2,3-Dihydro-1H-indazoles by Rhodium Catalysis

Significance

The rhodium-catalyzed reaction of arylhydrazines 1 with olefins 2 to provide 2,3-dihydro-1H-indazoles 3 via a Heck-type reaction followed by an intramolecular Michael addition is reported. The reaction was optimized in terms of catalyst, additive, solvent, reaction time, and temperature. A control experiment established that the presence of catalyst and oxidant is crucial for the reaction to occur. The reaction scope was studied, and many electron-withdrawing olefins were tested. Moderate yields of products were obtained when bulky alkenes were used. Substitution in the arylhydrazine moiety 1 did not significantly change the reaction yield, and olefins with electron-withdrawing and -donating substituents can be used. However, a drastic decrease of the yield was observed when an ortho substituent was present. Changes of the N-protecting group to Et and n-Bu also decreased the yield. The final products 4 and 5 were obtained by a deprotection protocol involving the reaction of the respective compound 3 with 2 M HCl in EtOH for 30 minutes.

Comment

The synthesis of the indazole motif is currently studied due to the importance of this type of heterocycle and its wide biological activities. Traditional synthetic routes to indazoles usually involve condensation and metal-catalyzed intramolecular amination of arylhydrazones. In this work, advantage is taken of a rhodium-catalyzed process to promote C–H bond activation followed by C–N bond formation as the principal step to afford the indazole ring system. The starting materials are prepared by a well-established procedure which involves the reaction of aryl-substituted amines with NaNO₂, SnCl₂, and HCl in H₂O. The reaction scope was well studied. The major limitation of this method is the poor result observed for ortho-substituted acyl arylhydrazones, showing that steric hindrance plays an important role in the process.