Org Prep Daily

October 25, 2010

diaminotriazoles from anilines

Filed under: procedures — milkshake @ 3:04 pm

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Dimethylamide of p-aminobenzoic acid 6.00g (36.54 mmol) and (PhO)2C=N-CN 10.14g (Aldrich; 42.56 mmol) in anhydrous THF 60mL was refluxed under nitrogen on a 80C oil bath for 2 days. [Note 1] The cooled reaction mixture was concentrated on rotovap. The obtained oily residue was diluted with anh. THF 20mL and cooled to 0C. Anhydrous hydrazine 1M solution in THF 60mL (Aldrich) was added, the mixture was stirred on ice for 15 min and at ambient temperature for 20 min, then placed on a 70C oil bath and refluxed under nitrogen for 30 min. The reaction mixture was cooled to room temperature, the precipitated product was collected by filtration and washed with MTBE  (tBuOMe), then dried by suction and on highvac. Y= 10.48g of a white fluffy powder (90% th; as a 1:1 solvate with THF)

1H(d6-DMSO, 400MHz): 11.22 (br s, 1H), 8.94 (br s, 1H), 7.52(app d, 8.6Hz, 2H); 7.27(app d, 8.6Hz, 2H), 5.92(br s, 2H); 3.60(m, 4H, THF); 2.95(s, 6H), 1.76(m, 4H, THF); 13C(d6-DMSO, 100MHz): 170.47, 128.29, 114.44, 67.00(THF), 25.11(THF)

Note 1: 1 day reflux would have been enough.

Note 2: The starting aniline was prepared by hydrogenation of dimethylamide of p-nitrobenzoic acid (5% Pt-C, H2 baloon, EtOAc), which was obtained from p-nitrobenzoyl chloride and 40% aq. dimethylamine in THF, at -15 C. The yield was 90% over two steps.

14 Comments »

  1. Milkshake, I have a dumb question. I have never had access to any sort of hydrogen source in any of the labs where I have worked. When I’ve needed to reduce a nitro group in this fashion, I generally use zinc dust and aqueous ammonium chloride/acetic acid. Do you just have an H2 tank you can use to fill balloons? Or have you ever used one of those lovely archaic setups with HCl dropping on iron or zinc shavings?

    Comment by opsomath — October 25, 2010 @ 3:24 pm

  2. Personally I use three layers of balloons, stuck onto a cut 5-mL syringe with Luer lock, then plug a needle thru a septum to one end of a 3-way valve. For purge, the valve is also hooked on to house vacuum and N2 or, preferably, argon line. And I work in a lab that always has a (nearly empty, for some reason…) hydrogen tank. :)

    Comment by HPCC — October 25, 2010 @ 3:32 pm

  3. If you don’t have access to H2 in your lab, transfer hydrogenation usually does the trick for your usual nitro and azide reductions, debenzylations, etc… Ammonium formate + Pd/C in MeOH voila!

    Comment by tuky tuky — October 26, 2010 @ 4:32 pm

  4. For some reason I can’t see the structure of the final product on this prep. It seems to be obscured by the menu panel on the right. Would it be possible to reformat it?

    Thanks, and keep up the great work.

    Comment by Nick K — October 27, 2010 @ 6:00 pm

  5. Many thanks for reformatting the reaction scheme – I can see it perfectly now. Yes, I’m using a laptop with a very small screen, which might be why I couldn’t see the scheme in the first place. As for the azetidines, no, I make them by displacing mesylate from 1- (diphenymethyl)-3-mesyloxyazetidine with a secondary amine in acetonitrile/potassium carbonate. The displacement works well, but, for some reason the subsequent hydrogenolysis often won’t work. I was completely unaware of your method, which looks superb. Thanks for the suggestion.

    Comment by Nick K — October 29, 2010 @ 6:15 am

    • Nick, hi. It is not my method, I lifted the bicyclo-aziridine from the literature (and its openning with nucleophiles). The aziridine approach works reasonably well but the bicyclo aziridine is a smelly and volatile irritant and there is lots of butyl lithium needed for its preparation. I used 10M BuLi because it was cheaper to buy and more concentrated – but now I think using 2.5M BuLi would have been a better idea (to get a higher yield of the aziridine intermediate). I should have diluted it down with something like toluene or MTBE just before use, and add it from addition funnel rather than using a syringe – I think controlability of BuLi addition was an issue, hence the mediocre yield.
      Also, if one needs to determine the yield of the bicyclo aziridine intermediate, a good way to assay it is to quench the solution with neat formic acid, and evaporate to dryness. It produces 3-formyloxy azetidine salt with formic acid in high yield almost instantly.

      Comment by milkshake — October 29, 2010 @ 10:28 am

  6. Hello Milkshake, would it be possible to replace n-BuLi with, say, KOt-Bu? Also, could the reaction with the nucleophile be run in the same pot, without the distillation?

    Comment by Nick K — October 29, 2010 @ 10:57 am

    • A different base – I don’t know, but probably not. You may try LDA but then your distillate will contain lots of iPr2NH which would interfere in the next step.

      Some process people use n-hexyl lithium as a safer alternative to BuLi (HexLi is not pyrophoric and does not generate butane gas).

      I would definitely carry out the distillation step because it cleans up the intermediate.

      Comment by milkshake — October 29, 2010 @ 11:09 am

  7. Just wondering, do diaminotriazoles like that have any favorable biological properties? It looks like it might be a little low with respect to cell permeability

    Comment by partial agonist — October 29, 2010 @ 6:15 pm

    • it is an intermediate that I used for synthesizing something else. I usually do not post structures and procedures that describe active final compounds

      Comment by milkshake — October 31, 2010 @ 3:45 pm

  8. Hi MS,

    Bit off topic. I have trouble in isolating N-1 and N-3 benzyl substituted triazole regioisomers after the N-benzylation reaction.. I tried different solvent system (DCM: MeOH/EA: hexane etc..) for the column chromatographic isolation. Please suggest me if you have any experience.

    Thanks

    Marto

    Comment by marto — September 16, 2012 @ 1:50 pm

    • unfortunately I don’t know any general method how to do this

      Comment by milkshake — September 16, 2012 @ 7:23 pm


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