Elucidation of the Mechanism for the S - N-type Smiles Rearrangement on Pyridine Rings

Abstract

The Smiles rearrangement (SR) is an important strategy for synthesizing heterocyclic compounds. Many pyridine moiety-containing complexes are biologically active. Although the success has been archived in the development of the SR on the pyridine ring to obtain pyridine moiety-containing heterocyclic compounds, not much is known about the detailed SR mechanism. Here, we report a theoretical study on a typical S–N-type SR reaction involved in the synthesis of thiazinone-fused pyridines. We studied both the ipso-SR process and the direct nucleophilic substitution reactions on the ortho-positions to rationalize the experimentally observed ipso-SR product. The calculated results show the ipso-SR consists of two elementary steps, the intramolecular ipso-position substitution and subsequent ring closure, and the barrier for the rate-determining step is 65.98 kJ mol–1 and the overall reaction is exothermic by 116.94 kJ mol–1, confirming the reaction is kinetically feasible and thermodynamically favourable under mild experimental conditions (such as controlled microwave heating). The present results provide a clear picture for understanding the S–N-type SR on the pyridine ring to synthesize pyridine moiety-containing heterocycles.