4-Methylene-4H-3,1-benzoxazines have been prepared in excellent yields from the reaction of iminophosphorane derived of N-(2-acetylphenyl)-2-azidobenzamide with triphenylphosphine with isocyanates. This transformation involves an initial aza-Wittig reaction to give a carbodiimide, which undergoes ring closure across the enol form of the carboxamide group and eventually an unprecedent imino-benzoxazine-methylene-benzoxazine rearrangement. A slight variation allows the preparation of one analogue of the marine alkaloid rhopaladin D.The usual procedure for the synthesis of organic compounds involves stepwise formation of the individual bonds in the target molecule, however, in the last years there has been an upsurge of interest in the domino reactions in which several bonds can be formed in one sequence without isolation of the intermediates, changing reaction conditions, or adding reagents. 1Despite the increasing importance of the aza-Wittig reaction for the construction of a wide variety of nitrogen-containing heterocyclic ring systems, 2 the use of this synthetic methodology in consecutive processes is rather limited. 3Although the 4H-3,1-benzoxazine ring system displays an important biological activity and a wide variety of derivatives of this ring system have been used as fungicidal, anti-inflamatory agents, ostheoclasis inhibitors, antirheumatics and as DNA-binding antitumor agents, 4 a limited number of methods has been reported for the preparation of 4-alkylidene-4H-3,1-benzoxazines. The first approach is based on an aza-Wittig-type reaction of the iminophosphorane derivated from o-azidoacetophenone with isocyanates. 5 The second one is based on the metalation of N-(a-alkoxyalkyl)benzotriazoles and subsequent trapping of the intermediate with a variety of electrophiles. 6 A very recent approach involves a palladium-catalyzed cyclization-alkoxycarbonylation of various substituted 2-(trimethylsilanyl)ethynylaniline amide or urea derivatives. 7 We wish to report here an one-pot procedure for the preparation of the otherwise not readily available 4-methylene-4H-3,1-benzoxazines 5 from the readily prepared iminophosphorane 4. Compound 4 has been prepared by the following two steps: a) acylation of the 2-aminoacetophenone with o-azidobenzoyl chloride to give N-(2-acetylphenyl)-2-azidobenzamide 3 in 77% and b) Staudinger reaction of the azide 3 with triphenylphosphine to give the iminophosphorane 4 in 99% yield 8 (Scheme 1).Scheme 1 Synthesis of 4-methylene-4H-3,1-benzoxazine 7. Reagents and conditions: i) pyridine, CH 2 Cl 2 , 0 °C to r.t., 1 h; ii) Ph 3 P, CH 2 Cl 2 , 0 °C to r.t., 12 h; iii) RNCO, toluene, 1 h, r.t. to reflux, 6-14 h.
