Regio- and Stereoselective 1,3-Dipolar Cycloadditions to 6H-1,2-Oxazines Leading to New Heterobicyclic Compounds

Abstract

Typical 1,3-dipoles such as nitrile oxides, imines and ylides, as well as diazoalkanes, nitrones and azomethine ylides generally underwent smooth [3+2] cycloadditions to 6H-1,2-oxazines. The heterobicyclic adducts were obtained in moderate to very good yields, with excellent regioselectivities and high diastereoselectivity. The 6-ethoxy substituent of the 6H-1,2-oxazines strongly shields one face and thus leads to almost exclusive formation of exo-configured products. 6H-1,2-Oxazines are therefore sufficiently reactive and selective dipolarophiles. The regioselectivity of the 1,3-dipolar cycloadditions is briefly discussed considering steric and electronic effects. PM3 calculations did not lead to fully satisfactory results in predicting the observed high regioselectivities. Preliminary subsequent reactions of the heterobicyclic products involve chemoselective reductions with sodium cyanoborohydride or hydrogen in the presence of palladium, and a decarboxylative isoxazoline fragmentation reaction, stereoselectively furnishing the 5-cyano-4-hydroxy substituted 1,2-oxazine derivative in high yield.

Key words

cycloadditions - diazo compounds - 1,2-oxazines - bicyclic compounds - diastereoselectivity - regioselectivity

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