Regioselectivity of Michael additions to 3-(pyridin-3-yl or pyrimidin-2-yl)-propenoates and their N-oxides -: Experimental and theoretical studies

We demonstrate that nucleophilic addition to a, beta-unsaturated carbonyl compounds can be redirected from the usual beta-carbon (Michael) to an a-carbon re gio selectivity by attaching a pi-deficient aromatic substituent to the beta-carbon atom. In particular, propanethiol addition to 3-(pyridin-3-yl or pyrimidin-2-yl)propenoate gives a beta-carbon adduct, while addition to the corresponding more pi-deficient N-oxides gives the aadduct or a mixture of alpha- and beta-adducts. This adds to the number of carbon-carbon bond-forming reactions at the aposition of Michael receptors documented recently. Density functional calculations reveal that the re gio selectivity is due to a combination of reduction of the barrier for alpha-addition and increase of the barriers for beta-addition and carbonyl addition as the pi-deficient character of the aromatic substituent is increased. The calculations predict a significant solvent effect on the regioselectivity in some cases. The regioselectivity is also consistent with Hammett constants (T-. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005).