Sodium hydride → 4-((3-Fluorobenzyloxy)methyl)benzonitrile

HRID 1425713

Reaction equation

HRID 1425713 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[H-].[Na+].[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1)#[N:13].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([C:12]#[N:13])=[CH:15][CH:16]=1

Participants

6

Reactant 4

HCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 680083-Fluorobenzylic alcoholHCID 869964-(Bromomethyl)benzonitrile

Product 1

HCID 462235894-((3-Fluorobenzyloxy)methyl)benzonitrileYield 81.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
0 °C

Procedure

3-(Fluoro)benzylalcohol (5.00 g, 39.6 mmol) in THF (50 mL) was added dropwise at 0° C. to a THF (100 mL) suspension of NaH (60%, 6.3 g, 158.4 mmol). The mixture was stirred at 0° C. (30 min). Then, a THF solution of 4-cyanobenzylbromide (9.30 g, 47.6 mmol) was added dropwise at 0° C. and the mixture was stirred at room temperature (16 h). A saturated aqueous solution of NH4Cl (40 mL) was added dropwise at 0° C. and the layers were separated. The aqueous layer was washed with CH2Cl2 (60 mL). The organics layers were combined, dried (Na2SO4) and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with EtOAc/hexanes (0/10 to 1/9) as the eluant to obtain 4-((3-fluorobenzyloxy)methyl)benzonitrile as a colorless oil (7.80 g, 81%): Rf=0.65 (hexanes/EtOAc 8/2); IR (nujol) 2863, 2229, 1719, 1595, 1451, 1450, 1360, 1258, 1100, 1018, 945, 862, 790, 687, 554 cm−1; 1H NMR (CDCl3) δ 4.59 (s, CH2O), 4.61 (s, CH2O), 6.97-7.14 (m, 3 ArH), 7.26-7.37 (m, 1 ArH), 7.47 (d, J=7.5 Hz, 2 ArH), 7.65 (d, J=7.5 Hz, 2 ArH); 13C NMR (CDCl3) δ 71.2 (CH2O), 71.9 (CH2O), 113.4 (CCN), 114.4 (d, J=21.6 Hz, C2′ or C4′), 114.7 (d, J=21.6 Hz, C4′ or C2′), 118.8 (CN), 122.9 (d, J=2.3 Hz, C6′), 127.7 (ArC), 130.0 (d, J=9.2 Hz, C5′), 132.2 (ArC), 140.2 (d, J=8.0 Hz, C1′), 143.5 (ArC), 162.9 (d, J=244.8 Hz, C3′); HRMS (M+Cs+)(ESI+) 373.9957 [M+Cs+] (calcd for C15H12FNOCs+373.9954); Anal. Calcd. for C15H12FNO2: C, 74.67; H, 5.01; F, 7.87; N, 5.81. Found: C, 74.53; H, 4.93; F, 7.75; N, 5.81.

Workup

  1. stirringthe mixture was stirred at room temperature (16 h)
  2. customthe layers were separated
  3. washThe aqueous layer was washed with CH2Cl2 (60 mL)
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated under vacuum
  6. customThe residue was purified by flash column chromatography on silica gel with EtOAc/hexanes (0/10 to 1/9) as the eluant

Sources & evidence

ORD record
ord-5c71ebc683a6437bb1c8e3c32c1823ba
Source dataset
uspto-grants-2015_01
Patent number
US08933065B2

Linked notes

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