A new synthesis of 3-arylthioindoles as selective COX-2 inhibitors using PIFA

The direct 3-arylthiolation of 2-substituted indoles using phenyliodine(III)bis trifluoroacetate (PIFA) in (CF₃)₂CHOH with a wide variety of benzenethiols has been accomplished. In particular, indoles bearing a 6-MeSO₂ and either a 2-methyl or 2-carboxymethyl substituent could be 3-arylthiolated in good to excellent yields to afford the corresponding 3-arylthioindoles as selective COX-2 inhibitors. In a study varying the electronic nature of the 5-substituent of 2-CO₂Et indoles, it was discovered that the yield of the reaction improved as the substituent became more electron withdrawing. This result was consistent with a proposed mechanism involving benzenethiol displacement of an intermediate 3-IPh indole complex.