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

• Published in: ChemistrySelect (Weinheim) 2022-03, Vol.7 (10), p.n/a
• Main Authors: Kutskaya, Anastasia M., Serkov, Semyon A., Voronin, Vladimir V., Ledovskaya, Maria S., Polynski, Mikhail V.
• Format: Article
• Language: English
• Subjects: Cycloaddition; DFT modeling; Hammett studies; nitrile oxides; reaction mechanisms
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.202200174

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. In silico Hammett Studies for Optimization of Cycloaddition Reactions Targeting near‐zero substituent effect in an in silico Hammett study allowed us to tune a dipolar cycloaddition of vinyl ethers to nitrile oxides for a broad substrate scope. Substituted isoxazoles can be synthesized by a subsequent elimination of benzyl alcohol that proceed easily in acidic conditions.