The general procedure for the synthesis of 2-chloropyridine-4-carboxaldehyde from 2-chloro-4-hydroxymethylpyridine was as follows: in a 250 mL three-necked flask equipped with a cryogenic thermometer and two constant-pressure dropping funnels, a dichloromethane (15 mL) solution of oxalyl dichloride (1.24 g, 9.81 mmol) was added. The reaction system was cooled to -78 °C under nitrogen protection and stirred. The first constant pressure dropping funnel was connected to the nitrogen line and a dichloromethane (15 mL) solution of 2-chloro-4-hydroxymethylpyridine (0.94 g, 6.54 mmol) was added. A solution of anhydrous dimethyl sulfoxide (1.7 mL, 19.63 mmol) in dichloromethane (2 mL) was added to the other dropping funnel, and the solution was slowly added dropwise (25 min), keeping the reaction temperature between -60°C and -70°C. After the dropwise addition, the reaction system was slowly warmed up to -60 °C over 20 min, and then a dichloromethane solution of 2-chloro-4-hydroxymethylpyridine was added dropwise (50 min), maintaining the temperature between -50 °C and -60 °C. Subsequently, the reaction mixture was warmed to -45 °C over 30 min. The dropping funnel was washed with dichloromethane (2 x 5 mL) and a solution of triethylamine (480 μL, 6.51 mmol) in dichloromethane (4 mL) was added to the reaction mixture (10 min), and finally the mixture in the reaction flask was warmed up to 0 °C within 10 min. The reaction solution was transferred to a 500 mL dispensing funnel and 130 mL of 5% NH4Cl aqueous solution was added. The two phases were separated and the aqueous phase was extracted with dichloromethane (3 x 50 mL). The organic phases were combined, washed with 1 M phosphate buffer (pH=7; 4×100 mL), dried over MgSO4, filtered and concentrated. 2-Chloropyridine-4-carbaldehyde was obtained as an orange solid (0.740 g, 76% yield). Product characterization: mw: 141.57; yield: 76%; orange solid. rf: 0.35 (EtOAc:cyclohexane=30:70). 1H-NMR (CDCl3, δ): 7.65 (dd, 1H, J=5.0 Hz, J=1.3 Hz, ArH), 7.75 (d, 1H, J=1.3 Hz, ArH), 8.66 (d. 1H, J=5.0 Hz, ArH), 10.05 (s, 1H, CHO).
