex readily loses mol. hydrogen allowing for rapid room temp. hydrogen isotope exchange (HIE) at the hydridic positions and the α-C-H site of the ligand with deuterated solvents such as benzene-d6, toluene-d8 and THF-d8. The removal of 1-2 equiv of mol. H2 forms unsatd. iridium carbene trihydride (Ir-H3) or monohydride (Ir-H) compds. that are able to create further unsatn. by reversibly transferring a hydride to the ligand carbene carbon. These species are highly active hydrogen isotope exchange (HIE) catalysts using C6D6 or D2O as deuterium sources for the deuteration of a variety of substrates. By modifying conditions to influence the Ir-Hn speciation, deuteration levels can range from near exhaustive to selective only for sterically accessible sites. Preparative level deuterations of select substrates were performed allowing for procurement of >95% deuterated compds. in excellent isolated yields; the catalyst can be regenerated by treatment of residues with H2 and is still active for further reactions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFKgt7rE&md5=5334feab94cd4fc8ace7a31576640101
      .
      (k) Martin, J.; Eyselein, J.; Grams, S.; Harder, S. Hydrogen Isotope Exchange with Superbulky Alkaline Earth Metal Amide Catalysts. ACS Catal. 2020, 10, 7792– 7799,  DOI: 10.1021/acscatal.0c01359
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      19k
      Hydrogen Isotope Exchange with Superbulky Alkaline Earth Metal Amide Catalysts
      Martin, Johannes; Eyselein, Jonathan; Grams, Samuel; Harder, Sjoerd
      ACS Catalysis (2020), 10 (14), 7792-7799CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      Heavier alk. earth (Ae) metal amide complexes Ae(NR2)2 (Ae = Ca, Sr, Ba) were found to be highly active catalysts for hydrogen isotope exchange (HIE). The activities for D/H exchange between C6D6 and H2 strongly increase with metal size (Ca < Sr < Ba) and with amide bulk: N(SiMe3)2 < N(DIPP)(SiiPr3)< N(SiiPr3)2, DIPP = 2,6-diisopropylphenyl. At 120°C and pressures of 10-50 bar, no hydrogenation side-products are produced, and TONs of 205 and TOFs of 268, competitive with those for precious metal catalysts, have been achieved. The reverse H/D exchange between C6H6 and D2 is even faster by a factor 1.5-2. Substrates also include a range of substituted arenes. Alkyl-substituted arom. rings are preferably deuterated in acidic benzylic positions, and this tendency increases with the no. of alkyl-substituents. Although unactivated (sp3)C-H units could not be deuterated, the (sp3)Si-H function in primary, secondary, and tertiary alkylsilanes could be converted. Two different pathways for C6H6/D2 isotope exchange have been evaluated by DFT calcns.: (A) a deprotonation/protonation mechanism and (B) direct nucleophilic arom. substitution. Although the exact nature of the catalyst(s) is unclear, the first step is the conversion of Ae(NR2)2 with D2 into R2NAeD which can aggregate to larger clusters. Energy profiles with model catalysts (iPr3Si)2NAeD and [(Me3Si)2NAeD]2 (Ae = Ca or Ba) show that the direct nucleophilic arom. substitution is the most likely mechanism for deuteration of arenes. The key to this unusual reaction is the initial formation of a π-arene···Ae complex which is followed by the generation of an intermediate with a Meisenheimer anion. Heavier Ae metal amide complexes are, despite the lack of partially filled d-orbitals for substrate activation, potent catalysts for HIE.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFGqu7vP&md5=8eb89d2242ffeb2387892bf7897e5e48
      .
      (l) Dong, B.; Cong, X.; Hao, N. Silver-catalyzed regioselective deuteration of (hetero)arenes and α-deuteration of 2-alkyl azaarenes. RSC Adv. 2020, 10, 25475– 25479,  DOI: 10.1039/D0RA02358B
      [Crossref], [CAS], Google Scholar
      19l
      Silver-catalyzed regioselective deuteration of (hetero)arenes and α-deuteration of 2-alkyl azaarenes
      Dong, Baobiao; Cong, Xuefeng; Hao, Na
      RSC Advances (2020), 10 (43), 25475-25479CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
      A simple silver-catalyzed regioselective deuteration of (hetero)arenes and α-deuteration of 2-alkyl azaarenes was described. This strategy provides an efficient and practical avenue to access various deuterated electron-rich arenes, azaarenes and α-deuterated 2-alkyl azaarenes with good to excellent deuterium incorporation utilizing D2O as the source of deuterium atoms.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlWktLrM&md5=b19d03be82031a4d48bf60e53a772475
      .
      (m) Tlahuext-Aca, A.; Hartwig, J. F. Site-Selective Silver-Catalyzed C–H Bond Deuteration of Five-Membered Aromatic Heterocycles and Pharmaceuticals. ACS Catal. 2021, 11, 1119– 1127,  DOI: 10.1021/acscatal.0c04917
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      19m
      Site-Selective Silver-Catalyzed C-H Bond Deuteration of Five-Membered Aromatic Heterocycles and Pharmaceuticals
      Tlahuext-Aca, Adrian; Hartwig, John F.
      ACS Catalysis (2021), 11 (3), 1119-1127CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      Catalytic methods for the direct introduction of hydrogen isotopes into org. mols. are essential to the development of improved pharmaceuticals and to the alteration of their absorption, distribution, metab., and excretion (ADME) properties. However, the development of homogeneous catalysts for selective incorporation of isotopes in the absence of directing groups under practical conditions remains a long-standing challenge. Herein, a phosphine-ligated, silver-carbonate complex catalyzes the site-selective deuteration of C-H bonds in five-membered arom. heterocycles and active pharmaceutical ingredients that have been resistant to catalytic H/D exchange. The reactions occur with CH3OD as a low-cost source of the isotope. The silver catalysts react with five-membered heteroarenes lacking directing groups, tolerate a wide range of functional groups, and react in both polar and nonpolar solvents. Mechanistic expts., including deuterium kinetic isotope effects, detn. of kinetic orders, and identification of the catalyst resting state, support C-H bond cleavage from a phosphine-ligated, silver-carbonate intermediate as the rate-detg. step of the catalytic cycle.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXpt1Gjtg%253D%253D&md5=dad0980c9928b34214b70a3da1516416
    20. 20
      (a) Pony Yu, R.; Hesk, D.; Rivera, N.; Pelczer, I.; Chirik, P. J. Iron-catalysed tritiation of pharmaceuticals. Nature 2016, 529, 195– 199,  DOI: 10.1038/nature16464
      [Crossref], [PubMed], [CAS], Google Scholar
      20a
      Iron-catalysed tritiation of pharmaceuticals
      Pony Yu, Renyuan; Hesk, David; Rivera, Nelo; Pelczer, Istvan; Chirik, Paul J.
      Nature (London, United Kingdom) (2016), 529 (7585), 195-199CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      A thorough understanding of the pharmacokinetic and pharmacodynamic properties of a drug in animal models is a crit. component of drug discovery and development. Such studies are performed in vivo and in vitro at various stages of the development process-ranging from preclin. absorption, distribution, metab. and excretion (ADME) studies to late-stage human clin. trials-to elucidate a drug mol.'s metabolic profile and to assess its toxicity. Radiolabeled compds., typically those that contain 14C or 3H isotopes, are one of the most powerful and widely deployed diagnostics for these studies. The introduction of radiolabels using synthetic chem. enables the direct tracing of the drug mol. without substantially altering its structure or function. The ubiquity of C-H bonds in drugs and the relative ease and low cost assocd. with tritium (3H) make it an ideal radioisotope with which to conduct ADME studies early in the drug development process. Here we describe an iron-catalyzed method for the direct 3H labeling of pharmaceuticals by hydrogen isotope exchange, using tritium gas as the source of the radioisotope. The site selectivity of the iron catalyst is orthogonal to currently used iridium catalysts and allows isotopic labeling of complementary positions in drug mols., providing a new diagnostic tool in drug development.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xns1KhtA%253D%253D&md5=427730f28e4453669f007a1c2fbd1872
      .
      (b) Yang, H.; Zarate, C.; Palmer, W. N.; Rivera, N.; Hesk, D.; Chirik, P. J. Site-Selective Nickel-Catalyzed Hydrogen Isotope Exchange in N -Heterocycles and Its Application to the Tritiation of Pharmaceuticals. ACS Catal. 2018, 8, 10210– 10218,  DOI: 10.1021/acscatal.8b03717
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      20b
      Site-Selective Nickel-Catalyzed Hydrogen Isotope Exchange in N-Heterocycles and Its Application to the Tritiation of Pharmaceuticals
      Yang, Haifeng; Zarate, Cayetana; Palmer, W. Neil; Rivera, Nelo; Hesk, David; Chirik, Paul J.
      ACS Catalysis (2018), 8 (11), 10210-10218CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      A nickel-catalyzed method for the site-selective hydrogen isotope exchange (HIE) of C(sp2)-H bonds in nitrogen heteroarenes is described and applied to the tritiation of pharmaceuticals. The α-diimine nickel hydride complex [(iPrDI)Ni(μ2-H)]2 (iPrDI = N,N'-bis(2,6-diisopropylphenyl)-2,3-butanediimine) mediates efficient HIE when employed as a single component precatalyst or generated in situ from readily available and air-stable metal and ligand precursors (iPrDI, [(NEt3)Ni(OPiv)2]2 (Piv = pivaloyl) and (EtO)3SiH). The nickel catalyst offers distinct advantages over existing methods, including: (i) high HIE activity at low D2 or T2 pressure; (ii) tolerance of functional groups, including aryl chlorides, alcs., secondary amides, and sulfones; (iii) activity with nitrogen-rich mols. such as the chemotherapeutic imatinib; and (iv) the ability to promote HIE in sterically hindered positions generally inaccessible with other transition metal catalysts. Representative active pharmaceutical ingredients were tritiated with specific activities in excess of the thresholds required for drug absorption, distribution, metab., and excretion studies (1 Ci/mmol) and for protein receptor-ligand binding assays (15 Ci/mmol). The activity and selectivity of the nickel-catalyzed method are demonstrated by comparison with the current state-of-the-art single-site (iridium and iron) and heterogeneous (Raney nickel and rhodium black) catalysts. A pathway involving C(sp2)-H activation by a α-diimine nickel hydride monomer is consistent with the exptl. measured relative rate consts. for HIE with electronically disparate pyridines, the pressure-dependence of activity, positional selectivity preferences, and kinetic isotope effects.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslKqt7rO&md5=85a656c4b8bad6c2484088d08246f907
      .
      (c) Zarate, C.; Yang, H.; Bezdek, M. J.; Hesk, D.; Chirik, P. J. Ni(I)-X Complexes Bearing a Bulky α-Diimine Ligand: Synthesis, Structure, and Superior Catalytic Performance in the Hydrogen Isotope Exchange in Pharmaceuticals. J. Am. Chem. Soc. 2019, 141, 5034– 5044,  DOI: 10.1021/jacs.9b00939
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      20c
      Ni(I)-X Complexes Bearing a Bulky α-Diimine Ligand: Synthesis, Structure, and Superior Catalytic Performance in the Hydrogen Isotope Exchange in Pharmaceuticals
      Zarate, Cayetana; Yang, Haifeng; Bezdek, Mate J.; Hesk, David; Chirik, Paul J.
      Journal of the American Chemical Society (2019), 141 (12), 5034-5044CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The synthesis and spectroscopic characterization of a family of Ni-X (X = Cl, Br, I, H) complexes supported by the bulky α-diimine chelate N,N'-bis(1R,2R,3R,5S)-(-)-isopinocampheyl-2,3-butanediimine (ipcADI) are described. Diimine-supported, three-coordinate Ni(I)-X complexes are proposed as key intermediates in a host of catalytic transformations such as C-C and C-heteroatom cross-coupling and C-H functionalization but have until now remained synthetically elusive. A combination of structural, spectroscopic, electrochem., and computational studies were used to establish the electronic structure of each monomeric [(ipcADI)NiX] (X = Cl, Br, I) complex as a Ni(I) deriv. supported by a redox-neutral α-diimine chelate. The dimeric Ni hydride, [(ipcADI)Ni(μ2-H)]2, was prepd. and characterized by x-ray diffraction; however, magnetic measurements and 1H NMR spectroscopy support monomer formation at ambient temp. in THF soln. This Ni hydride was used as a precatalyst for the H isotope exchange (HIE) of C-H bonds in arenes and pharmaceuticals. By virtue of the multisite reactivity and high efficiency, the new Ni precatalyst provided unprecedented high specific activities (50-99 Ci/mmol) in radiolabeling, meeting the threshold required for radioligand binding assays. Use of air-stable and readily synthesized Ni precursor, [(ipcADI)NiBr2], broad functional group tolerance, and compatibility with polar protic solvents are addnl. assets of the Ni-catalyzed HIE method.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXktV2mtLg%253D&md5=e61f2c33405102c0fa94501aec43e9a3
      .
      (d) Corpas, J.; Viereck, P.; Chirik, P. J. C(sp2)–H Activation with Pyridine Dicarbene Iron Dialkyl Complexes: Hydrogen Isotope Exchange of Arenes Using Benzene- d6 as a Deuterium Source. ACS Catal. 2020, 10, 8640– 8647,  DOI: 10.1021/acscatal.0c01714
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      20d
      C(sp2)-H Activation with Pyridine Dicarbene Iron Dialkyl Complexes: Hydrogen Isotope Exchange of Arenes Using Benzene-d6 as a Deuterium Source
      Corpas, Javier; Viereck, Peter; Chirik, Paul J.
      ACS Catalysis (2020), 10 (15), 8640-8647CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      Treatment of pyridine dicarbene iron dialkyl complexes with low («1 atm) pressures of H2 in a benzene-d6 soln. promoted rapid hydrogen isotope exchange (HIE) of the C(sp2)-H bonds in both electron-poor and -rich arom. and heteroarom. rings with benzene-d6 as the deuterium source. The iron-catalyzed reaction proceeded with predictable regioselectivity, engaging sterically accessible C-H bonds including ortho-to-fluorine sites. The site selectivity for the catalytic HIE reaction was studied to identify the kinetic preferences for C-H activation. Structure-activity relationship studies with a series of iron precatalysts established that introduction of substituents at the 3- and 5-positions of pyridine of the pincer significantly accelerated HIE. Mechanistic studies identified N2 as an inhibitor of C-H activation, while H2 served to generate the active catalyst.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlGnsbnN&md5=1f5ba81b99827a5ff77f1f90d930f7ad
      .
      (e) Garhwal, S.; Kaushansky, A.; Fridman, N.; Shimon, L. J. W.; Ruiter, G. de. Facile H/D Exchange at (Hetero)Aromatic Hydrocarbons Catalyzed by a Stable Trans-Dihydride N-Heterocyclic Carbene (NHC) Iron Complex. J. Am. Chem. Soc. 2020, 142, 17131– 17139,  DOI: 10.1021/jacs.0c07689
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      20e
      Facile H/D Exchange at (Hetero)Aromatic Hydrocarbons Catalyzed by a Stable Trans-Dihydride N-Heterocyclic Carbene (NHC) Iron Complex
      Garhwal, Subhash; Kaushansky, Alexander; Fridman, Natalia; Shimon, Linda J. W.; Ruiter, Graham de
      Journal of the American Chemical Society (2020), 142 (40), 17131-17139CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Earth-abundant metal pincer complexes have played an important role in homogeneous catalysis during the last ten years. Yet, despite intense research efforts, the synthesis of iron PCcarbeneP pincer complexes has so far remained elusive. Here we report the synthesis of the first PCNHCP functionalized iron complex [(PCNHCP)FeCl2] (1) and the reactivity of the corresponding trans-dihydride iron(II) dinitrogen complex [(PCNHCP)Fe(H)2N2] (2). Complex 2 is stable under an atm. of N2 and is highly active for hydrogen isotope exchange at (hetero)arom. hydrocarbons under mild conditions (50°C, N2). With benzene-d6 as the deuterium source, easily reducible functional groups such as esters and amides are well tolerated, contributing to the overall wide substrate scope (e.g., halides, ethers, and amines). DFT studies suggest a complex assisted σ-bond metathesis pathway for C(sp2)-H bond activation, which is further discussed in this study.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvVWhsLjM&md5=00ac282ea45b4c91c160d6cfc6fbfae7
      .
      (f) Yang, H.; Hesk, D. Base metal-catalyzed hydrogen isotope exchange. J. Labelled Compd. Radiopharm. 2020, 63, 296– 307,  DOI: 10.1002/jlcr.3826
      [Crossref], [PubMed], [CAS], Google Scholar
      20f
      Base metal-catalyzed hydrogen isotope exchange
      Yang, Haifeng; Hesk, David
      Journal of Labelled Compounds and Radiopharmaceuticals (2020), 63 (6), 296-307CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
      A review. In this review article, recent development of base metal catalysts for hydrogen isotope exchange (HIE) and their applications in isotopic labeling of pharmaceutical compds. was described. These research efforts have resulted in the development of labeling approaches that complement traditional methods in terms of activity and selectivity, thus diversifying the methodologies available for isotope chemists.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitFClsbk%253D&md5=cf90d3eceba15c7050c42e16f4a7b92a
    21. 21
      (a) Chen, H.; Wedi, P.; Meyer, T.; Tavakoli, G.; van Gemmeren, M. Dual Ligand-Enabled Nondirected C–H Olefination of Arenes. Angew. Chem., Int. Ed. 2018, 57, 2497– 2501,  DOI: 10.1002/anie.201712235
      [Crossref], [CAS], Google Scholar
      21a
      Dual Ligand-Enabled Nondirected C-H Olefination of Arenes
      Chen, Hao; Wedi, Philipp; Meyer, Tim; Tavakoli, Ghazal; van Gemmeren, Manuel
      Angewandte Chemie, International Edition (2018), 57 (9), 2497-2501CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The application of the Pd-catalyzed oxidative C-H olefination of arenes, also known as the Fujiwara-Moritani reaction, has traditionally been limited by the requirement for directing groups on the substrate or the need to use the arene in large excess, typically as a (co)solvent. Herein, the development of a catalytic system is described that, through the combined action of two complementary ligands, makes it possible to use directing-group-free arenes as limiting reagents for the first time. The reactions proceed under a combination of both steric and electronic control and enable the application of this powerful reaction to valuable arenes, which cannot be utilized in excess.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsl2ntLk%253D&md5=966a3aab705104d27ed1d207fa56c313
      .
      (b) Chen, H.; Mondal, A.; Wedi, P.; van Gemmeren, M. Dual Ligand-Enabled Nondirected C–H Cyanation of Arenes. ACS Catal. 2019, 9, 1979– 1984,  DOI: 10.1021/acscatal.8b04639
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      21b
      Dual Ligand-Enabled Nondirected C-H Cyanation of Arenes
      Chen, Hao; Mondal, Arup; Wedi, Philipp; van Gemmeren, Manuel
      ACS Catalysis (2019), 9 (3), 1979-1984CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      Arom. nitriles are key structural units in org. chem. and, therefore, highly attractive targets for C-H activation. Herein, the development of an arene-limited, nondirected C-H cyanation based on the use of two cooperatively acting com. available ligands is reported. The reaction enables the cyanation of arenes by C-H activation in the absence of directing groups and is therefore complementary to established approaches.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlChtbY%253D&md5=4c1c3123572388727dea895b967045cd
      .
      (c) Mondal, A.; Chen, H.; Flämig, L.; Wedi, P.; van Gemmeren, M. Sterically Controlled Late-Stage C–H Alkynylation of Arenes. J. Am. Chem. Soc. 2019, 141, 18662– 18667,  DOI: 10.1021/jacs.9b10868
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      21c
      Sterically Controlled Late-Stage C-H Alkynylation of Arenes
      Mondal, Arup; Chen, Hao; Flaemig, Lea; Wedi, Philipp; van Gemmeren, Manuel
      Journal of the American Chemical Society (2019), 141 (47), 18662-18667CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Herein, a complementary approach based on an arene-limited nondirected C-H activation is presented. The reaction is predominantly controlled by steric rather than electronic factors and thereby gives access to a complementary product spectrum with respect to traditional methods. A broad scope as well as the suitability of this protocol for late-stage functionalization are demonstrated.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFGjtL7M&md5=a0fb0441a7eda517bbafcd2a6d04e401
      .
      (d) Chen, H.; Farizyan, M.; Ghiringhelli, F.; van Gemmeren, M. Sterically Controlled C–H Olefination of Heteroarenes. Angew. Chem., Int. Ed. 2020, 59, 12213– 12220,  DOI: 10.1002/anie.202004521
      [Crossref], [CAS], Google Scholar
      21d
      Sterically Controlled C-H Olefination of Heteroarenes
      Chen, Hao; Farizyan, Mirxan; Ghiringhelli, Francesca; van Gemmeren, Manuel
      Angewandte Chemie, International Edition (2020), 59 (29), 12213-12220CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The regioselective functionalization of heteroarenes is a highly attractive synthetic target due to the prevalence of multiply substituted heteroarenes in nature and bioactive compds. Some substitution patterns remain challenging: While highly efficient methods for the C2-selective olefination of 3-substituted five-membered heteroarenes are reported, analogous methods to access the 5-olefinated products have remained limited by poor regioselectivities and/or the requirement to use an excess of the valuable heteroarene starting material. Herein the authors report a sterically controlled C-H olefination using heteroarenes as the limiting reagent. The method enables the highly C5-selective olefination of a wide range of heteroarenes and is useful in the context of late-stage functionalization.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpsFeqsb0%253D&md5=08ef07201918e838fa6328ccc04535d9
      .
      (e) Mondal, A.; van Gemmeren, M. Catalyst-Controlled Regiodivergent C–H Alkynylation of Thiophenes. Angew. Chem., Int. Ed. 2021, 60, 742– 746,  DOI: 10.1002/anie.202012103
      [Crossref], [CAS], Google Scholar
      21e
      Catalyst-Controlled Regiodivergent C-H Alkynylation of Thiophenes
      Mondal, Arup; van Gemmeren, Manuel
      Angewandte Chemie, International Edition (2021), 60 (2), 742-746CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Alkynes are highly attractive motifs in org. synthesis due to their presence in natural products and bioactive mols. as well as their versatility in a plethora of subsequent transformations. A common procedure to insert alkynes into (hetero)arenes, such as the thiophenes studied herein, consists of a halogenation followed by a Sonogashira cross-coupling. The regioselectivity of this approach depends entirely on the halogenation step. Similarly, direct alkynylations of thiophenes were described that follow the same regioselectivity patterns. Herein the authors report the development of a palladium catalyzed C-H activation/alkynylation of thiophenes. The method is applicable to a broad range of thiophene substrates. For 3-substituted substrates where controlling the regioselectivity between the C2 and C5 position is particularly challenging, two sets of reaction conditions enable a regiodivergent reaction, giving access to each regioisomer selectively. Both protocols use the thiophene as limiting reagent and show a broad scope, rendering the authors' method suitable for late-stage modification.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit12htLrM&md5=bb7cdf1279b1d70d6e59593962a6ddc5
      .
      (f) Santiago, C.; Chen, H.; Mondal, A.; van Gemmeren, M. Dual Ligand-Enabled Late-Stage Fujiwara–Moritani Reactions. Synlett 2021,  DOI: 10.1055/s-0040-1706014
      [Crossref], Google Scholar
      There is no corresponding record for this reference.
    22. 22

      For selected examples of arene-limited nondirected C–H activations with palladium catalysts, see:

      (a) Wang, P.; Verma, P.; Xia, G.; Shi, J.; Qiao, J. X.; Tao, S.; Cheng, P. T. W.; Poss, M. A.; Farmer, M. E.; Yeung, K.-S.; Yu, J.-Q. Ligand-accelerated non-directed C–H functionalization of arenes. Nature 2017, 551, 489– 493,  DOI: 10.1038/nature24632
      [Crossref], [PubMed], [CAS], Google Scholar
      22a
      Ligand-accelerated non-directed C-H functionalization of arenes
      Wang, Peng; Verma, Pritha; Xia, Guoqin; Shi, Jun; Qiao, Jennifer X.; Tao, Shiwei; Cheng, Peter T. W.; Poss, Michael A.; Farmer, Marcus E.; Yeung, Kap-Sun; Yu, Jin-Quan
      Nature (London, United Kingdom) (2017), 551 (7681), 489-493CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
      The directed activation of carbon-hydrogen bonds (C-H) is important in the development of synthetically useful reactions, owing to the proximity-induced reactivity and selectivity that is enabled by coordinating functional groups. Palladium-catalyzed non-directed C-H activation could potentially enable further useful reactions, because it can reach more distant sites and be applied to substrates that do not contain appropriate directing groups; however, its development has faced substantial challenges assocd. with the lack of sufficiently active palladium catalysts. Currently used palladium catalysts are reactive only with electron-rich arenes, unless an excess of arene is used, which limits synthetic applications. Here we report a 2-pyridone ligand that binds to palladium and accelerates non-directed C-H functionalization with arene as the limiting reagent. This protocol is compatible with a broad range of arom. substrates and we demonstrate direct functionalization of advanced synthetic intermediates, drug mols. and natural products that cannot be used in excessive quantities. We also developed C-H olefination and carboxylation protocols, demonstrating the applicability of our methodol. to other transformations. The site selectivity in these transformations is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C-H functionalization.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVKqtb%252FF&md5=0e2e4a01e016ca4fdee2dd3b82b2dcf9
      .
      (b) Naksomboon, K.; Valderas, C.; Gómez-Martínez, M.; Álvarez-Casao, Y.; Fernández-Ibáñez, M. Á. S. O-Ligand-Promoted Palladium-Catalyzed C–H Functionalization Reactions of Nondirected Arenes. ACS Catal. 2017, 7, 6342– 6346,  DOI: 10.1021/acscatal.7b02356
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      22b
      S,O-Ligand-Promoted Palladium-Catalyzed C-H Functionalization Reactions of Nondirected Arenes
      Naksomboon, Kananat; Valderas, Carolina; Gomez-Martinez, Melania; Alvarez-Casao, Yolanda; Fernandez-Ibanez, M. Angeles
      ACS Catalysis (2017), 7 (9), 6342-6346CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      Pd(II)-catalyzed C-H functionalization of nondirected arenes has been realized using an inexpensive and easily accessible type of bidentate S,O-ligand. The catalytic system shows high efficiency in the C-H olefination reaction of electron-rich and electron-poor arenes. This methodol. is operationally simple, scalable, and can be used in late-stage functionalization of complex mols. The broad applicability of this catalyst has been showcased in other transformations such as Pd(II)-catalyzed C-H acetoxylation and allylation reactions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlKhtbrE&md5=777190e5ff159903eeb9dce1ecff2486
      .
      (c) Naksomboon, K.; Poater, J.; Bickelhaupt, F. M.; Fernández-Ibáñez, M. Á. para-Selective C–H Olefination of Aniline Derivatives via Pd/S,O-Ligand Catalysis. J. Am. Chem. Soc. 2019, 141, 6719– 6725,  DOI: 10.1021/jacs.9b01908
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      22c
      para-Selective C-H Olefination of Aniline Derivatives via Pd/S,O-Ligand Catalysis
      Naksomboon, Kananat; Poater, Jordi; Bickelhaupt, F. Matthias; Fernandez-Ibanez, M. Angeles
      Journal of the American Chemical Society (2019), 141 (16), 6719-6725CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Herein we report a highly para-selective C-H olefination of aniline derivs. by a Pd/S,O-ligand-based catalyst. The reaction proceeds under mild reaction conditions with high efficiency and broad substrate scope, including mono-, di-, and trisubstituted tertiary, secondary, and primary anilines. The S,O-ligand is responsible for the dramatic improvements in substrate scope and the high para-selectivity obsd. This methodol. is operationally simple, scalable, and can be performed under aerobic conditions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmt1Olt78%253D&md5=fae7d273161877fa52525fe5973afd98
      .
      (d) Zhao, Da; Xu, P.; Ritter, T. Palladium-Catalyzed Late-Stage Direct Arene Cyanation. Chem. 2019, 5, 97– 107,  DOI: 10.1016/j.chempr.2018.09.027
      [Crossref], [CAS], Google Scholar
      22d
      Palladium-Catalyzed Late-Stage Direct Arene Cyanation
      Zhao, Da; Xu, Peng; Ritter, Tobias
      Chem (2019), 5 (1), 97-107CODEN: CHEMVE; ISSN:2451-9294. (Cell Press)
      The first general late-stage aryl C-H cyanation with broad substrate scope and functional-group tolerance was reported. The reaction was enabled by a dual-ligand combination of quinoxaline and an amino acid-derived ligand. The method was applicable to direct cyanation of several marketed small-mol. drugs, common pharmacophores and org. dyes.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFSgs7Y%253D&md5=e8fcabf4edda48542ae8619ea53d799f
      .
      (e) Liu, L.-Y.; Yeung, K.-S.; Yu, J.-Q. Ligand-Promoted Non-Directed C–H Cyanation of Arenes. Chem. - Eur. J. 2019, 25, 2199– 2202,  DOI: 10.1002/chem.201805772
      [Crossref], [PubMed], [CAS], Google Scholar
      22e
      Ligand-Promoted Non-Directed C-H Cyanation of Arenes
      Liu, Luo-Yan; Yeung, Kap-Sun; Yu, Jin-Quan
      Chemistry - A European Journal (2019), 25 (9), 2199-2202CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The first example of a 2-pyridone accelerated non-directed C-H cyanation with an arene as the limiting reagent was reported. This protocol was compatible with a broad scope of arenes, including advanced intermediates, drug mols. and natural products. A kinetic isotope expt. (kH/kD=4.40) indicated that the C-H bond cleavage is the rate-limiting step. Also, the reaction is readily scalable, further showcasing the synthetic utility of this method.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVKqtr0%253D&md5=48dc42d76a9bf2a181434f9446863e48
      .
      (f) Liu, L.-Y.; Qiao, J. X.; Yeung, K.-S.; Ewing, W. R.; Yu, J.-Q. meta-Selective C–H Arylation of Fluoroarenes and Simple Arenes. Angew. Chem., Int. Ed. 2020, 59, 13831– 13835,  DOI: 10.1002/anie.202002865
      [Crossref], [CAS], Google Scholar
      22f
      meta-Selective C-H Arylation of Fluoroarenes and Simple Arenes
      Liu, Luo-Yan; Qiao, Jennifer X.; Yeung, Kap-Sun; Ewing, William R.; Yu, Jin-Quan
      Angewandte Chemie, International Edition (2020), 59 (33), 13831-13835CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Fluorine is known to promote ortho-C-H metalation. Based upon this reactivity, we employed an activated norbornene that traps the ortho-palladation intermediate and is then relayed to the meta position, leading to meta-selective C-H arylation of fluoroarenes. Deuterium expt. suggests that this meta-arylation is initiated by ortho C-H activation and the catalytic cycle is terminated by C-2 protonation. A dual-ligand system is crucial for the obsd. high reactivity and site selectivity. Applying this approach to simple benzene or other arenes also affords arylation products with good yield and site selectivity.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlGmsLbE&md5=949197fc4ceec310bf56d8e9f0106f8c
      .
      (g) Dhankhar, J.; González-Fernández, E.; Dong, C.-C.; Mukhopadhyay, T. K.; Linden, A.; Čorić, I. Spatial Anion Control on Palladium for Mild C-H Arylation of Arenes. J. Am. Chem. Soc. 2020, 142, 19040– 19046,  DOI: 10.1021/jacs.0c09611
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      22g
      Spatial Anion Control on Palladium for Mild C-H Arylation of Arenes
      Dhankhar, Jyoti; Gonzalez-Fernandez, Elisa; Dong, Chao-Chen; Mukhopadhyay, Tufan K.; Linden, Anthony; Coric, Ilija
      Journal of the American Chemical Society (2020), 142 (45), 19040-19046CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      C-H arylation of arenes without the use of directing groups is a challenge, even for simple mols., such as benzene. We describe spatial anion control as a concept for the design of catalytic sites for C-H bond activation, thereby enabling nondirected C-H arylation of arenes at ambient temp. The mild conditions enable late-stage structural diversification of biol. relevant small mols., and site-selectivity complementary to that obtained with other methods of arene functionalization can be achieved. These results reveal the potential of spatial anion control in transition-metal catalysis for the functionalization of C-H bonds under mild conditions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitF2iu77I&md5=8d9b9d70e7300d188d0eee474cfa9c88
      .
      (h) Yin, B.; Fu, M.; Wang, L.; Liu, J.; Zhu, Q. Dual ligand-promoted palladium-catalyzed nondirected C–H alkenylation of aryl ethers. Chem. Commun. 2020, 56, 3293– 3296,  DOI: 10.1039/D0CC00940G
      [Crossref], [PubMed], [CAS], Google Scholar
      22h
      Dual ligand-promoted palladium-catalyzed nondirected C-H alkenylation of aryl ethers
      Yin, Biao; Fu, Manlin; Wang, Lei; Liu, Jiang; Zhu, Qing
      Chemical Communications (Cambridge, United Kingdom) (2020), 56 (22), 3293-3296CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      Herein, a novel strategy for nondirected C-H alkenylation of alkyl aryl ethers (anisole, phenetole, Pr Ph ether, Bu Ph ether and benzyl Ph ether), cyclic aryl ethers (1,4-benzodioxane, 2,3-dihydrobenzofuran, dibenzofuran), and di-Ph oxide promoted by a dual ligand catalyst was demonstrated. This catalytic system readily achieved the highly efficient alkenylation of aryl ethers. Moreover, the proposed methodol. was successfully employed for the late-stage modification of complex drugs contg. the aryl ether motif. Interestingly, the compds. developed herein displayed fluorescent properties, which would facilitate their biol. applications.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlt1SksL4%253D&md5=47bb743a05a6d570437d5422d60178bc
    23. 23
      Wedi, P.; Farizyan, M.; Bergander, K.; Mück-Lichtenfeld, C.; van Gemmeren, M. Mechanism of the Arene-Limited Nondirected C–H Activation of Arenes with Palladium. Angew. Chem., Int. Ed. 2021, 60, 15641– 15649,  DOI: 10.1002/anie.202105092
      [Crossref], [CAS], Google Scholar
      23
      Mechanism of the Arene-Limited Nondirected C-H Activation of Arenes with Palladium
      Wedi, Philipp; Farizyan, Mirxan; Bergander, Klaus; Mueck-Lichtenfeld, Christian; van Gemmeren, Manuel
      Angewandte Chemie, International Edition (2021), 60 (28), 15641-15649CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Recently palladium catalysts have been discovered that enable the directing-group-free C-H activation of arenes without requiring an excess of the arene substrate, thereby enabling methods for the late-stage modification of complex org. mols. The key to success has been the use of two complementary ligands, an N-acyl amino acid and an N-heterocycle. Detailed exptl. and computational mechanistic studies on the dual-ligand-enabled C-H activation of arenes have led us to identify the catalytically active species and a transition state model that explains the exceptional activity and selectivity of these catalysts. These findings are expected to be highly useful for further method development using this powerful class of catalysts.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsVKmtb7L&md5=97dec3ebe74490b094ef215167e6c4f0
    24. 24
      The initial optimization studies were conducted using the reverse dedeuteration with deuterated HFIP-benzoate [D]1 as a model substrate. See:Uttry, A.; Mal, S.; van Gemmeren, M. Late-Stage β-C(sp3)–H Deuteration of Carboxylic Acids. J. Am. Chem. Soc. 2021, 143, 10895– 10901,  DOI: 10.1021/jacs.1c06474
      [ACS Full Text ACS Full Text], [CAS], Google Scholar
      24
      Late-Stageβ-C(sp3)-H Deuteration of Carboxylic Acids
      Uttry, Alexander; Mal, Sourjya; van Gemmeren, Manuel
      Journal of the American Chemical Society (2021), 143 (29), 10895-10901CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      In this study, the late-stage β-C(sp3)-H deuteration of free carboxylic acids was described. On the basis of the finding that C-H activation with catalysts was reversible, the de-deuteration process was first optimized. The resulting method used ethylenediamine-based ligands and could be used to achieve the desired deuteration when using a deuterated solvent. The reported method allowed for the functionalization of a wide range of free carboxylic acids with diverse substitution patterns, as well as the late-stage deuteration of bioactive mols. and related frameworks and enables the functionalization of nonactivated methylene β-C(sp3)-H bonds for the first time.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhs1WmtbvL&md5=05d377aac5516de2d0abcb0a576a146b

      See the SI for details.

  • Supporting Information

    Supporting Information

    ARTICLE SECTIONS
    Jump To

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.1c08233.

    • Optimization of the reaction conditions, preparative procedures, and analytical data for the compounds (PDF)


    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

PDF [ 2MB]

Pair your accounts.

Export articles to Mendeley

Get article