Rhodium-Catalyzed Synthesis Of Tetrahydrothiophene Derivatives

Tetrahydrothiophene derivatives have a variety of biological activities,and there are broad prospects for the synthesis of new tetrahydrothiophene derivatives,the study of reaction mechanisms,the development of pharmacological and biological activities and applications.In this paper,2-phenyltetrahydrothiophene-2-carboxylic acid ethyl ester was synthesized from 2-diazo-2-phenylethyl acetate and thiocyclobutane using rhodium acetate as catalyst,and the crystal structure of 2-phenyltetrahydrothiophene-2-carboxylic acid was determined.A variety of tetrahydrothiophene derivatives were synthesized by substrate expansion of diazo compounds and tetrahydrothiophene derivatives.The optimized conditions for the synthesis of ethyl 2-diazo-2-phenylacetate are:TsN3 0.24 mmol,ethyl phenylacetate 0.2 mmol,catalyst DBU 0.3 mmol,solvent anhydrous acetonitrile(2 mL),reaction at 30? for 3 h synthesis yield of 2-phenyl-2-diazoacetate can reach 88.9%.The optimized conditions for the synthesis of ethyl 2-phenyltetrahydrothiophene-2-carboxylate are:substrate 2-diazo-2-phenyl ethyl acetate 0.2 mmol,thiocyclobutane 0.24 mmol,and catalyst rhodium acetate(5 mol%),toluene(2 mL),the optimal temperature is 100?,the reaction time is 12 h yield of tetrahydrothiophene synthesis can reach 86.3%.The 2-diazo-2-aryl ethyl acetate and tetrahydrothiophene derivatives obtained by substrate expansion were confirmed by 1H NMR and 13C NMR.Density functional calculations show that the mechanism of Rh-catalyzed addition reaction of ethyl 2-phenyl-2-diazobenzeneacetate with sulfolane is:first,metal carbene is formed,and then the metal carbene is combined with sulfolane to form thallium Compound 4,followed by the breaking of the CS bond,may generate tetrahydrothiophene compound 5,seven-membered ring compound 7,and olefin compound 8.Through thermodynamic and kinetic analysis,the tetrahydrothiophene compound 5 is the dominant product,and the energy barrier of the transition state in this process is 30.6 kcal/mol and ?rGm?=-60.6 kcal/mol.