Potassium Carbonate → Methyl 2-(3,4-difluorophenyl)isonicotinate

HRID 1963129Notes

Reaction equation

HRID 1963129 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].[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[F:19].C(=O)([O-])[O-].[K+].[K+]>CO.Cl[Pd]Cl>[F:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:16]=[CH:17][C:18]=1[F:19]

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 27343373,4-Difluorobenzeneboronic acidHCID 2736842Methyl 2-chloropyridine-4-carboxylate

Product 1

HCID 66731610Methyl 2-(3,4-difluorophenyl)isonicotinateYield 80.1%

Reagents, catalysts & solvents 2

HCID 24290Palladium ChlorideCatalystHCID 887MethanolSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of methyl 2-chloroisonicotinate (5 g, 29.14 mmol), 3,4-difluorophenylboronic acid (5.06 g, 32.05 mmol), potassium carbonate (2.416 g, 17.48 mmol) and PdCl2 (dppf) (1.066 g, 1.46 mmol) was stirred in methanol (30 mL) and heated in a single-node microwave reactor at 100° C. for 30 min. The solvent was evaporated in vacuo. DCM (400 mL) and 8% NaHCO3 (aq) (400 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (400 mL). The combined organic phases were dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on three Biotage® KP-SIL 100 g columns. A gradient from 5% EtOAc in heptane over 2 CV followed by 5% to 20% of EtOAc in heptane over 9 CV was used as mobile phase. Methyl 2-(3,4-difluorophenyl)isonicotinate (5.82 g, 80%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 4.00 (s, 3H), 7.23-7.33 (m, 1H), 7.76-7.84 (m, 2H), 7.90-8.00 (m, 1H), 8.21-8.27 (m, 1H), 8.82 (dd, 1H).

Workup

  1. customThe solvent was evaporated in vacuo
  2. additionDCM (400 mL) and 8% NaHCO3 (aq) (400 mL) were added
  3. customthe phases separated
  4. extractionThe aqueous phase was extracted with DCM (400 mL)
  5. customThe combined organic phases were dried with a phase separator
  6. customevaporated in vacuo
  7. customThe residue was purified by automated flash chromatography on three Biotage® KP-SIL 100 g columns

Sources & evidence

ORD record
ord-1c89d08cbabb45d2b71b5d8e37590ed9
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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