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Synthesis of Schiff and Mannich Bases of Isatin Derivatives with 4-Amino-4,5-Dihydro-1H-1,2,4-Triazole-5-Ones

Ethyl imidate hydrochlorides 1 were prepared by passing HCl gas through solutions of substituted benzyl cyanides and absolute ethanol. Ethoxycarbonylhydrazones 2 were synthesized from the reaction of compounds 1 with ethyl carbazate. Treatment of 2 with hydrazine hydrate leads to the formation of substituted 4-amino-4,5-dihydro-1H-1,2,4-triazole-5-ones 3. Isatin and 5-chloroisatin were added to 3 to form Schiff bases 4 and N-Mannich bases 5 of these compounds were synthesized by reacting with formaldehyde and piperidine. Their chemical structures were confirmed by means of IR, 1H- and 13C-NMR data and by elemental analysis.

These biological data prompted us to synthesize new isatin derivatives bearing 1,2,4-triazole ring and the newly synthesized compounds were characterized by elemental analysis, IR, 1 H-and 13 C-NMR spectral data.

Results and Discussion
In the present study, ethyl imidate hydrochlorides 1 were prepared by passing HCl gas through solutions of o-or p-fluorobenzyl cyanide in absolute ethanol, followed by precipitation with ether. Ester ethoxycarbonyl hydrazones 2 were synthesized by the reactions of alkyl imidate hydrochlorides 1 with ethyl carbazate. Treatment of compounds 2 with hydrazine hydrate in water resulted in the formation of 3-o-fluorobenzyl-4-amino-4,5-dihydro-1H-1,2,4-triazole-5-one (3a) and 3-pfluorobenzyl-4-amino-4,5-dihydro-1H-1,2,4-triazole-5-one (3b), respectively. The substituted 4amino-4,5-dihydro-1H-1,2,4-triazoles 3 were condensed with isatin derivatives in the presence of a few drops of glacial acetic acid as a catalyst to produce Schiff bases 4 in rather good yields. Mannich base formation can take place at both the isatin and triazole NH protons, but it is known that the isatin NH proton is more active than the triazole one [32]. In addition, after the Mannich reactions, the 1 H-NMR spectra of compounds 5 show NH proton signals at around δ 11.00 ppm, which correspond to a triazole NH, so we conclude that in the current study, Mannich bases were formed by condensing the acidic imino group of isatin with formaldehyde and piperidine, instead of the triazole NH proton (Scheme 1).
Compounds 2 showed absorption bands at around 3277, 1720, and 1659 cm -1 regions, resulting from the NH, C=O, and C=N functions, respectively. Compounds 3 showed two peaks at around 3220 and 3165 cm -1 due to asymmetric and symmetric vibrations of the primary amino group. Compounds 4 and 5 showed two separate bands belonging to triazole indole C=O functions in the 1733-1750 and 1698-1710 cm -1 regions, and C=N stretching vibrations at around 1650 cm -1 . In the IR spectra of 5, triazole NH stretching vibrations were around 3200 cm -1 . The characteristic NH protons of compounds 2 were detected around δ 9.00 ppm. The characteristic NH 2 protons of compounds 3 were detected around δ 5.00 ppm. The 1 H-NMR spectra of 4 displayed the NH protons of the triazole moiety (δ 11.07-11.17 ppm) and the indole NH proton (δ 12.09-12.53) as two separate singlets. Compounds 5 displayed characteristic >N-CH 2 -N< signals at around δ 4.36 ppm (s, 2H, CH 2 ).
In the 13 C-NMR spectra of compounds 2a-b characteristic C=O signals appeared at around δ 171.00 ppm. The triazole C-3 and triazole C-5 signals of compounds 3a-b were recorded at δ 149.38 ppm (C-3) and δ 156.33 ppm (C-5). Characteristic triazole and indole C=O and the C=N carbon signals of compounds 4a-d were recorded at around δ 150 ppm, δ 165 ppm, and δ 150 ppm, respectively. In the 13 C-NMR spectra of compounds 5a-d characteristic >N-CH 2 -N< signals belonging to the Mannich bases were observed at around δ 171.00 ppm.

General
Melting points were determined on a Barnstead Electrothermal melting point apparatus and are uncorrected. 1 H-NMR and 13 C-NMR spectra (δ, ppm) were recorded in DMSO-d 6 solutions on a Varian-Mercury 200 MHz spectrometer using tetramethylsilane as the internal reference. The IR spectra (υ, cm -1 ) were obtained with a Perkin-Elmer 1600 FTIR spectrometer in KBr pellets. Elemental analyses were performed on a ECS 4010 Elemental Combustion System. The starting compounds, alkyl imidate hydrochlorides 1a-b, were synthesized by previously reported routes [34,35]. The necessary chemicals were purchased from Merck and Fluka companies.

Synthesis of Ethoxycarbonyl Hydrazones 2a-b
The corresponding ethyl imidate hydrochlorides (1a-b, 0.01 mol) was dissolved in absolute ethanol (50 mL) with ice-bath cooling, and ethyl carbazate (0.01 mol) dissolved in absolute ethanol (50 mL) was then added to this solution. After stirring for 6 h at 0-5 °C, the precipitate was filtered to remove the ammonium chloride which separated from the solution and the filtrate was evaporated at 30-35 °C under reduced pressure. The solid residue, after drying in a dessicator, was recrystallized from petroleum ether to yield compounds 2a-b.

Synthesis of Amino Compounds 3a-b
Compounds 2 (0.01 mol) were added to a solution of hydrazine hydrate (0.01 mol) in water (50 mL) and the mixture was refluxed for 5 h. On cooling, a precipitate was formed. This product was filtered and, after drying, was recrystallized from an appropriate solvent to give compounds 3a-b.

Synthesis of Schiff Bases 4a-d
Equimolar quantities (0.01 mol) of isatin or 5-chloroisatin and the corresponding amino compound 3a-b were dissolved in warm ethanol (50 mL) containing glacial acetic acid (0.5 mL). The reaction mixture was refluxed for 4 h and then kept at room temperature overnight. The resultant solid was washed with dilute ethanol, dried and recrystallized from ethanol-water (1:2) mixture to afford compounds 4a-d.

Synthesis of Mannich Bases 5a-d
The corresponding Schiff bases 4a-d (0.002 mol) were dissolved in absolute ethanol (100 mL). Then formaldehyde (37%, 0.5 mL) and piperidine (0.002 mol) were added dropwise with vigorous stirring. After combining all reagents, the reaction mixture was stirred at room temperature for 12 h. The mixture was cooled, the solid product was filtered and washed with petroleum ether. The solid that separated was recrystallized from ethanol-dioxane (1:2) to yield the title compounds 5a-d.