Org Prep Daily

November 14, 2006

2-Acetamido-5-chloropyridine-4-carboxylic acid

Filed under: procedures — milkshake @ 3:52 pm


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)


  1. Why do you use NaMnO4 instead of a KMnO4?

    Comment by transitionstate — November 16, 2006 @ 4:38 am

  2. NaMnO4 is highly soluble, it comes as a nice thick 40% wt solution from Aldrich that you can syringe in. Nothing essential, just a convenience.

    Comment by milkshake — November 16, 2006 @ 11:30 am

  3. Dear milkshake: did you ever tried to do an imine out of alfa-amino-pyridine? Interestingly, most of the classical routes didn’t work. Any ideas please?

    Comment by Coupling — January 29, 2007 @ 6:47 pm

  4. I have not – but I actualy made trityl imines from hindered ketones using trityl azide with trimethylphosphine and ketone (1:1:0.95) in THF, RT to 60C…

    2-Pyridyl azides are in equilibrium with the corresponding pyridotetrazoles – but the phosphine reduction to azaphosphorane is known to work with 2-pyridyl azides.

    Comment by milkshake — January 29, 2007 @ 9:41 pm

  5. Dear MS,

    I am trying for the oxidation of terminal alcohol in the presence of secondary amino group , subsequent cyclization and dehydration to a cyclic enamine derivative.

    Please suggest me the oxidation reagents for the conversion (I am planning for Py.SO3 initially ) and I am looking for cheaper oxidants for the scale up reaction.




    Comment by marto — July 5, 2013 @ 2:40 pm

    • This is going to be tricky. Since amines oxidize readily under conditions used for making aldehydes from alcohols, I do not know how to do such a transformation without protecting the NH and even then it is going to be very tricky because enamines are so sensitive – you would need to use super mild deprotecting conditions (in case of primary amine it would be easier because presumably you could start from azidoalcohol and reduce the azidoaldehyde with a phosphine). In case of unproteced secondary amine, will simply sulfonate the NH to form sulfamic acid. Anyway, I cant give you any better suggestion execpt for trying to re-design your synthetic scheme because what you are trying to do is almost unworkable and it somewhat surprises me that you don’t even noticed this problem, as an experienced chemist.

      Comment by milkshake — July 5, 2013 @ 7:42 pm

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