4-(5-Fluoro-2-pyridinyl)benzeneMethanol synthesis

Yield:1257426-54-2 46%

Reaction Conditions:

with sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride in ethanol;water;toluene at 89; for 3.33333 h;Inert atmosphere;

Steps:

2.AA

A stirred mixture of 4-(hydroxymethyl)phenylboronic acid (34) (501 mg, 3.30 mmol) and Pd(dppf)Cl₂ (338 mg, 0.462 mmol) in toluene (36 mL) and EtOH (18 mL) was degassed for 15 min (vacuum pump) and then N₂ was added. An aqueous solution of 2M Na₂CO₃ (9 mL, 18 mmol) was added by syringe and the stirred mixture was again degassed for 15 min, and then N₂ was added. 2-Bromo-5-fluoropyridine (110) (1.44 g, 8.18 mmol) was added by syringe and the resulting mixture was stirred at 89 ⁰C for 200 min. The cooled mixture was then diluted with aqueous NaHCO₃ (100 mL) and extracted with CH₂Cl₂ (5x 100 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with CH₂Cl₂ and 0-25% Et₂O/petroleum ether firstly gave foreruns, and then further elution with 33-50% Et₂O/petroleum ether gave [4-(5-fluoro-2-pyridinyl)phenyl]methanol (111) (307 mg, 46%) as a cream solid (following pentane trituration): mp 100-101 ⁰C; ¹H NMR (CDCl₃) δ 8.54 (d, J = 2.9 Hz, 1 H), 7.94 (dt, J = 8.4, 1.9 Hz, 2 H), 7.72 (ddd, J = 8.8, 4.2, 0.5 Hz, 1 H), 7.50- 7.43 (m, 3 H), 4.76 (d, J = 6.0 Hz, 2 H), 1.69 (t, J = 6.0 Hz, 1 H); HRESIMS calcd for C₁₂H_nFNO mlz [M + H]⁺ 204.0819, found 204.0824.

References:

WO2011/14774,2011,A1 Location in patent:Page/Page column 52