Acetic Acid → tert-Butyl 4-[4-(4-fluorophenyl)-2-methyl-5-pyrimidin-4-yl-1H-imidazol-1-yl]piperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

According to the method of J. A. Murry et al., J. Am. Chem. Soc. 2001, 123, 9696-9697, N-{(4-fluorophenyl)[(4-methylphenyl)sulfonyl]methyl}acetamide (C28) (250 mg, 0.778 mmol) and 5-(2-hydroxyethyl)-3,4-dimethyl-1,3-thiazol-3-ium iodide (44.5 mg, 0.156 mmol) were combined, and the reaction flask was evacuated and refilled with nitrogen gas twice. Dichloromethane (4 mL) was added, followed by pyrimidine-4-carbaldehyde (92.5 mg, 0.856 mmol), and the reaction mixture was heated to 35-40° C., then treated with triethylamine (1.63 mL, 11.7 mmol); the reaction was stirred at 35° C. for 1 hour, then cooled to room temperature. Aliquot: LCMS m/z 274.5 [(M+1) for N-[1-(4-fluorophenyl)-2-oxo-2-pyrimidin-4-ylethyl]acetamide (C29)]. After 2 hours at room temperature, the mixture was concentrated in vacuo, dissolved in ethanol (4 mL) and treated with acetic acid (0.22 mL, 3.8 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (358 mg, 1.79 mmol). The reaction was heated to reflux for 3 hours, then concentrated under reduced pressure and diluted with ethyl acetate and aqueous sodium bicarbonate solution until the mixture was basic. The mixture was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (Eluant: 5% methanol in ethyl acetate) provided the product. Yield: 60 mg, 0.14 mmol, 18%. LCMS m/z 438.6 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 9H), 1.95-2.00 (m, 2H), 2.12-2.23 (m, 2H), 2.61 (s, 3H), 2.68-2.77 (m, 2H), 4.21-4.33 (m, 2H), 4.65 (tt, J=12.4, 3.9 Hz, 1H), 6.97 (dd, J=8.7, 8.7 Hz, 2H), 7.12 (dd, J=5.2, 1.4 Hz, 1H), 7.29 (dd, J=8.8, 5.5 Hz, 2H), 8.54 (d, J=5.3 Hz, 1H), 9.27 (d, J=1.3 Hz, 1H).

Provenance & Evidence