Synthesis of novel pyridazine derivatives as potential antimicrobial agents

Article abstract of DOI:10.1080/17415993.2014.950661

A series of novel pyridazine derivatives incorporated with triazole, thiazolidine, imidazolidine, oxazine, and quinazoline moieties was synthesized by the reaction of [6-(4-phenoxyphenyl)pyridazin-3-yloxy]acetyl isothiocyanate with variety of nucleophilic

Full text of DOI:10.1080/17415993.2014.950661

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Synthesis of novel pyridazine
derivatives as potential antimicrobial
agents
Mohamed S. Behaloa, Iman A. Gad El-karima, Yvette A. Issaca &
Mohamed A. Faraga
a Department of Chemistry, Faculty of Science, Benha University,
Benha, 13518, Egypt
Published online: 26 Aug 2014.
To cite this article: Mohamed S. Behalo, Iman A. Gad El-karim, Yvette A. Issac & Mohamed A. Farag
(2014): Synthesis of novel pyridazine derivatives as potential antimicrobial agents, Journal of Sulfur
Chemistry, DOI: 10.1080/17415993.2014.950661
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Journal of Sulfur Chemistry, 2014
http://dx.doi.org/10.1080/17415993.2014.950661
Synthesis of novel pyridazine derivatives as potential
antimicrobial agents
Mohamed S. Behalo∗, Iman A. Gad El-karim, Yvette A. Issac and Mohamed A. Farag
Department of Chemistry, Faculty of Science, Benha University, Benha, 13518, Egypt
(Received 25 April 2014; accepted 28 July 2014)
A series of novel pyridazine derivatives incorporated with triazole, thiazolidine, imidazolidine,
oxazine, and quinazoline moieties was synthesized by the reaction of [6-(4-phenoxyphenyl)pyridazin-
3-yloxy]acetyl isothiocyanate with variety of nucleophilic reagents. The structures of all products were
confirmed and characterized by the elemental analysis and spectroscopic studies (IR, MS, 1H NMR).
Also, the products 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.
Ar1
O
N
O
O
CH3
Ar1
S
CN
Ph
A r
N
C
S
1
NC
N
COCH3
S
H
N
N
NH
Ar1
S
S
S
Ph
N
Ar1
N
HN
COAr1
O
N
O
O
O
Keywords: pyridazine; isothiocyanate; triazole; thiazolidine; antimicrobial activity
1. Introduction
In recent years considerable attention has been devoted to the chemistry of heteroallenes isoth-
iocyanate derivatives as they are considered as reactive key precursors in the heterocycles
synthesis due to their diverse reactions and also to their easy availability. On the other hand,
isothiocyanates are biologically interesting molecules that have established utility in the pharma-
ceutical applications. Benzyl isothiocyanate, 3- and 4-methoxybenzyl isothiocyanate, along with
∗Corresponding author. Email: mohamedbehalo@hotmail.com
c
ꢀ 2014 Taylor & Francis

2
M.S. Behalo et al.
several other structurally related compounds were evaluated for antimicrobial activity.[1] Also,
phenethyl isothiocyanate and sulforaphane inhibit carcinogenesis and tumorigenesis in certain
circumstances.[2]
Several methods were employed in the synthesis of isothiocyanates, including the reac-
tion of amine derivatives with carbon disulfide [3–8] or thiophosgene,[9–11] treatment of the
carboxylic acid derivatives with ammonium thiocyantes [12–15] and pyrolysis of thiourea
derivative in o-dichlorobenzene.[16] In addition, many natural isothiocyanates from plants were
used as anticancer agents [17,18] and produced by enzymatic conversion of metabolites called
glucosinolates.[19]
It was also reported that pyridazine derivatives were used as effective antitumor,[20] and
antimicrobial [21–23] agents.
In view of these considerations and in continuation of our research interest for the synthesis
of biologically active heterocycles,[24–27] the present work proceeded with the synthesis of
new heterocyclic systems including pyridazine moiety and triazole, thiazolidine, imidazolidine,
oxazine, and quinazoline moieties.
2. Result and discussion
Schemes 1–4 show the synthetic pathways to prepare the target compounds 5–19. Synthesis
of the key substrate, [6-(4-phenoxyphenyl)pyridazin-3-yloxy]acetyl isothiocyanate 5 proceeded
via a series of reactions. Initially, diphenyl ether reacted with maleic anhydride and catalytic
amount of anhydrous aluminum chloride under Friedel–Crafts conditions to give 4-oxo-4-
(4-phenoxyphenyl)-but-2-enoic acid (1).[28]
OH
OCH2COOH
O
ClCH2COOH
N
N
N
N
+
NH2NH2.H2O
Ar
COOH
(1)
Ar
(2)
Ar
(3)
SOCl2
O
OCH2COCl
OCH2C
N C S
N
N
N
N
NH4SCN
Ar
Ar
(5)
(4)
O
Ar =
Scheme 1. Synthetic pathway of [6-(4-phenoxyphenyl)pyridazin-3yloxy] acetyl isothio-
cyanate 5.
Acid 1 can have two sterioisomeric structures, Z and E forms (Figure 1), but on the basis of
1
the H NMR spectrum, two doublet signals were detected for the two olefinic protons at 6.64

Journal of Sulfur Chemistry
3
CN
CH C
Ar1
CN
O
N
O
Ar1
O
CH3
CH3COCH2COCH3
S
CN
Ph
NC
Ar1
N
C S
N
COCH3
(5)
(6)
S
(7)
CNCH2COOEt
CN
S
O
N
O
Ar1
(8)
OCH2
N
N
O
Ar1
=
,
Ar =
,
Ar
Scheme 2. Reaction of isothiocyanate 5 with carbon nucleophiles.
H
N NH
N
S
Ac2O
PhCONHNH2
HN
O
Ph
S
N
Ar1
HN
Ph
O
Ar1
O
(10)
(9)
N
Ar1
S
Ph NH NH2
N
NH
(11)
Ph
O
H
N
NH2
H
N
S
Ar1
Ac2O
O
Ar1
N
C S
S
NH
Ar1
COOH
N
(5)
COOH
O
O
(13)
(12)
S
H2NCH2COOH
HN
N COAr1
O
(14)
Scheme 3. Reaction of isothiocyanate 5 with nitrogen nucleophiles.

4
M.S. Behalo et al.
NH2
OH
OH
H
N
H
N
Ar1
O
N
-H2S
C
S
C
O
Ar1COHN
(15)
(16)
OCH3
O
Ph
N
Ph-CH=N-C6 H4 OCH3
O
N
Ar1
N C S
Ar1
S
(5)
(17)
S
S
COAr1
O
N
HSCH2COOH
Ac2O
Ar1CONH-CS-SCH2-COOH
(18)
(19)
OCH2
N
N
O
Ar1 =
,
Ar =
,
Ar
Scheme 4. Synthesis of heterocycles 15–19.
O
H
O
H
COOH
R
R
COOH
H
H
E
Z
Figure 1. Z and E forms of acid 1.
and 7.85 ppm with coupling constant value of J = 15 Hz. Accordingly, (1) exists predominately
in the E form.[29]
Reaction of acid 1 with hydrazine hydrate in ethanol under reflux afforded pyridazin-3-ol 2
that reacts with chloroacetic acid to give pyridazinylacetic acid 3. The structure assigned for
compound 3 was based on the microanalytical and spectroscopic data.
Treatment of acid 3 with thionyl chloride followed by the reaction with ammonium thio-
cyanate afforded isothiocyanate 5 as a reactive key precursor that reacted in situ with different
nucleophiles like (carbon, nitrogen, and sulfur nucleophiles) to furnish the desired products.
Thus, refluxing of isothiocyanate 5 with benzylidene malononitrile as a carbon nucleophile in
dry toluene gave substituted oxazine 6 via [4+2] cycloaddition mechanism. Also, the reaction
of active methylene compounds like acetylacetone and ethyl cyanoacetate with isothiocyanate 5
afforded oxazines 7 and 8, respectively, Scheme 2.
Triazole derivatives are biologically interesting molecules that have established utility in
the pharmaceutical and the agrochemical industries. Thus, treatment of isothiocyanate 5 with
nitrogen nucleophiles as benzoylhydrazine in dry acetone furnished N-(N-benzoylhydrazine
carbothioyl)-2-[6-(4-phenoxyphenyl)pyridazin-3-yloxy]acetamide (9). Refluxing of the latter

Journal of Sulfur Chemistry
5
in acetic anhydride afforded triazolethione heterocycle 10. Also, isothiocyanate 5 reacted
with phenylhydrazine to furnish 5-[6-(4-phenoxyphenyl)pyridazin-3-yloxymethyl]-1-phenyl-
1,2-dihydro-[1,2,4]triazol-3-thione (11), Scheme 3.
The reactivity of isothiocyanate 5 toward amino acids was also investigated. Thus, its reaction
with anthranilic acid resulted in the formation of thiourea derivative 12 which upon cycliza-
tion afforded quinazoline 13, On the other hand, treatment of (5) with glycine resulted in the
formation of imidazolidine 14.
o-Amino phenol reacted with isothiocyanate 5 in dry acetone to afford thiourea derivative 15.
Heating of thiourea derivative 15 above its melting point afforded benzoxazole moiety 16. Mass
spectrum of compound 15 showed molecular ion peak at m/z = 472(M+) and its fragmentation
pattern is given in Figure 2.
On the other hand, synthesis of 3-(4-methoxyphenyl)-6-[6-(4-phenoxyphenyl)pyridazin-
3-yloxymethyl]-2-phenyl-2,3-dihydro-[1,3,5]oxadiazine-4-thione (17) was achieved from
the reaction of bezylidenanisidine. In addition, the reaction of thioglycolic acid as
sulfur nucleophile with isothiocyanate 5 afforded 3-{2-[6-(4-phenoxyphenyl)pyridazin-
3-yloxy]acetylamino}-2,3-dithioxopropionic acid (18) which upon cyclization furnished 3-[2-
[6-(4-phenoxyphenyl)pyridazin-3-yloxy]acetyl}-2-thioxothiazolidin-5-one (19), Scheme 4.
3. Antimicrobial 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 and Klebsiella bacilli. They were also evaluated in vitro for their antifun-
gal potential against Candida albicanand Aspergillus niger. Chloramphenicol and Terbinafine
were used as standard antibacterial and antifungal agents 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 [30] 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 dimethylsulfoxide.
The Gram (+ve) test organism and Gram (-ve) test organism were applied using eight spore
suspension of each test organism separately spreaded over a petri dish containing a solid nutrient
agar medium of the following composition (g/1): Beef extract, 3.0; tryptone, 5.0; agar, 15.0;
and distilled water, 1000.0. After immediately fresh inoculation of the tested organism, a well
per each Petri dish was made, and the 0.1 gm of the tested compound was filled the 6 mm in
diameter well, respectively, then incubated at 37◦C for 48 h. the diameter of the inhibition zones
was measured in mm.
Also the antifungal and antiyeast activities were tested using spore suspension of each tested
organism separately, spreaded over Petri dish containing solid Czapeks Dox agar of the following
composition (g/I).
Sucrose, 30.0; MgSO4, 0.5; KCl, 0.5; FeSO4, 0.01; NaNO3, 3.0; K2HPO4, 1.0; Agar, 20.0;
and distilled water, 1000.0.
After immediately fresh inoculation of the test organism, a 6 mm well per each Petri dish was
made, and the tested compounds were added to fill wells, respectively, and then incubated at
28◦C for seven days.
The results revealed that the majority of the synthesized compounds showed varying degrees
of inhibition against the tested microorganisms. It has been observed through the results in

6
M.S. Behalo et al.
+
.
HO
O
C
H
N
S
C
H
N
b
a
O
O CH2
e
N
N
d
c
M+. = 472
(15)
(25%)
a
b
e
d
+
+
c
HO
HO
S
Ph
O
H
+
+C
N
m/z = 169 (25%)
m/z = 77 (87%)
m/z = 152 (41.7%)
m/z = 93
(41.7%)
HO
S
H
+
HN
C
N
m/z = 167 (16.7%)
HO
O
S
H
N
H
+
H2C
C
C
N
m/z = 209 (54%)
+
.
H
HO
S
O
CH
C
Ar1
C
Ar1 OCH
C
O
N
H
N
O
H
OH
+.
SH
H
N
NH
C
OH
S
H
N
C
NH2
.
NH3
+
m/z = 168
(25%)
OCH2
S
C
N
+
OH
N
N
O
Ar1
=
Ar =
,
,
m/z = 58(100%)
Ar
Figure 2. Fragmentation pattern of compound 15.
Table 1 that compounds 10, 13, and 17 were highly active against gram-positive bacteria and
compounds 6, 7, 11 were highly active against gram-negative bacteria.
Triazole 10 and oxazine 6 possess a potent antibacterial activity against S. cocci and E. Coli,
respectively, when compared with Chloramphenicol while 1,3,5-oxadiazine-4-thione 17 dis-
played the highest activity against Bacillus substilis. On the other hand, most of the tested

Journal of Sulfur Chemistry
7
Table 1. Biological activities of the synthesized compounds.
Compound no.
S. cocci B. substili◦s E. Coli K. bacilli C. albicans A. niger
3
6
7
8
10
11
12
13
15
22
–
20
28
24
–
23
17
20
28
–
22
20
21
–
23
22
18
24
25
12
26
–
–
12
14
16
–
17
23
12
17
–
–
10
–
–
15
16
–
10
19
–
22
–
25
–
26
24
21
20
18
16
21
–
–
12
21
–
26
–
18
–
30
17
19
15
26
–
–
23
–
Chloramphenicol
Terbinafine
26
Numbers represent the extent of the zone diameter (r mm) inhibition of either fungal growth or bacterial
cells for each compound; (–) no inhibition was observed, for example compound not active; (r) > 10 mm,
slightly active; (r) > 15 mm, moderately active and (r) > 20 mm, high active.
compounds showed inhibitory effects toward tested fungi and quinazoline 13 exhibited the
highest activity (Table 1).
4. Conclusion
The present study describes the synthesis of series of heterocyclic systems as oxazines, triazoles
and quinazolines using heteroallene, [5-(4-phenoxyphenyl)pyridazin-3-yloxy]acetyl isothio-
cyanate as reactive key precursor and the chemical structures of the compounds were elucidated
1
by IR, MS, H, and 13C NMR. The antibacterial and the antifungal activities for some of the
synthesized compounds were investigated, and it was observed that compounds 6, 10, 13, and 17
showed the highest activity against the tested bacteria and fungi.
5. Experimental
Melting points were determined by the capillary tube method, and the thermometer was uncor-
rected. Mass spectra were obtained on an Agilent 1100 HPLC-MS instrument. 1H NMR spectra
were run in DMSO-d6, with TMS as the internal standard, on a Bruker ARX-300 instrument
operating at 300 MHz. IR spectra (KBr disks) were recorded on a Bruker IFS 55 instrument.
Elemental analysis was performed with a Carlo-Erba 1106 elemental analysis instrument.
5.1. Synthesis of 4-oxo-4-(4-phenoxyphenyl)-but-2-enoic acid (1)
Anhydrous aluminum chloride (0.01 mol) was added to a mixture of diphenyl ether (0.01 mol)
and maleic anhydride (0.01 mol) in tetrachloroethane (30 ml) within 20 min. in ice bath. The
reaction mixture was stirred for 5 h and left overnight. Then poured onto ice/HCl. The separated
solid product was filtered off and crystallized from benzene.
Yield, 80%; m.p. 115–117◦C. IR (KBr, ν cm−1): 3428 (OH), 1696, 1659 (2CO), 1582 (C C);
=
1H NMR (DMSO-d6), δ ppm: 6.64 (d, 1H, α-CH olefinic, J = 15 Hz), 7.85 (d, 1H, β CH
olefinic, J = 15 Hz), 7.03–8.09 (m, 9H, Ar-H), 13.17 (s, 1H, OH exchangeable); 13C NMR δ =
114.21, 121.52, 128.45, 130.33, 131.22, 140.43, 144.41, 149.37, 154.35, 156.13, 165.26, 172.33,

8
M.S. Behalo et al.
185.64; MS: m/z: 268 (M+, 53%), 223(5%), 197(100%), 93(4%), 99(10%). Anal. calc. for
C16H12O4(268.27): C, 71.64%; H, 4.51%. Found: C, 71.73%; H, 4.61%.
5.2. Synthesis of 5-(4-phenoxyphenyl) pyridazine -3-ol (2)
A solution of acid 1 (0.01 mol) and hydrazine hydrate (0.01 mol) in 20 ml ethanol was heated
under reflux for 5 h. The solid that separated after cooling was crystallized from dioxan to give
pyridazine 2.
Yield, 75%; m.p. 208–210◦C. IR (KBr, ν cm−1): 3401–3225 (OH,NH), 1655 (CO), 1589
1
=
(C C); H NMR(CDCl3) δ ppm: 6.86–7.45(m, 11H, Ar-H), 8.02 (s, 1H, NH, exchangeable),
8.12 (s, 1H, OH); MS: m/z: 265 (M+1, 16), 264 (M+, 100%), 207(41%), 195(14%), 114(16%),
102(15%), 77(51%). Anal. calc. for C16H12N2O2(264.28): C, 72.72%; H, 4.58%; N, 10.60%.
Found: C, 72.84%; H, 4.68%; N, 10.69%.
5.3. Synthesis of [5-(4-phenoxyphenyl)pyridazin-3-yloxy]acetic acid (3)
A solution of pyridazine 2 (0.01 mol) and chloroacetic acid (0.01 mol) in 30 ml ethanol and 10 ml
sodium hydroxide (10%) was refluxed on water bath for 5 h. The content of the experiment was
poured onto ice and HCl. The formed solid was collected by filtration and crystallized from
dioxan to give acid 3.
Yield, 65%; m.p. 328–330◦C. IR (KBr, ν cm−1): 3419–3237 (OH), 2924 (CH-aliphatic),
1685 (CO), 1588 (C C); 1H NMR (CDCl3) δ ppm: 4.33 (s, 2H, OCH2), 7.56–7.95 (m,
=
11H, Ar-H), 10.65 (s,1H, OH, exchangeable); 13C NMR δ = 74.28, 114.12, 121.25, 126.45,
127.15, 128.24, 130.53, 131.12, 140.43, 145.21, 149.37, 154.25, 162.53, 174.67. Anal. calc. for
C18H14N2O4(322.32): C, 67.08%; H, 4.38%; N, 8.69%. Found: C, 67.18%; H, 4.47%; N, 8.80%.
5.4. Synthesis of [5-(4-phenoxyphenyl)pyridazin-3-yloxy]acetyl isothio- cyanate (5)
Acid 3 (0.01 mol) in little amount of thionyl chloride was heated under reflux for 2 h. Excess
of thionyl chloride was removed by evaporation under vacuum to leave solid acid chloride 4.
Solid ammonium thiocyanate (0.01 mol) was added to stirred solution of [5-(3-phenoxyphenyl)
pyridazine-3-yloxy]acetylchloride (4) (0.01 mol) in dry acetone (20 ml). The reaction mixture
was stirred for 1.5 h at room temperature, the precipitated ammonium chloride was removed by
filtration to leave a clear solution of isothiocyanate derivative 5 in acetone that is used in situ.
5.5. Synthesis of 2-[5-(4-phenoxyphenyl)pyridazine-3-yloxymethyl]-6-phenyl-4-thioxo-4H-
[1,3]oxazine-5,5-dicarbonitrile (6)
A mixture of isothiocyanate 5 (0.01 mol) and benzylidenemalononitrile (0.01 mol) in toluene
(30 ml) was heated under reflux for 4 h. The separated solid was collected by filtration and
crystallized from petroleum ether to give compound 6.
Yield, 60%; m.p.170–172◦C. IR (KBr, ν cm−1) 2927 (CH2), 2163 (C≡N), 1640 (C N), 1339
=
1
=
(C S); H NMR (DMSO-d6) δ ppm: 4.21 (s, 2H, OCH2), 4.92 (s, 1H, OCH), 6.98–8.02 (m,
16H, Ar-H). Anal. calc. for C29H18N5O3S (516.56): C, 67.43%; H, 3.51%; N, 13.56%. Found:
C, 67.53%; H, 3.60%; N, 13.67%.

Journal of Sulfur Chemistry
9
5.6. General procedures for synthesis of products 7 and 8
To a solution of isothiocyanate 5 (0.01 mol) in dry acetone (20 ml), acetyl acetone or ethyl-
cyanoacetate (0.01 mol) and triethyl amine (1 ml) was added. The reaction mixture was refluxed
for 4 h. then poured onto into ice. The separated solid was crystallized from methanol and
benzene to give 7, 8, respectively.
5.6.1. 1-{6-methyl-4-[5-(4-phenoxyphenyl)pyridazin-3-yloxymethyl]-2-thioxo-2H-
[1,3]oxazin-5-yl}-ethanone (7)
1
Yield, 60%; m.p. 218–220◦C; IR (KBr, ν cm−1): 1660 (CO), 1599 (C N), 1305 (C S); H NMR
(DMSO-d6) δ ppm: 2.22 (s, 3H, CH3), 3.12 (s, 3H, COCH3), 3.95 (s, 2H, OCH2), 7.03–8.11 (m,
11H, Ar-H); 13C NMR δ = 16.15, 23.43, 74.24, 105.35, 114.42, 121.15, 126.35, 127.45, 128.24,
130.13, 131.12, 140.33, 145.41, 149.27, 154.15, 161.34, 162.13, 165.55, 190.32, 212.12; MS: m/z:
445(M+,10%), 282 (10%), 227(12%), 59(100%). Anal. calc. for C24H19N3O4S (445.50): C,
64.71%; H, 4.30%; N, 9.43%. Found: C, 64.80%; H, 4.42%; N, 9.56%.
=
=
5.6.2. 6-oxo-4-[5-(4-phenoxyphenyl)pyridazin-3-yloxymethyl]-2-thioxo-5,6-dihydro-2H-
[1,3]oxazine-5-carbonitrile (8)
Yield, 50%; m.p. 140–142◦C. IR (KBr, ν cm−1) 2102 (C N), 1710 (CO), 1591 (C N),
≡≡
=
1
=
1241(C S); H NMR (CDCl3), δ ppm: 4.70 (s, 2H, OCH2), 5.04 (s, 1H, OCH), 7.30–8.24 (m,
11H, Ar-H); MS: m/z: 430(M+1, 61%). Anal. calc. for C22H13N4O4S (429.44): C, 61.53; H,
3.05%; N, 13.05%. Found: C, 61.62%; H, 3.17%; N, 13.18%.
5.7. Synthesis of N-(N-benzoylhydrazinocarbothioyl)-2-[5-(4-phenoxy-phenyl)pyridazin-3-
yloxy] acetamide (9)
A mixture of isothiocyanate (5) (0.01 mol) and bezoylhydrazine (0.01 mol) in acetone was heated
under reflux for 4 h. The solid that separated was cystallized from ethanol to give product (9).
Yield, 52%; m.p. 150–152◦C. IR (KBr, ν cm−1): 3295–3380 (NH), 1688 (C O), 1606 (C C),
=
=
=
=
1589 (C N), 1248 (C S). Anal. calc. for C26H21N5O4S (499.55): C, 62.51%; H, 4.24%; N,
14.02%. Found: C, 62.60%; H, 4.35%; N, 14.13%.
5.8. Synthesis of 2-[6-(4-phenoxyphenyl)pyridazin-3-yloxy]-1-(3-phenyl-5-thioxo-1,5-
dihydro[1,2,4]triazole-4-yl) ethanone (10)
A solution of compound 9 (0.01 mol) in acetic anhydride (5 ml) was heated under reflux for
4 h, the separated solid product was collected by filtration and crystallized from ethanol to give
triazole 10.
Yield, 52%; m.p. 178–180◦C. IR (KBr, ν cm−1): 3310 (NH), 1690 (C O), 1595 (C N), 1320
=
=
1
=
(C S); H NMR (CDCl3), δ ppm: 3.88 (s, 2H, OCH2), 9.24 (s, 1H, NH), 6.97–8.08 (m, 16H,
Ar-H); MS: m/z: 481 (M+, 36%). Anal. calc. for C26H19N4O3S (481.23): C, 64.89%; H, 3.98%;
N, 11.64%. Found: C, 64.98%; H, 4.06%; N, 11.75%.

10 M.S. Behalo et al.
5.9. Synthesis of 5-[6-(4-phenoxyphenyl)pyridazin-3-yloxymethyl]-1-phenyl-1,2-dihydro-
[1,2,4]triazol-3-thione (11)
A mixture of isothiocyanate 5 (0.01 mol) and phenyl hydrazine (0.01 mol) in dry acetone (30 ml)
was heated under reflux for 2 h. After cooling, the precipitated solid was collected by filtration
and crystallized from toluene to give crystals of triazole 11.
Yield, 50%; m.p.165–167◦C. IR (KBr, ν cm−1): 3370 (NH), 1610 (C N), 1590 (C C), ν
=
=
1
=
1239 (C S); H NMR (CDCl3), δ ppm: 3.96 (s, 2H, OCH2), 8.86 (s, 1H, NH), 6.88–7.92 (m,
16H, Ar-H). Anal. calc. for C25H19N5O2S(453.52): C, 66.21%; H, 4.23%; N, 15.44%. Found: C,
66.32%; H, 4.34%; N, 15.57%.
5.10. Synthesis of 2-(2-{2-[6-(4-phenoxyphenyl)pyridazin-3-yloxy]-acetyl}thioureido)
benzoic acid (12)
An equimolar amount of isothicyanate 5 and anthranilic acid (0.01 mol) in acetone (20 ml) was
heated under reflux for 4 h. The reaction mixture was then allowed to cool and the separated solid
product was collected by filtration and crystallized from petroleum ether to give 12.
Yield, 65%; m.p. 180–182◦C. IR (KBr, ν cm−1): 3472 (OH), 3372 (NH), 2977 (CH2), ν 1617–
1
=
=
1690 (CO), 1595 (C N), 1217 (C S); H NMR (DMSO-d6), δ ppm: 4.12 (s, 2H, OCH2), 8.33,
9.62 (2s, 2H, 2NH), 7.12–8.10 (m, 15H, Ar-H); MS: m/z = 500(M+, 22%), 452 (23.8%), 305
(23.8%), 277 (14.3%), 147 (28.6%), 119 (100%). Anal. calc. for C26H20N4O5S (500.53): C,
62.39%; H, 4.03%; N, 11.19%. Found: C, 62.50%; H, 4.16%; N, 11.30%.
5.11. Synthesis of 3-{2-[6-(4-phenoxyphenyl)pyridazin-3-yloxy]acetyl}-2-thioxo-2,3-
dihydro-1H-quinazolin-4-one (13)
Compound 12 (0.01 mol) was heated in acetic anhydride (5 ml) under reflux for 4 h. The solid
that separated was crystallized from petroleum ether to give product 13.
Yield, 55%; m.p. 223–225◦C. IR (KBr, ν cm−1): 3310–3392 (NH), 1670–1650 (2 C O), ν
=
1
=
1220 (C S). H NMR (CDCl3), δ ppm: 3.92 (s, 2H, OCH2), 7.31–7.95 (m, 15H, Ar-H), 10.93
(s, 1H, NH, exchangeable). Anal. calc. for C26H18N4O4S (483.01): C, 64.65%; H, 3.76%; N,
11.59%. Found: C, 64.77%; H, 3.84%; N, 11.60%.
5.12. Synthesis of 4-Mercapto-4-{2-[6-(4-phenoxyphenyl)pyridazin-3-yloxy]acetyl}
thioureido) benzoic acid (14)
To a solution of isothiocyanate (5) (0.01 mol) in acetone, glycine (0.01 mol) and pyridine (2 ml)
were added and refluxed for 4 h. The reaction mixture was cooled and poured onto ice/HCl. The
separated solid product was collected by filtration, washed with water, dried, and crystallized
from benzene to give (14).
Yield, 55%; m.p. 229–231◦C. IR (KBr, ν cm−1): 3322 (NH), 2660 (SH), 1655–1695 (C O), ν
=
1292 (CS). MS: m/z = 420(M+, 35), 211(84%), 199 (100%). 1H NMR (CDCl3), δ ppm: 2.30 (s,
2H, CH2), 4.75 (s, 2H, OCH2), 7.15–7.95 (m, 11H, Ar-H), 8.44 (s, 1H, NH), 10.01 (s, 1H, SH).
Anal. calc. for C21H16N4O4S (420.41): C, 59.99%; H, 3.84%; N, 13.33%. Found: C, 60.13%; H,
3.95%; N, 13.44%.

Journal of Sulfur Chemistry 11
5.13. Synthesis of 1-(2-hydroxyphenyl)-3- {2-[6-(4-phenoxyphenyl)
pyridazine-3-yloxy]-acetyl}thiourea (15)
o-Aminophenol (0.01 mol) was added to solution of isothiocyanate 5 (0.01 mol) in dry acetone
(30 ml) and the reaction mixture was heated under reflux for 2 h. After cooling, the separated
solid was filtered off and crystallized from benzene to give thiourea derivative 15.
Yield, 55%; m.p. 120–122◦C. IR (KBr, ν cm−1): 3409–3250 (OH, NH), 1685 (C O),ν 1288
=
+
=
(C S); MS: m/z = 472(M , 25%), 304 (20%), 209(54%), 169 (25%), 168(25%), 167(16.7%),
152(41%), 93(41.7%), 77(87%), 58(100%). Anal. calc. for C25H20N4O4S (472.52): C, 63.35%;
H, 4.27%; N, 11.85%. Found: C, 63.67%; H, 4.14%; N, 11.98%.
5.14. Synthesis of N-benzoxazole-2-yl-2-[6-(4-phenoxyphenyl)pyridazin-3-yloxy]acetamide
(16)
Compound 15 (0.01 mol) was heated above its melting point for 2 h. The produced solid was
crystallized from benzene to give 16.
1
Yield, 57%; m.p. 154–156◦C; IR (KBr, ν cm−1): 3230 (NH), 1665 (C O), ν 1590(C N); H
NMR (CDCl3), δ ppm: 4.18 (s, 2H, OCH2), 6.99–7.92 (m, 15H, Ar-H), 10.18 (s, 1H, NH); MS:
m/z = 438(M+, 42%). Anal. calc. for C25H18N4O4 (438.60): C, 68.46%; H, 4.14%; N, 12.77%.
Found: C, 68.57%; H, 4.27%; N, 12.86%.
=
=
5.15. Synthesis of 3-(4-methoxyphenyl)-6-[6-(4-phenoxyphenyl)
pyridazin-3-yloxymethyl]-2-phenyl-2,3-dihydro[1,3,5]oxadiazine-4-thione (17)
Isothiocyanate 5 (0.01 mol) was added to a solution of benzylideneanisidine (0.01 mol) in dry
toluene (30 ml). The reaction mixture was refluxed for 3 h, then allowed to cool to room temper-
ature. The separated solid product was collected and crystallized from benzene/pet.ether to give
17.
Yield, 60%; m.p. 189–191◦C; IR (KBr, ν cm−1): 3031 (CH aromatic), 2920 (CH-aliphatic),
1
=
1595 (C N), 1337 (CS), 1080 (C–O–C); H NMR (DMSO-d6) δ ppm: 3.32 (s, 3H, CH3), 3.88
(s, 2H, OCH2), 4.72 (s, 1H, CH), 7.02–7.85 (m, 20H, Ar-H). Anal. calc. for C23H16N4O4S
(444.47): C,62.15%; H, 3.63%; N, 12.61%. Found: C, 62.28%; H, 3.74%; N, 12.74%.
5.16. Synthesis of 3-{2-[6-(4-phenoxyphenyl)pyridazine-3-yloxyl]acetyl
amino}-2,3-dithioxopropionic acid (18)
A solution of 5 (0.01 mol) in dry acetone (30 ml) and thioglycolic acid (0.01 mol) was heated
under reflux for 4 h. The solid that separated was recrystallized from petroleum ether to give 18.
Yield, 57%; m.p. 159–161◦C; IR (KBr, ν cm−1) 3434–3190 (NH, OH), 1709 (CO carboxylic),
1
=
1684 (CO), 1240 (C S); H NMR (DMSO-d6) δ ppm: 4.48 (s, 2H, OCH2), 6.90 –7.95 (m, 11H,
Ar-H), 10.21 (s, 1H, NH), (11.82 (s, 1H, OH); MS: m/z = 455(M+, 23%), 304(38%), 151(30%),
134(76%), 106(54%), 77(88%), 51(100%). Anal. calc. for C21H17N3O5S2 (455.51): C,55.37%;
H, 3.76%; N, 9.23%. Found: C, 55.50%; H, 3.65%; N, 9.36%.
5.17. Synthesis of 3-[2-[6-(4-phenoxyphenyl)pyridazin-3-yloxy]acetyl}-2-thioxothiazolidin-
5-one (19)
Acid 18 (0.01 mol) was refluxed for 4 h.in acetic anhydride (5 ml). The solid that separated was
recrystallized from petroleum ether to give thiazolidinone 19.

12 M.S. Behalo et al.
1
Yield, 55%; m.p. 127–129◦C; IR (KBr, ν cm−1): 1665–1690 (2 CO), ν 1250(C S). H NMR
(CDCl3): δ = 2.52 (s, 2H, CH2), 3.95 (s, 2H, OCH2), 7.02–7.91 (m, 11H, Ar–H). Anal. calc.
for C21H15N3O4S2(437.38): C,57.67%; H, 3.46%; N, 9.61%. Found: C, 57.80%; H, 3.57%; N,
9.72%.
=
Acknowledgements
The authors wish to thank Botany Department, Faculty of Science, Benha University, Egypt for biological activity
screening.
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