Metal-Free Transfer Hydrogenation Catalysis by B(C6F5)3

COMMUNICATION pubs.acs.org/Organometallics

Metal-Free Transfer Hydrogenation Catalysis by B(C6F5)3 Jeffrey M. Farrell, Zachariah M. Heiden, and Douglas W. Stephan* Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada, M5S 3H6

bS Supporting Information ABSTRACT: The activation of amines by B(C6F5)3 is shown to effect the catalytic racemization of a chiral amine. Extending this strategy to a bimolecular process, catalytic transfer hydrogenation of imines, enamines, and N-heterocycles is demonstrated using iPr2NH as the source of hydrogen and a catalytic amount of the Lewis acid B(C6F5)3.

T

he advent of organocatalysis offers new and insightful strategies for a variety of chemical transformations.1 10 Such strategies offer access to creative molecular syntheses and control of stereochemistry. In addition, there are logistical and cost advantages associated with processes that avoid removal of trace metal residues from transition-metal catalysts. A complementary metal-free strategy to catalysis involves the use of main group species. Indeed, in an overview of organocatalysis, Jacobsen and McMillan5 noted that “Lewis acid-catalyzed processes... will likely be among the important future advances.” Interestingly, this view was foreshadowed with the 1925 finding of the Meerwein Pondorf reduction,11,12 in which aluminum alkoxides effect the transfer of hydrogen from isopropanol to unsaturated ketones. Subsequently, Corey and Helal demonstrated enantioselective transfer hydrogenations of ketones employing BH3 as the reductant.13 More recently, the first reports of enantioselective organocatalytic reductions of R,β-unsaturated aldehydes14,15 have led to a plethora of chiral Brønsted acidcatalyzed transfer hydrogenations employing Hantzsch esters as the hydrogen source.3,16 Following the report of the heterolytic cleavage of H2 by “frustrated Lewis pairs” (FLPs),17,18 we described the use of Lewis acids for the catalytic hydrogenation of imines, aziridines, and protected nitriles.19,20 Subsequently, the research groups of Erker,21,22 Rieger,23 and Soos24 extended and broadened the range of applications of FLP-based catalysts to include enamines, silyl enol ethers, and enones. Recently, Klankermayer has elegantly extended such systems for asymmetric catalysis.25,26 While these efforts have focused on H2 as the reductant, alternative sources of reducing equivalents have received recent attention. Berke and co-workers27,28 have clearly demonstrated the reduction of imines and polar olefins employing BH3NH3 as the source of H2. In seeking alternative sources of H2 for transfer hydrogenations, we noted that Basset and co-workers29 had reported that the stoichiometric reaction of B(C6F5)3 and Et2NPh did not afford an adduct. Instead, these authors confirmed that an equilibrium was established between free borane, amine, the salt [Et2NHPh][HB(C6F5)3], and the zwitterion [EtPhNdCHCH2B(C6F5)3]. Resconi and co-workers30 made similar observations for r 2011 American Chemical Society

Figure 1. Proton NMR spectra of (a) R-CH and (b) CH3 signals from catalytic racemization of (R,R)-1 (1 mol % B(C6F5)3, C6D5Br, 25 °C).

the reaction of Et2NH and B(C6F5)3, whereas Rieger and coworkers23 reported an analogous equilibrium involving iPr2NH and B(C6F5)3. These observations stand in contrast to the 1966 report of Massey and Park in which classical amine adducts of B(C6F5)3 were reported.31 The reversibility of these hydride abstractions suggested two ramifications to us. Herein, we show that the analogous abstraction of hydride from chiral amines provides a strategy for facile and catalytic amine racemization. Moreover, activation of an amine in this manner provides a source of hydride and proton that can be exploited for metal-free, Lewis acid-catalyzed transfer hydrogenations. The reaction of bis((R)-1-phenylethyl)amine, (R,R-1), in the presence of 1 mol % B(C6F5)3 was found to result in conversion of the optically pure amine to an equilibrium mixture of diastereomers.32 This was evident by 1H NMR spectroscopy with the appearance of an additional doublet at 1.25 ppm attributable to the methyl groups and a quartet at 3.7 ppm resulting from the benzylic protons over the course of 96 h corresponding to the meso compound (R,S-1) (Figure 1). The resulting diastereomeric ratio of meso/dl was found to be ca. 1:2. The racemization of the chiral amine was accelerated with Received: July 3, 2011 Published: August 02, 2011 4497

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Organometallics Scheme 1. Catalytic Racemization of a Chiral Amine

increasing concentration of borane and increasing temperature. For example, warming the reaction to 80 °C led to complete racemization in minutes, whereas use of 10 mol % B(C6F5)3 at 25 °C also gave complete racemization in 4 h. Racemization of both chiral centers was confirmed by X-ray crystallography as addition of HCl to the reaction afforded crystals of racemic (R,R/S,S) [(Ph(Me)CH)2NH2][Cl] 2.33 In a similar fashion, 10 mol % of the cationic boranes [Cy3PC6F4B(C6F5)2][B(C6F5)4] and [tBu2(H)PC6F4B(C6F5)2][B(C6F5)4]34,35 were found to racemize (S,S)-1. In contrast, 10 mol % of the chiral borane derived from 2-phenyl-2-bornene, C16H20B(C6F5)2,26 effected racemization of (S,S)-1 to a much lesser extent, affording a 7:1 diastereomeric ratio after 24 h at 80 °C. This observation is consistent with the ability of this borane to effect the enantioselective catalytic reduction of a series of imines under H2 and milder conditions.26 The reduced capacity of this borane to effect racemization may be attributed to a combination of reduced Lewis acidity and increased steric crowding precluding hydride abstraction. Probing this process in more detail, the stoichiometric reaction of (S,S-1) and B(C6F5)3 was observed to give a mixture of the salt [(Ph(Me)CH)2NH2][HB(C6F5)3] 3 and the zwitterion (Ph(Me)CH)NHdC(Ph)CH2B(C6F5)3 4 (Scheme 1).36 This observation is consistent with hydride abstraction and deprotonation of amine 1, affording 3 and a transient ketimine that reacts with B(C6F5)3 to give 4.36 By analogy to the work of Basset,29 Resconi,30 and Rieger,23 4 is thought to exist in equilibrium with ketimine and B(C6F5)3 (Scheme 1). Proton NMR data for 3 are consistent with the racemization of the chiral centers, inferring that the formation of 3 and 4 are in equilibrium with 1 and B(C6F5)3. Addition of H2 to the reaction mixture of 3 and 4 afforded a 1:2 mixture of two diastereomers of 3, as evidenced by the 1H NMR spectrum. The presence of the borate anion was confirmed by a 1:1:1:1 quartet at 3.20 ppm that collapsed to a broad singlet at 3.27 ppm upon 11B decoupling and a doublet at 24.3 ppm in the 11B NMR spectrum. X-ray crystallography showed the centrosymmetric space group of the isolated crystals to be P21/c, consistent with the cocrystallization of racemic isomers (R,R/S,S) of [(Ph(Me)CH)2NH2][HB(C6F5)3] 3 demonstrating that isomerization of both of the chiral centers can occur. In this case, a close approach of the boron-bound hydride and an NH proton was found to be 1.955(3) Å, analogous to that seen in related phosphonium salts. While transition metal-based homogeneous and heterogeneous catalysts as well as enzymatic approaches to racemization of chiral amines have been reported,37 44 this is the first to utilize highly electrophilic boranes to effect this isomerization. Clearly, this must be an important consideration in the design of FLP systems for asymmetric hydrogenations.

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Table 1. B(C6F5)3-Catalyzed Transfer Hydrogenationsa,b

a Twenty-four hours at 100 °C. Yields determined by 1H NMR spectroscopy. b Mixture of diastereomers.

As the above racemization proceeds via hydride abstraction, followed by readdition, we reasoned that abstraction of hydride from an amine and delivery to another substrate, with concurrent proton transfer, would offer a strategy to catalytic transfer hydrogenation. To probe this possibility, the imine substrate PhCHdNtBu was combined with 1 mol % B(C6F5)3 in neat iPr2NH.45 The approximate 100-fold excess of amine is presumed to be a driving force in the transfer hydrogenation. Upon heating to 100 °C for 24 h, NMR data revealed the formation of PhCH2NHtBu in 70% yield (see Table 1). Increasing the catalyst loading to 5 mol % resulted in >98% yield of the target amine PhCH2NHtBu over 24 h at 100 °C. The resulting amines are readily separated from the catalyst by chromatography through silica. Similarly, less basic imines of the form PhCHdNAr (Ar = Ph, C6H2Me3) were hydrogenated to greater than 98% yield in neat iPr2NH, although it was necessary to employ 20 mol % of the B(C6F5)3 catalyst. Although the ketimine PhC(Me)dNPh was hydrogenated in only 37% yield, application of these transfer hydrogenation conditions to the imine precursor of the commercialized antidepressant sertraline resulted in a 90% yield of 4498

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Organometallics the diastereomeric mixture of the product. The enamines 1-(1cyclohexen-1-yl)-piperidine and 2-methylene-1,3,3-trimethylindoline were also quantitatively reduced by this transfer hydrogenation protocol. Application of this transfer hydrogenation protocol to N-heterocyclic substrates resulted in lower yields. For example, 8-methylquinoline was reduced to 8-methyl-1,2,3, 4-tetrahydroquinoline in 56% yield, whereas the aziridine cis-(PhCH)2NPh was reduced to give PhN(CH2Ph)2 in 27% yield. In both cases, the residual starting material was the only other product. The formation of PhN(CH2Ph)2 is presumably derived from the thermally induced C C bond cleavage of the aziridine,46 affording an azomethine ylide47,48 that then undergoes reaction via proton and hydride transfer. This stands in contrast to the B(C6F5)3-catalyzed hydrogenation of cis-1,2, 3-triphenylaziridine that proceeds via the protonation of aziridine from hydrogen splitting, followed by N C bond scission, to give PhCH2CH(Ph)NHPh.19 In conclusion, we have demonstrated that the activation of amines by B(C6F5)3 via hydride abstraction is evident from the catalytic racemization of a chiral amine. Moreover, this abstraction can be exploited for catalytic transfer hydrogenation of imines, enamines, and N-heterocycles. This chemistry represents a rare example of metal-free transfer hydrogenation. While other reports have employed the pyridine derivative Hantzsch’s ester as the source of H2,3,16 this approach employs the readily accessible iPr2NH. Further studies of these and other main group-based metal-free catalysts in a variety of catalytic processes is the subject of ongoing study.

’ ASSOCIATED CONTENT

bS

Supporting Information. Synthetic, experimental, and crystallographic details. This material is available free of charge via the Internet at http://pubs.acs.org.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

’ ACKNOWLEDGMENT The financial support of LANXESS Inc., NSERC of Canada, and the Ontario Centres of Excellence is gratefully acknowledged. D.W.S. is grateful for the award of a Killam Research Fellowship 2009-2011 and a Canada Research Chair. Z.M.H. is grateful for the award of an Ontario Postdoctoral Fellowship. We would like to dedicate this work to Professor Christian Bruneau on the occasion of his 60th birthday. ’ REFERENCES (1) Weiner, B.; Szymanski, W.; Janssen, D. B.; Minnaard, A. J.; Feringa, B. L. Chem. Soc. Rev. 2010, 39, 1656. (2) Vicario, J. L.; Badia, D. ChemCatChem 2010, 2, 375. (3) Rueping, M.; Sugiono, E.; Schoepke, F. R. Synlett 2010, 852. (4) Nielsen, M.; Jacobsen, C. B.; Holub, N.; Paixao, M. W.; Joergensen, K. A. Angew. Chem., Int. Ed. 2010, 49, 2668. (5) Jacobsen, E. N.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20618. (6) Buckley, B. R.; Neary, S. P. Annu. Rep. Prog. Chem., Sect. B: Org. Chem. 2010, 106, 120. (7) Alba, A.-N. R.; Companyo, X.; Rios, R. Chem. Soc. Rev. 2010, 39, 2018.

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(8) Ueda, M.; Kano, T.; Maruoka, K. Org. Biomol. Chem. 2009, 7, 2005. (9) Enders, D.; Wang, C.; Liebich, J. X. Chem.—Eur. J. 2009, 15, 11058. (10) Buckley, B. R. Annu. Rep. Prog. Chem., Sect. B: Org. Chem. 2009, 105, 113. (11) Meerwein, H.; Schmidt, R. Justus Liebigs Ann. Chem. 1925, 444, 221. (12) Ponndorf, W. Angew. Chem. 1926, 39, 138. (13) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986. (14) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 127, 32. (15) Yang, J. W.; Hechavarria Fonseca, M. T.; List, B. Angew. Chem., Int. Ed. 2004, 43, 6660. (16) Ouellet, S. G.; Walji, A. M.; Macmillan, D. W. C. Acc. Chem. Res. 2007, 40, 1327. (17) Welch, G. C.; Juan, R. R. S.; Masuda, J. D.; Stephan, D. W. Science 2006, 314, 1124. (18) Welch, G. C.; Stephan, D. W. J. Am. Chem. Soc. 2007, 129, 1880. (19) Chase, P. A.; Welch, G. C.; Jurca, T.; Stephan, D. W. Angew. Chem., Int. Ed. 2007, 46, 8050. (20) Chase, P. A.; Jurca, T.; Stephan, D. W. Chem. Commun. 2008, 1701. (21) Spies, P.; Schwendemann, S.; Lange, S.; Kehr, G.; Fr€ohlich, R.; Erker, G. Angew. Chem., Int. Ed. 2008, 47, 7543. (22) Wang, H. D.; Fr€ ohlich, R.; Kehr, G.; Erker, G. Chem. Commun. 2008, 5966. (23) Sumerin, V.; Schulz, F.; Nieger, M.; Leskela, M.; Repo, T.; Rieger, B. Angew. Chem., Int. Ed. 2008, 47, 6001. (24) Eros, G.; Mehdi, H.; Papai, I.; Rokob, T. A.; Kiraly, P.; Tarkanyi, G.; Soos, T. Angew. Chem., Int. Ed. 2010, 49, 6559. (25) Chen, D. J.; Klankermayer, J. Chem. Commun. 2008, 2130. (26) Chen, D. J.; Wang, Y. T.; Klankermayer, J. Angew. Chem., Int. Ed. 2010, 49, 9475. (27) Yang, X. H.; Zhao, L. L.; Fox, T.; Wang, Z. X.; Berke, H. Angew. Chem., Int. Ed. 2010, 49, 2058. (28) Yang, X. H.; Fox, T.; Berke, H. Chem. Commun. 2011, 47, 2053. (29) Millot, N.; Santini, C. C.; Fenet, B.; Basset, J. M. Eur. J. Inorg. Chem. 2002, 3328. (30) Focante, F.; Mercandelli, P.; Sironi, A.; Resconi, L. Coord. Chem. Rev. 2006, 250, 170. (31) Massey, A. G.; Park, A. J. J. Organomet. Chem. 1964, 2, 245. (32) (R,R)-bis(Phenylethyl)amine (0.273 g, 1.21 mmol) was transferred with 1 mol % B(C6F5)3 (6.2 mg, 0.0121 mmol) in 1 mL of C6D5Br to a J-Young NMR tube. The tube was sealed and immersed in an oil bath at 80 °C. Conversion to a mixture of diastereomers was observed by 1 H NMR spectroscopy. (33) Crystallographic data for 2: C16H20ClN, MW = 261.78, T = 150 K, space group = monoclinic, P21/n, a = 7.5592(6) Å, b = 18.2567(14) Å, c = 10.8792(8) Å, β = 92.180(4)o, V = 1500.3(2) Å3, Z = 4, μ = 0.238 mm 1, measured reflections = 13779, independent reflections = 4571, parameters = 165, Rint = 0.0531, R = 0.0511, Rw = 0.1417, GOF = 0.905. 3: C34H21BF15N, MW = 739.33, T = 150 K, space group = monoclinic, P21/c, a = 10.5576(6) Å, b = 11.9278(6) Å, c = 24.2325(13) Å, β = 98.135(2)o, V = 4674.4(4) Å3, Z = 4, μ = 0.159 mm 1, measured reflections = 21558, independent reflections = 6876, parameters = 482, Rint = 0.0630, R = 0.0523, Rw = 0.1221, GOF = 0.967. (34) Welch, G. C.; Prieto, R.; Dureen, M. A.; Lough, A. J.; Labeodan, O. A.; Holtrichter-Rossmann, T.; Stephan, D. W. Dalton Trans. 2009, 1559. (35) Welch, G. C.; Cabrera, L.; Chase, P. A.; Hollink, E.; Masuda, J. D.; Wei, P. R.; Stephan, D. W. Dalton Trans. 2007, 3407. (36) Heiden, Z. M.; Stephan, D. W. Chem. Commun. 2011, 47, 5729. (37) Ahn, Y.; Ko, S.-B.; Kim, M.-J.; Park, J. Coord. Chem. Rev. 2008, 252, 647. (38) Blacker, A. J.; Stirling, M. J.; Page, M. I. Org. Process Res. Dev. 2007, 11, 642. (39) Jerphagnon, T.; Gayet, A. J. A.; Berthiol, F.; Ritleng, V.; Mrsic, N.; Meetsma, A.; Pfeffer, M.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. Chem.—Eur. J. 2009, 15, 12780. 4499

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(40) Paetzold, J.; B€ackvall, J. E. J. Am. Chem. Soc. 2005, 127, 17620. (41) Pamies, O.; B€ackvall, J.-E. Chem. Rev. 2003, 103, 3247. (42) Pamies, O.; Ell, A. H.; Samec, J. S. M.; Hermanns, N.; Backvall, J.-E. Tetrahedron Lett. 2002, 43, 4699. (43) Thalen, L. K.; Zhao, D.; Sortais, J.-B.; Paetzold, J.; Hoben, C.; B€ackvall, J.-E. Chem.—Eur. J. 2009, 15, 3403. (44) Samec, J. S. M.; B€ackvall, J.-E.; Andersson, P. G.; Brandt, P. Chem. Soc. Rev. 2006, 35, 237. (45) Typical experimental conditions: In a glovebox, B(C6F5)3 (18.2 mg, 0.0355 mmol, 20 mol %) was dissolved in dry iPr2NH (2.5 mL, 1.8 g, 17 mmol), and the solution was added to tBuNdCHPh (28.7 mg, 0.177 mmol). The resulting solution was transferred to a 25 mL bomb with a sealable Teflon tap and magnetic stir bar. The reaction vessel was sealed, removed from the glovebox, and stirred at 100 °C for 24 h, after which it was cooled to room temperature and quenched by the addition of silica. Subsequently, the mixture was eluted through a short silica column, the filtrate concentrated, and the conversion determined by 1H NMR in CDCl3. (46) Heine, H. W.; Peavy, R. Tetrahedron Lett. 1965, 35, 3123. (47) Huisgen, R.; Scheer, W.; Szeimies, G.; Huber, H. Tetrahedron Lett. 1966, 7, 397. (48) Heine, H. W.; Peavy, R.; Durbetaki, A. J. Org. Chem. 1966, 31, 3924.

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