Synthesis of Indoles via Oxidative Coupling of Acetanilides with Acetylenes

Significance

Reported here is the rapid synthesis of indoles 3 via the rhodium-catalyzed oxidative coupling of acetanilides 1 and internal alkynes 2. Extensive optimization with regard to the catalyst, additives and solvent led to the preferred conditions detailed above. Both electron-rich and -deficient acetanilides participate well in the reaction. Substrates bearing an ortho-substituent are also tolerated. When a meta-substituent is present, cyclization is directed to the least sterically hindered position. Experiments to probe the reaction mechanism using deuterated substrates and solvents suggest that initial rhodation on the aniline occurs at both ortho-positions, and that only the least hindered regioisomer undergoes ­cyclization to give the observed regioselectivity. Removal of the acetyl group was achieved in >90% yield in all cases on standard treatment with KOH or K₂CO₃ in MeOH-CH₂Cl₂.