2H‑Indazoles by Condensation−Cadogan Reductive Cyclization

Significance

Reported is the one-pot synthesis of 2H-indazoles by the reaction of o-nitrobenz­aldehydes with anilines followed by treatment with tri-n-butylphosphine. The scope of the reaction is demonstrated by the use of a variety of benzaldehydes and aromatic or aliphatic amines. Nitrobenzaldehydes bearing both electron-donating (e.g., R¹ = 4-NMe₂, 4-OMe) and -withdrawing (e.g., R¹= 4-CF₃, 4-CN, 4-CO₂Me) groups are tolerated to form the corresponding 2H-indazoles. However, R¹= 3-OMe fails to form the product. Furthermore, a variety of anilines and aminopyridines (e.g. R² = 2,6-Me₂-4-ClC₆H₂, 3-F₃CC₆H₄, 2-py) are also successful reaction partners. When optically pure α-methyl benzylamine was employed, the reaction led to the desired product A with complete retention of stereochemistry.

Comment

Indazoles are a novel class of transient receptor potential A1 antagonists (L. Rooney et al. J. Med. Chem. 2014, 57, 5129). Several methods to construct 2H-indazoles are reported, including a copper salt promoted oxidative cyclization of ­aromatic alkynyl triazenes (Y. Fang, C. Wang, S. Su, H. Yu, Y. Huang Org. Biomol. Chem. 2014, 12, 1061). The present method uses the Cadogan reductive cyclization to form 2H-indazoles under mild reaction conditions. The report concluded that addition of tri-n-butylphosphine is required after the condensation reaction to afford the indazole without isolation of the imine intermediate.