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A practical catalytic reductive amination of carboxylic acids.

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.

SUBMITTER: Stoll EL

PROVIDER: S-EPMC8161228 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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A practical catalytic reductive amination of carboxylic acids.

Stoll Emma L EL Tongue Thomas T Andrews Keith G KG Valette Damien D Hirst David J DJ Denton Ross M RM

Chemical science 20200812 35

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)<sub>2</sub>-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 ...[more]

PMID: 34123174

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