Synthesis of 2-Phosphorus-Substituted Indoles via Ring Expansion of Benzocyclobutenone Oxime Sulfonates.

A method for the synthesis of 2-phosphorus-substituted indoles via ring expansion of benzocyclobutenone oxime sulfonates, which were prepared via the [2 + 2] cycloaddition of benzynes and ketene acetals, and subsequent oximization and sulfonylation was developed. The reaction occurs by addition of the phosphate anion or phosphine oxide anion to the C═N bond of oxime sulfonates, followed by ring expansion to provide 2-phosphorus-substituted indoles. This method was applicable to the synthesis of 2-phosphorus-substituted indoles with a wide variety of substitution patterns on the benzene ring and at the 3-position, as well as to a 2-phosphorus-substituted 4-aza-indole. An indol-2-ylphosphonic acid and a 2-phosphaneylindole were obtained by a transformation of the corresponding products. This protocol was applied to synthesize a duocarmycin SA phosphonate analogue, which exhibited greater cytotoxicity against HeLa S3 and KPL-4 cells than duocarmycin SA.