Ammonia → 1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethanamine

Participants

Reaction Steps

A mixture of 1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethanone (941 mg, 2.263 mmol), ammonia (5.7 mL of a 2.0 M solution in EtOH, 11.31 mmol) and titanium(IV) isopropoxide (1.34 mL, 4.53 mmol) was stirred at RT in a tightly stoppered flask for 16 h. At the conclusion of this period, the mixture was treated with anhydrous 1,2-DCE (2 mL), cooled in an ice bath and then treated with sodium borohydride (128 mg, 3.39 mmol) in portions. After 45 min, the mixture had changed to a thick foamy mixture. As a result, 1,2-DCE (3 mL) was added to facilitate stirring and the reaction was stirred for an additional 2 h. After this time, the mixture was poured into aqueous concentrated NH4OH (5 mL), diluted with CH2Cl2 (115 mL) and stirred vigorously for 30 min before being filtered through Celite. The filtrate was placed in a separatory funnel and the phases separated. The aqueous phase was extracted with CH2Cl2 (3 times). The combined extracts were washed with brine, dried (MgSO4) and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel using EtOAc and 5% MeOH/CH2Cl2 as eluents to provide 1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethanamine (490 mg, 1.175 mmol, 51.9% yield) as a pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 7.18 (1 H, d, J=8.79 Hz), 6.50 (1 H, d, J=2.42 Hz), 6.41-6.47 (1 H, m), 6.30 (1 H, s), 4.22 (1 H, dd, J=13.84, 3.52 Hz), 3.91-3.99 (1 H, m), 3.87 (3 H, s), 3.69 (2 H, d, J=8.57 Hz), 3.22-3.28 (1 H, m), 2.65-2.75 (2 H, m), 2.33 (3 H, s), 1.89-1.98 (1 H, m), 1.84 (1 H, d, J=9.67 Hz), 1.53-1.63 (3 H, m).

Provenance & Evidence