Synthesis Of 3-Thienylmalonic Acid And Nucleophilic Reaction Of Aryl Halides

3-Thienylmalonic acid and its diesters are useful intermediates in the preparation of specific semi-synthetic antibiotics, especially Ticarpenin. In this work, the synthetic routes of 3-thienylmalonic acid and the coordination catalytic reactions were studied, and a new method for the preparation of 3-iodothiophene was proposed.In this paper, diethyl 3-thienylmalonate was synthesized by two routes. The intermediates and final product were characterized by MS.Diethyl 3-thienylmalonate was prepared directly by condensation between 3-bromothiophene and diethyl malonate sodium in THF in the presence of Cu(acac)2. The yield of diethyl 3-thienylmalonate was 21.9% based on 3-bromothiophene.3-Iodothiophene was prepared by coordination catalytic iodination, in brief, 3-bromothiophene reacted with KI in n-butanol in the presence of CuI/N,N'-dimethylethane-1,2-diamine catalyst system. The optimum conditions were as follow: mole ratio of 3-Bromothiophene:KI:CuI:N,N'-dimethylethane-1,2-diamine was 20:40:1:2, and 40ml n-butanol was employed as solvent per mole 3-bromothiophene, the proper reaction temperature was 120℃. The highest yield reached 91%.3-Iodothiophene was converted to diethyl 3-thienylmalonate by reacting with diethyl malonate sodium in a mixture solvent (DMF/diethyl malonate) in the presence of CuBr. The yield of diethyl 3-thienylmalonate was 76.3% based on 3-iodothiophene.Synthesis of diethyl 3-thienylmalonate from 3-bromothiophene through iodination and condensation reaction resulted an improved yield(68.73% rather than 21.9%) in spite of the lengthy reaction sequence.3-Thienylmalonic acid was obtained by hydrolysis of the corresponding diethyl ester with NaOH in 50% ethanol, stepwise acidifying and recrystallization from ethyl acetate/benzene in a yield of 78%.In addition, five compounds were prepared through coordination catalytic reaction, whose structures were characterized by MS.