1,3-Dipolar cycloaddition reaction of indoles with tosyl azide, subsequent dehydroaromatization and ring-opening cascade: a computational study

The mechanism of the reaction of N-methylindoles with tosyl azide to afford 3-diazoindolin-2-imines and 2-iminoindolines has been studied computationally at the DFT M06/6-311G(d,p) level. The formation of 3-diazoindolin-2-imine is found to proceed via a concerted [3 + 2] addition followed by dehydroaromatization and subsequent ring opening rather than via a concerted [3 + 2] addition followed by ring opening and subsequent dehydroaromatization. The initial [3 + 2] cycloaddition is the rate-determining step with an activation barrier of 17.0 kcal/mol. The formation of 2-iminoindoline is also found to proceed via the initial [3 + 2] cycloaddition followed by a dinitrogen extrusion in a concerted fashion and subsequent 1,2-hydride shift. The rate-determining step for the formation of 2-iminoindoline is either the initial [3 + 2] cycloaddition or the dinitrogen extrusion depending on the nature of indole used. The two competing steps after the initial [3 + 2] cycloaddition are the dehydroaromatization and dinitrogen extrusion step. Dehydroaromatization of dihydrotriazoloindole with singlet oxygen molecule has a barrier of 1.9 kcal/mol and reaction energy of − 54.6 kcal/mol, while with triplet oxygen molecule has high activation barrier of 27.2 kcal/mol and reaction energy of 25.7 kcal/mol leading to the formation of radical intermediates (HOO· + A·). Dehydroaromatization in the absence of oxygen is thermodynamically and kinetically not feasible due to the high activation barrier of 97.5 kcal/mol associated with this process under this condition. Thus, the dehydroaromatization step is predicted to occur with singlet oxygen. Also, dehydroaromatization of dihydrotriazoloindole by singlet oxygen molecule is kinetically and thermodynamically favored over the dinitrogen extrusion by 15.4 kcal/mol and 43.4 kcal/mol, respectively. The low activation barrier of the dehydroaromatization step by singlet oxygen compared to the dinitrogen extrusion step means that 3-diazoindolin-2-imine would be formed solely under this condition, confirming the experimental observation of Sheng et al. (Org Lett 16(4):1244–1247, 2014). In inert atmosphere, 2-iminoindoline becomes viable because the activation barrier for the initial loss of H2 that is likely to lead to the formation of 3-diazoindolin-2-imine is 85.5 kcal/mol higher than the dinitrogen extrusion step for the formation of 2-iminoindoline.