SOLID-PHASE SYNTHESIS OF BENZOPIPERAZINONES

This article describes an efficient method for the solid phase synthes is of benzopiperazinones (1,2,3,4-tetrahydroquinoxalin-2-ones) with fo ur independently variable functional groups. Commercially available. 4 -fluoro-3-nitrobenzoic acid (FNBA) was anchored directly to Wang resin and to amino acid-containing Wang resin. Treatment of these resins wi th amino acid derivatives afforded enantiomerically pure aniline inter mediates via an ipso-fluoro displacement in high yields. Reduction of the aromatic nitro group with aqueous 2 M SnCl2, followed by spontaneo us intramolecular cyclization, afforded benzopiperazinones in good yie lds. Complete acylation of the aniline site (N4) was achieved using se veral chloro-or thiochloroformates and NaHCO3 in anhyd THF/DMF sit 80 degrees C under an argon atmosphere. Alkylation of the anilide nitroge n (N1) with lithiated (S)-(-)-4-benzyl-2-oxazolidinone and benzyl brom ide afforded alkylated benzopiperazinones in good yields with a high e nantiomeric excess (>95% ee). A number of side reactions including rac emization were discovered in our studies and are addressed.