Direct Preparation of Amides from Amine Hydrochloride Salts and Orthoesters: A Synthetic and Mechanistic Perspective

Abstract

The conversion of a wide range of primary and secondary aliphatic and a few arylamine hydrochloride salts to their corresponding acetamides with trimethyl orthoacetate is described. Mechanistic studies using NMR and gas chromatography–mass spectrometry techniques indicate these reactions proceed via an O-methylimidate intermediate that undergoes in situ demethylation by chloride, affording the corresponding acetamides. Synthetically, this reaction represents a practical, high-yielding protocol with a simple workup for the rapid conversion of amine hydrochloride salts to acetamides.

GRAPHICAL ABSTRACT

Keywords:

• Acylation
• amides
• amine hydrochlorides
• imidate ion
• microwave heating
• orthoesters

ACKNOWLEDGMENT

The authors thank James A. Ciaccio for obtaining the GC-MS data and making helpful comments on the manuscript.

SUPPLEMENTAL MATERIAL

Full experimental details and IR, ¹H NMR, and HRMS data for this article can be accessed on the publisher’s website.