A Simple One-Pot Synthesis of Benzoxazine-2,4-diones and Benzothiazine-2,4-diones (original) (raw)

A simple and efficient procedure has been developed for a one-pot synthesis of substituted benzoxazine-2,4-diones and benzothiazine-2,4-diones directly from salicylic acid (or thiosalicylic acid) and amines. Synthetic chemists are becoming increasingly interested in the synthesis of substituted benzoxazine-2,4diones due to their utility in pharmacology 1-4 and photography. 5 Hence, considerable effort has been devoted to the preparation of benzoxazine-2,4-diones by using a wide variety of synthetic approaches, including palladium-catalyzed cyclocarbonylation of o-iodophenols with heterocumulenes, 6 reaction of phenyl salicylate with isocyanates, 7 cyclization of salicylic acid with isothiocyanate in the presence of silver trifluoroacetate, 8 preparation from salicylamide 9 and other methods. 10 In this paper, we describe a new and efficient process for the synthesis of substituted benzoxazine-2,4-diones in one pot directly from salicylic acid and amines. Initially, compound (4a) was prepared by cyclization of salicylamide with ethyl chloroformate according to the known procedure, 11 which took three steps from commercially available acetylsalicyloyl chloride. Scheme 1 illustrates this synthetic approach. Reaction of acetylsalicyloyl chloride with 3,4-dimethoxyphenethylamine was carried out to give acetylsalicylamide (2a), and then compound (2a) was deacetylated with triethylamine/methanol to afford salicylamide (3a). Compound (3a) was cyclized with ethyl chloroformate to give compound (4a). We realized that the existing methods include multi-step procedures, use of expensive catalyst or conversion of amine to isocyanates for synthesis of benzoxazine-2,4-dione derivatives, which provided us impetus to develop a simple and practical method to synthesize benzoxazine-2,4-dione derivatives. We found that benzoxazine-2,4-dione derivatives could be prepared in a one-pot reaction directly from salicylic acid and amines (Scheme 1). Salicylic acid was treated with ethyl chloroformate and the reaction mixture was evaporated at reduced pressure to remove unreacted ethyl chloroformate. Stirring the resulting residue with amines in the presence of triethylamine afforded the substituted benzoxazine-2,4