Org Prep Daily

November 9, 2006

Who ordered a phenol?

Filed under: mechanisms, procedures — milkshake @ 3:41 pm

Some time ago I was making very dull series of isatin-hydrazones by a simple condensation reaction and everything worked as expected until I run into a curious problem:

Apparently the 4-chloro on the isatin got displaced with water. But there was no water in the reaction mixture (except for the one equivalent generated during the condensation) and there was no trace of the expected trichloro derivative nor any ethoxy-containing product in the reaction mixture:

4,6,7-trichloro-5-methoxyindolin-2-one (0.5 mol MeOH adduct) 296.5mg (1.00mmol) and p-hydroxyphenacetyl hydrazide 166.5mg (1.00mmol) in anhydrous ethanol 10 mL was heated in a pressure glass flask to 130-140C for 1 day (26 hours) . The reaction mixture was allowed to cool to RT and crystallize overnight. The precipitated product was collected by filtration, washed with EtOH and dried on highvac. Y=337mg (82%) of a pale-yellow crystalline solid, in 95% purity by HPLC.

1H(d6-DMSO, 400MHz): 12.517(br s, 1H), 11.629(br s, 1H), 10.862(s, 1H), 9.276(br s, 1H), 7.128(app d, 8.6Hz, 2H), 6.693(br d, 7.8Hz, 2H), 3.958(br s, 2H), 3.742(s, 3H) There is also 15% of a minor rotamer signals in the 1H(d6-DMSO) spectra: 12.983(br s, 1H), 11.550(br s, 1H); LC/MS (+cAPCI): 410(412, 408; M+1), 276(278, loss of acyl); LC/MS(-cAPCI): 410(408, M-1)

I believe the only conceivable explanation of what happened is that somehow the water molecule got delivered by intramolecular participation of the acyl group. Here is a hairy mechanistic proposal that I came up with:


I think the best way to confirm it would be by using 18-O carbonyl labeled starting materials to see where the oxygen label ends up. But this is not a piece-of-cake study. The only other corroboration I found was in a reaction with the corresponding diaminotriazole (please see the post on tetracyclic compounds from Oct 10), which also gave an irregular product:


This does not prove anything except that the 4-chlorine on the isatine is reactive in displacement with a nucleophile, which should not be a surprise. So I am still not certain on how the phenol got there. Please, let me know what you think.


  1. Pretty nifty. Do you really have to use such harsh conditions to make a hydrazone? It would seem to me that it is easier to form the hydrazone than displace the Cl – did you try under more gentle conditions?

    Comment by Jean-Claude Bradley — November 9, 2006 @ 5:22 pm

  2. These isatin hydrazones have cis/trans isomerism about the C=N-NH and the trans isomer tends to be the kinetic product (actualy you end up with a mix at lower temperature where trans predominates). Upon heating the trans cleanly equilibrates to cis. We needed the cis isomers for our medchem project so I heated them all quite high to ensure a complete equilibration (sometimes the solubility of these hydrazones was quite poor hence the large solvent volume and one-day long heating). I don’t know if this has any bearing on this case – but it would be interesting to run it at lower temperatures, to see if there are any observale intermediates.

    Comment by milkshake — November 9, 2006 @ 5:47 pm

  3. Did you consider the possibility that the product is from nucleophilic displacement of the chloride by the hydrazine (leaving the isatin carbonyl intact)? This would result in the same mass and nominally the same NMR, and mechanistically is easier to rationalize than the single water molecule produced in the reaction being consumed in 82% yield…

    Just a thought.

    Comment by Russ — November 10, 2006 @ 10:50 am

  4. Russ, I cannot exclude what you have suggested just based on proton spectra. I think the produced compound is probably a hydrazone rather than an isatin: The compound was biologicaly active (with a EC50 within the expected range) and it was pale yellow – I have seen lots of isatins during this project and they were all deep red or brown. But it is definitely a possibility. The easiest way to go about it would be C13 comparison of the starting material with this product and with some related hydrazone compound with a correct structure. (IR might be of some help too.) Thank you for the suggestion, I have not considered this isomer possibility.

    Comment by milkshake — November 10, 2006 @ 11:38 am

  5. “IR might be some help too.” – I bet it’s been a while since anyone’s said that out loud!


    Comment by Russ — November 10, 2006 @ 12:00 pm

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