Lithium Hexamethyldisilazide → 3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzonitrile

Participants

Reaction Conditions

Reaction Steps

Lithium bis(trimethylsilyl)amide (1M in THF, 36.0 mL, 36.0 mmol) was added to 100 mL of THF and cooled to −78° C. 2-Chloro-4-methylpyrimidine (3.07 g, 23.9 mmol) in 20 mL of THF was added dropwise over 10 minutes. The addition funnel was rinsed with 10 mL of THF. The reaction was stirred 20 minutes, and 3-cyano-N-methyl-N-(methyloxy)benzamide (see Organic Lett. 2006, 8, 4843-4846) (5.00 g, 26.3 mmol) in 25 mL of THF was added dropwise over 10 minutes. The addition funnel was rinsed with 10 mL of THF. The reaction was stirred for one hour and allowed to warm to 0° C. The reaction was quenched with saturated ammonium chloride solution and poured into H2O and EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford the product contaminated with 3-cyano-N-methyl-N-(methyloxy)benzamide. The mixture was triturated with 30% EtOAc in hexanes, filtered, and the solid washed with 30% EtOAc in hexanes followed by hexanes. The yellow solid was collected to provide 1.56 g (25%) of the title compound as an approximately 1:1 mixture of ketone and enol tautomers. 1H NMR (400 MHz, DMSO-d6) δ [Enol tautomer] 13.45 (s, 1H), 6.70 (s, 1H); [Ketone tautomer]-4.72 (s, 2H); [Aromatic protons] 8.72 (d, J=5.1 Hz, 1H), 8.62 (d, J=5.3 Hz, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 8.26 (d, J=7.9 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 8.13 (d, J=7.9 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.76 (t, J=7.9 Hz, 1H), 7.70 (t, J=7.9 Hz, 1H), 7.56 (d, J=5.1 Hz, 1H), 7.33 (d, J=5.3 Hz, 1H).

Provenance & Evidence