A computational study of the mechanism as well as the regio-and stereoselectivities of the intramolec-ular 1,3-dipolar cycloaddition (IMDC) of nitrone–alkene 1, derived from 2-allylthiobenzaldehyde, has been carried out using DFT methods...
moreA computational study of the mechanism as well as the regio-and stereoselectivities of the intramolec-ular 1,3-dipolar cycloaddition (IMDC) of nitrone–alkene 1, derived from 2-allylthiobenzaldehyde, has been carried out using DFT methods at the MPWB1K/6-31G(d,p) level of theory. The four possible pathways , fused and bridged regioisomeric modes, and the two stereoisomeric approaches endo and exo for the IMDC reaction are analyzed and discussed. Analysis of the potential energy surface showed that this IMDC reaction kinetically favors formation of the isoxazolidine generated from the fused-endo pathway. The obtained results corroborate very well with the published experimental data. Analysis of TS geome-tries and bond order indicate that these IMDC reactions proceeded through a one-step synchronous mechanism for the fused modes and is asynchronous for the bridged modes. Introduction Over the past few decades, polyheterocyclic compounds have been extensively studied for their varied application in the fields of biology, material science, and supramolecular chemistry. 1 Many methods have been reported in the literature for the synthesis of these molecules, however short and efficient syntheses still remain a challenge for synthetic organic chemists. Existing methods require high dilution reaction conditions and long reaction times. The intramolecular 1,3-dipolar cycloaddition (IMDC) of nitrone– alkene compounds is a versatile and efficient protocol for the stereo-and regioselective construction of complex heterocyclic architectures having both nitrogen and oxygen atoms in a five-membered unit. 2 The fused and bridged mode of the IMDC which afford fused or bridged isoxazolidines, respectively, are both key intermediates in the syntheses of natural products or analogues with biological importance. 3 These reactions are characterized by high regioselectivity and stereoselectivity and are useful in organic synthesis. A tremendous amount of theoretical and experimental work devoted to the study of the mechanism and selectivities of IMDC reactions can be found in the literature. Xiang theoretically studied, 4 through DFT methods, the regioselectivity of the IMDC reaction of various N-3-alkenylnitrones and found that the position of the substituent played a major role in both the determination of selectivity and the reaction rate. Purushothaman et al. 5 have synthesized bicyclic pyrrolidine and pyrrolizidine grafted macrocycles through an IMDC reaction between azomethine ylides and dipolarophiles, of which the alkenyl-aldehydes derived from salicylaldehyde were reacted with secondary amino acids to generate azomethine ylides, which were trapped intramolecularly by suitable dipolarophiles to give the corresponding macrocycles in moderate yields. Recently, Saubern et al. 6 reported the intramolecular cycloaddi-tion of nitrone–alkene 1, generated in situ from the corresponding 2-(allylthio)benzaldehyde, for the synthesis of the corresponding tricyclic isoxazolidines. They found that this reaction exclusively gave a single cycloadduct originating from the fused-endo pathway (Scheme 1). Our aim of the present letter was to undertake a computational investigation of the regio-and stereoselectivities observed experimentally by Saubern et al. in order to shed light on the factors that controlled the selectivity and influenced the mechanism of this IMDC reaction.
