Methyl 2-chloropyridine-4-carboxylate → Methyl 2-(3,5-difluorobenzyl)isonicotinate

HRID 1963317Notes

Reaction equation

HRID 1963317 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].[Cl-].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:17][Zn+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:17][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]

Participants

5

Reactant 2

HCID 2736842Methyl 2-chloropyridine-4-carboxylateHCID 178505923HCID 178505923, compound

Product 1

HCID 66731588Methyl 2-(3,5-difluorobenzyl)isonicotinateYield 86.4%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

Methyl 2-chloroisonicotinate (5.600 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) were dissolved in THF (100 mL) under nitrogen, then (3,5-difluorobenzyl)zinc(II) chloride (0.5 M in THF, 100 mL, 50.00 mmol) was added and the resulting solution was stirred at 60° C. for 3 h before it was cooled to room temperature and quenched with methanol (50.0 mL). The mixture was diluted with EtOAc and washed with satd NH4Cl. The organic phase was dried and concentrated. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column, eluent isocratic heptane/EtOAc 8:2 for 2 CV, then a gradient from 20% to 50% of EtOAc in heptane over 6 CV was used as mobile phase. Methyl 2-(3,5-difluorobenzyl)isonicotinate (7.42 g, 86%) was isolated as an oil. 1H NMR (400 MHz, cdcl3) δ 3.94 (s, 3H), 4.18 (s, 2H), 6.66 (tt, 1H), 6.74-6.82 (m, 2H), 7.67-7.75 (m, 2H), 8.67-8.75 (m, 1H). MS m/z 264 (M+H)+

Workup

  1. temperaturewas cooled to room temperature
  2. customquenched with methanol (50.0 mL)
  3. additionThe mixture was diluted with EtOAc
  4. washwashed with satd NH4Cl
  5. customThe organic phase was dried
  6. concentrationconcentrated
  7. customThe residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column, eluent isocratic heptane/EtOAc 8:2 for 2 CV

Sources & evidence

ORD record
ord-8aa44a3b6b884c5ea56c14e19c6bda84
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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