Abstract

Direct C(sp3)–C(sp2) bond formation under transition-metal-free conditions offers an atom-economical, inexpensive and environmentally benign alternative to traditional transition-metal-catalysed cross-coupling reactions. A new chemo- and regioselective coupling protocol between 3-aryl-substituted-1,1-diphenyl-2-azaallyl derivatives and vinyl bromides has been developed. This is the first transition-metal-free cross-coupling of azaallyls with vinyl bromide electrophiles and delivers allylic amines in excellent yields (up to 99%). This relatively simple and mild protocol offers a direct and practical strategy for the synthesis of high-value allylic amine building blocks that does not require the use of transition metals, special initiators or photoredox catalysts. Radical clock experiments, electron paramagnetic resonance studies and density functional theory calculations point to an unprecedented substrate-dependent coupling mechanism. Furthermore, an electron paramagnetic resonance signal was observed when the N-benzyl benzophenone ketimine was subjected to silylamide base, supporting the formation of radical species upon deprotonation. The unique mechanisms outlined herein could pave the way for new approaches to transition-metal-free C–C bond formations.

  • Compound

    (E)-N-(1,3-diphenylallyl)-1,1-diphenylmethanimine

  • Compound

    (E)-1,1-diphenyl-N-(3-phenyl-1-(p-tolyl)allyl)methanimine

  • Compound

    (E)-N-(1-(4-methoxyphenyl)-3-phenylallyl)-1,1-diphenylmethanimine

  • Compound

    (E)-N-(1-(4-fluorophenyl)-3-phenylallyl)-1,1-diphenylmethanimine

  • Compound

    (E)-N-(1-(4-chlorophenyl)-3-phenylallyl)-1,1-diphenylmethanimine

  • Compound

    (E)-N-(1-(3,5-difluorophenyl)-3-phenylallyl)-1,1-diphenylmethanimine

  • Compound

    (E)-N-(1-(3,5-bis(trifluoromethyl)phenyl)-3-phenylallyl)-1,1-diphenylmethanimine

  • Compound

    (E)-1,1-diphenyl-N-(3-phenyl-1-(o-tolyl)allyl)methanimine

  • Compound

    (E)-1,1-diphenyl-N-(3-phenyl-1-(pyridin-2-yl)allyl)methanimine

  • Compound

    (E)-1,1-diphenyl-N-(3-phenyl-1-(pyridin-3-yl)allyl)methanimine

  • Compound

    (E)-1,1-diphenyl-N-(3-phenyl-1-(thiophen-2-yl)allyl)methanimine

  • Compound

    (E)-N-(3-(4-(tert-butyl)phenyl)-1-phenylallyl)-1,1-diphenylmethanimine

  • Compound

    (E)-N-(3-(4-methoxyphenyl)-1-phenylallyl)-1,1-diphenylmethanimine

  • Compound

    (E)-N-(3-(4-fluorophenyl)-1-phenylallyl)-1,1-diphenylmethanimine

  • Compound

    (E)-1,1-diphenyl-N-(1-phenyl-3-(4-(trifluoromethyl)phenyl)allyl)methanimine

  • Compound

    (E)-N-(3-(3-methoxyphenyl)-1-phenylallyl)-1,1-diphenylmethanimine

  • Compound

    (E)-1,1-diphenyl-N-(1-phenyl-3-(3-(trifluoromethyl)phenyl)allyl)methanimine

  • Compound

    (E)-1,1-diphenyl-N-(1-phenyl-3-(o-tolyl)allyl)methanimine

  • Compound

    N-(3-methyl-1-phenylbut-2-en-1-yl)-1,1-diphenylmethanimine

  • Compound

    N-(2-cyclohexylidene-1-phenylethyl)-1,1-diphenylmethanimine

  • Compound

    (E)-3-phenyl-1-(thiophen-2-yl)prop-2-en-1-amine

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Acknowledgements

The authors acknowledge the National Science Foundation (CHE-1464744 to P.J.W. and CHE-1464778 to M.C.K.) and the National Institutes of Health (GM-104349 to P.J.W. and GM-087605 to M.C.K.) for financial support. J.A. acknowledges support from Ministerio de Educación, Cultura y Deporte, Subprograma Estatal de Movilidad, Salvador de Madariaga. Computational support was provided by XSEDE on SDSC Gordon (TG-CHEM120052). This work was also financially supported by a SICAM Fellowship by Jiangsu National Synergetic Innovation Center for Advanced Materials. The authors thank S. Montel of UPenn and K. Scheidt of Northwestern University for discussions.

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Affiliations

  1. Department of Chemistry, Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104, USA

    • Minyan Li
    • , Osvaldo Gutierrez
    • , Simon Berritt
    • , Ana Pascual-Escudero
    • , Ahmet Yeşilçimen
    • , Xiaodong Yang
    • , Javier Adrio
    • , Georgia Huang
    • , Marisa C. Kozlowski
    •  & Patrick J. Walsh
  2. Department of Biochemistry and Biophysics, EPR Laboratory, University of Pennsylvania, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA

    • Eiko Nakamaru-Ogiso
  3. Institute of Advanced Synthesis (IAS), School of Chemistry and Molecular Engineering (SCME), Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing Tech University (Nanjing Tech), 30 South Puzhu Road, Nanjing 211816, China

    • Patrick J. Walsh

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Contributions

M.L. and P.J.W. conceived and designed the experiments. M.L., S.B., A.P.-E., A.Y., X.Y., J.A. and G.H. performed the research. O.G. and M.C.K. designed and performed the DFT computational study. M.L. and E.N.-O. performed the EPR study. M.L., O.G., M.C.K. and P.J.W. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Marisa C. Kozlowski or Patrick J. Walsh.

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DOI

https://doi.org/10.1038/nchem.2760

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