34730-20-6

2-Acetyl-4-chlorothiophene is an oxychloride that belongs to the family of thiourea derivatives. It is synthesized by reacting phosphorus oxychloride with 2,3-dichloroacetophenone in a solvent such as dioxane or acetonitrile. The final product is purified by means of vacuum distillation and recrystallization from diethyl ether, hexane, and chlorinated hydrocarbons.

Pd(OAc)2 catalysed the direct arylation of some functionalized halothiophene derivatives allowing the synthesis in only one step of polyfunctionalized arylated thiophenes. In the presence of 2-acetyl-4-chlorothiophene and various aryl bromides, the 5-arylation products were obtained in moderate to high yields employing only 0.5 mol% catalyst. Researchers studied the coupling of 2-acetyl-4-chlorothiophene with several aryl bromides employing 0.5 mol% Pd(OAc)2 as the catalyst and KOAc as the base. These phosphine-free catalyst reaction conditions allowed the successful coupling of several aryl bromides to more simple thiophene derivatives. Using such conditions, the 5-arylated thiophenes were obtained with high isolated yields. With this procedure, the priority for the arylation of this 2,4-disubstituted thiophene is the 5-position. Moreover, no formation of by-products, such as thiophene oligomers, due to the oxidative addition of this chlorothiophene to palladium was detected during these reactions[1]. 

The general procedure for the synthesis of 2-acetyl-4-chlorothiophene from 2-acetylthiophene was as follows: 1-(2-thienyl)ethanone (5 g, 39.6 mmol) was dissolved in CHCl3 (50 mL) at 0 °C and AlCl3 (16 g, 0.119 mol) was added in batches. After 30 min of reaction, a solution of Cl2 in CCl4 (0.4 M) was added slowly and dropwise through the addition funnel. The reaction mixture was gradually warmed to 25 °C over 12 h and subsequently partitioned between ice water and dichloromethane. The organic layer was washed with 1N NaOH solution, dried over Na2SO4, concentrated and purified by column chromatography (silica gel, 0.5% EtOAc in hexane solution) to afford 2-acetyl-4-chlorothiophene (2.3 g, 36% yield) as a yellow oil.LC-MS (ES) m/z = 161 (M + H)+.

[1] Kassem Beydoun, Henri Doucet. “Palladium-catalyzed direct 5-arylation of formyl- or acetyl-halothiophene derivatives.” Journal of Organometallic Chemistry 696 9 (2011): Pages 1749-1759.