Model calculations of chemical interactions. Part 7.—Role of vicinial delocalization in the regiochemical control of the cycloaddition of diazomethane and formonitrile oxide to methyl vinyl ether

Abstract

In strict accordance with the preceding theoretical and experimental studies on diastereofacial selectivity, we undertook a study of regioselectivity in 1,3-dipolar cycloadditions; the examples chosen included the reactions of alkyl vinyl ethers with diazomethane, the most famous and difficult regiochemical experiment in the literature of 1,3-dipolar cycloadditions and one that has yet to find a well grounded explanation, and with formonitrile oxide, a small 1,3-dipole with a fairly high dipole moment that is capable of enhancing any eventual role of electrostatic effects.

The cycloaddition of methyl vinyl ether (MVE) with diazomethane was checked experimentally and found to afford 3-methoxy-1-pyrazoline as the only characterized and highly abundant adduct, although the formation of minor amounts of the other regioisomer could not be ruled out definitely.

Concerted transitions structures (TS) were calculated at different levels of theory: 3-methoxy-1-pyrazoline and 5-methoxy-2-isoxazoline were found, in agreement with experiment, to be the favoured regioadducts of the reactions with diazomethane and formonitrile oxide, respectively. In both cases the favoured transition structures were ‘earlier’ than the unfavoured one, and had anti-conformations of the O—Me substituent, in spite of the lower stability of the anti conformation in free MVE.

According to our analysis, the regioselectivity of MVE 1,3-dipolar cycloadditions and the main features of the transition structures can be explained as follows: the largest vicinal stabilization is traceable to the four-electron three-centre π conjugation between the π lone pair and the π bond of the allylic fragment O—CC, which is also largely responsible for the rotameric potential-energy profile of MVE. In the TSs these vicinal interactions are differently perturbed, in the different regioisomeric approaches, the more favourable perturbation dictating the regiochemistry; in our examples, the favourable approach occurs when the C⋯X bond (X = N, O) is formed on the substituted carbon atom. This very same perturbation is also the origin of the earliness of the favoured TS and of the consequent weakness of its incipinet bond stabilization. The conformational features of the TSs are significantly affected by electrostatic effects.