Potassium Carbonate → (4-(3-Cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid

HRID 1500202Notes

Reaction equation

HRID 1500202 reaction equation
[C:1]([C:3]1[CH:4]=[C:5](F)[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])#[N:2].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.O>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[O:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][CH:16]=1)#[N:2]

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 27343604-Hydroxyphenylboronic acidHCID 27375515-Fluoro-2-(trifluoromethyl)benzonitrileHCID 21962138N,N-Dimethylformamide--water (1/1)

Product 1

HCID 89815591(4-(3-Cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 3-cyano-4-trifluoromethyl-1-fluorobenzene (70, g, 0.37, mol, Oakwood), 4-hydroxyphenylboronic acid (50, g, 0.36, mol, Boron Molecular), K2CO3, (70, g) and DMF/water (400, mL/40, mL) was heated to 100° C. for 3, h. After cooling to RT, the mixture was diluted with water (1, L) and extracted with EtOAc (1.5, L). The organic layer was washed with water (0.5, L) and brine, concentrated and purified by chromatographed over silica gel with 4% MeOH in chloroform to give (4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid as pink solid (50, g, 45%). 1H NMR (400, MHz, CD3OD) 7.70-7.70, (3H, m), 7.35, (1H, d, J=2.4, Hz), 7.24, (1H, dd, J=2.2, & 8.8, Hz), 7.00, (2H, d, J=7.7, Hz). [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17, mg, 0.022 mmol, Aldrich) was added to a mixture of 2-(6-bromopyridin-2-yl)-2-hydroxyacetamide (50, mg, 0.22, mmol), (4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid (100, mg, 0.32, mmol) and cesium carbonate (140, mg, 0.43 mmol) in EtOH/DME/water (2, mL/2, mL/1, mL) at room temperature. The reaction mixture was flushed with argon, then, shaken at 90° C. for 3, h. After cooling to RT, the reaction was quenched with water (2, mL), and extracted with EtOAc (10 mL). The organic layer was separated, concentrated and purified by reverse-phase prep HPLC (C18, 0-100% 0.1% TFA in water/0.1% TFA in ACN) to give 2-(6-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2-hydroxyacetamide (Cpd. No. 6) as off-white solid (45, mg, 50%). LC/MS: m/z=414.1, [M+H]+, ; 1H NMR (400, MHz, DMSO-d6) 8.15, (2H, d, J=8.4, Hz), 7.93 (1H, d, J=9.2, Hz), 7.82-7.86, (3H, m), 7.37-7.45, (3H, m), 7.26, (2H, d, J=9.2, Hz), 4.95, (1H, s).

Workup

  1. temperatureAfter cooling to RT
  2. extractionextracted with EtOAc (1.5, L)
  3. washThe organic layer was washed with water (0.5, L) and brine
  4. concentrationconcentrated
  5. custompurified
  6. customby chromatographed over silica gel with 4% MeOH in chloroform

Sources & evidence

ORD record
ord-2af2f7022bb5413c8207be062b061914
Source dataset
uspto-grants-2015_12
Patent number
US09206127B2

Reaction notes

Loading…