The Construction Of Full-spectrum Fluoromethyl Sulfones Via The Same Oxygenation-state Strategy

Sulfones is an important drug skeleton in drug design,which can regulate the stability,lipid solubility and metabolism of drug molecules.Due to the small atomic radius and large electronegativity of fluorine atom,the introduction of fluorine atom or fluorine-containing groups improves the metabolic stability,lipophilicity and bioavailability.In recent years,it has been found that the introduction of fluorine atoms into the methyl sulfone structure can significantly improve the drug activity in vivo.However,there are few methods for the synthesis of related structure.Traditional methods for the construction of fluorinated-methyl sulfones include oxidation of sulfone and fluorination of sulfone,which are limited by the poor economy of redox,the poor compatibility of functional groups or the need for prefabricated substrates.The same oxidation-state introduction of hypervalentsulfur strategy which means that the number of oxygen atoms attached to the sulfur atom remains unchanged in the reaction for the synthesis of diversity hypervalent sulfur-containing compounds has been achieved by our group,which strategy can avoid theusing of equivalent oxidant.We start from the green and cheap inorganic sulfur salt thiourea dioxide,and realize the three-component coupling of aryl halide and fluorine block under the palladium catalysis.The raw materials needed for this reaction are readily availableand the experimental operation is simple.Remarkably,we can achieve the construction of mono-,di-,and tri-fluoromethyl sulfones by changing the types of fluorine blocks.To further demonstrate the practicality and applicability of the full-spectrum fluoromethyl sulfonation protocol,clinically applied methyl-sulfone-containing pharmaceuticals were isostered via the current cross-coupling strategy with fluoromethyl sulfones installation at the last stage,highlighting the attractiveness of this protocol for drug discovery.Mechanistic studies further demonstrated that sulfinate is the key intermediate and C—F---H—C interactions between thiourea dioxide and halogenofluorocarbons plays a key role in the reaction.