N-Alkylation by Hydrogen Borrowing: Pharmaceutical Applications and Comparison with Other Methods

Anju Nalikezhathu; Travis J. Williams

doi:10.1055/a-2646-8383

Synthesis, Table of Contents

Synthesis 2025; 57(20): 2893-2908
DOI: 10.1055/a-2646-8383

Short Review

N-Alkylation by Hydrogen Borrowing: Pharmaceutical Applications and Comparison with Other Methods

Authors

Anju Nalikezhathu

¹Medicinal Chemistry, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States (Ringgold ID: RIN4355)
Travis J. Williams

²Donald P. and Katherine B. Loker Hydrocarbon Institute, Wrigley Institute for Environment and Sustainability, and Department of Chemistry, University of Southern California, Los Angeles, CA, United States (Ringgold ID: RIN5116)

Abstract

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Abstract

Formation of C–N bonds is a quintessential transformation in organic synthesis. Among the various methods to access them, hydrogen borrowing catalysis offers a green, atom-economical, and cost-effective approach, with water being the sole by-product. In this reaction, amines are alkylated using alcohol coupling partners in the presence of a transition metal catalyst. Several catalytic systems have been developed and utilized in the synthesis of pharmaceutical intermediates and complex natural products, thereby replacing conventional amination reactions with hydrogen borrowing reactions that deliver improved selectivity and yield. In this short review, we compare hydrogen borrowing N-alkylation with other classical and modern C–N bond forming reactions and discuss applications in pharmaceutical synthesis.

Keywords

N-alkylation - Hydrogen borrowing - Amine alkylation - C–N bond formation - Natural products - Pharmaceutical intermediates - Catalysis

Full Text

References

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