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1-Bromo-4-(trifluoromethoxy)benzene → 1-(3-Bromo-4-fluorophenyl)-1-(tetrahydropyrimidin-2-yl)-1-[4-(trifluoromethoxy)phenyl]methanol

HRID 272661
Notes
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Reaction equation

HRID 272661 reaction equation
[Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[Br:14][C:15]1[CH:16]=[C:17]([CH:26]=[CH:27][C:28]=1[F:29])[C:18]([CH:20]1[NH:25][CH2:24][CH2:23][CH:22]=[N:21]1)=[O:19]>C1COCC1.C(OCC)(=O)C.[Cl-].[NH4+].[Cu]I>[Br:14][C:15]1[CH:16]=[C:17]([C:18]([CH:20]2[NH:25][CH2:24][CH:23]=[CH:22][NH:21]2)([C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=2)[OH:19])[CH:26]=[CH:27][C:28]=1[F:29]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 3

HCID 5210081-Bromo-4-(trifluoromethoxy)benzeneHCID 5462224MagnesiumHCID 574239842-(3-Bromo-4-fluorobenzoyl)-2,3,4,5-tetrahydropyrimidine

Product 1

HCID 688985801-(3-Bromo-4-fluorophenyl)-1-(tetrahydropyrimidin-2-yl)-1-[4-(trifluoromethoxy)phenyl]methanolYield 277.6%

Reagents, catalysts & solvents 4

HCID 24350
Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)
Catalyst
HCID 8028TetrahydrofuranSolvent3×
HCID 8857Ethyl AcetateSolvent
HCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of magnesium (2.13 g, 87.7 mmol) in THF at 50° C. is treated dropwise with a solution of 1-bromo-4-(trifluoromethoxy)benzene (21.1 g, 87.7 mmol) in THF over a period of 20 min., stirred at 50° C. for an additional 1.5 h, cooled to room temperature, treated with copper(I) iodide (0.13 g, 0.70 mmol) and a solution of 2-(3-bromo-4-fluorobenzoyl)-2,3,4,5-tetrahydropyrimidine (10.0 g, 14.9 mmol) in THF, heated at 65° C. overnight, cooled to room temperature and diluted with ethyl acetate and saturated aqueous ammonium chloride. The phases are separated. The organic phase is washed sequentially with water and brine, dried over sodium sulfate, and concentrated to afford 18.5 g of a brown oil. The oil is purified by flash chromatography (silica, 90:10:0.5 methylene chloride/methanol/concentrated ammonium hydroxide as eluent) to afford the title compound as a yellow oil, 10.0 g (64% yield), identified by NMR and mass spectral analyses. 1H NMR (300 MHz, CDCl3) δ 7.60 (dd, J=6.4, 2.3 Hz, 1H), 7.41 (dd, J=6.9, 2.0 Hz, 2H), 7.28-7.20 (m, 3H), 7.10 (t, J=8.3 Hz, 1H), 3.50 (m, 6H), 1.96 (m, 2H); ESI MS m/z 447 [C18H15BrF4N2O2+H]+.

Workup

  1. temperaturecooled to room temperature
  2. temperaturecooled to room temperature
  3. customThe phases are separated
  4. washThe organic phase is washed sequentially with water and brine
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-17e844162025476ea6b7f65b539bee06
Source dataset
uspto-grants-2008_11
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07456186B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes