Formaldehyde → HCID 58874500, compound

Participants

Reaction Steps

Five individual round-bottomed thick-walled glass vials were charged with stir bars, (R)-(+)-3-aminoquinuclidine dihydrochloride (440 mg, 2.21 mmol), ammonium acetate (195 mg, 2.53 mmol), 1-(5-bromo-thiophen-2-yl)-2,2-dihydroxyethanone (500 mg, 2.21 mmol), formaldehyde (37%, aqueous—210 μL, 2.53 mmol) and glacial AcOH/water (1:1, 3.5 mL). All vials were crimp sealed and subjected to microwave radiation for 20 minutes at 120° C. The resultant mixtures were combined, diluted with water, basified to pH˜13 with 20% NaOH (aq), and extracted with CHCl3 (5×60 mL) and EtOAc (2×40 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated by rotary evaporation to a brown gummy residue. The material was subjected to flash chromatography (SiO2—120 grams; gradient elution: 5-10% 4N NH3/MeOH—EtOAc at 90 mL/min over 48 min) to provide a ˜2:1 regio-isomeric mixture of 5- and 4-bromothienyl-imidazolyl compounds as an orange-tan gum (1.186 g, 33%) as determined by 1H NMR signal integration. The mixture was subsequently purified by SFC with 25% MeOH/CO2 with 0.5% DMEA at 50 mL/min, monitoring at 280 nm, to give (R)-3-[4-(5-bromo-thiophen-2-yl)-imidazol-1-yl]-1-azabicyclo[2.2.2]octane (Example 6) was obtained as a pale orange solid (283 mg, 8%). Mass spectrum (API+) M+1: 338 (100%); 1H NMR (300 MHz, CDCl3) δ 1.53 (m, 1H), 1.63-1.87 (m, 3H), 2.13 (app q, J=3.1 Hz, 1H), 2.81-3.04 (m, 4H), 3.14 (dd, J=14.5, 5.3 Hz, 1H), 3.48 (ddd, J=14.5, 9.7, 1.8 Hz, 1H), 4.22 (m, 1H), 6.97 (app q, J=4 Hz, 2H), 7.15 (d, J=1.3 Hz, 1H), 7.57 (d, J=1.3 Hz, 1H).

Provenance & Evidence