Dichloromethane → (R)-8-fluoro-9-(3-hydroxy-3-(5-methylisoxazol-3-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 (80 mg, 0.21 mmol) in piperidine (2 mL) was introduced (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (158 mg, 1.04 mmol) and copper(I) iodide (2 mg, 0.01 mmol). The resulting solution was de-oxygenated by nitrogen bubbling for five minutes following which tetrakis(triphenylphosphine)palladium(0) (12 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 2 hr. After concentration of the reaction mixture in vacuo, the residue was slurried in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate (5 mL), water (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. The dry-loaded material was purified by silica gel flash column chromatography (eluent: DCM containing a 0-4% gradient of 7M ammonia in methanol) to furnish the title compound (27 mg, 0.066 mmol, 31%) as a rusty-brown solid: 1H NMR (500 MHz, d4-methanol) δ 1.63 (d, J=11.03 Hz, 2H), 1.90 (s, 3H), 2.45 (s, 3H), 2.91-3.00 (m, 2H), 3.46 (td, J=7.09, 4.10 Hz, 1H), 3.66 (td, J=8.12, 3.94 Hz, 1H), 6.33 (s, 1H), 6.94 (d, J=10.09 Hz, 1H), 8.31 (d, J=7.25 Hz, 1H); M+1=407.

Provenance & Evidence