Halo-Trifluoromethylthiolation Of Sulfur Ylides

Fuorine as the most electronegative and abundant element on the earth,now have been used in pharmaceuticals,functional materials,and agrochemicals.Owing to its high Hansch lipophilicity parameter??=1.44?and strong electron-withdrawing ability,the trifluoromethylthio?SCF₃?group,which could improve the physico-chemical and biophysical properties of organic molecules,has attracted the attention of many researchers^[1-3].At the same time,organic halides can be used as versatile intermediates and building blocks,and they are widely applied in the synthesis of agrochemicals,pharmaceuticals and natural products.Therefore,it is of great significance to develop a simple and efficient method to selectively introduce halogen atoms and thiotrifluoromethyl groups into organic molecules simultaneously.Sulfur ylides have a good reactivity.It has a carbanion and a vicinal sulfur cation which make it can be regarded as a strong nucleophilic reagent with leaving group.Based on these properties we have developed two series of reactions.One is1,1-difunctionalized halo-trifluoromethylthiolation;the other is halo-trifluoromethylthiolation involving ring opening of cyclic thioether.This article will introduce these two parts in detail.In this study of 1,1-difunctionalized halo-trifluoromethylthiolation,we chose sulfonium salts as substrates to generate sulfur ylides in situ under alkaline condition.Munavalli's SCF₃reagent was used as the trifluoromethylthio source,and dichlorosulfoxide as the chlorine source.Under the advance of water this reaction proceed successfully at room temperature.We expanded 21 substrates.The yield of the reactions were between 68-96%.This method works well on aryl-modified substrates and can also tolerate substrates that contain other aromatic rings or have an ester bond structure.An excellent yield can be obtained on a gram-scale.But unfortunately,we found these products are difficult to derivatize while we want toretain trifluoromethylthio group.When it attached to the same carbon with the halogen atom,trifluoromethylthio group became more active and easily removed during the reaction.In this study of halo-trifluoromethylthiolation involving ring opening of cyclic thioether,we refer to the method of 1,1-halo-trifluoromethylthiolation.This method was carried out by changing the solvents,the equivalent of chlorine and the additives.In this reaction,we have also expanded 21 substrates,all of which have obtained ideal yield.In the process of derivatization of the final products,we can get the derivatization product which retains the thiotrifluoromethyl group smoothly.First,we ruled the free radical mechanism of the reaction out according to the experimental phenomenon.We further speculate the mechanism of the reaction by controlling the experiment,step-by-step reaction and the presence or absence of chlorine source and water.One of the possible mechanisms:under the action of alkali,sulfonium salts convert into sulfur ylides in situ.Then the sulfur ylide react with Munavalli's SCF₃reagent and dichlorosulfoxide to obtain trifluoromethyl substituted sulfurous acyl chloride.This compound removes sulfurous acyl chloride group under the action of water.When the steric hindrance of the thioether is large,chloride attacks on carbanion to get a 1,1-halotrifluoromethylation products.In the presence of lithium chloride and the thioether with a small steric hindrance,chloride ions attack the carbon on the thioether ring that adjacent to sulfur to obtain the halotrifluoromethane product with thioether ring opening.But this mechanism can not explain the experimental phenomenon of non dichlorosulfoxide chloride source,so it needs to be further improved.In this paper,two mild and efficient methods for the 1,1-difunctionalized halo-trifluoromethylthiolation and halo-trifluoromethylthiolation involving ring opening of cyclic thioether have been shown in detail.