2-(bromomethyl)-6-chlorobenzonitrile

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-(4-(4-methoxybenzoyl)piperidin-1-yl)pyrrolidin-2-one (70 mg, 0.23 mmol) and 2-(bromomethyl)-6-chlorobenzonitrile (80 mg, 0.35 mmol) in tetrahydrofuran (1 mL) and dimethylformamide (0.1 mL) was added sodium hydride (46 mg, 1.2 mmol, 60% in mineral oil). The mixture was stirred at ambient temperature for 30 minutes. Dichloromethane and methanol were added slowly to quench the reaction. Then the mixture was filtered through a short pad of silical gel column, the solvent was removed in vacuo, and the residue was purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0) first and then (methanol: dichloromethane, 1:99 to 10:90) to give brown oil which is further purified by HPLC to give a colorless product. 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 2H), 7.45 (t, J=8.0 Hz, 1H), 7.35-7.41 (m, 1H), 7.30 (d, J=7.5 Hz, 1H), 6.87 (m, J=9.0 Hz, 2H), 4.62 (q, J=15.6 Hz, 2H), 3.80 (s, 3H), 3.50 (t, J=9.0 Hz, 1H), 3.11-3.37 (m, 3H), 2.94-3.11 (m, 1H), 2.75-2.94 (m, 2H), 2.28-2.54 (m, 1H), 2.09-2.28 (m, 1H), 1.90-2.09 (m, 1H), 1.66-1.90 (m, 4H). HRMS calculated for C25H26ClN3O3 452.1741. found (ESI, [M+H]+), 452.1760. to quench the reaction Then the mixture was filtered through a short pad of silical gel column the solvent was removed in vacuo the residue was purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0) first (methanol: dichloromethane, 1:99 to 10:90) to give brown oil which is further purified by HPLC to give a colorless product

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-chloro-6-methylbenzonitrile (2.0 g, 13 mmol) and N-bromosuccinimide (2.6 g, 15 mmol) in carbon tetrachloride (20 mL) was added azobisisobutyronitrile (0.20 g, 1.2 mmol). The mixture was refluxed for 3 h and then cooled, diluted with dichloromethane and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resultant oil was purified via flash column chromatography (ethyl acetate:hexane, 0:100 to 30:70) to yield white solid product (1.4 g, 46%). 1H NMR (400 MHz, CDCl3) δ 7.43-7.59 (m, 3H), 4.64 (s, 2H). The mixture was refluxed for 3 h cooled washed with water and brine The organic phase was dried over anhydrous sodium sulfate filtered concentrated in vacuo The resultant oil was purified via flash column chromatography (ethyl acetate:hexane, 0:100 to 30:70)