Tetrahydrofuran → 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile

HRID 1409400Notes

Reaction equation

HRID 1409400 reaction equation
Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.C1COCC1.C([O-])([O-])=O.[Na+].[Na+].[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[N:28]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=[N:29]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C1(C)C=CC=CC=1>[Cl:10][C:4]1[CH:3]=[C:2]([C:32]2[N:28]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][O:22]3)[N:29]=[CH:30][CH:31]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]

Participants

9

Reactant 4

HCID 8028TetrahydrofuranHCID 10340Sodium CarbonateHCID 70104204-Bromo-2-chlorobenzonitrileHCID 115872081-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Product 1

HCID 706562532-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrileYield 91%

Reagents, catalysts & solvents 4

HCID 74236Tetrabutylammonium BromideCatalystHCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolvent2×HCID 1140TolueneSolvent

Conditions

Temperature
42 °C

Procedure

4-Bromo-2-chlorobenzonitrile (30 g, 139 mmol), 90 ml of THF and 360 ml of toluene were placed in reaction vessel under nitrogen atmosphere. Bis(triphenylphosphine)-palladium(II) chloride (4.57 g, 6.51 mmol), Na2CO3 (33.1 g, 312 mmol), 180 ml of water and tetrabutylammonium bromide (0.894 g, 2.77 mmol) were added. The reaction mixture was heated up to 42° C. 1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (42.4 g; 152 mmol) was added in three portions within one hour. The reaction was agitated at 42° C. for one hour followed with addition of 180 ml of water and cool down. The reaction mixture was filtered and layers separated. Organic phase was washed with 400 ml of water. The layers were separated and the toluene phase was distilled close to dryness. 180 ml of ethanol was added to the warm residue and the mixture was cooled down to 5° C. for three hours. The precipitate was filtered and washed with cold ethanol. 36.4 g of the title compound was obtained after vacuum drying. 1H-NMR (400 MHz, DMSO-d6): δ 1.48-1.70 (m, 3H), 1.78-1.86 (m, 1H), 1.90-2.00 (m, 1H), 2.29-2.46 (m, 1H), 3.55-3.68 (m, 1H), 3.93-4.04 (m, 1H), 5.29 (dd, 1H), 6.72 (d, 1H), 7.65 (d, 1H), 7.72 (dd, 1H), 7.92 (d, 1H), 8.13 (d, 1H).

Workup

  1. temperaturecool down
  2. filtrationThe reaction mixture was filtered
  3. customlayers separated
  4. washOrganic phase was washed with 400 ml of water
  5. customThe layers were separated
  6. distillationthe toluene phase was distilled
  7. customclose to dryness
  8. addition180 ml of ethanol was added to the warm residue
  9. temperaturethe mixture was cooled down to 5° C. for three hours
  10. filtrationThe precipitate was filtered
  11. washwashed with cold ethanol

Sources & evidence

ORD record
ord-cb6f52f56b5249b48f517cffae7fed5e
Source dataset
uspto-grants-2014_12
Patent number
US08921378B2

Reaction notes

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