Methylhydrazine → 3-(4-Fluorobenzyl)-5-(3-iodophenyl)-1-methyl-1h-pyrazole

HRID 916707Notes

Reaction equation

HRID 916707 reaction equation
N(C(C)C)C(C)C.[Li]CCCC.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([I:22])[CH:17]=1)=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](OC)=O)=[CH:26][CH:25]=1.[CH3:35][NH:36][NH2:37]>C1COCC1.CCO.C(O)(=O)C>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([I:22])[CH:17]=3)[N:36]([CH3:35])[N:37]=2)=[CH:26][CH:25]=1

Participants

9

Reactant 5

HCID 6061MethylhydrazineHCID 7912DiisopropylamineHCID 84449Ethanone, 1-(3-iodophenyl)-HCID 2733233Methyl 2-(4-fluorophenyl)acetateHCID 178418339Butyllithium

Product 1

HCID 587573783-(4-Fluorobenzyl)-5-(3-iodophenyl)-1-methyl-1h-pyrazole

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 702EthanolSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

A solution of iPr2NH (11.2 mL, 80 mmol) in THF (100 mL) was cooled in an ice/salt bath and nBuLi (80 mmol) in hexanes (1.6M, 50 mL) was added dropwise. The solution was stirred for 1 h, then cooled to −78° C. A solution of 3-iodoacetophenone (19.7 g, 80 mmol) in THF (30 mL) was added dropwise and stirred for 1 h at −78° C., then a solution of methyl 4-fluorophenylacetate (13.4 g, 80 mmol) in THF (30 mL) was added. The mixture was stirred for 24 h while warming to RT. Acetic acid (9 mL) and EtOH (100 mL) were added, followed by MeNHNH2 (4.2 mL, 80 mmol). The mixture was heated to 60° C. for 1 h and, after cooling, the solvent was removed under reduced pressure. The residue was partitioned between CH2Cl2 and H2O, the CH2Cl2 layer was separated and retained and the aqueous layer re-extracted with CH2Cl2. The combined organic extracts were washed with brine, dried (MgSO4), and evaporated. The residue was purified by silica chromatography eluting with 50-80% CH2Cl2/iso-hexane to yield 3-(4-fluorobenzyl)-5-(3-iodophenyl)-1-methyl-1H-pyrazole, as the second of two pyrazole isomers, as a brown oil (4.5 g, 15%). 1H NMR (CDCl3, 500 MHz) δ 7.72 (1H, s), 7.69 (1H, d, J=8.0 Hz), 7.31 (1H, d, J=8.0 Hz), 7.26-7.20 (2H, m), 7.13 (1H, t, J=8.0 Hz), 6.96 (2H, t, J=8.8 Hz), 6.01 (1H, s), 3.93 (2H, s), 3.81 (3H, s). MS (ES+) C17H14FIN2 requires: 392, found: 393 (M+H+).

Workup

  1. stirringstirred for 1 h at −78° C.
  2. stirringThe mixture was stirred for 24 h
  3. temperaturewhile warming to RT
  4. temperatureThe mixture was heated to 60° C. for 1 h
  5. temperatureafter cooling
  6. customthe solvent was removed under reduced pressure
  7. customThe residue was partitioned between CH2Cl2 and H2O
  8. customthe CH2Cl2 layer was separated
  9. extractionthe aqueous layer re-extracted with CH2Cl2
  10. washThe combined organic extracts were washed with brine
  11. dry with materialdried (MgSO4)
  12. customevaporated
  13. customThe residue was purified by silica chromatography
  14. washeluting with 50-80% CH2Cl2/iso-hexane

Sources & evidence

ORD record
ord-794139f11c754c41a25a097995131638
Source dataset
uspto-grants-2007_09
Patent number
US07271191B2

Reaction notes

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