Breaking the regioselectivity rule for acrylate insertion in the Mizoroki–Heck reaction

Abstract

In modern methods for the preparation of small molecules and polymers, the insertion of substrate carbon–carbon double bonds into metal–carbon bonds is a fundamental step of paramount importance. This issue is illustrated by Mizoroki–Heck coupling as the most prominent example in organic synthesis and also by catalytic insertion polymerization. For unsymmetric substrates H2C = CHX the regioselectivity of insertion is decisive for the nature of the product formed. Electron-deficient olefins insert selectively in a 2,1-fashion for electronic reasons. A means for controlling this regioselectivity is lacking to date. In a combined experimental and theoretical study, we now report that, by destabilizing the transition state of 2,1-insertion via steric interactions, the regioselectivity of methyl acrylate insertion into palladium–methyl and phenyl bonds can be inverted entirely to yield the opposite "regioirregular" products in stoichiometric reactions. Insights from these experiments will aid the rational design of complexes which enable a catalytic and regioirregular Mizoroki–Heck reaction of electron-deficient olefins.