Potassium Phosphate, Tribasic → 2-Chloro-4-(4-fluoro-2-methoxyphenyl)pyridine

HRID 593278Notes

Reaction equation

HRID 593278 reaction equation
Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([O:19][CH3:20])[CH:11]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:4]1[CH:3]=[C:2]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][C:12]=2[O:19][CH3:20])[CH:7]=[CH:6][N:5]=1

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 2782672(4-Fluoro-2-methoxyphenyl)boronic acidHCID 38477704-Bromo-2-chloropyridine

Product 1

HCID 584326092-Chloro-4-(4-fluoro-2-methoxyphenyl)pyridineYield 45%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8857Ethyl AcetateSolventHCID 218864351,4-Dioxane--water (1/1)Solvent

Conditions

Temperature
145 °C

Procedure

A mixture of 4-bromo-2-chloropyridine (1.92 g, 10 mmol), (4-fluoro-2-methoxyphenyl)boronic acid (1.70 g, 10 mmol) and K3PO4 (4.24 g, 20 mmol) in dioxane/water 10:1 (20 mL) was degassed with a stream of nitrogen for 10 min. After addition of Pd(dppf)Cl2 (816 mg, 1 mmol) the reaction mixture was heated at 145° C. for 90 minutes in a microwave oven. It was diluted with EtOAc and washed twice with sat. aq. NaHCO3 solution and once with brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (cHex/EtOAc 100:0 to 60:40) to yield the desired product A2 as a white solid (1.07 g, 45%). 1H NMR (400 MHz, d6-DMSO, 300K) δ 3.81 (s, 3H), 6.87 (dt, J=8.5 Hz, J=3.5 Hz, 1H), 7.05 (dd, J=11.4 Hz, J=2.5 Hz, 1H), 7.44 (dd, J=8.5 Hz, J=6.8 Hz, 1H), 7.48 (dd, J=5.3 Hz, J=1.5 Hz, 1H), 7.55 (m, 1H), 8.38 (d, J=5.3 Hz, 1H). MS (ES) C12H9ClFNO requires: 237. found: 238 (M+H)+.

Workup

  1. customwas degassed with a stream of nitrogen for 10 min
  2. washwashed twice with sat. aq. NaHCO3 solution and once with brine
  3. dry with materialThe organic layer was dried over MgSO4
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was purified by flash chromatography on silica gel (cHex/EtOAc 100:0 to 60:40)

Sources & evidence

ORD record
ord-95bd043ba3fb45448a63cf729d7a3ed7
Source dataset
uspto-grants-2016_01
Patent number
US09242937B2

Reaction notes

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