Production of Pyridine Synthons by Biotransformations of Benzene Precursors and Their Cyclization with Nitrogen Nucleophiles

Biotransformation of benzene and derivatives has been used to accumulate meta-ring fission products of several catechols, including catechol, 3- and 4- methylcatechols, and 3- (trifluoromethyl) catechol. Dilute solutions of these yellow highly absorbing products were used to examine reaction conditions that affect their facile cyclizations with nitrogen nucleophiles, principally NH₃. The effects of NH₄⁺/NH₃ concentration, pH and temperature on the non-enzymic cyclizations of 2-hydroxymuconic semialdehyde to 2-picolinate and its substituted derivatives have been characterised. As expected, the enzymic product from 3-(trifluoromethyl) catechol cyclised 20 times more slowly than that from 3-methylcatechol under identical reaction conditions. Most of the biological and chemical transformations were studied in very dilute solutions for the convenience of optical absorbance measurements. Because of the known sensitivity of the spectral shifts and extinction coefficients to minor changes in pH between 4 and 8 both of the pyridine synthons (vinylogous β-dicarbonyls) generated by ring cleavage of the catechols and of the 2-picolinates, the pK_a values were determined for the pH-dependent tautomeric shifts of the reactants and products so that reasonably accurate assessments of the stoichiometries of the cyclizations could be made. The yield of pyridines from the ring cleavage synthons was usually 71 to 95 per cent. Other nitrogen nucleophiles (methylamine, hydroxylamine, hydrazine and phenylhydrazine) also reacted with the ring-fission products but the putative N-substituted 2-picolinates were not characterised.