Enantioselective Decarboxylative Cyanation Employing Cooperative

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Cite This: J. Am. Chem. Soc. 2017, 139, 15632-15635

Enantioselective Decarboxylative Cyanation Employing Cooperative Photoredox Catalysis and Copper Catalysis Dinghai Wang,† Na Zhu,† Pinhong Chen,† Zhenyang Lin,*,‡ and Guosheng Liu*,† †

State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China ‡ Department of Chemistry, the Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China S Supporting Information *

Scheme 1. Merging Photocatalysis into Asymmetric Decarboxylation (PC = photocatalyst)

ABSTRACT: The merger of photoredox catalysis with asymmetric copper catalysis have been realized to convert achiral carboxylic acids into enantiomerically enriched alkyl nitriles. Under mild reaction conditions, the reaction exhibits broad substrate scope, high yields and high enantioselectivities. Furthermore, the reaction can be scaled up to synthesize key chiral intermediates to bioactive compounds.

C

arboxylic acids are stable and readily available, which makes decarboxylative coupling a useful reaction in organic synthesis.1 Among them, the thermodynamically favorable radical decarboxylation reactions have received much attention.2 Recently, a new strategy by merging transition metal (TM) catalysis into the decarboxylation reaction has been applied to cross-coupling reactions,3 in which carboxylic acids act as both carbon nucleophiles and electrophiles by releasing CO2. However, formation of highly reactive carbon-centered radical makes asymmetric decarboxylative coupling extremely difficult. In the last decades, asymmetric radical transformations (ARTs) using TM catalysis have become a powerful method.4,5 Trapping alkyl radical by reactive chiral TM species was generally invovled as a key step in these reactions. With this strategy, asymmetric decarboxylative arylation reactions by cooperative photocatalysis and nickel catalysis were first disclosed by Fu and MacMillian.6 Notably, two key species, an alkyl radical produced by photocatalysis via reductive quenching cycle and a chiral arylNi(II) species generated through oxidative addition (OA) were formed in parallel (Scheme 1a). Subsequently, Reisman and coworkers reported a Ni-catalyzed asymmetric decarboxylative vinylation reaction without photoredox activation.7 As part of our efforts to develop ARTs reactions,8,9 we have demonstrated that a benzylic radical generated via a radical replay process can be trapped by a reactive chiral copper(II) cyanide enantioselectively, delivering optically pure benzyl nitriles efficiently.8 The key reactive L*CuII(CN)2 (L* = bisoxazoline, Box) species was generated via a single electron oxidation of L*CuI, using electrophilic F+ reagents or CF3+ reagents as oxidant (cycle C in Scheme 1b). Recently, N-hydroxy-phthalimide (NHP) esters 1 have been extensively studied in radical decarboxylation reactions.1d,3a,10 Asymmetric decarboxylative cyanation represents one of most efficient and straightforward strategies to convert achiral carboxylic acids into enantiomer-enriched alkyl nitriles, which © 2017 American Chemical Society

prompted us to test the feasibility.11 Compared to the previously used F+ and CF3+ reagent,8 unfortunately the relatively inert N− O bond of NHP ester 1a failed to oxidize L*CuI, and the decarboxylation reaction did not occur.12 Thus, we postulated that how to initiate the radical decarboxylation of the NHP ester and generate L*CuII cyanide species is critical to the success of the designed reaction. Herein, we communicate the catalytic asymmetric radical decarboxylative cyanation by merging photoredox catalysis with copper catalysis. Recent studies on photocatalyzed decarboxylation of NHP esters reveals that the excited photocatalyst (PC*) can transfer an electron to NHP ester 1 and form PC+, and the formed anionic radical of NHP ester undergoes radical decarboxylation to generate benzylic radical.13,14 Inspired by these reports, we hypothesized that if the strongly oxidizing PC+ could be used to oxidize L*CuICN to form L*CuIICN rapidly,15 the L*CuIICN species can further react with TMSCN, followed by combining with the benzyl radical to give coupling product 2 (cycle B). With chiral ligands, the asymmetric decarboxylative reaction could give Received: September 14, 2017 Published: October 17, 2017 15632

DOI: 10.1021/jacs.7b09802 J. Am. Chem. Soc. 2017, 139, 15632−15635

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Journal of the American Chemical Society Table 1. Reaction Optimizationa

showed that the reaction in p-xylene (PXL) gave the product in 11% yield with slightly better ee (88%, entry 6). Pleasingly, mixed solvent of DMF and p-xylene provided the product in 83% yield with 87% ee (entry 7). Furthermore, decreasing the catalysts loading is beneficial to give better results. When Ir(ppy)3 was decreased to 0.5 mol % and CuBr to 1 mol %, product 2a was obtained in 98% yield with 87% ee (Table 1, entry 8). No reaction occurred in dark (Table 1, entry 9), and both the photocatalyst and the Cu catalyst were essential to the asymmetric radical decarboxylative cyanation (Table 1, entries 10−11).22 Other imides in substrate were also examined. As shown in Table 1 (bottom), the substrates 1ab and 1ac were also tested in the reaction under the optimal reaction conditions, giving the product 2a with the similar yields and same enantioselectivies. In contrast, 1ad and 1ae having a higher LUMO are not suitable for the reaction. These results indicated that conjugate imides (1a, 1ab and 1ac) could accommodate an incoming electron better than unconjugated imides (1ad and 1ae) (for details, see SI). With the optimized reaction condition in hand, the substrate scope and functional group tolerance were further examined. As shown in Table 2, various NHP esters derived from simple carboxylic acids were compatible to the reaction condition to provide the corresponding products 2a−2r in good yields (71− 99%) and excellent enantioselectivities (82−99% ee). In contrast, substrates with bulky steric hindrance (2i, 2o, 2r) provided higher enantioselectivities. A series of functional

a

The reactions were conducted in 0.1 mmol scale with photocatalyst (mol%) and CuBr (mol%) in solvent (1 mL), irradiated with 12 W blue LED. bCrude 1H NMR yield with CH3NO2 as internal standard. c Enantiomeric excess (ee) values determined by HPLC on a chiral stationary phase, dIsolated yield in 0.2 mmol scale. eln dark. . [Ir]-1 = Ir(ppy)2(dtbbpy)PF6. [Ir]-2 = Ir(dFCF3ppy)2(dtbbpy)PF6. [Ru] = Ru(bpy)3Cl2· 6H2O. PXL = p-xylene.

Table 2. Substrate Scopea

rise to enantiomer-enriched organic nitriles (Scheme 1b, left).16 The key step of the oxidation of L*Cu(I) by PC+ makes the resulting oxidative quenching cycle (A) to distinguish the mechanisms of our previous studies (Scheme 1b, right)8 and nickel catalyzed photoredox reactions in the literature (Scheme 1a).6 We measured the reduction potential of 1a to be Ep0/−1 = −1.33 V vs SCE in MeCN.17 The commonly used photocatalyst Ir(ppy)3 (ppy = 2-phenylpyridine) could be a sufficiently strong electron donor to reduce NHP ester 1a directly from its excited state {(E1/2red[IrIV/IrIII*]) = −1.73 V vs SCE in MeCN}.18 Meanwhile, the oxidized photocatalyst Ir(ppy)3+ exhibits a strong oxidative power {E1/2red[IrIV/IrIII] = +0.77 V vs SCE in MeCN},18 which could oxidize L*CuICN to generate L*CuIICN (L* = L1), {E1/2red[CuII/CuI] = +0.36 V vs SCE in MeCN}.17 Thus, our initial study focused on the reaction of 1a and TMSCN under irradiation of 12 W blue LEDs, with Ir(ppy)3 (2 mol %) and CuBr (10 mol %)/L1 (12 mol %) in DMF at room temperature. To our delight, the decarboxylative cyanation reaction proceeded smoothly, yielding the desired product 2a in 87% yield with 84% ee (Table 1, entry 1). Other photocatalysts with higher oxidation potential, such as Ir(ppy)2(dtbbpy)PF6 ([Ir]-1) {E1/2red[IrIV/IrIII] = +1.21 V vs SCE in MeCN},19 Ir(dFCF3ppy)2(dtbbpy)PF6 ([Ir]-2) {E1/2red[IrIV/IrIII] = +1.69 V vs SCE in MeCN}20 and Ru(bpy)3Cl2 ([Ru]) {E1/2red[RuIII/ RuII] = +1.29 V vs SCE in MeCN}21 did not affect the enantioselectivity (84% ee), with slightly lower yields (entries 2− 4). The organic photocatalyst Eosin Y was not suitable for the decarboxylative cyanation (entry 5). Further solvent screening

a

All the reactions were conducted in 0.2 mmol scale. bIsolated yields and enantiomeric excess (ee) values were determined by HPLC on a chiral stationary phase. d65 h.

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DOI: 10.1021/jacs.7b09802 J. Am. Chem. Soc. 2017, 139, 15632−15635

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Journal of the American Chemical Society Scheme 2. Synthetic Applications

Scheme 3. Mechanistic Investigation

radical scavenger was subjected to our model reaction, the decarboxylative cyanation was inhibited completely, and the new product 6 generated from the resultant benzylic radical trapped by TEMPO was obtained in 37% yield (Scheme 3a). Second, the reaction of radical clock substrate 7 under the standard conditions still gave a major decarboxylative cyanation product 8 in 49% yield with 75% ee, along with a ring-opening/cyanation product 9 in 12% yield (Scheme 3b). Third, when the reaction of the chiral NHP ester 10 was performed by copper catalyst with (1R,2S)-L1 or copper catalyst with (1S,2R)-L1 respectively, the product 11 was obtained with opposite configurations (Scheme 3c). These evidence strongly support a radical decarboxylative process of our reaction. In addition, the results in entries 8−11 (Table 1) revealed that the decarboxylation of NHP ester indeed undergoes via a photoredox catalysis process, and the sequential asymmetric cyanation was catalyzed by copper (Scheme 1b). Finally, Stern−Volmer fluorescence quench experiments demonstrated that the emission intensity of IrIII* is diminished in the presence of substrate 1d, rather than (L1)Cu(I) catalyst, presumably signifying an one-electron reduction event of the substrate to form corresponding radical anion. Thus, a photoredox catalysis involving reductive quenching cycle is less likely in this reaction (For more detailed discussions, see SI). In summary, we have developed a novel enantioselective decarboxylative radical cyanation reaction by merging photocatalysis with copper catalysis, which provides a straightforward access to chiral alkyl nitriles with high yields and enantioselectivity. The tolerance of broad functional groups allows the method to be used in further synthetic application. Mechanistically, both benzylic radicals and reactive chiral copper(II) species are generated from photocatalysis cycle. Further expansion of this new cooperative strategy by photocatalysis and metal catalysis is under progress.

groups, such as halide, ether and ester, were very well tolerated. Notably, aryl boronic ester (Bpin) was also tolerated in the reaction to provide product 2k with excellent enantioselectivity (94% ee), which allows for the further transformation. In addition, functional groups such as alkene, alkyne and anthracenyl ring incompatible in our pervious C−H cyanation could survive in the current reaction condition to give desired products 2v, 2w and 2u in good yields (92%, 66% and 90%, respectively) with excellent ee values (93% and 92% ee). Excitingly, NHP esters containing heterocycles including thianaphthenyl and pyridyl were also suitable for the decarboxylative cyanation to give products 2x and 2y in good yields and ee. Finally, for the commercially available racemic arylpropanoic acids commonly used as anti-inflammatory drugs, such as ibuprofen (2a), ketoprofen (2z), flurbiprofen (3a), loxoprofen (3b), pranoprofen (3c), carprofen (3d) and zaltoprofen (3e), the related NHP esters were suitable to the asymmetric cyanation to yield the corresponding enantiomerenriched benzylic nitriles in good to excellent yields (59−98%) with good enantioselectivities (82−92% ee). Unfortunately, the NHP esters derived from secondary aliphatic carboxylic acids, which involves nonbenzylic carbon radicals, provided poor enantioselectivity. To demonstrate the preparative utility of our method, the enantioselective decarboxylative radical cyanation was conducted on a 270 mmol scale with low catalyst loading (0.13 mol % Ir(ppy)3 and 0.26 mol % CuBr/L1), delivering the desired product 2d in 95% yield with 88% ee, albeit in a prolonged time (Scheme 2a). In addition, the chiral alkyl nitriles can be obtained from carboxylic acids in one-pot: after condensation of carboxylic acid with NHP, the unpurified NHP ester was subjected to our standard conditions, providing the optically enriched nitriles 3a, 3b and 3e in goods yields and good ee (Scheme 2b); compared to the reaction of the pure NHP esters, there was no significant loss of the reaction efficiency and enantioselectivity. Furthermore, the enantiomer-enriched alkyl nitriles could be easily hydrogenated to give the corresponding amines 4 and 5 in excellent yields without loss of enantiomeric excess, which were regarded as key intermediates for the synthesis of chiral antidepressant active molecule (R)-phenibut and weight-lossing drug (R)-Lorcaserin (Scheme 2c). To gain some insights into the plausible mechanism, some control experiments were conducted. First, when TEMPO as a

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b09802. Experimental details and characterization data (PDF) NMR spectrum of new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected] ORCID

Zhenyang Lin: 0000-0003-4104-8767 15634

DOI: 10.1021/jacs.7b09802 J. Am. Chem. Soc. 2017, 139, 15632−15635

Communication

Journal of the American Chemical Society

(8) For the asymmetric cyanantion, see: (a) Zhang, W.; Wang, F.; McCann, S. D.; Wang, D.; Chen, P.; Stahl, S. S.; Liu, G. Science 2016, 353, 1014. (b) Wang, F.; Wang, D.; Wan, X.; Wu, L.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2016, 138, 15547. (c) Wang, D.; Wang, F.; Chen, P.; Lin, Z.; Liu, G. Angew. Chem., Int. Ed. 2017, 56, 2054. (9) For the asymmetric arylation, see: (a) Wu, L.; Wang, F.; Wan, X.; Wang, D.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2017, 139, 2904. (b) Wang, D.; Wu, L.; Wang, F.; Wan, X.; Chen, P.; Lin, Z.; Liu, G. J. Am. Chem. Soc. 2017, 139, 6811. (10) For the pioneering studies on NHP esters, see: (a) Okada, K.; Okamoto, K.; Oda, M. J. Am. Chem. Soc. 1988, 110, 8736. (b) Okada, K.; Okamoto, K.; Morita, N.; Okubo, K.; Oda, M. J. Am. Chem. Soc. 1991, 113, 9401. (c) Schnermann, M. J.; Overman, L. E. Angew. Chem., Int. Ed. 2012, 51, 9576. (d) Pratsch, G.; Lackner, G. L.; Overman, L. E. J. Org. Chem. 2015, 80, 6025. (11) The classic multisteps process involves a chiral resolution, see: (a) Miyagi, K.; Moriyama, K.; Togo, H. Eur. J. Org. Chem. 2013, 2013, 5886. Recently, Waser reported a radical decarboxylative cyanation reaction via photocatalysis, which involves a radical electrophilic cyanation, see: (b) Le Vaillant, F.; Wodrich, M. D.; Waser, J. Chem. Sci. 2017, 8, 1790. (12) During manuscript preparation, Peters and Fu reported a photoinduced and copper-catalyzed a decarboxylative amination reaction, in which copper catalyst bearing both bisnitrogen and xantphos ligands are essential. For details, see: Zhao, W.; Wurz, R. P.; Peters, J. C.; Fu, G. C. J. Am. Chem. Soc. 2017, 139, 12153. (13) For reviews on photocatalysis, see: (a) Yoon, T. P.; Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527. (b) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102. (c) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322. (14) For the recent studies on the photocatalysis decarboxylation of NHP ester, see references 1d, 3a and 10. In these reactions, the generated carbon-center radical generally reacts with electrophile, or undergoes a further oxidation by PC+ to give a carbocation and a subsequential nucleophilic attack. In these pathways, it is difficult to carry out asymmetric reaction, and only racemic product was provided. (15) Ye, Y.; Sanford, M. S. J. Am. Chem. Soc. 2012, 134, 9034. (16) In our previous study of asymmetric cyanation of styrenes, (Box) CuICN is demonstrated as really catalyst, and (Box)CuII(CN)2 is the active species to trap benzylic radical. For details, see ref 8b. (17) The reduction potential of 1a and oxidation potential of L1/CuBr were measured by electrochemistry in CH3CN. For details, see SI. (18) Flamigni, L.; Barbieri, A.; Sabatini, C.; Ventura, B.; Barigelletti, F. Top. Curr. Chem. 2007, 281, 143. (19) Slinker, J. D.; Gorodetsky, A. A.; Lowry, M. S.; Wang, J.; Parker, S.; Rohl, R.; Bernhard, S.; Malliaras, G. G. J. Am. Chem. Soc. 2004, 126, 2763. (20) Lowry, M. S.; Goldsmith, J. I.; Slinker, J. D.; Rohl, R.; Pascal, R. A.; Malliaras, G. G.; Bernhard, S. Chem. Mater. 2005, 17, 5712. (21) Kalyanasundaram, K. Coord. Chem. Rev. 1982, 46, 159. (22) Without copper catalyst, substrate 1a was completely exhausted to give trace amount of 2a, but provided the oxygenation product 2a′ in 50% yield (see entry 11 in Table 1, and equation below), which generated from nucleophilic attck of benzylic carbocation by DMF. Meanwhile, the side product 2a′ was not detected in the reaction of entry 8. These observation revealed that the benzylic radical can be oxidized by by IrIV to form carbocation. But in the presence of L*Cu(I) catalyst, the oxidation of L*Cu(I) by IrIV is prior to the radical oxidation, resulting an exclusive cyanation reaction with high ee.

Guosheng Liu: 0000-0003-0572-9370 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the National Basic Research Program of China (973-2015CB856600), the National Nature Science Foundation of China (Nos. 21532009, 21421091 and 21472217), the Science and Technology Commission of Shanghai Municipality (Nos. 17XD1404500 and 17JC1401200), the Strategic Priority Research Program (No. XDB20000000) and the Key Research Program of Frontier Science (QYZDJSSW-SLH055) of the Chinese Academy of Sciences. This research was also supported by the Key Laboratory of Functional Molecular Engineering of Guangdong Province (2016kf02, South China University of Technology).

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DOI: 10.1021/jacs.7b09802 J. Am. Chem. Soc. 2017, 139, 15632−15635