Cesium carbonate → Methyl 4-(4-chloro-2-fluorophenyl)-2-methylnicotinate

HRID 1398335Notes

Reaction equation

HRID 1398335 reaction equation
Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[CH:15]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=2)=[C:16]([F:23])[CH:15]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 75806TricyclohexylphosphineHCID 4193595(4-Chloro-2-fluorophenyl)boronic acidHCID 84070460Methyl 4-chloro-2-methylpyridine-3-carboxylate

Product 1

HCID 86710334Methyl 4-(4-chloro-2-fluorophenyl)-2-methylnicotinateYield 17%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 31374DimethylacetamideSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of methyl 4-chloro-2-methylnicotinate (4 g, 21.55 mmol), (4-chloro-2-fluorophenyl)boronic acid (4.13 g, 23.71 mmol), tricyclohexylphosphine (1.813 g, 6.47 mmol), Pd(OAc)2 (0.484 g, 2.155 mmol) and Cs2CO3 (14.04 g, 43.1 mmol) in DMA (15 mL) was purged with nitrogen for 5 min and heated at 100° C. overnight (14 h). After cooling, the reaction mixture was filtered through diatomaceous earth (Celite®). DMA was removed under reduced pressure and the residue was diluted with ethyl acetate (10 mL). The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (EtOAc-hexane) to afford methyl 4-(4-chloro-2-fluorophenyl)-2-methylnicotinate (1 g, 3.58 mmol, 17% yield) as a red oil. LC/MS, (ESI) m/z 280.1 [(M+H)+, calcd for C14H12ClFNO2 280.0]; LC/MS retention time (method D): tR=0.80 min.

Workup

  1. customwas purged with nitrogen for 5 min
  2. temperatureAfter cooling
  3. filtrationthe reaction mixture was filtered through diatomaceous earth (Celite®)
  4. customDMA was removed under reduced pressure
  5. additionthe residue was diluted with ethyl acetate (10 mL)
  6. concentrationThe organic phase was concentrated under reduced pressure
  7. custompurified by silica gel column chromatography (EtOAc-hexane)

Sources & evidence

ORD record
ord-d24c9ceb747b49ac902475b439b81cac
Source dataset
uspto-grants-2014_12
Patent number
US08901305B2

Reaction notes

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