Synthesis of some new pyrimidothienopyridazines and related heterocycles

Article abstract of DOI:10.1002/jccs.200500046

5-Amino-3,4-diphenylthieno[2,3-c]pyridazine-6-carbonitrile 2a was reacted with propylene diamine to give tetrahydropyrimidinyl derivative 3. The latter compound (3) underwent certain cyclocondensation reactions to produce pyrimidothienopyridazines 4-6. Al

Full text of DOI:10.1002/jccs.200500046

Journal of the Chinese Chemical Society, 2005, 52, 303-308
303
Synthesis of Some New Pyrimidothienopyridazines and Related
Heterocycles
Sh. M. Radwan, A. M. Kamal El-Dean and E. A. Bakhite*
Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
5-Amino-3,4-diphenylthieno[2,3-c]pyridazine-6-carbonitrile 2a was reacted with propylene diamine to
give tetrahydropyrimidinyl derivative 3. The latter compound (3) underwent certain cyclocondensation reac-
tions to produce pyrimidothienopyridazines 4-6. Also, the reactions of 5-amino-3,4-diphenylthieno[2,3-
c]pyridazine-6-carboxamide with heterocyclic aldehydes and/or cycloalkanones were carried out and their
products were identified. Moreover, some novel pyridazinothienopyrimidobenzimidazoles 14-17 were syn-
thesized.
Keywords: Thienopyridazines; Pyrimidothienopyridazines; Benzimidazoles; Pyrimidines; Spiro com-
pounds.
INTRODUCTION
It is interesting to note that many pyridazine derivatives
Reaction of 6-cyano-5-amino-3,4-diphenylthieno[2,3-
c]pyridaine (2a) with propylene diamine in the presence of
carbon disulfide gave the tetrahydropyrimidinyl derivative
3.8 The latter compound upon reaction with triethyl orth-
formate or benzaldehyde, in refluxing acetic acid,9 gave the
corresponding tetrahydropyrimido[1²,2²:1¢,6¢]pyrimido-
[4¢,5¢;4,5]thieno[2,3-c]pyridazines 4 and 5, respectively. On
the other hand, treatment of compound 3 in a mixture of ace-
tic acid and hydrochloric acid with sodium nitrite solution at
low temperature led to the formation of 8,9-diphenyl-2,3,4-
trihydropyrimido[1²,2²-f]pyridazino[3¢,4¢:4,5]thieno[2,3-
d]triazine (6) (Scheme II).
have antihypertensive1 and cardiotonic activity.2 Also other
pyridazine derivatives serve as insecticides, miticides and
nematocides.3 In view of the above benefits and in continua-
tion of our work on the synthesis and reactivity of pyrida-
zines,4-7 we aimed, in this work, to prepare some new hetero-
cycles containing thieno[2,3-c]pyridazine moiety condensed
with other heterocyclic ones hoping that some of them will
have biological activities.
When 5-amino-3,4-diphenylthieno[2,3-c]pyridazine-
6-carboxamide (2b) was allowed to react with heterocyclic
aldehydes in boiling acetic acid, a cyclocondensation reac-
tion occurred and tetrahydropyrimidothienopyridazines 7a,b
were obtained (Scheme III). The carboxamide 2b was also re-
acted with cyclopentanone or cyclohexanone upon refluxing
in glacial acetic acid or in ethanol containing a few drops of
HCl. In view of an earlier report10 and the spectral data, the
products of this reaction were identified as spiro compounds
9a,b rather than Schiff bases 8a,b. Thus, the IR spectra of the
products showed two absorption bands at 3400, 3200 cm-1
characteristic for (2NH) and an absorption band at 1650 cm-1
for (C=O). The IR spectra revealed also the absence of any
bands corresponding to a NH2 group. The 1H NMR spectra in
DMSO-d6 showed no signal equivalent to a CONH2 group but
showed two singlets at d 4.4 equivalent to (NH) and at d 6.5 to
(NH). The proposed pathway of this reaction is depicted in
INVESTIGATIONS, RESULTS AND DISCUSSION
The starting compounds, 6-functionalized 5-amino-
3,4-diphenylthieno[2,3-c]pyridazines 2a-c were prepared by
reaction of 4-cyano-4,5-diphenylpyridazine-3(2H)-thione
(1) with the respective halocompounds.
Scheme I
Ph
Ph
Ph
CN
S
Ph
NH2
R
ClCH2R / K2CO3
N
N
N
N
S
H
2a, R=CN
b, R=CONH2
1
c, R=CONHPh

304 J. Chin. Chem. Soc., Vol. 52, No. 2, 2005
Radwan et al.
Scheme II
Ph
N
Ph
N
N
N
N
N
S
6
HNO2
Ph
Ph
NH2
Ph
NH2
CN
Ph
H2N-(CH2)3-NH2
CS2
H
N
N
N
N
S
N
S
2a
N
3
HC(OC2H5)3
PhCHO / AcOH
H
Ph
N
Ph
Ph
N
Ph
Ph
N
N
H
N
N
N
N
S
N
S
N
4
5
Refluxing of 5-amino-3,4-diphenyl-6-(N-phenyl)car-
Scheme III
bamoylthieno[2,3-c]pyridazine (2c) with acetic anhydride
for 6 hours led to the formation of oxazinone derivative 11
rather the pyrimidinone 10.11 The pathway of this reaction is
given in Scheme IV.
Ph
N
H
N
Ph
X
CHO
X
H
AcOH
N
NH
S
O
7a, X = O
b, X = S
Scheme IV
O
Ph
N
H
Ph
Ph
N
Ph
N
(CH2)n
Ph
NH2
Ph
NHCOCH3
CONHPh
2b
HO
(CH2)n
Ac2O
AcOH or
EtOH / HCl
N
NH2
S
N
N
N
S
CONHPh
S
O
A
2c
-H2O
(route a)
A
-H2O
(route b)
PhNH2
H2O
Ph
N
Ph
Ph
N
H
Ph
N
CH3
Ph
N
Ph
N
O
CH3
Ph
Ph
Ph
N
N
(CH2)n
NH2
N
O
(CH2)n
N
N
N
N
N
S
N
S
S
S
H
O
O
9a, n=1
b, n=2
O
10
11
8a, n=1
b, n=2
The pyridazinethione 1 reacts also with 2-chlorometh-
Scheme III. Thus, this reaction involves the formation of ad-
dition product A which may undergo spontaneous dehydra-
tion to give the expected products 8a,b or 9a,b via two proba-
ble routes (a and b) (Scheme III).
yl-1H-benzimidazole in refluxing ethanol containing sodium
acetate to afford the intermediate 12 which underwent intra-
molecular Thorpe-Ziegler cyclization12 upon heating with
sodium ethoxide in ethanol to give 5-amino-6-(1H-benzimi-

Synthesis of New Pyrimidothienopyridazines and Derivatives
J. Chin. Chem. Soc., Vol. 52, No. 2, 2005 305
dazol-2-yl)-3,4-diphenylthieno[2,3-c]pyridazine derivative
EXPERIMENTAL
13 (Scheme V).
All melting points are uncorrected and measured on a
Scheme V
Gallan-Kamp apparatus. IR spectra were recorded on a
Shimadzu 470 IR-spectrophotometer (KBr; u
in cm-1).
max
N
1H-NMR spectra on a Varian EM-390, 90 MHz spectrometer
with TMS as internal standard (d in ppm); MS on a Jeol
JMS-600 mass spectrometer and elemental analyses on an
Elementar Analyses system GmbH VARIOEL V2.3 July 1998
CHNS Mode.
Ph
N
Ph
N
H
CH2Cl
Ph
CN
Ph
CN
S
H
N
N
N
SCH2
N
AcONa
H
N
12
1
EtONa
6-Functionalized 5-amino-3,4-diphenylthieno[2,3-c]pyr-
idaines 2a-c
Ph
NH2
Ph
H
N
These compounds were prepared according to our pre-
vious method.13-15
N
N
S
N
13
5-Amino-3,4-diphenyl-6-(1,4,5,6-tetrahydropyrimidin-2-
yl)thieno[2,3-c]pyridazine (3)
The latter compound (13) was used as a versatile
compound for the building of other new heterocyclic sys-
tems. Thus, its reactions with triethyl orthoformate, acetic
anhydride and/or aromatic aldehydes, gave pyridazino-
[3²,4²:4¢,5¢]thieno[2¢,3¢:4,5]pyrimido[1,6-a]benzimidazole
derivatives 14, 15 and 16, respectively. Also, treatment of
compound 13 in acetic acid and hydrochloric acid mixture
with sodium nitrite solution produced pyridazino[3²,4²;4¢,5¢]-
thieno[2¢,3¢;4,5]triazino[1,6-a]benzimidazole derivative (17)
(Scheme VI).
To a mixture of compound 2a (3.28 g, 0.01 mol) and
propylene diamine (6 mL), 1 mL of carbon disulfide was
added dropwise. The resulting mixture was heated on a water
bath for 6 h. After cooling, the separated product was filtered
off, washed with water and recrystallized (ethanol) to give 3
(80%), m.p. 213-215 °C. IR: 3450-3350 cm-1 (NH2, NH) and
1600 cm-1 (C=N). 1H NMR (DMSO-d6): 2.1-2.2 (m, 2H, py-
rimidine ring), 2.6-2.7 (2H, m, pyrimidine ring), 3.5-3.6 (m,
2H, pyrimidine ring), 6.5 (s, 2H, NH2), 6.7 (s, 1H, NH) and
7.3-7.5 (m, 10H, ArH). Anal. calcd. for C22H19N5S (385.46):
C, 68.54; H, 4.96; N, 18.16; S, 8.31. Found: C, 68.32; H, 4.91;
N, 17.96; S, 8.05.
Scheme VI
Ph
Ph
N
N
R
HC(OC2H5)3 or
Ac2O
13
3,4-Diphenyl-8,9,10-trihydropyrimido[1²,2²:1¢,6¢]pyrimido-
[4¢,5¢:4,5]thieno[2,3-c]pyridazine (4)
N
N
N
S
Compound 3 (0.78 g, 0.002 mol) and triethyl orthfor-
mate (8 mL) were heated under reflux for 2 h. The precipitate
that formed on cooling was collected and recrystallized (ace-
tic acid) to give 4 (83%), m.p. 296-298 °C. IR: 1620 cm-1
HNO2
14, R=H
15, R=CH3
ArCHO /
AcOH
Ph
Ph
H
H
N
1
Ph
N
(C=N). H NMR (CF3CO2D): 2.4-2.5 (m, 2H, pyrimidine),
Ph
Ar
N
2.7-2.8 (m, 2H, pyrimidine), 3.7-3.8 (m, 2H, pyrimidine),
7.2-7.6 (m, 10H, ArH) and 8.3 (s, 1H, pyrimidine). Anal.
calcd. for C23H17N5S (395.45): C, 69.85; H, 4.33; N, 17.69; S,
8.10. Found: C, 69.58; H, 4.23; N, 17.49; S, 7.93.
N
N
N
N
N
S
N
S
N
N
17
16a , Ar = C6H5
b, Ar = 4-CH3OC6H4
c, Ar = 4-NO2C6H4
3,4,6-Triphenyl-5,6,8,9,10-pentahydropyrimido[1²,2²:1¢,6¢]-
pyrimido[4¢,5¢:4,5]thieno[2,3-c]pyridazine (5)
The structural formulas of all newly synthesized com-
pounds were confirmed by elemental and spectroscopic anal-
A mixture of 3 (0.78 g, 0.002 mol) and benzaldehyde
(0.22 g, 0.002 mol) in glacical acetic acid (10 mL) was
yses (cf. experimental section).

306 J. Chin. Chem. Soc., Vol. 52, No. 2, 2005
Radwan et al.
refluxed for 4 h. The solid product that formed was collected
Compound 9a
and recrystallized (acetic acid) to afford 5 (76%); m.p.
It was obtained from 2b and cyclopentanone in 69%
yield; m.p. 331-333 °C (ethanol), IR: 3400, 3200 cm-1 (2NH)
and 1650 cm-1 (C=O). 1H NMR (DMSO-d6); 1.6-1.8 (m, 4H,
cyclopentane), 2.0-2.2 (m, 4H, cyclopentane) and 7.2-7.6 (m,
10H, ArH), 4.4 (s, 1H, NH), 6.5 (s, 1H, NH). Anal. calcd. for
C24H20N4OS (412.48): C, 69.87; H, 4.88; N, 13.59; S, 7.77.
Found: C, 69.64; H, 4.66; N, 13.23; S, 7.54.
1
302-304 °C. IR: 3450 cm-1 (NH) and 1620 cm-1 (C=N). H
NMR (CF3CO2D): 2.1-2.2 (m, 2H, pyrimidine), 2.4-2.5 (m,
2H, pyrimidine), 3.6-3.7 (m, 2H, pyrimidine), 6.2 (s, 1H, CH)
and 7.2-7.6 (m, 15H, ArH). Anal. calcd. For C29H23N5S
(475.57): C, 73.23; H, 5.30; N, 14.72; S, 6.74. Found: C,
72.97; H, 5.12; N, 14.53; S, 6.56.
3,4-Diphenyl-8,9,10-trihydropyrimido[1²,2²-f]pyridazino -
[3¢,4¢;4,5]thieno[2,3-e]triazine (6)
Compound 9b
It was obtained from 2b and cyclohexanone in 71%
yield; m.p. 323-325 °C (ethanol). IR: 3400, 3200 cm-1 (2NH)
and 1650 cm-1 (C=O). 1H NMR (DMSO-d6): 1.6-1.8 (m, 6H,
cyclohexane), 2.0-2.2 (m, 4H, cyclohexane) and 7.5-7.7 (m,
10H, ArH), 4.4 (s, 1H, NH), 6.5 (s, 1H, NH). Anal. calcd. for
C25H22N4OS (426.50): C, 70.39; H, 5.19; N, 13.13; S, 7.15.
Found: C, 70.01; H, 4.92; N, 12.80; S, 6.91.
To compound 3 (0.78 g, 0.002 mol) in a mixture of ace-
tic acid (9 mL) and hydrochloric acid (3 mL) was added with
stirring a solution of sodium nitrite (0.2 g in 5 mL H2O). After
addition, stirring was continued for 5 h. The formed product
was filtered off and recrystallized (acetic acid) to afford 6
(72%); m.p. 203-205 °C. IR: 1620 cm-1 (C=N). Anal. Calcd.
for C22H16N6S (396.44): C, 66.64; H, 4.06; N, 21.19; S, 8.08.
Found: C, 66.32; H, 3.89; N, 20.97; S, 7.88.
Reaction of thieno[2,3-c]pyridazine 2c with acetic anhy-
dride; formation of oxazino[4¢,5¢:4,5]thieno[2,3-c]pyrid-
azine derivative (11)
Reaction of thieno[2,3-c]pyridazine 2b with heterocyclic
aldehydes or cycloalkanones; formation of tetrahydro-
pyrimido[4¢,5¢;4,5]thieno[2,3-c]pyridazine derivatives
(7a,b) and (9a,b)
Compound 2c (0.84 g, 0.002 mol) and acetic anhydride
(15 mL) were heated under reflux for 5 h. Upon cooling, the
precipitate formed was collected and recrystallized (ethanol)
to give 11 (72%), m.p. 260-262 °C. IR: 1740 cm-1 (C=O) and
General procedure
1
A mixture of 2b (0.002 mol) and hetrocyclic aldehy-
dehyde or cycloalkanones (0.002 mol) in acetic acid (10 mL)
was refluxed for 4 h. After cooling, the solid product sepa-
rated was filtered off and recrystallized from the proper sol-
vent to give compounds 7a,b or 9a,b respectively.
1600 cm-1 (C=N). H NMR (CDCl3); 2.6 (s, 3H, CH3) and
7.3-7.7 (m, 10H, ArH). Anal. calcd. for C21H13N3O2S (371.39):
C, 67.90; H, 3.52; N, 11.31; S, 8.63. Found: C, 67.62; H, 3.43;
N, 11.02; S, 8.42.
Reaction of pyridazinethione 1 with 2-chloromethyl-1H-
benzimidazole; formation of benzimidazolylthieno[2,3-c]-
pyridazine derivative 12
Compound 7a
It was obtained from 2b and thiophene-2-carboxalde-
hyde in 73% yield; m.p. 271-273 °C (acetic acid). IR: 3350-
3250 cm-1 (NH) and 1650 cm-1 (C=O). 1H NMR (CF3CO2D):
6.6 (s, 1H, CH) and 7.2-7.7 (m, 13H, ArH and thiophene pro-
tons). Anal. calcd. for C24H16N4OS2 (440.51): C, 65.43; H,
3.66; N, 12.71; S, 14.55. Found: C, 65.11; H, 3.48; N, 12.54;
S, 14.33.
A mixture of compound 1 (2.89 g, 0.01 mol), 2-chloro-
methyl-1H-benzimidazole (1.66 g, 0.01 mol) and sodium ac-
etate trihydrate (3.0 g) in ethanol (30 mL) was heated under
reflux for 2 h. The product which separated on cooling was
collected and recrystallized (ethanol) to give 12 (83%), m.p.
322-324 °C. IR: 3250 cm-1 (NH), 2200 cm-1 (CºN). 1H NMR
(CF3CO2D): 5.2 (s, 2H, CH2) and 7.2-7.8 (m, 14H, ArH).
Anal. calcd. for C25H17N5S (419.47): C, 71.57; H, 4.08; N,
16.69; S, 7.64. Found: C, 71.16; H, 3.97; N, 16.49; S, 7.51.
Compound 7b
It was obtained from 2b and furfural in 76% yield; m.p.
262-264 °C (ethanol-chloroform). IR: 3350-3250 cm-1 (NH)
and 1650 cm-1 (C=O). 1H NMR (CF3CO2D): 5.9-6.0 (m, 2H,
furan), 6.3-6.3 (m, 1H, furan), 6.5 (s, 1H, CH) and 7.3-7.7 (m,
10H, ArH). Anal. calcd. for C24H16N4O2S (424.45): C, 67.90;
H, 3.79; N, 13.19; S, 7.55. Found: C, 67.58; H, 3.71; N,
12.92; S, 7.43.
3.4-Diphenyl-5-amino-6-(benzimidazol-2-yl)-thieno[2,3-c]-
pyridazine (13)
A suspension of 12 (2.1 g, 0.005 mol) in sodium eth-
oxide solution (0.5 g sodium in 50 mL ethanol) was heated
under reflux for 15 min. The solid product separating upon

Synthesis of New Pyrimidothienopyridazines and Derivatives
J. Chin. Chem. Soc., Vol. 52, No. 2, 2005 307
treatment with acetic acid was collected and recrystallized
(acetic acid) to afford 13 (63%), m.p. > 360 °C. IR: 3400, 3300,
3150 cm-1 (NH) and 1600 cm-1 (C=O). 1H NMR (CF3CO2D):
7.3-7.7 (m, 14H, ArH). Anal. calcd. for C25H17N5S (419.47):
C, 71.57; H, 4.08; N, 16.69; S, 7.64. Found: C, 71.23; H, 4.92;
N, 16.39; S, 7.49.
1H NMR (CF3CO2D): 3.9 (s, 3H, CH3), 5.7 (s, 1H, CH) and
7.3-7.8 (m, 18H, ArH). Anal. calcd. for C33H23N5OS (537.60):
C, 73.72; H, 4.31; N, 13.02; S, 5.96. Found: C, 73.51; H, 4.03;
N, 12.88; S, 5.62.
Compound 16c
It was in 79% yield, m.p. 325-327 °C (acetic acid). IR:
3445 cm-1 (NH) and 1600 cm-1 (C=N). 1H NMR (CF3CO2D):
5.8 (s, 1H, CH) and 7.2-7.8 (m, 18H, ArH). Anal. Calcd. for
C32H20N6O2S (552.57): C, 69.55; H, 3.64; N, 15.20; S, 5.80.
Found: C, 69.23; H, 3.52; N, 15.01; S, 5.72.
3,4-Diphenylpyridazino[3²,4²:4¢,5¢]thieno[2¢,3¢:4,5]pyrimi-
do[1,6-a]benzimidazole (14)
Compound 13 (0.82 g, 0.002 mol) and triethyl orthfor-
mate (8 mL) were heated under reflux for 2 h. After cooling,
the precipitate formed was filtered off, washed with petro-
leum ether and recrystallized (acetic acid) to give 14 (87%),
m.p. > 360 °C. IR: 1610 cm-1 (C=N). 1H NMR (CF3CO2D);
7.3-7.9 (m, 14H, ArH) and 8.2 (s, 1H, pyrimidine). Anal.
calcd. for C26H15N5S (429.47): C, 72.70; H, 3.52; N, 16.30; S,
7.46. Found: C, 72.57; H, 3.45; N, 16.02; S, 7.13.
3,4-Diphenylpyridazino[3²,4²:4¢,5¢]thieno[2¢,3¢:4,5]tri-
azino[1,6-a]benzimidazole (17)
To compound 13 (0.82 g, 0.002 mol) in a mixture of
acetic acid (9 mL) and hydrochloric acid (3 mL) was added
with stirring a solution of sodium nitrite (0.2 g in 5 mL H2O).
After addition, stirring was continued for 5 h. The product
that formed was filtered off and recrystallized (acetic acid) to
afford 17 (62%), m.p. 240-242 °C. IR: 1620 cm-1 (C=N).
Anal. calcd. for C25H14N6S (430.46): C, 69.75; H, 3.27; N,
19.52; S, 7.44. Found: C, 69.55; H, 3.12; N, 19.33; S, 7.23.
3,4-Diphenyl-6-methylpyridazino[3²,4²:4¢,5¢]thieno-
[2¢,3¢:4,5]pyrimido[1,6-a]benzimidazole (15)
Compound 13 (0.42 g, 0.001 mol) and acetic anhydride
(15 mL) were heated under reflux for 5 h. Upon cooling, the
precipitate that formed was collected and recrystallized (ace-
tic acid) to afford 15 (64%), m.p. > 360 °C. IR: 1620 cm-1
(C=N). 1H NMR (CF3CO2D); 3.3 (s, 3H, CH3) and 7.3-7.9 (m,
14H, ArH). Anal. calcd. for C27H17N5S (443.49): C, 73.11; H,
3.86; N, 15.79; S, 7.22. Found: C, 72.84; H, 3.66; N, 15.56; S,
6.95.
Received May 28, 2004.
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