A Practical Catalytic Reductive Amination of Carboxylic Acids

Stoll, Emma; Tongue, Thomas; Andrews, Keith G.; Valette, Damien; Hirst, David J.; Denton, Ross Matthew

Abstract

We report reductive alkylation reactions of amines using carboxylic acids as nominal electrophiles. The two-step reaction exploits the dual reactivity of phenylsilane and involves a silane-mediated amidation followed by a Zn(OAc)2-catalyzed amide reduction. The reaction is applicable to a wide range of amines and carboxylic acids and has been demonstrated on a large scale (305 mmol of amine). The rate differential between the reduction of tertiary and secondary amide intermediates is exemplified in a convergent synthesis of the antiretroviral medicine maraviroc. Mechanistic studies demonstrate that a residual 0.5 equivalents of carboxylic acid from the amidation step is responsible for the generation of silane reductants with augmented reactivity, which allow secondary amides, previously unreactive in zinc/phenylsilane systems, to be reduced.

Citation

Stoll, E., Tongue, T., Andrews, K. G., Valette, D., Hirst, D. J., & Denton, R. M. (2020). A Practical Catalytic Reductive Amination of Carboxylic Acids. Chemical Science, 11(35), 9494-9500 . https://doi.org/10.1039/d0sc02271c

• Journal Article Type: Article
• Acceptance Date: Aug 12, 2020
• Online Publication Date: Aug 12, 2020
• Publication Date: Sep 21, 2020
• Deposit Date: Aug 20, 2020
• Publicly Available Date: Aug 20, 2020
• Journal: Chemical Science
• Print ISSN: 2041-6520
• Electronic ISSN: 2041-6539
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Issue: 35
• Pages: 9494-9500
• DOI: https://doi.org/10.1039/d0sc02271c
• Public URL: https://nottingham-repository.worktribe.com/output/4831352
• Publisher URL: https://pubs.rsc.org/en/content/articlelanding/2020/sc/d0sc02271c#!divAbstract