Multi-component coupling reactions of aldehydes and amides with maleic anhydride: synthesis of 7-oxo-6-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acids

A new protocol for the synthesis of a series of 7-oxo-6-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acids from simple aldehydes, amides and maleic anhydride was developed. Key step is an efficient three-component coupling reaction of two molecules of aldehyde with an amide to give a 1-acylamino-1,3-butadiene derivative which easily undergoes Diels–Alder addition to maleic anhydride. Thermic rearrangement of the cycloadducts affords the bicyclic target compounds. The new one-pot protocol gives higher yields than standard multi-step sequences due to the selective in situ trapping of one acylamino diene isomer. The target compounds can be further elaborated into arenes, cage molecules and natural product precursors.