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

HRID 1398282Notes

Reaction equation

HRID 1398282 reaction equation
Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([F:22])[CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>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.O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=2)=[C:15]([F:22])[CH:14]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 4193595(4-Chloro-2-fluorophenyl)boronic acidHCID 12574055Methyl 4-chloronicotinate

Product 1

HCID 86695906Methyl 4-(4-chloro-2-fluorophenyl)nicotinateYield 42%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
85 °C

Procedure

Methyl 4-chloronicotinate (20 g, 117 mmol), (4-chloro-2-fluorophenyl)boronic acid (22.4 g, 128 mmol), Pd(Ph3P)4 (9.4 g, 8.16 mmol) and Cs2CO3 (114 g, 350 mmol) were taken in a solvent mixture of 1,4-dioxane (400 mL) and water (30 mL) and purged with nitrogen for 5 min and heated to 85° C. After overnight stirring at this temperature the reaction mixture was diluted with ethyl acetate and filtered through a bed of diatomaceous earth (Celite®). The bed was further washed with ethyl acetate. Combined filtrate was washed with water (1×100 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the crude product which was purified via combi flash (gradient of methanol and chloroform) to afford methyl 4-(4-chloro-2-fluorophenyl)nicotinate (13 g, 48.9 mmol, 42%, with purity of 77% by LC/MS) as a brown solid. LC/MS (ESI) m/e 266.0 [(M+H)+, calcd for C13H10ClFNO2 266.1]; LC/MS retention time (method B): tR=1.69 min.

Workup

  1. custompurged with nitrogen for 5 min
  2. additionwas diluted with ethyl acetate
  3. filtrationfiltered through a bed of diatomaceous earth (Celite®)
  4. washThe bed was further washed with ethyl acetate
  5. washCombined filtrate was washed with water (1×100 mL)
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated under reduced pressure
  8. customto afford the crude product which
  9. customwas purified via combi flash (gradient of methanol and chloroform)

Sources & evidence

ORD record
ord-976413eaf58e448dacd6c7da8b9d6edf
Source dataset
uspto-grants-2014_12
Patent number
US08901305B2

Reaction notes

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