5-chloropyrazolo[1,5-a]pyridine

1101120-37-9

1101120-47-1

General procedure for the synthesis of 5-chloropyrazolo[1,5-a]pyridin-5-amine (7o) from pyrazolo[1,5-a]pyridin-5-amine (7l): firstly, aqueous extraction of ester 3l (1.29 g, 2.98 mmol) was carried out at pH 12, followed by a decarboxylation reaction to give pyrazolo[1,5-a]pyridin-5-amine (7l) as a light brown solid ( 310 mg, 78% yield). Its 1H NMR (400 MHz, CDCl3) data were as follows: δ 8.23 (d, J = 7.4 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.22 (dd, J = 7.4, 2.4 Hz, 1H), 6.13 (d, J = 2.0 Hz, 1H), 3.81 (s, 2H).LC-MS (APCI+) showed m/z 134 (MH+, 100%). Next, an aqueous solution (1 mL) of NaNO2 (27 mg, 0.39 mmol) was slowly added dropwise to a solution of concentrated HCl (1 mL) of 7l (40 mg, 0.30 mmol) and CuCl (74 mg, 0.75 mmol) for more than 2 min at 0 °C. After 30 min of reaction, the reaction mixture was heated to 80°C and kept for 15 min, then cooled to room temperature. The pH was adjusted to 10 with 1 M NaOH solution, filtered through a diatomaceous earth plug and washed with CH2Cl2. The filtrate layer was separated and the aqueous layer was extracted with CH2Cl2. The organic extracts were combined, dried with Na2SO4 and the solvent was removed under vacuum. Purification by column chromatography (eluent: hexane:EtOAc = 3:1) afforded 5-chloropyrazolo[1,5-a]pyridine (7o) as a white solid (6 mg, 13% yield). Its 1H NMR (400 MHz, CDCl3) data were as follows: δ 8.38 (d, J = 7.4 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 6.71 (dd, J = 7.4, 2.2 Hz, 1H), and 6.47 (d, J = 1.8 Hz, 1H).LC- MS (APCI+) showed m/z 153 (MH+, 35Cl, 100%), 155 (MH+, 37Cl, 30%). Finally, 7o (6 mg, 0.039 mmol) underwent a Vilsmeier reaction to give 4o (7 mg, 100% yield) as a white solid.