(Trimethylsilyl)acetonitrile → 1-(5-(cyanomethyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

Participants

Reaction Conditions

Reaction Steps

To a mixture of Xantphos (0.049 g, 0.084 mmol), Pd2(dba)3 (0.077 g, 0.084 mmol) and 1-(5-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.500 g, 0.838 mmol) in N,N-dimethylformamide (0.838 ml) was added (trimethylsilyl)acetonitrile (0.138 ml, 1.006 mmol) followed by zinc difluoride (0.061 g, 0.587 mmol). The flask was sealed under an atmosphere of nitrogen and heated at 100° C. overnight. The reaction was diluted with water and extracted with DCM (×2). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was taken up in DCM and purified via MPLC, eluting with 0-100% ethyl acetate in heptanes with a 5% DCM additive, followed by reverse-phase preparative HPLC (XBridge Prep C18 column, 10 micron OBD, 19×100 mm), 0.1% TFA in CH3CN/H2O, gradient 25% to 95% over 12 min to provide 1-(5-(cyanomethyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.092 g, 0.165 mmol, 19.72% yield) as a light-yellow solid. 1-(5-(cyanomethyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (92 mg) was taken up in 2.5 mL of DCM and 2.5 mL of TFA and was heated under microwave irradiation for 1 h at 70° C. until complete deprotection. The reaction mixture was concentrated in vacuo. The crude material was purified by reverse-phase preparative HPLC (XBridge Prep C18 column, 10 micron OBD, 19×100 mm), 0.1% TFA in CH3CN/H2O, gradient 25% to 70% over 12 min to provide 1-(5-(cyanomethyl)-2-methoxyphenyl))-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.011 g, 0.025 mmol, 3.01% yield) as a white solid. MS (ESI, pos. ion) m/z: [M+1] 437.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.68 (s, 3 H) 4.03 (s, 2 H) 6.44 (d, J=1.76 Hz, 1 H) 6.71 (d, J=9.02 Hz, 1 H) 6.79 (d, J=9.64 Hz, 1 H) 7.30 (d, J=2.28 Hz, 1 H) 7.34 (d, J=8.60 Hz, 1 H) 7.55 (dd, J=8.60, 2.28 Hz, 1 H) 7.84 (dd, J=8.97, 2.23 Hz, 1 H) 8.22 (d, J=9.74 Hz, 1 H) 8.36 (d, J=2.18 Hz, 1 H) 8.73 (d, J=1.87 Hz, 1 H) 11.64 (s, 1 H).

Provenance & Evidence