Addition of Azoles and Amines to Unsymmetrical Fumaric Esters

The regioselectivity of nucleophilic addition of azoles to unsymmetrical fumarates yielding the corresponding (+/-)-2-azol-1-ylsuccinates has been studied. The major regioisomer has been identified as the one obtained from the attack of the azole to the more congestive side of the double bond. These results have been interpreted in terms of HOMO-LUMO interactions using semiempirical AM1 molecular orbital calculations. Addition of amines as alternative heteronucleophiles has been also explored to confirm the regioselectivity. Neutral hydrolysis of the two n-butyl ethyl (+/-)-2-imidazol-1-ylsuccinate regioisomers 8a and 8b has shown that this hydrolysis takes place faster than with the corresponding symmetrical di-n-butyl (+/-)-2-imidazol-1-ylsuccinate, and the apparent rate of hydrolysis is independent of the size of the alcohol moiety.