An efficient one-pot protocol for regioselective synthesis of 3-aryl-6,8-dialkyl-7-thioxo-7,8-dihydropyrimido[4,5-c ] pyridazine-5(6 H)-ones

Article abstract of DOI:10.1080/17415993.2012.745126

A series of 3-aryl-6,8-dialkyl-7-thioxo-7,8-dihydropyrimido[4,5-c] pyridazine-5(6H)-one derivatives have been regioselectively synthesized via the one-pot three-component reaction of 1,3-dimethylthiobarbituric acid and 1,3-diethylthiobarbituric acid with various arylglyoxals in the presence of hydrazinium dihydrochloride in warm ethanol. These new substituted pyrimidopyridazines may be potential monoamine oxidase inhibitors.

Full text of DOI:10.1080/17415993.2012.745126

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An efficient one-pot protocol
for regioselective synthesis of
3-aryl-6,8-dialkyl-7-thioxo-7,8-
dihydropyrimido[4,5-c]
pyridazine-5(6H)-ones
Jabbar Khalafy a , Mehdi Rimaz b , Hossein Rabiei a & Leila Panahi a
a Chemistry Department, Urmia University, PO Box 57154, Urmia,
Iran
b Department of Chemistry, Payame Noor University, PO Box
19395-3697, Tehran, Iran
Version of record first published: 27 Nov 2012.
To cite this article: Jabbar Khalafy , Mehdi Rimaz , Hossein Rabiei & Leila Panahi
(2012): An efficient one-pot protocol for regioselective synthesis of 3-aryl-6,8-dialkyl-7-
thioxo-7,8-dihydropyrimido[4,5-c] pyridazine-5(6H)-ones, Journal of Sulfur Chemistry,
DOI:10.1080/17415993.2012.745126
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Journal of Sulfur Chemistry, 2012
http://dx.doi.org/10.1080/17415993.2012.745126
An efficient one-pot protocol for regioselective synthesis of
3-aryl-6,8-dialkyl-7-thioxo-7,8-dihydropyrimido[4,5-c]
pyridazine-5(6H)-ones
Jabbar Khalafya*, Mehdi Rimazb, Hossein Rabieia and Leila Panahia
aChemistry Department, Urmia University, PO Box 57154, Urmia, Iran; bDepartment of Chemistry, Payame
Noor University, PO Box 19395-3697, Tehran, Iran
(Received 18 September 2012; final version received 28 October 2012)
A series of 3-aryl-6,8-dialkyl-7-thioxo-7,8-dihydropyrimido[4,5-c]pyridazine-5(6H)-one derivatives have
been regioselectively synthesized via the one-pot three-component reaction of 1,3-dimethylthiobarbituric
acid and 1,3-diethylthiobarbituric acid with various arylglyoxals in the presence of hydrazinium dihy-
drochloride in warm ethanol. These new substituted pyrimidopyridazines may be potential monoamine
oxidase inhibitors.
Keywords: pyrimido[4,5-c]pyridazines; regioselective; one-pot; arylglyoxal; thiobarbituric acid
1. Introduction
Multicomponent reactions (MCRs) in which several reactions are combined into one synthetic
operation have been used extensively to form the carbon–carbon bonds in synthetic chemistry (1).
Such reactions offer a wide range of possibilities for the efficient construction of highly complex
molecules in a single procedural step, thus avoiding the complicated purification operations and
allowing savings of both solvents and reagents. Thus, they are perfectly amenable to automation
for combinatorial synthesis (2). A major challenge of modern drug discovery is the design of
highly efficient chemical reaction sequences that provide maximum structural complexity and
diversity with a minimum number of synthetic steps to assemble compounds with interesting
properties; therefore, in the past decade, there has been tremendous development in three- and
four-component reactions and great progress continues in the development of new MCRs (3, 4).
The pyridazine structural framework and hetero-fused analogs as important privileged hete-
rocyclic scaffolds continue to attract attention due to their wide variety of interesting biological
*Corresponding author. Email: jkhalafi@yahoo.com; j.khalafi@urmia.ac.ir
© 2012 Taylor & Francis

2
J. Khalafy et al.
CH3
N
H
N
H
N
N
O
N
S
N
O
N
N
N
NH
NH
N
Ar
Ar
CH3
O
O
Ar
O
1
2
3
Figure 1. Some substituted pyrimidopyridazines.
activities (5). The synthesis and utility of many pyridazine derivatives such as analgesics, insecti-
cidals, fungicidals, cardiotonics and bacteriocides have been reported (6–13). Carotti et al. have
reported that the 3-arylpyrimido[4, 5-c]pyridazine-5, 7(6H, 8H)-diones possess monoamine oxi-
dase (MAO) inhibitory activity and substituents on the diazine nucleus modulate the inhibitory
activity (14). MAO is a ubiquitous membrane-bound, flavin-containing enzyme, which is partic-
ularly abundant in the liver and brain (15). MAO is located intracellularly in the mitochondrial
outer membranes of neuronal, glial and other cells and catalyzes the oxidative deamination of
monoamine neurotransmitters both from endogenous and exogenous sources to the corresponding
aldehydes with consumption of oxygen and production of hydrogen peroxide, thereby affecting
the concentrations of neurotransmitter amines as well as many xenobiotic ones (16–18).
Among our recent research on the synthesis of pyridazine derivatives (19–25), we have
reported the synthesis of some substituted pyrimidopyridazines 1–3 as potential MAO inhibitors
(Figure 1) (22, 23).
In this paper, we report the synthesis of new 3-aryl-6,8-dimethyl-7-thioxo-7,8-dihydro
pyrimido[4,5-c]pyridazine-5(6H)-one and 3-aryl-6,8-diethyl-7-thioxo-7,8-dihydropyrimido[4,5-
c]pyridazine-5(6H)-one derivatives. The synthetic method for the preparation of these new
heterocycles involves the one-pot three-component reaction of arylglyoxals with 1,3-dimethyl-
2-thiobarbituric acid and 1,3-diethyl-2-thiobarbituric acid in the presence of hydrazinium
dihydrochloride in warm ethanol.
2. Results and discussion
Arylglyoxals 4 were obtained from the oxidation of their corresponding acetophenones 5 using
selenium dioxide as shown in Scheme 1 (26).
O
CH3
O
SeO2
H
Ar
Ar
Dioxane/Water
reflux
O
5
4
Scheme 1. Synthesis of arylglyoxal.
1,3-Dimethyl-2-thiobarbituric acid 9 and 1,3-diethyl-2-thiobarbituric acid 10 were obtained
from the reaction of 1,3-dimethyl-2-thiourea 6 and 1,3-diethyl-2-thiourea 7 with diethyl malonate
8 in ethanol under reflux (Scheme 2) (27).
The reactions were performed by adding arylglyoxals 11–21 to mixtures of thiobarbituric acids
9 and 10 in ethanol at 50◦C in the presence of a molar ratio of hydrazinium dihydrochloride
(Scheme 3). After 45–60 min, the mixture solidified and the product isolated by filtration. The
products 22–41 were obtained in good yields after recrystallization from methanol.
Twenty examples of the conversion of arylglyoxals to various substituted pyrimidopyridazines
are listed in Table 1.

Journal of Sulfur Chemistry
3
Scheme 2. Synthesis of substituted thiobarbituric acids.
R
O
O
N
N
S
R
H
NH2NH2.2HCl
EtOH/ 500C
45-60 min
N
N
+
Ar
N
Ar
R
O
O
N
R
S
O
11-21
9, R=Me
10, R=Et
22-41
Scheme 3. Synthesis of 3-aryl-6,8-dialkyl-7-thioxo-7,8-dihydropyrimido[4,5-c]pyridazine-
5(6H)-ones.
In contrast to dimethylbarbituric acid, which forms 4-aryl substituted systems in the case of
thiones, that is, 1,3-dimethyl and 1,3-diethylthiobarbituric acids, all of the observed products were
characterized as 3-aryl substituted pyrimidopyridazines with no evidence for production of the
4-aryl substituted isomers. The structures of all the compounds were characterized by the singlet
1
at ca. 8.50 ppm in the H NMR spectrum that is assigned to H-4. The regioselective formation
of 3-aryl substituted pyrimidopyridazines 22–41 was unambiguously secured by X-ray crystal
structure analysis of compound 24 (Figure 2) (see the Supporting Information for data of the
X-ray single-crystal structure determination of compound 24).
The suggested mechanism for selective formation of 3-aryl substituted pyrimidopyridazines as
depicted in Scheme 4 involves an initial Knoevenagel condensation between the formyl group
on arylglyoxal 18 and enolic form of thiobarbituric acid 42. This was followed by double imine
condensation of hydrazine with the 1,4-dicarbonyl compound 44 leading to the formation of the
observed product 40 (Scheme 4). Attack of thiobarbituric acid enol and Knoevenagel reaction
occurred exclusively at the more reactive aldehyde than at the least reactive ketone carbonyl in
the arylglyoxal. We suspect the enol content of the thiobarbituric acid is considerably greater
than that of barbituric acid under the reaction conditions, and hence is more reactive toward the
carbonyl group than the hydrazine.
3. Conclusion
In conclusion, we have described one-pot three-component reactions of arylglyox-
als with 1,3-dimethyl-2-thiobarbituric acid and 1,3-diethyl-2-thiobarbituric acid in the
presence of hydrazinium dihydrochloride for the synthesis of 3-aryl-6,8-dimethyl-7-
thioxo-7,8-dihydropyrimido[4,5-c]pyridazine-5(6H)-ones and 3-aryl-6,8-diethyl-7-thioxo-7,8-
dihydropyrimido[4,5-c]pyridazine-5(6H)-ones, respectively. This synthetic strategy has the
advantages of high regioselectivity, good yields, convenient procedure and mild reaction con-
ditions. According to Carotti’s report on MAO inhibitory property of the pyrimidopyridazine
component (14), these new derivatives may show similar biological activity and their potential
pharmacological properties are under assessment.

4
J. Khalafy et al.
Table 1. List of substituted pyrimido[4,5-c]pyridazines.
Arylglyoxal
6,8-Dimethylpyrimidopyridazine
6,8-Diethylpyrimidopyridazine
CH2CH3
CH3
N
N
S
N
N
S
COCHO
N
N
N
N
CH2CH3
CH3
O
O
11
22
33
CH2CH3
CH3
N
N
N
N
S
N
N
S
COCHO
N
N
N
N
CH2CH3
CH3
O
O
Br
Cl
Br
Cl
12
Br
23
34
35
CH3
N
CH2CH3
S
N
S
COCHO
N
N
N
N
CH3
CH2CH3
O
O
13
Cl
24
CH3
N
CH2CH3
N
S
N
N
S
COCHO
N
N
N
N
CH3
CH2CH3
O
O
F
F
14
F
25
36
CH3
CH2CH3
N
N
S
N
N
S
COCHO
N
N
N
N
CH3
CH2CH3
O
O
15
H3CO
H3CO
OCH3
26
37
CH3
N
CH2CH3
N
S
N
N
S
COCHO
N
N
N
N
CH3
CH2CH3
O
O
O2N
O2N
16
NO2
27
38
CH2CH3
CH3
N
N
S
N
N
S
N
N
COCHO
N
N
CH3
CH2CH3
O
O
Br
28
39
17
Br
Br
(Continued)

Journal of Sulfur Chemistry
5
Table 1. Continued
Arylglyoxal
6,8-Dimethylpyrimidopyridazine
6,8-Diethylpyrimidopyridazine
CH2CH3
CH3
N
N
S
N
N
S
N
N
COCHO
N
N
CH3
CH2CH3
O
O
H3CO
29
40
OCH3
OCH3
18
CH3
N
CH2CH3
N
S
N
N
S
COCHO
N
N
N
N
CH3
CH2CH3
O
O
O
O
O
19
O
O
30
O
41
CH3
CH2CH3
N
N
S
N
N
S
N
N
COCHO
N
N
CH3
CH2CH3
O
O
H3CO
H3CO
H3CO
20
31
not formed
CH2CH3
OCH3
OCH3
OCH3
CH3
N
N
S
N
N
S
N
N
COCHO
N
N
CH3
CH2CH3
O
O
H3CO
21
HO
HO
OH
32
not formed
OCH3
OCH3
Figure 2. Oak Ridge thermal ellipsoid plot representation of compound 24.
4. Experimental
4.1. General procedures
Freshly distilled solvents were utilized throughout, and anhydrous solvents were dried according
to Perrin and Armarego (28). Melting points were determined on Electrothermal Engineering
IA9200 apparatus. Infrared (IR) spectra were recorded on a Thermonicolet (Nexus 670) Fourier

6
J. Khalafy et al.
OCH3
H
OCH3
O
H3C
S
N
O
NH2NH2.2HCl
N
H3C
S
H
N
N
N
CH3
N
path b
path a
CH3
45
not formed
O
O
S
N
CH3
43
O
H+
O
N
H
CH3
-H2O
OH
42
O
H+
OCH3
18
O
H
O
H3C
S
CH3
N
N
OCH3
NH2NH2.2HCl
O
S
O
N
CH3
44
N
CH3
O
9
O
H
N
H3C
S
N
OCH3
N
N
CH3
40
Scheme 4. Proposed mechanism for synthesis of 3-aryl-6,8-dialkyl-7-thioxo-7,8-dihydro
pyrimido[4,5-c]pyridazine-5(6H)-ones.
transform IR spectrometer, using KBr discs. 1H NMR and 13C NMR measurements were recorded
on a Bruker spectrometer in CDCl3 using TMS as the internal reference. Mass spectra were
recorded on a Varian Matt 311 spectrometer and relative abundances of fragments are quoted in
parentheses after the m/z values. Microanalyses were performed on a Leco Analyzer 932.
4.2. General procedure for the synthesis of 3-aryl-6,8-dimethyl-7-thioxo-7,
8-dihydropyrimido[4,5-c]pyridazine-5(6H)-ones
A mixture of 1,3-dimethyl-2-thiobarbituric acid (1 mmol), arylglyoxal (1 mmol) and hydrazinium
dihydrochloride (1 mmol) in absolute ethanol (10 ml) was stirred at 50◦C.After 45 min, the formed
precipitate was filtered and washed with excess ethanol. The crude products were recrystallized
from methanol.
4.2.1. 3-Phenyl-6,8-dimethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]pyridazin-5(6H)-one (22)
Yellow powder, 89%, mp 260◦C (dec.).1H NMR (CDCl3, 300 MHz) δ: 3.92 (s, 3H, Me), 4.42 (s,
3H, Me), 7.56–7.59 (m, 3H, Ar), 8.17 (dd, J1 = 7.2 Hz, J2 = 1.8 Hz, 2H, Ar), 8.54 (s, 1H, Ar).
13C NMR (CDCl3, 75.5 MHz) δ: 35.81, 37.04, 114.69, 121.86, 126.82, 129.57, 130.65, 134.65,
150.72, 157.14, 158.61, 177.74. IR (KBr) ν: 2946, 1694, 1605, 1456, 1408, 1381, 1358, 1105,
988, 788, 726 cm−1. Mass spectrum m/z(%): 284 [M+, 98], 241 (74), 196 (61), 140 (100), 115
(67), 102 (62), 77 (52), 60 (94), 51 (48). Anal. Calcd for C14H12N4OS: C 59.14, H 4.25, N 19.70;
found: C 59.17, H 4.29, N 19.55.

Journal of Sulfur Chemistry
7
4.2.2. 3-(4-Bromophenyl)-6,8-dimethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]
pyridazin-5(6H)-one (23)
Brown powder, 80%, mp 235◦C (dec.). 1H NMR (CDCl3, 300 MHz) δ: 3.80 (s, 3H, Me), 4.37 (s,
3H, Me), 7.71 (d, J = 7.8 Hz, 2H, Ar), 8.05 (d, J = 7.8 Hz, 2H, Ar), 8.49 (s, 1H, Ar).13C NMR
(CDCl3, 75.5 MHz) δ: 35.87, 37.07, 114.65, 121.60, 125.39, 128.24, 132.56, 133.60, 150.86,
156.11, 158.49, 177.69. IR (KBr) ν: 2934, 1689, 1647, 1591, 1427, 1360, 1277, 1101, 1006, 740,
594, 460 cm−1. Mass spectrum m/z(%): 364 [M+, 100], 362 (91), 319 (67), 290 (26), 182 (53),
155 (68), 139 (48), 113 (39), 101 (45), 74 (48). Anal. Calcd for C14H11BrN4OS: C 46.29, H 3.05,
N 15.42; found: C 46.35, H 3.07, N 15.33.
4.2.3. 3-(4-Chlorophenyl)-6,8-dimethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]
pyridazin-5(6H)-one (24)
1
Yellow powder, 74%, mp 239◦C (dec.). H NMR (CDCl3, 300 MHz) δ: 3.91 (s, 3H, Me), 4.41
(s, 3H, Me), 7.55 (d, J = 8.4 Hz, 2H, Ar), 8.12 (d, J = 8.4 Hz, 2H, Ar), 8.49 (s, 1H, Ar). 13C
NMR (CDCl3, 75.5 MHz) δ: 35.85, 37.05, 114.64, 121.59, 128.01, 129.6, 133.15, 137.01, 150.82,
156.03, 158.50, 177.69. IR (KBr) ν: 3055, 1688, 1595, 1430, 1360, 1278, 1097, 1010, 837, 788,
460 cm−1. Mass spectrum m/z (%): 320 [M++2, 43], 318 [M+, 100], 303 (25), 273 (63), 174
(85), 138 (71), 74 (85), 57 (68), 43 (97). Anal. Calcd for C14H11ClN4OS: C 52.75, H 3.48, N
17.58; found: C 52.74, H 3.53, N 17.50.
4.2.4. 3-(4-Flourophenyl)-6,8-dimethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]
pyridazin-5(6H)-one (25)
Yellow powder, 70%, mp 234◦C (dec.).1H NMR (CDCl3, 300 MHz) δ: 3.91 (s, 3H, Me), 4.41
(s, 3H, Me), 7.23–7.27 (m, 2H, Ar), 8.15–8.19 (m, 2H, Ar), 8.47 (s, 1H, Ar). 13C NMR (CDCl3,
75.5 MHz) δ: 35.82, 37.03, 114.65, 116.59, 121.47, 128.73, 128.84, 130.89, 130.93, 150.67,
156.16, 158.5, 162.76, 166.09, 177.71. IR (KBr) ν: 3058, +1690, 1597, 1432, 1348, 1232, 1095,
847, 741, 580, 426 cm−1. Mass spectrum m/z(%): 302 [M , 100], 287 (15), 257 (50), 228 (23),
200 (11), 174 (25), 158 (23), 120 (18). Anal. Calcd for C14H11FN4OS: C 55.62, H 3.67, N 18.53;
found: C 55.68, H 3.74, N 18.48.
4.2.5. 3-(4-Methoxyphenyl)-6,8-dimethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]
pyridazin-5(6H)-one (26)
Cream powder, 78%, mp 237◦C (dec.).1H NMR (CDCl3, 300 MHz) δ: 3.79 (s, 3H, Me), 3.91 (s,
3H, Me), 4.35 (s, 3H, Me), 7.09 (d, J = 8.7 Hz, 2H, Ar), 8.14 (d, J = 8.7 Hz, 2H, Ar), 8.46 (s,
1H, Ar).13C NMR (CDCl3, 75.5 MHz) δ: 35.80, 37.03, 55.47, 113.96, 114.76, 121.03, 127.10,
128.26, 150.29, 156.85, 158.72, 161.77, 177.63. IR (KBr) ν: 2935, 1692, 1603, 1425, 1377, 1360,
1271, 1249, 1099, 832, 743, 451 cm−1. Mass spectrum m/z(%): 314 [M+, 100], 269 (27), 256
(31), 170 (37), 149 (41), 132 (38), 57 (47), 43 (51). Anal. Calcd for C15H14N4O2S: C 57.31, H
4.49, N 17.82; found: C 57.35, H 4.50, N 17.70.
4.2.6. 3-(4-Nitrophenyl)-6,8-dimethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]
pyridazin-5(6H)-one (27)
Yellow powder, 92%, mp 293◦C (dec.). 1H NMR (CDCl3, 300 MHz) δ: 3.92 (s, 3H, Me), 4.43 (s,
3H, Me), 8.37 (d, J = 7.8 Hz, 2H, Ar), 8.44 (d, J = 7.8 Hz, 2H, Ar), 8.61 (s, 1H, Ar).13C NMR

8
J. Khalafy et al.
(CDCl3, 75.5 MHz) δ: 35.90, 37.10, 122.40, 124.38, 124.81, 127.63, 128.00, 140.22, 154.75,
158.01, 161.71, 186.70. IR (KBr) ν: 2945, 1688, 1573, 1433, 1340, 1275, 1094, 851, 725, 687,
530 cm−1. Mass spectrum m/z (%): 329 [M+, 5], 229 (8), 149 (12), 111 (15), 97 (30), 69 (88),
43 (100). Anal. Calcd for C14H11N5O3S: C 51.06, H 3.37, N 21.27; found: C 51.03, H 3.45, N
21.16.
4.2.7. 3-(3-Bromophenyl)-6,8-dimethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]
pyridazin-5(6H)-one (28)
Yellow powder, 79%, mp 214◦C (dec.).1H NMR (CDCl3, 300 MHz) δ: 3.91 (s, 3H, Me), 4.41 (s,
3H, Me), 7.44 (t, J = 6.9 Hz, 1H, Ar), 7.67 (d, J = 6.9 Hz, 1H, Ar), 8.07 (d, J = 6.9 Hz, 1H, Ar),
8.35 (s, 1H, Ar), 8.49 (s, 1H, Ar). 13C NMR (CDCl3, 75.5 MHz) δ: 35.86, 37.06, 114.61, 121.86,
123.60, 125.25, 129.85, 130.78, 133.46, 136.65, 150.98, 155.63, 158.44, 177.71. IR (KBr) ν:
2941, 1698, 1571, 1450, 1412, 1356, 1308, 1101, 992, 792, 736, 680 cm−1. Mass spectrum m/z
(%): 364 [M+ + 2, 18], 362 [M+, 20], 319 (13), 220 (17), 182 (20), 155 (41), 139 (29), 81 (50),
69 (98), 57 (90), 43 (100). Anal. Calcd for C14H11BrN4OS: C 46.29, H 3.05, N 15.42; found: C
46.33, H 3.10, N 15.30.
4.2.8. 3-(3-Methoxyphenyl)-6,8-dimethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]
pyridazin-5(6H)-one (29)
Brown powder, 85%, mp 208◦C (dec.).1H NMR (CDCl3, 300 MHz) δ: 3.85 (s, 3H, Me), 3.92 (s,
3H, Me), 4.40 (s, 3H, Me), 7.08 (d, 8.7 Hz, 1H, Ar), 7.46 (t, J = 8.7 Hz, 1H, Ar), 7.65 (d, J =
8.7 Hz, 1H, Ar), 7.78 (s, 1H, Ar), 8.50 (s, 1H, Ar).13C NMR (CDCl3, 75.5 MHz) δ: 35.82, 37.04,
55.51, 111.47, 114.65, 116.98, 119.08, 121.98, 130.31, 135.92, 150.77, 156.81, 158.60, 160.45,
177.69. IR (KBr) ν: 2945, 1684, 1594, 1469, 1407, 1355, 1256, 1102, 1029, 871, 735 cm−1. Mass
spectrum m/z (%): 314 [M+, 34], 269 (27), 256 (31), 170 (37), 149 (41), 132 (38), 57 (47), 43
(51). Anal. Calcd for C15H14N4O2S: C 57.31, H 4.49, N 17.82; found: C 57.34, H 4.48, N 17.72.
4.2.9. 3-(1,3-Benzodioxol-5-yl)-6,8-dimethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]
pyridazin-5(6H)-one (30)
Brown powder, 69%, mp 242◦C (dec.).1H NMR (CDCl3, 300 MHz) δ: 3.85 (s, 3H, Me), 3.92 (s,
3H, Me), 4.40 (s, 3H, Me), 7.08 (d, 8.7 Hz, 1H,Ar), 7.46 (t, J =8.7 Hz, 1H,Ar), 7.65 (d, J =8.7 Hz,
1H, Ar), 7.78 (s, 1H, Ar), 8.50 (s, 1H, Ar).13C NMR (CDCl3, 75.5 MHz) δ: 35.82, 37.04, 55.51,
111.47, 114.65, 116.98, 119.08, 121.98, 130.31, 135.92, 150.77, 156.81, 158.60, 160.45, 177.69.
IR (KBr) ν: 2945, 1684, 1594, 1469, 1407, 1355, 1256, 1102, 1029, 871, 735 cm−1. Mass spectrum
m/z(%): 314 [M+, 34], 269 (27), 256 (31), 170 (37), 149 (41), 132 (38), 57 (47), 43 (51). Anal.
Calcd for C15H12N4O3S: C 54.87, H 3.68, N 17.06; found: C 54.81, H 3.71, N 16.90.
4.2.10. 3-(3,4-Dimethoxyphenyl)-6,8-dimethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]
pyridazin-5(6H)-one (31)
Orange powder, 71%, mp 238◦C (dec.).1H NMR (CDCl3, 300 MHz) δ: 3.89 (s, 3H, Me), 4.01 (s,
3H, Me), 4.27 (s, 3H, Me), 4.38 (s, 3H, Me), 7.03 (d, J = 8.4 Hz, 1H, Ar), 7.63 (d, J = 8.4 Hz,
1H, Ar), 7.91 (s, 1H, Ar), 8.48 (s, 1H, Ar). 13C NMR (CDCl3, 75.5 MHz) δ: 35.83, 37.03, 56.06,
56.14, 109.23, 111.31, 114.83, 119.72, 121.22, 127.25, 149.82, 150.37, 151.39, 156.63, 158.72,
177.56. IR (KBr) ν: 2843, 1690, 1592, 1475, 1425, 1265, 1147, 1020, 872, 738, 430 cm−1. Mass
spectrum m/z (%): 344 [M+, 100], 329 (10), 299 (11), 270 (7), 216 (4), 200 (6), 162 (6), 147

Journal of Sulfur Chemistry
9
(4), 91 (7). Anal. Calcd for C16H16N4O3S: C 55.80, H 4.68, N 16.27; found: C 55.86, H 4.72, N
16.18.
4.2.11. 3-(4-Hydroxy-3-methoxyphenyl)-6,8-dimethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]
pyridazin-5(6H)-one (32)
Yellow powder, 65%, mp 329◦C (dec.).1H NMR (CDCl3, 300 MHz) δ: 3.71 (s, 3H, Me), 3.89 (s,
3H, Me), 4.21 (s, 3H, Me), 6.92 (d, J = 8.4 Hz, 1H, Ar), 7.67 (d, J =8.4 Hz, 1H, Ar), 7.77 (s, 1H,
Ar), 8.50 (s, 1H, Ar), 9.56 (br, 1H, OH). 13C NMR (CDCl3, 75.5 MHz) δ: 35.86, 37.03, 56.20,
110.66, 116.19, 116.43, 120.53, 120.99, 126.33, 148.70, 149.50, 150.82, 156.62, 159.19, 178.11.
IR (KBr) ν: 3376, 3063, 2968, 1689, 1465, 1376, 1268, 1099, 873, 788 cm−1. Mass spectrum m/z
(%): 330 [M+, 2], 313 (7), 149 (14), 111 (18), 97 (38), 71 (50), 57 (97), 43 (100). Anal. Calcd for
C15H14N4O3S: C 54.53, H 4.27, N 16.96; found: C 54.59, H 4.30, N 16.83.
4.3. General procedure for the synthesis of 3-aryl-6,8-diethyl-7-thioxo-7,8-dihydropyrimido
[4,5-c]pyridazine-5(6H)-ones
A mixture of 1,3-diethyl-2-thiobarbituric acid (1 mmol), arylglyoxal (1 mmol) and hydrazinium
dihydrochloride (1 mmol) in absolute ethanol (10 ml) was stirred at 50ºC for 60 min. After the
appropriate time the formed precipitate was filtered and washed with excess ethanol 96◦. The
crude products were purified via recrystallization from methanol.
4.3.1. 3-Phenyl-6,8-diethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]pyridazin-5(6H)-one (33)
Cream powder, 76%, mp 179°C (dec.).1H NMR (CDCl3, 300 MHz) δ: 1.38 (t, J = 6.9 Hz, 3H,
Me), 1.51 (t, J = 6.9 Hz, 3H, Me), 4.72 (q, J = 6.9 Hz, 2H, CH2), 5.23 (q, J = 6.9 Hz, 2H, CH2),
7.56–7.58 (m, 3H,Ar), 8.17 (d, J = 6.9 Hz, 2H,Ar), 8.53 (s, 1H,Ar).13C NMR (CDCl3, 75.5 MHz)
δ: 11.79, 12.04, 43.95, 45.07, 114.98, 121.77, 126.77, 129.31, 130.51, 134.79, 150.11, 157.06,
158.09, 176.30. IR (KBr) ν: 2927, 1689, 1600, 1438, 1388, 1305, 1223, 1104, 1021, 879 cm−1
.
Mass spectrum m/z (%): 313 [M+, 1], 284 (100), 239 (63), 210 (33), 182 (18), 156 (35), 140
(44), 102 (19). Anal. Calcd for C16H16N4OS: C 61.52, H 5.16, N 17.93; found: C 61.59; H 5.17;
N 17.80.
4.3.2. 3-(4-Bromophenyl)-6,8-diethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]
pyridazin-5(6H)-one (34)
Yellow powder, 81%, mp 257◦C (dec.).1H NMR (CDCl3, 300 MHz) δ: 1.38 (t, J = 6.9 Hz, 3H,
Me), 1.51 (t, J = 6.9 Hz, 3H, Me), 4.72 (q, J = 6.9 Hz, 2H, CH2), 5.23 (q, J = 6.9 Hz, 2H, CH2),
7.71 (d, J = 8.4 Hz, 2H, Ar), 8.05 (d, J = 8.4 Hz, 2H, Ar), 8.48 (s, 1H, Ar). 13C NMR (CDCl3,
75.5 MHz) δ: 11.76, 12.02, 43.97, 45.07, 114.94, 121.50, 125.29, 128.15, 132.55, 133.72, 150.25,
155.99, 157.93, 176.28. IR (KBr) ν: 2924, +1695, 1500, 1432, 1380, 1308, 1224, 1032, 885,
745 cm−1. Mass spectrum m/z (%): 392 [M + 2, 4], 390 [M+, 5], 167 (6), 149 (17), 129 (7),
111 (15), 85 (39), 57 (100), 41 (86). Anal. Calcd for C16H15BrN4OS: C 49.11, H 3.86, N 14.32;
found: C 49.09, H 3.90, N 14.20.

10 J. Khalafy et al.
4.3.3. 3-(4-Chlorophenyl)-6,8-diethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]
pyridazin-5(6H)-one (35)
Yellow powder, 73%, mp 235◦C (dec.).1H NMR (CDCl3, 300 MHz) δ: 1.38 (t, J = 6.9 Hz, 3H,
Me), 1.49 (t, J = 6.9 Hz, 3H, Me), 4.72 (q, J = 6.9 Hz, 2H, CH2), 5.21 (q, J = 6.9 Hz, 2H, CH2),
7.53 (d, J = 7.8 Hz, 2H, Ar), 8.11 (d, J = 7.8 Hz, 2H, Ar), 8.47 (s, 1H, Ar).13C NMR (CDCl3,
75.5 MHz) δ: 11.77, 12.04, 44.00, 45.10, 114.96, 121.58, 127.96, 129.60, 133.22, 136.93, 150.19,
155.92, 157.96, 176.24. IR (KBr) ν: 2932, 1686, 1579, 1439, 1383, 1228, 1011, 834, 743 cm−1
.
Mass spectrum m/z (%): 348 [M+ + 2, 3], 346 [M+, 6], 317 (10), 174 (14), 149 (18), 111 (15),
97 (29), 71 (82), 57 (84), 43 (100). Anal. Calcd for C16H15ClN4OS: C 55.41, H 4.36, N 16.15;
found: C 55.46, H 4.40, N 16.01.
4.3.4. 3-(4-Flourophenyl)-6,8-diethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]
pyridazin-5(6H)-one (36)
Cream powder, 71%, mp 209◦C (dec.).1H NMR (CDCl3, 300 MHz) δ: 1.38 (t, J = 6.9 Hz, 3H,
Me), 1.49 (t, J = 6.9 Hz, 3H, Me), 4.72 (q, J = 6.9 Hz, 2H, CH2), 5.21 (q, J = 6.9 Hz, 2H, CH2),
7.21–7.25 (m, 2H, Ar), 8.10–8.14 (m, 2H, Ar), 8.46 (s, 1H, Ar).13C NMR (CDCl3, 75.5 MHz)
δ: 11.79, 12.04, 43.98, 45.08, 115.00, 116.31, 116.60, 121.49, 128.70, 128.81, 130.96, 131.00,
150.06, 156.06, 158.01, 162.73, 166.06, 176.24. IR (KBr) ν: 2932, 1685, 1602, 1572, 1435, 1383,
1337, 1309, 1228, 1105, 791, 580 cm−1. Mass spectrum m/z (%): 330 [M+, 10], 301 (17), 259
(10), 214 (7), 149 (30), 97 (23), 69 (85), 43 (100). Anal. Calcd for C16H15FN4OS: C 58.17, H
4.58, N 19.96; found: C 58.16, H 4.65, N 19.88.
4.3.5. 3-(4-Methoxyphenyl)-6,8-diethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]
pyridazin-5(6H)-one (37)
Yellow powder, 79%, mp 195°C (dec.).1H NMR (CDCl3, 300 MHz) δ: 1.39 (t, J = 6.6 Hz, 3H,
Me), 1.51 (t, J = 6.6 Hz, 3H, Me), 3.91 (s, 3H, Me), 4.72 (q, J = 6.6 Hz, 2H, CH2), 5.22 (q,
J = 6.6 Hz, 2H, CH2), 7.09 (d, J = 8.4 Hz, 2H, Ar), 8.14 (d, J = 8.7 Hz, 2H, Ar), 8.46 (s, 1H,
Ar).13C NMR (CDCl3, 75.5 MHz) δ: 11.82, 12.03, 43.92, 45.00, 114.72, 55.45, 115.00, 120.89,
127.21, 128.16, 149.64, 156.72, 158.16, 161.68, 176.15. IR (KBr) ν: 2932, 1686, 1606, 1431,
1285, 1105, 1023, 841, 747 cm−1. Mass spectrum m/z (%): 342 [M+, 90], 313 (100), 286 (18),
271 (22), 254 (10), 226 (24), 170 (25), 127 (11). Anal. Calcd for C17H18N4O2S: C 59.63, H 5.30,
N 16.36; found: C 59.68, H 5.33, N 16.30.
4.3.6. 3-(4-Nitrophenyl)-6,8-diethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]
pyridazin-5(6H)-one (38)
Yellow powder, 91%, mp 275◦C (dec.). 1H NMR (CDCl3, 300 MHz) δ: 1.39 (t, J = 6.6 Hz, 3H,
Me), 1.52 (t, J = 6.6 Hz, 3H, Me), 4.73 (q, J = 6.6 Hz, 2H, CH2), 5.24 (q, J = 6.6 Hz, 2H, CH2),
8.37 (d, J = 8.4 Hz, 2H, Ar), 8.44 (d, J = 8.4 Hz, 2H, Ar), 8.60 (s, 1H, Ar).13C NMR (CDCl3,
75.5 MHz) δ: 11.71, 12.04, 44.10, 45.20, 114.86, 122.42, 124.39, 127.57, 140.61, 149, 150.70,
154.68, 157.70, 176.32. IR (KBr) ν: 2897, 1688, 1455, 1377, 1243, 1104, 868, 738 cm−1. Mass
spectrum m/z(%): 357 [M+, 6], 342 (15), 313 (19), 229 (12), 149 (13), 97 (34), 69 (88), 43 (100).
Anal. Calcd for C16H15N5O3S: C 53.77, H 4.23, N 19.60; found: C 53.81, H 4.25, N 19.47.

Journal of Sulfur Chemistry 11
4.3.7. 3-(3-Bromophenyl)-6,8-diethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]
pyridazin-5(6H)-one (39)
Brown powder, 70%, mp 232°C (dec.).1H NMR (CDCl3, 300 MHz) δ: 1.38 (t, J = 6.9 Hz, 3H,
Me), 1.51 (t, J = 6.9 Hz, 3H, Me), 4.72 (q, J = 6.9 Hz, 2H, CH2), 5.26 (q, J = 6.9 Hz, 2H, CH2),
7.45 (t, J = 8.1 Hz, 1H, Ar), 7.68 (d, J = 7.2 Hz, 1H, Ar), 8.08 (d, J = 7.2 Hz, 1H, Ar), 8.38 (s,
1H, Ar), 8.49 (s, 1H, Ar). 13C NMR (CDCl3, 75.5 MHz) δ: 11.74, 12.02, 43.99, 45.11, 114.95,
121.80, 125.07, 129.85, 130.76, 133.41, 136.78, 150.40, 155.56, 157.90, 176.33. IR (KBr) ν:
2929, 1694, 1507, 1429, 1382, 1304, 1222, 1044, 791, 736, 677 cm−1. Mass spectrum m/z (%):
392 [M++2, 32], 390 [M+, 43], 363 (58), 319 (28), 276 (26), 139 (37), 113 (38), 86 (41), 57
(100), 41 (98). Anal. Calcd for C16H15BrN4OS: C 49.11, H 3.86, N 14.32; found: C 49.14, H
3.93, N 14.23.
4.3.8. 3-(3-Methoxyphenyl)-6,8-diethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]
pyridazin-5(6H)-one (40)
Yellow powder, 66%, mp 179◦C (dec.).1H NMR (CDCl3, 300 MHz) δ: 1.39 (t, J = 6.6 Hz, 3H,
Me), 1.52 (t, J = 6.6 Hz, 3H, Me), 3.93 (s, 3H, Me), 4.73 (q, J = 6.6 Hz, 2H, CH2), 5.24 (q,
J = 6.6 Hz, 2H, CH2), 7.09 (d, J = 7.8 Hz, 1H, Ar), 7.47 (t, J = 7.8 Hz, 1H, Ar), 7.68 (d, J =
7.8 Hz, 1H, Ar), 7.81 (s, 1H, Ar), 8.51 (s, 1H, Ar). 13C NMR (CDCl3, 75.5 MHz) δ: 11.78, 12.05,
43.96, 45.06, 55.52, 111.48, 114.98, 117.01, 119.102, 121.94, 130.31, 136.10, 150.19, 156.82,
158.06, 160.50, 176.31. IR (KBr) ν: 2931, 1686, 1595, 1433, 1382, 1311, 1228, 1107, 1022, 870,
742 cm−1. Mass spectrum m/z (%): 342 [M+, 71], 313 (100), 285 (29), 258 (50), 226 (25), 115
(2421), 85 (22), 57 (43), 41 (42). Anal. Calcd for C17H18N4O2S: C 59.63, H 5.30, N 16.36; found:
C 59.70, H 5.35, N 16.22.
4.3.9. 6,8-Diethyl-3-(1,3-Benzodioxol-5-yl)-7-thioxo-7,8-dihydropyrimido[4,5-c]
pyridazin-5(6H)-one (41)
Yellow powder, 67%, mp 177◦C (dec.).1H NMR (CDCl3, 300 MHz) δ: 1.38 (t, J = 6.6 Hz, 3H,
Me), 1.50 (t, J = 6.6 Hz, 3H, Me), 4.71 (q, J = 6.6 Hz, 2H, CH2), 5.22 (q, J = 6.6 Hz, 2H, CH2),
6.08 (s, 2H, CH2), 6.98 (d, J = 7.8 Hz, 1H,Ar), 7.63 (d, J = 7.8 Hz, 1H,Ar), 7.73 (s, 1H,Ar), 8.41
(s, 1H, Ar). 13C NMR (CDCl3, 75.5 MHz) δ: 11.81, 12.04, 43.94, 45.04, 101.74, 106.91, 108.98,
114.99, 121.25, 121.30, 128.98, 149.79, 148.88, 149.86, 156.56, 158.10, 176.16. IR (KBr) ν:
2897, 1688, 1430, 1375, 1243, 1032, 868, 738 cm−1. Mass spectrum m/z (%): 356 [M+, 37], 327
(32), 191 (100), 149 (54), 111 (34), 85 (48), 57 (93), 41 (70). Anal. Calcd for C17H16N4O3S: C
57.29, H 4.52, N 15.72; found: C 57.35, H 4.55, N 15.62.
Acknowledgements
Financial support from the research council of Urmia University is greatly acknowledged and our sincere gratitude to Dr
A. Choudhury (Missouri S&T, USA) for his assistance with X-ray crystallography.
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