Abstract
A general procedure for the synthesis of amides via the direct condensation of carboxylic acids and amines in the presence of TiCl4 is reported. The amidation reaction was performed in pyridine at 85 °C with a wide range of substrates providing the corresponding amide products in moderate to excellent yields and high purity. The reaction proceeds with low yields when both the carboxylic acid and the amine are sterically hindered. The process takes place with nearly complete preservation of the stereochemical integrity of chiral substrates.
Highlights
Amide is a key functional group in organic chemistry for its widespread occurrence in peptide and non-peptide natural products, therapeutic small molecules, and new polymeric materials [1,2,3,4].The most general way for obtaining amides involves the activation of the carboxylic function by means the conversion of carboxylic acids into the corresponding acid chlorides [5,6,7,8]
We report the successful TiCl4-mediated synthesis of secondary and tertiary amides starting from various carboxylic acid and amine precursors
Optimization of amidation reaction conditions was performed by choosing benzoic acid as model substrate
Summary
Amide is a key functional group in organic chemistry for its widespread occurrence in peptide and non-peptide natural products, therapeutic small molecules, and new polymeric materials [1,2,3,4].The most general way for obtaining amides involves the activation of the carboxylic function by means the conversion of carboxylic acids into the corresponding acid chlorides [5,6,7,8]. The use of Zirconium(IV) catalysts for the direct amidation of carboxylic acids and amines was reported [17]. Both aliphatic and aromatic carboxylic acids were converted in secondary and tertiary amides in 62–99% yield with 2–10 mol% catalyst loading.
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