Pivalic acid → 5-(5-chloro-2-difluoromethoxyphenyl)-4-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole

HRID 529737Notes

Reaction equation

HRID 529737 reaction equation
[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)([O-:3])=[O:2].Br[C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][CH:26]([F:28])[F:27].C(=O)([O-])[O-].[K+].[K+].CC(C)(C)C(O)=O>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C12(P(C34CC5CC(CC(C5)C3)C4)CCCC)CC3CC(CC(C3)C1)C2>[Cl:24][C:22]1[CH:23]=[CH:18][C:19]([O:25][CH:26]([F:27])[F:28])=[C:20]([C:8]2[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH:21]=1

Participants

8

Reactant 4

HCID 6417Pivalic acidHCID 11430Potassium CarbonateHCID 463115372-Bromo-4-chloro-1-(difluoromethoxy)benzeneHCID 58405687HCID 58405687, compound

Product 1

HCID 1238242275-(5-chloro-2-difluoromethoxyphenyl)-4-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazoleYield 78%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 11371790Bis(adamantan-1-yl)(butyl)phosphaneCatalystHCID 31374DimethylacetamideSolvent

Conditions

Temperature
130 °C

Procedure

To a solution of 4-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole (preparation described in WO2011003065) (46.5 g, 191 mmol) in DMA (350 mL) was added 2-bromo-4-chloro-1-difluoromethoxybenzene (64.0 g, 248 mmol), palladium (II) acetate (2.15 g, 9.6 mmol), di-(adamantyl)-n-butylphosphine (5.0 g, 13.4 mmol), potassium carbonate (79.2 g, 573 mmol) and trimethylacetic acid (5.27 g, 51.6 mmol). The mixture was degassed with nitrogen for 10 minutes then heated at 130° C. for 8 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate and washed with water and brine, dried (MgSO4), filtered and evaporated. The resultant crude material was purified by flash chromatography on silica eluting with 0-10% EtOAc in cyclohexane to afford 5-(5-chloro-2-difluoromethoxyphenyl)-4-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole (62.4 g, 78%). 1H NMR (400 MHz, CDCl3) δ: (ppm) 8.24 (s, 1H), 7.52-7.53 (m, 2H), 6.39 (t, 1H), 5.29-5.30 (m, 2H), 3.63-3.64 (m, 2H), 0.90 (s, 9H).

Workup

  1. customThe mixture was degassed with nitrogen for 10 minutes
  2. temperatureto cool to room temperature
  3. additiondiluted with ethyl acetate
  4. washwashed with water and brine
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. customevaporated
  8. customThe resultant crude material was purified by flash chromatography on silica eluting with 0-10% EtOAc in cyclohexane

Sources & evidence

ORD record
ord-c2d925b977ff45c09ae164709cf9e987
Source dataset
uspto-grants-2016_05
Patent number
US09346815B2

Reaction notes

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