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


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.


  1. 1

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

    Google Scholar 

  2. 2

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

    Google Scholar 

  3. 3

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

    CAS  Article  Google Scholar 

  4. 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).

    CAS  Article  Google Scholar 

  5. 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).

    CAS  Article  Google Scholar 

  6. 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).

    CAS  Article  Google Scholar 

  7. 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).

    CAS  Article  Google Scholar 

  8. 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).

    CAS  Article  Google Scholar 

  9. 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).

    CAS  Article  Google Scholar 

  10. 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).

    CAS  Article  Google Scholar 

  11. 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).

    CAS  Article  Google Scholar 

  12. 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. 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).

    CAS  Article  Google Scholar 

  14. 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).

    CAS  Article  Google Scholar 

  15. 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).

    CAS  Article  Google Scholar 

  16. 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).

    CAS  Article  Google Scholar 

  17. 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).

    CAS  Article  Google Scholar 

  18. 18

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

    CAS  Article  Google Scholar 

  19. 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).

    CAS  Article  Google Scholar 

  20. 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).

    CAS  Article  Google Scholar 

  21. 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).

    CAS  Article  Google Scholar 

  22. 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).

    CAS  Article  Google Scholar 

  23. 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).

    CAS  Article  Google Scholar 

  24. 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. 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).

    CAS  Article  Google Scholar 

  26. 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).

    CAS  Article  Google Scholar 

  27. 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).

    CAS  Article  Google Scholar 

  28. 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. 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).

    CAS  Article  Google Scholar 

  30. 30

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

    CAS  Article  Google Scholar 

  31. 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).

    CAS  Article  Google Scholar 

  32. 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).

    CAS  Article  Google Scholar 

  33. 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).

    CAS  Article  Google Scholar 

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

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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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