Regioselectivity and steric effects in the phosphorus oxychloride -mediated synthesis of methyl substituted dibenzo naphthyridines

The reaction of m-toluidine with malonic acid in the presence of phosphorus oxychloride predominantly yielded
the 5-methyl isomer (1a), with minor formation of the 7-methyl isomer (1b). Density functional theory (DFT)
calculations at the B3LYP/6-311++G(d,p) level showed that the 7-methyl isomer is thermodynamically more stable by 6.59 kcal mol⁻¹, indicating that the experimentally favored 5-methyl isomer forms under kinetic control. The preferential formation of 1a is attributed to steric and kinetic effects during cyclization. Owing to the inseparability of the two isomers, subsequent reactions afforded mixtures of angular and linear dibenzo- naphthyridines, characterized by ¹H NMR and confirmed by GC–MS analysis. Overall, this study provides insight into the regioselectivity and steric effects governing dibenzo-naphthyridine formation, highlighting a case where kinetic control overrides thermodynamic stability.