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Formaldehyde → 2-(Hydroxymethyl)-4-(trifluoromethyl)phenol

HRID 392912
Notes
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Reaction equation

HRID 392912 reaction equation
C=O.[F:3][C:4]([F:13])([F:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C1(B(O)O)C=CC=CC=1.[C:23](O)(=[O:26])CC.OO>C1C=CC=CC=1.C1COCC1.O>[OH:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([F:12])([F:13])[F:3])=[CH:10][C:9]=1[CH2:23][OH:26]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 5

HCID 712FormaldehydeHCID 784Hydrogen PeroxideHCID 1032Propionic AcidHCID 66827Phenylboronic AcidHCID 678744-(Trifluoromethyl)phenol

Product 1

HCID 233631292-(Hydroxymethyl)-4-(trifluoromethyl)phenolYield 70.6%

Reagents, catalysts & solvents

3
HCID 241BenzeneSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

Paraformaldehyde (3.4 g, 0.114 mol) was added in 0.5 g portions over a six hour period to a refluxing mixture of 4-trifluoromethyl phenol (2.3 g, 0.0142 mol), phenyl boronic acid (2.1 g, 0.017 mol) and proprionic acid (530 μL, 7 mmol) in benzene with the azeotropic removal of water (Dean-Stark trap). When the addition was complete, the reaction was heated for an additional hour, then cooled with an ice bath, diluted with THF (30 mL) and treated with 5 mL of 30% hydrogen peroxide solution. After stirring for one hour, the mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was washed with NaHSO3 solution (1×50 mL), brine (1×50 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (30% ethyl acetate/hexanes) to afford 950 mg (35%) of the title compound as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.42 (d, 1H, J=9.1 Hz); 7.3 (s, 1H); 6.95 (d, 1H, J=9.1 Hz); 4.89 (s, 2H);

Workup

  1. additionWhen the addition
  2. temperaturethe reaction was heated for an additional hour
  3. temperaturecooled with an ice bath
  4. customthe mixture was partitioned between water (50 mL) and ethyl acetate (50 mL)
  5. washThe organic layer was washed with NaHSO3 solution (1×50 mL), brine (1×50 mL)
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified by flash chromatography (30% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-81500cb4265c40f2b2387409994cb0c0
Source dataset
uspto-grants-2004_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US06803457B1

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes