Model Reactions Which Establish a Facile Reduction of Pyridoxal Phosphate and Analogs by 1,4-Dihydropyridines

A kinetic study of the reaction of pyridine-4-carboxaldehydes with 1,4-dihydropyridines is reported. 3-Hydroxypyridine-4-carboxaldehyde (PyrCHO), but not pyridine-4-carboxaldehyde, is reduced to the corresponding alcohol by N¹-(n-propyl)-1,4-dihydronicoiinamide (NPrNH) in refluxing methanol. Under the same conditions, PyrCHO and pyridoxal are reduced by 2,6-dimethyl-3,5-dicarboethoxy-1,4-dihydropyridine (Hantzsch ester, HE). Pyridoxal phosphate (pyridoxal-P) and pyridoxal are readily reducible by HE and NPrNH in ca. 50% aqueous methanol at 30°. The apparent second-order rate constants for the reaction of HE with pyridoxal are comparable at 30° in aqueous methanol and in boiling neat methanol. Inclusion of 5 × 10^-3 M EDTA or 1.2 × 10^-3 M hydroquinone in buffered aqueous methanol reaction mixtures of NPrNH and pyridoxal-P did not influence the rate, and nmr product analysis of the reaction of HE and pyridoxal in both refluxing CH₃OD and 48% CH₃OD-D₂O (30°) established solvent deuterons not to be incorporated into product pyridoxine. These results establish the reduction to be a non-free-radical mediated direct hydrogen transfer from dihydropyridine to aldehyde which does not require trace metals as catalysts. In separate experiments, metal ion catalysis of the reduction of pyridoxal-P and PyrCHO by HE was established. The order of metal ion catalysis (Ni²⁺ > Co²⁺ > Zn²⁺ > Mn²⁺ > Mg²⁺ > 0) was found to be that previously established for complexation to pyridine and salicylaldehyde (Brewer, D. G., and Wong, P. T. T. (1966), Can. J. Chem. 44, 1407; Mellor, D. P. and Maley, L. (1947), Nature (London) 159, 370; Martell, A. E., and Calvin, M. (1952), “Chemistry of the Metal Chelate Compounds,” New York, N. Y., Prentice-Hall, p 546). From the pH dependence of the apparent second-order rate constants for the reaction of pyridoxal-P with HE and NPrNH, the individual second-order rate constants for reduction of the various ionic species of pyridoxal-P were calculated. The rates of dihydropyridine reduction were found to parallel the rates of imine formation (Auld, D. S., and Bruice, T. C. (1967a), J. Amer. Chem. Soc. 89, 2083) and transamination (Auld, D. S., and Bruice, T. C. (1967b), J. Amer. Chem. Soc. 89,2090) for like ionic species (Table VI).