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Cu-catalysed intramolecular radical enantioconvergent tertiary β-C(sp3)–H amination of racemic ketones

Nature Catalysis volume 3, pages 539–546 (2020)Cite this article

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Abstract

In contrast to the wealth of enantioselective prochiral C(sp3)–H functionalization that is transition-metal-catalysed, the enantioconvergent transformation of racemic tertiary C(sp3)–H bonds (pKa > 25) still represents a vastly uncharted domain. The mechanistic limitation is partial or complete chirality retention, which is inherent to developed enantioselective C–H functionalization catalysis and poses the major challenge in establishing such a process. To this end, we herein describe the combination of decoupled hydrogen atom abstraction with asymmetric copper catalysis for enantioconvergent tertiary β-C(sp3)–H amination of racemic ketones. This method, when allied with follow-up transformations, provides facile access to a range of enantioenriched compounds featuring quaternary stereocentres. We anticipate that this work will inspire the future design of generally efficient catalysts for enantioconvergent transformations of racemic tertiary C(sp3)–H bonds.

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Fig. 1: Design of catalytic enantioconvergent tertiary C(sp3)–H functionalization.
Fig. 2: Substrate scope of the N-sulfonylhydrazone moiety.
Fig. 3: Scope of the tertiary C(sp3)–H moiety, synthetic practicality and applications.
Fig. 4: Mechanistic studies and proposal.

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Data availability

The findings of this study are available within the paper and its Supplementary Information. Crystallographic parameters for compounds 14 and 62 are available free of charge from the Cambridge Crystallographic Data Centre under CCDC 1923926 (14) and 1923927 (62). All data are available from the authors upon reasonable request.

References

  1. You, S.-L. (ed.) Asymmetric Functionalization of C–H Bonds (The Royal Society of Chemistry, 2015).

  2. Newton, C. G., Wang, S.-G., Oliveira, C. C. & Cramer, N. Catalytic enantioselective transformations involving C–H bond cleavage by transition-metal complexes. Chem. Rev. 117, 8908–8976 (2017).

    Article  CAS  Google Scholar 

  3. Saint-Denis, T. G., Zhu, R.-Y., Chen, G., Wu, Q.-F. & Yu, J.-Q. Enantioselective C(sp 3)‒H bond activation by chiral transition metal catalysts. Science 359, eaao4798 (2018).

  4. Davies, H. M. L. & Manning, J. R. Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion. Nature 451, 417–424 (2008).

    Article  CAS  Google Scholar 

  5. Che, C.-M., Lo, V. K.-Y., Zhou, C.-Y. & Huang, J.-S. Selective functionalisation of saturated C–H bonds with metalloporphyrin catalysts. Chem. Soc. Rev. 40, 1950–1975 (2011).

    Article  CAS  Google Scholar 

  6. Roizen, J. L., Harvey, M. E. & du Bois, J. Metal-catalyzed nitrogen-atom transfer methods for the oxidation of aliphatic C–H bonds. Acc. Chem. Res. 45, 911–922 (2012).

    Article  CAS  Google Scholar 

  7. Davies, H. M. L. & Liao, K. Dirhodium tetracarboxylates as catalysts for selective intermolecular C–H functionalization. Nat. Rev. Chem. 3, 347–360 (2019).

    Article  CAS  Google Scholar 

  8. Lu, H. & Zhang, X. P. Catalytic C–H functionalization by metalloporphyrins: recent developments and future directions. Chem. Soc. Rev. 40, 1899–1909 (2011).

    Article  CAS  Google Scholar 

  9. Lewis, J. C., Coelho, P. S. & Arnold, F. H. Enzymatic functionalization of carbon–hydrogen bonds. Chem. Soc. Rev. 40, 2003–2021 (2011).

    Article  CAS  Google Scholar 

  10. Milan, M., Bietti, M. & Costas, M. Enantioselective aliphatic C–H bond oxidation catalyzed by bioinspired complexes. Chem. Commun. 54, 9559–9570 (2018).

    Article  CAS  Google Scholar 

  11. Wang, Y., Wen, X., Cui, X. & Zhang, X. P. Enantioselective radical cyclization for construction of 5-membered ring structures by metalloradical C–H alkylation. J. Am. Chem. Soc. 140, 4792–4796 (2018).

    Article  CAS  Google Scholar 

  12. Bhat, V., Welin, E. R., Guo, X. & Stoltz, B. M. Advances in stereoconvergent catalysis from 2005 to 2015: transition-metal-mediated stereoablative reactions, dynamic kinetic resolutions, and dynamic kinetic asymmetric transformations. Chem. Rev. 117, 4528–4561 (2017).

    Article  CAS  Google Scholar 

  13. Choi, J. & Fu, G. C. Transition metal–catalyzed alkyl-alkyl bond formation: another dimension in cross-coupling chemistry. Science 356, eaaf7230 (2017).

  14. Kainz, Q. M. et al. Asymmetric copper-catalyzed C–N cross-couplings induced by visible light. Science 351, 681–684 (2016).

    Article  CAS  Google Scholar 

  15. Wendlandt, A. E., Vangal, P. & Jacobsen, E. N. Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction. Nature 556, 447–451 (2018).

    Article  CAS  Google Scholar 

  16. Wang, Z., Yin, H. & Fu, G. C. Catalytic enantioconvergent coupling of secondary and tertiary electrophiles with olefins. Nature 563, 379–383 (2018).

    Article  CAS  Google Scholar 

  17. Zhang, X. et al. An enantioconvergent halogenophilic nucleophilic substitution (SN2X) reaction. Science 363, 400–404 (2019).

    Article  CAS  Google Scholar 

  18. Yang, Y., Cho, I., Qi, X., Liu, P. & Arnold, F. H. An enzymatic platform for the asymmetric amination of primary, secondary and tertiary C(sp 3)–H bonds. Nat. Chem. 11, 987–993 (2019).

    Article  CAS  Google Scholar 

  19. Paradine, S. M. et al. A manganese catalyst for highly reactive yet chemoselective intramolecular C(sp 3)–H amination. Nat. Chem. 7, 987–994 (2015).

    Article  CAS  Google Scholar 

  20. Barton, D. H. R., Beaton, J. M., Geller, L. E. & Pechet, M. M. A new photochemical reaction. J. Am. Chem. Soc. 83, 4076–4083 (1961).

    Article  CAS  Google Scholar 

  21. Hofmann, A. W. Ueber die einwirkung des broms in alkalischer lösung auf die amine. Ber. Dtsch. Chem. Ges. 16, 558–560 (1883).

    Article  Google Scholar 

  22. Löffler, K. & Freytag, C. Über eine neue bildungsweise von N-alkylierten pyrrolidinen. Ber. Dtsch. Chem. Ges. 42, 3427–3431 (1909).

    Article  Google Scholar 

  23. Sharma, A. & Hartwig, J. F. Metal-catalysed azidation of tertiary C–H bonds suitable for late-stage functionalization. Nature 517, 600–604 (2015).

    Article  CAS  Google Scholar 

  24. Mukherjee, S., Maji, B., Tlahuext-Aca, A. & Glorius, F. Visible-light-promoted activation of unactivated C(sp 3)–H bonds and their selective trifluoromethylthiolation. J. Am. Chem. Soc. 138, 16200–16203 (2016).

    Article  CAS  Google Scholar 

  25. Liu, Z. et al. Copper‐catalyzed remote C(sp 3)−H trifluoromethylation of carboxamides and sulfonamides. Angew. Chem. Int. Ed. 58, 2510–2513 (2019).

    Article  CAS  Google Scholar 

  26. Salamone, M. & Bietti, M. Tuning reactivity and selectivity in hydrogen atom transfer from aliphatic C–H bonds to alkoxyl radicals: role of structural and medium effects. Acc. Chem. Res. 48, 2895–2903 (2015).

    Article  CAS  Google Scholar 

  27. Cherney, A. H., Kadunce, N. T. & Reisman, S. E. Enantioselective and enantiospecific transition-metal-catalyzed cross-coupling reactions of organometallic reagents to construct C–C bonds. Chem. Rev. 115, 9587–9652 (2015).

    Article  CAS  Google Scholar 

  28. Fu, G. C. Transition-metal catalysis of nucleophilic substitution reactions: a radical alternative to SN1 and SN2 processes. ACS Cent. Sci. 3, 692–700 (2017).

    Article  CAS  Google Scholar 

  29. Gu, Q.-S., Li, Z.-L. & Liu, X.-Y. Copper(i)-catalyzed asymmetric reactions involving radicals. Acc. Chem. Res. 53, 170–181 (2020).

    Article  CAS  Google Scholar 

  30. Dong, X.-Y. et al. A general asymmetric copper-catalysed Sonogashira C(sp 3)–C(sp) coupling. Nat. Chem. 11, 1158–1166 (2019).

    Article  CAS  Google Scholar 

  31. Zhang, W. et al. Enantioselective cyanation of benzylic C–H bonds via copper-catalyzed radical relay. Science 353, 1014–1018 (2016).

    Article  CAS  Google Scholar 

  32. Li, J. et al. Site-specific allylic C–H bond functionalization with a copper-bound N-centred radical. Nature 574, 516–521 (2019).

    Article  CAS  Google Scholar 

  33. Gao, D.-W., Zheng, J., Ye, K.-Y., Zheng, C. & You, S.-L. in Asymmetric Functionalization of C–H Bonds 199–202 (The Royal Society of Chemistry, 2015).

  34. Ma, J. et al. Visible-light-activated asymmetric β-C–H functionalization of acceptor-substituted ketones with 1,2-dicarbonyl compounds. J. Am. Chem. Soc. 139, 17245–17248 (2017).

    Article  CAS  Google Scholar 

  35. Rottmann, M. et al. Spiroindolones, a potent compound class for the treatment of malaria. Science 329, 1175–1180 (2010).

    Article  CAS  Google Scholar 

  36. Wang, X. et al. Aromatic spiroketal bisphosphine ligands: palladium-catalyzed asymmetric allylic amination of racemic Morita–Baylis–Hillman adducts. Angew. Chem. Int. Ed. 51, 9276–9282 (2012).

    Article  CAS  Google Scholar 

  37. Ji, X. & Huang, H. Synthetic methods for 1,3-diamines. Org. Biomol. Chem. 14, 10557–10566 (2016).

    Article  CAS  Google Scholar 

  38. Salaün, J. in Small Ring Compounds in Organic Synthesis VI 1–67 (Springer, 2000).

  39. Dalpozzo, R., Lattanzi, A. & Pellissier, H. Applications of chiral three-membered rings for total synthesis: a review. Curr. Org. Chem. 21, 1143–1191 (2017).

    Article  CAS  Google Scholar 

  40. Cvrtila, I., Fanlo-Virgós, H., Schaeffer, G., Monreal Santiago, G. & Otto, S. Redox control over acyl hydrazone photoswitches. J. Am. Chem. Soc. 139, 12459–12465 (2017).

    Article  CAS  Google Scholar 

  41. Duan, X.-Y., Yang, X.-L., Jia, P.-P., Zhang, M. & Han, B. Hydrazonyl radical-participated tandem reaction: a strategy for the synthesis of pyrazoline-functionalized oxindoles. Org. Lett. 17, 6022–6025 (2015).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Financial support for this work was provided by the National Natural Science Foundation of China (nos. 21722203, 21702093, 21831002 and 21801116), Guangdong Provincial Key Laboratory of Catalysis (no. 2020B121201002), Guangdong Innovative Program (no. 2019BT02Y335), Guangdong Basic and Applied Basic Research Foundation (no. 2019A1515110822), Shenzhen Special Funds (nos. JCYJ20170412152435366, JCYJ20180302180235837 and JCYJ20180302174416591), Shenzhen Nobel Prize Scientists Laboratory Project (no. C17783101), and SUSTech Special Fund for the Construction of High-Level Universities (no. G02216303).

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Author notes

  1. These authors contributed equally: Chang-Jiang Yang, Chi Zhang, Qiang-Shuai Gu.

Authors and Affiliations

  1. Shenzhen Grubbs Institute and Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, China

    Chang-Jiang Yang, Chi Zhang, Jia-Heng Fang, Yan Sun, Yu Tian & Xin-Yuan Liu

  2. Academy for Advanced Interdisciplinary Studies and Department of Chemistry, Southern University of Science and Technology, Shenzhen, China

    Qiang-Shuai Gu, Liu Ye & Zhong-Liang Li

  3. Shaanxi Key Laboratory of Phytochemistry, College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji, China

    Xiao-Long Su

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  1. Chang-Jiang Yang
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Contributions

C.-J.Y., C.Z. and Q.-S.G. designed the experiments and analysed the data. C.-J.Y., C.Z., J.-H.F., X.-L.S., L.Y., Y.S., Y.T. and Z.-L.L. performed the experiments. All authors participated in writing the manuscript. X.-Y.L. conceived and supervised the project.

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Correspondence to Xin-Yuan Liu.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–4, Tables 1–4, Methods, NMR spectra, HPLC spectra and references.

Crystallographic Data 1

Crystallographic data for compound 14

Crystallographic Data 2

Crystallographic data for compound 62

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Yang, CJ., Zhang, C., Gu, QS. et al. Cu-catalysed intramolecular radical enantioconvergent tertiary β-C(sp3)–H amination of racemic ketones. Nat Catal 3, 539–546 (2020). https://doi.org/10.1038/s41929-020-0460-y

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