Description
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.
Uses
2-Acetyl-4-chlorothiophene serves as a precursor in the synthesis of various arylated thiophene derivatives.[2]
Reactions
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].
Synthesis
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)+.
References
[1] Beydoun, K., & Doucet, H. (2011). Palladium-catalyzed direct 5-arylation of formyl- or acetyl-halothiophene derivatives. Journal of Organometallic Chemistry, 696(9), 1749–1759. https://doi.org/10.1016/j.jorganchem.2010.12.021
[2] Bensaid, S., & Doucet, H. (2012). Solvent‐Free Palladium‐Catalyzed Direct Arylation of Heteroaromatics with Aryl Bromides. ChemSusChem, 5(8), 1559–1567. https://doi.org/10.1002/cssc.201100771
