Water → Methyl 5-chloro-2-(4-fluorobenzyl)nicotinate

HRID 1293205Notes

Reaction equation

HRID 1293205 reaction equation
Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Zn+])=[CH:17][CH:16]=1.O>O1CCCC1.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>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]

Participants

6

Reactant 3

HCID 962WaterHCID 2764318Methyl 2,5-DichloronicotinateHCID 178505764HCID 178505764, compound

Product 1

HCID 57572307Methyl 5-chloro-2-(4-fluorobenzyl)nicotinateYield 88%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
60 °C

Procedure

To a stirred solution of methyl 2,5-dichloronicotinate (Journal of Chemical and Engineering Data 1981, 26, 332, 350 mg, 1.70 mmol) and tetrakis(triphenylphosphine)palladium(0) (196 mg, 0.17 mmol) in tetrahydrofuran (6 mL) was added a 0.5 M solution of 4-fluorobenzylzinc chloride in tetrahydrofuran (4.08 mL, 2.04 mmol) at 0° C. under nitrogen. The resulting mixture was heated at 60° C. for 16 h. The mixture was poured into water (50 mL) and the aqueous mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (6/1) to afford 416 mg (88%) of the title compounds as colorless oil: 1H-NMR (CDCl3) δ 8.64 (1H, d, J=2.6 Hz), 8.17 (1H, d, J=2.6 Hz), 7.24–7.20 (2H, m), 6.96–6.90 (2H, m), 4.50 (2H, s), 3.89 (3H, s).

Workup

  1. extractionthe aqueous mixture was extracted with ethyl acetate (100 mL)
  2. dry with materialThe organic layer was dried over magnesium sulfate
  3. concentrationconcentrated under reduced pressure
  4. customThe residue was purified
  5. customby flush column chromatography on silica gel eluting with hexane/ethyl acetate (6/1)

Sources & evidence

ORD record
ord-8f4a1d1a20174d92b8c60851634f40e3
Source dataset
uspto-grants-2007_07
Patent number
US07238714B2

Reaction notes

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