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Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 5℃; for 0.25 h; Stage #2: at 5 - 60℃;
A flask is charged with NaH (60percent dispersion in mineral oil, 0.72 g, 18.0 mmol) then suspended in DMF (30 mL) and cooled to 5° C. To this mixture is added benzyl alcohol (1.04 mL, 10.0 mmol) drop-wise. The mixture is stirred for 15 minutes then 4-chloropyridine-HCl (1.00 g, 6.67 mmol) is added in three portions over 5 min. The resulting mixture is stirred at 5° C. for 10 min then warmed to 60° C. and stirred for 1.5 h. The mixture is then cooled to 23° C., treated with water, and extracted with EtOAc. The combined organics are dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, 5percent EtOAc in hexanes to 50percent EtOAc in hexanes) gives the title intermediate (1.10 g, 89percent).
89%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 5℃; for 0.25 h; Stage #2: at 5 - 60℃; for 1.75 h;
Example 3 Synthesis of 4-(benzyloxy)pyridine. A flask is charged with NaH (60percent dispersion in mineral oil, 0.72 g, 18.0 mmol) then suspended in DMF (30 mL) and cooled to 5 °C. To this mixture is added benzyl alcohol (1.04 mL, 10.0 mmol) drop-wise. The mixture is stirred for 15 minutes then 4-chloropyridine-HCl (1.00 g, 6.67 mmol) is added in three portions over 5 min. The resulting mixture is stirred at 5 °C for 10 min then warmed to 60 °C and stirred for 1.5 h. The mixture is then cooled to 23 °C, treated with water, and extracted with EtOAc. The combined organics are dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, 5percent EtOAc in hexanes to 50percent EtOAc in hexanes) gives the title intermediate (1.10 g, 89percent).
Reference：
[1] Journal of Organic Chemistry, 2017, vol. 82, # 24, p. 13756 - 13767
[2] Patent: US2011/275627, 2011, A1, . Location in patent: Page/Page column 60
[3] Patent: EP2331541, 2011, A1, . Location in patent: Paragraph 0070; 0071
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[ 2683-66-1 ]
[ 49826-70-2 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 10, p. 1752 - 1757
[2] Synlett, 2005, # 9, p. 1389 - 1392
[3] Journal of Organic Chemistry, 1959, vol. 24, p. 330,332
[4] Chemical and Pharmaceutical Bulletin, 1959, vol. 7, p. 149
General procedure: Phenol (0.5 mmol), benzyl bromide(1.2 mmol) and KOH (2.0 mmol) was added to the DES (1 mL) and heated at temperature (80°C) for 2 h. After cooling to room temperature water was added and the product was extracted with ethyl acetate (1 3 mL) andanalyzed by GC–MS after the addition of hexamethylbenzene as an internal standard. The product was purified using column chromatography on silica gel(hexane/EtOAc::99:1). The pure product was characterized by 1H NMR and 13CNMR.Table 4 Comparison of different methodologies for benzylation of phenols with benzyl bromide
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