Nitrogen → {2-[3-(5-Acetyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-ethyl}-methyl-carbamic acid tert-butyl ester

Participants

Reaction Conditions

Reaction Steps

To a mixture of [2-(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-ethyl]-methyl-carbamic acid tert-butyl ester (285.5 mg, 0.8 mmol), (5-acetylthiophen-2-yl)boronic acid [206551-43-1] (157.3 mg, 0.9 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (354.8 mg, 1.5 mmol), and [1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (63.4 mg, 0.1 mmol) contained in a 25 mL round bottomed flask was added a solution of 30% (v/v) water in 1,2-dimethoxyethane (12.5 mL) and a magnetic stir bar. The reaction pot was fitted to a reflux condenser, lowered into an ambient temperature oil bath, and the system taken through 10 evacuation/N2 blanket cycles while being rapidly stirred. The rapidly stirred, N2 blanketed, reaction was heated to an oil bath temperature of 85° C. for 17 h then cooled and partitioned between brine and ethyl acetate. The phase separated extract was dried (MgSO4), evaporated, flash chromatographed (silica gel eluted with 100% ethyl acetate) and crystallized (ethyl acetate/heptane) to provide {2-[3-(5-acetyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-ethyl}-methyl-carbamic acid tert-butyl ester as 121.3 mg of yellow powder, mp. 174-175° C. 1H NMR (400 MHz, DMSO-d6) δ ppm (rotamers present) 1.11 (br. s., 6H) 1.39 (br. s., 3H) 2.54 (s, 3H) 2.87 (br. s., 2H) 2.92 (br. s., 1H) 3.32 (s, 1H) 3.52 (br. s., 3H) 3.62 (br. s., 1H) 7.78-7.85 (m, 2H) 7.96 (d, J=4.29 Hz, 1H) 8.14 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 26.95, 28.16, 28.50, 34.07, 46.09, 78.50, 113.14, 123.02, 124.18, 126.13, 130.89, 134.37, 137.71, 138.38, 141.77, 154.32, 155.43, 191.11. LRMS (ESI) m/z 416.2 [(M+H)]+, calc'd for C14H20BrN6O2: 415.52.

Provenance & Evidence