2,4,6-Trichlorobenzoyl Chloride

2,4,6-Trichlorobenzoyl chloride is often used for the Yamaguchi esterification and macrolactonization. The Yamaguchi esterification is the rapid and mild esterification method in the presence of 4-dimethylaminopyridine (DMAP) using a mixed anhydride, which is prepared from 2,4,6-trichlorobenzoyl chloride and the carboxylic acid. ^1–3) The features of this esterification are as follows: 1) the reaction is conducted under high-dilution conditions to minimize intermolecular coupling; 2) the mixed anhydride is dissolved and slowly added to a refluxing solution of DMAP in aromatic hydrocarbons (e.g. benzene, toluene); 3) usually several equivalents of DMAP, as a catalyst for acylation, are used. It is especially useful in the synthesis of macrolactones with intramolecular esterification, called the Yamaguchi macrolactonization. ^1,4)

Typical procedure¹⁾: A mixture of the seco acid (272 mg) and triethylamine (153 µL) in THF (10 mL) is stirred for 10 min at room temperature, and then 2,4,6-trichlorobenzoyl chloride (160 µL) is added. After stirring for 2 h at room temperature, the resulting precipitate is filtered and washed with a small amount of THF. The filtrate is diluted with benzene (500 mL) and slowly added to a refluxing solution of DMAP (732 mg) in benzene (100 mL) over a period of 40 h. The reaction mixture is washed successively with a saturated aqueous citric acid solution, water, an aqueous sodium hydrogen carbonate, and water, and dried over anhydrous magnesium sulfate. Concentration of the filtrate under reduced pressure affords a crude product. The product is separated by preparative TLC (eluent: diethyl ether / benzene = 2 / 1) on silica gel to give 116 mg of the lactone (46 % yield).