Solid-phase synthesis of quinoxaline, thiazine, and oxazine analogs through a benzyne intermediate

A solid-phase synthetic route to quinoxaline, thiazine, and oxazine analogs is described. N-Alloc-3-amitio-3-(2,4-difluoro-5-nitrophenyl)propanoic acid was tethered to Rink resin via its carboxylic acid group. The 4-arylfluorine was displaced with a primary amine, alcohol, or thiol to create, respectively, a resin bound aniline, phenol, or thiophenol derivative with one diversity element and one single atom (e.g., N, S, or 0) diversity point. A fused heterocyclic system was subsequently created via a benzyne heterocyclization initiated by dehydrofluorination with strong base. Acid treatment released the desired products in high yield and moderate purity. (c) 2005 Elsevier Ltd. All rights reserved.