Org Prep Daily

October 10, 2006

3,4-diamino-5-(4′-hydroxybenzyl)-triazole and the Abominable Tetracyclic Monster

Filed under: procedures — milkshake @ 8:23 pm

tetracycles.gif 

2-amino-5-(p-hydroxybenzyl)-oxadiazole 11.525g (60.28mmol) was suspended in a mixture of water 80mL and anhydrous hydrazine 20mL and the mixture was refluxed under nitrogen on oil bath (190-200C) for 16 hours. The mixture was allowed to cool to RT and crystallize for 3 hours, then placed into a refrigerator (+5C) overnight. The crystallized product was quickly collected by filtration, rinsed with ice-cold water and dried by suction. The crude product was re-crystallized from water (250mL, refrigerator +5C overnight). Y=4.431g (35.5%) of the diaminotriazole as a white crystalline solid, about 95% pure by NMR. [The impurity is 4-amino-3,5-bis-(p-hydroxybenzyl)-triazole.]

1H(d6-DMSO, 400MHz): 9.234(br s, 1H), 7.034(app d, 8.6Hz, 2H), 6.664(app d, 8.6Hz, 2H), 5.453(br s, 2H), 5.338(s, 2H), 3.772(s, 2H); LC/MS(+cAPCI): 206(-cAPCI): 204

3,4-diamino-5-(p-hydroxybenzyl)-triazole 133.5mg (0.65mmol) and 4,7-dichloroisatin 130mg (0.60mmol) suspension in trifluoroethanol 8mL and water 4mL was stirred in a pressure glass tube at 125C for 2 hours. The stirring was continued at RT for additional 2 hours, the precipitated product was collected by filtration, washed with a mixture of methanol-water 1:1 (20mL) and then with a small volume of freezer-cooled methanol (-15C, 2mL). The product was dried on highvac. Y=209mg (90.5%) of a bright canary-yellow crystalline solid.

1H(d6-DMSO, 400MHz): 12.864(br s, 1H), 9.259(s, 1H), 7.797(d, 8.6Hz, 1H), 7.406(d, 8.6Hz, 1H), 7.250(app d, 8.6Hz, 2H), 6.674(app d, 8.6Hz, 2H), 4.408(s, 2H); LC/MS: (+cAPCI): 387, 385, (-cAPCI):385, 383

The hydrazinolysis of oxadiazole (followed by triazole ring closure) is messy but the desired product fortunately crystallizes out.

The yield of the corresponding 3,4-diamino-5-(p-fluorobenzyl)-triazole was better, probably because of its lower solubility: 2-amino-5-(p-fluorobenzyl)-oxadiazole 10.182g (52.7 mmol) with water 80mL and anh. hydrazine 20mL was refluxed under N2 for 24 hours (oil bath 190-200C). The mixture was let to crystallize at RT, overnight. The crude product was collected by filtration, washed with ice-cold water (10mL) and re-crystallized from water 60mL (+5C, overnight). Y=6.210g of diaminotriazole (56.5%) as a white crystalline solid, 95% pure. 1H(d6-DMSO, 400MHz): 7.267(app dd, 8.6Hz, 5.5Hz, 2H), 7.097(app t, 9.0Hz, 2H), 5.509(br s, 2H), 5.399(s, 2H), 3.884(s, 2H); 19F(d6-DMSO, 376.5MHz): -117.14(m, 1F)

10 Comments »

  1. i’m not familar with this sort of heterocycle chemistry, why is trifluoroethanol used for the solvent?

    Comment by kiwi — October 10, 2006 @ 10:23 pm

  2. I first tried ethanol with couple of these isatins and it did not work too great and the products were muddy and hard to filter and not very pure – and I thought maybe it needed stronger protonation (to help the amide C=O to cyclize onto the second amino) so I tried aqueous trifluoroethanol and it worked well. Next I tried neat acetic acid and it was completely disappointing. (Later I found out that using straight ethylene glycol really improves this cyclization especialy with alkyl-substituted isatins that are slightly less reactive. I dislike running reactions in antifreeze but the resulting tetracycles are greasy so they precipitate.)

    Some years ago, Brian Stoltz was giving his staurosporine grad research talk and he was doing a fancy carbene Rh-catalyzed- diazolactam cyclization with 2,2′-bisindolyl. Somebody asked why his procedure used tert-butyl methyl ketone as a solvent. Brian told us that in desperation, he went to stockroom, loaded all liquid substances with less than 12 carbons onto a cart, brought them to his lab and started trying them as solvents, one after another.  (Oh, and his bisindolyl was made by melting oxalic acid bisanilide with excess of neat tBuOK as a solvent at 350C)

    Comment by milkshake — October 10, 2006 @ 10:56 pm

  3. Why don’t you get a six membered tetrazine in the hydrazinolysis instead of a diaminotriazole, or am i missing something obvious?

    Comment by sks — October 10, 2006 @ 11:39 pm

  4. It puzzled me too – I found this method somewhere in old german literature, and it worked. One possibility I could think of is conjugation. Dihydrotetrazine is not aromatic, triazole is. Maybe things eventualy equilibrate to triazole.
    Or maybe one gets some dihydrotetrazine in there too – and it just does not crystallize out of the mixture.

    (You know, tetrazines are quite reactive, they are like DEAD – they want to get reduced. No way they would be produced, with all that hydrazine excess around. One needs to use oxidant like lead tetraacetate, to get them from the dihydro.)

    Comment by milkshake — October 10, 2006 @ 11:52 pm

  5. thanks, that makes sense. i’ll have to remember that next time i need a weak acid. but won’t try the molten tBuOK quite so readily!

    Comment by kiwi — October 11, 2006 @ 12:40 am

  6. I´m having already nightmares with that heterocyclic monster.

    Comment by homolumo — October 11, 2006 @ 9:45 am

  7. That is a truly hideous beast!

    Comment by Jose — October 12, 2006 @ 6:19 pm

  8. How would you support the regiochemistry of the second transformation (the condensation)?

    Comment by milo — October 13, 2006 @ 2:13 pm

  9. As for the regiochemistry of the second step, I would guess it is the result of more nucleophilic amino group reacts with the more electrophilic carbonyl group first.

    Comment by diketene — October 13, 2006 @ 2:25 pm

  10. My original guess was the same like Diketene just said. When I tried the reaction there was always only single a regioisomer. It was active (the other one should not be) and I also found literature precedents for similar diaminotriazoles that gave the same isomer in condensation with isatins. The situation becomes more complicated with arylglyoxals ArCOCHO [or ArCOCH(OH)2]  –  the undesired regioisomer (N-NH2 adding to the aldehyde) was the major product in all common solvents. But I found out that I could actualy reverse the ratio of the two regioisomers by running the condensation in presence of a buffer like AcOH+pyridine or KH2PO4 – So it is plausible that the regioselectivity is also controlable by protonation due to differing basicities and nucleophilicities of the two aminos.

    Comment by milkshake — October 13, 2006 @ 2:57 pm


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