Synthesis of Benzisoxazoles by [3+2] Cycloaddition of Nitrile Oxides with Arynes

Significance

Reported is an efficient and convenient method for the synthesis of benzisoxazoles 5 by the [3+2] cycloaddition of in situ generated arynes 3 with nitrile oxides 4 . The methodology is based on previous results (F. Shi, J. P. Waldo, Y. Chen, R. C. Larock Org. Lett. 2008, 10, 2409) which showed that both benzyne 3 and nitrile oxide 4 intermediates may be generated by fluoride ion induced reactions of 1 and 2, respectively. The optimized conditions involve use of an excess of the benzyne precursor 1 and slow addition of the chlorooximes 2. The scope of this reaction was investigated with different aryne precursors as well as with a variety of chlorooximes (R^³ = aromatics with EDGs and EWGs, alkenyl, alkyl, heterocycles) providing the benzisoxazoles in moderate to good yields. Use of an unsymmetrical benzyne afforded regioisomeric mixtures 5 (5a/5b = 1.8:1) whose formation was rationalized by dominance of electronic factors over steric effects.