Sodium Carbonate → 4-(2-Fluoropyridin-4-yl)-2-(methylthio)pyrimidine

HRID 1774141Notes

Reaction equation

HRID 1774141 reaction equation
Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[F:10][C:11]1[CH:16]=[C:15](B(O)O)[CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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].C(Cl)Cl>[F:10][C:11]1[CH:16]=[C:15]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)[CH:14]=[CH:13][N:12]=1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 27833962-Fluoropyridine-4-boronic acidHCID 457875314-Bromo-2-(methylsulfanyl)pyrimidine

Product 1

HCID 866966454-(2-Fluoropyridin-4-yl)-2-(methylthio)pyrimidineYield 90.5%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 218864351,4-Dioxane--water (1/1)Solvent

Conditions

Temperature
85 °C

Procedure

A suspension of 4-bromo-2-(methylthio)pyrimidine (7.00 g, 34.1 mmol), 2-fluoropyridin-4-ylboronic acid (5.05 g, 35.8 mmol), Na2CO3 (10.9 g, 102 mmol) and Pd(dppf)Cl2 CH2Cl2 (1.40 g, 1.71 mmol) in dioxane/H2O (100 mL; 1:1) was heated to 85° C. under an Ar balloon for 2 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate (200 mL) and water (100 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (1×). The organics were dried, filtered and concentrated. The crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (3:1) to give 4-(2-fluoropyridin-4-yl)-2-(methylthio)pyrimidine (6.83 g, 90%) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 8.85 (d, J=5.2 Hz, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.11 (m, 1H), 7.96 (d, J=5.2 Hz, 1H), 7.92 (s, 1H), 2.62 (s, 3H); m/z (APCI-pos) M+1=222.1.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. concentrationconcentrated
  3. additionThe residue was diluted with ethyl acetate (200 mL) and water (100 mL)
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted with ethyl acetate (1×)
  6. customThe organics were dried
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude product was purified via column chromatography
  10. washeluting with hexanes/ethyl acetate (3:1)

Sources & evidence

ORD record
ord-aa98d8f7124c45e0a75c79c06822bfaa
Source dataset
uspto-grants-2016_02
Patent number
US09259470B2

Reaction notes

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