Acyl phthalimides are important precursors for the formation of biologically active N, O-acetals and many acyl phthalimides possess anxiolytic, antibacterial, and antifungal properties essential in medicinal chemistry. Additionally, when reacted with primary amines, acyl phthalimides act as amide precursors for proteins, pesticides, and polymers. Traditional methods for the synthesis of acyl phthalimides have focused on the direct reaction of phthalimide with acyl chlorides and anhydrides as electrophiles. While such direct synthetic methods have been proven effective, they make use of highly reactive reagents that decompose readily in presence of water and have known toxicity and health deliberating effects. In the past decade, only one new methodology using an expensive rhodium catalyst for cross-acylation, has been developed to access acyl phthalimides. The design of metal-free reactions that make direct use of stable and commercially available carboxylic acids would represent a novel approach to the synthesis of acyl phthalimides. Herein, we present a method for the amination of carboxylic acids into acyl phthalimides using N-chlorophthalimide and triphenylphosphine. Inspired by the Mitsunobu reaction, we surmised that triphenylphosphine would react with N-chlorophthalimide to form the corresponding chlorophosphonium phthalimide salt, which would subsequently react with the carboxylic acid to form the desired acyl phthalimide and provide triphenylphosphineoxide as the only byproduct. Compared to traditional amide formation methodologies, this reaction does not require a secondary activating agent for the carboxylic acid, which makes it significantly more atom economical. Aliphatic, aromatic, benzylic, and allylic carboxylic acids were all observed to be suitable substrates for the reported methodology. Substrate scope, robustness of the reaction, as well as functional group compatibility and mechanistic work will be presented.

Direct acyl amide synthesis from carboxylic acids using N-haloimide reagents

2019 Spring National Meeting

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