5-Chloro-3-methyl-1-phenyl-1H-pyrazole → 5-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazole

HRID 2240150Notes

Reaction equation

HRID 2240150 reaction equation
Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.C([Li])(C)(C)C.Br[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:21]=1>C1COCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:29]1([O:28][C:22]2[CH:21]=[C:20]([C:2]3[N:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:5]=[C:4]([CH3:13])[CH:3]=3)[CH:25]=[CH:24][C:23]=2[O:26][CH3:27])[CH2:30][CH2:31][CH2:32][CH2:33]1

Participants

8

Reactant 3

HCID 27357715-Chloro-3-methyl-1-phenyl-1H-pyrazoleHCID 99703924-Bromo-2-(cyclopentyloxy)-1-methoxybenzeneHCID 178418306HCID 178418306, compound

Product 1

HCID 114508965-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazoleYield 27.8%

Reagents, catalysts & solvents 4

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

A solution of 5-chloro-3-methyl-1-phenyl-1H-pyrazole (61.8 mg, 0.32 mmol) in 5 mL of THF was cooled to −78° C. and t-butyllithium (0.47 mL, 1.7 M in heptane) was slowly added. The mixture was stirred at −78° C. for 1.5 hours and then zinc chloride (1.56 mL, 0.5 M) was added and after stirring at −78° C. for 15 minutes was warmed to room temperature. A solution containing 4-bromo-2-cyclopentyloxy-1-methoxybenzene (148 mg, 0.54 mmol) and Pd(PPh3)4 (35 mg, 0.03 mmol) in 1 mL of THF was added and the reaction was heated to 60° C. for 12 hours. The mixture was diluted with 20 mL of ethyl acetate and the organic layer was washed with 10 mL of a saturated ammonium chloride solution, 20 mL of water and 20 mL of brine. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by silica gel column chromatography using a gradient elution from 20% to 50% ethyl acetate in hexanes yielded 31 mg of 5-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazole. 1H-NMR (CDCl3, 300 MHz) δ 7.3 (m, 5H), 6.8 (m, 2H), 6.6 (d, 1H), 6.3 (s, 1H), 4.4 (m, 1H), 3.8 (s, 3H). 2.4 (s, 3H), 1.7-1.5 (m, 8H). (M+1)=349.1

Workup

  1. stirringafter stirring at −78° C. for 15 minutes
  2. temperaturewas warmed to room temperature
  3. additionwas added
  4. temperaturethe reaction was heated to 60° C. for 12 hours
  5. washthe organic layer was washed with 10 mL of a saturated ammonium chloride solution, 20 mL of water and 20 mL of brine
  6. dry with materialThe organic layer was dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customPurification by silica gel column chromatography
  10. washa gradient elution from 20% to 50% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-4cc2332a0174450a8bb7eee9adab5da6
Source dataset
uspto-grants-2010_05
Patent number
US07723348B2

Reaction notes

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