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

Article abstract of DOI:10.1155/2011/658708

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

Full text of DOI:10.1155/2011/658708

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2011, 8(3), 1180-1185
http://www.e-journals.net
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
ASHVIN D. PANCHAL and PRAVIN M. PATEL*
Industrial Chemistry Department, V.P. & R.P.T.P. Science College
Vallabh Vidyangar- 388120. Anand, Gujarat. India
drpravinpatel@rediffmail.com
Received 5 October 2010; Accepted 16 December 2010
Abstract: 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
1
compounds were characterized by H NMR and IR spectroscopic studies. The
purity of the compounds was checked by thin layer chromatography.
Keywords: Triazole, Pyrazoline, N-(5-(Substitutedphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4H-1,2,4-
triazol-4-amine, 3-(Substitutedphenyl)-N-(4H-1,2,4-triazol-4-yl)acrylamide.
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 anti-
inflammatories, CNS stimulants, sedatives, antianxiety compounds, antimicrobial agents1-3 and
antimycotic ones such as fluconazole, intraconazole, voriconazole4,5. There are marketed drugs
containing the 1,2,4-triazole group, e.g., triazolam6, Alprazolam7, Etizolam8 and Furacylin9. 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 antibacterial10–12
,
antidepressant13 anticonvulsant14–16
antihypertensive17 antioxidant18 antitumor19 and anticancer activities20,21. Recently these
classes of compounds are reported to possess potential antiviral activity against flavivirus22

1181
PRAVIN M. PATEL et al.
and HIV23. 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
1
spectrometer using KBr disc, 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 CDCl3.
The homogeneity of the products was checked by TLC using silica gel GF254 (E.Merck) and
the eluent system was a mixture of acetone - pet.ether in 2:8 proportions.
General procedure for the preparation of N-(4H-1,2,4-triazol-4-yl)acetamide(2)
To a solution of 4-amino-4H-1,2,4-triazole (0.01 mol) in dry benzene (50 mL),
acetylchloride (0.01 mol) was added drop by drop at 0-5 °C. The reaction mixture was
stirred for 1 h and kept overnight. The reaction mixture was distilled off and then poured
onto ice. The solid thus obtained was recrystallized from suitable solvent. Physical,
analytical data are given in Table 1.
Table 1. Physical data of synthesized compounds 2, 3a-e and 4a-e
M.P., Yield,
Mol.
Formula
C4H6N4O
Mol.
Wt.
126
248
257
264
244
230
262
271
278
258
244
Solvent used for
recryllization
Methanol
Compound
R
oC
%
84
74
70
69
72
65
60
50
55
58
54
-
155
159
186
225
126
196
198
254
2
Methanol
Ethanol
4-Cl
C11H9ClN4O
C13H15N5O
C15H12N4O
C12H12N4O2
C11H10N4O2
C11H11ClN6
C13H17N7
C15H14N6
C12H14N6O
C11H12N6O
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
4-N(CH3)
Naphthalene
3-OCH3
2-OH
Acetone
Methanol
Ethanol
Ethanol
4-Cl
4-N(CH3)
Ethanol
Ethanol-Water
Ethanol
Naphthalene >300
3-OCH3
2-OH
162
214
Methanol-Water
General procedure for the preparation of 3-(substitutedphenyl)-N-(4H-1,2,4-triazol-
4-yl)acrylamide(3a–3e)
A solution of N-(4H-1,2,4-triazol-4-yl)acetamide (0.01 mol) in absolute ethanol (50 mL)
was refluxed with various aromatic aldehydes in the presence of 2% NaOH (5 mL) for 10 h,

Synthesis of Substituted Triazole
1182
concentrated, cooled and poured onto ice. The solids thus obtained were recrystallized from
appropriate solvents. Physical, analytical and spectroscopic data of compounds are given
below.
3-(4-Chlorophenyl)-N-(4H-1,2,4-triazol-4-yl)acrylamide(3a)
White crystals, yield 74%, m.p. 159 oC; TLC (Acetone: Toluene, 2:8). IR: (KBr, cm-1) 3426
(N-H), 3123 (Ar C-H stretch), 2925 and 2852 (C-H stretch), 1691 (NH-C=O), 1653
(CH=CH of –Carbonyl-CH=CH-), 1595 (C=N in triazole ring), 1513 (C=C of aromatic
1
ring), 762 (C-Cl). H NMR (400 MHz, CDCl3) δ/ppm: 8.31 (ss, 1H, N-H), 7.40-7.38
(d, 1H, -CO-CH=), 7.99-7.97 (d, 1H, =CH-Ar), 7.49-7.47 (d, 2H, Ar-H), 7.84-7.81 (d, 2H,
Ar-H), 8.80 (ss, 2H, -CH=N in triazole ring).
General procedure for the preparation of N-(5-(substitutedphenyl)-4,5-dihydro-1H-
pyrazol-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.
N-(5-(4-Chlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4H-1,2,4-triazol-4-amine(4a)
o
Yellowish crystals, yield 60%, m.p. 198 C; TLC (Acetone: Pet.ether, (2:8). IR: (KBr, cm-1)
3110 (N–H), 3070 (Ar CH stretch), 2985 and 2930 (C-H stretch), 1630 (C=N) in pyrazoline
1
ring, 1580 (N-N) in pyrazoline ring, 1380 (C–N). H NMR (400 MHz, CDCl3) δ/ppm: 7.45
(d, 2H, Ar–H), 7.79 (d, 2H, Ar-H), (s, 1H, -NH- missing), 7.26 (s, 1H, NH in pyrazoline ring),
7.78-7.76 (dd, 2H, CH2 in pyrazoline ring), 8.60 (s, 2H, CH=N in triazole ring).
N-(5-(4-(Dimethylamino)phenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4H-1,2,4-triazol-4-
amine (4b)
Yellowish crystals, yield 50%, m.p. 254 oC; TLC (Acetone: Pet.ether, (2:8). IR: (KBr, cm-1) 3410
(N–H), 3060 (Ar CH stretch), 2915 and 2840 (C-H stretch), 1610 (C=N) in pyrazoline ring, 1520
(N-N) in pyrazoline ring, 1360 (C–N). 1H NMR (400 MHz, CDCl3) δ/ppm: 7.69 (d, 2H, Ar–H),
7.71 (d, 2H, Ar–H), (s, 1H, -NH- missing), 7.25 (s, 1H, NH in pyrazoline ring), 6.72-6.70
(dd, 2H, CH2 in pyrazoline ring), 8.58 (s, 2H, CH=N in triazole ring), 3.02 (s, 6H, N-(CH3)2).
N-(5-(Naphthalen-1-yl)-4,5-dihydro-1H-pyrazol-3-yl)-4H-1,2,4-triazol-4-amine(4c)
Yellowish crystals, yield 55%, m.p. >300 oC; TLC (Acetone: Pet.ether, (2:8). IR: (KBr, cm-1)
3420 (N–H), 3080 (Ar CH stretch), 2940 and 2860 (C-H stretch), 1580 (C=N) in pyrazoline
ring, 1510 (N-N) in pyrazoline ring, 1325 (C–N). 1H NMR (400 MHz, CDCl3) δ/ppm: 7.91-
7.40 (m, 7H, Ar–H of Naphthalene), (s, 1H, -NH- missing), 7.28 (s, 1H, NH in pyrazoline
ring), 7.73-7.71 (dd, 2H, CH2 in pyrazoline ring), 9.68 (s, 2H, CH=N in triazole ring).
N-(5-(3-Methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4H-1,2,4-triazol-4-amine (4d)
o
Greenish crystals, yield 58%, m.p. 162 C; TLC (Acetone: Pet.ether, (2:8). IR: (KBr, cm-1)
3140 (N–H), 3020 (Ar CH stretch), 2910 and 2830 (C-H stretch), 1600 (C=N) in pyrazoline
ring, 1515 (N-N) in pyrazoline ring, 1300 (C–N). 1H NMR (400 MHz, CDCl3) δ/ppm: 6.97-
6.94 (d, 2H, Ar–H), 7.77 (d, 1H, Ar-H), 7.80 (d, 1H, Ar-H), (s, 1H, -NH- missing), 7.25
(s, 1H, NH in pyrazoline ring), 7.78-7.79 (dd, 2H, CH2 in pyrazoline ring), 8.62 (s, 2H,
CH=N in triazole ring), 3.85 (s, 3H, Ar-OCH3).

1183
PRAVIN M. PATEL et al.
2-(3-(4H-1,2,4-triazol-4-ylamino)-4,5-dihydro-1H-pyrazol-5-yl)phenol(4e)
Shiny greenish crystals, yield 54%, m.p. 214 oC; TLC (Acetone: Pet.ether, (2:8). IR: (KBr, cm-1)
3440 (N–H), 3010 (Ar CH stretch), 2970 and 2860 (C-H stretch), 1620 (C=N) in pyrazoline ring,
1
1570 (N-N) in pyrazoline ring, 1360 (C–N), 1260, 1040 (C-O). H NMR (400 MHz, CDCl3)
δ/ppm: 7.41-6.95 (m, 4H, Ar–H), (s, 1H, -NH- missing), 7.30 (s, 1H, NH in pyrazoline ring), 7.34-
7.32 (dd, 2H, CH2 in pyrazoline ring), 8.71 (s, 2H, CH=N in triazole ring), 11.38 (s, 1H, Ar-OH).
Results and Discussion
N-(5-(Substitutedphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-4H-1,2,4-triazol-4-amine (4a–e) were
synthesized according to the method shown in Scheme 1. In the first step, synthesis of N-(4H-
1,2,4-triazol-4-yl)acetamide were carried out by the acetylation of 4-amino-1,2,4-triazole by
acetyl chloride and products were purified by recrystallization from suitable solvent (75–85%
yield). Then in second step, synthesis of chalcone carried out by the reaction of N-(4H-1,2,4-
triazol-4-yl)acetamide and different aromatic aldehyde with 2% NaOH in absolute ethanol and
the products were purified by recrystallization from suitable solvents. In last step, synthesis of
pyrazoline derivatives by undergoes cyclization of chalcones with hydrazine hydrate in the
presence of few drops of HCl in absolute ethanol.
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).
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.
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

Synthesis of Substituted Triazole
1184
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.
Figure 2. Pharmacophore mapping of pyrazoline derivative
1
Structures of compounds 4a–e were confirmed by IR and 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-Ha and 4-Hb protons of pyrazoline ring. The J values were
calculated for above signals and found to be around 8 Hz. 5-H proton (δ around 7.44-7.41 ppm)
of pyrazoline ring showed a multiplet pattern of J value around 13 Hz and most likely
interacting with 4-Ha and 4-Hb protons.
Conclusion
This study describes the synthesis of novel substituted pyrazoline derivatives and their
characterization by IR and 1H NMR spectroscopic techniques successfully.
Acknowledgment
The author’s wishes to express their thanks to, Principal, V.P. & R.P.T.P. Science College,
the Head and Staff of Industrial Chemistry Department for providing laboratory facility.
References
1.
2.
Heindel N D and Reid J R, J Heterocycl Chem., 1980, 17, 1087.
Holla B S, Kalluraya B, Sridhar K R, Drake E, Thomas L M, Bhandary K K and
Levine M J, Eur J Med Chem., 1994, 29, 301-308.
3.
Mathew V, Keshavayya J, Vidya V P, Acharya and Reddy B M, Eur J Med Chem.,
2006, 41, 1048.
4.
5.
The Merck Index, Merck Co. Inc., Twelfth Ed., USA, 1996.
Haber J, Present Status and Perspectives on Antimycoties with Systematic Effects,
Cas Lek Cesk., 2001, 140, 596.
6.
Brucato A, Coppola A, Gianguzza S and Provenzano P M, Boll Soc Ital Biol Sper.,
1978, 54, 1051.
7.
8.
Coffen D L and Fryer R I, U.S. Patent 1974, 3, 849, 434; Chem Abstr., 1975, 82, 73044v.
Shiroki M, Tahara T and Araki K, Jap Patent, 75100096, 1975, Chem Abstr., 1976,
84, 59588k.
9.
Povelitsa F D and Gural A G, Antibiotiki Moscow, 1973, 18, 71; Chem Abstr., 1973,
78, 93044.

1185
PRAVIN M. PATEL et al.
10. Ali M A, Shaharyar M, Siddiqui A A, Sriram D, Yogeeswari P and Clercq E D, Acta
Pol Pharma Drug Res., 2007, 63, 435-439.
11. Shaharyar M, Siddiqui A A and Ali M A, Bioorg Med Chem Lett., 2006, 16,
4571-4554.
12. Chimenti F, Bizzarri B, Manna F, Bolasco A, Secci D, Chimenti P, Granese A,
Rivanera D, Lilli D, Scaltritoc M M and Brenciaglia M I, Bioorg Med Chem Lett.,
2005, 15, 603-607.
13. Prasad Y R, Rao A L, Prasoona K, Murali K and Kumar P R, Bioorg Med Chem Lett.,
2005, 15, 5030-5034.
14. Parmar S S, Pandey B R, Dwivedi C and Harbinson R D, J Pharm Sci., 1974, 63,
1152-1155.
15. Soni N, Pande K, Kalsi R, Gupta T K, Parmar S S and Barthwal J P, Res Commun
Chem Pathol Pharmacol., 1987, 56, 129-132.
16. Batulin Y M, Farmakol Toksikol., 1968, 31, 533.
17. Turan-Zitouni G, Chevallet P, Kilic F S and Erol K, Eur J Med Chem., 2000, 35, 635.
18.
Jeong T-S, Kim K S, Kim J-R, Cho K- H Lee S and Lee W S, Bioorg Med Chem Lett.,
2004, 14, 2719-2723.
19. Johnson M, Brent Younglove B, Lee L, LeBlanc R, Holt Jr H, Hills P, Mackay H,
Brown T, Mooberry S L and Lee M, Bioorg Med Chem Lett., 2007, 17, 5897-5901.
20. Manna F, Chimenti F, Fioravanti R, Bolasco A, Secci D, Chimenti P, Ferlini C and
Scambia G, Bioorg Med Chem Lett., 2005, 15, 4632-4635.
21. Roecker A J, Coleman P J, Mercer S P, Schreier J D, Buser C A, Walsh E S,
Hamilton K, Lobell R B, Tao W, Diehl R E, South V J, Davide J P, Kohl N E, Yan Y,
Kuo L C, Li C, Fernandez-Metzler C, Mahan E A, Prueksaritanontd T and Hartmana G D,
Bioorg Med Chem Lett., 2007, 17(20), 5677-5682.
22. Puig-Basagoiti F, Tilgner M, Forshey B M, Philpott S M, Espina N G, Wentworth D E,
Goebel S J, Masters P S, Falgout B, Ren P, Ferguson D M and Shi P-Y, Antimicrob
Agents Chemother., 2006, 50, 1320-1329.
23. Ali M A, Shaharyar M, Siddiqui A A, Sriram D, Yogeeswari P and Clercq E D, Acta
Pol Pharma Drug Res., 2007, 63, 423-428.

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