Catalytic Asymmetric β-C–H Functionalizations of Ketones via

Letter Cite This: Org. Lett. 2018, 20, 1672−1675

pubs.acs.org/OrgLett

Catalytic Asymmetric β‑C−H Functionalizations of Ketones via Enamine Oxidation Lihui Zhu,†,‡ Long Zhang,†,‡,§ and Sanzhong Luo*,†,‡,§ †

Key Laboratory of Molecular Recognition and Function, Chinese Academy of Sciences, Beijing 100190, China College of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100490, China § Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China ‡

S Supporting Information *

ABSTRACT: A chiral primary amine catalyzed oxidative β-C−H functionalization of ketone is described. The reaction proceeds via ketone enamine oxidation by IBX and enables highly enantioselective remote C−H functionalization of both cyclic and acyclic ketones, generating chiral ketones bearing β-stereocenters.

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Scheme 1. Tandem Oxidative Iminium Catalysis

unctionalizations and transformations of carbonyl compounds are fundamental processes that undergo constant rebirth in organic synthesis.1 Typical carbonyl chemistry relies on the polarized ipso-carbon, as well as the resulting acidic αC−H. Recent advances in inert bond C−H activation have allowed for β- or remote C−H bond functionalizations,2 and enantioselective processes have also been developed by merging with the established asymmetric catalysis.3 In this regard, aminocatalysis has also become a viable approach for enantioselective remote C−H functionalizations of aldehydes and ketones. On the basis of redox properties of enamine intermediate,4−7 two strategies, 5πe catalysis6 and oxidative iminium catalysis,7 have been developed to enable β-C−H functionalizations of aldehydes and ketones. In the latter case, a nucleophilic enamine is directly oxidized into an electrophilic iminium ion, which then participates in typical conjugate addition processes (Scheme 1). Wang7a and Hayashi7b have independently developed oxidative iminium catalysis of aldehydes. However, the reactions with ketones have not been achieved so far. Our group has developed chiral primary amines as viable catalysts for enantioselective transformations of aldehydes and ketones.8 Recently, we developed a dehydrogenative desymmetrization of 4-substituted cyclohexanones via a ketone− enamine oxidaton.8f In the process of further explorations of this catalytic procedure, it was realized that the asymmetric βC−H functionalization of ketones remained an unsolved issue in general. Herein, we report a chiral primary amine catalyzed enantioselective β-C−H functionalization of simple ketones utilizing commercially available IBX (2-iodoxybenzoic acid) as oxidant under mild conditions (Scheme 1). © 2018 American Chemical Society

In this work, 4-hydroxycoumarin, a classic nucleophile in the conjugate addition chemistry,9 was chosen as a test nucleophile due to its importance as a versatile intermediate in both pharmaceutical ingredients and natural product synthesis.10 Ultimately, the oxidative β-functionalization process was found to proceed effectively under the catalysis of our previously developed chiral primary amine catalyst with commercially available IBX as oxidant (see the Supporting Information for optimization details). Under the standard conditions, we chose cyclohexanone 2a and 4-hydroxycoumarine 3a as the model substrates with IBX as oxidant under the catalysis of primary amine 1, generating the desired product 4a in 97% yield and 94% ee at 0 °C in air (Table 1, entry 1). Both amine catalyst 1 and IBX were essential for the reaction and their absence resulted in virtually no reaction (Table 1, entries 2 and 3). Received: February 11, 2018 Published: March 7, 2018 1672

DOI: 10.1021/acs.orglett.8b00508 Org. Lett. 2018, 20, 1672−1675

Letter

Organic Letters Table 1. Screening and Optimizationa

Scheme 2. Substrate Scopea

entry

variation from standard conditions

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12

none without 1 without IBX without PFBA TsOH instead of PFBA 50 mol % K2CO3 rt −20 °Cd DCM Et2O 2a/3a = 1:1 2a/3a = 3:1

97 6 NR 79 trace 43 95 96 83 55 76 95

eec (%) 94

73 racemic 87 95 82 72 91 94

a Reactions were performed at 0 °C in 0.5 mL of MeCN with 2a (0.2 mmol), 3a (0.1 mmol), IBX (0.12 mmol), 1 (20 mol %), and PFBA (30 mol %) in air, 24 h. b1H NMR yield based on coumarine with trimethoxybenzene as internal standard. cEnantioselectivity determined via HPLC analysis. d72 h. IBX = 2-iodoxybenzoic acid, PFBA = pentafluorobenzoic acid.

Weak acid additive was found to be critical for both activity and enantioselectivity (entry 4 vs 1) and the use of strong acid or base additive led to no reaction or racemic product, respectively (Table 1, entries 5 and 6). When the reaction temperature (0 °C) was raised to ambient temperature, the enantioselectivity dropped to 87% ee (Table 1, entry 7). Further decrease of the reaction temperature only slightly improved enantioselectivity with serious sacrifice of reaction rate (Table 1, entry 8). Acetonitrile was identified as the optimal solvent, and the reaction in other solvents such as DCM and Et2O led to inferior results in terms of both yield and enantioselectivity (Table 1, entries 9 and 10). The optimal ratio of 2a/3a was found to be 2:1, further increase the ratio did not lead to any improvements (Table 1, entries 12). It is noted that when cyclohexenone, instead of the saturated cyclohexanone, was used as substrate in the absence of IBX, the reactivity was comparable but the enantioselectivity was dropped due to background reaction (Figure 1), highlighting the appeal of this oxidative sequence.

a Reactions were performed at 0 °C in 0.5 mL of MeCN with 2a (0.2 mmol), 3a (0.1 mmol), IBX (0.12 mmol), 1 (20 mol %), and PFBA (30 mol %) in air, 24 h. Isolated yield. Enantioselectivity determined via HPLC analysis. b48 h. cSee the SI for details.

very well. The reaction also tolerated 4-disubstituted cyclohexanones (Scheme 2, 4m and 4n). Larger cyclic ketones were also tested, showing good reactivity and high enantioselectivity (Scheme 2, 4o and 4p). Unfortunately, cyclopentanone did not work, and no reaction was observed under the present conditions. To our delight, aliphatic acyclic ketones could also be applied to the reaction conditions with equally good performance in extended reaction period (Scheme 2, 4q−u), significantly expanding the utility of this process. In an one-pot two-stage reaction, the desymmetrization of 4-substituted cyclohexanone could also be coupled with conjugated addition to afford the desired product in 86% yield and with 82% ee as a single diastereoisomer (Scheme 2, 4v). To further illustrate the reaction scope, other nucleophiles such as 1H-benzotrizaole and dimethyl malonate were also tested, showing good yield and moderate enantioselectivity (Figure 2). To demonstrate the practicability of this transformation, we performed a scaleup example with 5 mmol of 3a and 10 mmol of 2a as substrate, generating 1.23 g product without loss of yield or enantioselectivity (Figure 3). On the basis of experimental observation and previous studies of IBX-mediated enamine dehydrogenation, a detailed catalytic cycle is proposed in Scheme 3.11 Enamine A is formed from substrate 2a and primary amine 1, which would be readily dehydrogenated to unsaturated iminium B by IBX through a covalent intermediate.8f Primary amine is considered to be

Figure 1. Conjugate addition using cyclohexenone.

With the optimized conditions in hand, we then explored the scope of the substrates. The electronic effect on the coumarin ring was shown to be fully tolerable, both electron-rich and electron-deficient coumarins could be applied to give good yield and high enantioselectivity (Scheme 2, 4a−i). Other coumarin analogues, such as quinolinone derivative, pyran-2one, and 4-naphthopyran-2-one (Scheme 2, 4j−l), also worked 1673

DOI: 10.1021/acs.orglett.8b00508 Org. Lett. 2018, 20, 1672−1675

Letter

Organic Letters

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Experimental procedures, characterization data, and 1H NMR and 13C NMR spectra and HPLC traces (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Sanzhong Luo: 0000-0001-8714-4047 Notes

Figure 2. Other nucleophiles.

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Natural Science Foundation of China (21390400, 21521002, 21572232, and 21672217) and the Chinese Academy of Science (QYZDJ-SSW-SLH023) for financial support. S.L. is supported by the National Program of Topnotch Young Professionals.

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Figure 3. Scale-up reaction.

Scheme 3. Proposed Mechanism

crucial to achieve this nontrivial ketone-enamine dehydrogenation for its space tolerance. Subsequent Si-facial nucleophilic addition to iminium B via transition state C affords the Sselective product 4a. A steric mode can be applied to account for the facial selectivity. In this model, the charged N−H−N Hbonding fixes the comformation of iminium ion and meanwhile renders the tertiary amine moiety block the Re-face. The role of weak acid additive is to facilitate enamine formation as previously verified,8a,b thus favoring enamine-based catalytic turnover. As a result, the enol-based background reaction was largely overrode, leading to better stereocontrol. In conclusion, we have developed a catalytic asymmetric βC−H functionalization of ketones via enamine oxidation. The reaction proceeds smoothly with both cyclic and acyclic ketones under mild conditions in high yield with excellent enantioselectivity. This unique cascade process is expected to achieve wide application in natural product synthesis and the pharmaceutical industry.

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REFERENCES

(1) For selected reviews, see: (a) Huang, Z.; Dong, G. Tetrahedron Lett. 2014, 55, 5869−5889. (b) Jensen, K. L.; Dickmeiss, G.; Jiang, K.; Albrecht, L.; Jørgensen, K. A. Acc. Chem. Res. 2012, 45, 248−264. (c) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Nature 2014, 510, 485−496. (d) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633−658. (e) Deng, Y.; Kumar, S.; Wang, H. Chem. Commun. 2014, 50, 4272−4284. (f) Kim, D.-S.; Park, W.-J.; Jun, C.-H. Chem. Rev. 2017, 117, 8977−9015. (2) For selected reviews, see: (a) Qin, Y.; Zhu, L.; Luo, S. Chem. Rev. 2017, 117, 9433−9520. (b) Inamdar, S. M.; Shinde, V. S.; Patil, M. T. Org. Biomol. Chem. 2015, 13, 8116−8162. (c) Oliveira, M. T.; Luparia, M.; Audisio, D.; Maulide, N. Angew. Chem., Int. Ed. 2013, 52, 13149− 13152. (d) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307−9387. (e) He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Chem. Rev. 2017, 117, 8754−8786. (3) For selected examples on asymmetric remote C−H functionalization of carbonyls, see: (a) Zhang, F.-L.; Hong, K.; Li, T.-J.; Park, H.; Yu, J.-Q. Science 2016, 351, 252−256. (b) Fu, Z.; Xu, J.; Zhu, T.; Leong, W. W. Y.; Chi, Y. R. Nat. Chem. 2013, 5, 835−839. (c) Chen, G.; Gong, W.; Zhuang, C.; Andra, M. S.; Chen, Y.-Q.; Hong, X.; Yang, Y.-F.; Liu, T.; Houk, K. N.; Yu, J.-Q. Science 2016, 353, 1023. (4) For selected reviews on aminocatalysis, see: (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471−5569. (b) Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416−5470. (c) Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006, 2001−2011. (d) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79−87. (e) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178−2189. (f) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138−6171. (5) For enamine oxidation through SET process, see: (a) Comito, R. J.; Finelli, F. G.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 9358−9361. (b) Jui, N. T.; Garber, J. A.; Finelli, F. G.; MacMillan, D. W. C. J. Am. Chem. Soc. 2012, 134, 11400−11403. (c) Pham, P. V.; Ashton, K.; MacMillan, D. W. C. Chem. Sci. 2011, 2, 1470−1473. (d) Mastracchio, A.; Warkentin, A. A.; Walji, A. M.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 20648−20651. (e) Devery, J. J.; Conrad, J. C.; MacMillan, D. W. C.; Flowers, R. A. Angew. Chem., Int. Ed. 2010, 49, 6106−6110. (f) Jui, N. T.; Lee, E. C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10015−10017. (g) Van Humbeck, J. F.; Simonovich, S. P.; Knowles, R. R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10012−10014. (h) Um, J. M.; Gutierrez, O.; Schoenebeck, F.; Houk, K. N.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 6001−6005. (i) Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 5027−5029. (j) Wilson, J. E.; Casarez, A. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 11332−11334. (k) Conrad, J. C.; Kong, J.; Laforteza, B. N.; MacMillan, D. W. C. J.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00508. 1674

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Organic Letters Am. Chem. Soc. 2009, 131, 11640−11641. (l) Amatore, M.; Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2009, 48, 5121−5124. (m) Graham, T. H.; Jones, C. M.; Jui, N. T.; MacMillan, D. W. C. J. Am. Chem. Soc. 2008, 130, 16494−16495. (n) Kim, H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2008, 130, 398−399. (o) Jang, H. Y.; Hong, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 7004−7005. (p) Beeson, T. D.; Mastracchio, A.; Hong, J. B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582−585. (q) Capacci, A. G.; Malinowski, J. T.; McAlpine, N. J.; Kuhne, J.; Macmillan, D. W. C. Nat. Chem. 2017, 9, 1073−1077. (6) For 5πe-catalysis, see: (a) Jeffrey, J. L.; Petronijević, F. R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2015, 137, 8404−8407. (b) Terrett, J. A.; Clift, M. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2014, 136, 6858−6861. (c) Petronijević, F. R.; Nappi, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 18323−18326. (d) Pirnot, M. T.; Rankic, D. A.; Martin, D. B.; MacMillan, D. W. C. Science 2013, 339, 1593−1596. (7) For oxidative iminium process, see: (a) Zhang, S.-L.; Xie, H.-X.; Zhu, J.; Li, H.; Zhang, X.-S.; Li, J.; Wang, W. Nat. Commun. 2011, 2, 211−217. (b) Hayashi, Y.; Itoh, T.; Ishikawa, H. Angew. Chem., Int. Ed. 2011, 50, 3920−3924. (c) Zhu, J.; Liu, J.; Ma, R.; Xie, H.; Li, J.; Jiang, H.; Wang, W. Adv. Synth. Catal. 2009, 351, 1229−1232. (d) Liu, J.; Zhu, J.; Jiang, H.; Wang, W.; Li, J. Chem. - Asian J. 2009, 4, 1712− 1716. (e) Hayashi, Y.; Itoh, T.; Ishikawa, H. Adv. Synth. Catal. 2013, 355, 3661−3669. (f) Zhao, Y.-L.; Wang, Y.; Hu, X.-Q.; Xu, P.-F. Chem. Commun. 2013, 49, 7555−7556. (g) Kang, Y. K.; Kim, D. Y. Chem. Commun. 2014, 50, 222−224. (h) Suh, C. W.; Woo, S. B.; Kim, D. Y. Asian J. Org. Chem. 2014, 3, 399−402. (i) Zeng, X.; Ni, Q.; Raabe, G.; Enders, D. Angew. Chem., Int. Ed. 2013, 52, 2977−2980. (j) Zhou, X.L.; Wang, P.-S.; Zhang, D.-W.; Liu, P.; Wang, C.-M.; Gong, L.-Z. Org. Lett. 2015, 17, 5120−5123. (8) (a) Zhang, L.; Luo, S. Synlett 2012, 23, 1575−1589. (b) Zhang, L.; Fu, N.; Luo, S. Acc. Chem. Res. 2015, 48, 986−997. (c) Yang, Q.; Zhang, L.; Ye, C.; Luo, S.; Wu, L.-Z.; Tung, C.-H. Angew. Chem., Int. Ed. 2017, 56, 3694−3698. (d) Fu, N.; Li, L.; Yang, Q.; Luo, S. Org. Lett. 2017, 19, 2122−2125. (e) Wang, D.; Zhang, L.; Luo, S. Org. Lett. 2017, 19, 4924−4927. (f) Zhu, L.; Zhang, L.; Luo, S. Angew. Chem., Int. Ed. 2018, 57, 2253−2258. (9) (a) Halland, N.; Hansen, T.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 4955−4957. (b) Kim, H.; Yen, C.; Preston, P.; Chin, J. Org. Lett. 2006, 8, 5239−5242. (c) Xie, J.-W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J.-G.; Chen, Y.-C. Org. Lett. 2007, 9, 413−415. (d) Zhu, X.; Lin, A.; Shi, Y.; Guo, J.; Zhu, C.; Cheng, Y. Org. Lett. 2011, 13, 4382−4385. (e) Leven, M.; Neudörfl, J. M.; Goldfuss, B. Beilstein J. Org. Chem. 2013, 9, 155−165. (f) Xiao, B.-X.; Yan, R.-J.; Gao, X.-Y.; Du, W.; Chen, Y.-C. Org. Lett. 2017, 19, 4652−4655. (10) (a) Murray, R. D. H.; Mendez, J.; Brown, R. A. The Natural Coumarins: Occurrence, Chemistry and Biochemistry; John Wiley & Sons: New York, 1982. (b) Kennedy, R. O.; Thornes, R. D. Coumarins: Biology, Applications and Mode of Action; John Wiley & Sons: Chichester, 1997. (c) Fylaktakidou, K. C.; Hadjipavlou-Litina, D. J.; Litinas, K. E.; Nicolaides, D. N. Curr. Pharm. Des. 2004, 10, 3813− 3833. (11) For mechanistic study on IBX as oxidant, see: (a) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Sugita, K. J. Am. Chem. Soc. 2002, 124, 2212−2220. (b) Nicolaou, K. C.; Sugita, K.; Baran, P. S.; Zhong, Y.-L. J. Am. Chem. Soc. 2002, 124, 2221−2232. (c) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, Z. S.; Hunt, K. W.; Kranich, R.; Vega, J. A. J. Am. Chem. Soc. 2002, 124, 2233−2244. (d) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L. J. Am. Chem. Soc. 2002, 124, 2245−2258. (e) Nicolaou, K. C.; Mathison, J. N.; Montagnon, T. J. Am. Chem. Soc. 2004, 126, 5192−5201.

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DOI: 10.1021/acs.orglett.8b00508 Org. Lett. 2018, 20, 1672−1675