Journal
SYNTHESIS-STUTTGART
Volume 54, Issue 16, Pages 3595-3604Publisher
GEORG THIEME VERLAG KG
DOI: 10.1055/a-1817-1965
Keywords
amidation; N,N-dimethylformamide; carboxylic acid; potassium-tert-butoxide
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Funding
- National Natural Foundation of China [22071185]
- Fundamental Research Funds for the Central Universities [2042019kf0008]
- Wuhan University
- National Natural Science Foundation of China
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In this study, a practical and efficient KOtBu-facilitated amination of carboxylic acids with N,N-dimethylamine was described. This method is applicable for the transformation of various aliphatic and aromatic carboxylic acids and can be used for the late-stage dimethylamidation of complex drug molecules.
Herein a practical and efficient potassium tert-butoxide (KOtBu)-facilitated amination of carboxylic acids with N,N-dimethylamine is described. In the presence of catalytic amount of KOtBu, a variety of aliphatic and aromatic carboxylic acids are transformed to N,N-dimethylamides using DMF as the dimethylamine reagent with the assistance of trimethylacetic anhydride. The applicability of this protocol is demonstrated by late-stage dimethylamidation of complex drug molecules. A plausible reaction mechanism involving KOtBu-facilitated in situ amine generation from formamide decomposition and anhydride-mediated condensation is proposed on the basis of mechanistic investigations.
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