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A Fluorinated Ligand Enables Room-Temperature and Regioselective Pd-Catalyzed Fluorination of Aryl Triflates and Bromides
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† Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
‡ Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
*[email protected]
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Cite this: J. Am. Chem. Soc. 2015, 137, 41, 13433–13438
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https://doi.org/10.1021/jacs.5b09308
Published September 28, 2015

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Abstract

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A new biaryl monophosphine ligand (AlPhos, L1) allows for the room-temperature Pd-catalyzed fluorination of a variety of activated (hetero)aryl triflates. Furthermore, aryl triflates and bromides that are prone to give mixtures of regioisomeric aryl fluorides with Pd-catalysis can now be converted to the desired aryl fluorides with high regioselectivity. Analysis of the solid-state structures of several Pd(II) complexes, as well as density functional theory (DFT) calculations, shed light on the origin of the enhanced reactivity observed with L1.

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Introduction

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The preparation of fluorine-containing aromatic compounds (ArF) has been a long-standing challenge in organic synthesis. (1) While these compounds are highly prized in the pharmaceutical (2) and agrochemical industries, (3) methods to access aryl fluorides selectively, under mild and general reaction conditions, remain elusive. Since the advent of the Balz–Schiemann (4) reaction and the Halex (5) process, significant advances have been made toward this end, (6) especially with regard to transition metal-catalyzed methods. (7) In analogy to the practicality, simplicity, and generality of Pd(0)/Pd(II)-catalyzed aryl carbon–heteroatom bond-forming processes, the coupling of aryl (pseudo)halides with simple metal fluoride salts (“F–”) (Figure 1a) would be ideal. However, several challenges associated with developing such a process have been revealed both experimentally (8) and theoretically. (9) Among these difficulties are the formation of stable [LPd(II)F]2 dimers and competitive P–F and P–C bond formation, which suggests a high barrier for C–F reductive elimination (Figure 1a). To circumvent the difficult reductive elimination from Pd(II) complexes, electrophilic fluorine sources (“F+”) have been employed to oxidize the metal center to Pd(III) or Pd(IV) intermediates from which reductive elimination is more facile. (10)
The desired C–F reductive elimination from [LPdAr(F)] is unique to biaryl monophosphine-ligated complexes, and has been observed stoichiometrically, (11) albeit at high temperatures and with substrates that contain activated (12) aryl groups. Subsequently, it was discovered that incorporating a substituent at the C3′ position of the biaryl monophosphine ligand, for example, as in HGPhos ((L2), Figure 1b), gives rise to a more active catalyst system. (13)

Figure 1

Figure 1. (a) The proposed catalytic cycle for Pd-catalyzed fluorination. (b) A Pd(II) complex with L2 highlighted in red. The interaction between ligand-bound Pd(II) and C1′ is shown by a dashed line. (c) Biaryl monophosphine ligand (Alphos, L1).

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While these discoveries have shown that Pd(II)-catalyzed fluorination is indeed viable, several problems remain. Most importantly, the generation of regioisomeric byproducts (14) (presumably through a Pd–benzyne intermediate) lowers the yield of the desired product and renders purification difficult or even impossible. Additionally, the use of elevated reaction temperatures is required to achieve full conversion of the starting materials. To address these issues, which we ascribe to the difficult C–F reductive elimination from Pd(II) complexes, we sought to design a ligand to improve this elementary step as well as the overall efficiency of the catalytic transformation. As shown in Figure 1b, biaryl monophosphine ligands coordinate to the Pd(II) metal center in a bidentate fashion, making contacts through both the phosphine and the C1′ carbon of the adjacent aromatic ring. (15) Because reductive elimination from Pd(II) complexes is typically favored from a three-coordinate intermediate, (16) we hypothesized that modification at C3′ with an electron-withdrawing group would diminish the donation of electron density from C1′ to the Pd(II) metal center, providing an intermediate with more three-coordinate character and thereby generating a more active catalyst.

Results and Discussion

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To test our hypothesis, we designed and synthesized a ligand that was less electron-rich than the previously reported L2. This was accomplished by removing the methoxy group adjacent to the dialkylphosphino group on the “upper” aromatic ring and replacing the hydrogen atoms of the pendant 4-(n-Bu)Ph group at C3′ with fluorines (17) (Figure 1c). The synthesis of L1 is described in Scheme 1. Lithium–halogen exchange of 2,4,6-triisopropylbromobenzene with n-BuLi followed by nucleophilic addition into hexafluorobenzene provides perfluoro biaryl L1a. To improve solubility of the final ligand and prevent subsequent nucleophilic additions into the activated perfluoro aromatic, n-BuLi was added at −78 °C to give the alkylated product via SNAr, which was then halogenated using N-iodosuccinimide and H2SO4 to yield L1b. Terphenyl L1c was prepared by nucleophilic addition of L1b into a benzyne intermediate, generated from 3-fluoroanisole, followed by quenching the resulting aryl anion with bromine at −30 °C. Treatment of L1c with t-BuLi at −78 °C followed by the addition of CuCl and Ad2PCl and then heating to 140 °C overnight furnished L1 in 82% yield (25% yield over five steps). The synthesis was amenable to scale up as more than 10 g of L1 was prepared in a single batch.

Scheme 1

Scheme 1. Synthesis of L1 and Pd(0) Precatalyst 1a
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Scheme aReagents and conditions: (a) THF, −78 °C, n-BuLi, 1 h; added to C6F6 in THF, 0 °C to rt, 2 h, 87%. (b) THF, −78 °C, n-BuLi, 30 min, 99%. (c) AcOH, EtOAc, H2SO4, N-iodosuccinimide, 50 °C, 17 h, 80%. (d) THF, −78 °C, t-BuLi, 1 h; added to 3-fluoroanisole and n-BuLi in THF, −78 to −25 °C, 44%. (e) THF, −78 °C, t-BuLi, 1 h; CuCl −78 °C to rt; Ad2PCl, toluene, 140 °C, 18 h, 82%. (f) [COD·Pd(CH2TMS)2], pentane, rt, 48 h, 78%.

The highly active Pd(0) precatalyst [(L1Pd)2·COD] (1) was prepared in 78% yield by treating L1 with an equivalent of [COD·Pd(CH2TMS)2] in pentane, which could be easily isolated and stored under an inert atmosphere (Scheme 1). (18, 19) Because of the electron-rich nature and high reactivity of biaryl monophosphine-ligated Pd(0) complexes, there exist only a few structurally characterized examples. (20) We have previously described several Pd(0) precatalysts, of which indirect evidence was obtained suggesting an empirical formula of [(LPd)n·COD] (n = 1–2); however, the insolubility of these complexes precluded structural characterization by single-crystal X-ray diffraction. (13c, 18) Single crystals of 1 suitable for X-ray diffraction were obtained providing the first structural evidence for this class of precatalyst (Figure 2). Complex 1 crystallizes in the triclinic centrosymmetric space group P1̅ with half a molecule of 1 and three molecules of benzene per asymmetric unit. The second half of 1 is generated by the crystallographic inversion center. The full molecule is a binuclear complex in which each Pd atom is chelated by one L1 ligand. Located between the two palladium centers is a cyclooctadiene molecule (COD), which coordinates through its two double bonds to the metal atoms in a side-on fashion that can be described as η2. This results in a distorted trigonal planar coordination environment for the palladium atoms with the following angles: P–Pd–C1′, 88°; P–Pd–COD, 135°; and C1′–Pd–COD, 137°.

Figure 2

Figure 2. Crystal structure of [(L1Pd)2·COD] (1). Thermal ellipsoids are shown at 50% probability; hydrogen atoms and residual benzene molecules are omitted for clarity.

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The reactivity of L1 and L2 was compared by preparing analogous [LPdAr(F)] complexes and examining the formation of the ArF resulting from the stoichiometric C–F reductive elimination from the Pd(II) intermediates at room temperature (Scheme 2). These reactions were performed in the presence and absence of added aryl bromide, which serves as a trapping agent for the resulting Pd(0) that is formed after reductive elimination. (21, 13a) After a period of 12 h, the L1-supported complex provides approximately twice the amount of the desired product than that bearing L2. Both L1- and L2-ligated complexes provided the ArF product and are the first examples of room-temperature C–F reductive elimination from isolated [LPd(Ar)F] complexes.

Scheme 2

Scheme 2. Stoichiometric C–F Reductive Elimination from Pd(II) Complexes at Room Temperaturea
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Scheme aYields determined by 19F NMR. bNo ArBr added. cArBr (R = C(O)n-Bu). dArBr (R = n-Bu).

The enhanced reactivity in the stoichiometric process exhibited by the L1-supported Pd(Ar)F complex was successfully extended to the catalytic reaction. By using 1, a variety of activated (hetero)aromatic triflates (Table 1) were transformed to the fluoride derivatives at room temperature. (22) A range of functional groups were tolerated in this transformation, including nitro (2), formyl (3), methyl ketone (4), redox active anthraquinone (5), and sulfonamide/tertiary amine (6). Heteroaryl triflates were also competent substrates as flavone 7, quinolines 8 and 9, and quinazoline 10 derivatives were prepared in high yields. Notably, XAV939, (23) a tankyrase inhibitor and potential cancer therapeutic, could be fluorinated to give 11, demonstrating the applicability of this method to fluorinate medicinally relevant compounds. Additionally, aryl triflates can be selectively transformed in the presence of aryl chlorides, leaving a reactive handle for downstream modifications (12–14). While the long reaction times at room temperature speak to the stability of the catalyst, the transformation can be completed in 24 h by increasing the temperature even while lowering the catalyst loading (Table 1, 7 and 9).
Table 1. Room-Temperature Fluorination of Aryl Triflatesa
Table a

Isolated yields are reported as an average of two runs. Reaction conditions unless otherwise noted: Aryl triflate (1 mmol), CsF (3 mmol), tol or 2-MeTHF (10 mL).

Table b

0.50 mmol scale.

Table c

19F NMR yield.

Table d

Aryl bromide (0.5 mmol), KF (0.25 mmol), AgF (1.0 mmol), tol (5 mL). tol = toluene, 2-MeTHF = 2-methyl tetrahydrofuran.

With our previously described catalyst systems, (11, 13, 14) mixtures of regioisomeric aryl fluorides are sometimes formed during the Pd-catalyzed nucleophilic fluorination reaction. (14) In general, substrates with para electron-donating groups or meta substitution are plagued by this undesired reaction pathway. Previously, by using cyclohexane as the solvent, the amount of regioisomer formation could be reduced. In some instances, however, the quantity of undesired regioisomer formed was still significant.
To probe the effectiveness of catalysts derived from 1 to further suppress the formation of regioisomeric byproducts, we examined 4-(n-Bu)PhOTf (X = OTf) and 4-(n-Bu)PhBr (X = Br) as model substrates (Table 2). With either aryl electrophile, the L2-supported precatalyst provides substantial amounts of undesired isomer B (entry 1). The enhanced reactivity of 1, however, allows for the use of lower reaction temperatures than were previously possible (entry 2, X = OTf), revealing a temperature dependence on the formation of B (entries 3–5, X = OTf). The same temperature dependence is not observed for aryl bromides, although using 1 diminishes the amount of B formed. Currently, we have no explanation for this dichotomy.
Table 2. Temperature Dependence on Regioisomer Formationa,b
Table a

Yields were determined by 19F NMR. Numbers in parentheses indicate % conversion of the starting material.

Table b

The reaction time was 48 h.

The success of 1 in suppressing the formation of B with 4-(n-Bu)phenyl triflate or bromide prompted us to study the reaction of a number of substrates that are prone to give regioisomeric mixtures of ArF products. As shown in Table 3, a variety of aryl triflates and bromides converted to the corresponding aryl fluorides in high yield with >100:1 selectivity for the desired regioisomer (15–21, 23–25). Previously, substrates with strongly electron-donating groups in the para position, such as −OMe, have been the most challenging substrates for this methodology. For example, 4-methoxyphenyl triflate (15) and 4-bromoanisole (13c) have previously been shown to form the undesired meta isomer as the major product. Using 1, the observed selectivity is reversed and the desired product dominates (22). Several fluorinated analogues of biologically active compounds were also prepared to give (±)-naproxen 23, diethylstilbesterol 24, and tyrosine 25 derivatives with exceptional selectivity. No loss in stereochemical integrity was observed with 25 under the reaction conditions, and reduction (ArH) was only observed for 16 (0.75%), 19 (0.64%), and 22 (0.52%) (see the Supporting Information). (24)
Table 3. Regioselective Fluorinationa,b,c
Table a

Isolated yields are reported as an average of two runs. Reaction conditions unless otherwise noted: Aryl triflate (1 mmol), CsF (3 mmol), cy (10 mL).

Table b

Aryl bromide (1 mmol), KF (0.5 mmol), AgF (2.0 mmol), cy (10 mL).

Table c

0.5 mmol scale.

Table d

19F NMR yield.

Table e

No regioisomer detected by 19F NMR. cy = cyclohexane.

To gain further insight into the enhanced reactivity of 1, we prepared the [LPd(Ar)Br] complexes, from the reaction of 4-(n-Bu)PhBr and CODPd(CH2TMS)2 using L1 and L2 as supporting ligands (Figure 3) (see the Supporting Information). The respective complexes were characterized in the solid state using single-crystal X-ray diffraction. The initial hypothesis from which the design of L1 derived predicts that significant lengthening of the C1′–Pd bond would be observed with the more electron-deficient supporting ligand (L1). In fact, only a slight increase in this bond length in D was apparent, as compared to that seen with C (see the Supporting Information).
By overlaying the crystal structures of C and D, a more subtle difference was, however, revealed (Figure 3c). With C, the pendant 4-(n-Bu)Ph group of the ligand is shifted toward the Pd-bound bromide to form an aromatic CH′···Br contact of 3.874(3) Å (measured from C to Br), which is in agreement with typical aromatic CH···Br interaction distances found in the solid state (3.7–4.2 Å; measured from C to Br). (25) The perfluorinated aryl group of D lacks the required hydrogen atom to achieve the same attractive interaction, giving a C···Br distance of 4.370(2) Å. The analogous [LPd(Ar)F] complexes were synthesized (E and F), and single-crystal X-ray analysis of E shows that this behavior is conserved, with E exhibiting an aromatic CH···F interaction distance of 3.387(3) Å (measured from C to F) (Figure 3d). Typical aromatic CH···F interaction distances found in the solid state range from 3.3 to 3.7 Å (measured from C to F). (25) Unfortunately, all attempts to obtain single crystals of F suitable for X-ray diffraction yielded decomposition and/or pseudocrystalline material.

Figure 3

Figure 3. (a) Schematic of [L2Pd(Ar)X] complexes C and E where L2 is highlighted in red. (b) Schematic of [L1Pd(Ar)X] complexes D and F. (c) Crystal structure overlay of C and D. C is shown in red. Hydrogen atoms and an isopropyl group are omitted for clarity. (d) Crystal structure of E highlighting the intramolecular CH···F contact. Hydrogen atoms and the n-butyl group on the Pd-bound aryl omitted for clarity. Thermal ellipsoids are shown at 50% probability.

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Short CH···F contacts are frequently observed in structurally characterized Pd–F complexes. They serve to stabilize the Pd–F bond by alleviating electronic repulsions between the lone pairs on the fluoride atom and the filled d-orbitals of Pd. (8) As shown in the solid state, E achieves this Pd–F bond stabilization intramolecularly while F cannot. The lack of an intramolecular CH···F interaction in F results in ground-state destabilization relative to E, which may account for the observed enhancement in reactivity.
Density functional theory (DFT) calculations were carried out to compare complexes E and F and gain further insight into the stabilizing CH···F interaction that was observed in the solid-state structure of E. To reduce conformational complexity, the Pd-bound 4-(n-Bu)Ph of complexes E and F was replaced with a phenyl group in our computational study, giving complexes E′ and F′, respectively. The calculated ground-state structure of E′ is in good agreement with the crystallographic data of E, exhibiting an attractive CH···F contact (3.24 Å, measured from C to F) (Figure 4a). Furthermore, NPA (natural population analysis) charge calculations of complex E′ showed that the Pd–bound fluorine atom bears a partial negative charge of −0.700 and the hydrogen atom at the 2 position of the pendant 4-(n-Bu)Ph group carries a partial positive charge of +0.251. Taken together, these analyses clearly indicate the presence of an intramoleuclar stabilizing interaction. As anticipated, this interaction is absent in complex F′, which lacks the necessary hydrogen atom required for this attractive interaction (Figure 4b). In addition, NPA charge analysis of complex F′ reveals that both the Pd-Bound fluorine atom and the fluorine atom at the 2 position of the pendant 4-(n-Bu)Ph group carry a partial negative charge (−0.690 and −0.318, respectively), further demonstrating the lack of an attractive interaction in complex F′.

Figure 4

Figure 4. Computed ground-state structures of complexes E′ and F′. Geometries were optimized at the B3LYP/6-31G(d)-SDD(Pd) level of theory. Hydrogen atoms are omitted for clarity. (a) The CH···F interaction of complex E′ is 3.24 Å, measured from C to F. (b) Complex F′ showing the lack of an intermolecular stabilizing interaction.

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Additionally, we performed DFT calculations of the C–F bond-forming reductive elimination step for complexes E′ and F′ (Figure 5). This process involves a three-membered transition state where the C–F bond is being formed while the Pd–F and the Pd–C bonds are being broken in a concerted fashion. The calculations showed that the C–F reductive elimination of complex F′ (Figure 5b) has an activation barrier (ΔG⧧) 0.7 kcal/mol lower than that of complex E′ (Figure 5a), which is in agreement with the experimentally observed enhanced reactivity of the L1-based catalyst.

Figure 5

Figure 5. Energies were computed at the M06/6-311+G(d,p)-SDD(Pd)/SMD(toluene) level of theory with geometries optimized at the B3LYP/6-31G(d)-SDD(Pd) level. Hydrogen atoms are omitted for clarity. (a) Transition state minimization of complex E′. (b) Transition state minimization of complex F′.

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Conclusion

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A new ligand (L1) that allows for room-temperature C–F reductive elimination from [LPd(Ar)F] has been developed. The enhanced reactivity was exploited to provide aryl fluorides from aryl triflates and bromides with greater than 100:1 selectivity for the desired regioisomer. Crystallographic analysis of several Pd complexes revealed that L2 provides a stabilizing intramolecular aromatic CH···F interaction, which is not accessible with L1, giving rise to a more active catalyst system. Finally, DFT calculations were performed comparing complexes E′ and F′ corroborating the observations made in the solid state. This study provides insights into ligand structure, which should aid in the discovery and design of more effective catalysts for C–F bond formation.

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.5b09308.

  • Additional procedural, crystallographic, and spectral data (PDF)

  • X-ray data for six complexes (CIF)

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

Author Information

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  • Corresponding Author
    • Stephen L. Buchwald - Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States;  Email: [email protected]
  • Authors
    • Aaron C. Sather - Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
    • Hong Geun Lee - Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
    • Valentina Y. De La Rosa - Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
    • Yang Yang - Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States;  Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
    • Peter Müller - Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
  • Notes
    The authors declare the following competing financial interest(s): MIT has obtained patents for the ligands/precatalysts that are described in this Article from which S.L.B. and former/current co-workers receive royalty payments.

Acknowledgment

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This work is dedicated to the grandfather of A.C.S. (Albert B. Sather; AlPhos, L1). We thank Drs. Yiming Wang, Michael Pirnot, and John Nguyen for assistance with the preparation of the manuscript. We thank the National Institutes of Health (NIH) for financial support of this research (R01GM46059). A.C.S. thanks the NIH for a postdoctoral fellowship (1F32GM108092-01A1). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. V.Y.D.L.R. thanks the MIT UROP program. We thank Prof. Peng Liu (University of Pittsburgh) for help with computational studies. Calculations were performed at the Center for Simulation and Modeling at the University of Pittsburgh. The X-ray diffractometer was purchased with the help of funding from the National Science Foundation (CHE 0946721).

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    A review. The task of inventing and developing active ingredients with useful biol. activities requires a search for novel chem. substructures. This process may trigger the discovery of whole classes of chems. of potential com. interest. Similar biol. effects can often be achieved by completely different compds. However, compds. within a given structural family may exhibit quite different biol. activities depending on their interactions with different intracellular proteins like enzymes or receptors. By varying the functional groups and structural elements of a lead compd., its interaction with the active site of the target protein, as well as its physicochem., pharmacokinetic, and dynamic properties can be improved. In this context, the introduction of fluorine into active ingredients has become an important concept in the quest for a modern crop protection product with optimal efficacy, environmental safety, user friendliness, and economic viability. Fluorinated org. compds. represent an important and growing family of com. agrochems. A no. of recently developed agrochem. candidates represent novel classes of chem. compds. with new modes of action; several of these compds. contain new fluorinated substituents. However, the complex structure-activity relationships assocd. with biol.-active mols. mean that the introduction of fluorine can lead to either an increase or a decrease in the efficacy of a compd., depending on its changed mode of action, physicochem. properties, target interaction, or metabolic susceptibility and transformation. Therefore, it is still difficult to predict the sites in a mol. at which fluorine substitution will result in optimal desired effects.
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    Successful fluorine-containing herbicide agrochemicals
    Fujiwara, Tomoya; O'Hagan, David
    Journal of Fluorine Chemistry (2014), 167 (), 16-29CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
    A review. Of the herbicides licensed worldwide, currently around 25% contain at least one fluorine atom and many contain multiple fluorines in the form of difluoro- and trifluoromethyl groups. Fluorine-contg. compds. have made a significant contribution to the development of products for the agrochems. industry and many organofluorine entities have found stable market positions. In this review we highlight the most important fluorinated herbicides in terms of their global use. The compds. are grouped by mode of action. A synthesis route is described for each compd. although the synthesis presented may not actually be the industrial process.
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    Aromatic fluorine compounds. I. A new method for their preparation
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    Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1927), 60B (), 1186-90CODEN: BDCBAD; ISSN:0365-9488.
    Contrary to the earlier belief, the diazonium fluoborates (cf. C. A. 21, 1070) decomp. smoothly and quietly on warming: ArN2BF4 → ArF + N2 + BF3. There are no side reactions. Because of their slight soly. they can be obtained in dry form readily and in good yield and they are very stable; they can even be recrystd. from hot H2O and are entirely insensitive to shock. On decompn. they yield the fluoride in many cases almost quant. and in pure form even when the diazonium fluoborate has not previously been especially purified. In general the appropriate amine is diazotized in as concd. soln. in HCl as possible, pptd. with excess of HBF4, (about 40%), washed with HBF, alc. and Et2O, dried in vacuo and heated in a fractionating flask (the glass is practically not attacked at all) connected with a condenser, the gaseous BF3 being absorbed in H2O or NaOH. Phenyldiazonium fluoborate (yield 63 %), becomes slightly pink 80°, decomps. 121-2°, d425 1.53, yields almost 100% PhF, b. 86°. p-Tolyldiazonium fluoborate (67%), decomps. 110°, d425 1.48; MeC6H4F (97%), b756 116°. m-Xylyldiazonium fluoborate (31%; the yield Can easily be increased), decomps. 108°, d425 1.50; 2,4-e2C6H2F (almost 100%, b749 143-40°. α.Naphthyldiazonium fluoborate (62%), decomps. 113°; α-C10H7F(98%),b17110°, b758 215°. Diphenylene-4,4'-bisdiazonium fluoborate (64%),turns pink about 130°, foams 157°, d425 1.73; (P-FC6H4)2, m. 94-5°, d425 1.328. o-,m-and p-Nitrophenyl-diazonium fluoborates (yields, 74, 80, 100%, resp.), decomp. 135°, 178°, 156°, d425 1.69, 1.66, 1.66.
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    Beyond the Balz-Schiemann Reaction: The Utility of Tetrafluoroborates and Boron Trifluoride as Nucleophilic Fluoride Sources
    Cresswell, Alexander J.; Davies, Stephen G.; Roberts, Paul M.; Thomson, James E.
    Chemical Reviews (Washington, DC, United States) (2015), 115 (2), 566-611CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. This Review offers a dedicated account of tetrafluoroborates and boron fluorides as nucleophilic fluoride sources for C-F bond formation, comprehensive to the end of 2013.
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    Silver-Catalyzed Late-Stage Fluorination
    Tang, Pingping; Furuya, Takeru; Ritter, Tobias
    Journal of the American Chemical Society (2010), 132 (34), 12150-12154CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Carbon-fluorine bond formation by transition metal catalysis is difficult, and only a few methods for the synthesis of aryl fluorides have been developed. All reported transition-metal-catalyzed fluorination reactions for the synthesis of functionalized arenes are based on palladium. Here, we present silver catalysis for carbon-fluorine bond formation. For example, reacting 4-EtO2CC6H4SnBu3 with Ag2O/NaOTf/NaHCO3/MeOH gave 92% of 4-FC6H4CO2Et. Our report is the first example of the use of the transition metal silver to form carbon-heteroatom bonds by cross-coupling catalysis. The functional group tolerance and substrate scope presented here have not been demonstrated for any other fluorination reaction to date.
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    Transition metal catalysis and nucleophilic fluorination
    Hollingworth, Charlotte; Gouverneur, Veronique
    Chemical Communications (Cambridge, United Kingdom) (2012), 48 (24), 2929-2942CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    A review. Transition metal catalyzed transformations using fluorinating reagents have been developed extensively for the prepn. of synthetically valuable fluorinated targets. This is a topic of crit. importance to facilitate lab. and industrial chem. synthesis of fluorine contg. pharmaceuticals and agrochems. Translation to 18F-radiochem. is also emerging as a vibrant research field because functional imaging based on Positron Emission Tomog. (PET) is increasingly used for both diagnosis and pharmaceutical development. This review summarizes how fluoride sources have been used for the catalytic nucleophilic fluorination of various substrates inclusive of aryl triflates, alkynes, allylic halides, allylic esters, allylic trichloroacetimidates, benzylic halides, tertiary alkyl halides and epoxides. Until recently, progress in this field of research has been slow in part because of the challenges assocd. with the dual reactivity profile of fluoride (nucleophile or base). Despite these difficulties, some remarkable breakthroughs have emerged. This includes the demonstration that Pd(0)/Pd(II)-catalyzed nucleophilic fluorination to access fluoroarenes from aryl triflates is feasible, and the first examples of Tsuji-Trost allylic alkylation with fluoride using either allyl chlorides or allyl precursors bearing O-leaving groups. More recently, allylic fluorides were also made accessible under iridium catalysis. Another reaction, which has been greatly improved based on careful mechanistic work, is the catalytic asym. hydrofluorination of meso epoxides. Notably, each individual transition metal catalyzed nucleophilic fluorination reported to date employs a different F-reagent, an observation indicating that this area of research will benefit from a larger pool of nucleophilic fluoride sources. In this context, a striking recent development is the successful design, synthesis and applications of a fluoride-derived electrophilic late stage fluorination reagent. This new class of reagents could greatly benefit preclin. and clin. PET imaging.
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    Copper-Mediated Fluorination of Aryl Iodides
    Fier, Patrick S.; Hartwig, John F.
    Journal of the American Chemical Society (2012), 134 (26), 10795-10798CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The synthesis of aryl fluorides has been studied intensively because of the importance of aryl fluorides in pharmaceuticals, agrochems., and materials. The stability, reactivity, and biol. properties of aryl fluorides can be distinct from those of the corresponding arenes. Methods for the synthesis of aryl fluorides, however, are limited. We report the conversion of a diverse set of aryl iodides to the corresponding aryl fluorides. This reaction occurs with a cationic copper reagent and silver fluoride. Preliminary results suggest this reaction is enabled by a facile reductive elimination from a cationic arylcopper(III) fluoride.
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    Copper-catalyzed fluorination of 2-pyridyl aryl bromides
    Mu, Xin; Zhang, Hao; Chen, Pinhong; Liu, Guosheng
    Chemical Science (2014), 5 (1), 275-280CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    A novel copper-catalyzed fluorination of aryl bromides using AgF as the fluorine source was developed. In this transformation a pyridyl directing group was essential for successful catalytic fluorination. A XANES/EXAFS study supported the proposed mechanism whereby the pyridyl group was essential to stabilize a Cu(I) intermediate and accelerate oxidative addn. of the aryl bromide. Further mechanistic studies implicated a Cu(I/III) catalytic cycle in this Cu(I)-catalyzed fluorination, and that final aryl C-F bond formation possibly proceeded through an irreversible reductive elimination of a ArCu(III)-F species. This rare report of catalytic fluorination by a copper catalyst provides a valuable foundation for further development of Cu(I)-catalyzed fluorination of aryl halides.
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    Cu(OTf)2-Mediated Fluorination of Aryltrifluoroborates with Potassium Fluoride
    Ye, Yingda; Schimler, Sydonie D.; Hanley, Patrick S.; Sanford, Melanie S.
    Journal of the American Chemical Society (2013), 135 (44), 16292-16295CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    This Communication describes the Cu(OTf)2-mediated fluorination of aryltrifluoroborates with KF. The reaction proceeds under mild conditions (at 60° over 20 h) and shows a broad substrate scope and functional group tolerance. The Cu is proposed to play two sep. roles in this transformation: (1) as a mediator for the aryl-F coupling and (2) as an oxidant for accessing a proposed CuIII(aryl)-(F) intermediate.
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    Palladium fluoride complexes: one more step toward metal-mediated C-F bond formation
    Grushin, Vladimir V.
    Chemistry - A European Journal (2002), 8 (5), 1006-1014CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH)
    A review contg., refs. on complexes of Pd contg. a Pd-F bond, both fluorides and bifluorides, which were synthesized and fully characterized in the solid state and in soln. Reactivity studies of the Pd fluoride complexes revealed their unexpected stability and unusual chem. properties, different from the hydroxo, chloro, bromo, and iodo analogs. A novel efficient method to generate naked fluoride was developed using [(Ph3P)2Pd(F)Ph]. The naked fluoride from the Pd source fluorinated CH2Cl2, deprotonated CHCl3, and catalyzed di- and trimerization of hexafluoropropene under uncommonly mild conditions.
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    Aryl-Fluoride Reductive Elimination from Pd(II): Feasibility Assessment from Theory and Experiment
    Yandulov, Dmitry V.; Tran, Ngon T.
    Journal of the American Chemical Society (2007), 129 (5), 1342-1358CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    DFT methods were used to elucidate features of coordination environment of Pd(II) that could enable Ar-F reductive elimination as an elementary C-F bond-forming reaction potentially amenable to integration into catalytic cycles for synthesis of organofluorine compds. with benign stoichiometric sources of F-. Three-coordinate T-shaped geometry of PdIIAr(F)L (L = NHC, PR3) was shown to offer kinetics and thermodn. of Ar-F elimination largely compatible with synthetic applications, whereas coordination of strong 4th ligands to Pd or assocn. of H bond donors with F each caused pronounced stabilization of Pd(II) reactant and increased activation barrier beyond the practical range. Decreasing donor ability of L promotes elimination kinetics via increasing driving force and para-substituents on Ar exert a sizable SNAr-type TS effect. Synthesis and characterization of the novel [Pd(C6H4-4-NO2)ArL(μ-F)]2 (L = P(o-Tolyl)3, 17; P(t-Bu)3, 18) revealed stability of the fluoride-bridged dimer forms of the requisite PdIIAr(F)L as the key remaining obstacle to Ar-F reductive elimination in practice. Interligand steric repulsion with P(t-Bu)3 served to destabilize dimer 18 by 20 kcal/mol, estd. with DFT relative to PMe3 analog, yet was insufficient to enable formation of greater than trace quantities of Ar-F; C-H activation of P(t-Bu)3 followed by isobutylene elimination was the major degrdn. pathway of 18 while Ar/F‾ scrambling and Ar-Ar reductive elimination dominated thermal decompn. of 17. However, use of Buchwald's L = P(C6H4-2-Trip)(t-Bu)2 provided the addnl. steric pressure on the [PdArL(μ-F)]2 core needed to enable formation of aryl-fluoride net reductive elimination product in quantifiable yields (10%) in reactions with both 17 and 18 at 60° over 22 h.
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    Versatile Pd(OTf)2·2H2O-Catalyzed ortho-Fluorination Using NMP as a Promoter
    Wang, Xisheng; Mei, Tian-Sheng; Yu, Jin-Quan
    Journal of the American Chemical Society (2009), 131 (22), 7520-7521CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Pd(OTf)2·2H2O-catalyzed ortho-fluorination of triflamide-protected benzylamines is reported. The use of N-fluoro-2,4,6-trimethylpyridinium triflate as the F+ source and NMP as a promoter is crucial for this reaction. The conversion of triflamide into a wide range of synthetically useful functional groups makes this fluorination protocol broadly applicable in medicinal chem. and synthesis.
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    Palladium(III)-Catalyzed Fluorination of Arylboronic Acid Derivatives
    Mazzotti, Anthony R.; Campbell, Michael G.; Tang, Pingping; Murphy, Jennifer M.; Ritter, Tobias
    Journal of the American Chemical Society (2013), 135 (38), 14012-14015CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A practical, palladium-catalyzed synthesis of aryl fluorides from arylboronic acid derivs. is presented. The reaction is operationally simple and amenable to multigram-scale synthesis. Evaluation of the reaction mechanism suggests a single-electron-transfer pathway, involving a Pd-(III) intermediate that has been isolated and characterized.
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    Palladium-Catalyzed Fluorination of Carbon-Hydrogen Bonds
    Hull, Kami L.; Anani, Waseem Q.; Sanford, Melanie S.
    Journal of the American Chemical Society (2006), 128 (22), 7134-7135CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The development of a new Pd-catalyzed method for the fluorination of carbon-hydrogen bonds is described. A key step of these transformations involves palladium-mediated carbon-fluorine coupling, a much sought after, but previously unprecedented, transformation. These reactions were successfully achieved under oxidative conditions using electrophilic N-fluoropyridinium reagents. Microwave irradn. in the presence of catalytic palladium acetate served as optimal conditions for the fluorination of C-H bonds in a variety of substituted 2-arylpyridine and 8-methylquinoline derivs.
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    Palladium(II)-Catalyzed Selective Monofluorination of Benzoic Acids Using a Practical Auxiliary: A Weak-Coordination Approach
    Chan, Kelvin S. L.; Wasa, Masayuki; Wang, Xisheng; Yu, Jin-Quan
    Angewandte Chemie, International Edition (2011), 50 (39), 9081-9084, S9081/1-S9081/127CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Monofluorination of N-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl]benzamides with N-fluoro-2,4,6-trimethylpyridinium triflate (I) gave ortho-fluorinated products. Use of MeCN as the solvent was essential for obtaining high monoselectivity. The catalyst used was [Pd(OTf)2(MeCN)4]. Fluorination in PhCF3 with 3 equiv of I at 120 °C for 2 h afforded the desired difluorinated products in good yields, accompanied by less than 5% of the corresponding monofluorinated products. Base-catalyzed hydrolysis of the amides readily furnished the corresponding fluorinated benzoic acids in excellent yields.
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    Pd(PPh3)4-catalyzed direct ortho-fluorination of 2-arylbenzothiazoles with an electrophilic fluoride N-fluorobenzenesulfonimide (NFSI)
    Ding, Qiuping; Ye, Changqing; Pu, Shouzhi; Cao, Banpeng
    Tetrahedron (2014), 70 (2), 409-416CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
    An efficient protocol was developed for regio-selective Pd-catalyzed direct ortho-fluorination of 2-arylbenzo[d]thiazoles using N-fluorobenzenesulfonimide (NFSI) as the F+ source, and L-proline as the crucial promoter. The present method offered a practical route to synthesize valuable fluorinated products, which are of potential importance in the pharmaceutical and agrochem. industries.
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Cite this: J. Am. Chem. Soc. 2015, 137, 41, 13433–13438
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  • Abstract

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    Figure 1

    Figure 1. (a) The proposed catalytic cycle for Pd-catalyzed fluorination. (b) A Pd(II) complex with L2 highlighted in red. The interaction between ligand-bound Pd(II) and C1′ is shown by a dashed line. (c) Biaryl monophosphine ligand (Alphos, L1).

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    Scheme 1

    Scheme 1. Synthesis of L1 and Pd(0) Precatalyst 1a
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    Scheme aReagents and conditions: (a) THF, −78 °C, n-BuLi, 1 h; added to C6F6 in THF, 0 °C to rt, 2 h, 87%. (b) THF, −78 °C, n-BuLi, 30 min, 99%. (c) AcOH, EtOAc, H2SO4, N-iodosuccinimide, 50 °C, 17 h, 80%. (d) THF, −78 °C, t-BuLi, 1 h; added to 3-fluoroanisole and n-BuLi in THF, −78 to −25 °C, 44%. (e) THF, −78 °C, t-BuLi, 1 h; CuCl −78 °C to rt; Ad2PCl, toluene, 140 °C, 18 h, 82%. (f) [COD·Pd(CH2TMS)2], pentane, rt, 48 h, 78%.

    Figure 2

    Figure 2. Crystal structure of [(L1Pd)2·COD] (1). Thermal ellipsoids are shown at 50% probability; hydrogen atoms and residual benzene molecules are omitted for clarity.

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    Scheme 2

    Scheme 2. Stoichiometric C–F Reductive Elimination from Pd(II) Complexes at Room Temperaturea
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    Scheme aYields determined by 19F NMR. bNo ArBr added. cArBr (R = C(O)n-Bu). dArBr (R = n-Bu).

    Figure 3

    Figure 3. (a) Schematic of [L2Pd(Ar)X] complexes C and E where L2 is highlighted in red. (b) Schematic of [L1Pd(Ar)X] complexes D and F. (c) Crystal structure overlay of C and D. C is shown in red. Hydrogen atoms and an isopropyl group are omitted for clarity. (d) Crystal structure of E highlighting the intramolecular CH···F contact. Hydrogen atoms and the n-butyl group on the Pd-bound aryl omitted for clarity. Thermal ellipsoids are shown at 50% probability.

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    Figure 4

    Figure 4. Computed ground-state structures of complexes E′ and F′. Geometries were optimized at the B3LYP/6-31G(d)-SDD(Pd) level of theory. Hydrogen atoms are omitted for clarity. (a) The CH···F interaction of complex E′ is 3.24 Å, measured from C to F. (b) Complex F′ showing the lack of an intermolecular stabilizing interaction.

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    Figure 5

    Figure 5. Energies were computed at the M06/6-311+G(d,p)-SDD(Pd)/SMD(toluene) level of theory with geometries optimized at the B3LYP/6-31G(d)-SDD(Pd) level. Hydrogen atoms are omitted for clarity. (a) Transition state minimization of complex E′. (b) Transition state minimization of complex F′.

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      Mueller, Klaus; Faeh, Christoph; Diederich, Francois
      Science (Washington, DC, United States) (2007), 317 (5846), 1881-1886CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      A review. Fluorine substituents have become a widespread and important drug component, their introduction facilitated by the development of safe and selective fluorinating agents. Organofluorine affects nearly all phys. and adsorption, distribution, metab., and excretion properties of a lead compd. Its inductive effects are relatively well understood, enhancing bioavailability, for example, by reducing the basicity of neighboring amines. In contrast, exploration of the specific influence of carbon-fluorine single bonds on docking interactions, whether through direct contact with the protein or through stereoelectronic effects on mol. conformation of the drug, has only recently begun. Here, we review exptl. progress in this vein and add complementary anal. based on comprehensive searches in the Cambridge Structural Database and the Protein Data Bank.
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      (c) Smart, B. E. J. Fluorine Chem. 2001, 109, 3 DOI: 10.1016/S0022-1139(01)00375-X
      2c
      Fluorine substituent effects (on bioactivity)
      Smart, B. E.
      Journal of Fluorine Chemistry (2001), 109 (1), 3-11CODEN: JFLCAR; ISSN:0022-1139. (Elsevier Science S.A.)
      A review, with 32 refs.,. The characteristic effects of F and fluoroalkyl substituents on the physicochem. properties of mols. that are important to biol. activity of fluorinated compds. are highlighted. The influence of fluorination on acidity, H-bonding, and lipophilicity that affect compd. absorption and distribution is described. The current perspectives on F steric interactions and the controversial role of H-bonding involving the C-F bond are discussed.
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      (d) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH Verlag GmbH & Co. KGaA: New York, 2013; p 299.
      There is no corresponding record for this reference.
    3. 3
      (a) Jeschke, P. ChemBioChem 2004, 5, 570 DOI: 10.1002/cbic.200300833
      3a
      The unique role of fluorine in the design of active ingredients for modern crop protection
      Jeschke, Peter
      ChemBioChem (2004), 5 (5), 570-589CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. The task of inventing and developing active ingredients with useful biol. activities requires a search for novel chem. substructures. This process may trigger the discovery of whole classes of chems. of potential com. interest. Similar biol. effects can often be achieved by completely different compds. However, compds. within a given structural family may exhibit quite different biol. activities depending on their interactions with different intracellular proteins like enzymes or receptors. By varying the functional groups and structural elements of a lead compd., its interaction with the active site of the target protein, as well as its physicochem., pharmacokinetic, and dynamic properties can be improved. In this context, the introduction of fluorine into active ingredients has become an important concept in the quest for a modern crop protection product with optimal efficacy, environmental safety, user friendliness, and economic viability. Fluorinated org. compds. represent an important and growing family of com. agrochems. A no. of recently developed agrochem. candidates represent novel classes of chem. compds. with new modes of action; several of these compds. contain new fluorinated substituents. However, the complex structure-activity relationships assocd. with biol.-active mols. mean that the introduction of fluorine can lead to either an increase or a decrease in the efficacy of a compd., depending on its changed mode of action, physicochem. properties, target interaction, or metabolic susceptibility and transformation. Therefore, it is still difficult to predict the sites in a mol. at which fluorine substitution will result in optimal desired effects.
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      (b) Fujiwara, T.; O’Hagan, D. J. Fluorine Chem. 2014, 167, 16 DOI: 10.1016/j.jfluchem.2014.06.014
      3b
      Successful fluorine-containing herbicide agrochemicals
      Fujiwara, Tomoya; O'Hagan, David
      Journal of Fluorine Chemistry (2014), 167 (), 16-29CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)
      A review. Of the herbicides licensed worldwide, currently around 25% contain at least one fluorine atom and many contain multiple fluorines in the form of difluoro- and trifluoromethyl groups. Fluorine-contg. compds. have made a significant contribution to the development of products for the agrochems. industry and many organofluorine entities have found stable market positions. In this review we highlight the most important fluorinated herbicides in terms of their global use. The compds. are grouped by mode of action. A synthesis route is described for each compd. although the synthesis presented may not actually be the industrial process.
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    4. 4
      (a) Balz, G.; Schiemann, G. Ber. Dtsch. Chem. Ges. B 1927, 60, 1186 DOI: 10.1002/cber.19270600539
      4a
      Aromatic fluorine compounds. I. A new method for their preparation
      Balz, Gunther; Schiemann, Gunther
      Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1927), 60B (), 1186-90CODEN: BDCBAD; ISSN:0365-9488.
      Contrary to the earlier belief, the diazonium fluoborates (cf. C. A. 21, 1070) decomp. smoothly and quietly on warming: ArN2BF4 → ArF + N2 + BF3. There are no side reactions. Because of their slight soly. they can be obtained in dry form readily and in good yield and they are very stable; they can even be recrystd. from hot H2O and are entirely insensitive to shock. On decompn. they yield the fluoride in many cases almost quant. and in pure form even when the diazonium fluoborate has not previously been especially purified. In general the appropriate amine is diazotized in as concd. soln. in HCl as possible, pptd. with excess of HBF4, (about 40%), washed with HBF, alc. and Et2O, dried in vacuo and heated in a fractionating flask (the glass is practically not attacked at all) connected with a condenser, the gaseous BF3 being absorbed in H2O or NaOH. Phenyldiazonium fluoborate (yield 63 %), becomes slightly pink 80°, decomps. 121-2°, d425 1.53, yields almost 100% PhF, b. 86°. p-Tolyldiazonium fluoborate (67%), decomps. 110°, d425 1.48; MeC6H4F (97%), b756 116°. m-Xylyldiazonium fluoborate (31%; the yield Can easily be increased), decomps. 108°, d425 1.50; 2,4-e2C6H2F (almost 100%, b749 143-40°. α.Naphthyldiazonium fluoborate (62%), decomps. 113°; α-C10H7F(98%),b17110°, b758 215°. Diphenylene-4,4'-bisdiazonium fluoborate (64%),turns pink about 130°, foams 157°, d425 1.73; (P-FC6H4)2, m. 94-5°, d425 1.328. o-,m-and p-Nitrophenyl-diazonium fluoborates (yields, 74, 80, 100%, resp.), decomp. 135°, 178°, 156°, d425 1.69, 1.66, 1.66.
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      (b) Kirk, K. L.; Cohen, L. A. J. Am. Chem. Soc. 1973, 95, 4619 DOI: 10.1021/ja00795a026
      There is no corresponding record for this reference.
      (c) Cresswell, A. J.; Davies, S. G.; Roberts, P. M.; Thomson, J. E. Chem. Rev. 2015, 115, 566 DOI: 10.1021/cr5001805
      4c
      Beyond the Balz-Schiemann Reaction: The Utility of Tetrafluoroborates and Boron Trifluoride as Nucleophilic Fluoride Sources
      Cresswell, Alexander J.; Davies, Stephen G.; Roberts, Paul M.; Thomson, James E.
      Chemical Reviews (Washington, DC, United States) (2015), 115 (2), 566-611CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. This Review offers a dedicated account of tetrafluoroborates and boron fluorides as nucleophilic fluoride sources for C-F bond formation, comprehensive to the end of 2013.
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    5. 5
      Finger, G. C.; Kruse, C. W. J. Am. Chem. Soc. 1956, 78, 6034 DOI: 10.1021/ja01604a022
      There is no corresponding record for this reference.
    6. 6
      (a) Fujimoto, T.; Becker, F.; Ritter, T. Org. Process Res. Dev. 2014, 18, 1041 DOI: 10.1021/op500121w
      There is no corresponding record for this reference.
      (b) Sun, H.; DiMagno, S. G. Angew. Chem., Int. Ed. 2006, 45, 2720 DOI: 10.1002/anie.200504555
      There is no corresponding record for this reference.
      (c) Allen, L. J.; Muhuhi, J. M.; Bland, D. C.; Merzel, R.; Sanford, M. S. J. Org. Chem. 2014, 79, 5827 DOI: 10.1021/jo5003054
      There is no corresponding record for this reference.
      (d) Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2010, 49, 2219 DOI: 10.1002/anie.200905855
      There is no corresponding record for this reference.
    7. 7
      (a) Tang, P.; Furuya, T.; Ritter, T. J. Am. Chem. Soc. 2010, 132, 12150 DOI: 10.1021/ja105834t
      7a
      Silver-Catalyzed Late-Stage Fluorination
      Tang, Pingping; Furuya, Takeru; Ritter, Tobias
      Journal of the American Chemical Society (2010), 132 (34), 12150-12154CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Carbon-fluorine bond formation by transition metal catalysis is difficult, and only a few methods for the synthesis of aryl fluorides have been developed. All reported transition-metal-catalyzed fluorination reactions for the synthesis of functionalized arenes are based on palladium. Here, we present silver catalysis for carbon-fluorine bond formation. For example, reacting 4-EtO2CC6H4SnBu3 with Ag2O/NaOTf/NaHCO3/MeOH gave 92% of 4-FC6H4CO2Et. Our report is the first example of the use of the transition metal silver to form carbon-heteroatom bonds by cross-coupling catalysis. The functional group tolerance and substrate scope presented here have not been demonstrated for any other fluorination reaction to date.
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      (b) Furuya, T.; Kaiser, H. M.; Ritter, T. Angew. Chem., Int. Ed. 2008, 47, 5993 DOI: 10.1002/anie.200802164
      There is no corresponding record for this reference.
      (c) Hollingworth, C.; Gouverneur, V. Chem. Commun. 2012, 48, 2929 DOI: 10.1039/c2cc16158c
      7c
      Transition metal catalysis and nucleophilic fluorination
      Hollingworth, Charlotte; Gouverneur, Veronique
      Chemical Communications (Cambridge, United Kingdom) (2012), 48 (24), 2929-2942CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      A review. Transition metal catalyzed transformations using fluorinating reagents have been developed extensively for the prepn. of synthetically valuable fluorinated targets. This is a topic of crit. importance to facilitate lab. and industrial chem. synthesis of fluorine contg. pharmaceuticals and agrochems. Translation to 18F-radiochem. is also emerging as a vibrant research field because functional imaging based on Positron Emission Tomog. (PET) is increasingly used for both diagnosis and pharmaceutical development. This review summarizes how fluoride sources have been used for the catalytic nucleophilic fluorination of various substrates inclusive of aryl triflates, alkynes, allylic halides, allylic esters, allylic trichloroacetimidates, benzylic halides, tertiary alkyl halides and epoxides. Until recently, progress in this field of research has been slow in part because of the challenges assocd. with the dual reactivity profile of fluoride (nucleophile or base). Despite these difficulties, some remarkable breakthroughs have emerged. This includes the demonstration that Pd(0)/Pd(II)-catalyzed nucleophilic fluorination to access fluoroarenes from aryl triflates is feasible, and the first examples of Tsuji-Trost allylic alkylation with fluoride using either allyl chlorides or allyl precursors bearing O-leaving groups. More recently, allylic fluorides were also made accessible under iridium catalysis. Another reaction, which has been greatly improved based on careful mechanistic work, is the catalytic asym. hydrofluorination of meso epoxides. Notably, each individual transition metal catalyzed nucleophilic fluorination reported to date employs a different F-reagent, an observation indicating that this area of research will benefit from a larger pool of nucleophilic fluoride sources. In this context, a striking recent development is the successful design, synthesis and applications of a fluoride-derived electrophilic late stage fluorination reagent. This new class of reagents could greatly benefit preclin. and clin. PET imaging.
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      (d) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 10795 DOI: 10.1021/ja304410x
      7d
      Copper-Mediated Fluorination of Aryl Iodides
      Fier, Patrick S.; Hartwig, John F.
      Journal of the American Chemical Society (2012), 134 (26), 10795-10798CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The synthesis of aryl fluorides has been studied intensively because of the importance of aryl fluorides in pharmaceuticals, agrochems., and materials. The stability, reactivity, and biol. properties of aryl fluorides can be distinct from those of the corresponding arenes. Methods for the synthesis of aryl fluorides, however, are limited. We report the conversion of a diverse set of aryl iodides to the corresponding aryl fluorides. This reaction occurs with a cationic copper reagent and silver fluoride. Preliminary results suggest this reaction is enabled by a facile reductive elimination from a cationic arylcopper(III) fluoride.
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      (e) Ichiishi, N.; Brooks, A. F.; Topczewski, J. J.; Rodnick, M. E.; Sanford, M. S.; Scott, P. J. H. Org. Lett. 2014, 16, 3224 DOI: 10.1021/ol501243g
      There is no corresponding record for this reference.
      (f) Casitas, A.; Canta, M.; Solà, M.; Costas, M.; Ribas, X. J. Am. Chem. Soc. 2011, 133, 19386 DOI: 10.1021/ja2058567
      There is no corresponding record for this reference.
      (g) Mu, X.; Zhang, H.; Chen, P.; Liu, G. Chem. Sci. 2014, 5, 275 DOI: 10.1039/C3SC51876K
      7g
      Copper-catalyzed fluorination of 2-pyridyl aryl bromides
      Mu, Xin; Zhang, Hao; Chen, Pinhong; Liu, Guosheng
      Chemical Science (2014), 5 (1), 275-280CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      A novel copper-catalyzed fluorination of aryl bromides using AgF as the fluorine source was developed. In this transformation a pyridyl directing group was essential for successful catalytic fluorination. A XANES/EXAFS study supported the proposed mechanism whereby the pyridyl group was essential to stabilize a Cu(I) intermediate and accelerate oxidative addn. of the aryl bromide. Further mechanistic studies implicated a Cu(I/III) catalytic cycle in this Cu(I)-catalyzed fluorination, and that final aryl C-F bond formation possibly proceeded through an irreversible reductive elimination of a ArCu(III)-F species. This rare report of catalytic fluorination by a copper catalyst provides a valuable foundation for further development of Cu(I)-catalyzed fluorination of aryl halides.
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      (h) Truong, T.; Klimovica, K.; Daugulis, O. J. Am. Chem. Soc. 2013, 135, 9342 DOI: 10.1021/ja4047125
      There is no corresponding record for this reference.
      (i) Ye, Y.; Schimler, S. D.; Hanley, P. S.; Sanford, M. S. J. Am. Chem. Soc. 2013, 135, 16292 DOI: 10.1021/ja408607r
      7i
      Cu(OTf)2-Mediated Fluorination of Aryltrifluoroborates with Potassium Fluoride
      Ye, Yingda; Schimler, Sydonie D.; Hanley, Patrick S.; Sanford, Melanie S.
      Journal of the American Chemical Society (2013), 135 (44), 16292-16295CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      This Communication describes the Cu(OTf)2-mediated fluorination of aryltrifluoroborates with KF. The reaction proceeds under mild conditions (at 60° over 20 h) and shows a broad substrate scope and functional group tolerance. The Cu is proposed to play two sep. roles in this transformation: (1) as a mediator for the aryl-F coupling and (2) as an oxidant for accessing a proposed CuIII(aryl)-(F) intermediate.
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      (j) Wannberg, J.; Wallinder, C.; Ünlüsoy, M.; Sköld, C.; Larhed, M. J. Org. Chem. 2013, 78, 4184 DOI: 10.1021/jo400255m
      There is no corresponding record for this reference.
      (k) Noël, T.; Maimone, T. J.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 8900 DOI: 10.1002/anie.201104652
      There is no corresponding record for this reference.
    8. 8
      (a) Grushin, V. V. Acc. Chem. Res. 2010, 43, 160 DOI: 10.1021/ar9001763
      There is no corresponding record for this reference.
      (b) Grushin, V. V.; Marshall, W. J. Organometallics 2007, 26, 4997 DOI: 10.1021/om700469k
      There is no corresponding record for this reference.
      (c) Grushin, V. V. Chem. - Eur. J. 2002, 8, 1006 DOI: 10.1002/1521-3765(20020301)8:5<1006::AID-CHEM1006>3.0.CO;2-M
      8c
      Palladium fluoride complexes: one more step toward metal-mediated C-F bond formation
      Grushin, Vladimir V.
      Chemistry - A European Journal (2002), 8 (5), 1006-1014CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH)
      A review contg., refs. on complexes of Pd contg. a Pd-F bond, both fluorides and bifluorides, which were synthesized and fully characterized in the solid state and in soln. Reactivity studies of the Pd fluoride complexes revealed their unexpected stability and unusual chem. properties, different from the hydroxo, chloro, bromo, and iodo analogs. A novel efficient method to generate naked fluoride was developed using [(Ph3P)2Pd(F)Ph]. The naked fluoride from the Pd source fluorinated CH2Cl2, deprotonated CHCl3, and catalyzed di- and trimerization of hexafluoropropene under uncommonly mild conditions.
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    9. 9
      Yandulov, D. V.; Tran, N. T. J. Am. Chem. Soc. 2007, 129, 1342 DOI: 10.1021/ja066930l
      9
      Aryl-Fluoride Reductive Elimination from Pd(II): Feasibility Assessment from Theory and Experiment
      Yandulov, Dmitry V.; Tran, Ngon T.
      Journal of the American Chemical Society (2007), 129 (5), 1342-1358CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      DFT methods were used to elucidate features of coordination environment of Pd(II) that could enable Ar-F reductive elimination as an elementary C-F bond-forming reaction potentially amenable to integration into catalytic cycles for synthesis of organofluorine compds. with benign stoichiometric sources of F-. Three-coordinate T-shaped geometry of PdIIAr(F)L (L = NHC, PR3) was shown to offer kinetics and thermodn. of Ar-F elimination largely compatible with synthetic applications, whereas coordination of strong 4th ligands to Pd or assocn. of H bond donors with F each caused pronounced stabilization of Pd(II) reactant and increased activation barrier beyond the practical range. Decreasing donor ability of L promotes elimination kinetics via increasing driving force and para-substituents on Ar exert a sizable SNAr-type TS effect. Synthesis and characterization of the novel [Pd(C6H4-4-NO2)ArL(μ-F)]2 (L = P(o-Tolyl)3, 17; P(t-Bu)3, 18) revealed stability of the fluoride-bridged dimer forms of the requisite PdIIAr(F)L as the key remaining obstacle to Ar-F reductive elimination in practice. Interligand steric repulsion with P(t-Bu)3 served to destabilize dimer 18 by 20 kcal/mol, estd. with DFT relative to PMe3 analog, yet was insufficient to enable formation of greater than trace quantities of Ar-F; C-H activation of P(t-Bu)3 followed by isobutylene elimination was the major degrdn. pathway of 18 while Ar/F‾ scrambling and Ar-Ar reductive elimination dominated thermal decompn. of 17. However, use of Buchwald's L = P(C6H4-2-Trip)(t-Bu)2 provided the addnl. steric pressure on the [PdArL(μ-F)]2 core needed to enable formation of aryl-fluoride net reductive elimination product in quantifiable yields (10%) in reactions with both 17 and 18 at 60° over 22 h.
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    10. 10
      (a) Wang, X.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 7520 DOI: 10.1021/ja901352k
      10a
      Versatile Pd(OTf)2·2H2O-Catalyzed ortho-Fluorination Using NMP as a Promoter
      Wang, Xisheng; Mei, Tian-Sheng; Yu, Jin-Quan
      Journal of the American Chemical Society (2009), 131 (22), 7520-7521CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Pd(OTf)2·2H2O-catalyzed ortho-fluorination of triflamide-protected benzylamines is reported. The use of N-fluoro-2,4,6-trimethylpyridinium triflate as the F+ source and NMP as a promoter is crucial for this reaction. The conversion of triflamide into a wide range of synthetically useful functional groups makes this fluorination protocol broadly applicable in medicinal chem. and synthesis.
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      (b) Mazzotti, A. R.; Campbell, M. G.; Tang, P.; Murphy, J. M.; Ritter, T. J. Am. Chem. Soc. 2013, 135, 14012 DOI: 10.1021/ja405919z
      10b
      Palladium(III)-Catalyzed Fluorination of Arylboronic Acid Derivatives
      Mazzotti, Anthony R.; Campbell, Michael G.; Tang, Pingping; Murphy, Jennifer M.; Ritter, Tobias
      Journal of the American Chemical Society (2013), 135 (38), 14012-14015CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A practical, palladium-catalyzed synthesis of aryl fluorides from arylboronic acid derivs. is presented. The reaction is operationally simple and amenable to multigram-scale synthesis. Evaluation of the reaction mechanism suggests a single-electron-transfer pathway, involving a Pd-(III) intermediate that has been isolated and characterized.
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      (c) Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134 DOI: 10.1021/ja061943k
      10c
      Palladium-Catalyzed Fluorination of Carbon-Hydrogen Bonds
      Hull, Kami L.; Anani, Waseem Q.; Sanford, Melanie S.
      Journal of the American Chemical Society (2006), 128 (22), 7134-7135CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The development of a new Pd-catalyzed method for the fluorination of carbon-hydrogen bonds is described. A key step of these transformations involves palladium-mediated carbon-fluorine coupling, a much sought after, but previously unprecedented, transformation. These reactions were successfully achieved under oxidative conditions using electrophilic N-fluoropyridinium reagents. Microwave irradn. in the presence of catalytic palladium acetate served as optimal conditions for the fluorination of C-H bonds in a variety of substituted 2-arylpyridine and 8-methylquinoline derivs.
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      (d) Chan, K. S. L.; Wasa, M.; Wang, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2011, 50, 9081 DOI: 10.1002/anie.201102985
      10d
      Palladium(II)-Catalyzed Selective Monofluorination of Benzoic Acids Using a Practical Auxiliary: A Weak-Coordination Approach
      Chan, Kelvin S. L.; Wasa, Masayuki; Wang, Xisheng; Yu, Jin-Quan
      Angewandte Chemie, International Edition (2011), 50 (39), 9081-9084, S9081/1-S9081/127CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Monofluorination of N-[2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl]benzamides with N-fluoro-2,4,6-trimethylpyridinium triflate (I) gave ortho-fluorinated products. Use of MeCN as the solvent was essential for obtaining high monoselectivity. The catalyst used was [Pd(OTf)2(MeCN)4]. Fluorination in PhCF3 with 3 equiv of I at 120 °C for 2 h afforded the desired difluorinated products in good yields, accompanied by less than 5% of the corresponding monofluorinated products. Base-catalyzed hydrolysis of the amides readily furnished the corresponding fluorinated benzoic acids in excellent yields.
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      (f) Ball, N. D.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 3796 DOI: 10.1021/ja8054595
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      Pd(PPh3)4-catalyzed direct ortho-fluorination of 2-arylbenzothiazoles with an electrophilic fluoride N-fluorobenzenesulfonimide (NFSI)
      Ding, Qiuping; Ye, Changqing; Pu, Shouzhi; Cao, Banpeng
      Tetrahedron (2014), 70 (2), 409-416CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
      An efficient protocol was developed for regio-selective Pd-catalyzed direct ortho-fluorination of 2-arylbenzo[d]thiazoles using N-fluorobenzenesulfonimide (NFSI) as the F+ source, and L-proline as the crucial promoter. The present method offered a practical route to synthesize valuable fluorinated products, which are of potential importance in the pharmaceutical and agrochem. industries.
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      (i) Lou, S.-J.; Xu, D.-Q.; Xia, A.-B.; Wang, Y.-F.; Liu, Y.-K.; Du, X.-H.; Xu, Z.-Y. Chem. Commun. 2013, 49, 6218 DOI: 10.1039/c3cc42220h
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      Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; García-Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661 DOI: 10.1126/science.1178239
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      Reductive Elimination of Aryl Halides from Palladium(II)
      Roy, Amy H.; Hartwig, John F.
      Journal of the American Chemical Society (2001), 123 (6), 1232-1233CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Reductive elimination of aryl halide is induced by addn. of tri-tert-butylphosphine to arylpalladium(II) halide complexes, e.g. {Pd[P(o-tol)3](2-Me-5-t-Bu-C6H3)(μ-Cl)}2, and is favored thermodynamically over oxidative addn. Equil. consts. for the addn. and elimination processes show that an unusual mechanism for ligand exchange occurs to initiate the reductive elimination.
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      (a) Maimone, T. J.; Milner, P. J.; Kinzel, T.; Zhang, Y.; Takase, M. K.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, 18106 DOI: 10.1021/ja208461k
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      (b) Milner, P. J.; Maimone, T. J.; Su, M.; Chen, J.; Müller, P.; Buchwald, S. L. J. Am. Chem. Soc. 2012, 134, 19922 DOI: 10.1021/ja310351e
      13b
      Investigating the Dearomative Rearrangement of Biaryl Phosphine-Ligated Pd(II) Complexes
      Milner, Phillip J.; Maimone, Thomas J.; Su, Mingjuan; Chen, Jiahao; Muller, Peter; Buchwald, Stephen L.
      Journal of the American Chemical Society (2012), 134 (48), 19922-19934CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Monoligated L·Pd(II)(Ar)X complexes (L = dialkyl biaryl phosphine), e.g., I (R = NMe2, OMe, nBu, H, Ph, F, Cl, CHO, CN), were prepd. and studied in an effort to better understand an unusual dearomative rearrangement previously documented in these systems. Exptl. and theor. evidence suggest a concerted process involving the unprecedented Pd(II)-mediated insertion of an aryl group into an unactivated arene.
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      (c) Lee, H. G.; Milner, P. J.; Buchwald, S. L. J. Am. Chem. Soc. 2014, 136, 3792 DOI: 10.1021/ja5009739
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      Milner, P. J.; Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2014, 136, 15757 DOI: 10.1021/ja509144r
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      (a) Hoffmann, R. In IUPAC. Frontiers of Chemistry; Laidler, K. J., Ed.; Pergamon Press: Oxford, 1982; p 247.
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      (b) Tatsumi, K.; Hoffmann, R.; Yamamoto, A.; Stille, J. K. Bull. Chem. Soc. Jpn. 1981, 54, 1857 DOI: 10.1246/bcsj.54.1857
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      Reductive elimination of d8-organotransition metal complexes
      Tatsumi, Kazuyuki; Hoffmann, Roald; Yamamoto, Akio; Stille, John K.
      Bulletin of the Chemical Society of Japan (1981), 54 (6), 1857-67CODEN: BCSJA8; ISSN:0009-2673.
      A theor. anal. of 2 aspects of the mechanism of reductive elimination is presented: the effect of the central metal and peripheral ligands on the activation energy for reductive elimination from a 4-coordinate R2M(PR13)2 complex (R, R1 = alkyl; M = Ni, Pt, Pd) and the control of ligand asymmetry on cis-trans rearrangements and elimination pathways proceeding via 3-coordinate intermediates. In the 4-coordinate complex, the better the σ-donating capability of the leaving groups, the more facile the elimination. Stronger donor ligands trans to the leaving groups increase the elimination barrier. The barrier to reductive elimination in 4-coordinate complexes is controlled by the energy of an antisym. b2 orbital, which in turn depends on the energy of the metal levels. The activation energy for such direct reductive elimination is substantially lower for Ni than for Pt or Pd. T-shaped trans-PdLR2, arising from dissocn. of L in PdL2R2, encounters a substantial barrier to polytopal rearrangement to cis-PdLR2, which in turn has an open channel for reductive elimination of R2. If the leaving groups are poor donors, cis-trans isomerization in the 3--coordinate manifold should be easier than elimination.
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    17. 17
      (a) Yagupol’skii, L. M.; Ya Il’chenko, A.; Kondratenko, N. V. Russ. Chem. Rev. 1974, 43, 32 DOI: 10.1070/RC1974v043n01ABEH001787
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      (b) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165 DOI: 10.1021/cr00002a004
      17b
      A survey of Hammett substituent constants and resonance and field parameters
      Hansch, Corwin; Leo, A.; Taft, R. W.
      Chemical Reviews (Washington, DC, United States) (1991), 91 (2), 165-95CODEN: CHREAY; ISSN:0009-2665.
      Included in this review is an anal. of newer methods which can supplant this classic procedure for detn. of the title consts., 283 refs.
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      (a) Lee, H. G.; Milner, P. J.; Colvin, M. T.; Andreas, L.; Buchwald, S. L. Inorg. Chim. Acta 2014, 422, 188 DOI: 10.1016/j.ica.2014.06.008
      18a
      Structure and reactivity of [(L·Pd)n·(1,5-cyclooctadiene)] (n = 1-2) complexes bearing biaryl phosphine ligands
      Lee, Hong Geun; Milner, Phillip J.; Colvin, Michael T.; Andreas, Loren; Buchwald, Stephen L.
      Inorganica Chimica Acta (2014), 422 (), 188-192CODEN: ICHAA3; ISSN:0020-1693. (Elsevier B.V.)
      The structure of the stable Pd(0) precatalyst [(1,5-cyclooctadiene)(L·Pd)2] [L = AdBrettPhos = di-1-adamantyl(3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl-2-yl)phosphine] for the Pd-catalyzed fluorination of aryl triflates has been further studied by solid state NMR and x-ray crystallog. of the analogous N-phenylmaleimide complex. The reactivity of this complex with CDCl3 to form a dearomatized complex is also presented. In addn., studies suggest that related bulky biaryl phosphine ligands form similar complexes, although the smaller ligand BrettPhos forms a monomeric [(1,5-cyclooctadiene)(L·Pd)] species instead.
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      (b) Lee, H. G.; Milner, P. J.; Buchwald, S. L. Org. Lett. 2013, 15, 5602 DOI: 10.1021/ol402859k
      18b
      An Improved Catalyst System for the Pd-Catalyzed Fluorination of (Hetero)Aryl Triflates
      Lee, Hong Geun; Milner, Phillip J.; Buchwald, Stephen L.
      Organic Letters (2013), 15 (21), 5602-5605CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      The stable Pd(0) species [(1,5-cyclooctadiene)(L·Pd)2] (L = AdBrettPhos, I, R = adamantyl) has been prepd. and successfully evaluated as a precatalyst for the fluorination of aryl triflates derived from biol. active and heteroaryl phenols, challenging substrates for our previously reported catalyst system [e.g., estrone triflate → 3-fluorodeoxyestrone in 74% yield and >20:1 regioselectivity]. Addnl., this precatalyst activates at room temp. under neutral conditions, generates 1,5-cyclooctadiene as the only byproduct, and leads to overall cleaner reaction profiles.
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    19. 19

      The unreacted ligand could be reisolated from the reaction mixture, allowing 1 to be prepared on the gram scale without losing appreciable amounts of L1 (see the Supporting Information).

      There is no corresponding record for this reference.
    20. 20
      (a) Tschan, M. J. L.; García-Suárez, E. J.; Freixa, Z.; Launay, H.; Hagen, H.; Benet-Buchholz, J.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2010, 132, 6463 DOI: 10.1021/ja100521m
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      (b) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685 DOI: 10.1021/ja042491j
      20b
      Catalysts for Suzuki-Miyaura Coupling Processes: Scope and Studies of the Effect of Ligand Structure
      Barder, Timothy E.; Walker, Shawn D.; Martinelli, Joseph R.; Buchwald, Stephen L.
      Journal of the American Chemical Society (2005), 127 (13), 4685-4696CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Suzuki-Miyaura coupling reactions of aryl and heteroaryl halides with aryl-, heteroaryl- and vinylboronic acids proceed in very good to excellent yield with the use of 2-(2',6'-dimethoxybiphenyl)dicyclohexylphosphine, SPhos (1) (I). This ligand confers unprecedented activity for these processes, allowing reactions to be performed at low catalyst levels, to prep. extremely hindered biaryls and to be carried out, in general, for reactions of aryl chlorides at room temp. Addnl., structural studies of various 1·Pd complexes are presented along with computational data that help elucidate the efficacy that 1 imparts on Suzuki-Miyaura coupling processes. Moreover, a comparison of the reactions with 1 and with 2-(2',4',6'-triisopropylbiphenyl)diphenylphosphine (2) (II) is presented that is informative in detg. the relative importance of ligand bulk and electron-donating ability in the high activity of catalysts derived from ligands of this type. Further, when the aryl bromide becomes too hindered, an interesting C-H bond functionalization-cross-coupling sequence intervenes to provide product in high yield.
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      (c) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43, 1871 DOI: 10.1002/anie.200353615
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      (d) Andreu, M. G.; Zapf, A.; Beller, M. Chem. Commun. 2000, 2475 DOI: 10.1039/b006791l
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      Baranano, D.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 2937 DOI: 10.1021/ja00115a033
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    22. 22

      [(L1Pd)2·COD] (1) and [(L2Pd)2·COD] were compared as precatalysts for the conversion of an aryl bromide (4-bromovalerophenone) and an aryl triflate (4-pentanoylphenyl trifluoromethanesulfonate) to the corresponding aryl fluoride (4-fluorovalerophenone) at room temperature. The reactions were analyzed after 24 h, and these experiments revealed that the use of 1 catalyzes the transformation approximately 3 times faster than the use of [(L2Pd)2·COD] (see the Supporting Information).

      There is no corresponding record for this reference.
    23. 23
      Huang, S.-M. Nature 2009, 461, 614 DOI: 10.1038/nature08356
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    24. 24

      The reduction content (ArH) of 2, 21, and 10 was not determined.

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    25. 25
      Bissantz, C.; Kuhn, B.; Stahl, M. J. Med. Chem. 2010, 53, 5061 DOI: 10.1021/jm100112j
      25
      A Medicinal Chemist's Guide to Molecular Interactions
      Bissantz, Caterina; Kuhn, Bernd; Stahl, Martin
      Journal of Medicinal Chemistry (2010), 53 (14), 5061-5084CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A review.
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  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.5b09308.

    • Additional procedural, crystallographic, and spectral data (PDF)

    • X-ray data for six complexes (CIF)


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