A facile access to natural and unnatural dialkylsubstituted maleic anhydrides

A facile new route to the potential building blocks 2-bromomethyl-3-alkylmaleic anhydrides for the synthesis of natural and unnatural dialkylsubstituted maleic anhydrides has been demonstrated, starting from dimethyl citraconate () via NBS-bromination, SN2′ Grignard coupling reactions, hydrolysis, molecular bromine addition and dehydrative ring closure reactions pathway with 49–51% overall yield in 5-steps. Chemoselective allylic substitution of bromoatom in with Grignard reagents has been described to obtain the unsymmetrical maleic anhydride and symmetrically dialkylsubstituted maleic anhydrides in 55% yield. The naturally occurring 2-carboxymethyl-3-hexylmaleic anhydride () has been synthesized from via esterification, ozonolysis and an oxidation route. The synthesis of two naturally occurring 2-(β-carboxyethyl)-3-alkylmaleic anhydrides have been completed via a chemoselective diethylmalonate coupling reaction followed by acid induced hydrolysis. In our hands the SN2 or SN2′ coupling of Grignard reagent with to obtain and Reformatsky reaction with to obtain met with failure.