Cesium carbonate → (R)-N-(6-bromoisoquinolin-3-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine

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Reaction Steps

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.086 g, 0.377 mmol) in N,N-dimethylformamide (15 mL) was added Cs2CO3 (0.307 g, 0.943 mmol) and 6-bromo-3-isothiocyanatoisoquinoline (0.1 g, 0.377 mmol). The suspension was stirred at room temperature for 30 minutes. N,N′-Diisopropylcarbodiimide (0.176 mL, 1. 132 mmol) was then added and the mixture was stirred for a further 18 hours. The mixture was concentrated and purified by silica gel chromatography (5-25% [9.5:0.5 methanol:ammonium hydroxide]-ethyl acetate) to afford (R)—N-(6-bromoisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.054 g, 0.135 mmol, 36% yield) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 9.04 (1H, s), 7.80-8.05 (2H, m), 7.55 (1H, dd, J=8.81, 1.76 Hz), 7.37 (1H, br. s.), 4.10 (1H, d, J=10.58 Hz), 3.87 (1H, d, J=10.83 Hz), 3.68-3.77 (1H, m), 3.56-3.67 (1H, m), 3.29-3.49 (4H, m), 2.45 (1H, br. s.), 2.28-2.41 (1H, m), 1.86-2.15 (3H, m). LCMS:R.T.=1.76; [M+]+=387.21.

Provenance & Evidence