Termolecular one-pot synthesis of symmetrical azines of 4-acetyl-3-arylsydnones. Hydrazone and azine derivatives of 4-acetyl-3-arylsydnones, their spectral characterization and biological properties

Hydrazones of 4-acetyl-3-arylsydnones (2a-o) were prepared by heating 4-acetyl-3-arylsydnones (la-o) with excess of hy drazine hydrate and the corresponding symmetrical azines (3a-o) were obtained by a termolecular reaction of 4-acetyl-3-arylsydnones with hydrazine hydrate (2 : 1 ratio). Hydrazones and azines were screened for their antimicrobial activity and few of these compounds exhibit inhibitory action more than the reference drugs used. The synthesis, biological and pharmacological studies of a large number of sydnone derivatives have been reported from our laboratory 1- 3. In continuation of synthetic work on sydnones, we now report the synthesis of some hydrazones of 4-acetyl-3-arylsydnones 4 and termolecular one-step synthesis of the correspondir.g symmetrical azines by varying the stoichiometric quantity of 4-acetyl-3-arylsydnones (la-o) and the reagent hydrazine hydrate.

The synthesis, biological and pharmacological studies of a large number of sydnone derivatives have been reported from our laboratory 1 -3 . In continuation of synthetic work on sydnones, we now report the synthesis of some hydrazones of 4-acetyl-3-arylsydnones 4 and termolecular one-step synthesis of the correspondir.g symmetrical azines by varying the stoichiometric quantity of 4-acetyl-3arylsydnones (la-o) and the reagent hydrazine hydrate.
Results and discussion   The hydrazones (2a-o) were obtained by treating the 4acetyl-3-arylsydnones (la-o) with excess of hydrazine hydrate. These hydrazones were resistant to further reaction with aldehyde/ketone and also with another molecule of 4acetyl-3-arylsydnone, even after prolonged heating and the corresponding azines could not be prepared. The low reactivity of the -NH 2 group of the hydrazones may be attributed to the electron-withdrawing property of the sydnone ring which is a mesoionic dipolar heterocycle (Figs. 1 and 2). Hence, we thought of carrying out a termolecular reaction with two moles of 4-acetyl-3-arylsydnones (la-o) and one mole of hydrazine hydrate, since hydrazine hydrate is a symmetrical binucleophile it can readily react simultaneously with two carbonyl carbons. The azines (3a-o) were obtained in -85% yield in about 10 minutes (Scheme 1).
The IR spectra of all the hydrazones (2a-o) showed bands at 3424 cm-1 and 3388 cm-1 for asymmetric and symmetric vNH stretching. The bands at 1727 cm-1 and 1641 Schemel compounds showed a singlet at 8 2.37 (3H) for the methyl protons of the hydrazone group, and another broad peak at 8 10.40 (2H) for amino group (0 2 0 exchanged). The aromatic protons appeared in the region 8 6.40-7.00. The IR spectra of the azines (3a-o) exhibited band at 1741cm-1 and 1642 cm-1 due to Vc=O of the sydnone ring and vC=N· The absence of the -NH 2 band confirms the formation of azine. The 1 H NMR  resonance showed magnetic equivalence for the protons of one half of the molecule with the other. All these compounds showed a singlet at 8 3.9 (6H) corresponding to the methyl protons on the azine group and the aromatic protons appeared at 8 7.00-7.30. The formation of the azine was confirmed by the EI-Mass spectrum of a typical compound the p-chloro substituted derivative (30. The molecular ion at m/z 472 was not observed but the fragment at m/z 414, accounts for the loss of -NO and -CO from the sydnone ring. This fragmentation is typical of the sydnone ring. The IR spectra of the ar etyl derivatives of the hydrazones (4a-o) showed a broad band at 3300 cm-1 due to vNH stretching and 1758 crn-1 due to Vc=O of the sydnone ring, while the amide Vc=O appeared at 1659 cm-1 . 1 HNMR (DMSO-d 6 ) spectra showed a singlet at 8 2.60 (3H) for the methyl protons of -COCH 3 and 8 2.20 (3H) of hydrazone group. The -NH proton appeared at 8 10.3 (lH, 0 2 0 exchanged) and the aromatic protons were observed in the region of 8 7.41-7.38.
Antimicrobial activity : The preliminary antimicrobial testing has been carried out by cup-plate method. The antimicrobial activity was done against two pathogenic bacteria Escherichia coli and Pseudomonas pyocyanous and Asperigillus niger and Rhizocona bataticola as the fungal strains. The reference drugs used were Norfloxacin and Griseofulvin respectively. Compounds (2f, g, h, m, nand o) with halogen substitutions on the phenyl ring exhibited antibacterial act.ivity greater than the reference drug against both the bacteria, while only methyl (2b, c, k and I) group substitution increased the activity against both the fungi. The halogen substituted azines (3f, g and h) showed enhanced antibacterial activity against both the organisms compared to norfloxacin. Only the m-CI (3g) derivative was found to be more active against R. bataticoa while all the other compounds were moderately active. Amongst the acetyl derivatives (4a-o) only one derivative viz. 4-CI-3-F (4o) exhibited activity greater than the reference drug against E. coli while all the other compoum!s were moderately active against both the bacteria. The 4-bromo (4h) and 4-carbethoxy (4j) substitutions enhanced the antifungal activity against both the fungi, while other derivatives were moderately active (Tables 1-3).

Experimental
Melting points were determined in open capillary tube and are uncorrected. The IR spectra were recorded on Nicolet Impact-410 FT-IR spectrophotometer, using KBr pellets. 1 H NMR was recorded on Brucker Varian-300 MHz FT-NMR in DMSO-d 6 with TMS as an internal standard. Mass spectra were recorded on aMI Ver. 14 on UIC 002002. Elemental analysis was carried out using Heraus CHN rapid analyzer.
Synthesis ofhydrazones of4-acetyl-3-aryl sydnones (2ao) : 4-Acetyl-3-aryl sydnones (0.005 mol) were dissolved in ethanol (4 ml) containing 3-4 drops of acetic acid. Hydrazine hydrate (0.025 mol) was added and the reaction mixture warmed on a water-bath for 2 min. The reaction mixture was then diluted with water till turbidity was observed and warmed on water-bath for another 5 min, cooled and filtered. The bright orange crystalline compounds obtained were recrystallised from methanol. 2a