2,4-Difluorobenzaldehyde → 9-[1-(2,4-Difluoro-benzyl)-azetidin-3-yl]-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

Participants

Reaction Steps

A mixture of 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.18 g, 0.49 mmol), 2,4-difluorobenzaldehyde (64 μL, 0.59 mmol) and 4 Å molecular sieves in chloroform (7 mL) was heated to reflux for 3.5 hours. After cooling sodium triacetoxyborohydride (0.50 g, 2.36 mmol) was added and the mixture was stirred at RT overnight. Aqueous saturated sodium bicarbonate solution was added and the phases were separated. The aqueous phase was extracted with 10% MeOH/DCM (×4) and the combined organic phase was dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 50-100% EtOAc in cyclohexane) to give 372 (122 mg, 50%). LCMS: RT=8.65 min, [M+H]+=494. 1H NMR δ (ppm) (CDCl3): 8.31 (1H, d, J=2.33 Hz), 7.90 (1H, s), 7.33 (1H, q, J=7.71 Hz), 7.14 (1H, dd, J=8.27, 2.33 Hz), 7.01 (1H, d, J=8.26 Hz), 6.86-6.74 (2H, m), 5.94-5.84 (1H, m), 4.37 (2H, t, J=5.06 Hz), 3.83-3.73 (3H, m), 3.68 (2H, s), 3.39 (2H, t, J=5.07 Hz), 3.29-3.23 (2H, m), 1.61 (6H, d, J=6.65 Hz)

Provenance & Evidence