Diethyl Ether → HCID 90409026, compound

Participants

Reaction Steps

To a vigorously stirred mixed of Et2O (5 mL) and 40% KOH (1 mL) was added N-methyl-N′-nitro-N-nitrosoguanidine (1.00 g, 6.80 mmol) portionwise over 15 min at 0° C. Upon complete addition, stirring was stopped. The organic layer was separated and was dried with KOH pellets. The solution was poured onto a solution of (E)-methyl 5-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)pent-2-enoate (230 mg, 0.586 mmol) in THF (2 mL/mL). Pd(OAc)2 (13.16 mg, 0.059 mmol) was then added and the reaction was allowed to warm to rt and stirred for 1 h. The reaction was concentrated in vacuo and purified by flash chromatography on SiO2 (0 to 30% EtOAc:hexanes) to afford methyl 2-(2-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethyl)cyclopropanecarboxylate (149 mg, 63%) as clear oil. A mixture of the above ester (149 mg, 0.367 mmol) and 1 N aqueous NaOH (1.1 mL, 1.10 mmol) in THF (1 mL) was stirred at rt for 18 h and then concentrated in vacuo. The residue was acidified to pH 5 with 1 N aqueous HCl and extracted with EtOAc. The organic layer was washed with brine and concentrated in vacuo. The residue was purified by preparative HPLC (PHENOMENEX® Axia 5μ C18 30×100 mm column; detection at 220 nm; flow rate=40 mL/min; continuous gradient from 30% B to 100% B over 10 min+2 min hold time at 100% B, where A=90:10:0.1 H2O:MeOH:TFA and B=90:10:0.1 MeOH:H2O:TFA) to afford the title compound (110 mg, 73% yield) as a white solid. LCMS, [M−H]+=391.2. 1H NMR (500 MHz, CDCl3) δ 7.36-7.23 (m, 3H), 7.17-7.05 (m, 3H), 6.98 (d, J=7.7 Hz, 2H), 6.83 (dd, J=8.0, 1.7 Hz, 1H), 3.77 (s, 2H), 2.07-1.92 (m, 4H), 1.69-1.55 (m, 4H), 1.44-1.18 (m, 7H), 0.82-0.73 (m, 1H). HPLC-1: RT=12.3 min, purity=100%; HPLC-2: RT=10.2 min, purity=96.3%.

Provenance & Evidence