A detailed investigation into the oxidation mechanism of Hantzsch 1,4-dihydropyridines by ethyl #alpha#-cyanocinnamates and benzylidenemalonontriles

摘要

The mechanism for the oxidation of Hantzsch 1,4-dihydropyridine (HEH) by substituted ethyl #alpha#-cyanocinnamates (1) and benzyldenemalononitriles (2) has been critically investigated. Replacement of HEH by HEH-4,4-d_2 and HEH-N-d gave the observed kinetic isotope effects (KIE) of 5.3-6.0 and 1.2-1.3 for the reactions wiht 1 and 2, respectively, which suggests C_4-H bond dissociation is involved in the rate-limiting step and that the N-H bond dissociation is a non-limittin g step. The positive #rho# values of 1.78 and 1.67 for the reactions of HEH with 1 and 2 , respectively, clearly demonstrate the electrophilic nature of the substrates in the transition state (TS) and so indicate that the hydrogen lost form HEH must be a hydride-like species. Correlation analyses on the kinetics, KIE's and activation parameters showed excellent linear dependence on the electronic properties of remote substituents and added further credence to the proposed one-step hydride transfer mechanism. Detailed investigation of the activation parameters not only confirmed the direct H_T~- mechanism, but also revealed experimentally, for the first time, an entropy-controlled compact TS for the HEH-modeled NAD(P)H oxidations.