Solid-Phase Synthesis of Benzopiperazinones

This article describes an efficient method for the solid phase synthesis of benzopiperazinones (1,2,3,4-tetrahydroquinoxalin-2-ones) with four 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 with amino acid derivatives afforded enantiomerically pure aniline intermediates via an ipso-fluoro displacement in high yields. Reduction of the aromatic nitro group with aqueous 2 M SnCl 2, followed by spontaneous intramolecular cyclization, afforded benzopiperazinones in good yields. Complete acylation of the aniline site ( N4 ) was achieved using several chloro- or thiochloroformates and NaHCO 3 in anhyd THF/DMF at 80 °C under an argon atmosphere. Alkylation of the anilide nitrogen ( N1 ) with lithiated ( S )-(−)-4-benzyl-2-oxazolidinone and benzyl bromide afforded alkylated benzopiperazinones in good yields with a high enantiomeric excess (>95% ee). A number of side reactions including racemization were discovered in our studies and are addressed.