5-Chloro-2-pyridineacetonitrile

To the solution of 5-chloro-2-(chloromethyl)pyridine (CGenetech) (0.99 g, 6.1 mmol) in ethanol (8 mL) and H5-Chloro-2-pyridineacetonitrile [0447] tert-Butyl cyanoacetate (25.7 mL) was added to a dimethylsulfoxide (160 mL) suspension of sodium hydride (7.20g, a 60%-oil suspension) at room temperature for 1 hour under an argon atmosphere, and then the mixture was stirred at room temperature for 0.5 hours. A dimethylsulfoxide (7 mL) solution of 2, 5-dichloropyridine (10.0 g) was added to the reaction mixture, and then the reaction mixture was stirred at 120C for 3 hours. The reaction mixture was cooled and then poured into a saturated ammonium chloride aqueous solution, the precipitated solid was filtered off, and the product was washed with water and ethanol to obtain tert-butyl 2-(5-chloropyridin-2-yl)-2-cyanoacetate. The tert-butyl 2-(5-chloropyridin-2-yl)-2-cyanoacetate thus obtained was dissolved in acetonitrile (160 mL), p-toluenesulfonic acid (6.43 g) was added, and then the mixture was heated under reflux for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue thus obtained was purified by silica gel chromatography (n-hexane:ethyl acetate = 3:1) to obtain a title compound as a yellow oil (6.35 g). 1H-NMR (400 MHz, CDCl3) delta 3.93 (2H, s), 7.40 (1H, d, J = 7.9 Hz), 7.72 (1H, dd, J = 7.9, 2.4 Hz), 8.55 (1H, d, J = 2.4 Hz)General procedure: To a suspension of sodium hydride (7.20 g, 0.18 mol, 60% oil suspension) in DMSO (160 mL) was slowly added tert-butyl cyanoacetate (25.7 mL, 0.18mol) for 1 h at room temperature, and then the mixture was stirred at this temperature for 0.5 h. After the addition of a solution of 2-dichloropyridine substrate(67.6 mmol) in DMSO (7 mL), the mixture was heated at 120Cfor 3 h. After cooling, the mixture was poured into a saturated aqueous solution of ammonium chloride. The precipitate was collected by filtration, and washed with water and ethanol to give tert-butyl alpha-cyano-2-pyridineacetate intermediate as a crude material. To a solution of the material in acetonitrile (160mL) was added p-toluenesulfonic acid(6.43 g, 33.8 mmol), and then the mixture was heated to reflux for 1 h. The mixture was concentrated in vacuo. The crude material was purified by flash column chromatography ona silica gel(Hexane:AcOEt = 3:1) to give 5b and 5g.General procedure: To a solution of ethylo-mesitylsulfonylacetohydroxamic acid (2.14 g, 7.50 mmol) in 1, 4-dioxane (4 mL)was added a 70% aqueous solution ofhydrogenperchlorate (0.8 mL, 9.2 mmol), and the mixture was stirred at 0C for 0.5 h. After the addition of ice-water, theprecipitate was collected. The cake was dissolved in dichloromethane (20 mL)and dried over Na2SO4. To themixture was added a solution of 2-pyridineaceonitrile substrate(5.00 mmol) in dichloromethane (5 mL), and then the mixture was stirred at roomtemperature for 1 h. The mixture was concentratedin vacuo to give 1-aminopyridinium2, 4, 6-trimethylbenzenesulfonate intermediate as a crude material. To a solutionof the crude material in methanol (25 mL) was added potassium carbonate (1.38g, 9.98 mmol) at 0C, and then the mixture was stirred at room temperature for 2 h. After the addition of water, the mixture wasextracted with ethyl acetate, then washed with water and brine, and then driedover Na2SO4. Themixture was concentrated in vacuo. Thecrude material waspurified by flash column chromatography on a silica gel(Hexane:AcOEt) togive 1a-g.To the solution of 5-chloro-2-(chloromethyl)pyridine (CGenetech) (0.99 g, 6.1 mmol) in ethanol (8 mL) and H2O (6 mL) was added KCN (1.03 g, 15.9 mmol). The reaction mixture was heated at 100 C. for 1 h. The mixture was cooled, and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:3) to give (5-chloro-pyridin-2-yl)acetonitrile as a yellow oil (0.64 g, 69%).

Molecular Weight:152.58
XLogP3:1.2
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:152.0141259
Monoisotopic Mass:152.0141259
Topological Polar Surface Area:36.7
Heavy Atom Count:10
Complexity:149
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes