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.