Reaction #325905

Reaction equation

TMSCl

benzyl magnesium chloride

THF

n-BuLi

1-bromo-3-fluoro-5-(trifluoromethyl)benzene

4-fluoro-3-(trifluoromethyl)benzonitrile

→

1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine

Yield 44.0%

Solvents

ether

Et2O

Conditions

Workup

1. 1
   workup.STIRRINGThe resulting reddish mixture was stirred at −78° C. for 2 h
2. 2
   OtherThe dry ice bath was removed
3. 3
   workup.STIRRINGthe resulting slurry was stirred at room temperature for 2 h
4. 4
   TemperatureThe reaction was cooled to −78° C.
5. 5
   TemperatureThe resulting mixture was slowly warmed up to room temperature
6. 6
   workup.STIRRINGstirred at room temperature overnight
7. 7
   workup.ADDITION(NHC5 (100 mL) was added
8. 8
   workup.STIRRINGThe mixture was stirred at room temperature for 30 min
9. 9
   Extractionextracted with Et2O (2×)
10. 10
    Washwashed with 1N NaOH, H2O and brine
11. 11
    Dryingdried over Na2SO4
12. 12
    Filtrationfiltered
13. 13
    Concentrationconcentrated to dryness
14. 14
    OtherThe residue was purified by flash column chromatography (silica gel, hexanes:ethyl acetate)

Procedure

An ether solution (40 mL) of 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (2.0 g, 8.23 mmol) was stirred in an oven-dried round bottom flask at −78° C. under Ar. n-BuLi (2.5 M in hexanes, 3.6 ml, 9.05 mmol, 1.1 eq) was added dropwise. The resulting solution was stirred at −78° C. for 30 min. A solution of 4-fluoro-3-(trifluoromethyl)benzonitrile (1.55 g, 8.23 mmol, 1.0 eq) in Et2O (5 mL) was added dropwise. The resulting reddish mixture was stirred at −78° C. for 2 h. TMSCl (pretreated with Et3N (TMSCl:Et3N=10:1, v:v), 1.14 mL, 1.2 eq) was added dropwise. The dry ice bath was removed, and the resulting slurry was stirred at room temperature for 2 h. The reaction was cooled to −78° C. and a solution of benzyl magnesium chloride in THF (2.0 M, 8.4 m, 2 eq) was added dropwise. The resulting mixture was slowly warmed up to room temperature and stirred at room temperature overnight. (NHC5 (100 mL) was added. The mixture was stirred at room temperature for 30 min, extracted with Et2O (2×), washed with 1N NaOH, H2O and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, hexanes:ethyl acetate) to give 1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine (1.6 g, yield: 44%). LC-MS ESI 3.42 min 429.2 (M-NH3+H); 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 7.66 (dd, J=6.7, 2.3 Hz, 1H), 7.49-7.59 (m, 1H), 7.45 (s, 1H), 7.18-7.30 (m, 6H), 6.74 (d, J=6.9 Hz, 2H), 3.57 (m, 2H).

Source