Ligand-enabled cross-coupling of C(sp3)–H bonds with arylboron reagents via Pd(II)/Pd(0) catalysis

Abstract

There have been numerous developments in C–H activation reactions in the past decade. Attracted by the ability to functionalize molecules directly at ostensibly unreactive C–H bonds, chemists have discovered reaction conditions that enable reactions of C(sp2)–H and C(sp3)–H bonds with a variety of coupling partners. Despite these advances, the development of suitable ligands that enable catalytic C(sp3)–H bond functionalization remains a significant challenge. Herein we report the discovery of a mono-N-protected amino acid ligand that enables Pd(II)-catalysed coupling of γ-C(sp3)–H bonds in triflyl-protected amines with arylboron reagents. Remarkably, no background reaction was observed in the absence of ligand. A variety of amine substrates and arylboron reagents were cross-coupled using this method. Arylation of optically active substrates derived from amino acids also provides a potential route for preparing non-proteinogenic amino acids.

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Figure 1: Ligand-enabled C(sp3)–H activation.

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Acknowledgements

This work was supported by The Scripps Research Institute and the National Institutes of Health (NIGMS, 2R01GM084019). K.S.L.C. thanks the Agency for Science, Technology and Research (A*STAR) Singapore for a predoctoral fellowship. M.W. thanks Bristol Myers Squibb for a predoctoral fellowship. M.M. thanks Astellas Pharma Inc. for a postdoctoral fellowship. This is The Scripps Research Institute (TSRI) manuscript no. 25049.

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K.S.L.C. conceived the study, principally performed the experiments and wrote the manuscript, M.W. helped with conceiving the study and preparing the manuscript, L.C. and B.N.L. performed experiments on coupling-partner scope, M.M. helped with identifying the deprotection strategy and J-Q.Y. provided overall supervision. All the authors discussed the results and commented on the manuscript.

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Correspondence to Jin-Quan Yu.

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Chan, K., Wasa, M., Chu, L. et al. Ligand-enabled cross-coupling of C(sp3)–H bonds with arylboron reagents via Pd(II)/Pd(0) catalysis. Nature Chem 6, 146–150 (2014). https://doi.org/10.1038/nchem.1836

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