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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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 7–13 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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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.
The authors declare no competing interests.
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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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