Methyl 2-chloropyridine-4-carboxylate → Methyl 2-(3-fluorobenzyl)isonicotinate

HRID 1963270Notes

Reaction equation

HRID 1963270 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]=[CH:20][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]=[CH:20][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 178505699HCID 178505699, compound

Product 1

HCID 66731557Methyl 2-(3-fluorobenzyl)isonicotinateYield 85%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

Methyl 2-chloroisonicotinate (5.6 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) were dissolved in THF (100 mL) under nitrogen and (3-fluorobenzyl)zinc(II) chloride (0.5 M in THF) (100 mL, 50.00 mmol) was added. The brown solution was stirred at 60° C. for 4 h. The reaction was quenched by addition of methanol (50 mL), diluted with EtOAc and washed with NH4Cl. The organic layer was dried over Na2SO4, filtered and evaporated to yield a yellow oil. The compound was purified in 2 runs via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 8:2 for 2 CV, then linear gradient heptane/ethyl acetate 8:2 to 5:5 over 5 CV to yield methyl 2-(3-fluorobenzyl)isonicotinate (6.766 g, 85%) as a yellow oil. 1H NMR (400 MHz, cdcl3) δ 3.93 (s, 3H), 4.21 (s, 2H), 6.88-7.00 (m, 2H), 7.02-7.07 (m, 1H), 7.22-7.30 (m, 1H), 7.66-7.73 (m, 2H), 8.68-8.73 (m, 1H). MS m/z 246 (M+H)+

Workup

  1. customThe reaction was quenched by addition of methanol (50 mL)
  2. additiondiluted with EtOAc
  3. washwashed with NH4Cl
  4. dry with materialThe organic layer was dried over Na2SO4
  5. filtrationfiltered
  6. customevaporated
  7. customto yield a yellow oil
  8. customThe compound was purified in 2

Sources & evidence

ORD record
ord-e494ae94d683497183412f4f20f9bb02
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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