Tetrahydrofuran → 3-Chlorobenzyl alcohol

HRID 1058228Notes

Reaction equation

HRID 1058228 reaction equation
[Cl:1][C:2]1[CH:9]=CC(I)=C[C:3]=1CO.[H-].[Na+].C([Li])CCC.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[CH:27][C:28]([F:31])([F:30])[F:29])=[CH:22][CH:21]=1.[CH2:32]1[CH2:36][O:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:9]=[CH:34][C:33]([CH:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:28]([F:29])([F:30])[F:31])=[C:32]([CH2:36][OH:35])[CH:3]=1.[Cl:1][C:2]1[CH:3]=[C:32]([CH:33]=[CH:34][CH:9]=1)[CH2:36][OH:35]

Participants

7

Reactant 5

HCID 8028Tetrahydrofuran2×HCID 24758Sodium hydrideHCID 11030904N-(2,2,2-Trifluoroethylidene)-4-methoxyanilineHCID 671539432-Chloro-5-iodobenzyl alcoholHCID 178418339Butyllithium

Product 2

HCID 701173-Chlorobenzyl alcoholHCID 18672368N-{1-[4-chloro-2-(hydroxymethyl)phenyl]-2,2,2-trifluoroethyl}-N-(4-methoxyphenyl)amine

Conditions

Temperature
-78 °C

Procedure

A solution of 2-chloro-5-iodobenzyl alcohol (0.537 g, 2.0 mmol) in THF (10 mL) was added to sodium hydride (88 mg of a 60% dispersion in mineral oil, 2.2 mmol) at 0° C. with stirring under nitrogen. After 5 min the mixture was cooled to −78° C. and n-butyl-lithium (2.5 M in hexanes, 1.66 mL, 4.15 mmol) was added over 6 min. After a further 5 min a solution of N-(4-methoxyphenyl)-N-(-2,2,2-trifluoroethylidene)amine (0.406 g, 2.0 mmol) in THF (2 mL) was added over 5 min. After a further 5 min the reaction was quenched with saturated ammonium chloride solution and the mixture was warmed to ambient temperature and partitioned between ethyl acetate and brine. The organic layer was dried (Na2SO4) and evaporated to a gum which was purified by chromatography on silica (eluting with 2% methanol/chloroform) to give N-{1-[4-chloro-2-(hydroxymethyl)phenyl]-2,2,2-trifluoroethyl}-N-(4-methoxyphenyl)amine as a 1:1.7 mixture with 3-chlorobenzyl alcohol (0.38 g) as a gum: MS 346.4 (M+1).

Workup

  1. customAfter a further 5 min the reaction was quenched with saturated ammonium chloride solution
  2. temperaturethe mixture was warmed to ambient temperature
  3. custompartitioned between ethyl acetate and brine
  4. dry with materialThe organic layer was dried (Na2SO4)
  5. customevaporated to a gum which
  6. customwas purified by chromatography on silica (eluting with 2% methanol/chloroform)

Sources & evidence

ORD record
ord-13922c5d96384ed8b54f960f33316fb8
Source dataset
uspto-grants-2003_02
Patent number
US06515011B2

Reaction notes

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