Propionic Acid → 1-benzyl-N,N-dipropyl-5-(trifluoromethyl)-1H-pyrazol-3-amine

Participants

Reaction Conditions

Reaction Steps

To a 0° C. solution of propionic acid (12.4 mL, 166.0 mmol) in PhMe (15.0 mL) was added NaBH4 (1.96 g, 51.8 mmol) portionwise to control the bubbling. The mixture was stirred at 0° C. until the evolution of H2 ceased. Next, 1-benzyl-5-(trifluoromethyl)-1H-pyrazol-3-amine (625 mg, 2.59 mmol) in PhMe (10.0 mL) was then added dropwise via syringe. The resulting reaction mixture was heated at 110° C. overnight. Additional propionic acid (5.0 mL, 66.9 mmol) and NaBH4 (1.00 g, 25.9 mmol) were added, and the reaction mixture was stirred overnight at 110° C. The reaction mixture was then poured into EtOAc and 0.5N aq. NaOH solution (1:1). The layers were separated, and the organic layer was washed with 0.5N aq. NaOH solution. The aqueous layer was extracted with EtOAc (3×), and the combined organic extracts were washed with sat. aq. NaCl solution and dried over Na2SO4. Filtration and concentration in vacuo provided a crude residue which was purified by flash column chromatography (gradient from 0% to 20% EtOAc/hexanes) to give the title compound (597 mg, 64%) as a 4:1 mixture of regioisomers by 1H NMR. 1H NMR (CDCl3, major regioisomer) δ 7.41-7.25 (m, 3H), 7.19 (d, J=7.0 Hz, 2H), 6.22 (s, 1H), 5.34 (s, 2H), 2.82-2.72 (m, 4H), 1.48-1.33 (m, 4H), 0.78 (t, J=7.4 Hz, 6H); MS(ESI+) m/z 326.2 (M+H)+.

Provenance & Evidence