Application Of The New Generation CF₃SO₂-based Electrophilic Trifluoromethythiolation Reagents

Fluoroalkylthiolation,especially the trifluoromethythiolation has attracted more and more special interests.With of its high electron-withdrawing effect and admirable lipophilicity(?R = 1.44)which could improve the drug molecule's cellmembrane permeability and enhance its chemical and metabolic stability,compounds bearing this group are potentially important targets in the pharmaceutical and agrochemical fields.The introduction of trifluoromethylthio group(SCF3)has become one of the most hot topics in the field of organic synthesis.Papaers published in recent 3 years are more than the sum of the past.Two new generation "CF3SO2"-based electrophilic trifluoromethythiolation reagents CF3SO2Na and CF3SO2Cl are introduced in this paper.Electrophilic trifluoromethythiolation using CF3SO2Na and CF3SO2Cl with nucleophilic substrate like indoles,pyrroles and activated arenes are first examined.In addition,CF3 group in these two reagents is replaced with other fluoroalkylthio group such as CF2H,CF3CH2 and some perfluoroalkyl group like C8F17,and the method has been successfully extended for fluoroalkylthiolation.As a starting point,a copper-promoted method of direct electrophilic trifluoromethylthiolation using CF3SO2Na was developed.An efficient system of diethyl phosphite/CuCl/DMSO was investaged with the yields of 3-trifluoromethythiolated iodoles from 42%to 94%.Pyrroles and enamines were also examined and the desired products were obtained with the yields over 72%.The method has been extended for perfluoroalkylthiolation reactions using RfSO2Na in the same conditions with good yields(65-82%).Another similar electrophilic trifluoromethylthiolation reagent CF3SO2Cl is also introduced,which allows the trifluoromethylthiolation of indoles,pyrroles,activated arenes and thios.Reactions of a variety of indole were conducted under the optimized conditions of diethyl phosphite and occurred in good to excellent yields(72%-94%).Reaction of pyrroles with different substituted groups occurred to give the corresponding trifluoromethylthiolated pyrroles in good yield(over 85%).Activated arenes such as reacted with CF3SO2Cl in the presence of Iron(?)chloride occurred to give the corresponding trifluoromethylthiolated heteroarenes in moderate yields(55%-74%).Reactions of CF3SO2Cl with a variety of aryl thiols under the same conditions occurred in excellent yields(over 70%).The method has been successfully extended for other fluoromethylthiolation with indoles and pyrroles using CF2HSO2Cl,CF3CH2SO2Cl and RfSO2Cl.The results of CF3CH2S02C1 and CF2HS02C1 were similar to CF3S02C1(yields over 80%),but C4F9SO2Cl and C8F17SO2Cl were more negative than those of CF3SO2Cl(yields from 45%-63%).Direct difluoromethythiolation is another hot topic in recent years,the method of trifluoromethylthiolation has also been extended to difluoromethythiolation with indoles,pyrroles,azaindoles,and activated arenes after we successfully prepared the corresponding salt CF2HS02Na.Under the conditions of diethyl phosphite/TMSCl,a wide variety of difluoromethylthiolated products of indoles and pyrroles were produced in moderate to good yields(45%-93%),azaindoles,and electron-rich arenes were more negative.The reaction conditions were also used with CF3SO2Na and RfSO2Na,trifluoromethylthiolated indoles were produced in 77%-95%yields,perfluoroalkylthiolation(C4F9S and C8F17S)products could also obtained with lower yields.