Mild and ecofriendly tandem synthesis, and spectral and antimicrobial studies of n1-acetyl-5-aryl-3-(substituted styryl)pyrazolines

Article abstract of DOI:10.1080/10426500802388318

N1-acetyl-5-aryl-3-(substituted styryl)pyrazolines were synthesized by the cyclocondensation of 1,5-substituted diphenyl-1,4-pentadien-3-ones with hydrazine hydrate and a cyclizing agent such as acetic acid in ethanol. The title compounds were synthesized using conventional and solvent-free approaches, which involves mechano-chemical mixing, microwave-irradiation, and ultrasound-irradiation methods in the presence of a solid support. The synthesized compounds have been characterized by elemental analyses and spectral data (IR, PMR, and FAB-mass). All the synthesized compounds have been evaluated for their antibacterial and antifungal activities. Some compounds have shown promising biological activity.

Full text of DOI:10.1080/10426500802388318

This article was downloaded by: [University of Tennessee, Knoxville]
On: 27 December 2014, At: 14:12
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Phosphorus, Sulfur, and Silicon
and the Related Elements
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Mild and Ecofriendly Tandem
Synthesis, and Spectral and
Antimicrobial Studies of N1-
Acetyl-5-aryl-3-(substituted
styryl)pyrazolines
Vijai N. Pathak a , Rahul Joshi a , Jaimala Sharma a ,
Neetu Gupta a & Vijay Mohan Rao b
a Centre of Advanced Studies, Department of
Chemistry , University of Rajasthan , Jaipur, India
b Department of Botany , University of Rajasthan ,
Jaipur, India
Published online: 22 Jun 2009.
To cite this article: Vijai N. Pathak , Rahul Joshi , Jaimala Sharma , Neetu Gupta
& Vijay Mohan Rao (2009) Mild and Ecofriendly Tandem Synthesis, and Spectral
and Antimicrobial Studies of N1-Acetyl-5-aryl-3-(substituted styryl)pyrazolines,
Phosphorus, Sulfur, and Silicon and the Related Elements, 184:7, 1854-1865, DOI:
10.1080/10426500802388318
To link to this article: http://dx.doi.org/10.1080/10426500802388318
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views

expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Phosphorus, Sulfur, and Silicon, 184:1854–1865, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802388318
Mild and Ecofriendly Tandem Synthesis, and Spectral and
Antimicrobial Studies of N1-Acetyl-5-aryl-3-(substituted
styryl)pyrazolines
Vijai N. Pathak,1 Rahul Joshi,1 Jaimala Sharma,1
Neetu Gupta,1 and Vijay Mohan Rao2
1Centre of Advanced Studies, Department of Chemistry, University
of Rajasthan, Jaipur, India
2Department of Botany, University of Rajasthan, Jaipur, India
N1-acetyl-5-aryl-3-(substituted styryl)pyrazolines were synthesized by the cyclocon-
densation of 1,5-substituted diphenyl-1,4-pentadien-3-ones with hydrazine hydrate
and a cyclizing agent such as acetic acid in ethanol. The title compounds were syn-
thesized using conventional and solvent-free approaches, which involves mechano-
chemical mixing, microwave-irradiation, and ultrasound-irradiation methods in
the presence of a solid support. The synthesized compounds have been character-
ized by elemental analyses and spectral data (IR, PMR, and FAB-mass). All the
synthesized compounds have been evaluated for their antibacterial and antifungal
activities. Some compounds have shown promising biological activity.
Keywords Bischalcones; microwave-irradiation; pyrazolines; ultrasound-irradiation
INTRODUCTION
Pyrazoles1 and allied derivatives are well-known, biologically im-
portant, nitrogen-containing heterocyclic compounds associated with
various pharmacological activities such as COX-2 inhibiting,2
antimicrobial,3 antidepressant,4 antinociceptive,5 insecticidal,6 anti-
mycotic,7 anti-inflammatory,8 antibacterial,9 antiandrogenic,10 and
antiamoebic.11 A few nitrogen-containing five-membered heterocyclic
Received 13 February 2008; accepted 1 August 2008.
We express our sincere gratitude to Dr. K. P. Madhusunan, Deputy Director and Head,
SAIF, Central Drug Research Institute (CDRI), Lucknow, India, for elemental analyses
and spectral (IR, NMR, and FAB Mass) data. The authors are thankful to the coordinator
of the Centre of Advanced Studies, Department of Chemistry, for providing chemicals.
One of the authors (R. J.) is thankful to UGC, New Delhi, for financial support.
Address correspondence to Rahul Joshi, Centre of Advanced Studies, Department
of Chemistry, University of Rajasthan, Jaipur 302004, India. E-mail: pathakvijain@
yahoo.com
1854

Synthesis of of N1-Acetyl-5-aryl-3-(substituted styryl)pyrazolines
1855
compounds are reported to have been used in the treatment of Parkin-
son’s and Alzheimer’s diseases and cerebral edema.12,13
Pyrazoles and their derivatives are known to act as antitubercular14
and antitumor agents.15 They also have a vasoconstrictor and vasodila-
tor effect on hypoxia15 and play the role of PR-antagonist.17
α, β-Unsaturated carbonyl compounds (chalcones) have been used
as synthons in the preparation of various biologically active com-
pounds. Keeping these observations in view, we synthesized a num-
ber of bischalcones, and then these were condensed with hydrazine
hydrate and phenyl hydrazine to give pyrazolines as biologically ac-
tive molecules. In this method, hydrazone is formed as an inter-
mediate, which is than cyclized to the corresponding pyrazolines
in the presence of a suitable cyclizing agent such as glacial acetic
acid.18,19
The title compounds have been synthesized using various techniques
involving conventional and green chemistry routes, namely grindstone
chemistry,20 ultrasound,21–26 and microwave chemistry.27–29
In the light of the above facts, we report in this article the synthesis of
N1-acetyl-5-aryl-3-(substituted styryl)pyrazolines from 1,5-substituted
diphenyl-1,4-pentadien-3-ones. These compounds have been synthe-
sized using all the above-mentioned procedures, and a comparative
study has been done. Among the four methods used, the microwave
irradiation procedure was found to be the best one due to higher yields,
shorter reaction time, and enhanced selectivity.
A few representative compounds were screened for their antibac-
terial and antifungal activity, and some of the compounds exhibited
promising activity.
RESULTS AND DISCUSSION
Synthesis
1,5-Substituted diphenyl-1,4-pentadien-3-ones were synthesized by an
aldol condensation with substituted benzaldehydes and acetone in a
2:1 ratio in the presence of ethanolic NaOH solution. This bischal-
cone 3 was subjected to hydrazone formation via cyclization reac-
tion with hydrazine hydrate to give N1-acetyl-5-aryl-3-(substituted
styryl)pyrazolines 4. This reaction takes place through the mediation
of an appropriate α,β -unsaturated hydrazone, which immediately cy-
clizes to give a pyrazoline ring in the presence of a suitable cycliz-
ing agent such as glacial acetic acid under refluxing or irradiation
conditions (Scheme 1). N1-acetyl-5-aryl-3-(substituted styryl) pyrazo-
lines were synthesized by employing various reaction conditions. In

1856
V. N. Pathak et al.
SCHEME 1 X = H; 4 Cl; 4 OCH3; 2 OCH3; 3,4,5 (OCH3)3; 4F; 2 Cl; 3 F;
2F; 2,4 (Cl)2.
the conventional process, the bischalcone 3, hydrazine hydrate, and
glacial acetic acid used as a cyclizing agent were dissolved in ethanol
and refluxed for 10–30 h.
In contrast, under solvent-free conditions, the same reactants were
ground together using a mortar and pestle to afford target compounds
4, in higher yields and shorter reaction time. Under ultrasound-
irradiation conditions, the same reactants were dissolved in a small
quantity of ethanol, and the reaction mixture was sonochemically irra-
diated for 10–25 min. by using an ultrasonic bath. In the microwave-
irradiation conditions, the reactant 3, hydrazine hydrate, and a
calculated amount of glacial acetic acid over K2CO3 were irradiated
in a domestic microwave oven for 0.5–5 min. The results obtained are
tabulated in Table I.
The physical, spectral, and analytical data of compounds (4a–j) are
given in Tables II and III.
EXPERIMENTAL
All melting points were determined in open glass capillary tubes
and are uncorrected. The IR spectra (vmax in cm−1) were recorded

Synthesis of of N1-Acetyl-5-aryl-3-(substituted styryl)pyrazolines
1857
TABLE I Results and Conditions for the Synthesis of N1-Acetyl-5-
aryl-3-(substituted styryl)pyrazolines (4)
Time required
Yield (%)
Temp. (◦C)
i
ii
iii
iv
Compound
i
ii
iii
iv
min.
min.
min.
hrs.
i
ii
4a
4b
4c
4d
4e
4f
4g
4h
4i
90
91
89
84
92
94
88
90
87
79
86
87
85
80
87
91
84
78
82
76
80
78
80
73
82
80
76
70
78
70
73
70
75
68
76
75
69
64
65
63
0.5
2.5
1.0
0.8
2.7
2.9
3.2
3.0
2.5
3.0
10
12
15
20
12
22
25
22
15
25
25
25
20
35
28
30
38
36
25
35
12
14
24
24
18
25
28
24
18
15
70
50
65
60
62
70
75
68
70
55
30
30
30
30
30
30
30
30
30
30
4j
i. By Microwave irradiation with K2CO3; reactions were carried out in a LG
MS-194A domestic microwave oven with maximum 800W power.
ii. By ultrasound irradiation with ethanol; reactions were carried out in an
ultrasonic bath Toshniwal SW-4,150W with 37 KHz output frequency.
iii. By mechano-chemical mixing with Mg(HSO4)2.
iv. By conventional method.
on a Shimadzu IR 435U-04 infrared spectrophotometer using potas-
sium bromide pellets. PMR spectra were recorded on JEOL FX-90 Q
(89.55Hz) spectrometer using CDCl3 as a solvent. TMS was used as an
internal standard (chemical shift in δ ppm). Mass spectra were recorded
on Jeol SX-102 (FAB) mass spectrometer. The purity of compounds was
TABLE II Physical Data of N1-Acetyl-5-aryl-3-(substituted
styryl)pyrazolines (4)
Molecular
Weight
Melting
Compounds No.
X
Molecular Formula
C19H18N2O
Point(◦C)
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
4-Cl
4-OCH3
4-F
2-Cl
2,4-(Cl2)
3-F
2-OCH3
3,4,5-(OCH3)3
2-F
290
359
350
326
359
428
326
350
470
326
76
216
167
135
192
231
119
147
180
95
C
19H16Cl2N2O
C21H22N2O3
C
C
19H16F2N2O
19H16Cl2N2O
C19H14Cl4N2O
C19H16F2N2O
C21H22N2O3
C25H30N2O7
4j
C19H16F2N2O

1858

1859

1860
V. N. Pathak et al.
checked by TLC using silica gel-G as an adsorbent and UV light– or
iodine-accomplished visualization. The microwave-assisted reactions
were carried out in domestic MW oven (LG MS-194 A) with 800 W
and the ultrasound-assisted reactions were carried out in an ultrasonic
bath (Toshniwal SW-4) operating at 37 KHz output frequency.
1,5-substituted diphenyl-1,4-pentadien-3-ones 3 and N1-acetyl-5-
aryl-3-(substituted styryl)pyrazolines 4 were synthesized by the fol-
lowing routes.
1,5-Substituted diphenyl-1,4-pentadien-3-ones (3a–j)
Various 1,5-substituted diphenyl-1,4-pentadien-3-ones were prepared
by a method on the literature method (conventional).30
Ultrasound-Irradiation Method
A mixture of substituted benzaldehydes (5 mmol), acetone (2.5 mmol,
0.14 g), and ground sodium hydroxide pellets (0.5 g) was placed in a
conical flask. Ethanol (5 mL) was added, and the conical flask was
covered with porous parafilm. This reaction mixture was introduced
under ultrasonic waves at 12◦C for 10–15 min. using an ultrasonic
bath to afford the substituted bischalcones. This reaction mixture was
neutralized by pouring into ice cold 2N HCl. The solid was suction-
filtered, washed with water, dried, and recrystallized from rectified
spirit to afford the substituted bischalcones.
Microwave-Irradiation Method
1,5-Substituted diphenyl-1,4-pentadien-3-one 3 could not be synthe-
sized by using this method, due to the low boiling point of acetone
(56◦C).
N1-Acetyl-5-aryl-3-(substituted styryl)pyrazolines 4(a–j)
Ultrasound-Irradiation Method
A mixture of ground 1,5-substituted diphenyl-1,4-pentadien-3-one 3
(2 mmol), hydrazine hydrate (16%, 1 mL), and glacial acetic acid (1 mL)
was dissolved in ethanol (15 mL) in a conical flask (250 mL). The conical
flask was covered with porous parafilm. This reaction mixture was
introduced under ultrasonic waves at 30◦C for 5–25 min. (indicated in
Table I). After completion of the reaction, the alcohol was removed, and
the resultant residue was neutralized by pouring into ice cold NaHCO3
solution. The resultant solid was suction filtered, washed with water,
dried, and recrystallized from benzene.

Synthesis of of N1-Acetyl-5-aryl-3-(substituted styryl)pyrazolines
1861
Microwave-Assisted Solvent-Free Synthesis
A mixture of ground 1,5-substituted diphenyl-1,4-pentadien-3-one 3
(2 mmol), hydrazine hydrate (16%, 1 mL), and glacial acetic acid (1 mL)
impregnated on potassium carbonate as a solid support were placed
in a conical flask (250 mL), and this reaction mixture was irradiated
inside a microwave oven at 800 W for a few minutes (indicated in
Table I). After completion of the reaction, benzene was added to it. The
mixture was filtered, benzene was removed, and the resultant residue
was neutralized by pouring into ice cold NaHCO3 solution. The product
was suction-filtered, washed with water, dried, and recrystallized from
benzene. The catalyst left as a residue during filtration was washed
2–3 times with hot benzene and dried in vacuum for reuse.
Mechano-Chemical Mixing (Solvent-Free Synthesis)
A
mixture of 1,5-substituted diphenyl-1,4-pentadien-3-one 3
(2mmol), hydrazine hydrate (16%, 1 mL), Mg(HSO4)2 (0.3g), and glacial
acetic acid (1 mL) were ground together in a mortar using a pestle. An
orangish-colored tacky solid was obtained in 10–30 min. (indicated in
Table I). The reaction proceeds exothermically, as indicated by a rise in
temperature of 12–15◦C. After completion of the reaction, the reaction
mixture was neutralized by pouring into NaHCO3 solution. The product
was collected by filtration, washed with water, dried, and recrystallized
from benzene.
Conventional Method
A solution of 1,5-substituted diphenyl-1,4-pentadien-3-one 3 (2
mmol), hydrazine hydrate (16%, 1 mL), and glacial acetic acid (1 mL) in
ethanol was refluxed for 12–30 h. The reaction progress was monitored
by TLC. The reaction mixture was kept overnight at room temperature.
The reaction mixture was neutralized by pouring into ice cold NaHCO3
solution. The resulting solid was suction-filtered, washed with water,
dried, and recrystallized from benzene.
All the synthesized compounds along with their characteristics data
are given in Table II.
The comparative yields by all the four methods viz ultrasound-
irradiation, microwave-assisted, mechano-chemical, and conventional
are given in the Table I.
The structure of the synthesized compounds (4a–j) was confirmed
by their IR, 1H NMR, and FAB mass spectral analysis.

1862

1863

1864
V. N. Pathak et al.
Antimicrobial Activity
All the representative compounds were screened for their antimi-
crobial activity against the gram-negative bacteria Escherichia coli;
gram-positive bacteria Bacillus subtilis; fungi Candida albicans, a
diploid sexual fungus31; and Trichophyton rubrum, a causative agent
of dermatophytosis,32 which may cause infection in immunocomprised
hosts33 at different concentrations by disc diffusion method.34 Strep-
tomycin and Griseofulvin were used as standard drugs for evaluating
antibacterial and antifungal activities, respectively. Compounds 4b, 4f,
and 4i showed enhanced antibacterial and antifungal activity at 200
ppm, 400 ppm, 800 ppm, and 1000 ppm due to the presence of chlorine
and methoxy moieties attached with the pyrazole ring. Compounds 4f
and 4i showed very effective antibacterial compared to the other com-
pounds. The results obtained are presented in Tables IV and V.
REFERENCES
[1] S.M. Landge, A. Schmidt, V. Outerbridge, and B. To¨ro¨k, Synlett, 1600 (2007).
[2] R. Garg , A. Kurup , S. B. Mekapati, and C. Hansch, Chem. Rev., 103, 703 (2003).
[3] S. S. Kargaokar, P. H. Patel, M. J. Shah, and H. H. Parekh, Indian J. Pharmacol.,
58(6), 222 (1996).
[4] E. Palaska , M. Aytemin , T. Uzbay, and D. Erol , Eur. J. Med. Chem., 36, 539 (2001).
[5] A. Shafiee, M. Bagheri, M. Shekarchi, and M. Abdollahi, J. Pharmaceut Sci., 6(3),
360 (2003).
[6] S. Kristopher, M. Pesticides Biochem. Physiology, 81(2), 136 (2005).
[7] J. Matysiak and A. Niewiadomy, Bioorg. Med. Chem., 11(10), 2285 (2003).
[8] F. Flora, M. Hanna, and S. Adel, Bioorg. Med. Chem., 14(11), 3927 (2006).
[9] S. Shinde, W. Jadhav, R. Pawar, and S. Bhusare, J. Chinese Chem.Soc., 51, 775
(2004).
[10] G. Amr Ael, N. A. Abdel-Latif, and M.M. Abdalla, Bioorg. Med.Chem., 14(2), 373
(2006).
[11] M. Abid and A. Azam, Eur. J. Med. Chem., 40(9), 935 (2005).
[12] G. Ucar, N. Gokhan, A. Yesilada, and A.A. Bilgin, Neurosci. Lett., 382(3), 327 (2005).
[13] H. Yamashita, K. Okumaura, H. Luzika, and N. Ohto, Eur. Pat., 22691 (1989).
[14] P. T. Chovatia, J. D. Akabari, P. K. Kachhadia, P. D. Zalavadia, and H. S. Joshi, J.
Serb. Chem. Soc., 71(7), 713 (2007).
[15] V. Zsoldos Mady, A. Csampai, R. Szabo, E. Meszaros Alapi, J. Pasztor, F. Hudecz,
and P. Sohar, Chem. Med. Chem., 1(10), 1119 (2006).
[16] R. M. Wadsworth, Trends in Pharmacol. Sci., 15(2), 47 (1994).
[17] D. G. Jones, X. Liang, E. L. Stewart, R. A. Noe, L. S. Kallander, K. P. Madauss, S.
P. Williams, S. K. Thompson, D. W. Gray, and W. J. Hoekstra, Bioorg. Med. Chem.
Lett., 15(13), 3203 (2005).
[18] K. Vounauwers, Ber. Dt. Chem. Ges., 41, 4230 (1908).
[19] A. Baker and V.S. Butt, J. Chem. Soc., 2142 (1949).
[20] F. Toda, Ed., Topics in Current Chemistry, Vol. 254: Organic Solid State Reactions,
(Springer, Berlin, 2005), and references cited therein.

Synthesis of of N1-Acetyl-5-aryl-3-(substituted styryl)pyrazolines
1865
[21] S. Kenneth and J. Gareth, Annu. Rev. Mater. Sci., 29, 295 (1999).
[22] P. Mingos and D. R. Baghurst, Chem. Soc. Rev., 20, 1 (1991).
[23] C. Einhorn, J. Einhorn, M. J. Dickens, and J. L. Luche, Tetrahedron Lett., 31, 4129
(1990).
[24] J. L. Luche, Ed., Synthetic Organic Sonochemistry (Wiley-VCH, Weinheim, Ger-
many, 2005).
[25] T. J. Mason, Sonochemistry (Oxford University Press, Oxford, UK, 2000).
[26] B. To¨ro¨k, K. Bala´zsik, K. Felfo¨ldi, and M. Barto´k, Ultrasonics Sonochem., 8, 191
(2001).
[27] S. Varma, Green Chemistry, 1, 43 (1999).
[28] A. Loupy, Microwave in Organic Synthesis (Wiley-VCH, Weinheim, Germany, 2005).
[29] C.O. Kappe and A. Stadler, Microwave in Organic and Medicinal Chemistry (Wiley-
VCH, Weinheim, Germany (2005).
[30] P. N. Rao, Indian J. Pharma. Sci., 51(5), 207 (1989).
[31] K. J. Ryan, C. G. Ray, Eds., Sherris Medical Microbiology, 4th ed. (McGraw, New
York, 2004).
[32] R. Arenas, J. Dominguez-Cherrit, and L. M. Fernandez, Int. J. Dern., 34(2), 138
(1995).
[33] R. F. Squeo, R. Beer, D. Silver, I. Weitzman, and M. Grossman, Am. Acad. Dermatol.,
39, 379 (1998).
[34] R. Cruickshank, Medicinal Microbiology II, 12th ed. (Churchill Livingstone, Edin-
burgh, UK, 1975).