TY - JOUR

T1 - Negligible Substituent Effect as Key to Synthetic Versatility

T2 - a Computational-Experimental Study of Vinyl Ethers Addition to Nitrile Oxides

AU - Kutskaya, Anastasia M.

AU - Serkov, Semyon A.

AU - Voronin, Vladimir V.

AU - Ledovskaya, Maria S.

AU - Polynski, Mikhail V.

N1 - Publisher Copyright: © 2022 Wiley-VCH GmbH

PY - 2022/3/15

Y1 - 2022/3/15

N2 - 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.

AB - 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.

KW - Cycloaddition

KW - DFT modeling

KW - Hammett studies

KW - nitrile oxides

KW - reaction mechanisms

KW - 3,5-DISUBSTITUTED ISOXAZOLES

KW - VALDECOXIB

KW - MECHANISM

KW - 3+2 CYCLOADDITION REACTION

KW - REGIOSELECTIVITY

KW - 6-AMINOPENICILLANIC ACID

KW - DFT

KW - BASIS-SETS

KW - DENSITY-FUNCTIONAL THEORY

KW - DERIVATIVES

UR - http://www.scopus.com/inward/record.url?scp=85126789194&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/9308905f-ea5c-3652-b738-1960a244d714/

U2 - 10.1002/slct.202200174

DO - 10.1002/slct.202200174

M3 - Article

AN - SCOPUS:85126789194

VL - 7

JO - ChemistrySelect

JF - ChemistrySelect

SN - 2365-6549

IS - 10

M1 - e202200174

ER -