Reaction #59174

Reaction equation

HCl

tert-butyl nitrite

5,6-difluoro-1H-benzimidazol-2-amine

tert-butyl nitrite

→

2-chloro-5,6-difluoro-1H-benzimidazole

Yield 73.0%

Solvents

acetone

Conditions

Workup

1. 1
   Temperaturethe mixture was heated
2. 2
   workup.ADDITIONadded every 0.5 h)
3. 3
   TemperatureThe reaction mixture was then cooled to rt
4. 4
   Extractionextracted with ethyl acetate
5. 5
   DryingThe organic phase was dried over sodium sulfate
6. 6
   Concentrationconcentrated in vacuo

Procedure

Step 2 The procedure used was similar to that reported in J. Med. Chem. 40:811-818, 1997. To a mixture of copper(II) chloride (795 mg, 5.91 mmol) in acetone (20 mL) was added tert-butyl nitrite (0.53 mL, 4.43 mmol). The reaction mixture was stirred at rt for 20 minutes, 5,6-difluoro-1H-benzimidazol-2-amine (500 mg, 2.96 mmol) was then added, and the mixture was heated at reflux for 2 h (with additional portions of tert-butyl nitrite added every 0.5 h). The reaction mixture was then cooled to rt, treated with 2 N HCl, and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford 2-chloro-5,6-difluoro-1H-benzimidazole (580 mg, 73%), which was used without further purification in the next step. LC-MS m/z 189.2 (MH+), ret. time 1.96 min; 1H NMR (300 MHz, DMSO-d6) δ 7.62 (t, 2H), 13.5 (br s, 1H).

Source