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

Nature Chemistry volume 6, pages 146150 (2014) | Download Citation

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.

  • Compound C6H10F3NO4S

    (S)-Methyl 2-(trifluoromethylsulfonamido)butanoate

  • Compound C14H16F3NO6S

    (S)-Methyl 4-(4-methoxy-4-oxo-3-(trifluoromethylsulfonamido)butyl)benzoate

  • Compound C14H16F3NO6S

    (S)-Methyl 3-(4-methoxy-4-oxo-3-(trifluoromethylsulfonamido)butyl)benzoate

  • Compound C16H18F3NO8S

    (S)-Dimethyl 5-(4-methoxy-4-oxo-3-(trifluoromethylsulfonamido)butyl)isophthalate

  • Compound C12H14F3NO4S

    (S)-Methyl 4-phenyl-2-(trifluoromethylsulfonamido)butanoate

  • Compound C12H13F4NO4S

    (S)-Methyl 4-(4-fluorophenyl)-2-(trifluoromethylsulfonamido)butanoate

  • Compound C12H13F4NO4S

    (S)-Methyl 4-(3-fluorophenyl)-2-(trifluoromethylsulfonamido)butanoate

  • Compound C13H13F6NO4S

    (S)-Methyl 4-(4-(trifluoromethyl)phenyl)-2-(trifluoromethylsulfonamido)butanoate

  • Compound C13H13F6NO4S

    (S)-Methyl 4-(3-(trifluoromethyl)phenyl)-2-(trifluoromethylsulfonamido)butanoate

  • Compound C13H12F7NO4S

    (S)-Methyl 4-(3-fluoro-4-(trifluoromethyl)phenyl)-2-(trifluoromethylsulfonamido)butanoate

  • Compound C13H12F4N2O4S

    (S)-Methyl 4-(3-cyano-4-fluorophenyl)-2-(trifluoromethylsulfonamido)butanoate

  • Compound C12H13ClF3NO4S

    (S)-Methyl 4-(4-chlorophenyl)-2-(trifluoromethylsulfonamido)butanoate

  • Compound C12H13BrF3NO4S

    (S)-Methyl 4-(4-bromophenyl)-2-(trifluoromethylsulfonamido)butanoate

  • Compound C13H16F3NO5S

    (S)-Methyl 4-(4-methoxyphenyl)-2-(trifluoromethylsulfonamido)butanoate

  • Compound C14H18F3NO6S

    (S)-Methyl 4-(3,5-dimethoxyphenyl)-2-(trifluoromethylsulfonamido)butanoate

  • Compound C14H17F3N2O5S

    (S)-Methyl 4-(4-acetamidophenyl)-2-(trifluoromethylsulfonamido)butanoate

  • Compound C16H16F3NO4S

    (S)-Methyl 4-(naphthalen-2-yl)-2-(trifluoromethylsulfonamido)butanoate

  • Compound C16H16F3NO4S

    (S)-Methyl 4-(naphthalen-1-yl)-2-(trifluoromethylsulfonamido)butanoate

  • Compound C14H19BO4

    Methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

  • Compound C8H15NO3

    (R)-2-Acetamido-3,3-dimethylbutanoic acid

  • Compound C6H10F3NO4S

    (R)-Methyl 2-(trifluoromethylsulfonamido)butanoate

  • Compound C14H16F3NO6S

    (R)-Methyl 4-(4-methoxy-4-oxo-3-(trifluoromethylsulfonamido)butyl)benzoate

  • Compound C7H12F3NO4S

    (S)-Methyl 3-methyl-2-(trifluoromethylsulfonamido)butanoate

  • Compound C15H18F3NO6S

    Methyl 4-((3S)-4-methoxy-2-methyl-4-oxo-3-(trifluoromethylsulfonamido)butyl)benzoate

  • Compound C23H24F3NO8S

    (S)-Dimethyl 4,4'-(2-(2-methoxy-2-oxo-1-(trifluoromethylsulfonamido)ethyl)propane-1,3-diyl)dibenzoate

  • Compound C8H14F3NO4S

    (S)-Methyl 3,3-dimethyl-2-(trifluoromethylsulfonamido)butanoate

  • Compound C16H20F3NO6S

    (S)-Methyl 4-(4-methoxy-2,2-dimethyl-4-oxo-3-(trifluoromethylsulfonamido)butyl)benzoate

  • Compound C24H26F3NO8S

    (S)-Dimethyl 4,4'-(2-(2-methoxy-2-oxo-1-(trifluoromethylsulfonamido)ethyl)-2-methylpropane-1,3-diyl)dibenzoate

  • Compound C8H14F3NO4S

    (2S,3S)-Methyl 3-methyl-2-(trifluoromethylsulfonamido)pentanoate

  • Compound C16H20F3NO6S

    Methyl 4-((2R,3S)-2-ethyl-4-methoxy-4-oxo-3-(trifluoromethylsulfonamido)butyl)benzoate

  • Compound C6H10F3NO4S

    (R)-Methyl 2-methyl-3-(trifluoromethylsulfonamido)propanoate

  • Compound C12H14F3NO4S

    (R)-Methyl 2-benzyl-3-(trifluoromethylsulfonamido)propanoate

  • Compound C11H22F3NO3S

    N-(2-((tert-Butyldimethylsilyl)oxy)propyl)-1,1,1-trifluoromethanesulfonamide

  • Compound C17H26F3NO3S

    N-(2-((tert-Butyldimethylsilyl)oxy)-3-phenylpropyl)-1,1,1-trifluoromethanesulfonamide

  • Compound C12H16F3NO3S

    N-(3-(Benzyloxy)-2-methylpropyl)-1,1,1-trifluoromethanesulfonamide

  • Compound C18H20F3NO3S

    N-(2-Benzyl-3-(benzyloxy)propyl)-1,1,1-trifluoromethanesulfonamide

  • Compound C6H12F3NO2S

    1,1,1-Trifluoro-N-(2-methylbutyl)methanesulfonamide

  • Compound C12H16F3NO2S

    N-(2-Benzylbutyl)-1,1,1-trifluoromethanesulfonamide

  • Compound C8H8F3NO2S

    1,1,1-Trifluoro-N-(o-tolyl)methanesulfonamide

  • Compound C16H14F3NO4S

    Methyl 4-(2-(trifluoromethylsulfonamido)benzyl)benzoate

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

    • Kelvin S. L. Chan
    • , Masayuki Wasa
    • , Ling Chu
    • , Brian N. Laforteza
    • , Masanori Miura
    •  & Jin-Quan Yu

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jin-Quan Yu.

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https://doi.org/10.1038/nchem.1836

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