Mechanism of Akaline Cyclization of 2- (Substitution Benzamido)Benzamides to 4-Quinazolinones

The title amides cyclize rapidly to the corresponding quinazolin-4-ones in aqueous alkaline solution at 25 degrees C; the pseudo-first-order rate constants fit the empirical equation k(obs) = k(max) [OH-]/K-m + [OH-] + [OH-]K-2(m')) where K-m' is essentially zero for all except the 4-nitro species. The value of K-m measures the ionization of the neutral amide 1 to nonproductive conjugate base 2. Studies of the cyclization in alkali of 2-benzamido-N-methylbenzamide (1i) and 2-(N-methylbenzamido)benzamide (1j) indicate that 7 carries over 99% of the reaction flux and that the tautomer 8 does not contribute significantly. The ratio k(max)/K-m, is a composite rate constant first order in 1 and first order in [OH-]. The value of the Hammett rho for k(max)/K-m (0.67) is consistent with the above scheme where decomposition of 7 is rate limiting.