Synthesis and catalytic activity of imidazole analogues of pyrroloquinoline quinone (PQQ).

摘要

Pyrroloquinoline quinone (PQQ, methoxatin, 4,5-dihydro-4,5-dioxo-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxilic acid) is an oxido-reduction cofactor found in methylotropic bacteria. In mammals PQQ shows interesting vitamin-like properties. Earlier studies in our laboratory indicated that pyrrole ring isomers of PQQ, although presenting some useful catalytic properties, undergo rapid inactivation during the catalytic cycle. These findings led us to undertake the synthesis of imidazole analogues of this important prokaryotic cofactor. Our goal was to synthesize a series of imidazole analogues having different substituents at the 2-position and to compare the catalytic activity and inactivation kinetics of these compounds with those of analogues prepared earlier. The same general route was applied to the synthesis of the three imidazole analogues. Nitration of 2-methoxy-4-nitroaniline gave 2-methoxy-4,6-dinitroaniline which was then selectively reduced to yield 2-amino-6-methoxy-4-nitroaniline. The required 2-substituted imidazole could be obtained from condensation with either ethyl triethoxyacetate, acetic acid or formic acid to yield ethyl 6-nitro-4-methoxybenzimidazole-2-carboxylate, 6-nitro-4-methoxy-2-methylbenzimidazole or 6-amino-4-methoxybenzimidazole, respectively. After hydrogenation of the remaining nitro groups, the pyridine rings were assembled using the Doebner-von Miller conditions to generate 2-ethoxycarbonyl-4-methoxy-7,9-dimethoxycarbonyl-1H-imidazolo[5,4-f]quinoline, 4-methoxy-7,9-dimethoxycarbonyl-2-methyl-1H-imidazolo[5,4-f]quinoline and 4-methoxy-7,9-dimethoxycarbonyl-2H-imidazolo[5,4-f]quinoline. Cleavage of the methoxy groups required heating the compounds under vigorous reflux in 33% HBr in glacial acetic acid. The resulting phenols were oxidized to the quinone by Fremy's salt. The target compounds, potassium 4,5-dihydro-4,5-dioxo-2-methyl-1H-imidazolo[5,4-f]quinoline-7,9-dicarboxylate, potassium 4,5-Dihydro-4,5-dioxo-1H-imidazolo[5,4-f]quinoline-7,9-dicarboxylate and potassium 4,5-dihydro-4,5-dioxo-1H-imidazolo[5,4-f]quinoline-2,7,9-tricarboxylate were finally obtained after saponification of the corresponding esters. The trimethyl or dimethyl ester of the three newly synthesized imidazole analogues of PQQ were then assessed for catalytic activity. They all showed activity when used as catalysts in the aerobic autorecycling oxidation of benzylamine into benzaldehyde. 2,7,9-Trimethoxycarbonyl-1H-imidazolo[5,4-f]quinoline-4,5-dione was a good catalyst, whereas 7,9-dimethoxycarbonyl-2-methyl-1H-imidazolo[5,4-f]quinoline-4,5-dione and 7,9-dimethoxycarbonyl-1H-imidazolo[5,4-f]quinoline-4,5-dione underwent inhibition after one hour of reaction. None of the compounds synthesized in this study presented a catalytic activity as good as PQQ.