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α-Branched amines by catalytic 1,1-addition of C–H bonds and aminating agents to terminal alkenes

Abstract

α-Branched amines are present in hundreds of pharmaceutical agents and clinical candidates and are important targets for synthesis. Here, we show the convergent synthesis of α-branched amines from three readily accessible starting materials: aromatic C–H bond substrates, terminal alkenes and aminating agents. This reaction proceeds by an intermolecular formation of C–C and C–N bonds at the sp3 carbon branch site through an uncommon 1,1-alkene addition pathway. The reaction is carried out under mild conditions and has high functional group compatibility. Ethylene and propylene feedstock chemicals are effective alkene inputs, with ethylene in particular providing for the one-step synthesis of α-methyl branched amines, a motif prevalent in drug structures. The reaction is scalable and 1% loading of an air-stable dimeric rhodium precatalyst is effective for several different types of products. The use of chiral catalysts also enables the asymmetric synthesis of α-branched amines.

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Fig. 1: α-Branched amines.
Fig. 2: Aminating agent and C–H bond substrate scope for α-branched amine synthesis.
Fig. 3: Alkene scope for the modular synthesis of α-branched amines.
Fig. 4: Use of feedstock alkenes and asymmetric synthesis.
Fig. 5: Proposed catalytic cycle.
Fig. 6: Mechanistic experiments.

Data availability

Much of the data that support the results of this study are available in the Supplementary Information. Additional data are available from the corresponding author upon reasonable request. X-ray crystal data for structure 62 that established its absolute configuration are shown in Supplementary Fig. 9, Supplementary Tables 713 and are available free of charge from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/) under reference no. CCDC 1903974.

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Acknowledgements

This work was supported by the NIH (R35GM122473). The authors thank B. Mercado (Yale University) for solving the crystal structure of 62 and E. Paulson (Yale University) for stereochemical assignment of 64 using NMR methods.

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Authors

Contributions

S.M. and T.J.P. developed the reaction conditions, completed the scope and designed mechanistic experiments. S.M. co-prepared the manuscript with T.J.P. J.A.E. co-conceived the concept and co-prepared the manuscript with feedback from S.M. and T.J.P.

Corresponding author

Correspondence to Jonathan A. Ellman.

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Supplementary information

Supplementary Information

Supplementary Tables 1–13, Supplementary Figs, 1–9, Supplementary methods, Supplementary references

compound 62

Crystallographic Data for compound 62.

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Maity, S., Potter, T.J. & Ellman, J.A. α-Branched amines by catalytic 1,1-addition of C–H bonds and aminating agents to terminal alkenes. Nat Catal 2, 756–762 (2019). https://doi.org/10.1038/s41929-019-0330-7

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