Hydrolysis and Hydrazinolysis of Isatin-Based Ald-and Ketazines

The hydrolysis of isatin aldazine 4a–d afforded the unexpected 3,3-(hydrazine-1,2-diylidene)bis(indolin-2-one) (5) and 1,2di(arylidene)hydrazines 6a–d through dual hydrolysis of 4a–d. Amechanism to explain the formation of 5 and 6a–dwas proposed. In addition, the hydrazinolysis of 4a–d yielded 3-hydrazonoindolin-2-one (2) and 1,2-di(arylidene)hydrazines 6a–d instead of hydrazones 17a–d, while hydrazinolysis of isatin ketazine 5 gave the expected 3-hydrazonoindolin-2-one (2).These results indicated the ability of the title compounds for unusual hydrolysis and hydrazinolysis reactions.


Introduction
Isatin imines including Schiff bases 1b and isatin hydrazones 2, which are the product of condensation of amines or hydrazines with isatins 1a, respectively, are considered as a pharmacophore for diverse spectrum of biological activities [1][2][3][4][5] (Figure 1).They have been reported as anticancer agents where they were found to be inhibitors of tyrosine phosphatase Shp2 [6].Furthermore, they have been identified as kinase inhibitors and they also have been reported as cytotoxic agents towards U937 lymphoma cells [7].In addition, hydrazones 2 (R = -COAr) revealed a good cytotoxic activity against K562, MDA-MB-468, and HT-29 cell lines [8].
On the other hand, azines undergo hydrolysis to regenerate the hydrazine and aldehydes or ketones.However, ketazines are important intermediates in the production of hydrazine hydrate when subjected to hydrolysis processes [12].In addition, the reaction of azines with hydrazine (hydrazinolysis) regenerates the hydrazones [13].In light of the latter results and in continuation of our interest in the chemistry of isatin-based azines 4 and 5, we hope to report herein the unexpected results of hydrolysis and hydrazinolysis of isatin aldazines 4a-d and isatin ketazines 5.

Results and Discussion
In the reaction of 3-hydrazonoindolin-2-one (2) (R = H) with aldehydes 3a-d in glacial acetic acid for 12 h, at ambient temperature, isatin aldazines 4a-d were isolated extensively.The targeted aldazines 4a-d were also prepared by the reaction of 3-hydrazonoindolin-2-one (2) with aldehydes 3ad in refluxing ethanol, in the presence of catalytic amount of glacial acetic acid for 6 h (Scheme 1) [9].Hydrolysis of hydrazones 4a-d by their refluxing in H 2 O/AcOH afforded reddish precipitates during reflux in each case.These precipitates showed identical physical and chemical properties and they are not matched with the expected hydrazone 2 (R = H) (Scheme 1).
The 1 H NMR spectrum of the isolated precipitate did not show the characteristic signal of NH 2 of 2 and its mass  An authentic sample of compound 5 is prepared [10] and it was identical in all respects with the isolated compound in our hands.After evaporation of the filtrates of the latter reactions, they gave in each case a compound with melting points 97 ∘ C (Ar = Ph), 213 ∘ C (Ar = 4-Cl-C 6 H 4 ), 172 ∘ C (Ar = 4-MeO-C 6 H 4 ), and 225 ∘ C (Ar = 4-NO 2 -C 6 H 4 ), respectively.These values do not match this reported for 2, 217-219 ∘ C. Our attempts to explore these unknown compounds guided us to assign structure 1,2-di(arylidene)hydrazines 6ad for the isolated compounds.We found that the analytical data of authentic samples of isolated compounds is identical with those of 6a-d [17][18][19][20].Interestingly, refluxing 2 with aldehydes 3a-d in H 2 O/AcOH, 3,3  -(hydrazine-1,2diylidene)bis(indolin-2-one) (5) and aldazines 6a-d were also isolated.
Keeping in mind the reported data about the mechanism of hydrolysis of -C=N-imines [21], we are interested in proposing a mechanism to explain the formation of 3,3  -(hydrazine-1,2-diylidene)bis(indolin-2-one) (5) and 1,2-di(arylidene)hydrazines 6a-d.In this mechanism, dual acidic hydrolysis of aldazines 4a-d took place in their two nucleophilic centers which are accessible to attack by two protons from the acidic medium (Figure 2).The first pathway, in which acidic proton attack took place by the nitrogen of -N=C-Ar followed by hydrolysis to give intermediates 7(a-d)-10(a-d), respectively, yielded aldehydes 3a-d and 3-hydrazonoindolin-2-ones (2) which would not undergo further hydrolysis.The second pathway, in which the other According to the previous results and in light of behavior of hydrazine hydrate towards certain -N=N-containing compounds [12], we stimulated to explore the reactivity of hydrazine hydrate towards -N=C-function in aldazines 4ad.Thus, the reaction of 4a-d with hydrazine hydrate in refluxing ethanol afforded 3-hydrazonoindolin-2-one (2) and 1,2-di(arylidene)hydrazines 6a-d, respectively, instead of 2 and 17a-d (Scheme 2).

Figure 2 :
Figure 2: The proposed mechanism for the hydrolysis of isatin aldazines 4a-d in refluxing H 2 O/AcOH.