Pyridine → 2-(2-(1-(3-(3-Cyanophenoxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetic acid

Participants

Reaction Steps

A mixture of tert-butyl 2-(2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate (7F; 29 mg, 0.080 mmol), (3-cyanophenyl)boronic acid (24 mg, 0.160 mmol), TEA (0.2 mL, 1.44 mmol), pyridine (0.2 mL, 2.473 mmol), Cu(OAc)2 (16 mg, 0.088 mmol), 4A Molecular sieves (200 mg) in DCM (1 mL) was stirred under air at rt for 3 days. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (5 mL) and 1N aq. HCl (5 mL). The organic phase was washed with water (5 mL×5), dried (MgSO4), and concentrated in vacuo to provide the crude 3-cyanophenoxyphenyl t-butyl ester intermediate. This material was taken up in 1N aq. NaOH in MeOH (1 mL) and stirred at rt for 2 h, then was concentrated in vacuo. The residue was acidified to pH=5 with 1N aq. HCl and extracted with EtOAc. The organic layer was washed with brine and concentrated in vacuo. The crude material was purified by preparative LC/MS (Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 MeCN:water with 0.1% TFA; Mobile Phase B: 95:5 MeCN:water with 0.1% TFA; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min) to give the title compound (17 mg, 0.040 mmol, 50% yield) as a clear oil. LCMS [M−H]+=406.1; 1H NMR (DMSO-d6) δ: 7.62-7.55 (m, 2H), 7.47 (d, J=2.6 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.30 (dt, J=5.9, 2.8 Hz, 1H), 7.21 (d, J=7.8 Hz, 1H), 7.09 (s, 1H), 6.92 (dd, J=8.0, 2.4 Hz, 1H), 3.96 (s, 2H), 3.75 (s, 2H), 3.49 (t, J=6.8 Hz, 2H), 2.12-1.99 (m, 2H), 1.87-1.74 (m, 2H), 1.72-1.57 (m, 4H), 1.40 (t, J=6.8 Hz, 2H).

Provenance & Evidence