Application background and overview of 2-fluoropyridine-5-formyl chloride
2-Fluoropyridine-5-carboxylic acid chloride is an organic intermediate that can be prepared from 2-fluoropyridine-5-carboxylic acid and can be used in various acylation reactions.
Applications of 2-fluoropyridine-5-formyl chloride
2-Fluoropyridine-5-carboxyl chloride can be used to prepare 2-(6-fluoropyridin-3-yl)-4,5-dihydropyridazole.
To a stirred solution of 2-fluoro-5-pyridinecarboxylic acid (500 mg, 3.54 mmol) in dry dichloromethane (17 mL) at 0°C, add oxalyl chloride (1.35 g, 10.6 mmol) and DMF ( small amount). The reaction was allowed to warm to room temperature and stirred for 3 hours, and the solvent was removed in vacuo. The crude residue was then dissolved in anhydrous dichloromethane (17 mL) and cooled to 0 °C using an ice bath. Triethylamine (1.07g, 10.6mmol) was then added followed by ethanolamine (260mg, 4.25mmol) via syringe. The reaction was allowed to warm to room temperature and stir overnight. The reaction was then dry loaded onto silica gel and purified by silica flash column chromatography eluting with dichloromethane and methanol (0-5%) (methanol) to afford the amide product (287 mg, 1.56 mmol). No further purification or
Characterization, the amide is continued to produce oxazoline. According to general method B, use p-TsCl (506mg, 2.65mmol), NEt3 (300mg, 2.96mmol), DMAP (38mg, 0.31mmol) and dichloromethane (2.6mL) and stir. Then following General Procedure B(ii), using K2CO3 (647 mg, 4.68 mmol) and MeCN (3.1 mL), the colorless solid oxazoline product ( 191 mg, 32%, two steps). M.p.: 72-73℃; FTIR: vmax/cm , 935 (s), 853 (m), 834 (m); 1H NMR (MHz, CDCl3): δ8.76 (1H, d, J = 2.5Hz, CHar), 8.32 (1H, ddd, J = 8.5, 7.0, 2.5 Hz, CHar), 6.97 (1H, dd, J = 8.5, 2.5 Hz, CHar), 4.46 (2H, t, J = 9.5 Hz , CH2), 4.07 (2H, t, J = 9.5 Hz, CH-); 19F NMR (376.5MHz, CDCl3): δ-63.7; 13C NMR (100.6MHz, CDCl3): δ165.1 (d, J = 244.0Hz), 161.2, 148.3 (d, J = 16.0Hz), 141.2 (d, J = 9.0Hz), 122.3 ,109.6 (d, J = 37.5Hz), 68.1, 55.1; HRMS: m/z [MH] + C8H8FN2O calculation. 167.0615, found 167.0615.
General Procedure A: Add pyridine ester (1.0 equiv) to a dry round bottom flask and heat to 55°C with stirring. After reaching the desired temperature, ethanolamine (1.5 equiv) was added slowly via syringe and the reaction was stirred for 3 h of picoline, then cooled to room temperature and stirred for a further 18 h. The crude reaction mixture was then purified by flash column chromatography on silica gel eluting with dichloromethane and methanol (1% MeOH to 20% MeOH) or ethyl acetate (100%) to give the amide product.
General Method B: To a dry round bottom flask add amide (1.0 equiv) and dry dichloromethane (0.6 M). Add NEt3 (1.9 equiv) followed by DMAP (0.2 equiv) with stirring. and p-TsCl (1.7 eq.). The reaction mixture was stirred at room temperature overnight and diluted with dichloromethane and water. Then transfer the mixture to a separation funnel and partition the layers. The aqueous layer was further extracted with dichloromethane. The combined organic layers were dried over anhydrous MgSO4, the polycarbonate was filtered, and the obtained solvent was removed in vacuo. The crude residue is then subjected to cyclization conditions B(i) or B(ii) to provide the oxazoline product after purification.
NaOH and MeOH cyclization B (i): The crude residue was dissolved in MeOH (0.5 M) and NaOH (3.0 equiv) and added in one portion. The reaction mixture was stirred at room temperature for 2-3 hours, then the solvent was removed in vacuo. Dissolve the residue in dichloromethane and water and transfer to a separatory funnel. The layers were separated and the aqueous layer was further extracted with dichloromethane and ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with petroleum ether (40/60) and acetic acid with ethyl acetate (0% ethyl acetate to 100% ethyl acetate) to give the oxazoline product.
K2CO3 and MeCN cyclization B(ii)���Dissolve the crude residue in MeCN (0.5M) and K2CO3 (3.0 eq) and add it all at once. The reaction mixture was stirred at 85°C for 5 hours, then cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in dichloromethane and water and transferred to a separatory funnel. The layers were separated and the aqueous layer was further extracted with dichloromethane and ethyl acetate. The organic layers were combined, dried over anhydrous MgSO4, filtered and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether (40/60) and ethyl acetate (0% ethyl acetate to 100% ethyl acetate) to give the oxazoline product.
