One-Pot Transition-Metal-Free Synthesis of Weinreb Amides Directly from Carboxylic Acids

Abstract

Weinreb amides were prepared directly from carboxylic acids, N,O-dimethylhydroxylamine, and phosphorus trichloride in one pot at 60 °C in toluene in high yields, thus avoiding the separation of the moisture and air sensitive intermediate P[NMe(OMe)] 3 in advance. Sterically hindered carboxylic acids also give the corresponding Weinreb amides in excellent yields. Various functional groups are tolerated on the carboxylic acid. The method, which is a simple process and gives high yields, is suitable for large-scale production.

The Direct Conversion of Esters to Ketones Enabled by a Traceless Activating Group

“…First is the use of Weinreb amides, which stabilize and prevent the breakdown of the initial tetrahedral adduct formed upon nucleophilic addition, thereby favoring ketone formation over tertiary alcohol formation. This has become the standard approach for the net conversion of esters to ketones; however, it generally involves three discrete steps: ester hydrolysis, amide bond formation, and then reaction with a nucleophile . A second strategy to control monoalkylation is the use of enolate nucleophiles to form 1,3-dicarbonyl products that are deprotonated under the reaction conditions, thereby preventing overaddition.…”