Quantum chemical analysis of the molecular mechanism and selectivity of the 32CA reaction of nitrile oxides with 5-(ethylthio) furan-2(5H)-ones and N-substituted-2-azanorborn-5-ene

Abstract

Isoxazolines are well-known five-membered heterocyclic scaffolds that exhibit a variety of biological activities. These compounds can be synthesized via a 32CA reaction, but the stereo and the regiochemical factors affecting the formation of a targeted isoxazoline are not well understood despite the importance of this scaffolds. The mechanism and the selectivities of the 32CA reaction of acetonitrile oxides (1) with 5-(ethylthio) furan-2(5H)-ones (2) and benzonitrile oxides (5) with N-substituted-2-azanorborn-5-enes (4) for the formation of isoxazolines have been investigated at the M06-2X, in conjunction with the 6–311++G(d,p) basis set. The reaction between 1 and 2 proceeds with a clear-cut regio and diastereoselectivity. Substituting 4 with varying electronic and steric effects have minimal influence on the regio and stereoselectivity between 4 and 5. The exo cycloadducts are favored over the endo cycloadduct. Analysis of the electrophilic Pk+ and nucleophilic Pk− Parr functions at the different reaction sites in the 5-(ethylthio) furan-2(5H)-one indicates that the acetonitrile oxide adds across the atomic centers with the highest Mulliken atomic spin densities. Results from the global electron density transfer (GEDT) reveal the polar nature of the reactions.