A mixture of 2-amino-4-picoline 5.407g (50mmol), acetic acid 40mL and acetic anhydride 20mL (211mmol) was refluxed under Ar on oil bath (165-170C) for 90 min. The reaction mixture was cooled to 60C. A solution of tert-butyl hypochlorite 6.0mL(54.5 mmol) in acetic acid 40mL was added dropwise over 30 min (the addition funnel was washed with additional AcOH 10mL) and the mixture was then stirred at 60C for 8 hours. The mixture was quenched by adding water 3mL, stirred at 60C for 10 min, cooled and evaporated to dryness. The obtained semi-crystalline residue was suspended in ethanol 30mL, brought to reflux, diluted with hot water 70mL. The mixture was inoculated with a seed from crude material and allowed to crystallize at RT for 6 hours. The precipitated product was collected by filtration, washed with 3:7 ethanol-water mixture (50mL) , dried by suction and on highvac. Y=5.987g (65%) of large light-tan needles. 1H(d6-DMSO, 400MHz): 10.543(br s, 1H), 8.266(s, 1H), 8.071(br s, 1H), 2.332(s, 3H), 2.082(s, 3H)
Spatula-powdered 2-acetamido-5-chloro-4-picoline 2.908g (15.75mmol) was suspended in water 400mL and the mixture was heated to a gentle reflux on oil bath (140C). 40% aqueous NaMnO4 solution 26mL (35.25g, 99.4mmol; Aldrich) was added dropwise over 10 min into the refluxing mixture and the reflux was continued for 1 hour. The reaction mixture was removed from heating bath , charcoal 0.5g (as a slurry in some hot water) was added to absorb traces of unreacted starting material and the mixture was cooled to RT. Solid NaHSO3 3.5g was added and stirred for 10 min. The precipitated MnOx was removed by filtration and washed with 50mL of a 10:1 mixture of water+sat.NaCl. (Some salt is needed in washing to prevent MnOx colloid mud formation). The filtrates were acidified with conc. HCl 37.5%, 6.5g (=5.6mL). The mixture was placed into refrigerator overnight (+5C) . The collected product was washed with ice-cold 10:1 mix of water and sat.NaCl (2x15mL). The solids (containing some NaCl) were dried by suction and then dissolved in 99%+ EtOH 250mL under reflux, filtered while hot to remove NaCl, the filtrates were evaporated, the residue was suspended in acetonitrile 20ML, collected by filtration, washed with acetonitrile and dried on highvac to provide 1.373g of a pure product. Evaporating the combined acetonitrile+aqueous supernatants to a small volume and adjusting pH to 2-3, a second crop precipitated in refrigerator over weekend. After dissolving the product in anh EtOH, evaporating the filtrate and washing the precipitate with acetonitrile, a second crop of product 1.272g was obtained. The combined yield was 2.645g (78%) of a white crystalline solid.
1H(d6-DMSO, 400MHz): 14.100(br s, 1H), 10.834(br s, 1H), 8.473(s, 1H), 8.395(s, 1H), 2.110(s, 3H)