Diisopropylethylamine → 6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-4-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-quinoline

Participants

Reaction Conditions

Reaction Steps

A solution of 4-chloro-6-bromoquinoline (1.6 g, 6.63 mmol), diisopropylethylamine (1.93 mL, 11.05 mmol) in DMF (20 mL) under nitrogen was degassed by bubbling in nitrogen for 30 min. Tris(dibenzylideneacetone)dipalladium (506 mg, 0.552 mmol), Xantphos (640 mg, 1.105 mmol), and 6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (1.0 g, 5.525 mmol) were added. The reaction mixture was stirred at 100° C. for 18 h. The reaction mixture was cooled to room temperature, and partitioned between 1 N aqueous NaOH and 10% methanol/di-chloromethane. The aqueous layer was extracted with 10% methanol/dichloromethane (3×) and the combined organic layers were adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-6% methanol/dichloromethane afforded 468 mg of a (1:1) mixture of 4-chloro-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline and 6-bromo-4-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline as a beige solid. The (1:1) mixture (70 mg) was dissolved in DMF (0.5 mL), and 4-methyl-4H-[1,2,4]triazole-3-thiol (12 mg, 0.1 mmol) was added. The reaction mixture was stirred at 60° C. for 21 h then at 80° C. for 25 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between 1 N aqueous NaOH and 10% methanol/dichloromethane. The aqueous layer was extracted with 10% methanol/dichloromethane (2×) and the combined organic layers were adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-10% methanol/dichloromethane afforded 16 mg of 6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-4-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-quinoline as a cream color solid (78% yield).

Provenance & Evidence