Photocatalytic Hydroaminoalkylation of Styrenes with Unprotected Primary AlkylaminesClick to copy article linkArticle link copied!
- Hannah E. AskeyHannah E. AskeyDepartment of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.More by Hannah E. Askey
- James D. GraysonJames D. GraysonDepartment of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.More by James D. Grayson
- Joshua D. TibbettsJoshua D. TibbettsDepartment of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.More by Joshua D. Tibbetts
- Jacob C. Turner-DoreJacob C. Turner-DoreDepartment of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.More by Jacob C. Turner-Dore
- Jake M. HolmesJake M. HolmesDepartment of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.More by Jake M. Holmes
- Gabriele Kociok-KohnGabriele Kociok-KohnMaterials and Chemical Characterisation Facility (MC2), University of Bath, Claverton Down, Bath BA2 7AY, U.K.More by Gabriele Kociok-Kohn
- Gail L. WrigleyGail L. WrigleyOncology R&D, Research & Early Development, AstraZeneca, Darwin Building, 310, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.More by Gail L. Wrigley
- Alexander J. Cresswell*Alexander J. Cresswell*[email protected]Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.More by Alexander J. Cresswell
Abstract
Catalytic, intermolecular hydroaminoalkylation (HAA) of styrenes provides a powerful disconnection for pharmacologically relevant γ-arylamines, but current methods cannot utilize unprotected primary alkylamines as feedstocks. Metal-catalyzed HAA protocols are also highly sensitive to α-substitution on the amine partner, and no catalytic solutions exist for α-tertiary γ-arylamine synthesis via this approach. We report a solution to these problems using organophotoredox catalysis, enabling a direct, modular, and sustainable preparation of α-(di)substituted γ-arylamines, including challenging electron-neutral and moderately electron-rich aryl groups. A broad range of functionalities are tolerated, and the reactions can be run on multigram scale in continuous flow. The method is applied to a concise, protecting-group-free synthesis of the blockbuster drug Fingolimod, as well as a phosphonate mimic of its in vivo active form (by iterative α-C–H functionalization of ethanolamine). The reaction can also be sequenced with an intramolecular N-arylation to provide a general and modular access to valuable (spirocyclic) 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydronaphthyridines. Mechanistic and kinetic studies support an irreversible hydrogen atom transfer activation of the alkylamine by the azidyl radical and some contribution from a radical chain. The reaction is photon-limited and exhibits a zero-order dependence on amine, azide, and photocatalyst, with a first-order dependence on styrene.
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Introduction
Figure 1
Figure 1. (A) Prior art for catalytic γ-lactam synthesis from primary alkylamines. (B) Importance of γ-arylamines. (C) This work.
Results and Discussion
Reaction Optimization
Figure 2
Amine Scope
Figure 3
Figure 3. All reactions were carried out on a scale of 0.45 mmol. Isolated yields are reported. Notes: [a] 6% of inseparable, dialkylated product (wrt 1c). [b] With 3.0 equiv of amine. [c] With 1.0 equiv of amine. [d] The mass balance comprised a mixture of unidentified byproducts but no detectable starting materials. [e] 44% of unreacted amine 1l. [f] 46% of dialkylated product (wrt 1n). [g] 41% of dialkylated product (wrt 1s). [h] 54% of unreacted amine 1t and 6% styrene 6c. [i] 9% of dialkylated product (wrt 1u). [j] 9% of dialkylated product (wrt 1u). [k] Incomplete conversion to a complex mixture of products, which may include dialkylated material. [l] Isolated yield of Boc-protected 7zc (61:39 dr) plus 11% of the lactam derived from thermal lactamization of 7zc during workup. [m] 18% of dialkylated product (wrt 6c). [n] Incomplete conversion to a complex mixture of products. Boc = tert-butoxycarbonyl.
Scale Up in Continuous Flow
Styrene Scope
Figure 4
Figure 4. All reactions were carried out on a scale of 0.45 mmol. Isolated yields are reported. Notes: [a] Gave 40% NMR yield of 7ae along with 24% unreacted 6e and 6% of allylbenzene, plus other unidentified products. [b] Isolated as the phenol by oxidation the Bpin group with H2O2. [c] 22% of inseparable, debrominated product was also produced. [d] Yield given is for the N-Boc-protected derivative of 7ar, which proved easier to isolate. [e] 9% of a 1:2 telomer and 43% (wrt 6r) of reductive homocoupling product 1,4-di(pyrazin-2-yl)butane was also isolated. [f] The crude product mixture contained a 60:40 ratio of 7as to its debrominated analogue.
Synthesis of Fingolimod
Figure 5
Figure 5. (A) Application to a protecting group-free synthesis of Fingolimod (4). (B) One-pot synthesis of a phosphonate mimic (21) of Fingolimod phosphate by tandem sequential α-C–H alkylation of ethanolamine (1r). Note: [a] 23% of the dialkylation product of 1r with 17 was also isolated. TMS = trimethylsilyl.
Synthesis of 1,2,3,4-Tetrahydroquinolines
Figure 6
Figure 6. (A) Modular synthesis of 1,2,3,4-tetrahydroquinolines (THQs). In all cases except for 8an, the remaining mass balance comprised unreacted starting material. Note: [a] Obtained as an inseparable mixture with 8ac (14%), the proto-dechlorinated analogue of 8an. (B) Modular synthesis of 1,2,3,4-tetrahydronaphthyridines (THNs).
Proposed Catalytic Cycle and Mechanistic Analysis
Figure 7
Figure 7. (A) Proposed catalytic cycle. (B) Stern–Volmer luminescence quenching. (C) Irreversibility of the HAT step. (D) Variable time normalization (VTNA) kinetic analysis using automated flow chemistry.
Conclusion
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.1c07401.
All experimental procedures and compound characterization (PDF)
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Acknowledgments
This work was supported by the Engineering and Physical Sciences Research Council (EP/S028595/1 and EP/R020752/1). A.J.C. thanks the Royal Society for a University Research Fellowship (UF150533), the University of Bath for a Ph.D. studentship (H.E.A.), the EPSRC and Syngenta for an iCASE PhD studentship (J.C.T.-D.), and AstraZeneca for generous financial support. The authors gratefully acknowledge the technical staff within Chemistry at the University of Bath for technical support and assistance in this work, including the Material and Chemical Characterisation Facility (MC2) (https://doi.org/10.15125/mx6j-3r54). We also acknowledge valuable discussions with Dr. Darren Stead at AstraZeneca and thank Freddy Sweeten for assistance with starting material synthesis.
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- 3(a) Manßen, M.; Schafer, L. L. Early Transition Metal-Catalyzed Hydroaminoalkylation. Trends Chem. 2021, 3, 428– 429, DOI: 10.1016/j.trechm.2020.11.007Google Scholar3aEarly Transition Metal-Catalyzed HydroaminoalkylationManssen, Manfred; Schafer, Laurel L.Trends in Chemistry (2021), 3 (5), 428-429CODEN: TCRHBQ; ISSN:2589-5974. (Cell Press)There is no expanded citation for this reference.(b) Trowbridge, A.; Walton, S. M.; Gaunt, M. J. New Strategies for the Transition-Metal Catalyzed Synthesis of Aliphatic Amines. Chem. Rev. 2020, 120, 2613– 2692, DOI: 10.1021/acs.chemrev.9b00462Google Scholar3bNew Strategies for the Transition-Metal Catalyzed Synthesis of Aliphatic AminesTrowbridge, Aaron; Walton, Scarlett M.; Gaunt, Matthew J.Chemical Reviews (Washington, DC, United States) (2020), 120 (5), 2613-2692CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. In light of the ever-increasing importance of aliph. amines across the range of chem. sciences, this review aims to provide a concise overview of modern transition-metal catalyzed approaches to alkylamine synthesis and their functionalization. Selected examples of amine bond forming reactions include, hydroamination and hydroaminoalkylation, transition-metal catalyzed C(sp3)-H functionalization and transition-metal catalyzed visible-light-mediated light photoredox catalysis.(c) Edwards, P. M.; Schafer, L. L. Early transition metal-catalyzed C–H alkylation: hydroaminoalkylation for Csp3–Csp3 bond-formation in the synthesis of selectively substituted amines. Chem. Commun. 2018, 54, 12543– 12560, DOI: 10.1039/C8CC06445HGoogle Scholar3cEarly transition metal-catalyzed C-H alkylation: hydroaminoalkylation for Csp3-Csp3 bond formation in the synthesis of selectively substituted aminesEdwards, P. M.; Schafer, L. L.Chemical Communications (Cambridge, United Kingdom) (2018), 54 (89), 12543-12560CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review. In this feature article, various selectively substituted amines that can be accessed by hydroaminoalkylation, with a special focus on the development of early transition metal catalysts for their rapid, step and atom efficient assembly were discussed.
- 4(a) Manßen, M.; Deng, D.; Zheng, C. H. M.; DiPucchio, R. C.; Chen, D.; Schafer, L. L. Ureate Titanium Catalysts for Hydroaminoalkylation: Using Ligand Design to Increase Reactivity and Utility. ACS Catal. 2021, 11, 4550– 4560, DOI: 10.1021/acscatal.1c00014Google Scholar4aUreate Titanium Catalysts for Hydroaminoalkylation: Using Ligand Design to Increase Reactivity and UtilityManssen, Manfred; Deng, Danfeng; Zheng, Cameron H. M.; DiPucchio, Rebecca C.; Chen, Dafa; Schafer, Laurel L.ACS Catalysis (2021), 11 (8), 4550-4560CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)Herein, an earth-abundant and cost-efficient titanium catalyst generated in situ using com. available Ti(NMe2)4 and a simple to synthesize urea proligand was described. This system demonstrated high TOFs for hydroaminoalkylation with unactivated substrates and features easy to use com. available titanium amido precursors. Addnl., a high catalytic activity, scope of reactivity, and regioselectivity were all demonstrated in the transformation of unactivated terminal olefins with various alkyl and aryl secondary amines. Finally, syntheses of useful amine-contg. monomers suitable for the generation of amine-contg. materials, as well as amine-contg. building blocks for medicinal chem., were disclosed. These preparative methods avoid the necessity of glovebox techniques and were modified to be useful to all synthetic chemists.(b) Koperniku, A.; Schafer, L. L. Zirconium Catalyzed Hydroaminoalkylation for the Synthesis of α-Arylated Amines and N-Heterocycles. Chem. - Eur. J. 2021, 27, 6334– 6339, DOI: 10.1002/chem.202100014Google Scholar4bZirconium Catalyzed Hydroaminoalkylation for the Synthesis of α-Arylated Amines and N-HeterocyclesKoperniku, Ana; Schafer, Laurel L.Chemistry - A European Journal (2021), 27 (20), 6334-6339CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)The zirconium catalyzed hydroaminoalkylation of alkenes with N-aryl- and sterically demanding N-alkyl-α-arylated secondary amines by using com. available Zr(NMe2)4 is reported. N-phenyl- and N-isopropylbenzylamine are used as amine substrates to establish the alkene substrate scope. Exclusively linear products are obtained in the presence of bulky vinylsilanes. Challenging α-heteroarylated amines and functionalized alkene substrates are compatible with this easy to use catalyst, affording a new disconnection strategy for the atom- and step-economic prepn. of selectively substituted satd. α-arylated heterocycles.(c) Daneshmand, P.; Roşca, S.-C.; Dalhoff, R.; Yin, K.; DiPucchio, R. C.; Ivanovich, R. A.; Polat, D. E.; Beauchemin, A. M.; Schafer, L. L. Cyclic Ureate Tantalum Catalyst for Preferential Hydroaminoalkylation with Aliphatic Amines: Mechanistic Insights into Substrate Controlled Reactivity. J. Am. Chem. Soc. 2020, 142, 15740– 15750, DOI: 10.1021/jacs.0c04579Google Scholar4cCyclic Ureate Tantalum Catalyst for Preferential Hydroaminoalkylation with Aliphatic Amines: Mechanistic Insights into Substrate Controlled ReactivityDaneshmand, Pargol; Rosca, Sorin-Claudiu; Dalhoff, Rosalie; Yin, Kejun; DiPucchio, Rebecca C.; Ivanovich, Ryan A.; Polat, Dilan E.; Beauchemin, Andre M.; Schafer, Laurel L.Journal of the American Chemical Society (2020), 142 (37), 15740-15750CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The efficient and catalytic amination of unactivated alkenes with simple secondary alkyl amines is preferentially achieved. A sterically accessible, N,O-chelated cyclic ureate tantalum catalyst was prepd. and characterized by X-ray crystallog. This optimized catalyst can be used for the hydroaminoalkylation of 1-octene with a variety of aryl and alkyl amines, but notably enhanced catalytic activity can be realized with challenging N-alkyl secondary amine substrates. This catalyst offers turnover frequencies of up to 60 h-1, affording full conversion at 5 mol% catalyst loading in approx. 20 min with these nucleophilic amines. Mechanistic investigations, including kinetic isotope effect (KIE) studies, reveal that catalytic turnover is limited by protonolysis of the intermediate 5-membered azametallacycle. A Hammett kinetic anal. shows that catalytic turnover is promoted by electron rich amine substrates that enable catalytic turnover. This more active catalyst is shown to be effective for late stage drug modification.(d) Bielefeld, J.; Doye, S. Fast Titanium-Catalyzed Hydroaminomethylation of Alkenes and the Formal Conversion of Methylamine. Angew. Chem., Int. Ed. 2020, 59, 6138– 6143, DOI: 10.1002/anie.202001111Google Scholar4dFast Titanium-Catalyzed Hydroaminomethylation of Alkenes and the Formal Conversion of MethylamineBielefeld, Jens; Doye, SvenAngewandte Chemie, International Edition (2020), 59 (15), 6138-6143CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The scientific interest in catalytic hydroaminoalkylation reactions of alkenes has vastly increased over the past decade, but these reactions have struggled to become a viable option for general lab. or industrial use because of reaction times of several days. The titanium-based catalytic system introduced in this work not only reduces the reaction time by several orders of magnitude, into the range of minutes, but the catalyst also is easily available from common starting materials, at a cost of ∼1 euro per mmol of catalyst. The authors were also able to formally perform C-H activation of methylamine and achieve coupling to a broad variety of alkenes, through silyl protection of the amine and simple deprotection by water.(e) Warsitz, M.; Doye, S. Linear Hydroaminoalkylation Products from Alkyl-Substituted Alkenes. Chem. - Eur. J. 2020, 26, 15121– 15125, DOI: 10.1002/chem.202003223Google Scholar4eLinear Hydroaminoalkylation Products from Alkyl-Substituted AlkenesWarsitz, Michael; Doye, SvenChemistry - A European Journal (2020), 26 (66), 15121-15125CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)A new one-pot procedure that includes an initial alkene hydroaminoalkylation with an α-silylated amine substrate and a subsequent protodesilylation reaction that delivers linear hydroaminoalkylation products with high selectivity from simple alkyl-substituted alkenes was presented. For that purpose, new titanium catalysts were developed, which are able to activate the α-C-H bond of more challenging α-silylated amine substrates. In addn., a direct relationship between the ligand structure of the new catalysts and the obtained regioselectivity was described.
- 5Geik, D.; Rosien, M.; Bielefeld, J.; Schmidtmann, M.; Doye, S. Titanium-Catalyzed Intermolecular Hydroaminoalkylation of Alkenes with Tertiary Amines. Angew. Chem., Int. Ed. 2021, 60, 9936– 9940, DOI: 10.1002/anie.202100431Google Scholar5Titanium-Catalyzed Intermolecular Hydroaminoalkylation of Alkenes with Tertiary AminesGeik, Dennis; Rosien, Michael; Bielefeld, Jens; Schmidtmann, Marc; Doye, SvenAngewandte Chemie, International Edition (2021), 60 (18), 9936-9940CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The first cationic titanium catalyst system for the intermol. hydroaminoalkylation of alkenes with various tertiary alkylamines is presented. Corresponding reactions which involve the addn. of the α-C-H bond of a tertiary amine across the C-C double bond of an alkene take place at temps. close to room temp. with excellent regioselectivity to deliver the branched products exclusively. Interestingly, for selected amines, α-C-H bond activation occurs not only at N-Me but also at N-methylene groups.
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We use this term to refer to alkenes that do not readily participate as Michael acceptors in polar reactions with two-electron nucleophiles (e.g., non-conjugated alkenes, styrenes lacking π-acceptor substituents).
There is no corresponding record for this reference. - 7(a) Verma, P.; Richter, J. M.; Chekshin, N.; Qiao, J. X.; Yu, J.-Q. Iridium(I)-Catalyzed α-C(sp3)–H Alkylation of Saturated Azacycles. J. Am. Chem. Soc. 2020, 142, 5117– 5125, DOI: 10.1021/jacs.9b12320Google Scholar7aIridium(I)-Catalyzed α-C(sp3)-H Alkylation of Saturated AzacyclesVerma, Pritha; Richter, Jeremy M.; Chekshin, Nikita; Qiao, Jennifer X.; Yu, Jin-QuanJournal of the American Chemical Society (2020), 142 (11), 5117-5125CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Satd. azacycles are commonly encountered in bioactive compds. and approved therapeutic agents. The development of methods for functionalization of the α-methylene C-H bonds of these highly privileged building blocks is of great importance, esp. in drug discovery. While much effort has been dedicated towards this goal of using a directed C-H activation approach, the development of directing groups that are both general, as well as practical, remains a significant challenge. Herein, the design and development of novel amidoxime directing groups is described for Ir(I)-catalyzed α-C(sp3)-H alkylation of satd. azacycles using readily available olefins as coupling partners. This protocol extends the scope of satd. azacycles to piperidines, azepane, and tetrahydroisoquinoline that are incompatible with our previously reported directing group. A variety of olefin coupling partners, including previously unreactive di-substituted terminal olefins and internal olefins, are compatible with this transformation. The selectivity for a branched α-C(sp3)-alkylation product is also obsd. for the first time when acrylate is used as the reaction partner. The development of practical, one-step installation and removal protocols further add to the utility of amidoxime directing groups.(b) Tran, A. T.; Yu, J.-Q. Practical Alkoxythiocarbonyl Auxiliaries for Iridium(I)-Catalyzed C–H Alkylation of Azacycles. Angew. Chem., Int. Ed. 2017, 56, 10530– 10534, DOI: 10.1002/anie.201704755Google Scholar7bPractical Alkoxythiocarbonyl Auxiliaries for Iridium(I)-Catalyzed C-H Alkylation of AzacyclesTran, Anh T.; Yu, Jin-QuanAngewandte Chemie, International Edition (2017), 56 (35), 10530-10534CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The development of new and practical alkylated 3-pentoxythiocarbonyl auxiliaries, e.g., I for Ir(I)-catalyzed C-H alkylation of azacycles was described. This method allowed for the α-C-H alkylation of a variety of substituted pyrrolidines, piperidines and tetrahydroisoquinolines through alkylation with alkenes. While the practicality of these simple carbamate-type auxiliaries was underscored by the ease of installation and removal, the method's utility was demonstrated in its ability to functionalize biol. relevant L-proline and L-trans-hydroxyproline, delivering unique 2,5-dialkylated amino acid analogs that were not accessible by other C-H functionalization methods.(c) Lahm, G.; Opatz, T. Unique Regioselectivity in the C(sp3)–H α-Alkylation of Amines: The Benzoxazole Moiety as a Removable Directing Group. Org. Lett. 2014, 16, 4201– 4203, DOI: 10.1021/ol501935dGoogle Scholar7cUnique Regioselectivity in the C(sp3)-H α-Alkylation of Amines: The Benzoxazole Moiety as a Removable Directing GroupLahm, Guenther; Opatz, TillOrganic Letters (2014), 16 (16), 4201-4203CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)The benzoxazol-2-yl- substituent was found to act as a removable activating and directing group in the Ir-catalyzed alkylation of C(sp3)-H bonds adjacent to nitrogen in secondary amines. It can be easily introduced by oxidative coupling or by an SNAr reaction, and it can be removed by hydroxide or by hydride redn. For 1,2,3,4-tetrahydroisoquinolines, activation exclusively takes place in the 3-position. A variety of activated as well as unactivated terminal olefins are suitable reaction partners.(d) Schinkel, M.; Wang, L.; Bielefeld, K.; Ackermann, L. Ruthenium(II)-Catalyzed C(sp3)–H α-Alkylation of Pyrrolidines. Org. Lett. 2014, 16, 1876– 1879, DOI: 10.1021/ol500300wGoogle Scholar7dRuthenium(II)-Catalyzed C(sp3)-H α-Alkylation of PyrrolidinesSchinkel, Marvin; Wang, Lianhui; Bielefeld, Kris; Ackermann, LutzOrganic Letters (2014), 16 (7), 1876-1879CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A catalytic system comprising [RuCl2(PPh3)3], AgOTf, and BINAP enabled atom- and step-economical addns. of C(sp3)-H bonds onto unactivated alkenes under comparably mild reaction conditions. The pyridyl directing group was easily removed to furnish the corresponding (NH)-free amines with ample scope.
- 8Visible light photocatalysis in organic chemistry; Stephenson, C. R. J., Yoon, T., MacMillan, D. W. C., Eds.; Wiley-VCH: Berlin, 2018.Google ScholarThere is no corresponding record for this reference.
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Selected examples:
(a) Zhao, H.; Leonori, D. Minimization of Back-Electron Transfer Enables the Elusive sp3 C–H Functionalization of Secondary Anilines. Angew. Chem., Int. Ed. 2021, 60, 7669– 7674, DOI: 10.1002/anie.202100051Google Scholar9aMinimization of Back-Electron Transfer Enables the Elusive sp3 C-H Functionalization of Secondary AnilinesZhao, Huaibo; Leonori, DanieleAngewandte Chemie, International Edition (2021), 60 (14), 7669-7674CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Anilines are some of the most used class of substrates for application in photoinduced electron transfer. N,N-Dialkyl-derivs. enable radical generation α to the N-atom by oxidn. followed by deprotonation. This approach is however elusive to monosubstituted anilines owing to fast back-electron transfer (BET). Here we demonstrate that BET can be minimised by using photoredox catalysis in the presence of an exogenous alkylamine. This approach synergistically aids aniline SET oxidn. and then accelerates the following deprotonation. In this way, the generation of α-anilinoalkyl radicals is now possible and these species can be used in a general sense to achieve divergent sp3 C-H functionalization.(b) Grayson, J. D.; Cresswell, A. J. γ-Amino Phosphonates via the Photocatalytic α-C–H Alkylation of Primary Amines. Tetrahedron 2021, 81, 131896, DOI: 10.1016/j.tet.2020.131896Google Scholar9bγ-Amino phosphonates via the photocatalytic α-C-H alkylation of primary aminesGrayson, James D.; Cresswell, Alexander J.Tetrahedron (2021), 81 (), 131896CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)We report a simple photocatalytic protocol for the direct synthesis of γ-aminophosphonates via the α-C-H alkylation of unprotected, aliph. primary amines with di-Et vinylphosphonate. These motifs are valuable bioisosteres of γ-amino acids and O-phosphorylated amino alcs. Visible-light photoredox catalysis in combination with hydrogen atom transfer (HAT) catalysis is used to access the necessary α-amino radical intermediates for C-C bond formation. The procedure is also demonstrated on gram-scale in continuous flow for the synthesis of a racemic, protected deriv. of the mGlu agonist 2-amino-4-phosphonobutyric acid (AP4).(c) Leng, L.; Fu, Y.; Liu, P.; Ready, J. M. Regioselective, Photocatalytic α-Functionalization of Amines. J. Am. Chem. Soc. 2020, 142, 11972– 11977, DOI: 10.1021/jacs.0c03758Google Scholar9cRegioselective, Photocatalytic α-Functionalization of AminesLeng, Lingying; Fu, Yue; Liu, Peng; Ready, Joseph M.Journal of the American Chemical Society (2020), 142 (28), 11972-11977CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Photocatalytic α-functionalization of amines provided a mild and atom-economical means to synthesized α-branched amines. Prior examples featured sym. or electronically biased substrates. A controllable α-functionalization of amines in which regioselectivity can be tuned with minor changes to the reaction conditions.(d) Ryder, A. S. H.; Cunningham, W. B.; Ballantyne, G.; Mules, T.; Kinsella, A. G.; Turner-Dore, J.; Alder, C. M.; Edwards, L. J.; McKay, B. S. J.; Grayson, M. N.; Cresswell, A. J. Photocatalytic α-Tertiary Amine Synthesis via C–H Alkylation of Unmasked Primary Amines. Angew. Chem., Int. Ed. 2020, 59, 14986– 14991, DOI: 10.1002/anie.202005294Google Scholar9dPhotocatalytic α-Tertiary Amine Synthesis via C-H Alkylation of Unmasked Primary AminesRyder, Alison S. H.; Cunningham, William B.; Ballantyne, George; Mules, Tom; Kinsella, Anna G.; Turner-Dore, Jacob; Alder, Catherine M.; Edwards, Lee J.; McKay, Blandine S. J.; Grayson, Matthew N.; Cresswell, Alexander J.Angewandte Chemie, International Edition (2020), 59 (35), 14986-14991CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A practical, catalytic entry to α,α,α-trisubstituted (α-tertiary) primary amines by C-H functionalization has long been recognized as a crit. gap in the synthetic toolbox. The authors report a simple and scalable soln. to this problem that does not require any in situ protection of the amino group and proceeds with 100% atom-economy. The authors' strategy, which uses an org. photocatalyst in combination with azide ion as a hydrogen atom transfer (HAT) catalyst, provides a direct synthesis of α-tertiary amines, or their corresponding γ-lactams. The authors anticipate that this methodol. will inspire new retrosynthetic disconnections for substituted amine derivs. in org. synthesis, and particularly for challenging α-tertiary primary amines.(e) Cao, K.; Tan, S. M.; Lee, R.; Yang, S.; Jia, H.; Zhao, X.; Qiao, B.; Jiang, Z. Catalytic Enantioselective Addition of Prochiral Radicals to Vinylpyridines. J. Am. Chem. Soc. 2019, 141, 5437– 5443, DOI: 10.1021/jacs.9b00286Google Scholar9eCatalytic Enantioselective Addition of Prochiral Radicals to VinylpyridinesCao, Kangning; Tan, Siu Min; Lee, Richmond; Yang, Songwei; Jia, Hongshao; Zhao, Xiaowei; Qiao, Baokun; Jiang, ZhiyongJournal of the American Chemical Society (2019), 141 (13), 5437-5443CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Pyridine, one of the most important azaarenes, is ubiquitous in functional mols. The electronic properties of pyridine were exploited to trigger asym. transformations of prochiral species as a direct approach for accessing chiral pyridine derivs. However, the full potential of this synthetic strategy for the construction of enantioenriched γ-functionalized pyridines remains untapped. Here, the authors describe the first enantioselective addn. of prochiral radicals to vinylpyridines under cooperative photoredox and asym. catalysis mediated by visible light. The enantioselective reductive couplings of vinylpyridines with aldehydes, ketones, and imines were achieved by employing a chiral Bronsted acid to activate the reaction partners and provide stereocontrol via H-bonding interactions. Valuable chiral γ-secondary/tertiary hydroxyl- and amino-substituted pyridines were obtained in high yields with good to excellent enantioselectivities.(f) Ashley, M. A.; Yamauchi, C.; Chu, J. C. K.; Otsuka, S.; Yorimitsu, H.; Rovis, T. Photoredox-Catalyzed Site-Selective α-Csp3–H Alkylation of Primary Amine Derivatives. Angew. Chem., Int. Ed. 2019, 58, 4002– 4006, DOI: 10.1002/anie.201812227Google Scholar9fPhotoredox-Catalyzed Site-Selective α-C(sp3)-H Alkylation of Primary Amine DerivativesAshley, Melissa A.; Yamauchi, Chiaki; Chu, John C. K.; Otsuka, Shinya; Yorimitsu, Hideki; Rovis, TomislavAngewandte Chemie, International Edition (2019), 58 (12), 4002-4006CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The synthetic utility of tertiary amines to oxidatively generate α-amino radicals is well established, however, primary amines remain challenging because of competitive side reactions. This report describes the site-selective α-functionalization of primary amine derivs. through the generation of α-amino radical intermediates. Employing visible-light photoredox catalysis, primary sulfonamides are coupled with electron-deficient alkenes to efficiently and mildly construct C-C bonds. Interestingly, a divergence between intermol. hydrogen-atom transfer (HAT) catalysis and intramol. [1,5] HAT was obsd. through precise manipulation of the protecting group. This dichotomy was leveraged to achieve excellent α/δ site-selectivity.(g) Rossolini, T.; Leitch, J. A.; Grainger, R.; Dixon, D. J. Photocatalytic Three-Component Umpolung Synthesis of 1,3-Diamines. Org. Lett. 2018, 20, 6794– 6798, DOI: 10.1021/acs.orglett.8b02923Google Scholar9gPhotocatalytic Three-Component Umpolung Synthesis of 1,3-DiaminesRossolini, Thomas; Leitch, Jamie A.; Grainger, Rachel; Dixon, Darren J.Organic Letters (2018), 20 (21), 6794-6798CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A visible-light-mediated photocatalytic umpolung synthesis of 1,3-diamines from in situ-generated imines and dehydroalanine derivs. is described. Pivoting on a key nucleophilic addn. of photocatalytically generated α-amino radicals to electron-deficient alkenes, this three-component coupling reaction affords 1,3-diamines efficiently and diastereoselectively. The mild protocol tolerates a wide variety of functionalities including heterocycles, pinacol boronates, and aliph. chains. Application to biol. relevant α-amino-γ-lactam synthesis and extension to 1,3-aminoalcs. is also demonstrated.(h) Trowbridge, A.; Reich, D.; Gaunt, M. J. Multicomponent synthesis of tertiary alkylamines by photocatalytic olefin-hydroaminoalkylation. Nature 2018, 561, 522– 527, DOI: 10.1038/s41586-018-0537-9Google Scholar9hMulticomponent synthesis of tertiary alkylamines by photocatalytic olefin-hydroaminoalkylationTrowbridge, Aaron; Reich, Dominik; Gaunt, Matthew J.Nature (London, United Kingdom) (2018), 561 (7724), 522-527CODEN: NATUAS; ISSN:0028-0836. (Nature Research)A multicomponent reductive photocatalytic technol. was reported that combines readily available dialkylamines, carbonyls and alkenes to build architecturally complex and functionally diverse tertiary alkylamines in a single step. This olefin-hydroaminoalkylation process involved a visible-light-mediated redn. of in-situ-generated iminium ions to selectively furnish previously inaccessible alkyl-substituted α-amino radicals, which subsequently reacted with alkenes to form C(sp3)-C(sp3) bonds. The operationally straightforward reaction exhibited broad functional-group tolerance, facilitated the synthesis of drug-like amines that were not readily accessible by other methods and was amenable to late-stage functionalization applications, making it of interest in areas such as pharmaceutical and agrochem. research.(i) Ye, J.; Kalvet, I.; Schoenebeck, F.; Rovis, T. Direct α-alkylation of primary aliphatic amines enabled by CO2 and electrostatics. Nat. Chem. 2018, 10, 1037– 1041, DOI: 10.1038/s41557-018-0085-9Google Scholar9iDirect α-alkylation of primary aliphatic amines enabled by CO2 and electrostaticsYe, Juntao; Kalvet, Indrek; Schoenebeck, Franziska; Rovis, TomislavNature Chemistry (2018), 10 (10), 1037-1041CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)Primary aliph. amines are important building blocks in org. synthesis due to the presence of a synthetically versatile NH2 group. N-functionalization of primary amines is well established, but selective C-functionalization of unprotected primary amines remains challenging. Here, we report the use of CO2 as an activator for the direct transformation of abundant primary aliph. amines into valuable γ-lactams under photoredox and hydrogen atom transfer (HAT) catalysis. Exptl. and computational studies suggest that CO2 not only inhibits undesired N-alkylation of primary amines, but also promotes selective intermol. HAT by an electrostatically accelerated interaction between the in situ-generated neg. charged carbamate and the pos. charged quinuclidinium radical. This electrostatic attraction overwhelms the inherent bond dissocn. energies which suggest that HAT should occur unselectively. We anticipate that our findings will open up new avenues for amine functionalizations as well as selectivity control in HAT reactions.(j) McManus, J. B.; Onuska, N. P. R.; Nicewicz, D. A. Generation and Alkylation of α-Carbamyl Radicals via Organic Photoredox Catalysis. J. Am. Chem. Soc. 2018, 140, 9056– 9060, DOI: 10.1021/jacs.8b04890Google Scholar9jGeneration and Alkylation of α-Carbamyl Radicals via Organic Photoredox CatalysisMcManus, Joshua B.; Onuska, Nicholas P. R.; Nicewicz, David A.Journal of the American Chemical Society (2018), 140 (29), 9056-9060CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Strategies for the direct C-H functionalization of amines are valuable as these compds. comprise a no. of pharmaceuticals, agrochems. and natural products. This work describes a novel method for the C-H functionalization of carbamate-protected secondary amines via α-carbamyl radicals generated using photoredox catalysis. The use of the highly oxidizing, org. acridinium photoredox catalyst allows for direct oxidn. of carbamate-protected amines with high redox potentials to give the corresponding carbamyl cation radical. Following deprotonation, the resultant open-shell species can be intercepted by a variety of Michael acceptors to give elaborate α-functionalized secondary amines. The reaction proceeds under mild conditions without the requirement of exogenous redox mediators or substrate prefunctionalization. Addnl., we were able to showcase the utility of this methodol. through the enantioselective synthesis of the indolizidine alkaloid, (+)-monomorine I.(k) Lee, K. N.; Lei, Z.; Ngai, M.-Y. β-Selective Reductive Coupling of Alkenylpyridines with Aldehydes and Imines via Synergistic Lewis Acid/Photoredox Catalysis. J. Am. Chem. Soc. 2017, 139, 5003– 5006, DOI: 10.1021/jacs.7b01373Google Scholar9kβ-Selective Reductive Coupling of Alkenylpyridines with Aldehydes and Imines via Synergistic Lewis Acid/Photoredox CatalysisLee, Katarzyna N.; Lei, Zhen; Ngai, Ming-YuJournal of the American Chemical Society (2017), 139 (14), 5003-5006CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Umpolung (polarity reversal) strategies of aldehydes and imines have dramatically expanded the scope of carbonyl and iminyl chem. by facilitating reactions with non-nucleophilic reagents. Herein, we report the first visible light photoredox-catalyzed β-selective reductive coupling of alkenylpyridines with carbonyl or iminyl derivs. with the aid of a Lewis acid co-catalyst. Our process tolerates complex mol. scaffolds (e.g., sugar, natural product, and peptide derivs.) and is applicable to the prepn. of compds. contg. a broad range of heterocyclic moieties. Mechanistic investigations indicate that the key step involves single-electron-transfer redn. of aldehydes or imines followed by the addn. of resulting ketyl or α-aminoalkyl radicals to Lewis acid-activated alkenylpyridines.(l) Chu, L.; Ohta, C.; Zuo, Z.; MacMillan, D. W. C. Carboxylic Acids as A Traceless Activation Group for Conjugate Additions: A Three-Step Synthesis of (±)-Pregabalin. J. Am. Chem. Soc. 2014, 136, 10886– 10889, DOI: 10.1021/ja505964rGoogle Scholar9lCarboxylic Acids as A Traceless Activation Group for Conjugate Additions: A Three-Step Synthesis of (±)-PregabalinChu, Lingling; Ohta, Chisa; Zuo, Zhiwei; MacMillan, David W. C.Journal of the American Chemical Society (2014), 136 (31), 10886-10889CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The direct application of carboxylic acids as a traceless activation group for radical Michael addns. has been accomplished via visible light-mediated photoredox catalysis. Photon-induced oxidn. of a broad series of carboxylic acids, including hydrocarbon-substituted, α-oxy, and α-amino acids, provides a versatile CO2-extrusion platform to generate Michael donors without the requirement for organometallic activation or propagation. A diverse array of Michael acceptors is amenable to this new conjugate addn. strategy. An application of this technol. to a three-step synthesis of the medicinal agent pregabalin (commercialized by Pfizer under the trade name Lyrica) is also presented.(m) Miyake, Y.; Nakajima, K.; Nishibayashi, Y. Visible-Light-Mediated Utilization of α-Aminoalkyl Radicals: Addition to Electron-Deficient Alkenes Using Photoredox Catalysts. J. Am. Chem. Soc. 2012, 134, 3338– 3341, DOI: 10.1021/ja211770yGoogle Scholar9mVisible-Light-Mediated Utilization of α-Aminoalkyl Radicals: Addition to Electron-Deficient Alkenes Using Photoredox CatalystsMiyake, Yoshihiro; Nakajima, Kazunari; Nishibayashi, YoshiakiJournal of the American Chemical Society (2012), 134 (7), 3338-3341CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Synthetic use of α-aminoalkyl radicals formed by single electron oxidn. of amines is quite limited. Here the authors demonstrate addn. of α-aminoalkyl radicals to electron-deficient alkenes by visible-light-mediated electron transfer using transition metal polypyridyl complexes as photocatalysts, via a sequential redox pathway. - 10The non-catalytic HAA of unprotected primary amines with non-electrophilic alkenes necessitates a large excess of the amine partner (∼13–26 equiv) and forcing reaction conditions (>120 °C, ∼10 mol% peroxide) and gives extensive telomerization. See:Urry, W. H.; Juveland, O. O. Free Radical Additions of Amines to Olefins. J. Am. Chem. Soc. 1958, 80, 3322– 3328, DOI: 10.1021/ja01546a033Google Scholar10Free radical additions of amines to olefinsUrry, W. H.; Juveland, O. O.Journal of the American Chemical Society (1958), 80 (), 3322-8CODEN: JACSAT; ISSN:0002-7863.The free radical chain addns. of amines to olefins in the presence of peroxides or light yield higher homologous amines which are products of α-C alkylation. BuNH2 (370 g.), b77 -8°, n20D 1.4013, 28 g. 1-octene (I), b. 120-1° n20D 1.4090, and 4.5 g. (Me3CO)2 (II) (half-life in Bu3N at 125° 11.3 hrs., and at 135° 4.6 hrs.) heated 48 hrs. in a sealed tube at 123-6° and fractionated yielded 2.5 g. Me3COH, 12.35 g. I and BuNH2, 7.35 g. PrCH(NH2)C8H17 (III), b1 70-1°, n20D 1.4407, 3.0 g. distillate, b1 110-60°, n20D 1.4728, and 7.1 g. residue. PrCOC8H17 treated with HCO2H and HCO2NH4 yielded 34% III, b1 69-71°, n20D 1.4408. III gave with PhNCS a phenylthiourea deriv., m. 58-8.5°. III gave with HCl the III.HCl, m. 88.5-90°. III (1.7 g.) was obtained when 490 g. BuNH2 and 30 g. I were illuminated internally 120 hrs. with a Hg vapor lamp at 30-5°; 6.35 g. higher boiling residue was also formed. I (26 g.) and 4.5 g. II in 458 g. C6H13NH2 heated 60 hrs. at 124-7° and distd. gave 4 g. Me3COH, unchanged C6H13NH2, 16.0 g. AmCH(NH2)C8H17 (IV), b1, 84-5°, n20D 1.4435 (phenylthiourea deriv., m. 69-9.5°), 5.7 g. distillate, b1 120-55°, n20D 1.4560, and 12 g. residue. IV, b1 84-6°, n20D 1.4432, was also obtained from AmCOC8H17 with HCO2H and HCO2NH4. Me2CHNH2 (118 g.), 18 g. I, and 3 g. II heated 55 hrs. at 188-22° yielded 12 g. Me2C(NH2)C8H17, b1, 47-8°, n20D 1.4333 (HCl salt, m. 116-17°), 3.5 g. distillate, b1 80-120°, and 5.5 g residue. Cyclohexylamine (V) (497 g.), 25 g. I, and 6.0 g. II heated 53 hrs. at 124-8° and distd. gave 5.5 g. Me3COH and unchanged V and the following fractions: (1) 1.85 g., b1 88-9°, n20D 1.4788; (2) 2.7 g., b1 89-92° n20D 1.4772; (3) 4.0 g., b1 92°, n20D 1.4759; (4) 23 g. 1-amino-1-octylcyclohexane (VI), b1 95-7°, n20D 1.4657 (HCl salt, m. 107.5-8.5°; phenylthiourea deriv., m. 91-1.5°); (5) 4.8 g., b1, 150-65°, n20D 1.4770 (apparently a mixt. of VI and the addn. product from 2 moles I and 1 mole V); (5) 9.4 g., residue. Fractions 1, 2, and 3 combined and an aliquot (3.2 g.) hydrogenated gave 1 g. VI, b1 94-6°, n20D 1.4680. CH2:CHCH2OH (VII) (23 g.) and 5.0 g. II in 380 g. pyrrolidine heated 48 hrs. at 120-2° in a sealed tube and distd. gave 27.8 g. 2-(3-hydroxypropyl)pyrrolidine (VIII), b1 80-1°, n20D 1.4870, and 10.2 g. residue. VIII (4.25 g.) and 95 cc. 48% HBr heated 12 hrs. in a sealed tube at 100° and evapd. and the residue recrystd. from Me2CO yielded 2.5 g. 2-(3-bromopropyl)pyrrolidine.HBr (IX), m. 102-3°. IX (2.5 g.) added during 2.5 hrs. with stirring to 200 cc. 0.1N NaOH at 50°, cooled, treated with 3 g. PhSO2Cl, allowed to stand 1 hr., and steam-distd., the distillate extd. with Et2O, and the ext. treated with 2 g. picric acid yielded 1.5 g. pyrrolizidine picrate, m. 256.6-8°. Piperidine (X) (81 g.) and 1.1 g. II pressured 24 hrs. at 125° with 30-40 lb. C2H4 while adding an addnl. 1.8 g. II after 8 hrs., and the mixt. distd. yielded 2.7 g. Me3COH, 72 g. X, and 2.6 g. 2-ethylpiperidine, b52 73-5°, n20D 1.4544 (HCl salt, m. 180-1°; picrate, m. 130-1°; chloro platinate, m. 202-4°), and left 1.1 g. residue. II (1.2 g.) and 87 g. X kept 12 hrs. at 125° under 30-40 lb. MeCH:CH2 while adding an addnl. 1.8 g. II after hrs. and distd. gave 4 g. dl-coniine, b70 93°, n23D 1.4513 (HCl salt, m. 211-12°; platinichloride, m. 155-7°), 1.40 g. forerun, and 2.6 g. residue. X (360 g.), 23 g. 1-hexene, and 5 g. II heated 50 hrs. in a sealed tube at 122-5° and fractionated gave 3.7 g. Me3COH, 8.5 g. 1-hexene, and piperidine as forerun followed by 15.6 g. 2-hexylpiperidine (XI), b4.5 77-8°, n20D 1.4580, 2.8 g. distillate, b3 80-140°, n20D 1.4740, and 4.4 g. residue. α-Picoline (55.5 g.) treated with 30.2 g. AmBr and 27 g. NaNH2 yielded 60% XI, b5 80°, n20D 1.4575 (HCl salt, m. 162-3°). X (382 g.), 40 g. I, and 3 g. II kept 50 hrs. at 120° under N while being treated after 6 hrs. and after 12 hrs. with addnl. 2-g. portions II and the mixt. distd. yielded 6.3 g. Me3COH, 359.5 g. unchanged X, 9.5 g. I, b. 118-20°, 31.7 g. 2-octylpiperidine (XII), b1 89°, n20D 1.4589, 5.8 g. distillate, b1 145-55°, n20D 1.4683 (apparently condensation product of 1 mole X with 2 moles I), and 4.5 g. residue. 2-Octylpyridine (obtained in 65% yield by the reaction of 111 g. α-picoline with 1.2 moles C7H15Br, and 54 g. NaNH2) hydrogenated over PtO2 in AcOH yielded 95% XII, b1 89°, n20D 1.4587; phenylthiourea deriv., m. 95°; HCl salt, m. 155-6°; picrate, m. 78-80°. I (20.5 g.) in 207 g. X illuminated 168 hrs. with a quartz-Hg discharge tube at 30-5° gave 1 g. XII. X (385 g.), 19 g. VII, and 4.5 g. II heated 48 hrs. at 122-30° in a sealed tube and distd. gave 21.8 g. 2-(3-hydroxypropyl)piperidine (XIII), b1 93-5°, n25D 1.4890; HCl salt, m. 129-30°. X (340 g.), 19 g. VII, and 4.5 g. (EtMe2CO)2 kept 48 hrs. at 100° gave 2.3 g. XIII, b1, 93-5°, n20D 1.4900, and 4.2 g. residue. X (180 g.), 9 g. VII, and 1.5 g. (Me3CO.OCHMe)2 kept 50 hrs. at 95° gave 1.1 g. XIII and 2.6 g. residue. XIII (3 g.) in 60 cc. 48% HBr heated 12 hrs. at 100° and evapd. in vacuo, the residue recrystd. from Me2CO, the resulting 3.7 g. 2-(3-bromopropyl)piperidine, m. 180-2°, added during 2 hrs. at 50° to 2000 cc. 0.1N NaOH, cooled, treated with 3 g. PhSO2Cl, and steam-distd., the distillate (50 cc.) extd. with Et2O, and the ext. worked up gave 0.7 g. 1-azabicyclo[4.3.0]nonane, b32 86°, n21D 1.4697. X (374 g.), 21 g. CH2:CHCH2CN, and 5 g. II kept 72 hrs. at 120-4° yielded 20.7 g. 2-(3-cyanopropyl)piperidine, b1 59-60°, n20D 1.4748 (HCl salt, m. 135-6°), and 7.1 g. distillate, b1 100-40°, n20D 1.5024. 4-Pipecoline (198 g.), 10 g. VII, and 3 g. II heated 48 hrs. at 123-5° in a sealed tube gave 9.1 g. 4-Me deriv. of XIII, b1 99-100°, n20D 1.4875, and 8.0 g. residue. N-Methylpiperidine (284 g.), 20 g. I, and 6 g. II heated 48 hrs. at 122-6° in a sealed tube and distd. gave 6 g. 1-methyl-2-octylpiperidine (XIV), b1 84-5°, n20D 1.4593, 6.8 g. distillate, b1, 110-70°, n20D 1.4692, and 8.6 g. residue. HCO2H (18.9 g.), 14 g. 35% aq. CH2O, and 29 g. XII yielded 23.3 g. XIV, b1 85°, n20D 1.4590; XIV.MeI, m. 165°; XIV.EtI, m. 138-9°.
- 11
Non-electrophilic styrenes in photoredox-catalyzed, intermolecular HAA are scarce and limited to tertiary amines or N-Boc α-amino acids:
(a) Wu, Z.; Gockel, S.; Hull, K. Anti-Markovnikov Hydro(amino)alkylation of Vinylarenes via Photoredox Catalysis. Research Square Preprint 2021, DOI: 10.21203/rs.3.rs-366556/v1Google ScholarThere is no corresponding record for this reference.(b) Larionova, N.; Ondozabal, J. M.; Smith, E. G.; Cambeiro, X. A. A photocatalytic regioselective hydroaminoalkylation of aryl-substituted alkenes with simple amines. Org. Lett. 2021, 23, 5383– 5388, DOI: 10.1021/acs.orglett.1c01715Google Scholar11bA Photocatalytic Regioselective Direct Hydroaminoalkylation of Aryl-Substituted Alkenes with AminesLarionova, Natalia A.; Ondozabal, Jun Miyatake; Smith, Emily G.; Cambeiro, Xacobe C.Organic Letters (2021), 23 (14), 5383-5388CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A photocatalytic method for the α-selective hydroaminoalkylation of cinnamate esters has been developed. The reaction involves the regioselective addn. of α-aminoalkyl radicals generated from aniline derivs. or aliph. amines to the α-position of unsatd. esters. The scope of arom. alkenes was extended to styrenes undergoing hydroaminoalkylation with anti-Markovnikov selectivity, which confirms the importance of the arom. group at the β-position. Simple scale-up is demonstrated under continuous flow conditions, highlighting the practicality of the method.(c) Lovett, G. H.; Sparling, B. A. Decarboxylative Anti-Michael Addition to Olefins Mediated by Photoredox Catalysis. Org. Lett. 2016, 18, 3494– 3497, DOI: 10.1021/acs.orglett.6b01712Google Scholar11cDecarboxylative Anti-Michael Addition to Olefins Mediated by Photoredox CatalysisLovett, Gabrielle H.; Sparling, Brian A.Organic Letters (2016), 18 (14), 3494-3497CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)Decarboxylative coupling of carboxylic acids with activated olefins has been accomplished using visible light photoredox catalysis. The strategic placement of a radical-stabilizing arom. group at the β-position of the olefin component biases the regioselectivity of the addn., allowing reliable, facile access to anti-Michael-type products from readily available precursors. The scope of this methodol. was demonstrated with a range of carboxylic acids and appropriately substituted olefins and was applied toward a two-step synthesis of the antiarrhythmic agent encainide. - 12(a) Nagai, M.; Nagamoto, M.; Nishimura, T.; Yorimitsu, H. Iridium-Catalyzed sp3 C–H Alkylation of 3-Carbonyl-2-(alkylamino)pyridines with Alkenes. Chem. Lett. 2017, 46, 1176– 1178, DOI: 10.1246/cl.170373Google Scholar12aIridium-catalyzed sp3 C-H alkylation of 3-carbonyl-2-(alkylamino)pyridines with alkenesNagai, Masaki; Nagamoto, Midori; Nishimura, Takahiro; Yorimitsu, HidekiChemistry Letters (2017), 46 (8), 1176-1178CODEN: CMLTAG; ISSN:0366-7022. (Chemical Society of Japan)Iridium-catalyzed C-H alkylation of 3-carbonyl-2-(alkylamino)pyridines via secondary sp3 C-H activation adjacent to the nitrogen atom, with terminal alkenes proceeded to give the corresponding α-secondary amines such as I [R1 = Ph, NH2, pyrrolodin-1-yl, etc; R2 = CH2OH, 4-ClC6H4, Bn, etc.; R3 = Me, CH2CH3, Ph , etc.] in high yields. The reaction was efficiently catalyzed by a cationic iridium complex coordinated with 1,5-cyclooctadiene.(b) Pan, S.; Matsuo, Y.; Endo, K.; Shibata, T. Cationic iridium-catalyzed enantioselective activation of secondary sp3 C–H bond adjacent to nitrogen atom. Tetrahedron 2012, 68, 9009– 9015, DOI: 10.1016/j.tet.2012.08.071Google Scholar12bCationic iridium-catalyzed enantioselective activation of secondary sp3 C-H bond adjacent to nitrogen atomPan, Shiguang; Matsuo, Yusuke; Endo, Kohei; Shibata, TakanoriTetrahedron (2012), 68 (44), 9009-9015CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)A cationic Ir(I)-tolBINAP complex catalyzed an enantioselective C-C bond formation, which was initiated by secondary sp3 C-H bond cleavage adjacent to nitrogen atom. A wide variety of 2-(alkylamino)pyridines and alkenes were selectively transformed into the corresponding chiral amines with moderate to almost perfect enantiomeric excesses. E.g., reaction of 2-(ethylamino)pyridine and styrene gave (-)-I. Alkynes were also investigated as coupling partners. The effect of alkyl structure in substrates and directing groups were studied. This transformation represents the first example of a highly enantioselective C-H bond activation of a methylene group, not at allylic or benzylic position.(c) Pan, S.; Endo, K.; Shibata, T. Ir(I)-Catalyzed Enantioselective Secondary sp3 C–H Bond Activation of 2-(Alkylamino)pyridines with Alkenes. Org. Lett. 2011, 13, 4692– 4695, DOI: 10.1021/ol201907wGoogle Scholar12cIr(I)-Catalyzed Enantioselective Secondary sp3 C-H Bond Activation of 2-(Alkylamino)pyridines with AlkenesPan, Shiguang; Endo, Kohei; Shibata, TakanoriOrganic Letters (2011), 13 (17), 4692-4695CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A cationic Ir(I)-tolBINAP complex catalyzed an enantioselective C-C bond formation initiated by secondary sp3 C-H bond cleavage adjacent to a nitrogen atom. The reaction of 2-(alkylamino)pyridines with various alkenes gave chiral amines, e.g., I, in good yields with high enantiomeric excesses.
- 13Koperniku, A.; Foth, P. J.; Sammis, G. M.; Schafer, L. L. Zirconium Hydroaminoalkylation. An Alternative Disconnection for the Catalytic Synthesis of α-Arylated Primary Amines. J. Am. Chem. Soc. 2019, 141, 18944– 18948, DOI: 10.1021/jacs.9b10465Google Scholar13Zirconium Hydroaminoalkylation. An Alternative Disconnection for the Catalytic Synthesis of α-Arylated Primary AminesKoperniku, Ana; Foth, Paul J.; Sammis, Glenn M.; Schafer, Laurel L.Journal of the American Chemical Society (2019), 141 (48), 18944-18948CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Primary amine products have been prepd. using zirconium catalyzed hydroaminoalkylation of alkenes with N-silylated benzylamine substrates. Catalysis using com. available Zr(NMe2)4, affords an alternative disconnection to access α-arylated primary amines upon aq. work-up. Substrate dependent regio- and diastereoselectivity of the reaction is obsd. Bulky substituents on the terminal alkene exclusively generate the linear regioisomer. This atom-economic catalytic strategy for the synthesis of building blocks that can underwent further synthetic elaboration is highlighted in the prepn. of trifluoroethylated-α-arylated amines.
- 14(a) Bexrud, J. A.; Eisenberger, P.; Leitch, D. C.; Payne, P. R.; Schafer, L. L. Selective C–H Activation α to Primary Amines. Bridging Metallaaziridines for Catalytic, Intramolecular α-Alkylation. J. Am. Chem. Soc. 2009, 131, 2116– 2118, DOI: 10.1021/ja808862wGoogle Scholar14aSelective C-H activation α to primary amines. Bridging metallaaziridines for catalytic, intramolecular α-alkylationBexrud, Jason A.; Eisenberger, Patrick; Leitch, David C.; Payne, Philippa R.; Schafer, Laurel L.Journal of the American Chemical Society (2009), 131 (6), 2116-2118CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Primary 5- and 6-unsatd. aliph. amines undergo α-C-H-activation rather than intramol. hydroamination in the presence of Ti and Zr amido-complexes, resulting in stereoselective formation of cyclic amines. Selective benzylic α-C-H activation of benzylamine results in the prepn. of the first bridging metallaaziridine complex [(PhCONHAr-κO,κN)Ti(μ-PhCH2N-κN:κN)(μ-PhCH2N-κC,N:κN)(μ-PhCONHAr-κO:κN)Ti(PhCONHAr-κO,κN)] (2) for the catalytic α-alkylation of primary amines. Crystal structure of 2 is reported. Zirconium tetramide gave 2-pyridonate complex [(PyO)2Zr(NMe2)2] [3; PyO = 6-tert-butyl-3-phenyl-2-pyridinonato(1-)], which was also characterized by x-ray structural anal. Cyclization of RCH2NH2 (R = 2-(3-butenylphenyl), 2,2-diphenyl-6-heptenyl, 1-(4-pentenyl)cyclopentenyl, 7-heptenyl, 6-hexenyl) and CH2:CH(CH2)4CHPhNH2 catalyzed by zirconium complex 3 gave the corresponding 2-Me-1-tetralinamine, cyclohexane- and cyclopentanamines as a result of α-C-H activation, followed by cyclization of the reactive zirconaaziridine with pendant double bond. No nitrogen protecting groups are required for this reaction, which is capable of assembling quaternary chiral centers α to nitrogen. Preliminary mechanistic investigations suggest bridging metallaaziridine species are the catalytically active intermediates for this α-functionalization reaction, while monomeric imido complexes furnish azepane hydroamination products.(b) Kubiak, R.; Prochnow, I.; Doye, S. Titanium-Catalyzed Hydroaminoalkylation of Alkenes by C–H Bond Activation at sp3 Centers in the α-Position to a Nitrogen Atom. Angew. Chem., Int. Ed. 2009, 48, 1153– 1156, DOI: 10.1002/anie.200805169Google Scholar14bTitanium-catalyzed hydroaminoalkylation of alkenes by C-H bond activation at sp3 centers in the α-position to a nitrogen atomKubiak, Raphael; Prochnow, Insa; Doye, SvenAngewandte Chemie, International Edition (2009), 48 (6), 1153-1156CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Hydroaminoalkylations of alkenes, which take place by C-H bond activation in the α-position to nitrogen atoms, are catalyzed by various neutral titanium complexes. Primary as well as secondary amines can be used as substrates, and the reactions can be achieved intra- and intermolecularly.
- 15Chu, J. C. K.; Rovis, T. Complementary Strategies for Directed C(sp3)–H Functionalization: A Comparison of Transition-Metal-Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene Transfer. Angew. Chem., Int. Ed. 2018, 57, 62– 101, DOI: 10.1002/anie.201703743Google Scholar15Complementary Strategies for Directed C(sp3)-H Functionalization: A Comparison of Transition-Metal-Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene TransferChu, John C. K.; Rovis, TomislavAngewandte Chemie, International Edition (2018), 57 (1), 62-101CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The functionalization of C(sp3)-H bonds streamlines chem. synthesis by allowing the use of simple mols. and providing novel synthetic disconnections. Intensive recent efforts in the development of new reactions based on C-H functionalization have led to its wider adoption across a range of research areas. This Review discusses the strengths and weaknesses of three main approaches: transition-metal-catalyzed C-H activation, 1,n-hydrogen atom transfer, and transition-metal-catalyzed carbene/nitrene transfer, for the directed functionalization of unactivated C(sp3)-H bonds. For each strategy, the scope, the reactivity of different C-H bonds, the position of the reacting C-H bonds relative to the directing group, and stereochem. outcomes are illustrated with examples in the literature. The aim of this Review is to provide guidance for the use of C-H functionalization reactions and inspire future research in this area.
- 16For a comparison to the oxidation potential of other common amine classes, see:Roth, H. G.; Romero, N. A.; Nicewicz, D. A. Experimental and Calculated Electrochemical Potentials of Common Organic Molecules for Applications to Single-Electron Redox Chemistry. Synlett 2016, 27, 714– 723, DOI: 10.1055/s-0035-1561297Google Scholar16Experimental and Calculated Electrochemical Potentials of Common Organic Molecules for Applications to Single-Electron Redox ChemistryRoth, Hudson G.; Romero, Nathan A.; Nicewicz, David A.Synlett (2016), 27 (5), 714-723CODEN: SYNLES; ISSN:0936-5214. (Georg Thieme Verlag)Herein, we report half-peak potentials for over 180 org. substrates obtained via cyclic voltammetry. These values are of great use in assessing the thermodn. of an electron-transfer process. In addn., we disclose a simple computational method to det. redox potentials of org. substrates.
- 17Morozova, O. B.; Yurkovskaya, A. V. Aminium Cation Radical of Glycylglycine and its Deprotonation to Aminyl Radical in Aqueous Solution. J. Phys. Chem. B 2008, 112, 12859– 12862, DOI: 10.1021/jp807149aGoogle Scholar17Aminium Cation Radical of Glycylglycine and its Deprotonation to Aminyl Radical in Aqueous SolutionMorozova, Olga B.; Yurkovskaya, Alexandra V.Journal of Physical Chemistry B (2008), 112 (40), 12859-12862CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)The photochem. reaction between glycylglycine and triplet 4-carboxybenzophenone has been investigated using time-resolved chem. induced dynamic nuclear polarization (CIDNP). It is shown that the mechanism of the peptide reaction with triplet excited carboxybenzophenone is electron transfer from the amino group of the peptide, leading to the formation of an aminium cation radical that deprotonates to a neutral aminyl radical. Simulation of the CIDNP kinetics leads to an estn. of the paramagnetic relaxation time for the α-protons at the N-terminus at 20 to 40 μs with the best-fit value of 25 μs.
- 18Luo, J.; Zhang, J. Donor–Acceptor Fluorophores for Visible-Light-Promoted Organic Synthesis: Photoredox/Ni Dual Catalytic C(sp3)–C(sp2) Cross Coupling. ACS Catal. 2016, 6, 873– 877, DOI: 10.1021/acscatal.5b02204Google Scholar18Donor-Acceptor Fluorophores for Visible-Light-Promoted Organic Synthesis: Photoredox/Ni Dual Catalytic C(sp3)-C(sp2) Cross-CouplingLuo, Jian; Zhang, JianACS Catalysis (2016), 6 (2), 873-877CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)We describe carbazolyl dicyanobenzene (CDCB)-based donor-acceptor (D-A) fluorophores as a class of cheap, easily accessible, and efficient metal-free photoredox catalysts for org. synthesis. By changing the no. and position of carbazolyl and cyano groups on the center benzene ring, CDCBs with a wide range of photoredox potentials are obtained to effectively drive the energetically demanding C(sp3)-C(sp2) cross-coupling of carboxylic acids and alkyltrifluoroborates with aryl halides via a photoredox/Ni dual catalysis mechanism. This work validates the utility of D-A fluorophores in guiding the rational design of metal-free photoredox catalysts for visible-light-promoted org. synthesis.
- 19Le, C.; Liang, Y.; Evans, R. W.; Li, X.; MacMillan, D. W. C. Selective sp3 C–H alkylation via polarity-match-based cross-coupling. Nature 2017, 547, 79– 83, DOI: 10.1038/nature22813Google Scholar19Selective sp3 C-H alkylation via polarity-match-based cross-couplingLe, Chip; Liang, Yufan; Evans, Ryan W.; Li, Ximing; MacMillan, David W. C.Nature (London, United Kingdom) (2017), 547 (7661), 79-83CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)The functionalization of carbon-hydrogen (C-H) bonds is one of the most attractive strategies for mol. construction in org. chem. The hydrogen atom is considered to be an ideal coupling handle, owing to its relative abundance in org. mols. and its availability for functionalization at almost any stage in a synthetic sequence. Although many C-H functionalization reactions involve C(sp3)-C(sp2) coupling, there is a growing demand for C-H alkylation reactions, wherein sp3 C-H bonds are replaced with sp3 C-alkyl groups. Here, we describe a polarity-match-based selective sp3 C-H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis. This methodol. simultaneously uses three catalytic cycles to achieve hydridic C-H bond abstraction (enabled by polarity matching), alkyl halide oxidative addn., and reductive elimination to enable alkyl-alkyl fragment coupling. The sp3 C-H alkylation is highly selective for the α-C-H of amines, ethers and sulfides, which are commonly found in pharmaceutically relevant architectures. This cross-coupling protocol should enable broad synthetic applications in de novo synthesis and late-stage functionalization chem.
- 20Luo, Y.-R Comprehensive Handbook of Chemical Bond Energies; CRC Press: Boca Raton, FL, 2007.Google ScholarThere is no corresponding record for this reference.
- 21(a) Sim, B. A.; Griller, D.; Wayner, D. D. M. Reduction Potentials for Substituted Benzyl Radicals: pKa Values for the Corresponding Toluenes. J. Am. Chem. Soc. 1989, 111, 754– 755, DOI: 10.1021/ja00184a066Google Scholar21aReduction potentials for substituted benzyl radicals: pKa values for the corresponding toluenesSim, B. A.; Griller, D.; Wayner, D. D. M.Journal of the American Chemical Society (1989), 111 (2), 754-5CODEN: JACSAT; ISSN:0002-7863.The electrochem. redn. potentials of nine 3- and 4-substituted benzyl radicals were detd. by photomodulation voltammetry (PMV) in MeCN/di-tert-butylperoxide (9:1) contg. 0.1 M Bu4NClO4. The measured half-wave potentials for the redns. are close to E° and lead to ests. of the abs. pKa's for the toluenes in MeCN.(b) Wayner, D. D. M.; McPhee, D. J.; Griller, D. Oxidation and reduction potentials of transient free radicals. J. Am. Chem. Soc. 1988, 110, 132– 137, DOI: 10.1021/ja00209a021Google Scholar21bOxidation and reduction potentials of transient free radicalsWayner, D. D. M.; McPhee, D. J.; Griller, D.Journal of the American Chemical Society (1988), 110 (1), 132-7CODEN: JACSAT; ISSN:0002-7863.The oxidn. and redn. potentials of a variety of carbon-centered radicals have been measured by a technique that makes use of modulated photolysis for radical generation and phase-sensitive voltammetry for their detection. The measured half-wave potentials were close to the thermodynamically significant E° values for the arylmethyl radicals and led to ests. of pKa(R-H) and pKR(R-OH) as well as data for the solvation energies of these ions and radicals.
- 22Bortolamei, N.; Isse, A. A.; Gennaro, A. Estimation of standard reduction potentials of alkyl radicals involved in atom-transfer radical polymerization. Electrochim. Acta 2010, 55, 8312– 8318, DOI: 10.1016/j.electacta.2010.02.099Google Scholar22Estimation of standard reduction potentials of alkyl radicals involved in atom transfer radical polymerizationBortolamei, Nicola; Isse, Abdirisak A.; Gennaro, ArmandoElectrochimica Acta (2010), 55 (27), 8312-8318CODEN: ELCAAV; ISSN:0013-4686. (Elsevier B.V.)The redox properties of some alkyl radicals, which are important in atom transfer radical polymn. both as initiators and mimics of the propagating radical chains, have been investigated in CH3CN by an indirect electrochem. method based on homogeneous redox catalysis involving alkyl halides (RX) and electrogenerated arom. or heteroarom. radical anions (D·-). Dissociative electron transfer between RX and D·- yields an intermediate radical (R·), which further reacts with D·- either by radical coupling or by electron transfer. Examn. of the competition between these reactions, which depends on ED°D/D·-/D·-, allows detn. of the std. redn. potential of R· as well as the self-exchange reorganization energy λR·/R-·. The std. redn. potentials obtained for the radicals ·CH2CN, ·CH2CO2Et and ·CH(CH3)CO2Me are -0.72 ± 0.06, -0.63 ± 0.07 and -0.66 ± 0.07 V vs. SCE, resp. Quite high values of λR·/R- (from 122 to 164 kJ mol-1) were found for all radicals, indicating that a significant change of structure accompanies electron transfer to R·.
- 23Speckmeier, E.; Fischer, T. G.; Zeitler, K. A Toolbox Approach To Construct Broadly Applicable Metal-Free Catalysts for Photoredox Chemistry: Deliberate Tuning of Redox Potentials and Importance of Halogens in Donor–Acceptor Cyanoarenes. J. Am. Chem. Soc. 2018, 140, 15353– 15365, DOI: 10.1021/jacs.8b08933Google Scholar23A Toolbox Approach To Construct Broadly Applicable Metal-Free Catalysts for Photoredox Chemistry: Deliberate Tuning of Redox Potentials and Importance of Halogens in Donor-Acceptor CyanoarenesSpeckmeier, Elisabeth; Fischer, Tillmann G.; Zeitler, KirstenJournal of the American Chemical Society (2018), 140 (45), 15353-15365CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The targeted choice of specific photocatalysts has been shown to play a crit. role for the successful realization of challenging photoredox catalytic transformations. Herein, we demonstrate the successful implementation of a rational design strategy for a series of deliberate structural manipulations of cyanoarene-based, purely org. donor-acceptor photocatalysts, using 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) as a starting point. Systematic modifications of both the donor substituents as well as the acceptors' mol. core allowed us to identify strongly oxidizing as well as strongly reducing catalysts (e.g., for an unprecedented detriflation of unactivated naphthol triflate), which addnl. offer remarkably balanced redox potentials with predictable trends. Esp. halogen arene core substitutions are instrumental for our targeted alterations of the catalysts' redox properties. Based on their preeminent electrochem. and photophys. characteristics, all novel, purely org. photoredox catalysts were evaluated in three challenging, mechanistically distinct classes of benchmark reactions (either requiring balanced, highly oxidizing or strongly reducing properties) to demonstrate their enormous potential as customizable photocatalysts, that outperform and complement prevailing typical best photocatalysts.
- 24Ji, X.; Liu, Q.; Wang, Z.; Wang, P.; Deng, G.-J.; Huang, H. LiBr-promoted photoredox neutral Minisci hydroxyalkylations of quinolines with aldehydes. Green Chem. 2020, 22, 8233– 8237, DOI: 10.1039/D0GC01872DGoogle Scholar24LiBr-promoted photoredox neutral Minisci hydroxyalkylations of quinolines with aldehydesJi, Xiaochen; Liu, Qiong; Wang, Zhongzhen; Wang, Pu; Deng, Guo-Jun; Huang, HuawenGreen Chemistry (2020), 22 (23), 8233-8237CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)Photoredox-neutral hydroxyalkylations of quinolines I [R = H; R1 = H; RR1 = -CH=CHCH=CH-, -CH=C(OCH3)C(OCH3)=CH-; R2 = H, n-Bu, Cl; R3 = H; R2R3 = -CH=C(Br)CH=CH-; R4 = H, 4-phenylphenyl, 3-chlorophenyl, thiophen-2-yl, etc.] with aldehydes R5CHO (R5 = 2-bromo-5-fluorophenyl, thiophen-2-yl, naphthalen-2-yl, etc.), induced by sustainable visible light under mild conditions, are described. Non-toxic and inexpensive LiBr is found to be the key for the success of the atom-economical Minisci method. Combined with a highly oxidative photocatalyst and visible light irradn., the bromide additive mediates the H abstraction/acyl radical formation directly from aldehydes. The present mild photoredox neutral protocol provides an important alternative, esp. for the challenging Minisci hydroalkylations, as well as a promising approach for atom-economical Minisci reactions with broader N-heterocycle spectra.
- 25Ide, T.; Barham, J. P.; Fujita, M.; Kawato, K.; Egami, H.; Hamashima, Y. Regio- and chemoselective Csp3–H arylation of benzylamines by single electron transfer/hydrogen atom transfer synergistic catalysis. Chem. Sci. 2018, 9, 8453– 8460, DOI: 10.1039/C8SC02965BGoogle Scholar25Regio- and chemoselective Csp3-H arylation of benzylamines by single electron transfer/hydrogen atom transfer synergistic catalysisIde, Takafumi; Barham, Joshua P.; Fujita, Masashi; Kawato, Yuji; Egami, Hiromichi; Hamashima, YoshitakaChemical Science (2018), 9 (44), 8453-8460CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)A highly regio- and chemoselective Csp3-H arylation of benzylamines mediated by synergy of single electron transfer (SET) and hydrogen atom transfer (HAT) catalysis is reported. Under well precedented SET catalysis alone, the arylation reaction of N,N-dimethylbenzylamine proceeded via aminium radical cation formation and selectively targeted the N-Me group. In contrast, addn. of PhC(O)SH as a HAT catalyst precursor completely switched the regioselectivity to Csp3-H arylation at the N-benzylic position. Measurement of oxidn. potentials indicated that the conjugate base of PhC(O)SH is oxidized in preference to the substrate amine. The discovery of the thiocarboxylate as a novel HAT catalyst allowed for the selective generation of the sulfur-centered radical, so that the N-benzyl selectivity was achieved by overriding the inherent N-Me and/or N-methylene selectivity under SET catalysis conditions. While visible light-driven α-C-H functionalization of amines has mostly been demonstrated with aniline derivs. and tetrahydroisoquinolines (THIQs), our method is applicable to a variety of primary, secondary and tertiary benzylamines for efficient N-benzylic C-H arylation. Functional group tolerance was high, and various 1,1-diarylmethylamines, including an α,α,α-trisubstituted amine, were obtained in good to excellent yield (up to 98%). Importantly, the reaction is applicable to late-stage functionalization of pharmaceuticals.
- 26Rohe, S.; Morris, A. O.; McCallum, T.; Barriault, L. Hydrogen Atom Transfer Reactions via Photoredox Catalyzed Chlorine Atom Generation. Angew. Chem., Int. Ed. 2018, 57, 15664– 15669, DOI: 10.1002/anie.201810187Google Scholar26Hydrogen Atom Transfer Reactions via Photoredox Catalyzed Chlorine Atom GenerationRohe, Samantha; Morris, Avery O.; McCallum, Terry; Barriault, LouisAngewandte Chemie, International Edition (2018), 57 (48), 15664-15669CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The selective functionalization of chem. inert C-H bonds remains to be fully realized in achieving org. transformations that are redox-neutral, waste-limiting, and atom-economical. The catalytic generation of chlorine atoms from chloride ions is one of the most challenging redox processes, where the requirement of harsh and oxidizing reaction conditions renders it seldom utilized in synthetic applications. We report the mild, controlled, and catalytic generation of chlorine atoms as a new opportunity for access to a wide variety of hydrogen atom transfer (HAT) reactions owing to the high stability of HCl.The discovery of the photoredox mediated generation of chlorine atoms with Ir-based polypyridyl complex, [Ir(dF(CF3)ppy)2(dtbbpy)]Cl, under blue LED irradn. is reported.
- 27Zhou, R.; Goh, Y. Y.; Liu, H.; Tao, H.; Li, L.; Wu, J. Visible-Light-Mediated Metal-Free Hydrosilylation of Alkenes through Selective Hydrogen Atom Transfer for Si–H Activation. Angew. Chem., Int. Ed. 2017, 56, 16621– 16625, DOI: 10.1002/anie.201711250Google Scholar27Visible-Light-Mediated Metal-Free Hydrosilylation of Alkenes through Selective Hydrogen Atom Transfer for Si-H ActivationZhou, Rong; Goh, Yi Yiing; Liu, Haiwang; Tao, Hairong; Li, Lihua; Wu, JieAngewandte Chemie, International Edition (2017), 56 (52), 16621-16625CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Although there has been significant progress in the development of transition-metal-catalyzed hydrosilylations of alkenes over the past several decades, metal-free hydrosilylation is still rare and highly desirable. Herein, authors report a convenient visible-light-driven metal-free hydrosilylation of both electron-deficient and electron-rich alkenes that proceeds through selective hydrogen atom transfer for Si-H activation. The synergistic combination of the organophotoredox catalyst 4CzIPN with quinuclidin-3-yl acetate enabled the hydrosilylation of electron-deficient alkenes by selective Si-H activation while the hydrosilylation of electron-rich alkenes was achieved by merging photoredox and polarity-reversal catalysis.
- 28(a) Morisaki, K.; Morimoto, H.; Ohshima, T. Recent Progress on Catalytic Addition Reactions to N-Unsubstituted Imines. ACS Catal. 2020, 10, 6924– 6951, DOI: 10.1021/acscatal.0c01212Google Scholar28aRecent Progress on Catalytic Addition Reactions to N-Unsubstituted IminesMorisaki, Kazuhiro; Morimoto, Hiroyuki; Ohshima, TakashiACS Catalysis (2020), 10 (12), 6924-6951CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)A review. Catalytic addn. reactions to N-unsubstituted (N-unprotected) imines can provide a more straightforward synthesis of amines. This direct process eliminates the unnecessary protecting-group manipulations that are required with N-substituted (N-protected) imines and can contribute to the development of green chem. Although their use has been limited due to difficulties assocd. with the nature of N-unsubstituted imines, recently developed catalytic methods enable the use of N-unsubstituted imines as electrophiles in various catalytic addn. reactions. To facilitate an understanding of the state of the art development of synthetic methodologies, herein we review recent progress on catalytic addn. reactions to N-unsubstituted imines. An overview of the chem. of N-unsubstituted imines is given, followed by a summary of recent progress categorized according to the reaction type is . We hope this review will help to stimulate further development of greener syntheses of nitrogen-contg. compds.(b) Nicastri, M. C.; Lehnherr, D.; Lam, Y.-h.; DiRocco, D. A.; Rovis, T. Synthesis of Sterically Hindered Primary Amines by Concurrent Tandem Photoredox Catalysis. J. Am. Chem. Soc. 2020, 142, 987– 998, DOI: 10.1021/jacs.9b10871Google Scholar28bSynthesis of Sterically Hindered Primary Amines by Concurrent Tandem Photoredox CatalysisNicastri, Michael C.; Lehnherr, Dan; Lam, Yu-hong; DiRocco, Daniel A.; Rovis, TomislavJournal of the American Chemical Society (2020), 142 (2), 987-998CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Primary amines are an important structural motif in active pharmaceutical ingredients (APIs) and intermediates thereof, as well as members of ligand libraries for either biol. or catalytic applications. Many chem. methodologies exist for amine synthesis, but the direct synthesis of primary amines with a fully substituted α carbon center is an underdeveloped area. We report a method which utilizes photoredox catalysis to couple readily available O-benzoyl oximes with cyanoarenes to synthesize primary amines with fully substituted α-carbons. We also demonstrate that this method enables the synthesis of amines with α-trifluoromethyl functionality. Based on exptl. and computational results, we propose a mechanism where the photocatalyst engages in concurrent tandem catalysis by reacting with the oxime as a triplet sensitizer in the first catalytic cycle and a reductant toward the cyanoarene in the second catalytic cycle to achieve the synthesis of hindered primary amines via heterocoupling of radicals from readily available oximes.(c) Lehnherr, D.; Lam, Y.-h.; Nicastri, M. C.; Liu, J.; Newman, J. A.; Regalado, E. L.; DiRocco, D. A.; Rovis, T. Electrochemical Synthesis of Hindered Primary and Secondary Amines via Proton-Coupled Electron Transfer. J. Am. Chem. Soc. 2020, 142, 468– 478, DOI: 10.1021/jacs.9b10870Google Scholar28cElectrochemical Synthesis of Hindered Primary and Secondary Amines via Proton-Coupled Electron TransferLehnherr, Dan; Lam, Yu-hong; Nicastri, Michael C.; Liu, Jinchu; Newman, Justin A.; Regalado, Erik L.; DiRocco, Daniel A.; Rovis, TomislavJournal of the American Chemical Society (2020), 142 (1), 468-478CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Accessing hindered amines, particularly primary amines α to a fully substituted carbon center, is synthetically challenging. We report an electrochem. method to access such hindered amines starting from benchtop-stable iminium salts and cyanoheteroarenes. A wide variety of substituted heterocycles (pyridine, pyrimidine, pyrazine, purine, azaindole) can be utilized in the cross-coupling reaction, including those substituted with a halide, trifluoromethyl, ester, amide, or ether group, a heterocycle, or an unprotected alc. or alkyne. Mechanistic insight based on DFT data, as well as cyclic voltammetry and NMR spectroscopy, suggests that a proton-coupled electron-transfer mechanism is operational as part of a hetero-biradical cross-coupling of α-amino radicals and radicals derived from cyanoheteroarenes. Safety: cyanide may be released as a byproduct leading to release of toxic HCN.(d) Ushakov, D. B.; Gilmore, K.; Kopetzki, D.; McQuade, D. T.; Seeberger, P. H. Continuous-Flow Oxidative Cyanation of Primary and Secondary Amines Using Singlet Oxygen. Angew. Chem., Int. Ed. 2014, 53, 557– 561, DOI: 10.1002/anie.201307778Google Scholar28dContinuous-Flow Oxidative Cyanation of Primary and Secondary Amines Using Singlet OxygenUshakov, Dmitry B.; Gilmore, Kerry; Kopetzki, Daniel; McQuade, D. Tyler; Seeberger, Peter H.Angewandte Chemie, International Edition (2014), 53 (2), 557-561CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Primary and secondary amines can be rapidly and quant. oxidized to the corresponding imines by singlet oxygen. This reactive form of oxygen was produced using a variable-temp. continuous-flow LED-photoreactor with a catalytic amt. of tetraphenylporphyrin as the sensitizer. α-Aminonitriles were obtained in good to excellent yields when trimethylsilyl cyanide served as an in situ imine trap. At 25°C, primary amines were found to undergo oxidative coupling prior to cyanide addn. and yielded secondary α-aminonitriles. Primary α-aminonitriles were synthesized from the corresponding primary amines for the first time, by an oxidative Strecker reaction at -50°C. This atom-economic and protecting-group-free pathway provides a route to racemic amino acids, which was exemplified by the synthesis of tert-leucine hydrochloride from neopentylamine.
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The addition step may be slower than potential side reactions (e.g., benzylic radical dimerization) or be reversible and endergonic, such that catalytic turnover is impeded. However, the photocatalytic α-C–H alkylation of tertiary benzylic amines with electrophilic alkenes has been achieved via an SET oxidation–deprotonation approach; see ref (9c).
There is no corresponding record for this reference. - 30
In general, quantification of the HAT site selectivity was not possible, but minor unidentified byproducts were visible in the crude 1H NMR spectra for some compounds. We previously showed, both experimentally and theoretically, that the selectivity for α-C–H functionalization of cyclohexylamine versus cyclohexanol with photogenerated azidyl radical is >20:1, with cyclohexanol itself being α-C–H alkylated with methyl acrylate in only 12% yield in a standalone experiment; see ref (9d).
There is no corresponding record for this reference. - 31Cambié, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noël, T. Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment. Chem. Rev. 2016, 116, 10276– 10341, DOI: 10.1021/acs.chemrev.5b00707Google Scholar31Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water TreatmentCambie, Dario; Bottecchia, Cecilia; Straathof, Natan J. W.; Hessel, Volker; Noel, TimothyChemical Reviews (Washington, DC, United States) (2016), 116 (17), 10276-10341CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Continuous-flow photochem. in microreactors receives a lot of attention from researchers in academia and industry as this technol. provides reduced reaction times, higher selectivities, straightforward scalability, and the possibility to safely use hazardous intermediates and gaseous reactants. In this review, an up-to-date overview is given of photochem. transformations in continuous-flow reactors, including applications in org. synthesis, material science, and water treatment. In addn., the advantages of continuous-flow photochem. are pointed out and a thorough comparison with batch processing is presented.
- 34Constantin, T.; Zanini, M.; Regni, A.; Sheikh, N. S.; Juliá, F.; Leonori, D. Aminoalkyl radicals as halogen-atom transfer agents for activation of alkyl and aryl halides. Science 2020, 367, 1021– 1026, DOI: 10.1126/science.aba2419Google Scholar34Aminoalkyl radicals as halogen-atom transfer agents for activation of alkyl and aryl halidesConstantin, Timothee; Zanini, Margherita; Regni, Alessio; Sheikh, Nadeem S.; Julia, Fabio; Leonori, DanieleScience (Washington, DC, United States) (2020), 367 (6481), 1021-1026CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)Org. halides are important building blocks in synthesis, but their use in (photo)redox chem. is limited by their low redn. potentials. Halogen-atom transfer remains the most reliable approach to exploit these substrates in radical processes despite its requirement for hazardous reagents and initiators such as tributyltin hydride. In this study, we demonstrate that α-aminoalkyl radicals, easily accessible from simple amines, promote the homolytic activation of carbon-halogen bonds with a reactivity profile mirroring that of classical tin radicals. This strategy conveniently engages alkyl and aryl halides in a wide range of redox transformations to construct sp3-sp3, sp3-sp2, and sp2-sp2 carbon-carbon bonds under mild conditions with high chemoselectivity.
- 35Sanford, M. Fingolimod: A Review of Its Use in Relapsing-Remitting Multiple Sclerosis. Drugs 2014, 74, 1411– 1433, DOI: 10.1007/s40265-014-0264-yGoogle Scholar35Fingolimod: A Review of Its Use in Relapsing-Remitting Multiple SclerosisSanford, MarkDrugs (2014), 74 (12), 1411-1433CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Fingolimod (Gilenya) is an orally administered disease modifying agent (DMA) for use in relapsing-remitting multiple sclerosis (RRMS). In placebo-controlled trials in patients with RRMS with active disease, fingolimod 0.5 mg/day significantly reduced the annualized relapse rate (ARR) by approx. one-half over 2-yr trial periods. It also significantly increased the proportion of patients with no disability progression, reduced deterioration from baseline in the Extended Disability Status Scale score and reduced MRI markers of disease progression (new/newly enlarging brain lesions and percentage change in brain vol.). In a 12-mo, comparison with i.m. interferon β-1a (IFNβ- 1a) 30 μg/wk, the ARR in fingolimod 0.5 mg/day recipients was significantly lower than in IFNβ-1a recipients by one-half; fingolimod recipients also had significantly lower MRI markers of disease progression. In extensions to the pivotal clin. trials, fingolimod exposure for up to 4 years was assocd. with low relapse rates and continuing benefits in terms of disability and disease progression. In clin. trials, adverse events in fingolimod recipients were generally mild to moderate in severity. In the pivotal placebo-controlled trial, serious adverse events occurred in similar proportions of fingolimod 0.5 mg/day and placebo recipients. First-dose bradycardia and atrioventricular block, which are generally asymptomatic, were clin. important adverse events assocd. with fingolimod in placebo-controlled trials. The risk for serious cardiovascular adverse events at the approved fingolimod dosage appears to be low in patients without pre-existing cardiac conditions. Fingolimod is an efficacious therapy for RRMS that reduces relapses, disability progression, new brain lesions and loss of brain vol. It has an acceptable tolerability profile and provides a useful alternative treatment in patients with RRMS who have responded poorly to other DMAs.
- 36Parijat, P.; Kondacs, L.; Alexandrovich, A.; Gautel, M.; Cobb, A. J. A.; Kampourakis, T. High Throughput Screen Identifies Small Molecule Effectors That Modulate Thin Filament Activation in Cardiac Muscle. ACS Chem. Biol. 2021, 16, 225– 235, DOI: 10.1021/acschembio.0c00908Google Scholar36High Throughput Screen Identifies Small Molecule Effectors That Modulate Thin Filament Activation in Cardiac MuscleParijat, Priyanka; Kondacs, Laszlo; Alexandrovich, Alexander; Gautel, Mathias; Cobb, Alexander J. A.; Kampourakis, ThomasACS Chemical Biology (2021), 16 (1), 225-235CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)Current therapeutic interventions for both heart disease and heart failure are largely insufficient and assocd. with undesired side effects. Biomedical research has emphasized the role of sarcomeric protein function for the normal performance and energy efficiency of the heart, suggesting that directly targeting the contractile myofilaments themselves using small mol. effectors has therapeutic potential and will likely result in greater drug efficacy and selectivity. In this study, we developed a robust and highly reproducible fluorescence polarization-based high throughput screening (HTS) assay that directly targets the calcium-dependent interaction between cardiac troponin C (cTnC) and the switch region of cardiac troponin I (cTnISP), with the aim of identifying small mol. effectors of the cardiac thin filament activation pathway. We screened a com. available small mol. library and identified several hit compds. with both inhibitory and activating effects. We used a range of biophys. and biochem. methods to characterize hit compds. and identified fingolimod, a sphingosin-1-phosphate receptor modulator, as a new troponin-based small mol. effector. Fingolimod decreased the ATPase activity and calcium sensitivity of demembranated cardiac muscle fibers in a dose-dependent manner, suggesting that the compd. acts as a calcium desensitizer. We investigated fingolimod's mechanism of action using a combination of computational studies, biophys. methods, and synthetic chem., showing that fingolimod bound to cTnC repels cTnISP via mainly electrostatic repulsion of its pos. charged tail. These results suggest that fingolimod is a potential new lead compd./scaffold for the development of troponin-directed heart failure therapeutics.
- 37Mulakayala, N. A Comprehensive Review on Synthetic Approach for Fingolimod. Indian J. Adv. Chem. Sci. 2016, 4, 362– 366Google Scholar37A comprehensive review on synthetic approach for fingolimodMulakayala, NaveenIndian Journal of Advances in Chemical Science (2016), 4 (4), 362-366CODEN: IJACKX; ISSN:2320-0928. (KROS Publications)A review. Multiple sclerosis (MS) often consequences in chronic inflammatory and autoimmune disorders, and recent developments have lead to newer therapeutic options for the treatment of the disease. In this review, we have summarized the literature known synthetic strategies of fingolimod which is the key small mol., and the first oral drug candidate for MS which have been launched in the market.
- 38Urbano, M.; Guerrero, M.; Rosen, H.; Roberts, E. Modulators of the Sphingosine 1-phosphate receptor 1. Bioorg. Med. Chem. Lett. 2013, 23, 6377– 6389, DOI: 10.1016/j.bmcl.2013.09.058Google Scholar38Modulators of the Sphingosine 1-phosphate receptor 1Urbano, Mariangela; Guerrero, Miguel; Rosen, Hugh; Roberts, EdwardBioorganic & Medicinal Chemistry Letters (2013), 23 (23), 6377-6389CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A review. The Sphingosine 1-phosphate receptor (S1P-R) signaling system has proven to be of biol. and medical importance in autoimmune settings. S1P1-R is a validated drug target for multiple sclerosis (MS) for which FTY720 (Fingolimod), a S1P1,3-5-R pan-agonist, was recently approved as the first orally active drug for the treatment of relapsing-remitting MS. Transient bradycardia and long half-life are the FTY720 crit. pitfalls. This review provides the latest advances on next-generation S1P1-R modulators from 2012 up to date, with an overview of the chem. structures, structure-activity relationships, and relevant biol. and clin. properties.
- 39Mandala, S.; Hajdu, R.; Bergstrom, J.; Quackenbush, E.; Xie, J.; Milligan, J.; Thornton, R.; Shei, G. J.; Card, D.; Keohane, C. A. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 2002, 296, 346– 349, DOI: 10.1126/science.1070238Google Scholar39Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonistsMandala, Suzanne; Hajdu, Richard; Bergstrom, James; Quackenbush, Elizabeth; Xie, Jenny; Milligan, James; Thornton, Rosemary; Shei, Gan-Ju; Card, Deborah; Keohane, Carolann; Rosenbach, Mark; Hale, Jeffrey; Lynch, Christopher L.; Rupprecht, Kathleen; Parsons, William; Rosen, HughScience (Washington, DC, United States) (2002), 296 (5566), 346-349CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Blood lymphocyte nos., essential for the development of efficient immune responses, are maintained by recirculation through secondary Lymphoid organs. We show that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolite of the immunosuppressive agent FTY720. Both species were high-affinity agonists of at least four of the five S1P receptors. These agonists produce lymphopenia in blood and thoracic duct lymph by sequestration of lymphocytes in lymph nodes, but not spleen. S1P receptor agonists induced emptying of lymphoid sinuses by retention of lymphocytes on the abluminal side of sinus-lining endothelium and inhibition of egress into lymph. Inhibition of lymphocyte recirculation by activation of S1P receptors may result in therapeutically useful immunosuppression.
- 40(a) Chen, S.; Yang, L.; Shang, Y.; Mao, J.; Walsh, P. J. Base-Promoted Tandem Synthesis of 2-Azaaryl Tetrahydroquinolines. Org. Lett. 2021, 23, 1594– 1599, DOI: 10.1021/acs.orglett.0c04306Google Scholar40aBase-Promoted Tandem Synthesis of 2-Azaaryl TetrahydroquinolinesChen, Shuguang; Yang, Langxuan; Shang, Yongjia; Mao, Jianyou; Walsh, Patrick J.Organic Letters (2021), 23 (5), 1594-1599CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A novel method to synthesize 2-azaaryl tetrahydroquinolines by the base-promoted tandem reaction of azaaryl Me amines and styrene derivs. was reported (over 30 examples, yields up to 95%). Mechanistic probe expts. demonstrate that the deprotonation of the benzylic C-H bond and the addn. to the styrene vinyl group proceeds via the SNAr mechanism.(b) Warsitz, M.; Doye, S. Two-Step Procedure for the Synthesis of 1,2,3,4-Tetrahydroquinolines. Eur. J. Org. Chem. 2020, 2020, 6997– 7014, DOI: 10.1002/ejoc.202001337Google Scholar40bTwo-Step Procedure for the Synthesis of 1,2,3,4-Tetrahydro-quinolinesWarsitz, Michael; Doye, SvenEuropean Journal of Organic Chemistry (2020), 2020 (45), 6997-7014CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)A new two-step procedure that includes an initial regioselective intermol. hydroaminoalkylation of ortho-chlorostyrenes with N-methylanilines and a subsequent intramol. Buchwald-Hartwig amination gives direct access to 1,2,3,4-tetrahydroquinolines. The hydroaminoalkylation reaction of the ortho-chlorostyrenes is catalyzed by a 2,6-bis(phenylamino)pyridinato titanium complex which delivers the linear regioisomers with high selectivities. In addn., the formation of unexpected dihydroaminoalkylation products from styrenes and N-methylanilines is reported.
- 41Muthukrishnan, I.; Sridharan, V.; Menéndez, J. C. Progress in the Chemistry of Tetrahydroquinolines. Chem. Rev. 2019, 119, 5057– 5191, DOI: 10.1021/acs.chemrev.8b00567Google Scholar41Progress in the Chemistry of TetrahydroquinolinesMuthukrishnan, Isravel; Sridharan, Vellaisamy; Menendez, J. CarlosChemical Reviews (Washington, DC, United States) (2019), 119 (8), 5057-5191CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. This review summarizes the progress achieved in the chem. of tetrahydroquinolines, with emphasis on their synthesis, during the mid-2010 to early 2018 period.
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Based on a Scifinder search conducted in April 2021, with the following constraints applied: benzenoid-fused only, 800 MW max, no other ring fusions, only H/C/S attached to N, no isotopes/metals.
There is no corresponding record for this reference. - 43Hiesinger, K.; Dar’in, D.; Proschak, E.; Krasavin, M. Spirocyclic Scaffolds in Medicinal Chemistry. J. Med. Chem. 2021, 64, 150– 183, DOI: 10.1021/acs.jmedchem.0c01473Google Scholar43Spirocyclic Scaffolds in Medicinal ChemistryHiesinger, Kerstin; Dar'in, Dmitry; Proschak, Ewgenij; Krasavin, MikhailJournal of Medicinal Chemistry (2021), 64 (1), 150-183CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Spirocyclic scaffolds are incorporated in various approved drugs and drug candidates. The increasing interest in less planar bioactive compds. has given rise to the development of synthetic methodologies for the prepn. of spirocyclic scaffolds. In this Perspective, we summarize the diverse synthetic routes to obtain spirocyclic systems. The impact of spirocycles on potency and selectivity, including the aspect of stereochem., is discussed. Furthermore, we examine the changes in physicochem. properties as well as in in vitro and in vivo ADME using selected studies that compare spirocyclic compds. to their nonspirocyclic counterparts. In conclusion, the value of spirocyclic scaffolds in medicinal chem. is discussed.
- 44St. Denis, J. D.; Hall, R. J.; Murray, C. W.; Heightman, T. D.; Rees, D. C. Fragment-based drug discovery: opportunities for organic synthesis. RSC Med. Chem. 2021, 12, 321– 329, DOI: 10.1039/D0MD00375AGoogle Scholar44Fragment-based drug discovery: opportunities for organic synthesisSt. Denis, Jeffrey D.; Hall, Richard J.; Murray, Christopher W.; Heightman, Tom D.; Rees, David C.RSC Medicinal Chemistry (2021), 12 (3), 321-329CODEN: RMCSEZ; ISSN:2632-8682. (Royal Society of Chemistry)A review. This Review describes the increasing demand for org. synthesis to facilitate fragment-based drug discovery (FBDD), focusing on polar, unprotected fragments. In FBDD, X-ray crystal structures are used to design target mols. for synthesis with new groups added onto a fragment via specific growth vectors. This requires challenging synthesis which slows down drug discovery, and some fragments are not progressed into optimization due to synthetic intractability. We have evaluated the output from Astex's fragment screenings for a no. of programs, including urokinase-type plasminogen activator, hematopoietic prostaglandin D2 synthase, and hepatitis C virus NS3 protease-helicase, and identified fragments that were not elaborated due, in part, to a lack of com. available analogs and/or suitable synthetic methodol. This represents an opportunity for the development of new synthetic research to enable rapid access to novel chem. space and fragment optimization.
- 45Twigg, D. G.; Kondo, N.; Mitchell, S. L.; Galloway, W. R. D.; Sore, H. F.; Madin, A.; Spring, D. R. Partially Saturated Bicyclic Heteroaromatics as an sp3-Enriched Fragment Collection. Angew. Chem., Int. Ed. 2016, 55, 12479– 12483, DOI: 10.1002/anie.201606496Google Scholar45Partially Saturated Bicyclic Heteroaromatics as an sp3-Enriched Fragment CollectionTwigg, David G.; Kondo, Noriyasu; Mitchell, Sophie L.; Galloway, Warren R. J. D.; Sore, Hannah F.; Madin, Andrew; Spring, David R.Angewandte Chemie, International Edition (2016), 55 (40), 12479-12483CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Fragment-based lead generation has proven to be an effective means of identifying high-quality lead compds. for drug discovery programs. However, the fragment screening sets often used are principally comprised of sp2-rich arom. compds., which limits the structural (and hence biol.) diversity of the library. Herein, we describe strategies for the synthesis of a series of partially satd. bicyclic heteroarom. scaffolds with enhanced sp3 character. Subsequent derivatization led to a fragment collection featuring regio- and stereo-controlled introduction of substituents on the satd. ring system, often with formation of new stereocenters.
- 46Law, R. P.; Atkinson, S. J.; Bamborough, P.; Chung, C.-w.; Demont, E. H.; Gordon, L. J.; Lindon, M.; Prinjha, R. K.; Watson, A. J. B.; Hirst, D. J. Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain. J. Med. Chem. 2018, 61, 4317– 4334, DOI: 10.1021/acs.jmedchem.7b01666Google Scholar46Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second BromodomainLaw, Robert P.; Atkinson, Stephen J.; Bamborough, Paul; Chung, Chun-wa; Demont, Emmanuel H.; Gordon, Laurie J.; Lindon, Matthew; Prinjha, Rab K.; Watson, Allan J. B.; Hirst, David J.Journal of Medicinal Chemistry (2018), 61 (10), 4317-4334CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET bromodomains-BRD2, BRD3, BRD4, and BRDT-each contain two bromodomain modules. BET bromodomain inhibition is a potential therapy for various cancers and immunoinflammatory diseases, but few reported inhibitors show selectivity within the BET family. Inhibitors with selectivity for the first or second bromodomain are desired to aid investigation of the biol. function of these domains. Focused library screening identified a series of tetrahydroquinoxalines with selectivity for the second bromodomains of the BET family (BD2). Structure-guided optimization of the template improved potency, selectivity, and physicochem. properties, culminating in potent BET inhibitors with BD2 selectivity.
- 47Procopiou, P. A.; Anderson, N. A.; Barrett, J.; Barrett, T. N.; Crawford, M. H. J.; Fallon, B. J.; Hancock, A. P.; Le, J.; Lemma, S.; Marshall, R. P. Discovery of (S)-3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-l)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic αvβ6 Integrin Inhibitor for the Inhaled Treatment of Idiopathic Pulmonary Fibrosis. J. Med. Chem. 2018, 61, 8417– 8443, DOI: 10.1021/acs.jmedchem.8b00959Google Scholar47Discovery of (S)-3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic αvβ6 Integrin Inhibitor for the Inhaled Treatment of Idiopathic Pulmonary FibrosisProcopiou, Panayiotis A.; Anderson, Niall A.; Barrett, John; Barrett, Tim N.; Crawford, Matthew H. J.; Fallon, Brendan J.; Hancock, Ashley P.; Le, Joelle; Lemma, Seble; Marshall, Richard P.; Morrell, Josie; Pritchard, John M.; Rowedder, James E.; Saklatvala, Paula; Slack, Robert J.; Sollis, Steven L.; Suckling, Colin J.; Thorp, Lee R.; Vitulli, Giovanni; Macdonald, Simon J. F.Journal of Medicinal Chemistry (2018), 61 (18), 8417-8443CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of 3-aryl-(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, which involved rhodium catalyzed asym. 1,4-addn. of arylboronic acids in the presence of (R)-BINAP to a crotonate ester to provide the (S) abs. configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole and cyclic ether were screened in cell adhesion assays for affinity against αvβ1, αvβ3, αvβ5, αvβ6 and αvβ8 integrins. Several analogs with high affinity and selectivity for the αvβ6 integrin were identified. The analog I·HCl was found to have high affinity for αvβ6 integrin in a radioligand binding assay (pKi = 11), a long dissocn. half-life (7 h) , high soly. in saline at pH 7 (>71 mg/mL) and pharmacokinetic properties commensurate with inhaled dosing by nebulization. It was selected for further investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.
- 48Fairhurst, R. A.; Knoepfel, T.; Buschmann, N.; Leblanc, C.; Mah, R.; Todorov, M.; Nimsgern, P.; Ripoche, S.; Niklaus, M.; Warin, N. Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4. J. Med. Chem. 2020, 63, 12542– 12573, DOI: 10.1021/acs.jmedchem.0c01019Google Scholar48Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4Fairhurst, Robin A.; Knoepfel, Thomas; Buschmann, Nicole; Leblanc, Catherine; Mah, Robert; Todorov, Milen; Nimsgern, Pierre; Ripoche, Sebastien; Niklaus, Michel; Warin, Nicolas; Luu, Van Huy; Madoerin, Mario; Wirth, Jasmin; Graus-Porta, Diana; Weiss, Andreas; Kiffe, Michael; Wartmann, Markus; Kinyamu-Akunda, Jacqueline; Sterker, Dario; Stamm, Christelle; Adler, Flavia; Buhles, Alexandra; Schadt, Heiko; Couttet, Philippe; Blank, Jutta; Galuba, Inga; Trappe, Jorg; Voshol, Johannes; Ostermann, Nils; Zou, Chao; Berghausen, Jorg; Del Rio Espinola, Alberto; Jahnke, Wolfgang; Furet, PascalJournal of Medicinal Chemistry (2020), 63 (21), 12542-12573CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)FGF19 signaling through the FGFR4/β-klotho receptor complex has been shown to be a key driver of growth and survival in a subset of hepatocellular carcinomas, making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted a poorly conserved cysteine residue within the FGFR4 ATP-binding site at position 552, two positions beyond the gate-keeper residue. Several strategies for targeting this cysteine to identify FGFR4 selective inhibitor starting points are summarized which made use of both rational and unbiased screening approaches. The optimization of a 2-formylquinoline amide hit series is described in which the aldehyde makes a hemithioacetal reversible-covalent interaction with cysteine 552. Key challenges addressed during the optimization are improving the FGFR4 potency, metabolic stability, and soly. leading ultimately to the highly selective first-in-class clin. candidate roblitinib.
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We cannot exclude the possibility that azidyl radical may react initially with the DMF solvent to generate an α-carbamoyl radical by HAT with a C–H bond on one of the N-Me groups (BDE ≈ 105 kcal mol–1; see ref (20)) and that this radical may in turn be responsible for abstracting a hydrogen from the alkylamine. We thank a reviewer for this suggestion.
There is no corresponding record for this reference. - 50Bordwell, F. G. Equilibrium Acidities in Dimethyl Sulfoxide Solution. Acc. Chem. Res. 1988, 21, 456– 463, DOI: 10.1021/ar00156a004Google Scholar50Equilibrium acidities in dimethyl sulfoxide solutionBordwell, Frederick G.Accounts of Chemical Research (1988), 21 (12), 456-63CODEN: ACHRE4; ISSN:0001-4842.A review with 62 refs.
- 51Prieto, A.; Taillefer, M. Visible-Light Decatungstate/Disulfide Dual Catalysis for the Hydro-Functionalization of Styrenes. Org. Lett. 2021, 23 (4), 1484– 1488, DOI: 10.1021/acs.orglett.1c00189Google Scholar51Visible-Light Decatungstate/Disulfide Dual Catalysis for the Hydro-Functionalization of StyrenesPrieto, Alexis; Taillefer, MarcOrganic Letters (2021), 23 (4), 1484-1488CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)An efficient photoredox system, relied on decatungstate/disulfide catalysts, for the hydrofunctionalization of styrenes was described. In this methodol. the use of disulfide as a cocatalyst was shown to be crucial for the reaction efficiency. This photoredox system was employed for the hydro-carbamoylation, -acylation, -alkylation, and -silylation of styrenes, gave access to a large variety of useful building blocks and high-value mols. such as amides and unsym. ketones from simple starting materials.
- 52Cismesia, M. A.; Yoon, T. P. Characterizing chain processes in visible light photoredox catalysis. Chem. Sci. 2015, 6, 5426– 5434, DOI: 10.1039/C5SC02185EGoogle Scholar52Characterizing chain processes in visible light photoredox catalysisCismesia, Megan A.; Yoon, Tehshik P.Chemical Science (2015), 6 (10), 5426-5434CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)The recognition that Ru(bpy)32+ and similar visible light absorbing transition metal complexes can be photocatalysts for a variety of synthetically useful org. reactions has resulted in a recent resurgence of interest in photoredox catalysis. However, many of the crit. mechanistic aspects of this class of reactions remain poorly understood. In particular, the degree to which visible light photoredox reactions involve radical chain processes has been a point of some disagreement that has not been subjected to systematic anal. We have now performed quantum yield measurements to demonstrate that three representative, mechanistically distinct photoredox processes involve product-forming chain reactions. Moreover, we show that the combination of quantum yield and luminescence quenching expts. provides a rapid method to est. the length of these chains. Together, these measurements constitute a robust, operationally facile strategy for characterizing chain processes in a wide range of visible light photoredox reactions.
- 53Tagami, T.; Arakawa, Y.; Minagawa, K.; Imada, Y. Efficient Use of Photons in Photoredox/Enamine Dual Catalysis with a Peptide-Bridged Flavin–Amine Hybrid. Org. Lett. 2019, 21, 6978– 6982, DOI: 10.1021/acs.orglett.9b02567Google Scholar53Efficient Use of Photons in Photoredox/Enamine Dual Catalysis with a Peptide-Bridged Flavin-Amine HybridTagami, Takuma; Arakawa, Yukihiro; Minagawa, Keiji; Imada, YasushiOrganic Letters (2019), 21 (17), 6978-6982CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)An isoalloxazine (flavin) ring system and a secondary amine have been integrated through a short peptide linker with the aim of using photons as efficiently as possible in photoredox/enamine dual catalysis. We herein report a peptide-bridged flavin-amine hybrid that can catalyze α-oxyamination of aldehydes with TEMPO under weak blue light irradn. to achieve an extremely high quantum yield of reaction (Φ = 0.80).
- 54Burés, J. Variable Time Normalization Analysis: General Graphical Elucidation of Reaction Orders from Concentration Profiles. Angew. Chem., Int. Ed. 2016, 55, 16084– 16087, DOI: 10.1002/anie.201609757Google Scholar54Variable Time Normalization Analysis: General Graphical Elucidation of Reaction Orders from Concentration ProfilesBures, JordiAngewandte Chemie, International Edition (2016), 55 (52), 16084-16087CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The recent technol. evolution of reaction monitoring techniques has not been paralleled by the development of modern kinetic analyses. The analyses currently used disregard part of the data acquired, thus requiring an increased no. of expts. to obtain sufficient kinetic information for a given chem. reaction. Herein, we present a simple graphical anal. method that takes advantage of the data-rich results provided by modern reaction monitoring tools. This anal. uses a variable normalization of the time scale to enable the visual comparison of entire concn. reaction profiles. As a result, the order in each component of the reaction, as well as kobs , is detd. with just a few expts. using a simple and quick math. data treatment. This anal. facilitates the rapid extn. of relevant kinetic information and will be a valuable tool for the study of reaction mechanisms.
- 55
If the addition step of the α-amino radical 25 to the styrene 6 is reversible, then the concentration of benzylic radical 26 would exhibit a dependence on the concentration of styrene 6 (pre-equilibrium approximation). However, if the addition step is rapid and essentially irreversible, then saturation kinetics will occur and the concentration of benzylic radical 26 will become independent of styrene 6 concentration.
There is no corresponding record for this reference. - 56Bloh, J. Z. A Holistic Approach to Model the Kinetics of Photocatalytic Reactions. Front. Chem. 2019, 7, 128, DOI: 10.3389/fchem.2019.00128Google Scholar56A holistic approach to model the kinetics of photocatalytic reactionsBloh, Jonathan Z.Frontiers in Chemistry (Lausanne, Switzerland) (2019), 7 (), 128CODEN: FCLSAA; ISSN:2296-2646. (Frontiers Media S.A.)Understanding and modeling kinetics is an essential part of the optimization and implementation of chem. reactions. In the case of photocatalytic reactions this is mostly done one-dimensionally, i.e., only considering the effect of one parameter at the same time. However, as discussed in this study, many of the relevant reaction parameters have mutual interdependencies that call for a holistic multi-dimensional approach to accurately model and understand their influence. Such an approach is described herein, and all the relevant equations given so that researchers can readily implement it to analyze and model their reactions.
- 57(a) Ji, Y.; DiRocco, D. A.; Kind, J.; Thiele, C. M.; Gschwind, R. M.; Reibarkh, M. LED-Illuminated NMR Spectroscopy: A Practical Tool for Mechanistic Studies of Photochemical Reactions. ChemPhotoChem. 2019, 3, 984– 992, DOI: 10.1002/cptc.201900109Google Scholar57aLED-Illuminated NMR Spectroscopy: A Practical Tool for Mechanistic Studies of Photochemical ReactionsJi, Yining; Di Rocco, Daniel A.; Kind, Jonas; Thiele, Christina M.; Gschwind, Ruth M.; Reibarkh, MikhailChemPhotoChem (2019), 3 (10), 984-992CODEN: CHEMYH ISSN:. (Wiley-VCH Verlag GmbH & Co. KGaA)This Concept article highlights the development of a novel anal. tool, LED-NMR (a combination of in situ light illumination using a light-emitting diode and NMR spectroscopy) and its variant UVNMR (LED-NMR coupled with UV/Vis absorption spectroscopy), as well as their applications in the mechanistic investigation of light-induced transformations. The utility of these new tools has been demonstrated by providing rich kinetic and structural data of reaction species offering mechanistic insights into photochem. and photocatalytic reactions. Furthermore, NMR actinometry has been recently developed as a practical and simple method for quantum yield measurements. Quantum yield is an important parameter in photo-induced processes, but is rarely measured in practice because of the barriers assocd. with traditional actinometry. These new tools and techniques streamline measurements of the quantum efficiency while affording informative mechanistic insights into photochem. reactions. We anticipate these techniques will enable chemists to further advance the rapidly emerging photochem. field.(b) Tlahuext-Aca, A.; Candish, L.; Garza-Sanchez, R. A.; Glorius, F. Decarboxylative Olefination of Activated Aliphatic Acids Enabled by Dual Organophotoredox/Copper Catalysis. ACS Catal. 2018, 8, 1715– 1719, DOI: 10.1021/acscatal.7b04281Google Scholar57bDecarboxylative Olefination of Activated Aliphatic Acids Enabled by Dual Organophotoredox/Copper CatalysisTlahuext-Aca, Adrian; Candish, Lisa; Garza-Sanchez, R. Aleyda; Glorius, FrankACS Catalysis (2018), 8 (3), 1715-1719CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)Herein, we demonstrate a dual organophotoredox/copper catalytic strategy toward challenging decarboxylative olefination processes proceeding in high yields and selectivities. This operationally simple method uses photoactive org. mols. and Cu(II)-complexes as catalysts to provide rapid access to a wide variety of olefins from inexpensive synthetic and biomass-derived carboxylic acids under mild light-mediated conditions. Mechanistic investigations suggest that the reaction rate for this process is controlled solely by the incident photon flux.(c) Le, C.; Wismer, M. K.; Shi, Z.-C.; Zhang, R.; Conway, D. V.; Li, G.; Vachal, P.; Davies, I. W.; MacMillan, D. W. C. A General Small-Scale Reactor To Enable Standardization and Acceleration of Photocatalytic Reactions. ACS Cent. Sci. 2017, 3, 647– 653, DOI: 10.1021/acscentsci.7b00159Google Scholar57cA general small-scale reactor to enable standardization and acceleration of photocatalytic reactionsLe, Chi "Chip"; Wismer, Michael K.; Shi, Zhi-Cai; Zhang, Rui; Conway, Donald V.; Li, Guoqing; Vachal, Petr; Davies, Ian W.; MacMillan, David W. C.ACS Central Science (2017), 3 (6), 647-653CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)Photocatalysis for org. synthesis has experienced an exponential growth in the past 10 years. However, the variety of exptl. procedures that have been reported to perform photon-based catalyst excitation has hampered the establishment of general protocols to convert visible light into chem. energy. To address this issue, we have designed an integrated photoreactor for enhanced photon capture and catalyst excitation. Moreover, the evaluation of this new reactor in eight photocatalytic transformations that are widely employed in medicinal chem. settings has confirmed significant performance advantages of this optimized design while enabling a standardized protocol.
- 58
We became aware that Professor Gaunt at the University of Cambridge was engaged in related studies toward photocatalytic amine synthesis. We are grateful to the Gaunt group for kindly agreeing to submit their results concurrently with our own studies, and thank them for their generosity and collegiality. See:
Blackwell, J. H.; Harris, G. R.; Smith, M. A.; Gaunt, M. J. Modular Photocatalytic Synthesis of α-Trialkyl-α-Tertiary Amines. J. Am. Chem. Soc. 2021, DOI: 10.1021/jacs.1c07402Google ScholarThere is no corresponding record for this reference.
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Abstract
Figure 1
Figure 1. (A) Prior art for catalytic γ-lactam synthesis from primary alkylamines. (B) Importance of γ-arylamines. (C) This work.
Figure 2
Figure 3
Figure 3. All reactions were carried out on a scale of 0.45 mmol. Isolated yields are reported. Notes: [a] 6% of inseparable, dialkylated product (wrt 1c). [b] With 3.0 equiv of amine. [c] With 1.0 equiv of amine. [d] The mass balance comprised a mixture of unidentified byproducts but no detectable starting materials. [e] 44% of unreacted amine 1l. [f] 46% of dialkylated product (wrt 1n). [g] 41% of dialkylated product (wrt 1s). [h] 54% of unreacted amine 1t and 6% styrene 6c. [i] 9% of dialkylated product (wrt 1u). [j] 9% of dialkylated product (wrt 1u). [k] Incomplete conversion to a complex mixture of products, which may include dialkylated material. [l] Isolated yield of Boc-protected 7zc (61:39 dr) plus 11% of the lactam derived from thermal lactamization of 7zc during workup. [m] 18% of dialkylated product (wrt 6c). [n] Incomplete conversion to a complex mixture of products. Boc = tert-butoxycarbonyl.
Figure 4
Figure 4. All reactions were carried out on a scale of 0.45 mmol. Isolated yields are reported. Notes: [a] Gave 40% NMR yield of 7ae along with 24% unreacted 6e and 6% of allylbenzene, plus other unidentified products. [b] Isolated as the phenol by oxidation the Bpin group with H2O2. [c] 22% of inseparable, debrominated product was also produced. [d] Yield given is for the N-Boc-protected derivative of 7ar, which proved easier to isolate. [e] 9% of a 1:2 telomer and 43% (wrt 6r) of reductive homocoupling product 1,4-di(pyrazin-2-yl)butane was also isolated. [f] The crude product mixture contained a 60:40 ratio of 7as to its debrominated analogue.
Figure 5
Figure 5. (A) Application to a protecting group-free synthesis of Fingolimod (4). (B) One-pot synthesis of a phosphonate mimic (21) of Fingolimod phosphate by tandem sequential α-C–H alkylation of ethanolamine (1r). Note: [a] 23% of the dialkylation product of 1r with 17 was also isolated. TMS = trimethylsilyl.
Figure 6
Figure 6. (A) Modular synthesis of 1,2,3,4-tetrahydroquinolines (THQs). In all cases except for 8an, the remaining mass balance comprised unreacted starting material. Note: [a] Obtained as an inseparable mixture with 8ac (14%), the proto-dechlorinated analogue of 8an. (B) Modular synthesis of 1,2,3,4-tetrahydronaphthyridines (THNs).
Figure 7
Figure 7. (A) Proposed catalytic cycle. (B) Stern–Volmer luminescence quenching. (C) Irreversibility of the HAT step. (D) Variable time normalization (VTNA) kinetic analysis using automated flow chemistry.
References
This article references 58 other publications.
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- 2Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.; Thomas, A. W.; Wilson, D. M.; Wood, A. Organic Synthesis Provides Opportunities to Transform Drug Discovery. Nat. Chem. 2018, 10, 383– 394, DOI: 10.1038/s41557-018-0021-z2Organic synthesis provides opportunities to transform drug discoveryBlakemore, David C.; Castro, Luis; Churcher, Ian; Rees, David C.; Thomas, Andrew W.; Wilson, David M.; Wood, AnthonyNature Chemistry (2018), 10 (4), 383-394CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)Despite decades of ground-breaking research in academia, org. synthesis is still a rate-limiting factor in drug-discovery projects. Here we present some current challenges in synthetic org. chem. from the perspective of the pharmaceutical industry and highlight problematic steps that, if overcome, would find extensive application in the discovery of transformational medicines. Significant synthesis challenges arise from the fact that drug mols. typically contain amines and N-heterocycles, as well as unprotected polar groups. There is also a need for new reactions that enable non-traditional disconnections, more C-H bond activation and late-stage functionalization, as well as stereoselectively substituted aliph. heterocyclic ring synthesis, C-X or C-C bond formation. We also emphasize that syntheses compatible with biomacromols. will find increasing use, while new technologies such as machine-assisted approaches and artificial intelligence for synthesis planning have the potential to dramatically accelerate the drug-discovery process. We believe that increasing collaboration between academic and industrial chemists is crucial to address the challenges outlined here.
- 3(a) Manßen, M.; Schafer, L. L. Early Transition Metal-Catalyzed Hydroaminoalkylation. Trends Chem. 2021, 3, 428– 429, DOI: 10.1016/j.trechm.2020.11.0073aEarly Transition Metal-Catalyzed HydroaminoalkylationManssen, Manfred; Schafer, Laurel L.Trends in Chemistry (2021), 3 (5), 428-429CODEN: TCRHBQ; ISSN:2589-5974. (Cell Press)There is no expanded citation for this reference.(b) Trowbridge, A.; Walton, S. M.; Gaunt, M. J. New Strategies for the Transition-Metal Catalyzed Synthesis of Aliphatic Amines. Chem. Rev. 2020, 120, 2613– 2692, DOI: 10.1021/acs.chemrev.9b004623bNew Strategies for the Transition-Metal Catalyzed Synthesis of Aliphatic AminesTrowbridge, Aaron; Walton, Scarlett M.; Gaunt, Matthew J.Chemical Reviews (Washington, DC, United States) (2020), 120 (5), 2613-2692CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. In light of the ever-increasing importance of aliph. amines across the range of chem. sciences, this review aims to provide a concise overview of modern transition-metal catalyzed approaches to alkylamine synthesis and their functionalization. Selected examples of amine bond forming reactions include, hydroamination and hydroaminoalkylation, transition-metal catalyzed C(sp3)-H functionalization and transition-metal catalyzed visible-light-mediated light photoredox catalysis.(c) Edwards, P. M.; Schafer, L. L. Early transition metal-catalyzed C–H alkylation: hydroaminoalkylation for Csp3–Csp3 bond-formation in the synthesis of selectively substituted amines. Chem. Commun. 2018, 54, 12543– 12560, DOI: 10.1039/C8CC06445H3cEarly transition metal-catalyzed C-H alkylation: hydroaminoalkylation for Csp3-Csp3 bond formation in the synthesis of selectively substituted aminesEdwards, P. M.; Schafer, L. L.Chemical Communications (Cambridge, United Kingdom) (2018), 54 (89), 12543-12560CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review. In this feature article, various selectively substituted amines that can be accessed by hydroaminoalkylation, with a special focus on the development of early transition metal catalysts for their rapid, step and atom efficient assembly were discussed.
- 4(a) Manßen, M.; Deng, D.; Zheng, C. H. M.; DiPucchio, R. C.; Chen, D.; Schafer, L. L. Ureate Titanium Catalysts for Hydroaminoalkylation: Using Ligand Design to Increase Reactivity and Utility. ACS Catal. 2021, 11, 4550– 4560, DOI: 10.1021/acscatal.1c000144aUreate Titanium Catalysts for Hydroaminoalkylation: Using Ligand Design to Increase Reactivity and UtilityManssen, Manfred; Deng, Danfeng; Zheng, Cameron H. M.; DiPucchio, Rebecca C.; Chen, Dafa; Schafer, Laurel L.ACS Catalysis (2021), 11 (8), 4550-4560CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)Herein, an earth-abundant and cost-efficient titanium catalyst generated in situ using com. available Ti(NMe2)4 and a simple to synthesize urea proligand was described. This system demonstrated high TOFs for hydroaminoalkylation with unactivated substrates and features easy to use com. available titanium amido precursors. Addnl., a high catalytic activity, scope of reactivity, and regioselectivity were all demonstrated in the transformation of unactivated terminal olefins with various alkyl and aryl secondary amines. Finally, syntheses of useful amine-contg. monomers suitable for the generation of amine-contg. materials, as well as amine-contg. building blocks for medicinal chem., were disclosed. These preparative methods avoid the necessity of glovebox techniques and were modified to be useful to all synthetic chemists.(b) Koperniku, A.; Schafer, L. L. Zirconium Catalyzed Hydroaminoalkylation for the Synthesis of α-Arylated Amines and N-Heterocycles. Chem. - Eur. J. 2021, 27, 6334– 6339, DOI: 10.1002/chem.2021000144bZirconium Catalyzed Hydroaminoalkylation for the Synthesis of α-Arylated Amines and N-HeterocyclesKoperniku, Ana; Schafer, Laurel L.Chemistry - A European Journal (2021), 27 (20), 6334-6339CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)The zirconium catalyzed hydroaminoalkylation of alkenes with N-aryl- and sterically demanding N-alkyl-α-arylated secondary amines by using com. available Zr(NMe2)4 is reported. N-phenyl- and N-isopropylbenzylamine are used as amine substrates to establish the alkene substrate scope. Exclusively linear products are obtained in the presence of bulky vinylsilanes. Challenging α-heteroarylated amines and functionalized alkene substrates are compatible with this easy to use catalyst, affording a new disconnection strategy for the atom- and step-economic prepn. of selectively substituted satd. α-arylated heterocycles.(c) Daneshmand, P.; Roşca, S.-C.; Dalhoff, R.; Yin, K.; DiPucchio, R. C.; Ivanovich, R. A.; Polat, D. E.; Beauchemin, A. M.; Schafer, L. L. Cyclic Ureate Tantalum Catalyst for Preferential Hydroaminoalkylation with Aliphatic Amines: Mechanistic Insights into Substrate Controlled Reactivity. J. Am. Chem. Soc. 2020, 142, 15740– 15750, DOI: 10.1021/jacs.0c045794cCyclic Ureate Tantalum Catalyst for Preferential Hydroaminoalkylation with Aliphatic Amines: Mechanistic Insights into Substrate Controlled ReactivityDaneshmand, Pargol; Rosca, Sorin-Claudiu; Dalhoff, Rosalie; Yin, Kejun; DiPucchio, Rebecca C.; Ivanovich, Ryan A.; Polat, Dilan E.; Beauchemin, Andre M.; Schafer, Laurel L.Journal of the American Chemical Society (2020), 142 (37), 15740-15750CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The efficient and catalytic amination of unactivated alkenes with simple secondary alkyl amines is preferentially achieved. A sterically accessible, N,O-chelated cyclic ureate tantalum catalyst was prepd. and characterized by X-ray crystallog. This optimized catalyst can be used for the hydroaminoalkylation of 1-octene with a variety of aryl and alkyl amines, but notably enhanced catalytic activity can be realized with challenging N-alkyl secondary amine substrates. This catalyst offers turnover frequencies of up to 60 h-1, affording full conversion at 5 mol% catalyst loading in approx. 20 min with these nucleophilic amines. Mechanistic investigations, including kinetic isotope effect (KIE) studies, reveal that catalytic turnover is limited by protonolysis of the intermediate 5-membered azametallacycle. A Hammett kinetic anal. shows that catalytic turnover is promoted by electron rich amine substrates that enable catalytic turnover. This more active catalyst is shown to be effective for late stage drug modification.(d) Bielefeld, J.; Doye, S. Fast Titanium-Catalyzed Hydroaminomethylation of Alkenes and the Formal Conversion of Methylamine. Angew. Chem., Int. Ed. 2020, 59, 6138– 6143, DOI: 10.1002/anie.2020011114dFast Titanium-Catalyzed Hydroaminomethylation of Alkenes and the Formal Conversion of MethylamineBielefeld, Jens; Doye, SvenAngewandte Chemie, International Edition (2020), 59 (15), 6138-6143CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The scientific interest in catalytic hydroaminoalkylation reactions of alkenes has vastly increased over the past decade, but these reactions have struggled to become a viable option for general lab. or industrial use because of reaction times of several days. The titanium-based catalytic system introduced in this work not only reduces the reaction time by several orders of magnitude, into the range of minutes, but the catalyst also is easily available from common starting materials, at a cost of ∼1 euro per mmol of catalyst. The authors were also able to formally perform C-H activation of methylamine and achieve coupling to a broad variety of alkenes, through silyl protection of the amine and simple deprotection by water.(e) Warsitz, M.; Doye, S. Linear Hydroaminoalkylation Products from Alkyl-Substituted Alkenes. Chem. - Eur. J. 2020, 26, 15121– 15125, DOI: 10.1002/chem.2020032234eLinear Hydroaminoalkylation Products from Alkyl-Substituted AlkenesWarsitz, Michael; Doye, SvenChemistry - A European Journal (2020), 26 (66), 15121-15125CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)A new one-pot procedure that includes an initial alkene hydroaminoalkylation with an α-silylated amine substrate and a subsequent protodesilylation reaction that delivers linear hydroaminoalkylation products with high selectivity from simple alkyl-substituted alkenes was presented. For that purpose, new titanium catalysts were developed, which are able to activate the α-C-H bond of more challenging α-silylated amine substrates. In addn., a direct relationship between the ligand structure of the new catalysts and the obtained regioselectivity was described.
- 5Geik, D.; Rosien, M.; Bielefeld, J.; Schmidtmann, M.; Doye, S. Titanium-Catalyzed Intermolecular Hydroaminoalkylation of Alkenes with Tertiary Amines. Angew. Chem., Int. Ed. 2021, 60, 9936– 9940, DOI: 10.1002/anie.2021004315Titanium-Catalyzed Intermolecular Hydroaminoalkylation of Alkenes with Tertiary AminesGeik, Dennis; Rosien, Michael; Bielefeld, Jens; Schmidtmann, Marc; Doye, SvenAngewandte Chemie, International Edition (2021), 60 (18), 9936-9940CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The first cationic titanium catalyst system for the intermol. hydroaminoalkylation of alkenes with various tertiary alkylamines is presented. Corresponding reactions which involve the addn. of the α-C-H bond of a tertiary amine across the C-C double bond of an alkene take place at temps. close to room temp. with excellent regioselectivity to deliver the branched products exclusively. Interestingly, for selected amines, α-C-H bond activation occurs not only at N-Me but also at N-methylene groups.
- 6
We use this term to refer to alkenes that do not readily participate as Michael acceptors in polar reactions with two-electron nucleophiles (e.g., non-conjugated alkenes, styrenes lacking π-acceptor substituents).
There is no corresponding record for this reference. - 7(a) Verma, P.; Richter, J. M.; Chekshin, N.; Qiao, J. X.; Yu, J.-Q. Iridium(I)-Catalyzed α-C(sp3)–H Alkylation of Saturated Azacycles. J. Am. Chem. Soc. 2020, 142, 5117– 5125, DOI: 10.1021/jacs.9b123207aIridium(I)-Catalyzed α-C(sp3)-H Alkylation of Saturated AzacyclesVerma, Pritha; Richter, Jeremy M.; Chekshin, Nikita; Qiao, Jennifer X.; Yu, Jin-QuanJournal of the American Chemical Society (2020), 142 (11), 5117-5125CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Satd. azacycles are commonly encountered in bioactive compds. and approved therapeutic agents. The development of methods for functionalization of the α-methylene C-H bonds of these highly privileged building blocks is of great importance, esp. in drug discovery. While much effort has been dedicated towards this goal of using a directed C-H activation approach, the development of directing groups that are both general, as well as practical, remains a significant challenge. Herein, the design and development of novel amidoxime directing groups is described for Ir(I)-catalyzed α-C(sp3)-H alkylation of satd. azacycles using readily available olefins as coupling partners. This protocol extends the scope of satd. azacycles to piperidines, azepane, and tetrahydroisoquinoline that are incompatible with our previously reported directing group. A variety of olefin coupling partners, including previously unreactive di-substituted terminal olefins and internal olefins, are compatible with this transformation. The selectivity for a branched α-C(sp3)-alkylation product is also obsd. for the first time when acrylate is used as the reaction partner. The development of practical, one-step installation and removal protocols further add to the utility of amidoxime directing groups.(b) Tran, A. T.; Yu, J.-Q. Practical Alkoxythiocarbonyl Auxiliaries for Iridium(I)-Catalyzed C–H Alkylation of Azacycles. Angew. Chem., Int. Ed. 2017, 56, 10530– 10534, DOI: 10.1002/anie.2017047557bPractical Alkoxythiocarbonyl Auxiliaries for Iridium(I)-Catalyzed C-H Alkylation of AzacyclesTran, Anh T.; Yu, Jin-QuanAngewandte Chemie, International Edition (2017), 56 (35), 10530-10534CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The development of new and practical alkylated 3-pentoxythiocarbonyl auxiliaries, e.g., I for Ir(I)-catalyzed C-H alkylation of azacycles was described. This method allowed for the α-C-H alkylation of a variety of substituted pyrrolidines, piperidines and tetrahydroisoquinolines through alkylation with alkenes. While the practicality of these simple carbamate-type auxiliaries was underscored by the ease of installation and removal, the method's utility was demonstrated in its ability to functionalize biol. relevant L-proline and L-trans-hydroxyproline, delivering unique 2,5-dialkylated amino acid analogs that were not accessible by other C-H functionalization methods.(c) Lahm, G.; Opatz, T. Unique Regioselectivity in the C(sp3)–H α-Alkylation of Amines: The Benzoxazole Moiety as a Removable Directing Group. Org. Lett. 2014, 16, 4201– 4203, DOI: 10.1021/ol501935d7cUnique Regioselectivity in the C(sp3)-H α-Alkylation of Amines: The Benzoxazole Moiety as a Removable Directing GroupLahm, Guenther; Opatz, TillOrganic Letters (2014), 16 (16), 4201-4203CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)The benzoxazol-2-yl- substituent was found to act as a removable activating and directing group in the Ir-catalyzed alkylation of C(sp3)-H bonds adjacent to nitrogen in secondary amines. It can be easily introduced by oxidative coupling or by an SNAr reaction, and it can be removed by hydroxide or by hydride redn. For 1,2,3,4-tetrahydroisoquinolines, activation exclusively takes place in the 3-position. A variety of activated as well as unactivated terminal olefins are suitable reaction partners.(d) Schinkel, M.; Wang, L.; Bielefeld, K.; Ackermann, L. Ruthenium(II)-Catalyzed C(sp3)–H α-Alkylation of Pyrrolidines. Org. Lett. 2014, 16, 1876– 1879, DOI: 10.1021/ol500300w7dRuthenium(II)-Catalyzed C(sp3)-H α-Alkylation of PyrrolidinesSchinkel, Marvin; Wang, Lianhui; Bielefeld, Kris; Ackermann, LutzOrganic Letters (2014), 16 (7), 1876-1879CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A catalytic system comprising [RuCl2(PPh3)3], AgOTf, and BINAP enabled atom- and step-economical addns. of C(sp3)-H bonds onto unactivated alkenes under comparably mild reaction conditions. The pyridyl directing group was easily removed to furnish the corresponding (NH)-free amines with ample scope.
- 8Visible light photocatalysis in organic chemistry; Stephenson, C. R. J., Yoon, T., MacMillan, D. W. C., Eds.; Wiley-VCH: Berlin, 2018.There is no corresponding record for this reference.
- 9
Selected examples:
(a) Zhao, H.; Leonori, D. Minimization of Back-Electron Transfer Enables the Elusive sp3 C–H Functionalization of Secondary Anilines. Angew. Chem., Int. Ed. 2021, 60, 7669– 7674, DOI: 10.1002/anie.2021000519aMinimization of Back-Electron Transfer Enables the Elusive sp3 C-H Functionalization of Secondary AnilinesZhao, Huaibo; Leonori, DanieleAngewandte Chemie, International Edition (2021), 60 (14), 7669-7674CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Anilines are some of the most used class of substrates for application in photoinduced electron transfer. N,N-Dialkyl-derivs. enable radical generation α to the N-atom by oxidn. followed by deprotonation. This approach is however elusive to monosubstituted anilines owing to fast back-electron transfer (BET). Here we demonstrate that BET can be minimised by using photoredox catalysis in the presence of an exogenous alkylamine. This approach synergistically aids aniline SET oxidn. and then accelerates the following deprotonation. In this way, the generation of α-anilinoalkyl radicals is now possible and these species can be used in a general sense to achieve divergent sp3 C-H functionalization.(b) Grayson, J. D.; Cresswell, A. J. γ-Amino Phosphonates via the Photocatalytic α-C–H Alkylation of Primary Amines. Tetrahedron 2021, 81, 131896, DOI: 10.1016/j.tet.2020.1318969bγ-Amino phosphonates via the photocatalytic α-C-H alkylation of primary aminesGrayson, James D.; Cresswell, Alexander J.Tetrahedron (2021), 81 (), 131896CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)We report a simple photocatalytic protocol for the direct synthesis of γ-aminophosphonates via the α-C-H alkylation of unprotected, aliph. primary amines with di-Et vinylphosphonate. These motifs are valuable bioisosteres of γ-amino acids and O-phosphorylated amino alcs. Visible-light photoredox catalysis in combination with hydrogen atom transfer (HAT) catalysis is used to access the necessary α-amino radical intermediates for C-C bond formation. The procedure is also demonstrated on gram-scale in continuous flow for the synthesis of a racemic, protected deriv. of the mGlu agonist 2-amino-4-phosphonobutyric acid (AP4).(c) Leng, L.; Fu, Y.; Liu, P.; Ready, J. M. Regioselective, Photocatalytic α-Functionalization of Amines. J. Am. Chem. Soc. 2020, 142, 11972– 11977, DOI: 10.1021/jacs.0c037589cRegioselective, Photocatalytic α-Functionalization of AminesLeng, Lingying; Fu, Yue; Liu, Peng; Ready, Joseph M.Journal of the American Chemical Society (2020), 142 (28), 11972-11977CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Photocatalytic α-functionalization of amines provided a mild and atom-economical means to synthesized α-branched amines. Prior examples featured sym. or electronically biased substrates. A controllable α-functionalization of amines in which regioselectivity can be tuned with minor changes to the reaction conditions.(d) Ryder, A. S. H.; Cunningham, W. B.; Ballantyne, G.; Mules, T.; Kinsella, A. G.; Turner-Dore, J.; Alder, C. M.; Edwards, L. J.; McKay, B. S. J.; Grayson, M. N.; Cresswell, A. J. Photocatalytic α-Tertiary Amine Synthesis via C–H Alkylation of Unmasked Primary Amines. Angew. Chem., Int. Ed. 2020, 59, 14986– 14991, DOI: 10.1002/anie.2020052949dPhotocatalytic α-Tertiary Amine Synthesis via C-H Alkylation of Unmasked Primary AminesRyder, Alison S. H.; Cunningham, William B.; Ballantyne, George; Mules, Tom; Kinsella, Anna G.; Turner-Dore, Jacob; Alder, Catherine M.; Edwards, Lee J.; McKay, Blandine S. J.; Grayson, Matthew N.; Cresswell, Alexander J.Angewandte Chemie, International Edition (2020), 59 (35), 14986-14991CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A practical, catalytic entry to α,α,α-trisubstituted (α-tertiary) primary amines by C-H functionalization has long been recognized as a crit. gap in the synthetic toolbox. The authors report a simple and scalable soln. to this problem that does not require any in situ protection of the amino group and proceeds with 100% atom-economy. The authors' strategy, which uses an org. photocatalyst in combination with azide ion as a hydrogen atom transfer (HAT) catalyst, provides a direct synthesis of α-tertiary amines, or their corresponding γ-lactams. The authors anticipate that this methodol. will inspire new retrosynthetic disconnections for substituted amine derivs. in org. synthesis, and particularly for challenging α-tertiary primary amines.(e) Cao, K.; Tan, S. M.; Lee, R.; Yang, S.; Jia, H.; Zhao, X.; Qiao, B.; Jiang, Z. Catalytic Enantioselective Addition of Prochiral Radicals to Vinylpyridines. J. Am. Chem. Soc. 2019, 141, 5437– 5443, DOI: 10.1021/jacs.9b002869eCatalytic Enantioselective Addition of Prochiral Radicals to VinylpyridinesCao, Kangning; Tan, Siu Min; Lee, Richmond; Yang, Songwei; Jia, Hongshao; Zhao, Xiaowei; Qiao, Baokun; Jiang, ZhiyongJournal of the American Chemical Society (2019), 141 (13), 5437-5443CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Pyridine, one of the most important azaarenes, is ubiquitous in functional mols. The electronic properties of pyridine were exploited to trigger asym. transformations of prochiral species as a direct approach for accessing chiral pyridine derivs. However, the full potential of this synthetic strategy for the construction of enantioenriched γ-functionalized pyridines remains untapped. Here, the authors describe the first enantioselective addn. of prochiral radicals to vinylpyridines under cooperative photoredox and asym. catalysis mediated by visible light. The enantioselective reductive couplings of vinylpyridines with aldehydes, ketones, and imines were achieved by employing a chiral Bronsted acid to activate the reaction partners and provide stereocontrol via H-bonding interactions. Valuable chiral γ-secondary/tertiary hydroxyl- and amino-substituted pyridines were obtained in high yields with good to excellent enantioselectivities.(f) Ashley, M. A.; Yamauchi, C.; Chu, J. C. K.; Otsuka, S.; Yorimitsu, H.; Rovis, T. Photoredox-Catalyzed Site-Selective α-Csp3–H Alkylation of Primary Amine Derivatives. Angew. Chem., Int. Ed. 2019, 58, 4002– 4006, DOI: 10.1002/anie.2018122279fPhotoredox-Catalyzed Site-Selective α-C(sp3)-H Alkylation of Primary Amine DerivativesAshley, Melissa A.; Yamauchi, Chiaki; Chu, John C. K.; Otsuka, Shinya; Yorimitsu, Hideki; Rovis, TomislavAngewandte Chemie, International Edition (2019), 58 (12), 4002-4006CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The synthetic utility of tertiary amines to oxidatively generate α-amino radicals is well established, however, primary amines remain challenging because of competitive side reactions. This report describes the site-selective α-functionalization of primary amine derivs. through the generation of α-amino radical intermediates. Employing visible-light photoredox catalysis, primary sulfonamides are coupled with electron-deficient alkenes to efficiently and mildly construct C-C bonds. Interestingly, a divergence between intermol. hydrogen-atom transfer (HAT) catalysis and intramol. [1,5] HAT was obsd. through precise manipulation of the protecting group. This dichotomy was leveraged to achieve excellent α/δ site-selectivity.(g) Rossolini, T.; Leitch, J. A.; Grainger, R.; Dixon, D. J. Photocatalytic Three-Component Umpolung Synthesis of 1,3-Diamines. Org. Lett. 2018, 20, 6794– 6798, DOI: 10.1021/acs.orglett.8b029239gPhotocatalytic Three-Component Umpolung Synthesis of 1,3-DiaminesRossolini, Thomas; Leitch, Jamie A.; Grainger, Rachel; Dixon, Darren J.Organic Letters (2018), 20 (21), 6794-6798CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A visible-light-mediated photocatalytic umpolung synthesis of 1,3-diamines from in situ-generated imines and dehydroalanine derivs. is described. Pivoting on a key nucleophilic addn. of photocatalytically generated α-amino radicals to electron-deficient alkenes, this three-component coupling reaction affords 1,3-diamines efficiently and diastereoselectively. The mild protocol tolerates a wide variety of functionalities including heterocycles, pinacol boronates, and aliph. chains. Application to biol. relevant α-amino-γ-lactam synthesis and extension to 1,3-aminoalcs. is also demonstrated.(h) Trowbridge, A.; Reich, D.; Gaunt, M. J. Multicomponent synthesis of tertiary alkylamines by photocatalytic olefin-hydroaminoalkylation. Nature 2018, 561, 522– 527, DOI: 10.1038/s41586-018-0537-99hMulticomponent synthesis of tertiary alkylamines by photocatalytic olefin-hydroaminoalkylationTrowbridge, Aaron; Reich, Dominik; Gaunt, Matthew J.Nature (London, United Kingdom) (2018), 561 (7724), 522-527CODEN: NATUAS; ISSN:0028-0836. (Nature Research)A multicomponent reductive photocatalytic technol. was reported that combines readily available dialkylamines, carbonyls and alkenes to build architecturally complex and functionally diverse tertiary alkylamines in a single step. This olefin-hydroaminoalkylation process involved a visible-light-mediated redn. of in-situ-generated iminium ions to selectively furnish previously inaccessible alkyl-substituted α-amino radicals, which subsequently reacted with alkenes to form C(sp3)-C(sp3) bonds. The operationally straightforward reaction exhibited broad functional-group tolerance, facilitated the synthesis of drug-like amines that were not readily accessible by other methods and was amenable to late-stage functionalization applications, making it of interest in areas such as pharmaceutical and agrochem. research.(i) Ye, J.; Kalvet, I.; Schoenebeck, F.; Rovis, T. Direct α-alkylation of primary aliphatic amines enabled by CO2 and electrostatics. Nat. Chem. 2018, 10, 1037– 1041, DOI: 10.1038/s41557-018-0085-99iDirect α-alkylation of primary aliphatic amines enabled by CO2 and electrostaticsYe, Juntao; Kalvet, Indrek; Schoenebeck, Franziska; Rovis, TomislavNature Chemistry (2018), 10 (10), 1037-1041CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)Primary aliph. amines are important building blocks in org. synthesis due to the presence of a synthetically versatile NH2 group. N-functionalization of primary amines is well established, but selective C-functionalization of unprotected primary amines remains challenging. Here, we report the use of CO2 as an activator for the direct transformation of abundant primary aliph. amines into valuable γ-lactams under photoredox and hydrogen atom transfer (HAT) catalysis. Exptl. and computational studies suggest that CO2 not only inhibits undesired N-alkylation of primary amines, but also promotes selective intermol. HAT by an electrostatically accelerated interaction between the in situ-generated neg. charged carbamate and the pos. charged quinuclidinium radical. This electrostatic attraction overwhelms the inherent bond dissocn. energies which suggest that HAT should occur unselectively. We anticipate that our findings will open up new avenues for amine functionalizations as well as selectivity control in HAT reactions.(j) McManus, J. B.; Onuska, N. P. R.; Nicewicz, D. A. Generation and Alkylation of α-Carbamyl Radicals via Organic Photoredox Catalysis. J. Am. Chem. Soc. 2018, 140, 9056– 9060, DOI: 10.1021/jacs.8b048909jGeneration and Alkylation of α-Carbamyl Radicals via Organic Photoredox CatalysisMcManus, Joshua B.; Onuska, Nicholas P. R.; Nicewicz, David A.Journal of the American Chemical Society (2018), 140 (29), 9056-9060CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Strategies for the direct C-H functionalization of amines are valuable as these compds. comprise a no. of pharmaceuticals, agrochems. and natural products. This work describes a novel method for the C-H functionalization of carbamate-protected secondary amines via α-carbamyl radicals generated using photoredox catalysis. The use of the highly oxidizing, org. acridinium photoredox catalyst allows for direct oxidn. of carbamate-protected amines with high redox potentials to give the corresponding carbamyl cation radical. Following deprotonation, the resultant open-shell species can be intercepted by a variety of Michael acceptors to give elaborate α-functionalized secondary amines. The reaction proceeds under mild conditions without the requirement of exogenous redox mediators or substrate prefunctionalization. Addnl., we were able to showcase the utility of this methodol. through the enantioselective synthesis of the indolizidine alkaloid, (+)-monomorine I.(k) Lee, K. N.; Lei, Z.; Ngai, M.-Y. β-Selective Reductive Coupling of Alkenylpyridines with Aldehydes and Imines via Synergistic Lewis Acid/Photoredox Catalysis. J. Am. Chem. Soc. 2017, 139, 5003– 5006, DOI: 10.1021/jacs.7b013739kβ-Selective Reductive Coupling of Alkenylpyridines with Aldehydes and Imines via Synergistic Lewis Acid/Photoredox CatalysisLee, Katarzyna N.; Lei, Zhen; Ngai, Ming-YuJournal of the American Chemical Society (2017), 139 (14), 5003-5006CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Umpolung (polarity reversal) strategies of aldehydes and imines have dramatically expanded the scope of carbonyl and iminyl chem. by facilitating reactions with non-nucleophilic reagents. Herein, we report the first visible light photoredox-catalyzed β-selective reductive coupling of alkenylpyridines with carbonyl or iminyl derivs. with the aid of a Lewis acid co-catalyst. Our process tolerates complex mol. scaffolds (e.g., sugar, natural product, and peptide derivs.) and is applicable to the prepn. of compds. contg. a broad range of heterocyclic moieties. Mechanistic investigations indicate that the key step involves single-electron-transfer redn. of aldehydes or imines followed by the addn. of resulting ketyl or α-aminoalkyl radicals to Lewis acid-activated alkenylpyridines.(l) Chu, L.; Ohta, C.; Zuo, Z.; MacMillan, D. W. C. Carboxylic Acids as A Traceless Activation Group for Conjugate Additions: A Three-Step Synthesis of (±)-Pregabalin. J. Am. Chem. Soc. 2014, 136, 10886– 10889, DOI: 10.1021/ja505964r9lCarboxylic Acids as A Traceless Activation Group for Conjugate Additions: A Three-Step Synthesis of (±)-PregabalinChu, Lingling; Ohta, Chisa; Zuo, Zhiwei; MacMillan, David W. C.Journal of the American Chemical Society (2014), 136 (31), 10886-10889CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The direct application of carboxylic acids as a traceless activation group for radical Michael addns. has been accomplished via visible light-mediated photoredox catalysis. Photon-induced oxidn. of a broad series of carboxylic acids, including hydrocarbon-substituted, α-oxy, and α-amino acids, provides a versatile CO2-extrusion platform to generate Michael donors without the requirement for organometallic activation or propagation. A diverse array of Michael acceptors is amenable to this new conjugate addn. strategy. An application of this technol. to a three-step synthesis of the medicinal agent pregabalin (commercialized by Pfizer under the trade name Lyrica) is also presented.(m) Miyake, Y.; Nakajima, K.; Nishibayashi, Y. Visible-Light-Mediated Utilization of α-Aminoalkyl Radicals: Addition to Electron-Deficient Alkenes Using Photoredox Catalysts. J. Am. Chem. Soc. 2012, 134, 3338– 3341, DOI: 10.1021/ja211770y9mVisible-Light-Mediated Utilization of α-Aminoalkyl Radicals: Addition to Electron-Deficient Alkenes Using Photoredox CatalystsMiyake, Yoshihiro; Nakajima, Kazunari; Nishibayashi, YoshiakiJournal of the American Chemical Society (2012), 134 (7), 3338-3341CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Synthetic use of α-aminoalkyl radicals formed by single electron oxidn. of amines is quite limited. Here the authors demonstrate addn. of α-aminoalkyl radicals to electron-deficient alkenes by visible-light-mediated electron transfer using transition metal polypyridyl complexes as photocatalysts, via a sequential redox pathway. - 10The non-catalytic HAA of unprotected primary amines with non-electrophilic alkenes necessitates a large excess of the amine partner (∼13–26 equiv) and forcing reaction conditions (>120 °C, ∼10 mol% peroxide) and gives extensive telomerization. See:Urry, W. H.; Juveland, O. O. Free Radical Additions of Amines to Olefins. J. Am. Chem. Soc. 1958, 80, 3322– 3328, DOI: 10.1021/ja01546a03310Free radical additions of amines to olefinsUrry, W. H.; Juveland, O. O.Journal of the American Chemical Society (1958), 80 (), 3322-8CODEN: JACSAT; ISSN:0002-7863.The free radical chain addns. of amines to olefins in the presence of peroxides or light yield higher homologous amines which are products of α-C alkylation. BuNH2 (370 g.), b77 -8°, n20D 1.4013, 28 g. 1-octene (I), b. 120-1° n20D 1.4090, and 4.5 g. (Me3CO)2 (II) (half-life in Bu3N at 125° 11.3 hrs., and at 135° 4.6 hrs.) heated 48 hrs. in a sealed tube at 123-6° and fractionated yielded 2.5 g. Me3COH, 12.35 g. I and BuNH2, 7.35 g. PrCH(NH2)C8H17 (III), b1 70-1°, n20D 1.4407, 3.0 g. distillate, b1 110-60°, n20D 1.4728, and 7.1 g. residue. PrCOC8H17 treated with HCO2H and HCO2NH4 yielded 34% III, b1 69-71°, n20D 1.4408. III gave with PhNCS a phenylthiourea deriv., m. 58-8.5°. III gave with HCl the III.HCl, m. 88.5-90°. III (1.7 g.) was obtained when 490 g. BuNH2 and 30 g. I were illuminated internally 120 hrs. with a Hg vapor lamp at 30-5°; 6.35 g. higher boiling residue was also formed. I (26 g.) and 4.5 g. II in 458 g. C6H13NH2 heated 60 hrs. at 124-7° and distd. gave 4 g. Me3COH, unchanged C6H13NH2, 16.0 g. AmCH(NH2)C8H17 (IV), b1, 84-5°, n20D 1.4435 (phenylthiourea deriv., m. 69-9.5°), 5.7 g. distillate, b1 120-55°, n20D 1.4560, and 12 g. residue. IV, b1 84-6°, n20D 1.4432, was also obtained from AmCOC8H17 with HCO2H and HCO2NH4. Me2CHNH2 (118 g.), 18 g. I, and 3 g. II heated 55 hrs. at 188-22° yielded 12 g. Me2C(NH2)C8H17, b1, 47-8°, n20D 1.4333 (HCl salt, m. 116-17°), 3.5 g. distillate, b1 80-120°, and 5.5 g residue. Cyclohexylamine (V) (497 g.), 25 g. I, and 6.0 g. II heated 53 hrs. at 124-8° and distd. gave 5.5 g. Me3COH and unchanged V and the following fractions: (1) 1.85 g., b1 88-9°, n20D 1.4788; (2) 2.7 g., b1 89-92° n20D 1.4772; (3) 4.0 g., b1 92°, n20D 1.4759; (4) 23 g. 1-amino-1-octylcyclohexane (VI), b1 95-7°, n20D 1.4657 (HCl salt, m. 107.5-8.5°; phenylthiourea deriv., m. 91-1.5°); (5) 4.8 g., b1, 150-65°, n20D 1.4770 (apparently a mixt. of VI and the addn. product from 2 moles I and 1 mole V); (5) 9.4 g., residue. Fractions 1, 2, and 3 combined and an aliquot (3.2 g.) hydrogenated gave 1 g. VI, b1 94-6°, n20D 1.4680. CH2:CHCH2OH (VII) (23 g.) and 5.0 g. II in 380 g. pyrrolidine heated 48 hrs. at 120-2° in a sealed tube and distd. gave 27.8 g. 2-(3-hydroxypropyl)pyrrolidine (VIII), b1 80-1°, n20D 1.4870, and 10.2 g. residue. VIII (4.25 g.) and 95 cc. 48% HBr heated 12 hrs. in a sealed tube at 100° and evapd. and the residue recrystd. from Me2CO yielded 2.5 g. 2-(3-bromopropyl)pyrrolidine.HBr (IX), m. 102-3°. IX (2.5 g.) added during 2.5 hrs. with stirring to 200 cc. 0.1N NaOH at 50°, cooled, treated with 3 g. PhSO2Cl, allowed to stand 1 hr., and steam-distd., the distillate extd. with Et2O, and the ext. treated with 2 g. picric acid yielded 1.5 g. pyrrolizidine picrate, m. 256.6-8°. Piperidine (X) (81 g.) and 1.1 g. II pressured 24 hrs. at 125° with 30-40 lb. C2H4 while adding an addnl. 1.8 g. II after 8 hrs., and the mixt. distd. yielded 2.7 g. Me3COH, 72 g. X, and 2.6 g. 2-ethylpiperidine, b52 73-5°, n20D 1.4544 (HCl salt, m. 180-1°; picrate, m. 130-1°; chloro platinate, m. 202-4°), and left 1.1 g. residue. II (1.2 g.) and 87 g. X kept 12 hrs. at 125° under 30-40 lb. MeCH:CH2 while adding an addnl. 1.8 g. II after hrs. and distd. gave 4 g. dl-coniine, b70 93°, n23D 1.4513 (HCl salt, m. 211-12°; platinichloride, m. 155-7°), 1.40 g. forerun, and 2.6 g. residue. X (360 g.), 23 g. 1-hexene, and 5 g. II heated 50 hrs. in a sealed tube at 122-5° and fractionated gave 3.7 g. Me3COH, 8.5 g. 1-hexene, and piperidine as forerun followed by 15.6 g. 2-hexylpiperidine (XI), b4.5 77-8°, n20D 1.4580, 2.8 g. distillate, b3 80-140°, n20D 1.4740, and 4.4 g. residue. α-Picoline (55.5 g.) treated with 30.2 g. AmBr and 27 g. NaNH2 yielded 60% XI, b5 80°, n20D 1.4575 (HCl salt, m. 162-3°). X (382 g.), 40 g. I, and 3 g. II kept 50 hrs. at 120° under N while being treated after 6 hrs. and after 12 hrs. with addnl. 2-g. portions II and the mixt. distd. yielded 6.3 g. Me3COH, 359.5 g. unchanged X, 9.5 g. I, b. 118-20°, 31.7 g. 2-octylpiperidine (XII), b1 89°, n20D 1.4589, 5.8 g. distillate, b1 145-55°, n20D 1.4683 (apparently condensation product of 1 mole X with 2 moles I), and 4.5 g. residue. 2-Octylpyridine (obtained in 65% yield by the reaction of 111 g. α-picoline with 1.2 moles C7H15Br, and 54 g. NaNH2) hydrogenated over PtO2 in AcOH yielded 95% XII, b1 89°, n20D 1.4587; phenylthiourea deriv., m. 95°; HCl salt, m. 155-6°; picrate, m. 78-80°. I (20.5 g.) in 207 g. X illuminated 168 hrs. with a quartz-Hg discharge tube at 30-5° gave 1 g. XII. X (385 g.), 19 g. VII, and 4.5 g. II heated 48 hrs. at 122-30° in a sealed tube and distd. gave 21.8 g. 2-(3-hydroxypropyl)piperidine (XIII), b1 93-5°, n25D 1.4890; HCl salt, m. 129-30°. X (340 g.), 19 g. VII, and 4.5 g. (EtMe2CO)2 kept 48 hrs. at 100° gave 2.3 g. XIII, b1, 93-5°, n20D 1.4900, and 4.2 g. residue. X (180 g.), 9 g. VII, and 1.5 g. (Me3CO.OCHMe)2 kept 50 hrs. at 95° gave 1.1 g. XIII and 2.6 g. residue. XIII (3 g.) in 60 cc. 48% HBr heated 12 hrs. at 100° and evapd. in vacuo, the residue recrystd. from Me2CO, the resulting 3.7 g. 2-(3-bromopropyl)piperidine, m. 180-2°, added during 2 hrs. at 50° to 2000 cc. 0.1N NaOH, cooled, treated with 3 g. PhSO2Cl, and steam-distd., the distillate (50 cc.) extd. with Et2O, and the ext. worked up gave 0.7 g. 1-azabicyclo[4.3.0]nonane, b32 86°, n21D 1.4697. X (374 g.), 21 g. CH2:CHCH2CN, and 5 g. II kept 72 hrs. at 120-4° yielded 20.7 g. 2-(3-cyanopropyl)piperidine, b1 59-60°, n20D 1.4748 (HCl salt, m. 135-6°), and 7.1 g. distillate, b1 100-40°, n20D 1.5024. 4-Pipecoline (198 g.), 10 g. VII, and 3 g. II heated 48 hrs. at 123-5° in a sealed tube gave 9.1 g. 4-Me deriv. of XIII, b1 99-100°, n20D 1.4875, and 8.0 g. residue. N-Methylpiperidine (284 g.), 20 g. I, and 6 g. II heated 48 hrs. at 122-6° in a sealed tube and distd. gave 6 g. 1-methyl-2-octylpiperidine (XIV), b1 84-5°, n20D 1.4593, 6.8 g. distillate, b1, 110-70°, n20D 1.4692, and 8.6 g. residue. HCO2H (18.9 g.), 14 g. 35% aq. CH2O, and 29 g. XII yielded 23.3 g. XIV, b1 85°, n20D 1.4590; XIV.MeI, m. 165°; XIV.EtI, m. 138-9°.
- 11
Non-electrophilic styrenes in photoredox-catalyzed, intermolecular HAA are scarce and limited to tertiary amines or N-Boc α-amino acids:
(a) Wu, Z.; Gockel, S.; Hull, K. Anti-Markovnikov Hydro(amino)alkylation of Vinylarenes via Photoredox Catalysis. Research Square Preprint 2021, DOI: 10.21203/rs.3.rs-366556/v1There is no corresponding record for this reference.(b) Larionova, N.; Ondozabal, J. M.; Smith, E. G.; Cambeiro, X. A. A photocatalytic regioselective hydroaminoalkylation of aryl-substituted alkenes with simple amines. Org. Lett. 2021, 23, 5383– 5388, DOI: 10.1021/acs.orglett.1c0171511bA Photocatalytic Regioselective Direct Hydroaminoalkylation of Aryl-Substituted Alkenes with AminesLarionova, Natalia A.; Ondozabal, Jun Miyatake; Smith, Emily G.; Cambeiro, Xacobe C.Organic Letters (2021), 23 (14), 5383-5388CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A photocatalytic method for the α-selective hydroaminoalkylation of cinnamate esters has been developed. The reaction involves the regioselective addn. of α-aminoalkyl radicals generated from aniline derivs. or aliph. amines to the α-position of unsatd. esters. The scope of arom. alkenes was extended to styrenes undergoing hydroaminoalkylation with anti-Markovnikov selectivity, which confirms the importance of the arom. group at the β-position. Simple scale-up is demonstrated under continuous flow conditions, highlighting the practicality of the method.(c) Lovett, G. H.; Sparling, B. A. Decarboxylative Anti-Michael Addition to Olefins Mediated by Photoredox Catalysis. Org. Lett. 2016, 18, 3494– 3497, DOI: 10.1021/acs.orglett.6b0171211cDecarboxylative Anti-Michael Addition to Olefins Mediated by Photoredox CatalysisLovett, Gabrielle H.; Sparling, Brian A.Organic Letters (2016), 18 (14), 3494-3497CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)Decarboxylative coupling of carboxylic acids with activated olefins has been accomplished using visible light photoredox catalysis. The strategic placement of a radical-stabilizing arom. group at the β-position of the olefin component biases the regioselectivity of the addn., allowing reliable, facile access to anti-Michael-type products from readily available precursors. The scope of this methodol. was demonstrated with a range of carboxylic acids and appropriately substituted olefins and was applied toward a two-step synthesis of the antiarrhythmic agent encainide. - 12(a) Nagai, M.; Nagamoto, M.; Nishimura, T.; Yorimitsu, H. Iridium-Catalyzed sp3 C–H Alkylation of 3-Carbonyl-2-(alkylamino)pyridines with Alkenes. Chem. Lett. 2017, 46, 1176– 1178, DOI: 10.1246/cl.17037312aIridium-catalyzed sp3 C-H alkylation of 3-carbonyl-2-(alkylamino)pyridines with alkenesNagai, Masaki; Nagamoto, Midori; Nishimura, Takahiro; Yorimitsu, HidekiChemistry Letters (2017), 46 (8), 1176-1178CODEN: CMLTAG; ISSN:0366-7022. (Chemical Society of Japan)Iridium-catalyzed C-H alkylation of 3-carbonyl-2-(alkylamino)pyridines via secondary sp3 C-H activation adjacent to the nitrogen atom, with terminal alkenes proceeded to give the corresponding α-secondary amines such as I [R1 = Ph, NH2, pyrrolodin-1-yl, etc; R2 = CH2OH, 4-ClC6H4, Bn, etc.; R3 = Me, CH2CH3, Ph , etc.] in high yields. The reaction was efficiently catalyzed by a cationic iridium complex coordinated with 1,5-cyclooctadiene.(b) Pan, S.; Matsuo, Y.; Endo, K.; Shibata, T. Cationic iridium-catalyzed enantioselective activation of secondary sp3 C–H bond adjacent to nitrogen atom. Tetrahedron 2012, 68, 9009– 9015, DOI: 10.1016/j.tet.2012.08.07112bCationic iridium-catalyzed enantioselective activation of secondary sp3 C-H bond adjacent to nitrogen atomPan, Shiguang; Matsuo, Yusuke; Endo, Kohei; Shibata, TakanoriTetrahedron (2012), 68 (44), 9009-9015CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)A cationic Ir(I)-tolBINAP complex catalyzed an enantioselective C-C bond formation, which was initiated by secondary sp3 C-H bond cleavage adjacent to nitrogen atom. A wide variety of 2-(alkylamino)pyridines and alkenes were selectively transformed into the corresponding chiral amines with moderate to almost perfect enantiomeric excesses. E.g., reaction of 2-(ethylamino)pyridine and styrene gave (-)-I. Alkynes were also investigated as coupling partners. The effect of alkyl structure in substrates and directing groups were studied. This transformation represents the first example of a highly enantioselective C-H bond activation of a methylene group, not at allylic or benzylic position.(c) Pan, S.; Endo, K.; Shibata, T. Ir(I)-Catalyzed Enantioselective Secondary sp3 C–H Bond Activation of 2-(Alkylamino)pyridines with Alkenes. Org. Lett. 2011, 13, 4692– 4695, DOI: 10.1021/ol201907w12cIr(I)-Catalyzed Enantioselective Secondary sp3 C-H Bond Activation of 2-(Alkylamino)pyridines with AlkenesPan, Shiguang; Endo, Kohei; Shibata, TakanoriOrganic Letters (2011), 13 (17), 4692-4695CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A cationic Ir(I)-tolBINAP complex catalyzed an enantioselective C-C bond formation initiated by secondary sp3 C-H bond cleavage adjacent to a nitrogen atom. The reaction of 2-(alkylamino)pyridines with various alkenes gave chiral amines, e.g., I, in good yields with high enantiomeric excesses.
- 13Koperniku, A.; Foth, P. J.; Sammis, G. M.; Schafer, L. L. Zirconium Hydroaminoalkylation. An Alternative Disconnection for the Catalytic Synthesis of α-Arylated Primary Amines. J. Am. Chem. Soc. 2019, 141, 18944– 18948, DOI: 10.1021/jacs.9b1046513Zirconium Hydroaminoalkylation. An Alternative Disconnection for the Catalytic Synthesis of α-Arylated Primary AminesKoperniku, Ana; Foth, Paul J.; Sammis, Glenn M.; Schafer, Laurel L.Journal of the American Chemical Society (2019), 141 (48), 18944-18948CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Primary amine products have been prepd. using zirconium catalyzed hydroaminoalkylation of alkenes with N-silylated benzylamine substrates. Catalysis using com. available Zr(NMe2)4, affords an alternative disconnection to access α-arylated primary amines upon aq. work-up. Substrate dependent regio- and diastereoselectivity of the reaction is obsd. Bulky substituents on the terminal alkene exclusively generate the linear regioisomer. This atom-economic catalytic strategy for the synthesis of building blocks that can underwent further synthetic elaboration is highlighted in the prepn. of trifluoroethylated-α-arylated amines.
- 14(a) Bexrud, J. A.; Eisenberger, P.; Leitch, D. C.; Payne, P. R.; Schafer, L. L. Selective C–H Activation α to Primary Amines. Bridging Metallaaziridines for Catalytic, Intramolecular α-Alkylation. J. Am. Chem. Soc. 2009, 131, 2116– 2118, DOI: 10.1021/ja808862w14aSelective C-H activation α to primary amines. Bridging metallaaziridines for catalytic, intramolecular α-alkylationBexrud, Jason A.; Eisenberger, Patrick; Leitch, David C.; Payne, Philippa R.; Schafer, Laurel L.Journal of the American Chemical Society (2009), 131 (6), 2116-2118CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Primary 5- and 6-unsatd. aliph. amines undergo α-C-H-activation rather than intramol. hydroamination in the presence of Ti and Zr amido-complexes, resulting in stereoselective formation of cyclic amines. Selective benzylic α-C-H activation of benzylamine results in the prepn. of the first bridging metallaaziridine complex [(PhCONHAr-κO,κN)Ti(μ-PhCH2N-κN:κN)(μ-PhCH2N-κC,N:κN)(μ-PhCONHAr-κO:κN)Ti(PhCONHAr-κO,κN)] (2) for the catalytic α-alkylation of primary amines. Crystal structure of 2 is reported. Zirconium tetramide gave 2-pyridonate complex [(PyO)2Zr(NMe2)2] [3; PyO = 6-tert-butyl-3-phenyl-2-pyridinonato(1-)], which was also characterized by x-ray structural anal. Cyclization of RCH2NH2 (R = 2-(3-butenylphenyl), 2,2-diphenyl-6-heptenyl, 1-(4-pentenyl)cyclopentenyl, 7-heptenyl, 6-hexenyl) and CH2:CH(CH2)4CHPhNH2 catalyzed by zirconium complex 3 gave the corresponding 2-Me-1-tetralinamine, cyclohexane- and cyclopentanamines as a result of α-C-H activation, followed by cyclization of the reactive zirconaaziridine with pendant double bond. No nitrogen protecting groups are required for this reaction, which is capable of assembling quaternary chiral centers α to nitrogen. Preliminary mechanistic investigations suggest bridging metallaaziridine species are the catalytically active intermediates for this α-functionalization reaction, while monomeric imido complexes furnish azepane hydroamination products.(b) Kubiak, R.; Prochnow, I.; Doye, S. Titanium-Catalyzed Hydroaminoalkylation of Alkenes by C–H Bond Activation at sp3 Centers in the α-Position to a Nitrogen Atom. Angew. Chem., Int. Ed. 2009, 48, 1153– 1156, DOI: 10.1002/anie.20080516914bTitanium-catalyzed hydroaminoalkylation of alkenes by C-H bond activation at sp3 centers in the α-position to a nitrogen atomKubiak, Raphael; Prochnow, Insa; Doye, SvenAngewandte Chemie, International Edition (2009), 48 (6), 1153-1156CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Hydroaminoalkylations of alkenes, which take place by C-H bond activation in the α-position to nitrogen atoms, are catalyzed by various neutral titanium complexes. Primary as well as secondary amines can be used as substrates, and the reactions can be achieved intra- and intermolecularly.
- 15Chu, J. C. K.; Rovis, T. Complementary Strategies for Directed C(sp3)–H Functionalization: A Comparison of Transition-Metal-Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene Transfer. Angew. Chem., Int. Ed. 2018, 57, 62– 101, DOI: 10.1002/anie.20170374315Complementary Strategies for Directed C(sp3)-H Functionalization: A Comparison of Transition-Metal-Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene TransferChu, John C. K.; Rovis, TomislavAngewandte Chemie, International Edition (2018), 57 (1), 62-101CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The functionalization of C(sp3)-H bonds streamlines chem. synthesis by allowing the use of simple mols. and providing novel synthetic disconnections. Intensive recent efforts in the development of new reactions based on C-H functionalization have led to its wider adoption across a range of research areas. This Review discusses the strengths and weaknesses of three main approaches: transition-metal-catalyzed C-H activation, 1,n-hydrogen atom transfer, and transition-metal-catalyzed carbene/nitrene transfer, for the directed functionalization of unactivated C(sp3)-H bonds. For each strategy, the scope, the reactivity of different C-H bonds, the position of the reacting C-H bonds relative to the directing group, and stereochem. outcomes are illustrated with examples in the literature. The aim of this Review is to provide guidance for the use of C-H functionalization reactions and inspire future research in this area.
- 16For a comparison to the oxidation potential of other common amine classes, see:Roth, H. G.; Romero, N. A.; Nicewicz, D. A. Experimental and Calculated Electrochemical Potentials of Common Organic Molecules for Applications to Single-Electron Redox Chemistry. Synlett 2016, 27, 714– 723, DOI: 10.1055/s-0035-156129716Experimental and Calculated Electrochemical Potentials of Common Organic Molecules for Applications to Single-Electron Redox ChemistryRoth, Hudson G.; Romero, Nathan A.; Nicewicz, David A.Synlett (2016), 27 (5), 714-723CODEN: SYNLES; ISSN:0936-5214. (Georg Thieme Verlag)Herein, we report half-peak potentials for over 180 org. substrates obtained via cyclic voltammetry. These values are of great use in assessing the thermodn. of an electron-transfer process. In addn., we disclose a simple computational method to det. redox potentials of org. substrates.
- 17Morozova, O. B.; Yurkovskaya, A. V. Aminium Cation Radical of Glycylglycine and its Deprotonation to Aminyl Radical in Aqueous Solution. J. Phys. Chem. B 2008, 112, 12859– 12862, DOI: 10.1021/jp807149a17Aminium Cation Radical of Glycylglycine and its Deprotonation to Aminyl Radical in Aqueous SolutionMorozova, Olga B.; Yurkovskaya, Alexandra V.Journal of Physical Chemistry B (2008), 112 (40), 12859-12862CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)The photochem. reaction between glycylglycine and triplet 4-carboxybenzophenone has been investigated using time-resolved chem. induced dynamic nuclear polarization (CIDNP). It is shown that the mechanism of the peptide reaction with triplet excited carboxybenzophenone is electron transfer from the amino group of the peptide, leading to the formation of an aminium cation radical that deprotonates to a neutral aminyl radical. Simulation of the CIDNP kinetics leads to an estn. of the paramagnetic relaxation time for the α-protons at the N-terminus at 20 to 40 μs with the best-fit value of 25 μs.
- 18Luo, J.; Zhang, J. Donor–Acceptor Fluorophores for Visible-Light-Promoted Organic Synthesis: Photoredox/Ni Dual Catalytic C(sp3)–C(sp2) Cross Coupling. ACS Catal. 2016, 6, 873– 877, DOI: 10.1021/acscatal.5b0220418Donor-Acceptor Fluorophores for Visible-Light-Promoted Organic Synthesis: Photoredox/Ni Dual Catalytic C(sp3)-C(sp2) Cross-CouplingLuo, Jian; Zhang, JianACS Catalysis (2016), 6 (2), 873-877CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)We describe carbazolyl dicyanobenzene (CDCB)-based donor-acceptor (D-A) fluorophores as a class of cheap, easily accessible, and efficient metal-free photoredox catalysts for org. synthesis. By changing the no. and position of carbazolyl and cyano groups on the center benzene ring, CDCBs with a wide range of photoredox potentials are obtained to effectively drive the energetically demanding C(sp3)-C(sp2) cross-coupling of carboxylic acids and alkyltrifluoroborates with aryl halides via a photoredox/Ni dual catalysis mechanism. This work validates the utility of D-A fluorophores in guiding the rational design of metal-free photoredox catalysts for visible-light-promoted org. synthesis.
- 19Le, C.; Liang, Y.; Evans, R. W.; Li, X.; MacMillan, D. W. C. Selective sp3 C–H alkylation via polarity-match-based cross-coupling. Nature 2017, 547, 79– 83, DOI: 10.1038/nature2281319Selective sp3 C-H alkylation via polarity-match-based cross-couplingLe, Chip; Liang, Yufan; Evans, Ryan W.; Li, Ximing; MacMillan, David W. C.Nature (London, United Kingdom) (2017), 547 (7661), 79-83CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)The functionalization of carbon-hydrogen (C-H) bonds is one of the most attractive strategies for mol. construction in org. chem. The hydrogen atom is considered to be an ideal coupling handle, owing to its relative abundance in org. mols. and its availability for functionalization at almost any stage in a synthetic sequence. Although many C-H functionalization reactions involve C(sp3)-C(sp2) coupling, there is a growing demand for C-H alkylation reactions, wherein sp3 C-H bonds are replaced with sp3 C-alkyl groups. Here, we describe a polarity-match-based selective sp3 C-H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis. This methodol. simultaneously uses three catalytic cycles to achieve hydridic C-H bond abstraction (enabled by polarity matching), alkyl halide oxidative addn., and reductive elimination to enable alkyl-alkyl fragment coupling. The sp3 C-H alkylation is highly selective for the α-C-H of amines, ethers and sulfides, which are commonly found in pharmaceutically relevant architectures. This cross-coupling protocol should enable broad synthetic applications in de novo synthesis and late-stage functionalization chem.
- 20Luo, Y.-R Comprehensive Handbook of Chemical Bond Energies; CRC Press: Boca Raton, FL, 2007.There is no corresponding record for this reference.
- 21(a) Sim, B. A.; Griller, D.; Wayner, D. D. M. Reduction Potentials for Substituted Benzyl Radicals: pKa Values for the Corresponding Toluenes. J. Am. Chem. Soc. 1989, 111, 754– 755, DOI: 10.1021/ja00184a06621aReduction potentials for substituted benzyl radicals: pKa values for the corresponding toluenesSim, B. A.; Griller, D.; Wayner, D. D. M.Journal of the American Chemical Society (1989), 111 (2), 754-5CODEN: JACSAT; ISSN:0002-7863.The electrochem. redn. potentials of nine 3- and 4-substituted benzyl radicals were detd. by photomodulation voltammetry (PMV) in MeCN/di-tert-butylperoxide (9:1) contg. 0.1 M Bu4NClO4. The measured half-wave potentials for the redns. are close to E° and lead to ests. of the abs. pKa's for the toluenes in MeCN.(b) Wayner, D. D. M.; McPhee, D. J.; Griller, D. Oxidation and reduction potentials of transient free radicals. J. Am. Chem. Soc. 1988, 110, 132– 137, DOI: 10.1021/ja00209a02121bOxidation and reduction potentials of transient free radicalsWayner, D. D. M.; McPhee, D. J.; Griller, D.Journal of the American Chemical Society (1988), 110 (1), 132-7CODEN: JACSAT; ISSN:0002-7863.The oxidn. and redn. potentials of a variety of carbon-centered radicals have been measured by a technique that makes use of modulated photolysis for radical generation and phase-sensitive voltammetry for their detection. The measured half-wave potentials were close to the thermodynamically significant E° values for the arylmethyl radicals and led to ests. of pKa(R-H) and pKR(R-OH) as well as data for the solvation energies of these ions and radicals.
- 22Bortolamei, N.; Isse, A. A.; Gennaro, A. Estimation of standard reduction potentials of alkyl radicals involved in atom-transfer radical polymerization. Electrochim. Acta 2010, 55, 8312– 8318, DOI: 10.1016/j.electacta.2010.02.09922Estimation of standard reduction potentials of alkyl radicals involved in atom transfer radical polymerizationBortolamei, Nicola; Isse, Abdirisak A.; Gennaro, ArmandoElectrochimica Acta (2010), 55 (27), 8312-8318CODEN: ELCAAV; ISSN:0013-4686. (Elsevier B.V.)The redox properties of some alkyl radicals, which are important in atom transfer radical polymn. both as initiators and mimics of the propagating radical chains, have been investigated in CH3CN by an indirect electrochem. method based on homogeneous redox catalysis involving alkyl halides (RX) and electrogenerated arom. or heteroarom. radical anions (D·-). Dissociative electron transfer between RX and D·- yields an intermediate radical (R·), which further reacts with D·- either by radical coupling or by electron transfer. Examn. of the competition between these reactions, which depends on ED°D/D·-/D·-, allows detn. of the std. redn. potential of R· as well as the self-exchange reorganization energy λR·/R-·. The std. redn. potentials obtained for the radicals ·CH2CN, ·CH2CO2Et and ·CH(CH3)CO2Me are -0.72 ± 0.06, -0.63 ± 0.07 and -0.66 ± 0.07 V vs. SCE, resp. Quite high values of λR·/R- (from 122 to 164 kJ mol-1) were found for all radicals, indicating that a significant change of structure accompanies electron transfer to R·.
- 23Speckmeier, E.; Fischer, T. G.; Zeitler, K. A Toolbox Approach To Construct Broadly Applicable Metal-Free Catalysts for Photoredox Chemistry: Deliberate Tuning of Redox Potentials and Importance of Halogens in Donor–Acceptor Cyanoarenes. J. Am. Chem. Soc. 2018, 140, 15353– 15365, DOI: 10.1021/jacs.8b0893323A Toolbox Approach To Construct Broadly Applicable Metal-Free Catalysts for Photoredox Chemistry: Deliberate Tuning of Redox Potentials and Importance of Halogens in Donor-Acceptor CyanoarenesSpeckmeier, Elisabeth; Fischer, Tillmann G.; Zeitler, KirstenJournal of the American Chemical Society (2018), 140 (45), 15353-15365CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The targeted choice of specific photocatalysts has been shown to play a crit. role for the successful realization of challenging photoredox catalytic transformations. Herein, we demonstrate the successful implementation of a rational design strategy for a series of deliberate structural manipulations of cyanoarene-based, purely org. donor-acceptor photocatalysts, using 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) as a starting point. Systematic modifications of both the donor substituents as well as the acceptors' mol. core allowed us to identify strongly oxidizing as well as strongly reducing catalysts (e.g., for an unprecedented detriflation of unactivated naphthol triflate), which addnl. offer remarkably balanced redox potentials with predictable trends. Esp. halogen arene core substitutions are instrumental for our targeted alterations of the catalysts' redox properties. Based on their preeminent electrochem. and photophys. characteristics, all novel, purely org. photoredox catalysts were evaluated in three challenging, mechanistically distinct classes of benchmark reactions (either requiring balanced, highly oxidizing or strongly reducing properties) to demonstrate their enormous potential as customizable photocatalysts, that outperform and complement prevailing typical best photocatalysts.
- 24Ji, X.; Liu, Q.; Wang, Z.; Wang, P.; Deng, G.-J.; Huang, H. LiBr-promoted photoredox neutral Minisci hydroxyalkylations of quinolines with aldehydes. Green Chem. 2020, 22, 8233– 8237, DOI: 10.1039/D0GC01872D24LiBr-promoted photoredox neutral Minisci hydroxyalkylations of quinolines with aldehydesJi, Xiaochen; Liu, Qiong; Wang, Zhongzhen; Wang, Pu; Deng, Guo-Jun; Huang, HuawenGreen Chemistry (2020), 22 (23), 8233-8237CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)Photoredox-neutral hydroxyalkylations of quinolines I [R = H; R1 = H; RR1 = -CH=CHCH=CH-, -CH=C(OCH3)C(OCH3)=CH-; R2 = H, n-Bu, Cl; R3 = H; R2R3 = -CH=C(Br)CH=CH-; R4 = H, 4-phenylphenyl, 3-chlorophenyl, thiophen-2-yl, etc.] with aldehydes R5CHO (R5 = 2-bromo-5-fluorophenyl, thiophen-2-yl, naphthalen-2-yl, etc.), induced by sustainable visible light under mild conditions, are described. Non-toxic and inexpensive LiBr is found to be the key for the success of the atom-economical Minisci method. Combined with a highly oxidative photocatalyst and visible light irradn., the bromide additive mediates the H abstraction/acyl radical formation directly from aldehydes. The present mild photoredox neutral protocol provides an important alternative, esp. for the challenging Minisci hydroalkylations, as well as a promising approach for atom-economical Minisci reactions with broader N-heterocycle spectra.
- 25Ide, T.; Barham, J. P.; Fujita, M.; Kawato, K.; Egami, H.; Hamashima, Y. Regio- and chemoselective Csp3–H arylation of benzylamines by single electron transfer/hydrogen atom transfer synergistic catalysis. Chem. Sci. 2018, 9, 8453– 8460, DOI: 10.1039/C8SC02965B25Regio- and chemoselective Csp3-H arylation of benzylamines by single electron transfer/hydrogen atom transfer synergistic catalysisIde, Takafumi; Barham, Joshua P.; Fujita, Masashi; Kawato, Yuji; Egami, Hiromichi; Hamashima, YoshitakaChemical Science (2018), 9 (44), 8453-8460CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)A highly regio- and chemoselective Csp3-H arylation of benzylamines mediated by synergy of single electron transfer (SET) and hydrogen atom transfer (HAT) catalysis is reported. Under well precedented SET catalysis alone, the arylation reaction of N,N-dimethylbenzylamine proceeded via aminium radical cation formation and selectively targeted the N-Me group. In contrast, addn. of PhC(O)SH as a HAT catalyst precursor completely switched the regioselectivity to Csp3-H arylation at the N-benzylic position. Measurement of oxidn. potentials indicated that the conjugate base of PhC(O)SH is oxidized in preference to the substrate amine. The discovery of the thiocarboxylate as a novel HAT catalyst allowed for the selective generation of the sulfur-centered radical, so that the N-benzyl selectivity was achieved by overriding the inherent N-Me and/or N-methylene selectivity under SET catalysis conditions. While visible light-driven α-C-H functionalization of amines has mostly been demonstrated with aniline derivs. and tetrahydroisoquinolines (THIQs), our method is applicable to a variety of primary, secondary and tertiary benzylamines for efficient N-benzylic C-H arylation. Functional group tolerance was high, and various 1,1-diarylmethylamines, including an α,α,α-trisubstituted amine, were obtained in good to excellent yield (up to 98%). Importantly, the reaction is applicable to late-stage functionalization of pharmaceuticals.
- 26Rohe, S.; Morris, A. O.; McCallum, T.; Barriault, L. Hydrogen Atom Transfer Reactions via Photoredox Catalyzed Chlorine Atom Generation. Angew. Chem., Int. Ed. 2018, 57, 15664– 15669, DOI: 10.1002/anie.20181018726Hydrogen Atom Transfer Reactions via Photoredox Catalyzed Chlorine Atom GenerationRohe, Samantha; Morris, Avery O.; McCallum, Terry; Barriault, LouisAngewandte Chemie, International Edition (2018), 57 (48), 15664-15669CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The selective functionalization of chem. inert C-H bonds remains to be fully realized in achieving org. transformations that are redox-neutral, waste-limiting, and atom-economical. The catalytic generation of chlorine atoms from chloride ions is one of the most challenging redox processes, where the requirement of harsh and oxidizing reaction conditions renders it seldom utilized in synthetic applications. We report the mild, controlled, and catalytic generation of chlorine atoms as a new opportunity for access to a wide variety of hydrogen atom transfer (HAT) reactions owing to the high stability of HCl.The discovery of the photoredox mediated generation of chlorine atoms with Ir-based polypyridyl complex, [Ir(dF(CF3)ppy)2(dtbbpy)]Cl, under blue LED irradn. is reported.
- 27Zhou, R.; Goh, Y. Y.; Liu, H.; Tao, H.; Li, L.; Wu, J. Visible-Light-Mediated Metal-Free Hydrosilylation of Alkenes through Selective Hydrogen Atom Transfer for Si–H Activation. Angew. Chem., Int. Ed. 2017, 56, 16621– 16625, DOI: 10.1002/anie.20171125027Visible-Light-Mediated Metal-Free Hydrosilylation of Alkenes through Selective Hydrogen Atom Transfer for Si-H ActivationZhou, Rong; Goh, Yi Yiing; Liu, Haiwang; Tao, Hairong; Li, Lihua; Wu, JieAngewandte Chemie, International Edition (2017), 56 (52), 16621-16625CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Although there has been significant progress in the development of transition-metal-catalyzed hydrosilylations of alkenes over the past several decades, metal-free hydrosilylation is still rare and highly desirable. Herein, authors report a convenient visible-light-driven metal-free hydrosilylation of both electron-deficient and electron-rich alkenes that proceeds through selective hydrogen atom transfer for Si-H activation. The synergistic combination of the organophotoredox catalyst 4CzIPN with quinuclidin-3-yl acetate enabled the hydrosilylation of electron-deficient alkenes by selective Si-H activation while the hydrosilylation of electron-rich alkenes was achieved by merging photoredox and polarity-reversal catalysis.
- 28(a) Morisaki, K.; Morimoto, H.; Ohshima, T. Recent Progress on Catalytic Addition Reactions to N-Unsubstituted Imines. ACS Catal. 2020, 10, 6924– 6951, DOI: 10.1021/acscatal.0c0121228aRecent Progress on Catalytic Addition Reactions to N-Unsubstituted IminesMorisaki, Kazuhiro; Morimoto, Hiroyuki; Ohshima, TakashiACS Catalysis (2020), 10 (12), 6924-6951CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)A review. Catalytic addn. reactions to N-unsubstituted (N-unprotected) imines can provide a more straightforward synthesis of amines. This direct process eliminates the unnecessary protecting-group manipulations that are required with N-substituted (N-protected) imines and can contribute to the development of green chem. Although their use has been limited due to difficulties assocd. with the nature of N-unsubstituted imines, recently developed catalytic methods enable the use of N-unsubstituted imines as electrophiles in various catalytic addn. reactions. To facilitate an understanding of the state of the art development of synthetic methodologies, herein we review recent progress on catalytic addn. reactions to N-unsubstituted imines. An overview of the chem. of N-unsubstituted imines is given, followed by a summary of recent progress categorized according to the reaction type is . We hope this review will help to stimulate further development of greener syntheses of nitrogen-contg. compds.(b) Nicastri, M. C.; Lehnherr, D.; Lam, Y.-h.; DiRocco, D. A.; Rovis, T. Synthesis of Sterically Hindered Primary Amines by Concurrent Tandem Photoredox Catalysis. J. Am. Chem. Soc. 2020, 142, 987– 998, DOI: 10.1021/jacs.9b1087128bSynthesis of Sterically Hindered Primary Amines by Concurrent Tandem Photoredox CatalysisNicastri, Michael C.; Lehnherr, Dan; Lam, Yu-hong; DiRocco, Daniel A.; Rovis, TomislavJournal of the American Chemical Society (2020), 142 (2), 987-998CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Primary amines are an important structural motif in active pharmaceutical ingredients (APIs) and intermediates thereof, as well as members of ligand libraries for either biol. or catalytic applications. Many chem. methodologies exist for amine synthesis, but the direct synthesis of primary amines with a fully substituted α carbon center is an underdeveloped area. We report a method which utilizes photoredox catalysis to couple readily available O-benzoyl oximes with cyanoarenes to synthesize primary amines with fully substituted α-carbons. We also demonstrate that this method enables the synthesis of amines with α-trifluoromethyl functionality. Based on exptl. and computational results, we propose a mechanism where the photocatalyst engages in concurrent tandem catalysis by reacting with the oxime as a triplet sensitizer in the first catalytic cycle and a reductant toward the cyanoarene in the second catalytic cycle to achieve the synthesis of hindered primary amines via heterocoupling of radicals from readily available oximes.(c) Lehnherr, D.; Lam, Y.-h.; Nicastri, M. C.; Liu, J.; Newman, J. A.; Regalado, E. L.; DiRocco, D. A.; Rovis, T. Electrochemical Synthesis of Hindered Primary and Secondary Amines via Proton-Coupled Electron Transfer. J. Am. Chem. Soc. 2020, 142, 468– 478, DOI: 10.1021/jacs.9b1087028cElectrochemical Synthesis of Hindered Primary and Secondary Amines via Proton-Coupled Electron TransferLehnherr, Dan; Lam, Yu-hong; Nicastri, Michael C.; Liu, Jinchu; Newman, Justin A.; Regalado, Erik L.; DiRocco, Daniel A.; Rovis, TomislavJournal of the American Chemical Society (2020), 142 (1), 468-478CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Accessing hindered amines, particularly primary amines α to a fully substituted carbon center, is synthetically challenging. We report an electrochem. method to access such hindered amines starting from benchtop-stable iminium salts and cyanoheteroarenes. A wide variety of substituted heterocycles (pyridine, pyrimidine, pyrazine, purine, azaindole) can be utilized in the cross-coupling reaction, including those substituted with a halide, trifluoromethyl, ester, amide, or ether group, a heterocycle, or an unprotected alc. or alkyne. Mechanistic insight based on DFT data, as well as cyclic voltammetry and NMR spectroscopy, suggests that a proton-coupled electron-transfer mechanism is operational as part of a hetero-biradical cross-coupling of α-amino radicals and radicals derived from cyanoheteroarenes. Safety: cyanide may be released as a byproduct leading to release of toxic HCN.(d) Ushakov, D. B.; Gilmore, K.; Kopetzki, D.; McQuade, D. T.; Seeberger, P. H. Continuous-Flow Oxidative Cyanation of Primary and Secondary Amines Using Singlet Oxygen. Angew. Chem., Int. Ed. 2014, 53, 557– 561, DOI: 10.1002/anie.20130777828dContinuous-Flow Oxidative Cyanation of Primary and Secondary Amines Using Singlet OxygenUshakov, Dmitry B.; Gilmore, Kerry; Kopetzki, Daniel; McQuade, D. Tyler; Seeberger, Peter H.Angewandte Chemie, International Edition (2014), 53 (2), 557-561CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Primary and secondary amines can be rapidly and quant. oxidized to the corresponding imines by singlet oxygen. This reactive form of oxygen was produced using a variable-temp. continuous-flow LED-photoreactor with a catalytic amt. of tetraphenylporphyrin as the sensitizer. α-Aminonitriles were obtained in good to excellent yields when trimethylsilyl cyanide served as an in situ imine trap. At 25°C, primary amines were found to undergo oxidative coupling prior to cyanide addn. and yielded secondary α-aminonitriles. Primary α-aminonitriles were synthesized from the corresponding primary amines for the first time, by an oxidative Strecker reaction at -50°C. This atom-economic and protecting-group-free pathway provides a route to racemic amino acids, which was exemplified by the synthesis of tert-leucine hydrochloride from neopentylamine.
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The addition step may be slower than potential side reactions (e.g., benzylic radical dimerization) or be reversible and endergonic, such that catalytic turnover is impeded. However, the photocatalytic α-C–H alkylation of tertiary benzylic amines with electrophilic alkenes has been achieved via an SET oxidation–deprotonation approach; see ref (9c).
There is no corresponding record for this reference. - 30
In general, quantification of the HAT site selectivity was not possible, but minor unidentified byproducts were visible in the crude 1H NMR spectra for some compounds. We previously showed, both experimentally and theoretically, that the selectivity for α-C–H functionalization of cyclohexylamine versus cyclohexanol with photogenerated azidyl radical is >20:1, with cyclohexanol itself being α-C–H alkylated with methyl acrylate in only 12% yield in a standalone experiment; see ref (9d).
There is no corresponding record for this reference. - 31Cambié, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noël, T. Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment. Chem. Rev. 2016, 116, 10276– 10341, DOI: 10.1021/acs.chemrev.5b0070731Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water TreatmentCambie, Dario; Bottecchia, Cecilia; Straathof, Natan J. W.; Hessel, Volker; Noel, TimothyChemical Reviews (Washington, DC, United States) (2016), 116 (17), 10276-10341CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Continuous-flow photochem. in microreactors receives a lot of attention from researchers in academia and industry as this technol. provides reduced reaction times, higher selectivities, straightforward scalability, and the possibility to safely use hazardous intermediates and gaseous reactants. In this review, an up-to-date overview is given of photochem. transformations in continuous-flow reactors, including applications in org. synthesis, material science, and water treatment. In addn., the advantages of continuous-flow photochem. are pointed out and a thorough comparison with batch processing is presented.
- 34Constantin, T.; Zanini, M.; Regni, A.; Sheikh, N. S.; Juliá, F.; Leonori, D. Aminoalkyl radicals as halogen-atom transfer agents for activation of alkyl and aryl halides. Science 2020, 367, 1021– 1026, DOI: 10.1126/science.aba241934Aminoalkyl radicals as halogen-atom transfer agents for activation of alkyl and aryl halidesConstantin, Timothee; Zanini, Margherita; Regni, Alessio; Sheikh, Nadeem S.; Julia, Fabio; Leonori, DanieleScience (Washington, DC, United States) (2020), 367 (6481), 1021-1026CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)Org. halides are important building blocks in synthesis, but their use in (photo)redox chem. is limited by their low redn. potentials. Halogen-atom transfer remains the most reliable approach to exploit these substrates in radical processes despite its requirement for hazardous reagents and initiators such as tributyltin hydride. In this study, we demonstrate that α-aminoalkyl radicals, easily accessible from simple amines, promote the homolytic activation of carbon-halogen bonds with a reactivity profile mirroring that of classical tin radicals. This strategy conveniently engages alkyl and aryl halides in a wide range of redox transformations to construct sp3-sp3, sp3-sp2, and sp2-sp2 carbon-carbon bonds under mild conditions with high chemoselectivity.
- 35Sanford, M. Fingolimod: A Review of Its Use in Relapsing-Remitting Multiple Sclerosis. Drugs 2014, 74, 1411– 1433, DOI: 10.1007/s40265-014-0264-y35Fingolimod: A Review of Its Use in Relapsing-Remitting Multiple SclerosisSanford, MarkDrugs (2014), 74 (12), 1411-1433CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Fingolimod (Gilenya) is an orally administered disease modifying agent (DMA) for use in relapsing-remitting multiple sclerosis (RRMS). In placebo-controlled trials in patients with RRMS with active disease, fingolimod 0.5 mg/day significantly reduced the annualized relapse rate (ARR) by approx. one-half over 2-yr trial periods. It also significantly increased the proportion of patients with no disability progression, reduced deterioration from baseline in the Extended Disability Status Scale score and reduced MRI markers of disease progression (new/newly enlarging brain lesions and percentage change in brain vol.). In a 12-mo, comparison with i.m. interferon β-1a (IFNβ- 1a) 30 μg/wk, the ARR in fingolimod 0.5 mg/day recipients was significantly lower than in IFNβ-1a recipients by one-half; fingolimod recipients also had significantly lower MRI markers of disease progression. In extensions to the pivotal clin. trials, fingolimod exposure for up to 4 years was assocd. with low relapse rates and continuing benefits in terms of disability and disease progression. In clin. trials, adverse events in fingolimod recipients were generally mild to moderate in severity. In the pivotal placebo-controlled trial, serious adverse events occurred in similar proportions of fingolimod 0.5 mg/day and placebo recipients. First-dose bradycardia and atrioventricular block, which are generally asymptomatic, were clin. important adverse events assocd. with fingolimod in placebo-controlled trials. The risk for serious cardiovascular adverse events at the approved fingolimod dosage appears to be low in patients without pre-existing cardiac conditions. Fingolimod is an efficacious therapy for RRMS that reduces relapses, disability progression, new brain lesions and loss of brain vol. It has an acceptable tolerability profile and provides a useful alternative treatment in patients with RRMS who have responded poorly to other DMAs.
- 36Parijat, P.; Kondacs, L.; Alexandrovich, A.; Gautel, M.; Cobb, A. J. A.; Kampourakis, T. High Throughput Screen Identifies Small Molecule Effectors That Modulate Thin Filament Activation in Cardiac Muscle. ACS Chem. Biol. 2021, 16, 225– 235, DOI: 10.1021/acschembio.0c0090836High Throughput Screen Identifies Small Molecule Effectors That Modulate Thin Filament Activation in Cardiac MuscleParijat, Priyanka; Kondacs, Laszlo; Alexandrovich, Alexander; Gautel, Mathias; Cobb, Alexander J. A.; Kampourakis, ThomasACS Chemical Biology (2021), 16 (1), 225-235CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)Current therapeutic interventions for both heart disease and heart failure are largely insufficient and assocd. with undesired side effects. Biomedical research has emphasized the role of sarcomeric protein function for the normal performance and energy efficiency of the heart, suggesting that directly targeting the contractile myofilaments themselves using small mol. effectors has therapeutic potential and will likely result in greater drug efficacy and selectivity. In this study, we developed a robust and highly reproducible fluorescence polarization-based high throughput screening (HTS) assay that directly targets the calcium-dependent interaction between cardiac troponin C (cTnC) and the switch region of cardiac troponin I (cTnISP), with the aim of identifying small mol. effectors of the cardiac thin filament activation pathway. We screened a com. available small mol. library and identified several hit compds. with both inhibitory and activating effects. We used a range of biophys. and biochem. methods to characterize hit compds. and identified fingolimod, a sphingosin-1-phosphate receptor modulator, as a new troponin-based small mol. effector. Fingolimod decreased the ATPase activity and calcium sensitivity of demembranated cardiac muscle fibers in a dose-dependent manner, suggesting that the compd. acts as a calcium desensitizer. We investigated fingolimod's mechanism of action using a combination of computational studies, biophys. methods, and synthetic chem., showing that fingolimod bound to cTnC repels cTnISP via mainly electrostatic repulsion of its pos. charged tail. These results suggest that fingolimod is a potential new lead compd./scaffold for the development of troponin-directed heart failure therapeutics.
- 37Mulakayala, N. A Comprehensive Review on Synthetic Approach for Fingolimod. Indian J. Adv. Chem. Sci. 2016, 4, 362– 36637A comprehensive review on synthetic approach for fingolimodMulakayala, NaveenIndian Journal of Advances in Chemical Science (2016), 4 (4), 362-366CODEN: IJACKX; ISSN:2320-0928. (KROS Publications)A review. Multiple sclerosis (MS) often consequences in chronic inflammatory and autoimmune disorders, and recent developments have lead to newer therapeutic options for the treatment of the disease. In this review, we have summarized the literature known synthetic strategies of fingolimod which is the key small mol., and the first oral drug candidate for MS which have been launched in the market.
- 38Urbano, M.; Guerrero, M.; Rosen, H.; Roberts, E. Modulators of the Sphingosine 1-phosphate receptor 1. Bioorg. Med. Chem. Lett. 2013, 23, 6377– 6389, DOI: 10.1016/j.bmcl.2013.09.05838Modulators of the Sphingosine 1-phosphate receptor 1Urbano, Mariangela; Guerrero, Miguel; Rosen, Hugh; Roberts, EdwardBioorganic & Medicinal Chemistry Letters (2013), 23 (23), 6377-6389CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A review. The Sphingosine 1-phosphate receptor (S1P-R) signaling system has proven to be of biol. and medical importance in autoimmune settings. S1P1-R is a validated drug target for multiple sclerosis (MS) for which FTY720 (Fingolimod), a S1P1,3-5-R pan-agonist, was recently approved as the first orally active drug for the treatment of relapsing-remitting MS. Transient bradycardia and long half-life are the FTY720 crit. pitfalls. This review provides the latest advances on next-generation S1P1-R modulators from 2012 up to date, with an overview of the chem. structures, structure-activity relationships, and relevant biol. and clin. properties.
- 39Mandala, S.; Hajdu, R.; Bergstrom, J.; Quackenbush, E.; Xie, J.; Milligan, J.; Thornton, R.; Shei, G. J.; Card, D.; Keohane, C. A. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 2002, 296, 346– 349, DOI: 10.1126/science.107023839Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonistsMandala, Suzanne; Hajdu, Richard; Bergstrom, James; Quackenbush, Elizabeth; Xie, Jenny; Milligan, James; Thornton, Rosemary; Shei, Gan-Ju; Card, Deborah; Keohane, Carolann; Rosenbach, Mark; Hale, Jeffrey; Lynch, Christopher L.; Rupprecht, Kathleen; Parsons, William; Rosen, HughScience (Washington, DC, United States) (2002), 296 (5566), 346-349CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Blood lymphocyte nos., essential for the development of efficient immune responses, are maintained by recirculation through secondary Lymphoid organs. We show that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolite of the immunosuppressive agent FTY720. Both species were high-affinity agonists of at least four of the five S1P receptors. These agonists produce lymphopenia in blood and thoracic duct lymph by sequestration of lymphocytes in lymph nodes, but not spleen. S1P receptor agonists induced emptying of lymphoid sinuses by retention of lymphocytes on the abluminal side of sinus-lining endothelium and inhibition of egress into lymph. Inhibition of lymphocyte recirculation by activation of S1P receptors may result in therapeutically useful immunosuppression.
- 40(a) Chen, S.; Yang, L.; Shang, Y.; Mao, J.; Walsh, P. J. Base-Promoted Tandem Synthesis of 2-Azaaryl Tetrahydroquinolines. Org. Lett. 2021, 23, 1594– 1599, DOI: 10.1021/acs.orglett.0c0430640aBase-Promoted Tandem Synthesis of 2-Azaaryl TetrahydroquinolinesChen, Shuguang; Yang, Langxuan; Shang, Yongjia; Mao, Jianyou; Walsh, Patrick J.Organic Letters (2021), 23 (5), 1594-1599CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A novel method to synthesize 2-azaaryl tetrahydroquinolines by the base-promoted tandem reaction of azaaryl Me amines and styrene derivs. was reported (over 30 examples, yields up to 95%). Mechanistic probe expts. demonstrate that the deprotonation of the benzylic C-H bond and the addn. to the styrene vinyl group proceeds via the SNAr mechanism.(b) Warsitz, M.; Doye, S. Two-Step Procedure for the Synthesis of 1,2,3,4-Tetrahydroquinolines. Eur. J. Org. Chem. 2020, 2020, 6997– 7014, DOI: 10.1002/ejoc.20200133740bTwo-Step Procedure for the Synthesis of 1,2,3,4-Tetrahydro-quinolinesWarsitz, Michael; Doye, SvenEuropean Journal of Organic Chemistry (2020), 2020 (45), 6997-7014CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)A new two-step procedure that includes an initial regioselective intermol. hydroaminoalkylation of ortho-chlorostyrenes with N-methylanilines and a subsequent intramol. Buchwald-Hartwig amination gives direct access to 1,2,3,4-tetrahydroquinolines. The hydroaminoalkylation reaction of the ortho-chlorostyrenes is catalyzed by a 2,6-bis(phenylamino)pyridinato titanium complex which delivers the linear regioisomers with high selectivities. In addn., the formation of unexpected dihydroaminoalkylation products from styrenes and N-methylanilines is reported.
- 41Muthukrishnan, I.; Sridharan, V.; Menéndez, J. C. Progress in the Chemistry of Tetrahydroquinolines. Chem. Rev. 2019, 119, 5057– 5191, DOI: 10.1021/acs.chemrev.8b0056741Progress in the Chemistry of TetrahydroquinolinesMuthukrishnan, Isravel; Sridharan, Vellaisamy; Menendez, J. CarlosChemical Reviews (Washington, DC, United States) (2019), 119 (8), 5057-5191CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. This review summarizes the progress achieved in the chem. of tetrahydroquinolines, with emphasis on their synthesis, during the mid-2010 to early 2018 period.
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Based on a Scifinder search conducted in April 2021, with the following constraints applied: benzenoid-fused only, 800 MW max, no other ring fusions, only H/C/S attached to N, no isotopes/metals.
There is no corresponding record for this reference. - 43Hiesinger, K.; Dar’in, D.; Proschak, E.; Krasavin, M. Spirocyclic Scaffolds in Medicinal Chemistry. J. Med. Chem. 2021, 64, 150– 183, DOI: 10.1021/acs.jmedchem.0c0147343Spirocyclic Scaffolds in Medicinal ChemistryHiesinger, Kerstin; Dar'in, Dmitry; Proschak, Ewgenij; Krasavin, MikhailJournal of Medicinal Chemistry (2021), 64 (1), 150-183CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Spirocyclic scaffolds are incorporated in various approved drugs and drug candidates. The increasing interest in less planar bioactive compds. has given rise to the development of synthetic methodologies for the prepn. of spirocyclic scaffolds. In this Perspective, we summarize the diverse synthetic routes to obtain spirocyclic systems. The impact of spirocycles on potency and selectivity, including the aspect of stereochem., is discussed. Furthermore, we examine the changes in physicochem. properties as well as in in vitro and in vivo ADME using selected studies that compare spirocyclic compds. to their nonspirocyclic counterparts. In conclusion, the value of spirocyclic scaffolds in medicinal chem. is discussed.
- 44St. Denis, J. D.; Hall, R. J.; Murray, C. W.; Heightman, T. D.; Rees, D. C. Fragment-based drug discovery: opportunities for organic synthesis. RSC Med. Chem. 2021, 12, 321– 329, DOI: 10.1039/D0MD00375A44Fragment-based drug discovery: opportunities for organic synthesisSt. Denis, Jeffrey D.; Hall, Richard J.; Murray, Christopher W.; Heightman, Tom D.; Rees, David C.RSC Medicinal Chemistry (2021), 12 (3), 321-329CODEN: RMCSEZ; ISSN:2632-8682. (Royal Society of Chemistry)A review. This Review describes the increasing demand for org. synthesis to facilitate fragment-based drug discovery (FBDD), focusing on polar, unprotected fragments. In FBDD, X-ray crystal structures are used to design target mols. for synthesis with new groups added onto a fragment via specific growth vectors. This requires challenging synthesis which slows down drug discovery, and some fragments are not progressed into optimization due to synthetic intractability. We have evaluated the output from Astex's fragment screenings for a no. of programs, including urokinase-type plasminogen activator, hematopoietic prostaglandin D2 synthase, and hepatitis C virus NS3 protease-helicase, and identified fragments that were not elaborated due, in part, to a lack of com. available analogs and/or suitable synthetic methodol. This represents an opportunity for the development of new synthetic research to enable rapid access to novel chem. space and fragment optimization.
- 45Twigg, D. G.; Kondo, N.; Mitchell, S. L.; Galloway, W. R. D.; Sore, H. F.; Madin, A.; Spring, D. R. Partially Saturated Bicyclic Heteroaromatics as an sp3-Enriched Fragment Collection. Angew. Chem., Int. Ed. 2016, 55, 12479– 12483, DOI: 10.1002/anie.20160649645Partially Saturated Bicyclic Heteroaromatics as an sp3-Enriched Fragment CollectionTwigg, David G.; Kondo, Noriyasu; Mitchell, Sophie L.; Galloway, Warren R. J. D.; Sore, Hannah F.; Madin, Andrew; Spring, David R.Angewandte Chemie, International Edition (2016), 55 (40), 12479-12483CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Fragment-based lead generation has proven to be an effective means of identifying high-quality lead compds. for drug discovery programs. However, the fragment screening sets often used are principally comprised of sp2-rich arom. compds., which limits the structural (and hence biol.) diversity of the library. Herein, we describe strategies for the synthesis of a series of partially satd. bicyclic heteroarom. scaffolds with enhanced sp3 character. Subsequent derivatization led to a fragment collection featuring regio- and stereo-controlled introduction of substituents on the satd. ring system, often with formation of new stereocenters.
- 46Law, R. P.; Atkinson, S. J.; Bamborough, P.; Chung, C.-w.; Demont, E. H.; Gordon, L. J.; Lindon, M.; Prinjha, R. K.; Watson, A. J. B.; Hirst, D. J. Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain. J. Med. Chem. 2018, 61, 4317– 4334, DOI: 10.1021/acs.jmedchem.7b0166646Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second BromodomainLaw, Robert P.; Atkinson, Stephen J.; Bamborough, Paul; Chung, Chun-wa; Demont, Emmanuel H.; Gordon, Laurie J.; Lindon, Matthew; Prinjha, Rab K.; Watson, Allan J. B.; Hirst, David J.Journal of Medicinal Chemistry (2018), 61 (10), 4317-4334CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET bromodomains-BRD2, BRD3, BRD4, and BRDT-each contain two bromodomain modules. BET bromodomain inhibition is a potential therapy for various cancers and immunoinflammatory diseases, but few reported inhibitors show selectivity within the BET family. Inhibitors with selectivity for the first or second bromodomain are desired to aid investigation of the biol. function of these domains. Focused library screening identified a series of tetrahydroquinoxalines with selectivity for the second bromodomains of the BET family (BD2). Structure-guided optimization of the template improved potency, selectivity, and physicochem. properties, culminating in potent BET inhibitors with BD2 selectivity.
- 47Procopiou, P. A.; Anderson, N. A.; Barrett, J.; Barrett, T. N.; Crawford, M. H. J.; Fallon, B. J.; Hancock, A. P.; Le, J.; Lemma, S.; Marshall, R. P. Discovery of (S)-3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-l)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic αvβ6 Integrin Inhibitor for the Inhaled Treatment of Idiopathic Pulmonary Fibrosis. J. Med. Chem. 2018, 61, 8417– 8443, DOI: 10.1021/acs.jmedchem.8b0095947Discovery of (S)-3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic αvβ6 Integrin Inhibitor for the Inhaled Treatment of Idiopathic Pulmonary FibrosisProcopiou, Panayiotis A.; Anderson, Niall A.; Barrett, John; Barrett, Tim N.; Crawford, Matthew H. J.; Fallon, Brendan J.; Hancock, Ashley P.; Le, Joelle; Lemma, Seble; Marshall, Richard P.; Morrell, Josie; Pritchard, John M.; Rowedder, James E.; Saklatvala, Paula; Slack, Robert J.; Sollis, Steven L.; Suckling, Colin J.; Thorp, Lee R.; Vitulli, Giovanni; Macdonald, Simon J. F.Journal of Medicinal Chemistry (2018), 61 (18), 8417-8443CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of 3-aryl-(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, which involved rhodium catalyzed asym. 1,4-addn. of arylboronic acids in the presence of (R)-BINAP to a crotonate ester to provide the (S) abs. configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole and cyclic ether were screened in cell adhesion assays for affinity against αvβ1, αvβ3, αvβ5, αvβ6 and αvβ8 integrins. Several analogs with high affinity and selectivity for the αvβ6 integrin were identified. The analog I·HCl was found to have high affinity for αvβ6 integrin in a radioligand binding assay (pKi = 11), a long dissocn. half-life (7 h) , high soly. in saline at pH 7 (>71 mg/mL) and pharmacokinetic properties commensurate with inhaled dosing by nebulization. It was selected for further investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.
- 48Fairhurst, R. A.; Knoepfel, T.; Buschmann, N.; Leblanc, C.; Mah, R.; Todorov, M.; Nimsgern, P.; Ripoche, S.; Niklaus, M.; Warin, N. Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4. J. Med. Chem. 2020, 63, 12542– 12573, DOI: 10.1021/acs.jmedchem.0c0101948Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4Fairhurst, Robin A.; Knoepfel, Thomas; Buschmann, Nicole; Leblanc, Catherine; Mah, Robert; Todorov, Milen; Nimsgern, Pierre; Ripoche, Sebastien; Niklaus, Michel; Warin, Nicolas; Luu, Van Huy; Madoerin, Mario; Wirth, Jasmin; Graus-Porta, Diana; Weiss, Andreas; Kiffe, Michael; Wartmann, Markus; Kinyamu-Akunda, Jacqueline; Sterker, Dario; Stamm, Christelle; Adler, Flavia; Buhles, Alexandra; Schadt, Heiko; Couttet, Philippe; Blank, Jutta; Galuba, Inga; Trappe, Jorg; Voshol, Johannes; Ostermann, Nils; Zou, Chao; Berghausen, Jorg; Del Rio Espinola, Alberto; Jahnke, Wolfgang; Furet, PascalJournal of Medicinal Chemistry (2020), 63 (21), 12542-12573CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)FGF19 signaling through the FGFR4/β-klotho receptor complex has been shown to be a key driver of growth and survival in a subset of hepatocellular carcinomas, making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted a poorly conserved cysteine residue within the FGFR4 ATP-binding site at position 552, two positions beyond the gate-keeper residue. Several strategies for targeting this cysteine to identify FGFR4 selective inhibitor starting points are summarized which made use of both rational and unbiased screening approaches. The optimization of a 2-formylquinoline amide hit series is described in which the aldehyde makes a hemithioacetal reversible-covalent interaction with cysteine 552. Key challenges addressed during the optimization are improving the FGFR4 potency, metabolic stability, and soly. leading ultimately to the highly selective first-in-class clin. candidate roblitinib.
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We cannot exclude the possibility that azidyl radical may react initially with the DMF solvent to generate an α-carbamoyl radical by HAT with a C–H bond on one of the N-Me groups (BDE ≈ 105 kcal mol–1; see ref (20)) and that this radical may in turn be responsible for abstracting a hydrogen from the alkylamine. We thank a reviewer for this suggestion.
There is no corresponding record for this reference. - 50Bordwell, F. G. Equilibrium Acidities in Dimethyl Sulfoxide Solution. Acc. Chem. Res. 1988, 21, 456– 463, DOI: 10.1021/ar00156a00450Equilibrium acidities in dimethyl sulfoxide solutionBordwell, Frederick G.Accounts of Chemical Research (1988), 21 (12), 456-63CODEN: ACHRE4; ISSN:0001-4842.A review with 62 refs.
- 51Prieto, A.; Taillefer, M. Visible-Light Decatungstate/Disulfide Dual Catalysis for the Hydro-Functionalization of Styrenes. Org. Lett. 2021, 23 (4), 1484– 1488, DOI: 10.1021/acs.orglett.1c0018951Visible-Light Decatungstate/Disulfide Dual Catalysis for the Hydro-Functionalization of StyrenesPrieto, Alexis; Taillefer, MarcOrganic Letters (2021), 23 (4), 1484-1488CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)An efficient photoredox system, relied on decatungstate/disulfide catalysts, for the hydrofunctionalization of styrenes was described. In this methodol. the use of disulfide as a cocatalyst was shown to be crucial for the reaction efficiency. This photoredox system was employed for the hydro-carbamoylation, -acylation, -alkylation, and -silylation of styrenes, gave access to a large variety of useful building blocks and high-value mols. such as amides and unsym. ketones from simple starting materials.
- 52Cismesia, M. A.; Yoon, T. P. Characterizing chain processes in visible light photoredox catalysis. Chem. Sci. 2015, 6, 5426– 5434, DOI: 10.1039/C5SC02185E52Characterizing chain processes in visible light photoredox catalysisCismesia, Megan A.; Yoon, Tehshik P.Chemical Science (2015), 6 (10), 5426-5434CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)The recognition that Ru(bpy)32+ and similar visible light absorbing transition metal complexes can be photocatalysts for a variety of synthetically useful org. reactions has resulted in a recent resurgence of interest in photoredox catalysis. However, many of the crit. mechanistic aspects of this class of reactions remain poorly understood. In particular, the degree to which visible light photoredox reactions involve radical chain processes has been a point of some disagreement that has not been subjected to systematic anal. We have now performed quantum yield measurements to demonstrate that three representative, mechanistically distinct photoredox processes involve product-forming chain reactions. Moreover, we show that the combination of quantum yield and luminescence quenching expts. provides a rapid method to est. the length of these chains. Together, these measurements constitute a robust, operationally facile strategy for characterizing chain processes in a wide range of visible light photoredox reactions.
- 53Tagami, T.; Arakawa, Y.; Minagawa, K.; Imada, Y. Efficient Use of Photons in Photoredox/Enamine Dual Catalysis with a Peptide-Bridged Flavin–Amine Hybrid. Org. Lett. 2019, 21, 6978– 6982, DOI: 10.1021/acs.orglett.9b0256753Efficient Use of Photons in Photoredox/Enamine Dual Catalysis with a Peptide-Bridged Flavin-Amine HybridTagami, Takuma; Arakawa, Yukihiro; Minagawa, Keiji; Imada, YasushiOrganic Letters (2019), 21 (17), 6978-6982CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)An isoalloxazine (flavin) ring system and a secondary amine have been integrated through a short peptide linker with the aim of using photons as efficiently as possible in photoredox/enamine dual catalysis. We herein report a peptide-bridged flavin-amine hybrid that can catalyze α-oxyamination of aldehydes with TEMPO under weak blue light irradn. to achieve an extremely high quantum yield of reaction (Φ = 0.80).
- 54Burés, J. Variable Time Normalization Analysis: General Graphical Elucidation of Reaction Orders from Concentration Profiles. Angew. Chem., Int. Ed. 2016, 55, 16084– 16087, DOI: 10.1002/anie.20160975754Variable Time Normalization Analysis: General Graphical Elucidation of Reaction Orders from Concentration ProfilesBures, JordiAngewandte Chemie, International Edition (2016), 55 (52), 16084-16087CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The recent technol. evolution of reaction monitoring techniques has not been paralleled by the development of modern kinetic analyses. The analyses currently used disregard part of the data acquired, thus requiring an increased no. of expts. to obtain sufficient kinetic information for a given chem. reaction. Herein, we present a simple graphical anal. method that takes advantage of the data-rich results provided by modern reaction monitoring tools. This anal. uses a variable normalization of the time scale to enable the visual comparison of entire concn. reaction profiles. As a result, the order in each component of the reaction, as well as kobs , is detd. with just a few expts. using a simple and quick math. data treatment. This anal. facilitates the rapid extn. of relevant kinetic information and will be a valuable tool for the study of reaction mechanisms.
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If the addition step of the α-amino radical 25 to the styrene 6 is reversible, then the concentration of benzylic radical 26 would exhibit a dependence on the concentration of styrene 6 (pre-equilibrium approximation). However, if the addition step is rapid and essentially irreversible, then saturation kinetics will occur and the concentration of benzylic radical 26 will become independent of styrene 6 concentration.
There is no corresponding record for this reference. - 56Bloh, J. Z. A Holistic Approach to Model the Kinetics of Photocatalytic Reactions. Front. Chem. 2019, 7, 128, DOI: 10.3389/fchem.2019.0012856A holistic approach to model the kinetics of photocatalytic reactionsBloh, Jonathan Z.Frontiers in Chemistry (Lausanne, Switzerland) (2019), 7 (), 128CODEN: FCLSAA; ISSN:2296-2646. (Frontiers Media S.A.)Understanding and modeling kinetics is an essential part of the optimization and implementation of chem. reactions. In the case of photocatalytic reactions this is mostly done one-dimensionally, i.e., only considering the effect of one parameter at the same time. However, as discussed in this study, many of the relevant reaction parameters have mutual interdependencies that call for a holistic multi-dimensional approach to accurately model and understand their influence. Such an approach is described herein, and all the relevant equations given so that researchers can readily implement it to analyze and model their reactions.
- 57(a) Ji, Y.; DiRocco, D. A.; Kind, J.; Thiele, C. M.; Gschwind, R. M.; Reibarkh, M. LED-Illuminated NMR Spectroscopy: A Practical Tool for Mechanistic Studies of Photochemical Reactions. ChemPhotoChem. 2019, 3, 984– 992, DOI: 10.1002/cptc.20190010957aLED-Illuminated NMR Spectroscopy: A Practical Tool for Mechanistic Studies of Photochemical ReactionsJi, Yining; Di Rocco, Daniel A.; Kind, Jonas; Thiele, Christina M.; Gschwind, Ruth M.; Reibarkh, MikhailChemPhotoChem (2019), 3 (10), 984-992CODEN: CHEMYH ISSN:. (Wiley-VCH Verlag GmbH & Co. KGaA)This Concept article highlights the development of a novel anal. tool, LED-NMR (a combination of in situ light illumination using a light-emitting diode and NMR spectroscopy) and its variant UVNMR (LED-NMR coupled with UV/Vis absorption spectroscopy), as well as their applications in the mechanistic investigation of light-induced transformations. The utility of these new tools has been demonstrated by providing rich kinetic and structural data of reaction species offering mechanistic insights into photochem. and photocatalytic reactions. Furthermore, NMR actinometry has been recently developed as a practical and simple method for quantum yield measurements. Quantum yield is an important parameter in photo-induced processes, but is rarely measured in practice because of the barriers assocd. with traditional actinometry. These new tools and techniques streamline measurements of the quantum efficiency while affording informative mechanistic insights into photochem. reactions. We anticipate these techniques will enable chemists to further advance the rapidly emerging photochem. field.(b) Tlahuext-Aca, A.; Candish, L.; Garza-Sanchez, R. A.; Glorius, F. Decarboxylative Olefination of Activated Aliphatic Acids Enabled by Dual Organophotoredox/Copper Catalysis. ACS Catal. 2018, 8, 1715– 1719, DOI: 10.1021/acscatal.7b0428157bDecarboxylative Olefination of Activated Aliphatic Acids Enabled by Dual Organophotoredox/Copper CatalysisTlahuext-Aca, Adrian; Candish, Lisa; Garza-Sanchez, R. Aleyda; Glorius, FrankACS Catalysis (2018), 8 (3), 1715-1719CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)Herein, we demonstrate a dual organophotoredox/copper catalytic strategy toward challenging decarboxylative olefination processes proceeding in high yields and selectivities. This operationally simple method uses photoactive org. mols. and Cu(II)-complexes as catalysts to provide rapid access to a wide variety of olefins from inexpensive synthetic and biomass-derived carboxylic acids under mild light-mediated conditions. Mechanistic investigations suggest that the reaction rate for this process is controlled solely by the incident photon flux.(c) Le, C.; Wismer, M. K.; Shi, Z.-C.; Zhang, R.; Conway, D. V.; Li, G.; Vachal, P.; Davies, I. W.; MacMillan, D. W. C. A General Small-Scale Reactor To Enable Standardization and Acceleration of Photocatalytic Reactions. ACS Cent. Sci. 2017, 3, 647– 653, DOI: 10.1021/acscentsci.7b0015957cA general small-scale reactor to enable standardization and acceleration of photocatalytic reactionsLe, Chi "Chip"; Wismer, Michael K.; Shi, Zhi-Cai; Zhang, Rui; Conway, Donald V.; Li, Guoqing; Vachal, Petr; Davies, Ian W.; MacMillan, David W. C.ACS Central Science (2017), 3 (6), 647-653CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)Photocatalysis for org. synthesis has experienced an exponential growth in the past 10 years. However, the variety of exptl. procedures that have been reported to perform photon-based catalyst excitation has hampered the establishment of general protocols to convert visible light into chem. energy. To address this issue, we have designed an integrated photoreactor for enhanced photon capture and catalyst excitation. Moreover, the evaluation of this new reactor in eight photocatalytic transformations that are widely employed in medicinal chem. settings has confirmed significant performance advantages of this optimized design while enabling a standardized protocol.
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We became aware that Professor Gaunt at the University of Cambridge was engaged in related studies toward photocatalytic amine synthesis. We are grateful to the Gaunt group for kindly agreeing to submit their results concurrently with our own studies, and thank them for their generosity and collegiality. See:
Blackwell, J. H.; Harris, G. R.; Smith, M. A.; Gaunt, M. J. Modular Photocatalytic Synthesis of α-Trialkyl-α-Tertiary Amines. J. Am. Chem. Soc. 2021, DOI: 10.1021/jacs.1c07402There is no corresponding record for this reference.
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