Potassium Fluoride → 2-(5-Amino-6-benzyl-3-chloropyrazin-2-yl)-5-methoxybenzaldehyde

HRID 1620413Notes

Reaction equation

HRID 1620413 reaction equation
C(P(C(C)(C)C)C1N(C2C=CC=CC=2)C2C(C=1)=CC=CC=2)(C)(C)C.[NH2:25][C:26]1[C:31]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:30][C:29](Br)=[C:28]([Cl:40])[N:27]=1.[CH:41]([C:43]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:44]=1B(O)O)=[O:42].[F-].[K+]>C1COCC1.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].O>[NH2:25][C:26]1[N:27]=[C:28]([Cl:40])[C:29]([C:44]2[CH:45]=[CH:46][C:47]([O:49][CH3:50])=[CH:48][C:43]=2[CH:41]=[O:42])=[N:30][C:31]=1[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1

Participants

8

Reactant 4

HCID 522689Potassium FluorideHCID 27343652-Formyl-4-methoxybenzeneboronic acidHCID 111751332-(di-tert-butylphosphino)-N-phenylindoleHCID 866706762-Amino-3-benzyl-5-bromo-6-chloropyrazine

Product 1

HCID 866706772-(5-Amino-6-benzyl-3-chloropyrazin-2-yl)-5-methoxybenzaldehydeYield 76.9%

Reagents, catalysts & solvents 3

HCID 61538Palladium, di-mu-chlorobis(eta3-2-propenyl)di-CatalystHCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

Under an argon atmosphere, to a solution of allylpalladium(II) chloride dimer (160 mg, 437 μmol) in anhydrous THF (30 mL) was added 2-(di-tert-butylphosphino)-1-phenylindole (295 mg, 874 μmol) at room temperature, followed by stirring at room temperature for 10 minutes. Subsequently, to the mixture were successively added 2-amino-3-benzyl-5-bromo-6-chloropyrazine (5) (2.60 g, 8.74 mmol), 2-formyl-4-methoxyphenylboronic acid (6) (3.14 g, 17.4 mmol), potassium fluoride (2.60 g, 44.8 mmol) and water (160 μL, 8.88 mmol) at room temperature. The mixture was stirred overnight (14 hours) at room temperature without further treatment. After to this was added water, the product was extracted with ethyl acetate (×3). The combined organic extract was washed successively with water (×1) and brine (×1), and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=3/1) to give 2-(5-amino-6-benzyl-3-chloropyrazin-2-yl)-5-methoxybenzaldehyde (7) (2.37 g, 6.70 mmol, 76.9%) as a reddish brown solid. TLC Rf=0.27 (n-hexane/ethyl acetate=3/1); 1H NMR (500 MHz, CDCl3) δ 3.92 (s, 3H), 4.13 (s, 2H), 4.66 (s, 2H), 7.21-7.25 (m, 3H), 7.27-7.31 (m, 1H), 7.32-7.37 (m, 2H), 7.51-7.55 (m, 2H), 9.92 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 40.4, 55.7, 111.2, 120.7, 127.4, 128.4 (2C), 129.2 (2C), 132.5, 132.7, 135.7, 135.8, 137.8, 139.1, 144.1, 151.5, 160.0, 191.0.

Workup

  1. customat room temperature
  2. stirringThe mixture was stirred overnight (14 hours) at room temperature without further treatment
  3. extractionthe product was extracted with ethyl acetate (×3)
  4. extractionThe combined organic extract
  5. washwas washed successively with water (×1) and brine (×1)
  6. dry with materialdried over anhydrous sodium sulfate
  7. filtrationAfter filtration and concentration under reduced pressure
  8. customthe residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=3/1)

Sources & evidence

ORD record
ord-89d1f572a24447d9a7550c69b99320a1
Source dataset
uspto-grants-2014_07
Patent number
US08772484B2

Reaction notes

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