Computational study on the mechanism of transitionmetal-catalyzed formation of highly substitutedfuro [3,4-d] [1,2] oxazines

Abstract

The mechanism of gold(III)-catalyzed 1,3-dipolar [3þ3] cycloaddition reactions of2-(1-alkynyl)-2-alken-1-ones with nitrones to a®ord highly-substituted furo [3,4-d] [1,2]oxazines, which are useful as structural skeletons in biologically active compounds and assynthetic building blocks in organic synthesis, have been studied computationally. Theresults show that the reaction proceeds via the formation of a -complex in which the goldmoiety coordinates to the triple bond of the 2-(1-alkynyl)-2-alken-1-ones, resulting in anintramolecular cyclization of the gold intermediate to generate a carbocation intermediatewhich is trapped by the nucleophilic oxygen of the nitrone to form a furanyl–gold complex,which upon subsequent cyclization a®ords the furo [3,4-d] [1,2] oxazine as well as regeneratesthe gold catalyst. The highest activation barrier in the entire cycle is 19.5 kcal/mol whichaccompanies the intramolecular cyclization step. The activation barriers for the reactions of2-(1-alkynyl)2-alken-1-ones with electron-donating and cyclic substituents are generallylower compared to those of the parent 2-(1-alkynyl)2-alken-1-one while the reactions of2-(1-alkynyl)2-alken-1-ones with electron-withdrawing substituents have higher activationbarriers. Preliminary exploratory calculations on the possibility of replacing gold, an ex-pensive and rare metal, with a copper-based catalyst for the reaction, show that for the keyelementary steps, the Cu (III) catalyst is at least as active as the Au (III) complex, thusproviding a cheaper route to furo [3,4-d] [1,2] oxazine.