Negligible Substituent Effect as Key to Synthetic Versatility: a Computational‐Experimental Study of Vinyl Ethers Addition to Nitrile Oxides

Abstract

A tangible substituent effect may be perceived as a good feature in developing an organic reaction. This work demonstrates that, on the contrary, a zero-slope Hammet plot should be sought. The synthesis of isoxazoles by consecutive cycloaddition of nitrile oxides to vinyl ethers and alcohols elimination was studied computationally and experimentally. We performed a Hammett study in silico to demonstrate a negligible substituent effect (i. e., broad substrate scope) in the addition of benzyl vinyl ether to nitrile oxides. The modeling was performed at the ωB97X-V/def2-TZVP//PBE0-D4/def2-TZVP + SMD(benzene) level of theory within the RIJCOSX approximation. The experimental evaluation validated the computational model. A versatile methodology for synthesizing substituted isoxazolines and isoxazoles was proposed as the main result. We present this work as a successful example of how quantum chemical modeling can re-boost the classic Hammett approach to the optimization and design of organic synthetic methodologies. We anticipate further Hammett studies in silico, considering the current trend for data-driven chemical research.

[3 + 2] Cycloaddition of nitrile oxides to dichloropropenes and 1,3‐dichlorobut‐2‐ene: A regioselectivity issue

“…In addition, using thermodynamic equations, there is a possibility to quantitatively estimate the ratio of regioisomers formed [38,42], what cannot be achieved with MEDT. The successful application of thermodynamic approach for study of cycloaddition of NOs to alkenes has been demonstrated in a number of recent works [34][35][36][37][38]43].…”