Reactivity of pyridazin-3(2H) thiones

Article abstract of DOI:10.1002/hc.10157

4,6-Disubstituted pyridazin-3(2H)-thiones 3a-f were prepared by thiation of 4,6-disubstituted pyridazin-3(2H)-one 1a-f either with thiourea or phosphorus pentasulphide. The reactivity of 3a-f towards nucleophilic and electrophilic species under different

Full text of DOI:10.1002/hc.10157

Heteroatom Chemistry
Volume 14, Number 4, 2003
Reactivity of Pyridazin-3(2H ) Thiones
N. G. Kandile,1 H. T. Zaky,1 M. I. Mohamed,1 and Abdel-Sattar
S. Hamad Elgazwy2
1Department of Chemistry, Faculty of Girls, Ain Shams University, Heliopolis, 11757, Cairo, Egypt
2Department of Chemistry, Faculty of Science, Ain Shams University, Abbassia 11566, Cairo, Egypt
Received 20 November 2002; revised 10 February 2003
long time. Nannini et al. [6] have established that
ABSTRACT: 4,6-Disubstituted pyridazin-3(2H)-
the pyridazin-3(2H)-one ring displays analgesic and
thiones 3a–f were prepared by thiation of 4,6-disubs-
antiinflammatory activities beside antihypertensive
tituted pyridazin-3(2H)-one 1a–f either with thiourea
activity [7–9].
or phosphorus pentasulphide. The reactivity of 3a-f
towards nucleophilic and electrophilic species under
different conditions was studied successively. The
structure of the products was confirmed by NMR and
RESULTS AND DISCUSSION
In a previous study, we reported the synthesis of 4,6-
disubstituted pyridazin-3(2H)-one 1a–f [10–11]. Us-
ing a new method for their thiation we now obtained
the corresponding thiones 3a–f.
Reaction of 1a–f with phosphorus oxychloride
gave 3-chloropyridazines 2a–f, which by treatment
with thiourea in refluxing ethanol gave 3a–f in low
yield. These compounds were also obtained in a sim-
ilar yield from the reaction of 1a–f with phosphorus
pentasulphide in boiling xylene (Scheme 1).
mass spectral data. Mechanisms for their formation
ꢀ
C
are also proposed.
2003 Wiley Periodicals, Inc.
Heteroatom Chem 14:334–341, 2003; Published online
in Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.10157
INTRODUCTION
Divers biological and pharmacological activities
have been reported for diazines and related
compounds, for instance, many pyridazines are in
preclinical use [1,2]. While many diazinethiones
exhibit antiprotozoal, antiviral, bactericidal, and
fungicidal properties, probably by virtue of the tox-
The pyridazin-3(2H)thiones 3d–f react with
ethyl chloroacetate in the presence of anhydrous
K2CO3 in refluxing acetone to yield the correspond-
ing thioethers 4d–f in moderate to good (56–78%)
1
yields (Scheme 2). The H NMR spectrum of 4d–f
exhibits two singlets at δ 4.26 and 3.97 of methylene
protons CH2Ar and SCH2 respectively. These spectral
data are consistent with the data described by Yang
et al. [12].
opheric
N C S goup [3,4]. Usually, pyridazin-
3(2H)-ones are prepared from ꢀ-oxoalkanoic acid
derivatives and hydrazines [5]. Pyridazin-3(2H)-one
rings are of chemical and biological interest for a
3b reacted with acrylonitrile in refluxing ethanol
in the presence of alkaline medium (10%) to give
thioethers 5b in 65% yield. The H NMR spectrum
of 5b exhibits three singlets of methylene protons at
δ 4.12, 3.4, and 2.24 for CH2Ar, SCH2, and CH2C N
respectively. These spectral data are consistent with
the data of the related compound [13]. The reaction
of 3d–f with dimethylsulphate was also examined
1
Correspondence to: Abdel-Sattar S. Hamad Elgazwy, Group de
Quimica Organometalica, Departamento de Quimica Inorgan-
ica, Facultad de Quimica, Universidad de Murcia, Aptdo. 4021,
E-30071 Murcia, Spain; e-mail: abhamad@um.es.
Contract grant sponsor: Egyptian Scientific Research.
Contract grant sponsor: Ain Shams University.
Contract grant number: EG-Shams-1-2002.
2003 Wiley Periodicals, Inc.
c
ꢀ
334

Reactivity of Pyridazin-3(2H) Thiones 335
S
R
R
Ar
R
Ar
Ar
H2N
NH2
POCl3
N
N
N
S
N
N
Cl
N
H
O
reflux 5 h/Ethanol
H2N
NH2
2a-f
a) R= CH , Ar = O-CH O-C H -
Cl
1a-f
3
3
6 4
b) R = CH , Ar = 1-Naphthyl
3
c) R = CH , Ar = 2-Naphthyl
3
d) R = C H , Ar = O-CH O-C H -
6
5
3
6 4
e) R = p-CH -C H , Ar = O-CH O-C H -
3
6
4
3
6 4
f) R = p-Cl-C H , Ar = O-CH O-C H -
6
4
3
6 4
R
Ar
P2S5 /Xylene
N
N
H
S
3a-f
SCHEME 1
under different condition. When the reaction took
place in ethanol at room temperature in presence
of NaOH (20%), S-alkylation occured to yield
thioethers 6b,d,f in moderate (25–60%) yield. But
when the reaction was heated under reflux in acetone
in presence of K2CO3, N-alkylation occured to yield
N-methylpyridazin-3(2H) thiones 7d–f in good (60–
83%) yields.
Hydrazones formed by condensation with
thioketones are not only important for identification
purposes and occasionally as protecting groups but
the classical application is in the synthesis of hetero-
cyclic compounds [14–16]. Treatment of 3d–f with
hydrazine in neat at boiling point afforded hydra-
zones 8d–f in good (60–70%) yield.
In this sequence, the urea derivatives have re-
cently found applications [16]. 9e was prepared in
moderate (60%) yield by the reaction of 3e with
thiourea in refluxing ethanol. The reaction of 3a–b
with a mixture of formaldehyde and piperidine,
that is the condition of Mannich reaction, yielded
10a–b for biological importance. The1H NMR spec-
trum of 10a–b exhibits two doublet signals at δ 3.6
and 5.2 of the same coupling constant (J = 15 Hz)
for N CH2 . Condensation of 8d–f and 9e with
benzaldehyde in refluxing ethanol gave hydrazones
11d–f and phenylmethylenethiourea 12e in good
(40–65%) yield (Scheme 3). The synthesis of these
meet biological interest of thiacarbamide derivatives
[17]. All unknown structural products were com-
pletely characterized by spectroscopic (IR, NMR,
mass spectrometry, and analytical measurements).
O
CH
3
R
Cl
Ar
O
N
O
CH
3
N
R
S
refluxing acetone for 27
h/anhydrous K CO
O
S
2
3
4d-f
CN
Ar
N
CN
refluxing ethanol for 10
h/(10%)NaOH
N
5b
R
(CH ) SO ,
3 2
4
Ar
SCH
stirring in ethanol/NaOH
(20%), at RT
N
N
3
6b,d,f
R
Ar
(CH ) SO ,
3 2
4
refluxing in acetone for 27 h/
anhydrous K CO
N
3a-f
N
S
2
3
CH
3
7d-f
R
R
Ar
NH -NH / stirring and
heating for3h/ in neat
Ar
NHNH
2
2
N
N
N
NNH
2
N
2
H
8d-f
S
R
Ar
NHCSNH
H N
NH
2
2
N
N
9e
R
2
refluxing for 3 h/ Ethanol
EXPERIMENTAL
Ar
N
N
Melting points were determined on a Boetius hot-
stage apparatus and are uncorrected. Products were
characterized by comparison of their physical data
with those of known samples. IR spectra were
recorded on a Perkin-Elmer 781 and Pye Unicam
8725 spectrometers. NMR spectra were recorded in
N
S
HCHO/piperidine, refluxing
ethanolfor 3 h
10a-b
SCHEME 2

336 Kandile et al.
R
R
Ar
N
Ar
N
Benzaldehyde
refluxing for 3 h/ethanol
8d-f
N
N
N
N
N
N
H
H
11d-f
Ar
R
S
N
Benzaldehyde
refluxing for 3 h in ethanol
9e
N
N
H
N
12e
SCHEME 3
CDCl3 as solvent on a Bruker AC-200 spectrometer
with reference to the deuterium signal CDCl3 and the
data obtained using an IBM NR-200. TLC accom-
plished the purity determination of the substrates
and reaction monitoring on silica gel SILG/UV 254
plates. MS were recorded at 70 eV on a Varian
MAT-313 spectrometer. Elemental analyses were per-
formed by M-H-W Laboratories (Phoenix, AZ) at
Microanalytical Center of Cairo and Ain Shams
Universities.
6-Methyl-4-(2-naphthylmethyl)-3-chloropyridazine
2c. Colourless crystals 1.4 g, 52% yield, mp 125–
1
126◦C; IR (KBr pellet): 1570 (s) for (C N) cm−1; H
NMR (CDCl3, 200 MHz): δ 7.1–7.69 (m, 7H, Ar-H),
6.83 (s, 1H, 5-H) 4.25 (s, 2H, Ar-CH2), 2.68 (s, 3H,
6-CH3) ppm; Anal. calcd. for C16H13ClN2 (268.74);
C, 71.50; H, 4.87; Cl, 13.19; N, 10.42; found: C,
71.50; H, 4.90; N, 10.30; Cl, 13.30; HRMS calcd. for
C16H13ClN2 268.74; found 268.07.
6-Phenyl-4-(2-methoxybenzyl)-3-chloropyridazine
2d. Colourless crystal 1.63 g, 52% yield, mp 145–
147◦C; IR (KBr pellet): 1670 (v) for (C O), 1570
4-Aryl-6-alkyl-3-chloropyridazines 2a–f
1
General Procedure A. A suspension of 1a–f
(0.01 mol) in phosphorus oxychloride (5 ml) was
heated under reflux for 3 h and then poured into
crushed ice containing sodium hydroxide 10%. The
solid product formed in each case was washed with
water, collected by filtration, and recrystallized from
benzene to give the title compounds.
(s) for (C N) cm−1; H NMR (CDCl3, 200 MHz): δ
7.1–7.9 (m, 9H, Ar-H), 6.83 (s, 1H, 5-H) 4.25 (s, 2H,
Ar-CH2), 3.88 (s, 3H, OCH3) ppm; Anal. calcd. for
C18H15ClN2O (310.78); C, 69.56; H, 4.86; N, 9.01; Cl:
11.40; found: C, 69.00; H, 4.70; N, 8.80; Cl, 11.00;
HRMS calcd. for C18H15ClN2O 310.78; found 310.08.
6-(4-Methylphenyl)-4-(2-methoxybenzyl)-3-chloro-
pyridazine 2e. Colourless crystals 1.80 g, 55%
yield, mp 145–147◦C; IR (KBr pellet): 1670 (v) for
4-(2-Methoxybenzyl)-6-methyl-3-chloropyridazine
2a. Colourless crystals 1.37 g, 55% yield, mp
110–112◦C; IR (KBr pellet): 1544.5 (s) and 1457.9
(s) for (C N) cm−1; 1H NMR (CDCl3, 200 MHz):
δ 7.2–7.71(m, 4H, Ar-H), 6.91 (s, 1H, 5-H) 4.2 (s,
2H, Ar-CH2), 3.89 (s, 3H, OCH3), 2.67 (s, 3H,
6-CH3) ppm; Anal. calcd for C13H13ClN2O (248.71).;
C, 62.78; H, 5.26; Cl, 14.2545; N, 11.26; found: C,
63.00; H, 5.30; N, 11.10; Cl, 14.40; HRMS calcd. for
C13H13ClN2O 248.71; found 248.07.
1
(C O), 1570 (s) for (C N) cm−1; H NMR (CDCl3,
200 MHz): δ 7.23–7.82 (m, 8H, Ar-H), 6.69 (bs, 1H,
pyridazine-H4) 4.22 (s, 2H, Ar-CH2), 3.88 (s, 3H,
OCH3) 2.31 (s, 3H, CH3) ppm; Anal. calcd. for
C19H17ClN2O (324.81); C: 70.25; H: 5.27; N: 8.62; Cl:
10.91; found: C, 69.70; H, 5.00; N, 9.10; Cl, 10.20;
HRMS calcd. for C19H17ClN2O 324.81; found 324.10.
6-(4-Chlorophenyl)-4-(2-methoxybenzyl)-3-chloro-
pyridazine 2f. Colourless crystals 2.60 g, 75% yield,
mp 160–162◦C; IR (KBr pellet): 1670 (v) for (C O),
1570 (s) for (C N) cm−1; 1H NMR (CDCl3, 200
MHz): δ 7.3–7.77 (m, 8H, Ar-H), 6.74 (bs, 1H, 5-H)
4.23 (s, 2H, Ar-CH2), 3.87 (s, 3H, OCH3) 2.31 ppm;
Anal. calcd. for C18H14Cl2N2O (345.23); C: 62.62; H:
4.08; N: 8.11; Cl: 20.53; found: C, 62.00; H, 4.00;
N, 8.60; Cl, 19.98; HRMS calcd. for C18H14Cl2N2O
345.23; found 344.05.
6-Methyl-4-(1-naphthylmethyl)-3-chloropyridazine
2b. Colourless crystals 1.35 g, 50% yield, mp
130–132◦C; IR (KBr pellet): 1550 (s) for (C N)
1
cm−1; H NMR (CDCl3, 200 MHz): δ 7.3–7.69 (m,
7H, Ar-H), 6.85 (s, 1H, 5-H) 4.31 (s, 2H, Ar-CH2),
2.68 (s, 3H, 6-CH3) ppm; Anal. calcd. for C16H13 Cl
N2 (268.74); C, 71.50; H, 4.87; Cl, 13.19; N, 10.42;
found: C, 71.50; H, 4.90; N, 10.30; Cl, 13.30; HRMS
calcd. for C16H13ClN2 268.74; found 268.07.

Reactivity of Pyridazin-3(2H) Thiones 337
7.1–7.82 (m, 9H, Ar-H), 6.81 (s, 1H, 5-H) 4.21 (s,
2H, Ar-CH2), 3.85 (s, 3H, OCH3) ppm; Anal. calcd.
for C18H16N2OS (308.40); C: 70.10; H: 5.22; N: 9.08;
S: 10.39; found: C, 69.50; H, 4.80; N, 8.20; S, 9.80;
HRMS calcd. for C18H16N2OS 308.40; found 308.10.
6-Aryl-4-(arylmethyl) Pyridazin-3(2H)-Thiones
3a–f
General Procedure B. To a solution of 2a–f
(0.015 mol) in ethanol (50 mL) and thiourea (0.012
mol) was added. The reaction mixture was heated
under reflux for 3 h and then cooled. The solid prod-
uct, formed in each case, was collected by filtra-
tion and recrystallized from benzene for 3a–c and
from ethanol for 3d–f. Compounds 3a–f were shown
by direct comparison (mp and mixed mp) and also
GC/MS to be identical in all aspects with the au-
thentic products obtained by the action of phos-
phorus pentasulphide in boiling xylene upon 4,6-
disubstitutedpyridazin-3(2H)-ones 1a–f.
6-(4-Methylphenyl)-4-(2-methoxybenzyl)-pyrid-
azine-3(2H)-thione 3e. Colourless crystals 4.15
g, in 85% yield, mp 185–186◦C; IR (KBr pellet):
3000–3150, (br, NH), 1125–1135 (v) for (C S),
1560 (s) for (C N) cm−1; 1H NMR (CDCl3, 200
MHz): δ 8.41 (s, 1H, NH), 7.23–7.82 (m, 8H, Ar-H),
6.67 (s, 1H, 5-H) 4.21 (s, 2H, Ar-CH2), 3.81 (s, 3H,
OCH3) 2.32 (s, 3H, CH3) ppm; Anal. calcd. for
C19H18N2OS (322.42); C: 70.77; H: 5.626; N: 8.68;
S: 9.94; found: C, 71.40; H, 5.10; N, 9.20; S, 10.10;
HRMS calcd. for C19H18N2OS 322.42; found 322.11.
4-(2-Methoxybenzyl)-6-methyl-pyridazine-3(2H)-
thione 3a. Colourless crystals 2.98 g, 80% yield,
mp 206–208◦C; IR (KBr pellet): 3000–3150, (br,
NH), 1120–1130 (v) for (C S), 15580 (s) for (C N)
cm−1; 1H NMR (CDCl3, 200 MHz): δ 8.43 (s, 1H,
NH), 7.2–7.71 (m, 4H, Ar-H), 6.92 (s, 1H, 5-H) 4.15
(s, 2H, Ar-CH2), 3.83 (s, 3H, OCH3), 2.64 (s, 3H,
6-CH3) ppm; Anal. calcd. for C13H14N2OS (246.32);
C: 63.38; H: 5.72; N: 11.3724; S: 13.0151; found: C,
63.00; H, 5.50; N, 11.30; S, 12.80; HRMS calcd. for
C13H14N2OS 246.32; found 246.08.
6-(4-Chlorophenyl)-4-(2-methoxybenzyl)-pyrid-
azine-3(2H)-thione 3f. Colourless crystals 4.65 g,
90% yield, mp 225–226◦C; IR (KBr pellet): 3000–
3150, (br, NH), 1125–1135 (v) for (C S), 1560
1
(s) for (C N) cm−1; H NMR (CDCl3, 200 MHz): δ
8.41 (s, 1H, NH), 7.3–7.77 (m, 8H, Ar-H), 6.74 (bs,
1H, 5-H) 4.23 (s, 2H, Ar-CH2), 3.87 (s, 3H, OCH3)
ppm; Anal. calcd. for C18H15ClN2OS (342.84); C:
63.06; H: 4.40; Cl: 10.34; N: 8.17; S: 9.35; found: C,
63.30; H, 4.30; N, 8.40; S, 8.90; HRMS calcd. for
C18H15ClN2OS 342.84; found 342.06.
6-Methyl-4-(1-naphthylmethyl)-pyridazine-3(2H)-
thione 3b. Colourless crystals 3.2 g, 80% yield, mp
222–223◦C; IR (KBr pellet): 3005–3140, (br, NH),
1122–1135 (v) for (C S), 1560 (s) for (C N) cm−1;
1H NMR (CDCl3, 200 MHz): δ 8.44 (s, 1H, NH),
7.3–7.7 (m, 7H, Ar-H), 6.85 (s, 1H, 5-H) 4.31 (s, 2H,
Ar-CH2), 2.68 (s, 3H, 6-CH3) ppm; Anal. calcd. for
C16H14N2S (266.36); C: 72.14; H: 5.29; N: 10.51; S:
12.03; found: C, 72.20; H, 5.10; N, 10.70; S, 12.30;
HRMS calcd. for C16H14N2S 266.36; found 266.09.
Ethyl{[4,6-diarylpyridazin-3-yl]thio}acetates
4d–f
General Procedure C. To a solution of 3d–f (0.01
mol) in acetone (50 mL), ethyl chloroacetate (0.01
mol) was added in the presence of anhydrous K2CO3
(3 mol%). The reaction mixture was heated under
reflux for 27 h and then cooled. The solid product
formed in each case was collected by filtration and
recrystallized from ethanol to yield the title com-
pounds.
6-Methyl-4-(2-naphthylmethyl)-pyridazines-3(2H)-
thione 3c. Colourless crystals 3.4 g, 85% yield, mp
175–176◦C; IR (KBr pellet): 3005–3140, (br, NH),
1122–1135 (v) for (C S), 1560 (s) for (C N) cm−1;
1H NMR (CDCl3, 200 MHz): δ 8.44 (s, 1H, NH),
7.19–7.71 (m, 7H, Ar-H), 6.85 (s, 1H, 5-H) 4.22 (s,
2H, Ar-CH2), 2.68 (s, 3H, 6-CH3) ppm; Anal. calcd.
for C16H14N2S (266.36); C: 72.14; H: 5.29; N: 10.517;
S: 12.03; found: C, 72.20; H, 5.10; N, 10.70; S, 12.30;
HRMS calcd. for C16H14N2S 266.36; found 266.09.
Ethyl{[4-(2-methoxybenzyl)-6-phenylpyridazin-3-
yl]thio}acetate 4d. Colourless crystals 3.10 g, 78%
yield, mp 115–116◦C; IR (KBr pellet): 1735–1760 (v)
for (C O), 670 (v) for (C S), 1630 (s) for (C N)
1
cm−1; H NMR (CDCl3, 200 MHz): δ 6.95–7.66 (m,
9H, Ar-H), 6.78 (s, 1H, 5-H) 4.28 (s, 2H, Ar-CH2),
4.12 (q, 2H, J = 6.4 Hz, CH2CH3), 3.98 (s, 2H,
S CH2 CO), 3.87 (s, 3H, OCH3), 1.22 (t, 3H, J =
7.3 Hz, CH2CH3) ppm; Anal. calcd. for C22H22N2O3S
(394.49); C: 66.98; H: 5.62; N: 7.10114; S: 8.12;
Found: C, 67.30; H, 5.27; N, 7.50; S, 8.60; HRMS
calcd. for C18H16N2OS 394.49; found 394.136.
4-(2-Methoxybenzyl)-6-phenylpyridazine-3(2H)-
thione 3d. Colourless crystals 4.10 g, 88% yield, mp
190–191◦C; IR (KBr pellet): 3010–3150, (br, NH),
1124–1135 (v) for (C S), 1565 (s) for (C N) cm−1;
1H NMR (CDCl3, 200 MHz): δ 8.45 (s, 1H, NH),

338 Kandile et al.
Ethyl{[6-(4-methylphenyl)-4-(2-methoxybenzyl)-
from benzene for 6b and from ethanol for 6d,f to
pyridazin-3-yl]thio}acetate 4e. Colourless crystals
2.30 g, 56% yield, mp 106–108◦C; IR (KBr pellet):
1730–1762 (v) for (C O), 670 (v) for (C S), 1630
afford the title compounds.
6-Methyl-4-(1-naphthylmethyl)-3-(methylthio)-
pyridazine 6b. Colourless crystals 1.70 g, 60%
yield, mp 101–102◦C; IR (KBr pellet): 1620 (s) for
1
(s) for (C N) cm−1; H NMR (CDCl3, 200 MHz): δ
7.51–8.08 (m, 8H, Ar-H), 6.77 (s, 1H, 5-H) 4.22 (s,
2H, Ar-CH2), 4.12 (q, 2H, J = 6.4 Hz, CH2CH3), 3.97
(s, 2H, S CH2 CO), 3.87 (s, 3H, OCH3), 1.63 (s,
3H, CH3), 1.23 (t, 3H, J = 7.3 Hz, CH2CH3) ppm;
Anal. calcd. for C23H24N2O3S (408.51); C: 67.62; H:
5.92; N: 6.85; S: 7.84; found: C, 68.00; H, 5.60; N,
6.40; S, 7.30; HRMS calcd. for C23H24N2O3S 408.51;
found 408.15.
(C N), 675 (v) for (C S) cm−1; H NMR (CDCl3,
1
200 MHz): δ 7.55–8.66 (m, 7H, Ar-H), 6.73 (s, 1H,
5-H) 4.26 (s, 2H, Ar-CH2), 2.68 (s, 3H, 6-CH3), 2.63
(s, 3H, S CH3) ppm; Anal. calcd. for C17H16N2S
(280.38); C: 72.82; H: 5.75; N: 9.99; S: 11.43; found:
C, 72.81; H, 5.60; N, 9.80; S, 11.80; HRMS calcd. for
C17H16N2S 280.38; found 280.10.
Ethyl{[6-(4-chlorophenyl)-4-(2-methoxybenzyl)-
pyridazin-3-yl]thio}acetate 4f. Colourless crystals
3.40 g, 79% yield, mp 110–112◦C; IR (KBr pellet):
1736–1762 (v) for (C O), 675 (v) for (C S), 1620
4-(2-Methoxybenzyl)-3-(methylthio)-6-phenyl-
pyridazine 6d. Colourless crystals 1.63 g, 50%
yield, mp 135–136◦C; IR (KBr pellet): 1630 (s) for
1
(C N), 670 (v) for (C S) cm−1; H NMR (CDCl3,
1
(s) for (C N) cm−1; H NMR (CDCl3, 200 MHz): δ
200 MHz): δ 7.55–8.66 (m, 9H, Ar-H), 6.73 (s, 1H,
5-H), 4.22 (s, 2H, CH2), 3.87 (s, 3H, OCH3), 2.63
(s, 3H, S CH3) ppm; Anal. calcd. for C19H18N2OS
(322.42); C: 70.77; H: 5.62; N: 8.68; S: 9.94; found:
C, 71.20; H, 6.06; N, 8.60; S, 9.00; HRMS calcd. for
C19H18N2OS 322.42; found 322.11.
7.33–8.14 (m, 8H, Ar-H), 6.78 (s, 1H, 5-H) 4.26 (s,
2H, Ar-CH2), 4.12 (q, 2H, J = 6.4 Hz, CH2CH3), 3.98
(s, 2H, S CH2 CO), 3.82 (s, 3H, OCH3), 1.18
(t, 3H, J = 7.3 Hz, CH2CH3) ppm; Anal. calcd. for
C22H21ClN2O3S (428.93); C: 61.60; H: 4.93; Cl: 8.26;
N: 6.53; S: 7.47; found: C, 61.60; H, 4.94; N, 6.50;
S, 7.45, Cl, 8.40; HRMS calcd. for C22H21ClN2O3S
428.93; found 428.09.
6-(4-Chlorophenyl)-4-(2-methoxybenzyl)-3-(meth-
ylthio)pyridazine 6f. Colourless crystals 0.90 g, 25%
yield, mp 150–152◦C; IR (KBr pellet): 1736–1762 (v)
for (C O), 675 (v) for (C S), 1620 (s) for (C N)
3-{[6-Methyl-4-(1-naphthylmethyl)pyridazin-3-yl]-
1
thio}propanenitrile 5b. To
a
solution of 3b
cm−1; H NMR (CDCl3, 200 MHz): δ 6.98–7.56 (m,
(0.01 mol) in ethanol (20 mL), acrylonitrile (0.012
mol) was added in the presence of 10% sodium
hydroxide. The reaction mixture was heated under
reflux for 10 h, then cooled. The solid product was
collected by filtration and recrystallized from ben-
zene to give the title compounds 2.10 g, 65% yield,
mp 193–195◦C; IR (KBr pellet): 2260 (v) for (C N),
670 (v) for (C S), 1620 (s) for (C N) cm−1; 1H NMR
(CDCl3, 200 MHz): δ 7.55–8.56 (m, 7H, Ar-H), 6.78
(s, 1H, 5-H) 4.12 (s, 2H, Ar-CH2), 3.4 (t, 2H, J =
6.4 Hz, S CH2 CH2 ), 2.68 (s, 3H, 6-CH3), 2.23
(t, 2H, J = 6.4 Hz, S CH2 CH2 CN) ppm; Anal.
calcd. for C19H17N3S (319.42); C: 71.44; H: 5.36; N:
13.15; S: 10.03; found: C, 72.10; H, 5.40; N, 13.30;
S, 10.10; HRMS calcd. for C19H17N3S 319.42; found
319.11.
8H, Ar-H), 6.78 (s, 1H, 5-H), 4.26 (s, 2H, Ar-CH2),
3.87 (s, 3H, OCH3), 2.63 (s, 3H, S CH3) ppm;
Anal. calcd. for C19H17ClN2OS (356.87); C: 63.94; H:
4.80; N: 7.84; S: 8.98; found; C, 63.42; H, 4.77; N,
7.54; S, 8.95; HRMS calcd. for C19H17ClN2OS 356.87;
found 356.07.
4,6-Diaryl-2-methylpyridazine-3(2H) Thiones
7d–f
General Procedure E. To a solution of 3d–f (0.01
mol) in acetone, dimethyl sulphate (0.01 mol) was
added in the presence of anhydrous K2CO3 (0.03
mol). The reaction mixture was heated under reflux
for 27 h and then cooled to room temperature. The
solid product was collected by filtration and recrys-
tallized from ethanol to afford the title compounds.
4,6-Diaryl-3-(methylthio)pyridazines 6b,d,f
4-(2-Methoxybenzyl)-2-methyl-6-phenylpyrida-
zine-3(2H)-thione 7d. Colourless crystals 2.27 g,
70% yield, mp 129–130◦C; IR (KBr pellet): 1630
General Procedure D. To a solution of 3b,d,f
(0.01 mol) in ethanol, dimethyl sulphate (0.01 mol)
was added in the presence of NaOH 20%. The reac-
tion mixture was warmed for 20 min with continued
stirring and cooled to room temperature. The solid
product was collected by filtration and recrystallized
1
(s) for (C N), 1267–1274 (v) for (C S) cm−1; H
NMR (CDCl3, 200 MHz): δ 7.66–8.65 (m, 9H, Ar-H),
6.77 (s, 1H, 5-H), 4.26 (s, 2H, CH2), 3.88 (s, 3H,
OCH3), 3.33 (s, 3H, N CH3) ppm; Anal. calcd.

Reactivity of Pyridazin-3(2H) Thiones 339
for C19H18N2OS (322.42); C: 70.77; H: 5.62; N: 8.68;
S: 9.94; found: C, 71.20; H, 6.06; N, 8.60; S, 9.00;
HRMS calcd. for C19H18N2OS 322.42; found 322.11.
NH), 8.30 (s, 2H, NH), 7.14–7.90 (m, 8H, Ar-H),
6.90 (s, 1H, 5-H), 4.22 (s, 2H, CH2), 3.81 (s, 3H,
OCH3), 2.41 (s, 3H, CH3) ppm; Anal. calcd. for
C19H20N4O (320.39); C: 71.22; H: 6.29; N: 17.48;
found: C, 69.96; H, 6.31; N, 17.33; HRMS calcd. for
C19H20N4O 320.39; found 320.1.
4-(2-Methoxybenzyl)-6-(4-methylphenyl)-2-methyl-
pyridazine-3(2H)-thione 7e. Colourless crystals
2.80 g, 83% yield, mp 127–129◦C; IR (KBr pellet):
1630 (s) for (C N), 1267–1274 (v) for (C S) cm−1;
1H NMR (CDCl3, 200 MHz): δ 7.26–8.16 (m, 8H,
Ar-H), 6.76 (s, 1H, 5-H), 4.22 (s, 2H, CH2), 3.88
(s, 3H, OCH3), 3.32 (s, 3H, N CH3), 2,63 (s, 3H,
CH3) ppm; Anal. calcd. for C20H20N2OS (336.45); C:
71.39; H: 5.99; N: 8.32; S: 9.52; found: C, 70.83; H,
6.28; N, 8.09; S, 9.30; HRMS calcd. for C20H20N2OS
336.45; found 336.13.
(3E)-6-(4-Chlorophenyl)-4-(-2-Methoxybenzyl)-
pyridazin-3(2H)-one
Hydrazone
8f. Colourless
crystals 2.4 g, 70% yield, mp 146–148◦C; IR (KBr
pellet): 3100–3350 (br) for (NH), 1635 (s) for (C N)
cm−1; 1H NMR (CDCl3, 200 MHz): δ 8.60 (s, 1H,
NH), 8.37 (s, 2H, NH), 6.96–7.65 (m, 8H, Ar-H),
6.77 (s, 1H, 5-H), 4.27 (s, 2H, CH2), 3.87 (s, 3H,
OCH3) ppm; Anal. calcd. for C18H17ClN4O (340.81);
C: 63.43; H: 5.027; N: 16.43; found; C, 63.30; H, 5.10;
N, 16.02; S, 8.40; HRMS calcd. for C18H17ClN4O
340.81; found 340.10.
6-(4-Chlorophenyl)-4-(2-methoxybenzyl)-2-methyl-
pyridazine-3(2H)-thione 7f. Colourless crystals 2.15
g, 60% yield, mp 150–152◦C; IR (KBr pellet): 1630
1
(s) for (C N), 1267–1274 (v) for (C S) cm−1; H
N[4-(2-Methoxybenzyl)-6-(4-methylphenyl)-
NMR (CDCl3, 200 MHz): δ 7.66–8.65 (m, 8H, Ar-H),
6.78 (s, 1H, 5-H), 4.27 (s, 2H, CH2), 3.87 (s, 3H,
OCH3), 3.38 (s, 3H, N CH3) ppm. Anal. Calcd.
for C19H17ClN2OS (356.87); C: 63.94; H: 4.80; N:
7.84; S: 8.98; found; C, 63.42; H, 4.77; N, 7.54; S,
8.95; HRMS calcd. for C19H17ClN2OS 356.87; found
356.07.
pyridazin-3-yl]thiourea 9e
To a solution of 3e (0.01) in ethanol (50 ml), thiourea
(0.01 mol) was added. The reaction mixture was
heated under reflux for 3 h and then cooled. The solid
product was collected by filtration and recrystallized
from benzene to give 2.2 g, 60% yield, mp 130–132 ◦C;
IR (KBr pellet): 3100–3250 (br) for (NH), 1630 (s)
for (C N), 1267–1274 (v) for (C S) cm−1; H NMR
1
(CDCl3, 200 MHz): δ 8.55 (s, 1H, NH), 8.36 (s, 2H,
NH), 7.16–7.92 (m, 8H, Ar-H), 6.76 (s, 1H, 5-H), 4.22
(s, 2H, CH2), 3.88 (s, 3H, OCH3), 2,63 (s, 3H, CH3)
ppm; Anal. calcd. for C20H20N4OS (364.46); C: 65.91;
H: 5.53; N: 15.37; S: 8.79; found: C, 66.20; H, 6.03; N,
14.90; S, 8.80; HRMS calcd. for C20H20N4OS 364.46;
found 364.13.
(3E)-4,6-Diarylpyridazin-3(2H)-one Hydrazones
8d–f
General Procedure F. A mixture of 4,6-diarylpy-
ridazin-3(2H)-thiones 3d–f (0.01 mol) and hydrazine
hydrate (0.01 mol) was heated for 3–5 h and then al-
lowed to cool at room temperature. The solid prod-
uct was collected by filtration and recrystallized from
benzene to give the title compounds.
4-(2-Methoxybenzyl)-6-methyl-2-(piperidin-1-
ylmethyl)pyridazine-3(2H)-thiones 10a
(3E)-4-(-2-Methoxybenzyl)-6-phenylpyridazin-
3(2H)-one Hydrazone 8d. Colourless crystals 1.85
g, 60% yield, mp 174–175◦C; IR (KBr pellet): 3100–
To a suspension of 3a,b (0.01 mol) in ethanol and
mixture of formaldehyde (30 ml, 0.015 mol), piperi-
dine (0.01 mol) was added dropwise. The reaction
mixture was heated under reflux for 3 h and then
cooled, and the solvent evaporated. The solid prod-
uct was collected by filtration and recrystallized from
ethanol for 10a to give 2.42 g, 70% yield, mp 162–
164◦C; IR (KBr pellet): 1625 (s) for (C N), 1267–
1275 (v) for (C S) cm−1; 1H NMR (CDCl3, 200 MHz):
δ 6.90–7.13 (m, 4H, Ar-H), 6.78 (s, 1H, 5-H), 4.98 (d,
1H, J = 15.2 Hz, N CH2), 4.24 (s, 2H, CH2), 3.87 (s,
3H, OCH3), 3.77 (d, 1H, J = 15.2 Hz, N CH2), 3.15–
3.47 (m, 6H, pip), 2.68 (s, 3H, 6-CH3), 1.42–1.47 (m,
4H, pip-) ppm; Anal. calcd. for C19H25N3OS (343.49);
C: 66.43; H: 7.33; N: 12.23; S: 9.33; found; C, 63.30; H,
1
3150 (br) for (NH), 1630 (s) for (C N) cm−1; H
NMR (CDCl3, 200 MHz): δ 8.78 (s, 1H, NH), 8.32 (s,
2H, NH), 7.15–7.90 (m, 9H, Ar-H), 6.73 (s, 1H, 5-H),
4.23 (s, 2H, CH2), 3.88 (s, 3H, OCH3) ppm; Anal.
calcd. for C18H18N4O (306.36); C: 70.56; H: 5.9219;
N: 18.28; found: C, 70.95; H, 5.40; N, 18.72; HRMS
calcd. for C18H18N4O (306.36); found 306.14.
(3E)-4-(2-Methoxybenzyl)-6-(4-methylphenyl)-
pyridazin-3(2H)-one Hydrazone 8e. Colourless
crystals 2.25 g, 70% yield, mp 165–166◦C; IR (KBr
pellet): 3100–3250 (br) for (NH), 1630 (s) for (C N)
cm−1; 1H NMR (CDCl3, 200 MHz): δ 8.67 (s, 1H,

340 Kandile et al.
N2-[(3E)-6-(4-Chlorophenyl)-4-(2-methoxybenzyl)-
pyridazin-3(2H)-ylidene]-N1-[(1E)-phenylmethylene]-
hydrazones 11f. Colourless crystals 2.15 g, 60%
yield, mp 219–220◦C; IR (KBr pellet): 3100–3250 (br)
for (NH), 1635 (s) for (C N) cm−1; 1H NMR (CDCl3,
5.10; N, 16.02; S, 8.40; HRMS calcd. for C19H25N3OS
343.48; found 343.17.
4-(1-Naphtylmethyl)-6-methyl-2-(piperidin-1-
ylmethyl)pyridazine-3(2H)-thiones 10b
200 MHz): δ 8.80 (s, 1H, NH), 8.25 (s, 1H,
N CH),
Following the procedure of 10a the solid product
was collected by filtration and recrystallized from
benzene to give 2.55 g, 70% yield, mp 196–198◦C;
IR (KBr pellet): 1630 (s) for (C N), 1267–1274 (v)
for (C S) cm−1; 1H NMR (CDCl3, 200 MHz): δ 7.66–
8.65 (m, 7H, Ar-H), 6.77 (s, 1H, 5-H), 5.29 (d, 1H,
J = 15.2 Hz, N CH2), 4.26 (s, 2H, CH2), 3.77 (d, 1H,
J = 15.2 Hz, N CH2), 3.17–3.48 (m, 6H, pip), 2.68 (s,
3H, 6-CH3), 1.45–1.48 (m, 4H, pip-) ppm; Anal. calcd.
for C22H25N3S (363.52); C: 72.68; H: 6.93; N: 11.55;
S: 8.81; found; C, 72.40; H, 6.60; N, 11.20; S, 8.70;
HRMS calcd. for C22H25N3S 363.52; found 363.17.
7.26–8.19 (m, 9H, Ar-H), 7.93 (d, 2H, J = 8.6 Hz,
C6H4Cl), 7.41 (d, 2H, J = 8.6 Hz, C6H4Cl), 6.73 (s,
1H, 5-H), 4.26 (s, 2H, CH2), 3.88 (s, 3H, OCH3)
ppm; Anal. calcd. for C26H24ClN4O (428.92); C: 70.00;
H: 4.93; N: 13.06; Cl: 8.26; found; C, 70.46; H, 5.06;
N, 12.53; Cl, 8.60; HRMS calcd. for C25H21N4OCl
428.92; found 428.14.
N-[4-(2-Methoxybenzyl)-6-(4-methylphenyl)-
pyridazin-3-yl]-Nꢁ-[(1E)-phenylmethylene]-
thiourea 12e
To a solution of N[4-(2-methoxybenzyl)-6-(4-methyl-
phenyl)pyridazin-3-yl]thiourea 9e (0.01 mol) in
(50 ml) ethanol, benzaldehyde (0.01 mol) was added.
The reaction mixture was heated under reflux for 3 h
and then cooled to precipitate the products. By fol-
lowing the general procedure (G), the solid product
was collected by filtration and recrystallized from
benzene to afford 12e. (2.75 g, in 75% yield), mp
123–125◦C; IR (KBr pellet): 1630 (s) for (C N), 1267–
1274 (v) for (C S) cm−1; 1H NMR (CDCl3, 200 MHz):
δ 7.26–8.16 (m, 8H, Ar-H), 6.76 (s, 1H, 5-H), 4.22
(s, 2H, CH2), 3.88 (s, 3H, OCH3), 3.32 (s, 3H,
N CH3), 2.63 (s, 3H, CH3) ppm; Anal. calcd. for
C27H24N4OS (452.57); C: 71.65; H: 5.34; N: 12.37;
S: 7.08; found: C, 71.59; H, 5.80; N, 12.18; S, 6.27;
HRMS calcd. for C19H20N4O 452.57; found 452.16.
N1-[(1E)-Phenylmethylene]-N2-[(3E)-4-(2-
methoxybenzyl)-6-arylpyridazin-3(2H)-
ylidene]hydrazones 11d–f
General Procedure G. To a solution of 8d–f (0.01
mol) in 50 ml ethanol, benzaldehyde (0.01 mol) was
added. The reaction mixture was heated under reflux
for 3 h and then cooled. The solid product was col-
lected by filtration and recrystallized from benzene
to give the title compound.
N1-[(1E)-Phenylmethylene]-N2-[(3E)-4-(2-methoxy-
benzyl)-6-phenylpyridazin-3(2H)-ylidene]hydrazone
11d. Colourless crystals 1.6 g, 40% yield, mp
188–189◦C; IR (KBr pellet): 3100–3150 (br) for
1
(NH), 1630 (s) for (C N) cm−1; H NMR (CDCl3,
200 MHz): δ 8.78 (s, 1H, NH), 8.27 (s, 1H,
N CH),
7.15–8.12 (m, 14H, Ar-H), 6.74 (s, 1H, 5-H), 4.22 (s,
2H, CH2), 3.88 (s, 3H, OCH3) ppm; Anal. calcd.
for C25H22N4O (394.47); C: 76.1202; H: 5.62125; N:
14.2027; found; C, 76.65; H, 5.40; N, 13.82; HRMS
calcd. for C25H22N4O 394.47; found 394.17.
REFERENCES
[1] Tisler, M.; Stanovnik, B. In Comprehensive Hetero-
cyclic Chemistry; Katritzky, A. R.; Rees, C. W. (Eds.);
Pergamon Press: Oxford, 1984; Vol. 3, pp. 1–56.
[2] Kleemann, A.; Engel, J. Pharmazeutische Wirkstoffe,
Synthesen, Patente, 2nd ed.; Anwendungen, Thieme
Verlag: Stuttgart, 1982.
[3] (a) Dhal, P. N.; Achary, T. E.; Nayak, A. Indian J Chem
1975, 1–8; (b) Smith, R. J Indian Chem Soc 1975, 52,
734–735.
[4] Mallick, S. K.; Martin, A. R.; Lingard, R. G. J Med
Chem 1971, 14, 528–532.
[5] Coates, W. J. In Pyridazines and Their Benzo Deriva-
tives, Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. (Eds.);
R. C. Storr, Ed, Pergamon: Oxford, 1996; Vol. 6, pp.
1–91.
N1-[(3E)-4-(2-Methoxybenzyl)-6-(4-methylphenyl)-
pyridazin-3(2H)-ylidene]-N2-[(1E)-phenylmethylene]-
hydrazones 11e. Colourless crystals 2.05 g, 50%
yield, mp 202–203◦C; IR (KBr pellet): 3100–3150
1
(br) for (NH), 1634 (s) for (C N) cm−1; H NMR
(CDCl3, 200 MHz): δ 8.80 (s, 1H, NH), 8.25 (s, 1H,
N
CH), 7.26–8.19 (m, 9H, Ar-H), 7.82 (d, 2H,
J = 8.6 Hz, C6H4CH3), 7.32 (d, 2H, J = 8.6 Hz,
C6H4CH3), 6.73 (s, 1H, 5-H), 4.26 (s, 2H, −CH2),
3.88 (s, 3H, OCH3), 2.43 (s, 3H, −CH3) ppm; Anal.
calcd. for C26H24N4O (408.50); C: 76.44; H: 5.92; N:
13.71; found: C, 76.37; H, 6.05; N, 13.50; HRMS
calcd. for C25H24N4O 408.50; found 408.19.
[6] Nannini, G.; Biasoli, G.; Perrone, E.; Forgione, A.;
Buttinoni, A.; Ferrari, M. Eur J Med Chem Chim Ther
1979, 14, 53.
[7] Curran, M. V. J Med Chem 1974, 17, 273.

Reactivity of Pyridazin-3(2H) Thiones 341
[8] Mohareb, R. M.; Manhi, F. M. Heteroat Chem 2000,
11, 403.
[9] Mohareb, R. M.; El-Omran, F. A.; Jonathan Z. Ho.
Heteroat Chem 2001, 12, 168–174.
[10] Kandile, N. G.; El-Sawi, E. A.; Selim, V. R.; Ismail, M.
F. Acta Chem Hung 1988, 125, 631.
[11] Hamad, A.-S. S.; Hashem, A. I. Molecules 2000, 5,
895–907.
[12] Liu, Z.; Yang, G.; Qin, X. J Chem Technol Biotechnol
2001, 76, 1154–1158.
[13] (a) Goldoni, F.; Antolini, L.; Pourtois, G.; Schenning,
A. P. H. J. Jaussen, R. A. J.; Lazzaroui, R.; Bredas,
J.-L.; Mejer, E. W. Eur J Inorg Chem 2001, 821–828;
(b) Raslan, M. A.; Sayed, S. M.; Khalil, M. A.; Farag,
A. M. Heteroat Chem 2000, 11, 94–100.
[14] Ragnarsson, U. Chem Soc Rev 2001, 30, 205–213.
[15] (a) Hydrazine and its Derivatives in Kirk-Othmer Ecy-
clopedia of Chemical Technology; Wiley, New York,
4th edn., 1995, Vol.13. 2 L. A. Carpino, J. Am. Chem.
Soc., 1957, 79, 98–100; (b) Encyclopedia of reagents
for organic synthesis, ed. L. A. Paquette, Wiley, Chich-
ester, 1995.
[16] Huddleston, P. R.; Coutts, I. G. C. In Compre-
hensive Organic Functional Group Transformations,
Katritzky, A. R.; Meth-Cohn, O.; Rees, C. W.; (Eds.);
Pergamon/Elsevier: Oxford, 1995; Vol. 2, pp. 371–
383.
[17] Hassaneen, H. M.; Atta, S. M. S.; Fawzy, N. M.;
Hegazi, A. G.; Abdalla, F. A.; Abd El Rahman, A. H.
Arch Pharm Pharm Med Chem 2002, 6, 251–261.