KINETICS AND MECHANISM OF THE CYCLIZATION OF SUBSTITUTED N-PHENYL-2-METHYL-2-(2-AMINOPHENYL)PROPANAMIDES AND ANALOGS

The cyclization of six N-aryl-2-(2-aminophenyl)alkylamides has been st udied at various pH values. Compounds 1a, 2a and 3a had a similar leav ing group (4-methoxyaniline) and varying degrees of steric bulk adjace nt to the amide, while compounds 1a-1d had varying substituents on the leaving amine. The cyclization of all the compounds was found to be s ubject to general catalysis by acidic buffer components, with the buff er-independent pH profiles obeying the equation k(0) = k(H3O+.) [H3O+] + k(H2O). Bronsted analysis of the rate coefficients for buffer catal ysis gave alpha values of ca. 0.4 for all compounds. The relative obse rved pseudo-first-order rate coefficients at pH 6.6 for compounds 3a, 2a and 1a were 1, 9 and 800, respectively, indicating the importance o f 'stereopopulation control' (Milstein and Cohen, J. Am. Chem. Soc., 1 972, 94, 9158) on the rate of cyclization. However, cyclization rates were found to be independent of the electronic properties of the leavi ng amine. The mechanism of cyclization was considered to be rate-deter mining, concerted attack by the neutral amine, followed by proton tran sfer from a general acid to the amide oxygen.