Dichloromethane → (R)-8-fluoro-9-(3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl)-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide

Participants

Reaction Conditions

Reaction Steps

Into a pressure tube containing a solution of 8-fluoro-9-iodo-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide (73 mg, 0.19 mmol) in piperidine (2 mL) was introduced (2R)-2-(pyrimidin-2-yl)but-3-yn-2-ol (140 mg, 0.95 mmol) and copper(I) iodide (2 mg, 0.01 mmol). The resulting solution was de-oxygenated by nitrogen bubbling for five minutes then tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.01 mmol) was added. Nitrogen bubbling was continued for a further two minutes and the pressure tube closed under an atmosphere of nitrogen. The reaction mixture was warmed to 40° C. for 6 hr. After concentration of the reaction mixture in vacuo, the residue was slurried in ethyl acetate (20 mL) and washed with saturated aqueous sodium bicarbonate (2×5 mL), water (2×5 mL) and brine (5 mL). The organic extract was dried over sodium sulfate, filtered and the filtrate evaporated onto silica gel (−1.0 g) in vacuo. Purification of the dry-loaded material by silica gel flash column chromatography (eluent: DCM containing a 0-8% gradient of 7M ammonia in methanol) furnished the title compound (35 mg, 0.087 mmol, 46%) as a colorless solid: 1H NMR (500 MHz, d4-methanol) 61.64 (d, J=9.77 Hz, 2H), 1.97 (s, 3H), 2.96 (qd, J=7.88, 2.84 Hz, 2H), 3.43-3.50 (m, 1H), 3.66 (td, J=8.12, 4.26 Hz, 1H), 6.91 (d, J=10.09 Hz, 1H), 7.46 (t, J=4.89 Hz, 1H), 8.32 (d, J=7.57 Hz, 1H), 8.86 (d, J=5.04 Hz, 2H); M+H=404.

Provenance & Evidence