Generally applicable organocatalytic tetrahydropyranylation of hydroxy functionalities with very low catalyst loading

This paper presents the first acid-free, organocatalytic tetrahydropyran and 2-methoxypropene protection of alcohols, phenols, and other ROH derivatives utilizing privileged N,N'-bis[3,5bis(trifluoromethyl)phenyl]thiourea and a polystyrene-bound analogue. The reactions are broadly applicably (also on preparative scale), in particular, to acid-sensitive substrates such as aldol products, hydroxy esters, acetals, silyl-protected alcohols, and cyanohydrins. The catalytic efficiency is truly remarkably with turnover numbers of 100,000 and turnover frequencies of up to 5 700 h(-1) at catalyst loadings down to 0.001 mol%. The computationally supported mechanistic interpretation emphasizes the hydrogen bond assisted heterolysis of the alcohol and concomitant preferential stabilization of the oxyanion hole in the transition state.