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Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides

Nature Chemistry volume 9, pages 140–144 (2017)Cite this article

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Abstract

Saturated aza-heterocycles are highly privileged building blocks that are commonly encountered in bioactive compounds and approved therapeutic agents. These N-heterocycles are also incorporated as chiral auxiliaries and ligands in asymmetric synthesis. As such, the development of methods to functionalize the α-methylene C–H bonds of these systems enantioselectively is of great importance, especially in drug discovery. Currently, enantioselective lithiation with (–)-sparteine followed by Pd(0) catalysed cross-coupling to prepare α-arylated amines is largely limited to pyrrolidines. Here we report a Pd(II)-catalysed enantioselective α-C–H coupling of a wide range of amines, which include ethyl amines, azetidines, pyrrolidines, piperidines, azepanes, indolines and tetrahydroisoquinolines. Chiral phosphoric acids are demonstrated as effective anionic ligands for the enantioselective coupling of methylene C–H bonds with aryl boronic acids. This catalytic reaction not only affords high enantioselectivities, but also provides exclusive regioselectivity in the presence of two methylene groups in different steric environments.

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Figure 1: Examples of important chiral α-arylated cyclic amines and approaches for the construction of α-stereocentres.
Figure 2: Removal of the thioamide directing group.

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References

  1. Royer, J. Asymmetric Synthesis of Nitrogen Heterocycles (Wiley-VCH, 2009).

    Book  Google Scholar 

  2. Nugent, T. C. Chiral Amine Synthesis: Methods, Developments and Applications (Wiley-VCH, 2010).

    Book  Google Scholar 

  3. Campos, K. R. Direct sp3 C–H bond activation adjacent to nitrogen in heterocycles. Chem. Soc. Rev. 36, 1069–1084 (2007).

    Article  CAS  Google Scholar 

  4. Mitchell, E. A., Peschiulli, A., Lefevre, N., Meerpoel, L. & Maes, B. U. W. Direct α-functionalization of saturated cyclic amines. Chem. Eur. J. 18, 10092–10142 (2012).

    Article  CAS  Google Scholar 

  5. Beak, P., Kerrick, S. T., Wu, S. & Chu, J. Complex induced proximity effects: enantioselective syntheses based on asymmetric deprotonations of N-Boc-pyrrolidines. J. Am. Chem. Soc. 116, 3231–3239 (1994).

    Article  CAS  Google Scholar 

  6. Campos, K. R., Klapars, A., Waldman, J. H., Dormer, P. G. & Chen, C.-Y. Enantioselective, palladium-catalyzed α-arylation of N-Boc-pyrrolidine. J. Am. Chem. Soc. 128, 3538–3539 (2006).

    Article  CAS  Google Scholar 

  7. Beng, T. K. & Gawley, R. E. Application of catalytic dynamic resolution of N-Boc-2-lithiopiperidine to the asymmetric synthesis of 2-aryl and 2-vinyl piperidines. Org. Lett. 13, 394–397 (2011).

    Article  CAS  Google Scholar 

  8. Cordier, C. J., Lundgren, R. J. & Fu, G. C. Enantioconvergent cross-couplings of racemic alkylmetal reagents with unactivated secondary alkyl electrophiles: catalytic asymmetric Negishi α-alkylations of N-Boc-pyrrolidine. J. Am. Chem. Soc. 135, 10946–10949 (2013).

    Article  CAS  Google Scholar 

  9. Stead, D. et al. Asymmetric deprotonation of N-Boc piperidine: react IR monitoring and mechanistic aspects. J. Am. Chem. Soc. 132, 7260–7261 (2010).

    Article  CAS  Google Scholar 

  10. Spangler, J. E., Kobayashi, Y., Verma, P., Wang, D.-H. & Yu, J.-Q. α-Arylation of saturated azacycles and N-methylamines via palladium(II)-catalyzed C(sp3)−H coupling. J. Am. Chem. Soc. 137, 11876–11879 (2015).

    Article  CAS  Google Scholar 

  11. Xiao, K.-J. et al. Palladium(II)-catalyzed enantioselective C(sp3)–H activation using a chiral hydroxamic acid ligand. J. Am. Chem. Soc. 136, 8138–8142 (2014).

    Article  CAS  Google Scholar 

  12. Chan, K. S. L., Fu, H.-Y. & Yu, J.-Q. Palladium(II)-catalyzed highly enantioselective C–H arylation of cyclopropylmethylamines. J. Am. Chem. Soc. 136, 2042–2046 (2015).

    Article  Google Scholar 

  13. Nakanishi, M., Katayev, D., Besnard, C. & Kündig, E. P. Fused indolines by palladium-catalyzed asymmetric C–C coupling involving an unactivated methylene group. Angew. Chem. Int. Ed. 50, 7438–7441 (2011).

    Article  CAS  Google Scholar 

  14. Anas, S., Cordi, A. & Kagan, H. B. Enantioselective synthesis of 2-methyl indolines by palladium catalysed asymmetric C(sp3)–H activation/cyclisation. Chem. Commun. 47, 11483–11485 (2011).

    Article  CAS  Google Scholar 

  15. Martin, N., Pierre, C., Davi, M., Jazzar, R. & Baudoin, O. Diastereo- and enantioselective intramolecular C(sp3)–H arylation for the synthesis of fused cyclopentanes. Chem. Eur. J. 18, 4480–4484 (2012).

    Article  CAS  Google Scholar 

  16. Saget, T., Lemouzy, S. & Cramer, N. Chiral monodentate phosphines and bulky carboxylic acids: cooperative effects in palladium-catalyzed enantioselective C(sp3)–H functionalization. Angew. Chem. Int. Ed. 51, 2238–2242 (2012).

    Article  CAS  Google Scholar 

  17. Akiyama, T., Itoh, J., Yokota, K. & Fuchibe, K. Enantioselective Mannich-type reaction catalyzed by a chiral Brønsted acid. Angew. Chem. Int. Ed. 43, 1566–1568 (2004).

    Article  CAS  Google Scholar 

  18. Uraguchi, D. & Terada, M. Chiral Brønsted acid-catalyzed direct Mannich reactions via electrophilic activation. J. Am. Chem. Soc. 126, 5356–5357 (2004).

    Article  CAS  Google Scholar 

  19. Parmar, D., Sugiono, E., Raja, S. & Rueping, M. Complete field guide to asymmetric BINOL-phosphate derived Brønsted acid and metal catalysis: history and classification by mode of activation; Brønsted acidity, hydrogen bonding, ion pairing, and metal phosphates. Chem. Rev. 114, 9047–9153 (2014).

    Article  CAS  Google Scholar 

  20. Hamilton, G. L., Kang, E. J., Mba, M. & Toste, F. D. A powerful chiral counterion strategy for asymmetric transition metal catalysis. Science 317, 496–499 (2007).

    Article  CAS  Google Scholar 

  21. Mukherjee, S. & List, B. Chiral counteranions in asymmetric transition-metal catalysis: highly enantioselective Pd/Brønsted acid-catalyzed direct α-allylation of aldehydes. J. Am. Chem. Soc. 129, 11336–11337 (2007).

    Article  CAS  Google Scholar 

  22. Jiang, G., Halder, R., Fang, Y. & List, B. A highly enantioselective Overman rearrangement through asymmetric counteranion-directed palladium catalysis. Angew. Chem. Int. Ed. 50, 9752–9755 (2011).

    Article  CAS  Google Scholar 

  23. Chai, Z. & Rainey, T. J. Pd(II)/Brønsted acid catalyzed enantioselective allylic C−H activation for the synthesis of spirocyclic rings. J. Am. Chem. Soc. 134, 3615–3618 (2012).

    Article  CAS  Google Scholar 

  24. Wang, P.-S., Lin, H.-C., Zhai, Y.-J., Han, Z.-Y. & Gong, L.-Z. Chiral counteranion strategy for asymmetric oxidative C(sp3)–H/C(sp3)–H coupling: enantioselective α-allylation of aldehydes with terminal alkenes. Angew. Chem. Int. Ed. 53, 11218–11221 (2014).

    Article  Google Scholar 

  25. Engle, K. M. & Yu, J.-Q. Developing ligands for palladium(II)-catalyzed C–H functionalization: intimate dialogue between ligand and substrate. J. Org. Chem. 78, 8927–8955 (2013).

    Article  CAS  Google Scholar 

  26. Yan, S.-B., Zhang, S. & Duan, W.-L. Palladium-catalyzed asymmetric arylation of C(sp3)–H bonds of aliphatic amides: controlling enantioselectivity using chiral phosphoric amides/acids. Org. Lett. 17, 2458–2461 (2015).

    Article  CAS  Google Scholar 

  27. Zhang, D. et al. Enantioselective palladium(II) phosphate catalyzed three-component reactions of pyrrole, diazoesters, and imines. Angew. Chem. Int. Ed. 52, 13356–13360 (2013).

    Article  CAS  Google Scholar 

  28. Ding, J., Rybak, T. & Hall, D. G. Synthesis of chiral heterocycles by ligand-controlled regiodivergent and enantiospecific Suzuki–Miyaura cross-coupling. Nat. Commun. 5, 5474 (2014).

    Article  Google Scholar 

  29. Bailey, W. F., Beak, P., Kerrick, S. T., Ma, S. & Wiberg, K. B. An experimental and computational investigation of the enantioselective deprotonation of Boc-piperidine. J. Am. Chem. Soc. 124, 1889–1896 (2002).

    Article  CAS  Google Scholar 

  30. Hodgson, D. & Kloesges, J. Lithiation–electrophilic substitution of N-thiopivaloylazetidine. Angew. Chem. Int. Ed. 49, 2900–2903 (2010).

    Article  CAS  Google Scholar 

  31. Hodgson, D., Mortimer, C. L. & McKenna, J. M. Amine protection/α-activation with the tert-butoxythiocarbonyl group: application to azetidine lithiation−electrophilic substitution. Org. Lett. 17, 330–333 (2015).

    Article  CAS  Google Scholar 

  32. Li, X., Leonori, D., Sheikh, N. S. & Coldham, I. Synthesis of 1-substituted tetrahydroisoquinolines by lithiation and electrophilic quenching guided by in situ IR and NMR spectroscopy and application to the synthesis of salsolidine, carnegine and laudanosine. Chem. Eur. J. 19, 7724–7730 (2013).

    Article  CAS  Google Scholar 

  33. Mitch, C. H. et al. Discovery of aminobenzyloxyarylamides as κ opioid receptor selective antagonists: application to preclinical development of a κ opioid receptor antagonist receptor occupancy tracer. J. Med. Chem. 54, 8000–8012 (2011).

    Article  CAS  Google Scholar 

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Acknowledgements

We acknowledge The Scripps Research Institute and the National Institutes of Health (NIGMS, 2R01GM084019) for their financial support.

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Authors and Affiliations

  1. Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, 92037, California, USA

    Pankaj Jain, Pritha Verma, Guoqin Xia & Jin-Quan Yu

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  1. Pankaj Jain
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  2. Pritha Verma
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Contributions

P.J. developed the enantioselective arylation reaction. P.V. and G.X. expanded the substrate scope. J.-Q.Y. conceived and supervised the project. J.-Q.Y. and P.J. wrote the manuscript.

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Correspondence to Jin-Quan Yu.

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The authors declare no competing financial interests.

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Jain, P., Verma, P., Xia, G. et al. Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides. Nature Chem 9, 140–144 (2017). https://doi.org/10.1038/nchem.2619

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