2-Chloropyridine → 5-(4-fluorophenyl)-2-(pyridin-2-yloxymethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one

HRID 2046209Notes

Reaction equation

HRID 2046209 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[N:14]=[C:15]([CH2:17][OH:18])[CH:16]=[C:10]3[C:9]2=[O:19])=[CH:4][CH:3]=1.Cl[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[N:14]=[C:15]([CH2:17][O:18][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH:16]=[C:10]3[C:9]2=[O:19])=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 79772-ChloropyridineHCID 10796Cesium carbonateHCID 27342152-(Di-tert-butylphosphino)biphenylHCID 679743405-(4-Fluoro-phenyl)-2-hydroxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one

Product 1

HCID 679737795-(4-fluorophenyl)-2-(pyridin-2-yloxymethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-oneYield 64,752.602%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
120 °C

Procedure

Palladium (II) acetate (9 mg, 0.038 mmol) was added to a stirred suspension of 5-(4-fluoro-phenyl)-2-hydroxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.74 g, 2.83 mmol), 2-chloropyridine (0.4 mL, 4.25 mmol), cesium carbonate (1.84 g, 5.66 mmol) and (2-biphenylyl)di-tert-butylphosphine (0.17 g, 5.66 mmol) in toluene (15 mL) in a sealed tube and under nitrogen. The mixture was stirred at 120° C. for 16 hours, then filtered through a pad of diatomaceous earth and washed with AcOEt. The solvents were evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 100/0). The desired fractions were collected, the solvents evaporated in vacuo and triturated with DIPE to yield 5-(4-fluorophenyl)-2-(pyridin-2-yloxymethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (620 g, 65% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.12-4.20 (m, 2H), 4.54 (dd, J=6.9, 5.1 Hz, 2H), 5.44 (s, 2H), 6.81 (d, J=8.6 Hz, 1H), 6.90 (ddd, J=7.1, 5.2, 0.7 Hz, 1H), 7.03 (s, 1H), 7.08-7.17 (m, 2H), 7.28-7.35 (m, 2H), 7.55-7.63 (m, 1H), 8.19 (dd, J=5.0, 1.3 Hz, 1H).

Workup

  1. filtrationfiltered through a pad of diatomaceous earth
  2. washwashed with AcOEt
  3. customThe solvents were evaporated in vacuo
  4. customthe crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 100/0)
  5. customThe desired fractions were collected
  6. customthe solvents evaporated in vacuo
  7. customtriturated with DIPE

Sources & evidence

ORD record
ord-0c23d7d466984f32b7ef6b1efbc2b838
Source dataset
uspto-grants-2013_11
Patent number
US08592422B2

Reaction notes

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