Radical Anion-Promoted Chemoselective Cleavage Of Csp~2-S Bond Enables Transition-Metal-Free Formal Cross-Coupling Of Aryl Methyl Sulfones With Alcohols

As a fundamental functional group in organic chemistry and drug molecules,sulfones are widely used as reaction substrates or intermediates in organic synthesis.Because of their widely exisition and diverse structure properties,they are generally considered to have good chemical stability.What’s more,sulfones are commonly used as electrophiles in transition-metal-catalyzed cross-coupling reactions,which have become a hot research field and attracted continuous attention of chemical researchers.The literature surveies showed that sulfones can be used as general precursors for cross-coupling reactions,not only can be used as Csp³electrophiles in transition-metal-catalyzed cross-coupling reactions,but also as Csp²electrophiles to construct new carbon-carbon bonds or carbon-heteroatom bonds.Although some progress has been made in this field,most of the cross-coupling reactions involved transition-metal requirements.Therefore,sulfones as electrophiles mainly rely on the oxidative addition of transition-metals to C-S bonds.However,when alkyl aryl sulfones are used as cross-coupling reagents,since the bond dissociation energy of Csp³-S bonds is less than that of Csp²-S bonds,the inherent bond strength of different C-S bonds leads to poor chemical selectivity.In this research thesis,a novel transition-metal-free formal cross-coupling of readily available and general aryl methyl sulfones and alcohols to afford alkyl aryl ethers via a S_RN1 pathway is developed.An array of functional groups,especially medically relevant heterocycles as well as naturally occurring alcohols,were well tolerated.Two marked antitubercular drugs（Etocarlide and Isoxyl）were efficiently prepared employing this approach as the key step.Mechanistic investigations reveal a dimsyl-anion initiated radical chain process as the major pathway.The Csp²-S bond activation is steered by fragmentation of the radical anions of sulfones,which represents an appealing and complimentary reaction mode to oxidative addition of transition-metal catalysts.Density functional theory（DFT）calculations indicate that the reaction is through the formation of alkyl aryl ethers radical anion due to the lower free energy barrier in the rate-determining alkoxide anion radical nucleophilic addition step.