Synthesis of 3-(phenoxathiin-2-yl)-2-pyrazoline derivatives as new antibacterial and antifungal agents

Article abstract of DOI:10.1080/17415993.2010.497537

A new series of 3-(phenoxathiin-2-yl)-5-aryl-2-pyrazoline derivatives were synthesized from the reaction of 1-(phenoxathiin-2-yl)-3-phenyl/(4-chlorophenyl) propenones 1a and 1b with different nitrogen nucleophiles. The titled compounds were investigated for their antibacterial and antifungal activities and were compared with the standard drugs. Most of the synthesized compounds demonstrated potent to weak antimicrobial activity.

Full text of DOI:10.1080/17415993.2010.497537

This article was downloaded by: [University of Waikato]
On: 11 July 2014, At: 01:39
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
Journal of Sulfur Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/gsrp20
Synthesis of 3-(phenoxathiin-2-
yl)-2-pyrazoline derivatives as new
antibacterial and antifungal agents
Mohamed S. Behalo a
a Chemistry Department , Faculty of Science, Benha University ,
PO Box 13518, Benha, Egypt
Published online: 12 Aug 2010.
To cite this article: Mohamed S. Behalo (2010) Synthesis of 3-(phenoxathiin-2-yl)-2-pyrazoline
derivatives as new antibacterial and antifungal agents, Journal of Sulfur Chemistry, 31:4, 287-297,
DOI: 10.1080/17415993.2010.497537
To link to this article: http://dx.doi.org/10.1080/17415993.2010.497537
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

Journal of Sulfur Chemistry
Vol. 31, No. 4, August 2010, 287–297
Synthesis of 3-(phenoxathiin-2-yl)-2-pyrazoline derivatives as
new antibacterial and antifungal agents
Mohamed S. Behalo*
Chemistry Department, Faculty of Science, Benha University, PO Box 13518, Benha, Egypt
(Received 13 January 2010; final version received 26 May 2010)
A new series of 3-(phenoxathiin-2-yl)-5-aryl-2-pyrazoline derivatives were synthesized from the reaction
of 1-(phenoxathiin-2-yl)-3-phenyl/(4-chlorophenyl)propenones 1a and 1b with different nitrogen nucle-
ophiles. The titled compounds were investigated for their antibacterial and antifungal activities and were
compared with the standard drugs. Most of the synthesized compounds demonstrated potent to weak
antimicrobial activity.
Keywords: phenoxathiin; pyrazoline; thiazole; antimicrobial activity
1. Introduction
Pyrazoline derivatives are biologically interesting molecules that have established utility in the
pharmaceutical and the agrochemical industries. Among these derivatives, 1-(4-aryl-2-thiazolyl)-
3-(2-thienyl)-5-aryl-2-pyrazolines behave as effective antimicrobial agents (1, 2) and N-acetyl-
pyridinylpyrazolines have analgesic activity (3). It was also reported that 2-pyrazolines have
anticancer and anti-inflammatory activities (4, 5). Moreover, most of the compounds including
pyrazoline moiety, e.g. 1-thiocarbamoyl-2-pyrazolines, have been found to possess monoamine
oxidase inhibitory (6–10), antidepressant and anticonvulsant properties (11–14).
Several methods were employed in the synthesis of pyrazolines, including the condensation
of chalcones with hydrazine, hydrazine derivatives (15–18) and thiosemicarbazide under acidic
(15, 16) or basic (19, 20) conditions, and the cycloaddition of nitrilimines, generated in situ from
the corresponding hydrazonoyl halides by the action of a suitable base to carbon–carbon double
bonds of a suitable dipolarophile (21).
On the other hand, phenoxathiin is one of the rigidly folded tricyclic compounds that were
found to possess antitumor, monoamine oxidase inhibitory, antimicrobial activities (22–24) and
have promising florescent properties (25–27).
In addition, thiazole derivatives have occupied a unique position in the design and the synthesis
of novel biologically active agents that exert remarkable antimicrobial (28), anticancer (29, 30),
analgesic and anti-inflammatory (31) activities.
*Email: mohamedbehalo@hotmail.com
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2010 Taylor & Francis
DOI: 10.1080/17415993.2010.497537
http://www.informaworld.com

288 M.S. Behalo
In view of the above-mentioned facts and in continuation of our research interest for the syn-
thesis of biologically active heterocycles (32–35), I report herein the synthesis, antibacterial and
antifungal evaluation of some novel structures incorporating both phenoxathiin and pyrazoline
heterocycles. This combination was suggested in an attempt to investigate the effect of such
hybridization on the anticipated biological activities of molecules including both phenoxathiin
and pyrazoline moiety.
2. Results and discussion
The synthetic routes adopted for the synthesis of the titled compounds are depicted in Schemes
1–4.Thestartingchalcones,1-(phenoxathiin-2-yl)-3-phenyl/(4-chlorophenyl)-propenones1a and
1b in the present study were prepared from the reaction of 2-acetylphenoxathiin (36) and aromatic
aldehydes, namely benzaldehyde and 4-chlorobenzaldehyde (35, 36) (Scheme 1).
O
Ar1
Ar2
H2N–NHCSNH2
+
1a and 1b
Ar1
Ar2
Ar1
Ar2
O
S
N
S
H
NH
..
N
..
HN
NH2
NH2
x
Ar2
Ha
Hb
Hx
Ar2
Ar1
NH
N
Ar1
N
N
S
NH2
3a and 3b
S
NH2
2a and 2b
S
Ar
==
1
2a, Ar
= C H
2b, Ar
2
=
4-ClC6H4
6
5
2
O
Scheme 1. Synthetic route to pyrazolines 2a and 2b.
Chalcone 1 can have two stereoisomeric structures, Z and E forms (Figure 1), but on the basis
of the 1H NMR spectrum that showed two doublet signals for the two olefinic protons at 6.41 and
7.46 ppm with the coupling constant value J = 14.3 Hz, it seems to exist predominately in the E
form.
Synthesis of 3-(phenoxathiin-2-yl)-2-pyrazoline derivatives can be achieved by the reaction
of chalcones 1a and 1b with nitrogen nucleophiles such as thiosemicarbazide or hydrazine
derivatives. Thus, the treatment of chalcone 1 with thiosemicarbazide in refluxing ethanol and

Journal of Sulfur Chemistry 289
H
C
H
H
C
Ph
H
Ph
S
S
O
O
O
O
Z
E
Figure 1. Z and E forms of Chalcone 1a.
sodium hydroxide gave one isolable product whose mass spectrum is consistent with either struc-
ture 2 or 3 (Scheme 1). However, structure 2 (formed through hydrazone intermediate followed
by the addition of NH to the olefinic double bond) was established for the isolated products
1
1
on the basis of H NMR and IR spectra. H NMR spectrum of compound 2a revealed the sig-
nals of protons Ha, Hb and Hx of pyrazoline moiety as doublet of doublet at 3.28, 3.85 and
5.20 ppm, respectively, with coupling constants Jab = 17.7 Hz, Jax = 6.8 Hz and Jbx = 11.7 Hz.
Such coupling values are characteristic for the pyrazoline protons (20).
The reaction of pyrazolines 2a and 2b with phenacyl bromide derivatives in ethanol resulted
in the formation of the corresponding thiazolylpyrazolines 5a–5d through the non-isolable
intermediates 4a–4d (Scheme 2).
Ar1
Ar1
N
N
Ar1
Ar2
N
COCH2Br
Ar2
N
N
S
N
S
NH
O
Ar2
NH2
+
N
S
R1
2a and 2b
R1
4a–4d
R1
5a–5d
a
b
c
d
5
C6H5
C6H5
H
4-C6H4Cl
4-C6H4Cl
OCH3
Ar2
R1
H
OCH3
Scheme 2. Synthetic pathway of thiazolylpyrazolines 5a–5d.
A similar reaction of chalcones 1a and 1b with phenyl hydrazine, methyl hydrazine and
1
hydrazine hydrate afforded the corresponding products 6a–6f, respectively. H NMR spectra
of the latter products also revealed in each case doublet of doublet signals (c.f. Section 5). On
the other hand, the reaction of chalcones 1a and 1b with hydrazine hydrate in glacial acetic acid
afforded the corresponding N-acetylpyrazolines 7a and 7b. The latter can be formed also from
acetylation of pyrazolines 6a and 6d (Scheme 3).
Addition reaction of pyrazolines 6a and 6d with methyl and phenyl isothiocyanate
in the presence of triethylamine in ether provided the corresponding N-substituted-
thiocarbamoylpyrazolines 8a–8d. The spectral (IR, 1H NMR, MS) and the elemental analyses of
the products are all consistent with the assigned structures 8a–8d (Scheme 4).

290 M.S. Behalo
Ar1
O
EtOH
N
+
Ar1
Ar2
R2NHNH2
Ar2
N
R2
1a and 1b
6a–6f
NH2NH2
O
CH3COOH
c 2
A
R2
Ar2
6
6a, 6d
a
b
c
C6H5
C6H5
C6H5
H
Ar1
CH3
N
C6H5
H
Ar2
N
d
4-C6H4Cl
4-C6H4Cl
O
CH3
7a–7b
e
f
CH3
4-C6H4Cl
C6H5
Scheme 3. Synthesis of pyrazolines 6a–6f and N-acetylpyrazolines 7a–7b.
Ar1
Ar1
N
TEA
ether
Ar2
NHR3
+
R3NCS
N
N
Ar2
N
H
S
6a and 6d
8a–8d
a
b
c
d
8
C6H5
C6H5
C6H5
4-C6H4Cl
4-C6H4Cl
C6H5
Ar2
R3 CH3
CH3
Scheme 4. Synthesis of thiocarbamoylpyrazoline derivatives 8a–8d.
3. Biological activity
The synthesized compounds were tested for their in vitro antimicrobial activity against the Gram-
positive bacteria Staphylococcus cocci and Bacillus subtilis and the Gram-negative bacteria
Escherichia coli, Klebsiella bacilli and Pseudomonas aeruginosa. They were also evaluated
in vitro for their antifungal potential against Candida albican and Aspergillus niger. Chlo-
ramphenicol and Terbinafine were used as control drugs to evaluate the potency of the tested
compounds under the same conditions. The observed data on the antimicrobial activity of the
compounds and control drugs are given in Table 1.
Agar diffusion method was used for the determination of the preliminary antibacterial and
antifungal activity (37) and the results were recorded for each tested compound as the average
diameter of inhibition zones (r) of bacterial or fungal growth around the disks in millimeters at
100 μg concentrations in dimethyl sulfoxide.

Journal of Sulfur Chemistry 291
Table 1. Antimicrobial activity of the products.
Compound
S. cocci
B. subtilis
K. bacilli
P. aeruginosa
E. coli
C. albican
A. niger
2a
2b
5a
5b
5c
6a
6b
6d
6e
7a
7b
8a
8b
8c
C
18
25
28
26
31
15
12
18
16
20
24
31
30
33
35
–
22
28
30
27
33
16
17
19
14
22
26
36
33
35
37
–
18
18
23
20
24
12
14
15
11
19
20
25
24
26
40
–
16
16
19
18
26
10
11
10
11
19
23
27
27
28
38
–
18
15
23
18
25
13
13
18
13
23
24
28
25
24
42
–
22
22
28
23
18
16
15
18
16
24
26
35
38
41
–
19
24
31
18
23
14
18
14
15
23
28
39
40
36
–
T
40
42
Note: Numbers in the table represent the inhibition zone diameter (r, mm) of either fungal or bacterial growth for each compound;
r > 25 mm, highly active; r > 14 mm, moderately active; r > 10 mm, slightly active. C = Chloramphenicol as the standard
antibacterial agent and T = Terbinafine as the standard antifungal agent.
The results revealed that the majority of the synthesized compounds showed varying degrees
of inhibition against the tested microorganisms. Thiocarbamoylpyrazoline 8a showed the highest
potency against Gram-positive bacteria B. subtilis while pyrazoline 6e showed the lowest activity.
In general, the inhibitory activity against the Gram-positive bacteria was higher than that of the
Gram-negative bacteria. The pyrazoline derivatives 6a–6e displayed the least activity and the
pyrazolines 5c, 8a–8c showed a high activity against Gram-positive and Gram-negative bacteria
(inhibitory zone >25 mm). These compounds also possess a potent antifungal activity against
C. albican and A. niger when compared with Terbinafine. All the tested compounds showed
moderate (2a, 2b and 6a–6e) to high (5a, 8a and 8b) inhibitory effects towards tested fungi while
compound 8c exhibited the highest activity (Table 1).
4. Conclusion
The present study describes the synthesis of pyrazoline derivatives containing phenoxathiin moi-
1
ety, and the chemical structures of the compounds were elucidated by IR, MS, H NMR and
13C-NMR spectroscopy. The antibacterial and the antifungal activities for some of the synthesized
compounds were investigated, and it was observed that N-substituted-thiocarbamoyl pyrazolines
8a–8c showed a high activity against the tested bacteria and fungi.
5. Experimental
Melting points are uncorrected and FT-IR spectra were recorded on a JASCO FT-IR 660 Plus
spectrometer. NMR spectra were recorded on a Bruker Avance 400 (400 MHz) using CDCl3 as
the solvent. Column chromatography was run using silica gel 60 (70–230 mesh,Vetec), while TLC
was conducted on precoated silica gel polyester sheets (Kieselgel 60 F254, 0.20 mm, Merck). Mass
spectra were obtained using a Shimadzu GCMS-QP 1000 EX mass spectrometer in University of
Salento, Lecce, Italy.

292 M.S. Behalo
5.1. General procedures for the synthesis of chalcones (1a and 1b)
A mixture of 2-acetylphenoxathiin (0.01 mol), aromatic aldehyde (0.01 mol, benzaldehyde and
4-chlorobenzaldehyde) and sodium hydroxide (1 g in 10 ml water) in ethanol (30 ml) was stirred
at r.t. for about 3 h. The formed solid was washed, dried and purified to give yellow crystals of
chalcones 1a and 1b.
5.1.1. 1-(Phenoxathiin-2-yl)-3-phenylpropenone (1a)
1
Yield, 80%; m.p. 196–198 ◦C. IR: 1690 (CO) and 1610 cm−1 (C C); H NMR (CDCl3), δ ppm:
=
6.41 (d, 1H, α-CH olefinic, J = 14.3 Hz), 7.46 (d, 1H, β-CH olefinic, J = 14.3 Hz), 7.13–7.90
(m, 12H, Ar–H); MS: m/z: 330 (M+); Anal. calcd. for C21H14O2S (330.40): C, 76.34; H, 4.27%.
Found: C, 76.26; H, 4.13%.
5.1.2. 3-(4-Chlorophenyl)-1-(phenoxathiin-2-yl)propenone (1b)
1
Yield, 78%; m.p. 193–195 ◦C. IR: 1685 (CO) and 1603 cm−1 (C C); H NMR (CDCl3), δ ppm:
=
7.38 (d, 1H, α-CH olefinic, J = 14.6 Hz), 8.00 (d, 1H, β-CH olefinic, J = 14.6 Hz), 7.36–8.06
(m, 11H, Ar–H), Anal. calcd. for C21H13ClO2S (364.85): C, 69.13; H, 3.59%. Found: C, 69.02;
H, 3.43%.
5.2. Synthesis of 1-thiocarbamoyl-3-(phenoxathiin-2-yl)-5-aryl-2-pyrazoline (2a and 2b)
Thiosemicarbazide (0.01 mol) was added to a solution of chalcones 1a and 1b (0.01 mol) in ethanol
(30 ml) containing sodium hydroxide (0.02 mol) and all were refluxed for 6 h. After cooling, the
reaction mixture was poured into cold water and the resulted precipitate was filtered and washed.
The crude product was purified to give 2a and 2b.
5.2.1. 1-Thiocarbamoyl-3-(phenoxathiin-2-yl)-5-phenyl-2-pyrazoline (2a)
Yield: 81%, m.p. 212–214 ◦C. IR (cm−1): 3344, 3412 (NH2), 2927, 2853 (CH2), 1598 (C N),
1240 (CS); H NMR (CDCl3), δ ppm: 3.28 (dd, 1H, Ha, Jab = 17.7 Hz, Jax = 6.8 Hz), 3.85
=
1
(dd, 1H, Hb, Jab = 17.6 Hz, Jbx = 11.7 Hz), 5.20 (dd, 1H, Hx, Jax = 11.3 Hz, Jbx = 6.8 Hz),
6.95–8.10 (m, 12H, Ar–H), 8.23 (s, 2H, NH2, exchangeable); 13C NMR δ = 42.23 (CH2),
57.76 (CH), 113.52, 116.38, 118.12, 119.32, 120.13, 120.75, 122.30, 122.68, 128.70, 128.75,
130.16, 132.09, 148.06, 155.81 (phenoxathiin and phenyl carbons), 145.11 (C-3 pyrazoline),
191.26 (CS); MS: m/z: 403 (M+); Anal. calcd. for C22H17N3OS2 (403.52): C, 65.48; H, 4.25; N,
10.41%. Found: C, 65.68; H, 4.59; N, 10.70%.
5.2.2. 1-Thiocarbamoyl-5-(4-chlorophenyl)-3-(phenoxathiin-2-yl)-2-pyrazoline (2b)
Yield: 83%, m.p. 223–225 ◦C. IR (cm−1): 3335, 3387 (NH2), 2915, 2825 (CH2), 1615 (C N),
1295 (CS); H NMR (CDCl3), δ ppm: 3.36 (dd, 1H, Ha, Jab = 17.3 Hz, Jax = 7.5 Hz), 3.98
=
1
(dd, 1H, Hb, Jab = 17.1 Hz, Jbx = 12.5 Hz), 5.06 (dd, 1H, Hx, Jax = 11.8 Hz, Jbx = 7.7 Hz),
7.12–7.98 (m, 11H, Ar–H), 8.11 (s, 2H, NH2, exchangeable); 13C NMR δ = 43.86 (CH2), 59.16
(CH), 115.40, 116.23, 117.26, 117.56, 121.33, 121.87, 122.40, 126.64, 128.58, 129.25, 131.38,
139.13, 150.15, 157.65 (phenoxathiin and phenyl carbons), 142.80 (C-3 pyrazoline), 193.32 (CS);
Anal. calcd. For C22H16ClN3OS2 (437.97): C, 60.33; H, 3.68; N, 9.59%. Found: C, 60.49; H, 3.85;
N, 9.77%.

Journal of Sulfur Chemistry 293
5.3. General procedures for synthesis of 1-(4-aryl-2-thiazolyl)-3-(phenoxathiin-2-yl)-5-aryl-
2-pyrazoline (5a–5d)
A mixture of pyrazoline 2a and 2b (0.01 mol) and an equivalent amount of phenacyl bro-
mide derivatives namely phenacyl bromide and p-methoxyphenacyl bromide in ethanol (30 ml)
was heated under reflux for 2h and then left to cool. The solid product was filtered and
purified.
5.3.1. 1-(4-Phenyl-2-thiazolyl)-3-(phenoxathiin-2-yl)-5-phenyl-2-pyrazoline (5a)
1
Yield: 75%, m.p. 205–207 ◦C. IR (cm−1): 1620 (C N); H NMR (CDCl3), δ ppm: 3.17 (dd,
=
1H, Ha, Jab = 16.9 Hz, Jax = 7.5 Hz), 4.02 (dd, 1H, Hb, Jab = 17.5 Hz, Jbx = 8.1 Hz), 5.15
(dd, 1H, Hx, Jax = 7.1 Hz, Jbx = 12.6 Hz), 6.92 (s, 1H, thiazole–H), 6.96–8.02 (m, 17H, Ar–H);
13CNMR δ = 41.11 (CH2), 52.06 (CH), 103.42 (C-5 thiazole), 115.64, 117.14, 117.67, 118.20,
120.17, 121.43, 122.32, 122.56, 123.16, 128.36, 128.85,129.22, 130.45, 131.28, 136.85, 139.74,
151.62, 156.36 (phenoxathiin and phenyl carbons), 149.48 (C-3 pyrazoline), 150.38 (C-4 thiazole)
168.15 (C-2 thiazole); MS: m/z: 503 (M+); Anal. calcd. for C30H21N3OS2 (503.64): C, 71.54;
H, 4.20; N, 8.34%. Found: C, 71.42; H, 4.28; N, 8.43%.
5.3.2. 1-[4-(p-Methoxyphenyl)-2-thiazolyl]-3-(phenoxathiin-2-yl)-5-phenyl-2-pyrazoline (5b)
Yield: 69%, m.p. 186–188 ◦C. IR (cm−1): 1615 (C N); 1H NMR (CDCl3), δ ppm: 2.94
=
(s, 3H, OCH3), 3.42 (dd, 1H, Ha, Jab = 16.9 Hz, Jax = 6.9 Hz), 4.23 (dd, 1H, Hb, Jab = 17.2 Hz,
Jbx = 7.8 Hz), 4.83 (dd, 1H, Hx, Jax = 6.8 Hz, Jbx = 12.7 Hz), 6.77–7.95 (m, 16H, Ar–H), 6.85
(s, 1H, thiazole–H); MS: m/z: 533 (M+); Anal. calcd. for C31H23N3O2S2 (533.67): C, 69.77; H,
4.34; N, 7.87%. Found: C, 69.55; H, 4.41; N, 8.01%.
5.3.3. 1-(4-Phenyl-2-thiazolyl)-3-(phenoxathiin-2-yl)-5-(4-chlorophenyl)-2-pyrazoline (5c)
Yield: 74%, m.p. 201–203 ◦C. IR (cm−1): 1618 (C N); H NMR (CDCl3), δ ppm: 2.72 (dd, 1H,
1
=
Ha, Jab = 17.1 Hz, Jax = 7.3 Hz), 3.85 (dd, 1H, Hb, Jab = 17.1 Hz, Jbx = 7.9 Hz), 5.30 (dd, 1H,
Hx, Jax = 6.9 Hz, Jbx = 12.3 Hz), 6.65 (s, 1H, thiazole–H), 6.78–8.13 (m, 16H, Ar–H); Anal.
calcd. for C30H20ClN3OS2 (538.08): C, 66.96; H, 3.75; N, 7.81%. Found: C, 67.12; H, 3.86;
N, 7.90%.
5.3.4. 1-[4-(p-Methoxyphenyl)-2-thiazolyl]-3-(phenoxathiin-2-yl)-5-(4-chlorophenyl)-2-
pyrazoline (5d)
Yield: 72%, m.p. 210–212 ◦C. IR (cm−1): 1624 (C N); 1H NMR (CDCl3), δ ppm: 2.89
=
(s, 3H, OCH3), 3.12 (dd, 1H, Ha, Jab = 17.1 Hz, Jax = 7.2 Hz), 3.89 (dd, 1H, Hb, Jab = 17.5 Hz,
Jbx = 7.6 Hz), 5.20 (dd, 1H, Hx, Jax = 6.9 Hz, Jbx = 11.8 Hz), 6.97 (s, 1H, thiazole–H), 7.11–
8.02 (m, 15H, Ar–H); 13C NMR δ = 40.65 (CH2), 53.12 (CH), 54.32 (CH3), 101.06 (C-5
thiazole), 117.45, 118.36, 120.23, 121.12, 121.46, 121.78, 122.89, 123.41, 126.51, 128.38,129.13,
131.30, 131.74, 135.31, 141.13, 153.43, 157.42, 158.60 (phenoxathiin and phenyl carbons),
150.48 (C-3 pyrazoline), 151.22 (C-4 thiazole) 166.51 (C-2 thiazole); MS: m/z: 568 (M+);
Anal. calcd. for C31H22ClN3O2S2 (568.11): C, 65.54; H, 3.90; N, 7.40%. Found: C, 65.67; H,
3.96; N, 7.49%.

294 M.S. Behalo
5.4. Synthesis of pyrazolines (6a–6f)
To a solution of chalcone 1a or 1b (0.01 mol) in ethanol (30 ml), phenyl hydrazine, hydrazine
hydrate or methyl hydrazine (0.01 mol) was added. The reaction mixture was heated under reflux
for 4 h. After cooling, the precipitated solid was collected by filtration and purified to give the
corresponding pyrazoline.
5.4.1. 3-(Phenoxathiin-2-yl)-5-phenyl-2-pyrazoline (6a)
Yield: 78%, m.p. 241–243 ◦C. IR (cm−1): 3360 (NH), 2935, 2850 (CH2), 1596 (C N);
=
1H NMR (CDCl3), δ ppm: 3.44 (dd, 1H, Ha, Jab = 17.5 Hz, Jax = 6.8 Hz), 3.75 (dd, 1H, Hb,
Jab = 17.2 Hz, Jbx = 11.9 Hz), 4.69 (dd, 1H, Hx, Jax = 11.1 Hz, Jbx = 12.2 Hz), 7.21–7.95 (m,
12H, Ar–H), 9.3 (s, 1H, NH, exchangeable); MS: m/z: 344 (M+)T ;Anal. calcd. for C21H16N2OS
(344.43): C, 73.23; H, 4.68; N, 8.13%. Found: C, 73.32; H, 4.63; N, 8.19%.
5.4.2. 1-Methyl-3-(phenoxathiin-2-yl)-5-phenyl-2-pyrazoline (6b)
1
Yield: 71%, m.p. 210–212 ◦C. IR (cm−1): 2925, 2820 (CH2), 1610 (C N); H NMR (CDCl3),
=
δ ppm: 2.85 (s, 3H, CH3), 2.98 (dd, 1H, Ha, Jab = 17.2 Hz, Jax = 7.7 Hz), 3.45 (dd, 1H, Hb,
Jab = 17.2 Hz, Jbx = 11.7 Hz), 4.10 (dd, 1H, Hx, Jax = 11.5 Hz, Jbx = 8.2 Hz), 7.22–7.85 (m,
12H, Ar–H); 13C NMR 36.22 (NCH3), 39.90 (CH2), 63.79 (CH), 114.32, 116.87, 118.44, 120.12,
120.33, 120.69, 121.20, 122.77, 123.06, 126.52, 129.31, 133.72, 134.22, 155.03 (phenoxathiin
+
=
and phenyl carbons), 147.96 (C N); MS: m/z: 358 (M );Anal. calcd. for C22H18N2OS (358.46):
C, 73.71; H, 5.06; N, 7.82%. Found: C, 73.82; H, 5.09; N, 7.89%.
5.4.3. 3-(Phenoxathiin-2-yl)-1,5-diphenyl-2-pyrazoline (6c)
Yield: 74%, m.p. 216–218 ◦C. IR (cm−1): 2953, 2834 (CH2), 1585 (C N); H NMR (CDCl3),
1
=
δ ppm: 3.14 (dd, 1H, Ha, Jab = 17.1 Hz, Jax = 7.2 Hz), 3.82 (dd, 1H, Hb, Jab = 17.0 Hz,
Jbx = 12.4 Hz), 5.27 (dd, 1H, Hx, Jax = 7.2 Hz, Jbx = 12.3 Hz), 6.81–7.78 (m, 17H, Ar–H);
13C NMR 44.32 (CH2), 56.85 (CH), 113.22, 114.28, 115.16, 115.19, 115.25, 118.17, 118.76,
122.75, 122.81, 128.52, 129.06, 132.31, 132.78, 133.15, 137.21, 157.30, 159.95 (phenoxathiin
and phenyl carbons), 150.19 (C=N); MS: m/z: 420 (M+)T ;Anal. calcd. for C27H20N2OS (420.53):
C, 77.11; H, 4.79; N, 6.66%. Found: C, 77.20; H, 4.87; N, 6.61%.
5.4.4. 5-(4-Chlorophenyl)-3-(phenoxathiin-2-yl)-2-pyrazoline (6d)
Yield: 69%, m.p. 2+35–237 ◦C. IR (cm−1): 3372 (NH), 2923, 2840 (CH2), 1610 (C N); MS: m/z:
=
378 (M+), 379 (M + 1); Anal. calcd. for C21H15ClN2OS (378.88): C, 66.57; H, 3.99; N, 7.39%.
Found: C, 66.46; H, 3.86; N, 7.32%.
5.4.5. 5-(4-Chlorophenyl)-1-methyl-3-(phenoxathiin-2-yl)-2-pyrazoline (6e)
1
Yield: 70%, m.p. 224–226 ◦C. IR (cm−1): 2935, 2825 (CH2), 1605 (C N); H NMR (CDCl3),
=
δ ppm: 3.12 (s, 3H, CH3), 3.36 (dd, 1H, Ha, Jab = 16.8 Hz, Jax = 8.3 Hz), 3.80 (dd, 1H, Hb,
Jab = 17.2 Hz, Jbx = 11.1 Hz), 5.22 (dd, 1H, Hx, Jax = 11.8 Hz, Jbx = 7.8 Hz), 6.96–8.04 (m,
11H, Ar–H) Anal. calcd. for C22H17ClN2OS (392.90): C, 67.25; H, 4.36; N, 7.13%. Found:
C, 67.12; H, 4.43; N, 7.17%.

Journal of Sulfur Chemistry 295
5.4.6. 5-(4-Chlorophenyl)-3-(phenoxathiin-2-yl)-1-phenyl-2-pyrazoline (6f)
1
Yield: 68%, m.p. 206–208 ◦C. IR (cm−1): 2922, 2835 (CH2), 1615 (C N); H NMR (CDCl3),
δ ppm: 3.25 (m, 1H, Ha), 4.35 (dd, 1H, Hb, Jab = 17.1 Hz, Jbx = 7.6 Hz), 5.20 (dd, 1H, Hx, Jax =
8.2 Hz, Jbx = 12.3 Hz), 6.87–8.22 (m, 16H, Ar–H); Anal. calcd. for C27H19ClN2OS (454.97):
C, 71.28; H, 4.21; N, 6.16%. Found: C, 71.39; H, 4.28; N, 6.21%.
=
5.5. Synthesis of 1-acetyl-3-(phenoxathiin-2-yl)- 5-aryl-2-pyrazolines (7a and 7b)
A mixture of chalcone 1 (0.01 mol) and hydrazine hydrate (0.02 mol) in glacial acetic acid (20 ml)
was heated under reflux for 4 h. The reaction mixture was poured into ice and the product obtained
was filtered, washed with water, dried and purified.
5.5.1. 1-Acetyl-3-(phenoxathiin-2-yl)-5-phenyl-2-pyrazoline (7a)
1
Yield: 65%, m.p. 203–205 ◦C. IR (cm−1): 1710 (CO), 1640 (C N); H NMR (CDCl3), δ ppm:
=
3.18 (dd, 1H, Ha, Jab = 17.2 Hz, Jax = 7.1 Hz), 3.45 (s, 3H, COCH3), 3.75 (dd, 1H, Hb, Jab =
16.9 Hz, Jbx = 11.5 Hz), 4.97 (dd, 1H, Hx, Jax = 12.2 Hz, Jbx = 6.7 Hz), 6.87–7.96 (m, 12H,
Ar–H); Anal. calcd. for C23H18N2O2S (386.47): C, 71.48; H, 4.69; N, 7.25%. Found: C, 71.57;
H, 4.55; N, 7.15%.
5.5.2. 1-Acetyl-3-(phenoxathiin-2-yl)-5-(4-chlorophenyl)-2-pyrazoline (7b)
1
Yield: 67%, m.p. 211–213 ◦C. IR (cm−1): 1717 (CO), 1645 (C N); H NMR (CDCl3), δ ppm: 3.21
=
˙
(dd, 1H, Ha, Jab = 17.8 Hz, Jax = 8.2Hz), 3.39(s, 3H, COCH3), 3.88(dd, 1H, Hb, Jab = 17.3 Hz,
Jbx = 12.1 Hz), 4.82 (dd, 1H, Hx, Jax = 11.5 Hz, Jbx = 7.8 Hz), 6.98–8.11 (m, 11H,Ar–H); MS:
m/z: 420 (M+), 421 (M+ + 1); Anal. calcd. for C23H17ClN2O2S (420.91): C, 65.63; H, 4.07; N,
6.66%. Found: C, 65.74; H, 4.15; N, 6.71%.
5.6. General procedures for synthesis of 1-N-Substituted thiocarbamoyl-3-
(phenoxathiin-2-yl)-5-aryl-2-pyrazolines (8a–8d)
Methyl or phenyl isothiocyanate (0.01 mol) and few drops of triethylamine were added to the
solution of pyrazoline 6a or 6d (0.01 mol) in ether (20 ml) and all were stirred at room temperature
for 3 h. The mixture was evaporated to dryness and the residue was purified.
5.6.1. 1-N-Methylthiocarbamoyl-3-(phenoxathiin-2-yl)-5-phenyl-2-pyrazoline (8a)
1
Yield: 62%, m.p. 175–177 ◦C. IR (cm−1): 3365 NH, 1605 (C N), 1315 (C S); H NMR 3.11 (dd,
1H, Ha, Jab = 17.3 Hz, Jax = 8.4 Hz), 3.84 (dd, 1H, Hb, Jab = 16.9 Hz, Jbx = 12.3 Hz), 4.91
(dd, 1H, Hx, Jax = 11.7 Hz, Jbx = 8.3 Hz), 6.97–8.12 (m, 12H, Ar–H), 7.85 (b, H, NH); MS:
m/z: 417 (M+); Anal. calcd. for C23H19N3OS2 (417.55): C, 66.16; H, 4.59; N, 10.06%. Found:
C, 66.37; H, 4.68; N, 10.18%.
=
=
5.6.2. 1-N-Phenylthiocarbamoyl-3-(phenoxathiin-2-yl)-5-phenyl-2-pyrazoline (8b)
Yield: 58%, m.p. 162–164 ◦C. IR (cm−1): 3338 NH, 1618 (C N), 1321 (C S); H NMR 2.85
1
=
=
(dd, 1H, Ha, Jab = 17.1 Hz, Jax = 8.3 Hz), 3.32 (dd, 1H, Hb, Jab = 17.1 Hz, Jbx = 12.2 Hz),

296 M.S. Behalo
4.60 (dd, 1H, Hx, Jax = 11.6 Hz, Jbx = 8.1 Hz), 7.07–7.98 (m, 17H, Ar–H), 8.22 (bs, 1H, NH);
MS: m/z: 479 (M+);Anal. calcd. for C28H21N3OS2 (479.62): C, 70.12; H, 4.41; N, 8.76%. Found:
C, 70.02; H, 4.56; N, 8.64%.
5.6.3. 1-N-Methylthiocarbamoyl-3-(phenoxathiin-2-yl)-5-(4-chlorophenyl)-2-pyrazoline (8c)
Yield: 55%, m.p. 191–193 ◦C. IR (cm−1): 3350 NH, 1596 (C N), 1340 (C S); MS: m/z:
451 (M+),452 (M+ + 1);Anal. calcd. for C23H18ClN3OS2 (451.99): C, 61.12; H, 4.01; N, 9.30%.
Found: C, 61.38; H, 4.25; N, 9.38%.
=
=
5.6.4. 1-N-Phenylthiocarbamoyl-3-(phenoxathiin-2-yl)-5-(4-chlorophenyl)-2-pyrazoline (8d)
Yield: 60%, m.p. 197–199 ◦C. IR (cm−1): 3345 NH, 1610 (C N), 1332 (C S); H NMR 3.12
(dd, 1H, Ha, Jab = 16.8 Hz, Jax = 8.7 Hz), 3.47 (dd, 1H, Hb, Jab = 17.3 Hz, Jbx = 11.8 Hz),
4.66 (dd, 1H, Hx, Jax = 12.1 Hz, Jbx = 8.5 Hz), 6.89–7.93 (m, 16H, Ar–H), 8.75 (b, 1H, NH);
Anal. calcd. for C28H20ClN3OS2 (514.06): C, 65.42; H, 3.92; N, 8.17%. Found: C, 65.57; H, 4.02;
N, 8.05%.
1
=
=
Acknowledgement
The author wishes to thank Mrs Eman H. El-Doraidy, Botany Department, Faculty of Science, Benha University, Egypt,
for biological activity screening.
References
(1) Ozdemir, A.; Zitouni, G.T.; Kaplancikli, Z.A.; Revial, G.; Guven, K. Eur. J. Med. Chem. 2007, 42, 403–409.
(2) Kaplancikli, Z.A.; Zitouni, G.T.; Ozdemir, A.; Revial, G.; Guven, K. Phosphorus Sulfur Silicon Relat. Elem. 2007,
182, 749–764.
(3) Amr, A.E.; Maigali, S.S.; Abdulla, M.M. Monatsh Chem. 2008, 139, 1409–1415.
(4) Johnson, M.; Younglove, B.; Lee, L.; LeBlanc, R.; Holt, H.; Hills, P.; Mackay, H.; Brown, T.; Mooberry, S.L.; Lee,
M. Bioorg. Med. Chem. Lett. 2007, 17, 5897–5901.
(5) Udupi, R.H.; Kushnoor, A.S.; Bhat, A.R. Indian J. Heterocycl. Chem. 1998, 8, 63–66.
(6) Gokhan, N.; Yabanoglu, S.; Kupeli, E.; Salgın, U.; Ozgen, O.; Ucar, G.;Yesilada, A.; Kend, E.; Yesilada, A.; Bilgin,
A.A. Bioorg. Med. Chem. 2007, 15, 5775–5786.
(7) Gokhan, N.; Yesilada, A.; Ucar, G.; Erol, K.; Bilgin, A.A. Arch. Pharm. Pharm. Med. Chem. 2003, 336, 362–371.
(8) Ucar, G.; Gokhan, N.; Yesilada, A.; Bilgin, A.A. Neurosci. Lett. 2005, 382, 327–331.
(9) Gokhan, N.; Koyunoglu, S.;Yabanoglu, S.;Yelekci, K.; Ozgen, O.; Ucar, G.; Erol, K.; Kendi, E.;Yesilada,A. Bioorg.
Med. Chem. 2009, 17, 675–689.
(10) Chimenti, F.; Maccioni, E.; Secci, D.; Bolasco, A. J. Med. Chem. 2005, 48, 7113–7122.
(11) Palaska, E.; Aytemir, M.; Uzbay, I.T.; Erol, D. Eur. J. Med. Chem. 2001, 36, 539–543.
(12) Rajendra, P.Y.; Lakshmana, R.A.; Prasoona, L.; Murali, K.; Ravi, K.P. Bioorg. Med. Chem. Lett. 2005, 15, 5030–5034.
(13) Ozdemir, Z.; Kandilici, H.B.; Gumusel, B.; Calis, U.; Bilgin, A.A. Eur. J. Med. Chem. 2007, 42, 373–379.
(14) Ozdemir, Z.; Kandilici, H.B.; Gumusel, B.; Calis, U.; Bilgin,A.A. Arch. Pharm. Chem. Life Sci. 2008, 341, 701–707.
(15) Azarifar, D.; Ghasemnejad, H. Molecules 2003, 8, 642–648.
(16) Azarifar, D.; Shaebanzadeh, M. Molecules 2002, 7, 885–895.
(17) Ali, M.A.; Siddiqui, M.S. Eur. J. Med. Chem. 2007, 42, 268–275.
(18) Amir, M.; Kumar, H.; Khan, S.A. Bioorg. Med. Chem. Lett. 2008, 18, 918–922.
(19) Patel, V.M.; Desai, K.R. Arkivoc 2004, I, 123–129.
(20) Budakoti, A.; Bhat, A.R.; Athar, F.; Azam, A. Eur. J. Med. Chem. 2008, 43, 1749–1757.
(21) Hassaneen, H.M.; Hilal, R.H.; Elwan, N.M.; Harhash, A.; Shawali, A.S. J. Heterocycl. Chem. 1984, 21, 1013–1016.
(22) Rewcastle, G.W.; Atwell, G.J.; Palmer, B.D.; Denny, W.A. J. Med. Chem. 1991, 34, 491–496.
(23) Harferist, M.; Joyner, C.T.; Mize, P.D.; White, L.A. J. Med. Chem. 1994, 37, 2085–2089.
(24) Maior, O.; Gavriliu, D.; Stoia, S. South. Braz. J. Chem. 1995, 3, 79–88.
(25) Constantinescu, T.; Mischie, A.; Maior, O.; Badea, F.; Vasilescu, M.; Caproiu, M.T.; Socoteanu, R.; Nourescu, D.
Rev. Roum. Chim. 2000, 45, 1009–1018.
(26) Ionescua, S.; Gavriliu, D.; Maior, O.; Hillebrand, M. J. Photochem. Photobiol. A 1999, 124, 67–73.

Journal of Sulfur Chemistry 297
(27) Mischie, A.; Maior, O.; Badea, F.; Vasilescu, M.; Caragheorgheopol, A.; Caldararu, H.; Socoteanu, R.; Pencu, G.;
Constantinescu, T. Rev. Roum. Chim. 2001, 46, 107–113.
(28) Argyropoulou, I.; Geronikaki, A.; Vicini, P.; Zanib, F. Arkivoc 2009, vi, 89–102.
(29) Li, W.; Lu, Y.; Wang, Z.; Dalton, J.T.; Miller, D.D. Bioorg. Med. Chem. Lett. 2007, 17, 4113–4117.
(30) Al-Saadi, M.S.; Faidallah, H.M.; Rostom, S.A.F. Arch. Pharm. Chem. Life Sci. 2008, 341, 424–434.
(31) Rostom, S.A.; El-Ashmawy, I.M.; Abdel Razik, H.A.; Badr, M.H.; Ashour, M.A. Bioorg. Med. Chem. 2009, 17,
882–895.
(32) Attanasi, O.A.; Crescentini, L.D.; Favi, G.; Filippone, P.; Giorgi, G.; Mantellini, F.; Moscatelli, G.; Behalo, M.S.
Org. Lett. 2009, 11, 2265–2268.
(33) Issac, Y.A.; El-Karim, I.G.; Donia, S.G.; Behalo, M.S. Sulfur Lett. 2002, 25, 183–190.
(34) Issac, Y.A.; El-Karim, I.G.; Behalo, M.S.; Aly, A.A.; Donia, S.G. Olaj Szappan Kozmetika 2008, 57, 128–132.
(35) Behalo, M.S. Phosphorus Sulfur Silicon Relat. Elem. 2009, 184, 206–219.
(36) Lescot, E.; Buu-Hoi, N.P.; Xuong, N.D. J. Chem. Soc. 1956, 2408–2411.
(37) Leifert, C.; Chidbouree, S.; Hampson, S.; Workman, S.; Sigee, D.; Epton, H.A.S.; Harbour, A. J. Appl. Bacteriol.
1995, 78, 97–102.