Reaction Steps
To a stirred solution of (2R)-5′-bromo-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine] (Scheme 1, 3.2 g, 10.8 mmol) and (5-formyl-2-thienyl)boronic acid (3.37 g, 21.6 mmol) in 150 mL DME/H2O/EtOH (7:3:2), powdered Na2CO3 (4.58 g, 43.2 mmol) was added. The resulting mixture was purged with N2 at rt for 15 min, before the addition of dichloro[bis(triphenylphosphoranyl)]palladium (380 mg, 0.54 mmol). The reaction mixture was purged with N2 for another 15 min, before being heated in a 70° C. oil bath under N2 for 3-4 h. The reaction mixture was cooled and then concentrated under reduced pressure. The solid residue was treated with 150 mL CHCl3, and the resulting suspension was filtered through a short pad of diatomaceous earth (the filter cake was washed with ˜100 mL CHCl3). The combined filtrate was concentrated under reduced pressure. The blackish solid was taken into 0.5 M HCl (100-150 mL) and EtOAc (˜100 mL). The acidic aqueous layer was separated and the blackish organic layer was washed further with 0.5 M HCl (2×50 mL). The combined aqueous layers were then basified with 1 M NaOH to pH ˜12, and extracted with CHCl3 (100 mL, then 2×50 mL). The CHCl3 extracts were dried over MgSO4, filtered, and concentrated to give 3.5 g (99%) of 5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]thiophene-2-carbaldehyde. 1H NMR (500 MHz, CDCl3) δ 1.50 (dddd, J=12.8, 10.7, 6.7, 2.3 Hz, 1H), 1.68-1.72 (m, 2H), 2.03 (t, J=2.9 Hz, 1H), 2.22-2.26 (m, 1H), 2.78-2.95 (m, 3H), 2.97 (dd, J=14.7, 2.1 Hz, 1H), 3.01-3.05 (m, 1H), 3.08 (d, J=16.5 Hz, 1H), 3.40 (dd, J=14.7, 1.6 Hz, 1H), 3.48 (d, J=16.5 Hz, 1H), 7.29 (d, J=4.0 Hz, 1H), 7.68 (d, J=2.2 Hz, 1H), 7.72 (d, J=4.0 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H), 9.88 (s, 1H); MS ES+ m/z=327 (M+H+).
