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Direct α-alkylation of primary aliphatic amines enabled by CO2 and electrostatics

Abstract

Primary aliphatic amines are important building blocks in organic synthesis due to the presence of a synthetically versatile NH2 group. N-functionalization of primary amines is well established, but selective C-functionalization of unprotected primary amines remains challenging. Here, we report the use of CO2 as an activator for the direct transformation of abundant primary aliphatic amines into valuable γ-lactams under photoredox and hydrogen atom transfer (HAT) catalysis. Experimental and computational studies suggest that CO2 not only inhibits undesired N-alkylation of primary amines, but also promotes selective intermolecular HAT by an electrostatically accelerated interaction between the in situ-generated negatively charged carbamate and the positively charged quinuclidinium radical. This electrostatic attraction overwhelms the inherent bond dissociation energies which suggest that HAT should occur unselectively. We anticipate that our findings will open up new avenues for amine functionalizations as well as selectivity control in HAT reactions.

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Fig. 1: Strategies for α-functionalization of aliphatic amines.
Fig. 2: Reaction development.
Fig. 3: Exploration of substrate scope.
Fig. 4: Mechanistic and computational studies.

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Acknowledgements

The authors acknowledge financial support from NIGMS (T.R., GM125206), as well as partial support from the Catalysis Collaboratory for Light-activated Earth Abundant Reagents (C-CLEAR), which is supported by the National Science Foundation and the Environmental Protection Agency through the Network for Sustainable Molecular Design and Synthesis programme (NSFCHE-1339674, T.R.). Calculations were performed with computing resources granted by JARA-HPC from RWTH Aachen University under project ‘jara0091’. The authors thank J. Owen (Columbia University) for the use of his fluorometer.

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T.R. and J.Y. conceived the concept. T.R. directed the investigation. J.Y. performed the experiments and analysed the data. I.K. and F.S. carried out computational studies. J.Y., T.R., I.K. and F.S. collated the data, discussed the implications and prepared the manuscript.

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Correspondence to Franziska Schoenebeck or Tomislav Rovis.

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Supplementary information

Supplementary information

Materials and methods, synthesis and characterization of products, Supplementary Figures 1–13, Supplementary Tables 1–6, NMR Spectra and computational details

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All computed structures that are included in the main Supplementary information file

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Ye, J., Kalvet, I., Schoenebeck, F. et al. Direct α-alkylation of primary aliphatic amines enabled by CO2 and electrostatics. Nature Chem 10, 1037–1041 (2018). https://doi.org/10.1038/s41557-018-0085-9

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