2,6-Dichloronicotinonitrile

Brown yellow powder

Preparation of 2, 6-dichloropyridine-3-carbonitrile General procedure: Tris-(dibenzylideneacetone)-di-palladium (0)[Pd2dba3] (28 mg, 3 mol %), rac-BINAP (38 mg, 6 mol %), 1, 4-dioxane (3-5 mL) and a magnetic stirrer(Sigma-Aldrich, Darmstadt, Germany)) were added to an oven-dried 10 mL round bottomed flaskand purged with nitrogen. The flask was sealed and heated with stirring at 80 C in an oil bath for 5min. Thereafter, the appropriate carbonitrile substrate (1.0 mmol), 4-chlorophenol (128 mg, 2.0mmol)) and sodium tert-butoxide (1.5 mmol) were added and the sealed reaction heated at 110-120C for 24 h. The cooled reaction mixture was filtered, and the excess solvent removed in vacuo toleave a crude mixture which was re-dissolved in dichloromethane and filtered. The filtrate waswashed successively with aqueous saturated NaHCO3 (10 mL) and distilled water (2 × 10 mL). Afterdrying over anhydrous Na2SO4 and evaporating excess solvent, the crude mixture was purified bysilica gel flash column chromatography, eluting the target with 0% to 3% EtOAc/hexane.2, 6-Dichloronicotinonitrile (10.00 g, 57.8 mmol) was dissolved into 2M NH3-IPA (100 ml, 200 mmol) in a steel bomb behind a blast shield. The reaction vessel was sealed and heated to 90 C for 20 hours. Cooled to room temperature and stirred for 48 h. The heterogeneous reaction mixture was partitioned between EtOAc and a small amount of half-saturated NaHCCb. The aqueous phase was extracted with EtOAc (2x). The combined organics were washed with brine and dried over MgS04 before concentrating onto 16 g of celi te. Column chromatography (330 g S1O2, 0 to 50% EtOAc-hexane) afforded 6-amino-2-chloronicotinonitrile as the major product (5.14 g, 58%) with the minor product, 2-amino-6-chloronicotinonitrile also isolated (1.60 g, 18%). 1H NMR (400MHz, DMSO-d6) d 7.78 (d, 1-8.6 Hz, 11 1). 7.50 (s, 21 1). 6.46 (d, .1 8.6 Hz, H I): LC/MS [M+H] 195.0; LC RT = 1.082 min; (Column: Waters Xbridge; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; Temperature: 35 C; Gradient: 5-95 % B over in 4 min; Flow: 4.0 mL/rnin).General procedure: 2, 6-Dichloropyridine-3-carbonitrile (0.27 g, 1.6 mmol) and 1(1.35 g, 3.3 mmol) were dissolved in 1, 4-dioxane (20 mL) in nitrogenatmosphere. To this solution, aqueous potassium phosphate (2 M, 10 mL) and tertrakis(triphenylphosphine)palladium(0) (0.11 g, 0.1 mmol) were added. Thereafter, the mixture was refluxed for 48 h.The reaction mixture was then poured into water. The product wasextracted with chloroform, and the combined organic layers were washedwith water and dried over anhydrous MgSO4. After filtration withCelite 545 and solvent removal, the crude material was purified withcolumn chromatography on silica gel (eluent: dichloromethane/hexane, 2:1 v/v) and dried in a vacuum oven to obtain a yellow powder(yield=1.00 g, 96%). This compound was further purified by temperature-gradient sublimation in vacuum.