Toluene → HCID 178449871, compound

HRID 1916887Notes

Reaction equation

HRID 1916887 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([CH3:13])([CH3:12])[C:10]#[N:11].[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([F:22])[CH:16]=1.C[Al](C)C.C1(C)C=CC=CC=1>CC1C=CC=CC=1C>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:10](=[NH:11])[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])([CH3:13])[CH3:12])=[C:17]([F:22])[CH:16]=1

Participants

6

Reactant 4

HCID 1140TolueneHCID 1230504-Bromo-2-fluoroanilineHCID 16682925TrimethylaluminumHCID 58012232HCID 58012232, compound

Product 1

HCID 178449871HCID 178449871, compoundYield 46.6%

Reagents, catalysts & solvents 1

HCID 7237O-XyleneSolvent

Conditions

Temperature
100 °C

Procedure

2-(2,6-Dichlorophenyl)-2-methylpropanenitrile (20 g, 93 mmol) and 4-bromo-2-fluoroaniline (28.4 g, 149 mmol) were dissolved in anhydrous o-xylene (200 mL) and heated to 100° C. under N2. Trimethylaluminum (2 M) in toluene (140 mL, 280 mmol) was added drop-wise (˜0.9 mL per minute) over 2.5 hours while the reaction mixture was stirred at 100° C. After addition, the reaction mixture was stirred at 100° C. for 30 minutes, and then cooled to −5° C. The reaction mixture was very carefully quenched with potassium sodium tartrate (20 g in 100 mL water) (Caution: gas and heat formation). The reaction mixture was filtered through Celite 545. The filtrate was washed with 1N HCl (4×70 mL). The aqueous was neutralized with 2N NaOH and extracted with EtOAc (4×100 mL). The organics were combined, washed with brine, dried with Na2SO4, and concentrated on a rotary evaporator to afford 24 g of crude product. The crude product was recrystallized with 72 mL of MTBE and 240 mL of hexane to give N-(4-bromo-2-fluorophenyl)-2-(2,6-dichlorophenyl)-2-methylpropanimidamide (17.5 g, 43.3 mmol, 46.4% yield) as a white solid (purity: 99%). 1H-NMR (MeOD, 400 MHz) δ 7.42 (d, 2H, J=8.0 Hz), 7.30 (m, 2H), 7.16 (t, 1H, J=8.0 Hz), 6.93 (t, 1H, J=8.0 Hz), 2.11 (s, 6H); 13C-NMR (DMSO-d6, 100 MHz) δ 166.5, 156.1, 153.7, 140.6, 138.5, 135.9, 131.4, 128.6, 128.0, 125.7, 119.5, 112.9, 50.0, 29.2; MS m/e 403.09 (M+H+); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H3PO4, Solvent B: 90% MeOH/water with 0.2% H3PO4, gradient with 0-100% B over 4 minutes): 2.32 minutes.

Workup

  1. additionAfter addition
  2. stirringthe reaction mixture was stirred at 100° C. for 30 minutes
  3. temperaturecooled to −5° C
  4. customThe reaction mixture was very carefully quenched with potassium sodium tartrate (20 g in 100 mL water) (Caution: gas and heat formation)
  5. filtrationThe reaction mixture was filtered through Celite 545
  6. washThe filtrate was washed with 1N HCl (4×70 mL)
  7. extractionextracted with EtOAc (4×100 mL)
  8. washwashed with brine
  9. dry with materialdried with Na2SO4
  10. concentrationconcentrated on a rotary evaporator
  11. customto afford 24 g of crude product
  12. customThe crude product was recrystallized with 72 mL of MTBE and 240 mL of hexane

Sources & evidence

ORD record
ord-baf309616a6a40f6b8d03646c16ecc04
Source dataset
uspto-grants-2013_12
Patent number
US08618154B2

Reaction notes

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