Substituted Indazolobenzoxazines via One-Pot Intramolecular Bis-Heterocyclizations

Significance

Substituted indazolobenzoxazine B heterocycles have been synthesized from o-nitro derivative A by two sequential intramolecular heterocyclizations under basic conditions (KOH in alcoholic solvent) in one pot that presumably occurs via a nitroso imine intermediate. The intramolecular reaction is preferred to the competing intermolecular variant. In further reaction, the carboxylic acid at C9 position (indazole part of B) successfully underwent amidation with primary and secondary amines to give C in good yields. On the benzoxazine subunit of B, Sonogashira coupling was achieved successfully with terminal alkynes to give D, which upon 1,3-dipolar cyclo­addition reactions with three different nitroalkanes gave C5-substituted isoxazole derivative E.

Comment

Indazoles exhibit a wide range of biological activities, for example anti-angiogenic and antiviral (L.-J. Huang et al. Bioorg. Med. Chem. 2006, 14, 528; D. Kim et al. Bioorg. Med. Chem. Lett. 2001, 11, 3103). Benzo-1,3-oxazine derivatives also display biological activities including antianginal, antihypertensive, and antirheumatic (F. Benedini et al. J. Med. Chem. 1995, 38, 130; R. D. Clark et al. J. Med. Chem. 1983, 26, 657; H. Matsuoka et al. J. Med. Chem. 1997, 40, 105). Thus, it is envisioned that indazolobenzoxazines may show some biological importance. They have also been used in the doping of electroluminescent devices (Y. Sato, J. Murata JP 05311162, 1993). The current process is an intramolecular version of the previous findings by the same authors for the synthesis of 3-alkoxy-(2H)-indazoles from o-nitro­benzylamines via an N-N bond-forming hetero­cyclization reaction (A. D. Mills et al. J. Org. Chem. 2006, 71, 2687).