Synthesis of some new mixed azines, Schiff and Mannich bases of pharmaceutical interest related to isatin

1 Introduction

The chemistry of isatin (2,3-indolinedione) and its derivatives has been the subject of wide and increasing interest, due to their wide range of biological and pharmacological activities. The extensive literature dealing with the chemistry and pharmacological activities of isatin and related compounds has been reviewed [1–7]. In particular, much interest has centered around Schiff and N-Mannich bases of isatin, which possess a broad spectrum of action including antibacterial [8–14], anticonvulsant [15–17], anti-HIV [10, 18–21], antifungal [3–7, 10], cytotoxic and anticancer [3, 22–27] activities, and this has stimulated further research in this field. On the other hand, a number of azines and mixed azines are receiving attention owing to their promising antibacterial and antifungal [28–30], antimalarial [31], cytotoxic [32–34] and antioxidant [35] activity.

In view of this, the present work is largely concerned with attempts to extend the scope of the reaction of isatin and its N-Mannich bases with hydrazine and related compounds such as N-amino-heterocycles to include the synthesis of some new mixed azines and Schiff bases having a 2-indolinone moiety as a structural unit.

2 Results and discussion

In the present study, isatin (1) was treated with hydrazine to give the hydrazone 2 [36]. The reaction of 2 with the appropriate aromatic aldehyde afforded a series of mixed azines 3-(arylidenehydrazono)indolin-2-ones (3a–h) in good to excellent yields (Scheme 1).

Scheme 1:

Synthesis of 3-(arylidenehydrazono)indolin-2-ones (3a–h) and Mannich bases of 3b.

In addition, the reaction of hydrazone 2 with dialdehydes such as glyoxal leads to the formation of the bis-azine, which reacts further with glyoxal to give the N-hydroxyacetaldehyde derivative 4 as the end-product. The analytical and spectral data are consistent with the structures proposed for compounds 3a–h and 4. The mass spectra of 3a–h contain peaks of the respective molecular ions and showed very similar cleavage patterns. The base peak in the spectra of these compounds is due to the loss of C=O to give ions of type A (Scheme 2), except for compounds 3c and 3h, which showed intense peaks corresponding to the loss of C=O at m/z = 264 (86 %) and 271 (73 %), respectively. Cleavage at the azino group of compounds 3a–h leads to a peak at m/z = 145 due to the ion B. These spectral data are in line with the reported studies on the mass spectra of isatin and its derivatives [37–39].

Scheme 2:

Mass fragmentation pattern of 3a.

Although potentially interesting, the literature of Mannich bases related to azines is limited [33, 40]. The Mannich reaction of azines of the type 3 is of particular interest, because it provides access to mixed azines having a potential basic side chain of alkaloidal nature. This has been realized by treating 3-[(4-(dimethylamino)benzylidene)hydrazono]indolin-2-one (3b) with formaldehyde and piperidine, morpholine, tetrahydroisoquinoline and diethanolamine to give the corresponding N-Mannich bases 5a–d, respectively (Scheme 1).

The reaction of the mixed azine 3c with piperazine and formaldehyde proceeded equally well providing 1,1′-[piperazine-1,4-diylbis(methylene)]-bis[3-((4-methylbenzylidene)hydrazono)indolin-2-one] (6) (Scheme 3). It is interesting in this connection that treatment of 3c with glutaric dialdehyde and dimethylamine or piperidine led to the formation of the bis-(Mannich base) (7a) and the 1,1’-[1,5-di(piperidin-1-yl)] analogue 7b, respectively, via a double Mannich reaction.

Scheme 3:

Synthesis of bis-(Mannich bases) of the mixed azine 3c.

Although the utility of aromatic and heterocyclic amines in the synthesis of isatin Schiff bases was well established [1–6], the use of N-amino-heterocycles in such reactions was less widely recognized and had seen limited use [41]. The condensation of 1 or the Mannich base 8 with N-amino-heterocycles related to piperidine, morpholine and piperazine could be valuable in the synthesis of new isatin Schiff bases with an alkaloid partial structure, as depicted in Scheme 4.

Scheme 4:

Reaction of 1 or its Mannich base 8 with N-amino-heterocycles.

In view of that, 1 was treated with 1-aminopiperidine (9a) and 4-aminomorpholine (9b) to give 3-(piperidin-1-ylimino)indolin-2-one (10a) and the 3-(morpholinoimino) analogue 10b, respectively. A similar treatment of 1-(piperidinomethyl)isatin (8) [42] with 9a and 9b afforded the Schiff–Mannich bases 10c and 10d. Analogously, treating 1 and 8 with 1,4-diaminopiperazine (11) led to the formation of 12 and the bis-(Mannich base) 13, respectively. In addition, the Mannich reaction of 10a with formaldehyde and morpholine gave 1-(morpholinomethyl)-3-(piperidin-1-ylimino)indolin-2-one (14). A similar reaction takes place between 10b and piperazine yielding the bis-(Mannich base) 15. The formation of compounds 10–15 is of interest, because piperidine, morpholine and piperazine are significant classes of heterocycles and constituents of various important natural and synthetic bioactive compounds. In addition, Mannich bases incorporating a morpholine or piperazine moiety are known as antimicrobial agents [43–49].

On the other hand, the hydrazone 2 could conceivably function as a precursor to Schiff bases derived from N-amino-heterocycles. This has been achieved by the condensation of 2 with succinic anhydride to give 1-(2-oxoindolin-3-ylidenamino)pyrrolidine-2,5-dione (16). A similar reaction of 2 with phthalic anhydride and quinolinic anhydride led to the formation of compounds 17a and 17b, respectively. In addition, the pyrrolo[3,4-f]isoindole-1,3,5,7(2H,6H)-tetraone (18) was obtained from 2 and pyromellitic dianhydride (Scheme 5).

Scheme 5:

Condensation of the hydrazone 2 with acid anhydrides.

In the course of this study, the Schiff base 19 [50] has been used as a precursor for the synthesis of isatin Schiff bases incorporating a benzoylpiperidine, benzoylmorpholine and 1,4-dibenzoylpiperazine moiety. Thus, the Schiff bases 20a, 20b and 21 were obtained by treating 19 with the appropriate heterocyclic amine (Scheme 6).

Scheme 6:

Synthesis of Schiff and Mannich bases incorporating N-benzoyl-heterocycles.

Application of the Mannich reaction to the new Schiff bases 20a and 20b using piperidine and morpholine is of particular interest, because it offers access to compounds 22a and 22b, incorporating two piperidine or two morpholine moieties. The analogous reaction of 20a with piperazine afforded the 1,4-bis(3-imino-2-oxoindolinyl) substituted piperazine 23.

3 Experimental section

All melting points (uncorrected) were determined on a Gallenkamp electric melting point apparatus (Sanyo Gallenkamp, Southborough, UK). Elemental microanalyses were carried out on Carlo Erba 1108 Elemental Analyzer (Heraeus, Hanau, Germany) at the Microanalytical Unit, Faculty of Science, Cairo University. Infrared spectra were measured on a Mattson 5000 FTIR spectrometer (Mattson Instruments, Inc., Madison, WI, USA). ¹H and ¹³C NMR data were obtained in [D₆]DMSO solution on a Varian XL 300 MHz instrument (Varian, Inc., CA, USA) using TMS as the internal standard. Chemical shifts are reported in ppm (δ) downfield from internal TMS. Mass spectra were recorded on a GC-MS QP-1000 EX Shimadzu instrument (Shimadzu, Tokyo, Japan). The course of the reaction and the purity of the synthesized compounds were monitored by TLC using EM science silica gel coated plates, 0.25 nm, 60 GF 254 (Merck, Germany) with visualization by irradiation with an ultraviolet lamp. Compounds 4, 7a, 7b, 13, 17a, 17b, 18, 21 and 22a are of limited solubility in common ¹H NMR solvents. Compounds 2 [14], 8 [20] and 19 [22] were prepared as previously described. All chemicals used were of pure grade and were purchased from Aldrich, WI, USA.