Reactions of Substituted (Methylthio)benzylidene Meldrum's Acids with Secondary Alicyclic Amines in Aqueous DMSO. Evidence for Rate-Limiting Proton Transfer

Abstract

The replacement of the methylthio group of substituted methylthiobenzylidene Meldrum's acids (2-SMe-Z) by secondary alicyclic amines occurs by a three-step mechanism. The first step is a nucleophilic attachment of the amine to 2-SMe-Z to form a zwitterionic intermediate T(+/-)(A); the second step involves deprotonation of T(+/-)(A) to form T(-)(A); while the third step represents general acid-catalyzed conversion of T(-)(A) to products. At high amine and/or high KOH concentration nucleophilic attachment is rate limiting. At low amine and low KOH concentration the reaction follows a rate law that is characteristic for general base catalysis which, in principle, is consistent with either rate-limiting deprotonation of T(+/-)(A) or rate-limiting conversion of T(-)(A) to products. A detailed structure-reactivity analysis indicates that for the reactions with piperazine, 1-(2-hydroxyethyl)piperazine, and morpholine it is deprotonation of T(+/-)(A) that is rate limiting, while for the reaction with piperidine, conversion of T(-)(A) to products is rate limiting.