Dichloromethane → Methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)isonicotinate

HRID 1963211Notes

Reaction equation

HRID 1963211 reaction equation
Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=[C:23]([F:29])[C:24]=1[C:25]([F:28])([F:27])[F:26].C(Cl)Cl>CO.Cl[Pd]Cl.O>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:22]=[C:23]([F:29])[C:24]=1[C:25]([F:26])([F:27])[F:28]

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 2736842Methyl 2-chloropyridine-4-carboxylateHCID 667348552-(3,5-Difluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Product 1

HCID 66732493Methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)isonicotinateYield 53.3%

Reagents, catalysts & solvents 3

HCID 24290Palladium ChlorideCatalystHCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

Methyl 2-chloroisonicotinate (1,838 g, 10.71 mmol), potassium carbonate (0.888 g, 6.43 mmol) and PdCl2 (dppf) (0.233 g, 0.32 mmol) were added to a microwave vial. 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.3 g, 10.71 mmol) dissolved in MeOH (15 mL) was added and the reaction heated in a single node microwave reactor at 100° C. for a total of 40 min. DCM (100 mL) and water (100 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (100 mL). The combined organic phases were washed with brine (200 mL), dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. A gradient from 5% EtOAc in heptane over 3 CV followed by 5% to 30% of EtOAc in heptane over 9 CV was used as mobile phase. The product was collected using the wavelength 250 nm. Methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)isonicotinate (1.810 g, 53%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 3.99 (s, 3H), 7.74 (d, 2H), 7.86-7.89 (m, 1H), 8.27 (s, 1H), 8.86 (d, 1H).

Workup

  1. additionwas added
  2. customthe phases separated
  3. extractionThe aqueous phase was extracted with DCM (100 mL)
  4. washThe combined organic phases were washed with brine (200 mL)
  5. customdried with a phase separator
  6. customevaporated in vacuo
  7. customThe residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column
  8. customThe product was collected

Sources & evidence

ORD record
ord-7e59723b8b904e2abd50c00c2ffb4f3b
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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