Synthesis of N-(5-(Substitutedphenyl)- 4,5-dihydro-1H-pyrazol-3-yl)-4H-1,2,4-triazol- 4-amine from 4-Amino-4H-1,2,4-triazole

N-(4H-1,2,4-Triazol-4-yl)acetamide (2) were prepared by reaction of 4-amino-4H-1,2,4-triazole (1) with acetyl chloride in dry benzene. It has been reacted with various aromatic aldehyde to afford 3-(substitutedphenyl)-N(4H-1,2,4-triazol-4-yl)acrylamide (3a-e). The synthesis of N-(5-substitutedphenyl)4,5-dihydro-1H-pyrazol-3-yl)-4H-1,2,4-triazol-4-amine (4a-e) is achieved by the cyclisation of 3a-e with hydrazine hydrate in ethanol. The structures of synthesized compounds were characterized by H NMR and IR spectroscopic studies. The purity of the compounds was checked by thin layer chromatography.


Introduction
In the last few decades, the chemistry of 1,2,4-triazoles has received considerable attention owing to their synthetic and effective biological importance.1,2,4-Triazole moieties have been incorporated into a wide variety of therapeutically interesting drug candidates including antiinflammatories, CNS stimulants, sedatives, antianxiety compounds, antimicrobial agents [1][2][3] and antimycotic ones such as fluconazole, intraconazole, voriconazole 4,5 .There are marketed drugs containing the 1,2,4-triazole group, e.g., triazolam 6 , Alprazolam 7 , Etizolam 8 and Furacylin 9 .In addition to these important biological applications, 1,2,4-triazoles are also of great utility in preparative organic chemistry, for example, in the presence of various reagents, undergo different types of reactions to yield other heterocyclic compounds.
Pyrazolines and their derivatives have been found to possess a broad spectrum of biological activities such as antibacterial [10][11][12] , antidepressant 13 anticonvulsant [14][15][16] antihypertensive 17 antioxidant 18 antitumor 19 and anticancer activities 20,21 .Recently these classes of compounds are reported to possess potential antiviral activity against flavivirus 22 and HIV 23 .Our literature survey revealed that these classes of compounds are yet to be explored with 1,2,4-triazole ring system.In this study, only the HY-ALI feature associated with 'B' ring of the substituted pyrazoline moiety was changed by keeping the basic skeleton intact.

Figure 1 Experimental
Melting points were determined in open capillary tubes and are uncorrected.All the chemicals and solvents used were of laboratory grade and solvents were purified by suitable methods.IR (Infrared spectrum) (KBr, cm -1 ) were recorded on a Shimadzu-8400 FT-IR spectrometer using KBr disc, 1 H NMR spectra were recorded on a brucker avance II 400 NMR spectrometer using TMS as an internal standard (chemical shift in δ, ppm) in CDCl 3. The homogeneity of the products was checked by TLC using silica gel GF 254 (E.Merck) and the eluent system was a mixture of acetone -pet.ether in 2:8 proportions.

General procedure for the preparation of N-(5-(substitutedphenyl)-4,5-dihydro-1Hpyrazol-3-yl)-4H-1,2,4-triazol-4-amine(4a-e)
To a solution of compound (3a-3e) (0.02 mol) and 99% hydrazine hydrate (0.04 mol) in absolute ethanol and few drops of hydrochloric acid was added.The reaction mixtures were refluxed for 8-10 h, distilled in vacuum and cooled.The separated solids were filtered, washed with ether and recrystallized from appropriate solvents.Physical, analytical and spectroscopic data of compounds (4a-4e) are as follows.The yellow contour represents the hydrophobic aliphatic feature (HY-ALI), the yellow contour at ring represents ring aromatic feature (AR), the green contour represents hydrogen bond donor feature (HBD) and the red contour represents Hydrogen bond acceptor (HBA).Figure 2 shows the mapping of pyrazoline for all the pharmacophoric features except PI (positive ionisable).On the basis of pharmacophore mapping, we hypothesized that this type of substituted pyrazolines may show potential Pharmacological and biological activity.

Results and Discussion
Factors such as the structure and position of the substituents have profoundly influenced the rate of the reaction.The generally accepted interpretation of this reaction, involves the initial formation of an aryl hydrazone with subsequent nucleophilic attack of nitrogen upon the carbon-carbon double bond at β position of chalcones.Hence the electropositive nature of β carbon may control the overall rate of the reaction.The electropositive nature of β carbon is controlled by the aromatic ring directly connected to it.Halogens being electron withdrawing in nature significantly increase the positive character of β carbon lead to faster reaction while electron donating alkyl and alkoxy groups contributed for slower reaction.

Conclusion
This study describes the synthesis of novel substituted pyrazoline derivatives and their characterization by IR and 1 H NMR spectroscopic techniques successfully.

N-( 5 -Scheme 1 .
Scheme 1. Synthesis of N-(5-(substituted phenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4H-1,2, 4-triazol-4-amine (4a-e)The yellow contour represents the hydrophobic aliphatic feature (HY-ALI), the yellow contour at ring represents ring aromatic feature (AR), the green contour represents hydrogen bond donor feature (HBD) and the red contour represents Hydrogen bond acceptor (HBA).Figure2shows the mapping of pyrazoline for all the pharmacophoric features except PI (positive ionisable).On the basis of pharmacophore mapping, we hypothesized that this type of substituted pyrazolines may show potential Pharmacological and biological activity.Factors such as the structure and position of the substituents have profoundly influenced the rate of the reaction.The generally accepted interpretation of this reaction, involves the initial formation of an aryl hydrazone with subsequent nucleophilic attack of nitrogen upon

Figure 2 .
Figure 2. Pharmacophore mapping of pyrazoline derivative Structures of compounds 4a-e were confirmed by IR and 1 H NMR spectroscopic techniques.All of the pyrazolines possesses similar basic skeletal structure.Proton NMR signals were assigned by comparing the spectra of the products (4a-e) with their corresponding chalcones.Signals around δ value 7.76 and 7.78 ppm recorded as doublet of doublet (dd) were assigned to 4-H a and 4-H b protons of pyrazoline ring.The J values were calculated for above signals and found to be around 8 Hz.5-H proton (δ around 7.44-7.41ppm) of pyrazoline ring showed a multiplet pattern of J value around 13 Hz and most likely interacting with 4-H a and 4-H b protons.