1-isopropyl-3-methyl-1H-1,2,4-triazole → 10-Bromo-9-fluoro-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

Participants

Reaction Conditions

Reaction Steps

A solution of 1-isopropyl-3-methyl-1H-[1,2,4]triazole (in a 6:4 mixture with 1-isopropyl-5-methyl-1H-[1,2,4]triazole, 0.75 g, 3.6 mmol) in THF (10 mL) was cooled to −35° C. and treated with n-butyllithium (2.5M in hexanes, 1.45 mL, 3.63 mmol). Stirring was continued for 1 h maintaining the internal temperature of between −30° C. and −20° C. The mixture was then cooled to −30° C. and a solution of zinc chloride (0.5M in THF, 4.22 mL, 2.11 mmol) was added over 5 min. The reaction mixture was stirred at −25° C. for 30 min, then slowly warmed to RT and stirred at this temperature for 1 h. A suspension of 9-bromo-8-fluoro-2-iodo-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (1.046 g, 2.557 mmol) in THF (20 mL) was added followed by Pd(PPh3)4 (148 mg, 0.128 mmol) and the reaction mixture was stirred at 60° C. under a nitrogen atmosphere for 18 h. After cooling to RT, volatiles were removed in vacuo and the residue was partitioned between EtOAc (300 mL) and water. The aqueous phase was extracted with EtOAc (300 mL) and the combined organic layers were washed with water followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, eluent 100% EtOAc followed by gradient 0-8% MeOH in methyl acetate) affording 9-Bromo-8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a pale yellow solid (0.66 g, 64%). LCMS: RT 4.90 min [M+H]+ 405.9/407.9

Provenance & Evidence