Sodium Carbonate → {5-[3-Fluoro-4-(trifluoromethoxy)phenyl]-2-pyridinyl}methanol

HRID 1496923Notes

Reaction equation

HRID 1496923 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[O:17][C:18]([F:21])([F:20])[F:19].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:10][C:11]1[CH:12]=[C:13]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=2)[CH:14]=[CH:15][C:16]=1[O:17][C:18]([F:19])([F:20])[F:21]

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 27831933-Fluoro-4-(trifluoromethoxy)benzeneboronic acidHCID 5200169(5-Bromopyridin-2-yl)methanol

Product 1

HCID 49852040{5-[3-Fluoro-4-(trifluoromethoxy)phenyl]-2-pyridinyl}methanolYield 60%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 702EthanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
89 °C

Procedure

A stirred mixture of (5-bromo-2-pyridinyl)methanol (105) (753 mg, 4.00 mmol), 3-fluoro-4-(trifluoromethoxy)phenylboronic acid (56) (see Example 2G) (1.165 g, 5.20 mmol) and Pd(dppf)Cl2 (366 mg, 0.50 mmol) in toluene (40 mL) and EtOH (20 mL) was degassed for 15 min (vacuum pump) and then N2 was added. An aqueous solution of 2M Na2CO3 (10 mL, 20.0 mmol) was added by syringe and the stirred mixture was again degassed for 15 min, and then N2 was added. The resulting mixture was stirred at 89° C. for 2 h, and then cooled, diluted with aqueous NaHCO3 (120 mL) and extracted with CH2Cl2 (6×100 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 50-75% CH2Cl2/petroleum ether firstly gave foreruns, and then further elution with 75% CH2Cl2/petroleum ether and 0-0.5% MeOH/CH2Cl2 gave {5-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-pyridinyl}methanol (106) (687 mg, 60%) as a light yellow-brown solid: mp 51-53° C.; 1H NMR (CDCl3) δ 8.76 (d, J=1.9 Hz, 1H), 7.84 (dd, J=8.1, 2.3 Hz, 1H), 7.46-7.34 (m, 4H), 4.83 (d, J=5.1 Hz, 2H), 3.47 (t, J=5.2 Hz, 1H); HRESIMS calcd for C13H10F4NO2m/z [M+H]+ 288.0642, found 288.0641.

Workup

  1. customwas degassed for 15 min (vacuum pump)
  2. additionN2 was added
  3. customthe stirred mixture was again degassed for 15 min
  4. additionN2 was added
  5. temperaturecooled
  6. additiondiluted with aqueous NaHCO3 (120 mL)
  7. extractionextracted with CH2Cl2 (6×100 mL)
  8. customThe extracts were evaporated to dryness
  9. customthe residue was chromatographed on silica gel
  10. washElution with 50-75% CH2Cl2/petroleum ether firstly gave foreruns
  11. washfurther elution with 75% CH2Cl2/petroleum ether and 0-0.5% MeOH/CH2Cl2

Sources & evidence

ORD record
ord-8d2f35945ba84b25b9a7f9325913f402
Source dataset
uspto-grants-2015_12
Patent number
US09198913B2

Reaction notes

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