Amine Activation: ?Inverse? Dipeptide Synthesis and Amide Function Formation through Activated Amino Compounds

A copper(II)/HOBt-catalyzed procedure for the synthesis of dipeptides and general amides has been developed using microwave irradiation to considerably hasten the reaction. As an alternative to using traditional carboxylic acid activation, the method relies on the use of N-acyl imidazoles as activated amino partners. By doing so, a nonconventional way to reach dipeptides and amides has been proposed through the challenging and less studied N-* C direction synthesis. A series of dipeptides and general amides have been successfully synthesized, and the applicability of the method has been illustrated in gram-scale syntheses. The mild reaction conditions proposed are completely adequate for couplings in the presence of sensitive amino acids, affording the products without detectable racemization. Furthermore, experimental observations prompted us to propose a plausible reaction pathway for the couplings.

Automated summary

A copper(II)/HOBt-catalyzed microwave-assisted synthesis method for dipeptides and general amides has been developed. Instead of traditional carboxylic acid activation, the method utilizes N-acyl imidazoles as activated amino partners, providing a nonconventional approach for the synthesis of dipeptides and amides through the less studied N-* C direction. The method has been successfully applied in the synthesis of various dipeptides and amides on a gram-scale, and the mild reaction conditions allow for coupling reactions with sensitive amino acids without racemization. Experimental observations have led to the proposal of a plausible reaction pathway for the couplings.