[Synthesis]
A 1.0 M hexane solution of diethylzinc (27.3 mL, 27.3 mmol) was slowly added dropwise to a solution of dichloromethane (100 mL) containing 2,4,6-trichlorophenol (5.4 g, 27.3 mmol) at -40 °C. After stirring the reaction mixture for 15 minutes, diiodomethane (2.2 mL, 27.3 mmol) was added at the same temperature and stirring was continued for 15 minutes. Subsequently, 1-bromo-3-vinylbenzene (2.5 g, 13.7 mmol) was added to the reaction system, slowly warmed to room temperature and stirred overnight. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed sequentially with 1N HCl (twice), saturated sodium bicarbonate solution (twice), saturated sodium sulfite solution, 1N sodium hydroxide solution and saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated.GC-MS analysis showed that the reaction mixture contained 1-bromo-3-cyclopropylbenzene and unreacted 1-bromo-3-vinylbenzene. To remove 1-bromo-3-vinylbenzene, the crude product was reacted with potassium permanganate solution. This was done by adding an aqueous solution of potassium permanganate (1.5 g of potassium permanganate dissolved in 20 mL of water) drop by drop to a solution of tetrahydrofuran (40 mL) of the crude product (about 5 g) at 0 °C, followed by a slow warming to room temperature. After 1 h, the reaction mixture was diluted with ether, washed sequentially with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Purification by fast column chromatography using 100% hexane as eluent gave 1-bromo-3-cyclopropylbenzene (2.20 g, 81% yield). Next, a hexane solution of 1.6 M n-butyllithium (3.2 mL, 5.1 mmol) was added dropwise to a solution of 1-bromo-3-cyclopropylbenzene at -78 °C and stirred for 1 hour. Subsequently, the reaction mixture was transferred via cannula to a 250 mL round bottom flask pre-filled with dry ice and stirred for 1 hour. The reaction mixture was concentrated and the residue was diluted with water. The aqueous layer was washed with dichloromethane (3 times) and subsequently acidified to pH 2 with 1N HCl and extracted with ethyl acetate. The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 3-cyclopropylbenzoic acid (356 mg, 43% yield, white solid).1H NMR (DMSO-d6, ppm): δ 12.90 (bs, 1H), 7.71 (d, 1H), 7.64 (s, 1H), 7.34 (m, 2H), 2.01 ( m, 1H), 0.99 (m, 2H), 0.70 (m, 2H). |