4-Bromophenacyl bromide → (1R,3S,5R)-tert-butyl 3-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

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Reaction Steps

Hunig's Base (7.69 mL, 44.0 mmol) was added to a stirred solution of 2-bromo-1-(4-bromophenyl)ethanone (12.23 g, 44.0 mmol) and (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (10 g, 44 mmol) in dry MeCN (400 mL). The mixture was stirred for 16 h at RT. The solvent was removed in vacuo and the residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate solution and brine, dried (sodium sulfate), filtered and concentrated. In a pressure vessel the residue was taken up in xylene (400 mL) and ammonium acetate (33.9 g, 440 mmol) was added. The vessel was sealed and heated at 140° C. for 2 h. The solvent was removed in vacuo and the residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate solution (pH=9), brine, dried over sodium sulfate and concentrated. The crude product, as a reddish orange foam, was dissolved in methylene chloride and placed onto a 300 g Thompson silica gel cartridge (eluted with 20% B to 100% B for 4000 mL where Solvent B=ethyl acetate and Solvent A=hexanes) to yield (1R,3S,5R)-tert-butyl 3-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (16.67 g, 39.1 mmol, 88.8% yield) as a golden-brown foam. LC-MS retention time 1.762 min; m/z 403.94 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna S10 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min and an analysis time of 5 min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 7.62 (br d, J=8.6 Hz, 2H), 7.50 (br d, J=8.6 Hz, 2H), 7.37 (s, 1H), 4.66 (br s, 1H), 3.58 (br s, 1H), 2.56-2.47 (m, 1H), 2.36-2.27 (m, 1H), 1.75-1.67 (m, 1H), 0.97 (br s, 9H), 0.88-0.81 (m, 1H), 0.64-0.57 (m, 1H).

Provenance & Evidence