Study On The Syntheses Of Disubstituted Tetrahydrothiophene

Substituted tetrahydrothiophenes are important intermediates for the production of thiophenes,and also served as structural motifs in many biologically active molecules.Various approaches have been developed to prepare chiral tetrahydrothiophenes or the racemates.However,there are still challenges for the availability of both racemic and non racemic tetrahydrothiophenes.In our previous study,a three-step synthetic route for 4-acetoxy-2-propy-tetrahydro-thiophene was achieved starting from 1-hepten-4-ol through epoxidation,mesylation and intramolecular nucleophilic substitution of thioacetate ion.The generality of this method was investigated,the reaction conditions were optimized and the reaction mechanisms were proposed in this study.The steric hindrance effect of substituent at C-4 on the reaction was investigated.When the substituent of 1-alken-4-ols at C-4 was alkyl group,such as iso-propyl,tert-butyl,cyclohexyl or phenylethyl,4-acetoxytetrahydrothiophene was obtained at reflux in acetonitrile at 80?.The reaction mechanisms were depicted as follows:AcS~-underwent nucleophilic attack at C-1 and C-4,then intramolecular acetyl migrated,the obtained alkylsulphanyl anion reached an optimal conformation suitable for the intramolecular nucleophilic substitution via C-C single bond free rotation,which then cyclized to produce the product.The effect of reaction temperature was also investigated.The results showed that the high temperature(110?)promoted the cycliztion and the yield increased accordingly.The electronic effect of substituent at C-4 on the reaction was investigated.When the substituent of 1-alken-4-ols was aryl group,such as phenyl or p-methylphenyl,the acyclic triacetyl substituted product was obtained at 80?,whereas4-acetlthio-2-aryltetrahydrothiophene was produced at 110?.A possible pathway involving an intermediate of episulfide was proposed.The model experiment of episulfide ring confirmed the speculation was reasonable.The reason of acetylthio group at C-4instead of acetoxy may be as follows:the presence of the aryl group obstructed the C-C single bond free rotation for the intramolecular nucleophilic substitution,then the sulfide ion at C-1 attacked the C-2 to produce episulfide as key intermediate,which reacted with one more equiv of AcSH,cyclized to give the product.When p-trifluoromethylphenyl was attached to C-4 of 1-alken-4-ols,4-acetoxy-2-aryltetrahydrothiophene was obtained at 80? and 110? respectively.Due to the presence of the strong electron-withdrawing group at phenyl,such as trifluoromethyl,the sulfide ion may attack at C-4 easily,and then cyclized to obtain the product.Based on the above experiments,the electronic effect of alkyl at C-4 on the reaction was furtherexplored.When the substituent at C-4 was benzyl,4-acetoxy-2-benzyltetrahydrothiophene was obtained at 80?,while4-acetylthio-2-benzyltetrahydrothiophene was obtained at 110?.The results showed that the temperature maked significant effect on the reaction,so more study was needed to find the reason.A new method for preparing disubstituted tetrahydrothiophene was developed.This approach possesses several advantages,including the availability of 1-alken-4-ols,high yields for each step,convenient and environmental friendly procedure,which offers one more highly effective methodology for the syntheses of polysubstituted tetrahydrothiophenes.