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Catalytic C(sp3)–H bond activation in tertiary alkylamines

Abstract

The development of robust catalytic methods to assemble tertiary alkylamines provides a continual challenge to chemical synthesis. In this regard, transformation of a traditionally unreactive C–H bond, proximal to the nitrogen atom, into a versatile chemical entity would be a powerful strategy for introducing functional complexity to tertiary alkylamines. A practical and selective metal-catalysed C(sp3)–H activation facilitated by the tertiary alkylamine functionality, however, remains an unsolved problem. Here, we report a Pd(ii)-catalysed protocol that appends arene feedstocks to tertiary alkylamines via C(sp3)–H functionalization. A simple ligand for Pd(ii) orchestrates the C–H activation step in favour of deleterious pathways. The reaction can use both simple and complex starting materials to produce a range of multifaceted γ-aryl tertiary alkylamines and can be rendered enantioselective. The enabling features of this transformation should be attractive to practitioners of synthetic and medicinal chemistry as well as in other areas that use biologically active alkylamines.

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Fig. 1: Design plan towards γ-C(sp3)–H arylation of tertiary alkylamines.
Fig. 2: The γ-C(sp3)–H arylation of tertiary alkylamines.
Fig. 3: Applications and further advances of the γ-C–H arylation of tertiary alkylamines.

Data availability

The data that support the findings of this study are available within the paper and its supplementary information files. Raw data are available from the corresponding author on reasonable request.

References

  1. He, J., Wasa, M., Chan, K. S. L., Shao, Q. & Yu, J.-Q. Palladium-catalyzed transformations of alkyl C–H bonds. Chem. Rev. 117, 8754–8786 (2017).

    CAS  PubMed  Google Scholar 

  2. Davies, H. M. L. & Morton, D. Guiding principles for site selective and stereoselective intermolecular C–H functionalization by donor/acceptor rhodium carbenes. Chem. Soc. Rev. 40, 1857–1869 (2011).

    CAS  PubMed  Google Scholar 

  3. Capaldo, L. & Ravelli, D. Hydrogen atom transfer (HAT): a versatile strategy for substrate activation in photocatalyzed organic synthesis. Eur. J. Org. Chem. 15, 2056–2071 (2017).

    Google Scholar 

  4. Giri, R. et al. Palladium-catalyzed methylation and arylation of sp2 and sp3 C–H bonds in simple carboxylic acids. J. Am. Chem. Soc. 129, 3510–3511 (2007).

    CAS  PubMed  Google Scholar 

  5. Chen, G. et al. Ligand-enabled β-C–H arylation of α-amino acids without installing exogenous directing groups. Angew. Chem. Int. Ed. 56, 1506–1509 (2017).

    CAS  Google Scholar 

  6. He, C., Whitehurst, W. G. & Gaunt, M. J. Palladium-catalyzed C(sp)3–H bond functionalization of aliphatic amines. Chem 5, 1031–1058 (2019).

    CAS  Google Scholar 

  7. Lyons, T. W. & Sanford, M. S. Palladium-catalyzed ligand-directed C–H functionalization reactions. Chem. Rev. 110, 1147–1169 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Rouquet, G. & Chatani, N. Catalytic functionalization of C(sp2)–H and C(sp3)–H bonds by using bidentate directing groups. Angew. Chem. Int. Ed. 52, 11726–11743 (2013).

    CAS  Google Scholar 

  9. Zaitsev, V. G., Shabashov, D. & Daugulis, O. Highly regioselective arylation of sp3 C–H bonds catalyzed by palladium acetate. J. Am. Chem. Soc. 127, 13154–13155 (2005).

    CAS  PubMed  Google Scholar 

  10. He, G. & Chen, G. A practical strategy for the structural diversification of aliphatic scaffolds through the palladium-catalyzed picolinamide-directed remote functionalization of unactivated C(sp3)–H bonds. Angew. Chem. Int. Ed. 50, 5192–5196 (2011).

    CAS  Google Scholar 

  11. Chan, K. S. L. et al. Ligand-enabled cross-coupling of C(sp3)–H bonds with arylboron reagents via Pd(II)/Pd(0) catalysis. Nat. Chem. 6, 146–150 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Topczewski, J. J., Cabrera, P. J., Saper, N. I. & Sanford, M. S. Palladium-catalysed transannular C–H functionalization of alicyclic amines. Nature 531, 220–224 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wu, Y., Chen, Y.-Q., Liu, T., Eastgate, M. D. & Yu, J.-Q. Pd-catalyzed γ-C(sp3)–H arylation of free amines using a transient directing group. J. Am. Chem. Soc. 138, 14554–14557 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Xu, Y., Young, M. C., Wang, C., Magness, D. M. & Dong, G. Catalytic C(sp3)–H arylation of free primary amines with an exo directing group generated in situ. Angew. Chem. Int. Ed. 55, 9084–9087 (2016).

    CAS  Google Scholar 

  15. Liu, Y. & Ge, H. Site-selective C–H arylation of primary aliphatic amines enabled by a catalytic transient directing group. Nat. Chem. 9, 26–32 (2017).

    Google Scholar 

  16. Kapoor, M., Liu, D. & Young, M. C. Carbon dioxide-mediated C(sp3)–H arylation of amine substrates. J. Am. Chem. Soc. 140, 6818–6822 (2018).

    CAS  PubMed  Google Scholar 

  17. Roughley, S. D. & Jordan, A. M. The medicinal chemist’s toolbox: an analysis of reactions used in the pursuit of drug candidates. J. Med. Chem. 54, 3451–3479 (2011).

    CAS  PubMed  Google Scholar 

  18. Cernak, T., Dykstra, K. D., Tyagarajan, S., Vachal, P. & Krska, S. W. The medicinal chemist’s toolbox for late stage functionalization of drug-like molecules. Chem. Soc. Rev. 45, 546–576 (2016).

    CAS  PubMed  Google Scholar 

  19. Huang, L., Arndt, M., Gooβen, K., Heydt, H. & Gooβen, L. J. Late transition metal-catalyzed hydroamination and hydroamidation. Chem. Rev. 115, 2596–2697 (2015).

    CAS  PubMed  Google Scholar 

  20. Musacchio, A. J. et al. Catalytic intermolecular hydroaminations of unactivated olefins with secondary alkyl amines. Science 355, 727–730 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Pirnot, M. T., Wang, Y.-M. & Buchwald, S. L. Copper hydride catalyzed hydroamination of alkenes and alkynes. Angew. Chem. Int. Ed. 55, 48–57 (2016).

    CAS  Google Scholar 

  22. Perez, F., Oda, S., Geary, L. M. & Krische, M. J. Ruthenium-catalyzed transfer hydrogenation for C–C bond formation: hydrohydroxyalkylation and hydroaminoalkylation via reactant redox pairs. Top. Curr. Chem. 374, 35 (2016).

    Google Scholar 

  23. Matier, C. D., Schwaben, J., Peters, J. C. & Fu, G. C. Copper-catalyzed alkylation of aliphatic amines induced by visible light. J. Am. Chem. Soc. 139, 17707–17710 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Hanna, S., Holder, J. C. & Hartwig, J. F. A multicatalytic approach to the hydroaminomethylation of α-olefins. Angew. Chem. Int. Ed. 58, 3368–3372 (2019).

    CAS  Google Scholar 

  25. Trowbridge, A., Reich, D. & Gaunt, M. J. Multicomponent synthesis of tertiary alkylamines by photocatalytic olefin-hydroaminoalkylation. Nature 561, 522–527 (2018).

    CAS  PubMed  Google Scholar 

  26. Hsieh, S.-Y. & Bode, J. W. Lewis acid induced toggle from Ir(II) to Ir(IV) pathways in photocatalytic reactions: synthesis of thiomorpholines and thiazepanes from aldehydes and SLAP reagents. ACS Cent. Sci. 3, 66–72 (2017).

    CAS  PubMed  Google Scholar 

  27. Xie, L.-G. & Dixon, D. J. Tertiary amine synthesis via reductive coupling of amides with Grignard reagents. Chem. Sci. 8, 7492–7497 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Grogan, G. Synthesis of chiral amines using redox biocatalysis. Curr. Opin. Chem. Biol. 43, 15–22 (2018).

    CAS  PubMed  Google Scholar 

  29. Ouyang, K., Hao, W., Zhang, W.-X. & Xi, Z. Transition-metal-catalyzed cleavage of C–N single bonds. Chem. Rev. 115, 12045–12090 (2015).

    CAS  PubMed  Google Scholar 

  30. Lawrence, J. D., Takahashi, M., Bae, C. & Hartwig, J. F. Regiospecific functionalization of methyl C–H bonds of alkyl groups in reagents with heteroatom functionality. J. Am. Chem. Soc. 126, 15334–15335 (2004).

    CAS  PubMed  Google Scholar 

  31. Murphy, J. M., Lawrence, J. D., Kawamura, K., Incarvito, C. & Hartwig, J. F. Ruthenium-catalyzed regiospecific borylation of methyl C–H bonds. J. Am. Chem. Soc. 128, 13684–13685 (2006).

    CAS  PubMed  Google Scholar 

  32. Li, Q., Liskey, C. W. & Hartwig, J. F. Regioselective borylation of the C–H bonds in alkylamines and alkyl ethers. Observation and origin of high reactivity of primary C–H bonds beta to nitrogen and oxygen. J. Am. Chem. Soc. 136, 8755–8765 (2014).

    CAS  PubMed  Google Scholar 

  33. Lee, M. & Sanford, M. S. Platinum-catalyzed, terminal-selective C(sp3)–H oxidation of aliphatic amines. J. Am. Chem. Soc. 137, 12796–12799 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Mack, J. B. C., Gipson, J. D., Du Bois, J. & Sigman, M. S. Ruthenium-catalyzed C–H hydroxylation in aqueous acid enables selective functionalization of amine derivatives. J. Am. Chem. Soc. 139, 9503–9506 (2017).

    CAS  PubMed  Google Scholar 

  35. Howell, J. M., Feng, K., Clark, J. R., Trzepkowski, L. J. & White, M. C. Remote oxidation of aliphatic C–H bonds in nitrogen-containing molecules. J. Am. Chem. Soc. 137, 14590–14593 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Schultz, D. M. et al. Oxyfunctionalization of the remote C–H bonds of aliphatic amines by decatungstate photocatalysis. Angew. Chem. Int. Ed. 56, 15274–15278 (2017).

    CAS  Google Scholar 

  37. Ghose, A. K., Herbertz, T., Hudkins, R. L., Dorsey, B. D. & Mallamo, J. P. Knowledge-based central nervous system (CNS) lead selection and lead optimization for CNS drug discovery. ACS Chem. Neurosci. 3, 50–68 (2012).

    CAS  PubMed  Google Scholar 

  38. Ryabov, A. D., Sakodinskaya, I. & Yatsimirsky, A. Kinetics and mechanism of ortho-palladation of ring-substituted N,N-dimethylbenzylamines. J. Chem. Soc. Dalton Trans. 12, 2629–2638 (1985).

    Google Scholar 

  39. Nielsen, R. J. & Goddard, W. A. III Mechanism of the aerobic oxidation of alcohols by palladium complexes of N-heterocyclic carbenes. J. Am. Chem. Soc. 128, 9651–9660 (2006).

    CAS  PubMed  Google Scholar 

  40. Yang, Y.-F., Hong, X., Yu, J.-Q. & Houk, K. N. Experimental-computational synergy for selective Pd(II)-catalyzed C–H activation of aryl and alkyl groups. Acc. Chem. Res. 50, 2853–2860 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Cheng, G.-J. et al. Role of N-acyl amino acid ligands in Pd(II)-catalyzed remote C–H activation of tethered arenes. J. Am. Chem. Soc. 136, 894–897 (2014).

    CAS  PubMed  Google Scholar 

  42. Haines, B. E., Yu, J.-Q. & Musaev, D. G. Enantioselectivity model for Pd-catalyzed C–H functionalization mediated by the mono-N-protected amino acid (MPAA) family of ligands. ACS Catal. 7, 4344–4354 (2017).

    CAS  Google Scholar 

  43. Vasseur, A., Muzart, J. & Le Bras, J. Ubiquitous benzoquinones, multitalented compounds for palladium-catalyzed oxidative reactions. Eur. J. Org. Chem. 2015, 4053–4069 (2015).

    CAS  Google Scholar 

  44. Wu, Q. F. et al. Formation of α-chiral centers by asymmetric β-C(sp3)–H arylation, alkenylation, and alkynylation. Science 355, 499–503 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Saint-Denis, T. G., Zhu, R.-Y., Chen, G., Wu, Q.-F. & Yu, J.-Q. Enantioselective C(sp3)–H bond activation by chiral transition metal catalysts. Science 359, 747–759 (2018).

    Google Scholar 

  46. Mlynarski, S. N., Schuster, C. H. & Morken, J. P. Asymmetric synthesis from terminal alkenes by cascades of diboration and cross-coupling. Nature 505, 386–390 (2014).

    CAS  PubMed  Google Scholar 

  47. Chen, G. et al. Ligand-accelerated enantioselective methylene C(sp3)–H bond activation. Science 353, 1023–1027 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to the EPSRC UK National Mass Spectrometry Facility at Swansea University for HRMS analysis. We thank I. Michaelides (AstraZeneca) and M. Grayson (University of Bath) for useful discussion. We are grateful to La Caixa Foundation and the Cambridge European Trust (J.R.) and the Gates Cambridge Trust (N.J.F.) for scholarships, the EPSRC (EP/N031792/1), the Leverhulme Trust (RPG-2016-370 to M.N.), Mitsubishi (H.A.), H2020 Marie Curie Actions (702462 to M.N. and 656455 to M.E.B.) and the Royal Society for a Wolfson Merit Award (to M.J.G.)

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J.R., M.N. and M.J.G. conceived the project. J.R., M.N., H.A. and M.E.B. designed and performed the synthetic experiments. J.R. and N.J.F. designed and performed the computational studies. J.R., M.N., H.A., N.J.F. and M.J.G. prepared the manuscript.

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Correspondence to Matthew J. Gaunt.

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Supplementary information

Details of the materials and methods, experimental procedures, mechanistic studies, optimization studies, computational data and compound characterization data, including 1H NMR spectra, 13C NMR spectra and MS data.

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Rodrigalvarez, J., Nappi, M., Azuma, H. et al. Catalytic C(sp3)–H bond activation in tertiary alkylamines. Nat. Chem. 12, 76–81 (2020). https://doi.org/10.1038/s41557-019-0393-8

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