Synthesis
General procedure for the synthesis of methyl 4-chloro-3-formylbenzoate from methyl 4-chloro-3-methylbenzoate: a mixture of 17.0 mL of glacial acetic acid, 16.5 mL of acetic anhydride, and 2.5 mL of concentrated sulfuric acid was cooled in an ice bath. Subsequently, 1.84 g (0.01 mol) of methyl 4-chloro-3-methylbenzoate and 3 g of chromium trioxide (0.03 mol) were added in batches. The reaction mixture was stirred in an ice bath for 3 hours. Upon completion of the reaction, the reaction solution was slowly poured into 200.0 mL of ice water and stirred vigorously for 30 minutes. The resulting gray solid precipitate was collected by filtration and washed three times with 70.0 mL of water. The resulting solid was transferred to a 50.0 mL aubergine flask, 16.0 mL methanol, 16.0 mL water and 0.4 mL concentrated sulfuric acid were added and refluxed for 30 minutes. After the reaction, the residue was poured into water and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The ethyl acetate extracts were combined and washed sequentially with 80 mL of water and 80 mL of saturated saline, then dried with anhydrous sodium sulfate. After evaporation of the solvent, 1.35 g (yield 68.2%) of the yellow solid product methyl 4-chloro-3-formylbenzoate was obtained. Melting point: 131-133 °C. 1H NMR (300 MHz, DMSO-d6) δ: 3.90 (s, 3H, OCH3), 7.79 (d, 1H, Ar-H, J = 8.4 Hz), 8.18 (d, 1H, Ar-H, J = 8.4 Hz), 8.35 (s, 1H, Ar-H), 10.34 (s, 1H, CHO) IR (KBr, cm-1): 3425, 3082, 3003, 2953, 1726, 1720, 1689, 1188, 983, 759.MS [M + H]+: 199.1.
References
[1] European Journal of Medicinal Chemistry, 2015, vol. 90, p. 170 - 183
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 24, p. 10188 - 10204
