Synthesis of bipyrazole and 1,3,4-thiadiazole derivatives

Article abstract of DOI:10.3184/030823409X12528547964044

New hydrazonoyl bromides reacted with several C-nucleophiles to give the corresponding bipyrazoles. Treatment of 3-cyanoacetylpyrazole derivatives with phenyl isothiocyanate in potassium hydroxide followed by hydrazonoyl bromides gave the corresponding py

Full text of DOI:10.3184/030823409X12528547964044

630 RESEARCH PAPER
OCTOBER, 630–634
JOURNAL OF CHEMICAL RESEARCH 2009
Synthesis of bipyrazole and 1,3,4-thiadiazole derivatives
Kamal M. Dawood*, Eman A. Ragab and Ahmad M. Farag
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
New hydrazonoyl bromides reacted with several C-nucleophiles to give the corresponding bipyrazoles. Treatment
of 3-cyanoacetylpyrazole derivatives with phenyl isothiocyanate in potassium hydroxide followed by hydrazonoyl
bromides gave the corresponding pyrazolyl-1,3,4-thiadiazoles.
Keywords: pyrazoles, thiophenes, 1,3,4-thiadiazoles, hydrazonoyl bromides
The considerable pharmacological importance of pyrazole
derivatives1-3 has attracted a great deal of attention. In
addition, bis-pyrazole derivatives are involved in wide
variety of medical and pharmaceutical applications.4,5 1,3,4-
Thiadiazoles are also reported as highly anti-inflammatory,6,7
anticonvulsant6,8 and antimicrobial9 agents. Furthermore,
thiophene derivatives are known to have antiamoebic,10
molluscicidal11 and anti-inflammatory12,13 activity On the other
hand, the synthesis of combinatorial libraries of heterocyclic
compounds permits the testing of the biological properties
of a vast array of compounds. Routes to novel skeletons,
which could be synthesised using combinatorial methods, are
presently a major research objective. Hydrazonoyl halides
are key intermediates in the synthesis of several heterocyclic
systems.14 In continuation of our recent work aiming at the
synthesis of biologically active heterocyclic systems,15-26 we
report here a general route to several new polyheterocyclic
skeletons having pyrazole, and 1,3,4-thiadiazole moieties,
which could be adapted to the synthesis of small libraries.
Anal. for this purpose, 3-bromoacetylpyrazole 1 and 3-
cyanoacetylpyrazole 10 were found to be versatile substrates
for the achievement of our target.
Results and discussion
Treatment of the bromoacetylpyrazole 1 with dimethylsulfide
in refluxing methanol afforded the corresponding 1-(4-
cyano-1,5-diphenyl-1H-pyrazol-3-yl)-1-ethanone-2-dimethyl
sulfonium bromide (2) (Scheme 1). The sulfonium bromide
2 reacted with diazotised aromatic amines, in ethanol
CN
Ph
Ph
Ph
Ph
Ph
CN
CN
Me2S
Br
ArN2+ Cl-
S
Br
N
N
N
N
N
S
Ph
N
Br
N
NH
Ar
1
O
O
2
O
3
Me2S
Ph
Ph
CN
Br
N
N
N NH Ar
4
O
Ar
Ar; a: C6H5; b: p-CH3C6H4
CN
O
Ar
N
Ph
Ph
N
Ph
CN
N
CH2(COR)2
Ph
PhCOCH2CN
5
8
N
N
R
NaOEt / EtOH
N
NaOEt / EtOH
N
Ph
N
CN
9
Ph
CN
COR
O
6
NaOEt
N
Ph
N
CN
NC
EtOH
NH2NH2
O
10
Ar
N
CN
Ph
Ph
N
Ph
N
NC
N
N
R
N
Ph
Ph
Ph
N
N
N
7
N
N
R
Ar
NC
N
6,7
Ar
R
O
11
a
b
c
9a,11a: Ar = C6H5
9b,11b: Ar = p-CH3C6H4
C6H5
CH3
p-CH3C6H4
C6H5
CH3
C6H5
C6H5
d
p-CH3C6H4
Scheme 1
* Correspondent. E-mail: dr_dawood@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2009 631
buffered with sodium acetate, at 0–5°C to give the new
pyrazolylhydrazonoyl bromides 4a,b in good yields via loss
of dimethylsulfide from the non-isolable hydrazone sulfonium
bromide 3 (Scheme 1). The IR spectra of 4a,b revealed, in
each case, three characteristic absorptions near 3200, 2230
and 1650 cm-1 due to hydrazone-NH, nitrile and carbonyl
functions, respectively. The 1H NMR spectrum of 4b for
example, displayed a singlet signal at d 2.23 due to methyl
protons and a broad singlet signal (D2O-exchangeable) at
d 8.71, due to NH proton, in addition to a multiplet at d 7.01–
7.32 corresponding to the aromatic protons.
The reactivity of the new hydrazonoyl bromides 4a,b towards
various C-nucleophiles were investigated. Thus, reaction of 4a,b
with acetylacetone 5a in ethanolic sodium ethoxide solution,
afforded products identified as 3-(4-acetyl-1-aryl-5-methyl-1H-
pyrazol-3-carbonyl)-1,5-diphenyl-1H-pyrazole-3-carbonitrile
derivatives 6a,b (Scheme 1). Similarly, when the hydrazonoyl
bromides 4a,b were treated with dibenzoylmethane 5b under
the same reaction conditions, they afforded 3-(4-benzoyl-1-aryl-
5-phenyl-1H-pyrazol-3-carbonyl)-1,5-diphenyl-1H-pyrazole-
4-carbonitrile derivatives 6c,d, respectively (Scheme 1).
The structures of the isolated products 6a–d were established
on the basis of their elemental analyses and spectral data, as
well as their chemical transformations as outlined in Scheme 1.
The IR spectra of the reaction products showed, in each case,
two absorption bands in the region 1650–1690 cm-1 due to
two carbonyl groups. The 1H NMR spectrum of compound 6a
revealed two singlet signals at d 2.45 and 3.31 corresponding
to methyl and acetyl protons, respectively, in addition to a
multiplet in the region d 7.34–7.62 due to aromatic protons,
also the 1H NMR spectrum of 6d revealed one singlet at d 2.39
due to methyl protons in addition to a multiplet in the region
7.30–7.53 due to aromatic protons. Treatment of the pyrazoles
6a–d with hydrazine hydrate in refluxing ethanol afforded
products identified as the pyrazolo[3,4-d]pyridazine derivatives
7a–d (Scheme 1). The IR spectra of the isolated products 7a–d
were free of carbonyl absorptions.
are compatible with the 1,3,4-thiadiazole structures 14a,b.
Anal. for example, the IR spectra of the isolated products 14a,b
revealed, in each case, three absorption bands near 2210 cm-1
corresponding to nitrile functions and two carbonyl groups
1
near 1675 cm-1. The H NMR of compound 14b displayed a
singlet at d 2.29 and a multiplet at d 7.15–7.67 due to methyl
and aromatic protons, respectively. The mass spectrum of
compound 14b for example, exhibited a molecular ion peak at
m/z 757. These results indicated that the reaction of 10 with the
hydrazonoyl bromides 10a,b proceeded, in each case, via the
loss of hydrogen bromide followed by elimination of aniline
molecule from the non-isolable intermediate 13 (Scheme 2)
similar to our analogous reports.19,23
Treatment of the intermediate 13 with methyl iodide afforded
a
single product identified as 3-(2-cyano-3-methylthio-
3-phenylaminoacryloyl)-1,5-diphenyl-1H-pyrazole-4-
carbonitrile (15) (Scheme 2) based on its elemental analysis
and spectral data. The IR spectrum of 15 exhibited four
strong absorption bands at 3340, 2230, 2199 and 1710 cm-1
characteristic for one NH, two C≡N and one C=O functions,
respectively. The 1H NMR spectrum of 15 revealed two singlet
signals at d 2.25 and 13.71 due to SCH3 and NH protons
besides a multiplet at d 7.27–7.33 due to aromatic protons.
When compound 15 was treated with hydrazine hydrate in
refluxing ethanol it afforded a single product that was identified
as 1,5-diphenyl-5'-phenylamino-1H,2'H-3,3'-bipyrazolyl-4,4'-
dicarbonitrile (17) as shown in Scheme 2. The structure of the
latter product 17 was established according to its elemental
and spectral analyses.
The reaction of cyanoacetylpyrazole 10 with hydrazonoyl
chlorides 19a,b in ethanolic sodium ethoxide solution at room
temperature afforded, in each case, a single product based on
TLC analysis. The isolated products were assigned as 1H,1'H-
3,5'-bipyrazole derivatives 20a,b (Scheme 2) on the basis of
their elemental analyses and spectral data. The IR spectra of
compounds 20a,b showed in all cases the presence of two
nitrile absorption bands near 2230 and 2180 cm-1 and the lack
of amino and carbonyl functions as an evidence for ruling out
the structure 21.
In a similar manner, the hydrazonoyl bromides 4a,b react with
benzoylacetonitrile (8) in ethanolic sodium ethoxide solution, at
room temperature to afford products that were identified as 3-(4-
cyano-1-aryl-5-phenyl-1H-pyrazol-3-carbonyl)-1,5-diphenyl-
1H-pyrazole-4-carbonitrile derivatives 9a,b (Scheme 1).
The IR spectra of compounds 9a,b revealed, in each case, two
nitrile bands and one carbonyl absorption band near 2230 and
1650 cm-1, respectively. Their mass spectra revealed, in each
When the bromoacetylpyrazole 1 was treated with 2-
aminobenzimidazole, in refluxing ethanol it afforded a single
product that was identified as 2-(4-cyano-1,5-diphenyl-1H-
pyrazol-3-yl)-1H-imidazo[1,2-a]benzimidazole
(22),
as
shown in Scheme 3. The IR spectra of the isolated product
was free of absorption band characteristic for carbonyl group
and showed only one absorption band at 3380–3387 cm-1 due
to NH stretching. Moreover, the mass spectrum showed a
peak corresponding to its molecular ion.
1
case, a peak corresponding to molecular ion. The H NMR
spectrum of 9b displayed singlet signal at d 2.32 characteristic
for methyl protons, in addition to a multiplet signals at d 7.25–
7.53 due to aromatic protons.
In a similar fashion, the hydrazonoyl bromides 4a,b reacted
with cyanoacetylpyrazole derivative 10 in ethanolic sodium
ethoxide solution at room temperature and furnished, in each
case, one isolable product. On the basis of their spectral
analyses, the structures of the reaction products were identified
Experimental
Melting points were measured with a Gallenkamp apparatus.
The IR spectra were recorded on a Shimadzu FT-IR 8101 PC IR
spectrophotometer. The NMR spectra were recorded on a Varian
1
Mercury VX-300 NMR spectrometer. H NMR spectra were run at
300 MHz and 13C NMR spectra were run at 75.46 MHz in CDCl3
or DMSO-d6 using TMS as an internal standard. Chemical shifts
were related to that of the solvent. Mass spectra were measured
as
3'-(4-cyano-1,5-diphenyl-1H-pyrazol-3-carbonyl)-1,5-
diphenyl-1'-aryl-1H,1'H-3,5'-bipyrazol-4,4'-dicarbonitrile
11a,b (Scheme 1). The IR spectra of the isolated products
showed, in each case, two bands near 2225 cm-1 due to two
nitrile functions and a strong band near 1660 cm-1 due to
on
a GCMS-QP1000 EX spectrometer at 70 eV. Elemental
analyses were carried out at the Microanalytical Centre of Cairo
University. Bromoacetylpyrazole 1,23 benzoylacetonitrile (7),27 and
cyanoacetylpyrazole derivative 1024 were prepared according to the
literature procedures.
1-(4-Cyano-1,5-diphenyl-1H-pyrazol-3-yl)-1-ethanone-2-dimethyl-
sulfonium bromide (2): A mixture of 3-bromoacetyl-1,5-diphenyl-
1H-pyrazole-4-carbonitrile (1) (18.31 g, 50 mmol) and dimethyl
sulfide (6 mL) in absolute methanol (75 mL) was refluxed for
30 min. The reaction mixture was allowed to cool and the solid
product was collected by filtration, washed with methanol and finally
recrystallised from ethanol to give the dimethylsulfonium bromide
2 as colourless crystals in 75% yield; m.p. 150–152°C; IR (KBr)
1
carbonyl group. The H NMR spectrum of compound 11b
displayed a singlet signal at d 2.33 and a multiplet at 7.17–7.67
characteristic for p-tolyl and aromatic protons, respectively.
Treatment of a solution of the cyanoacetylpyrazole 10 in
DMF with phenyl isothiocyanate, in the presence of potassium
hydroxide, at room temperature followed by the addition of
an equimolar amount of the appropriate hydrazonoyl bromide
4a,b afforded, in each case, only one isolable product as
examined by TLC. The elemental analyses and spectral data

632 JOURNAL OF CHEMICAL RESEARCH 2009
Ph
NC
NC
N
Ph
N
Br
N
O
20
Ar
EtO2C
N
EtO2C
19
20a: Ar = C6H5
Ph
Ph
CN
O
20b: Ar = p-CH3C6H4
N
Ar
N
H
CN
N
EtO2C
EtONa / EtOH
N
CN
Ph
Ph
10
N
N
N
N
PhNCS
KOH
NH2
21
Ar
Ph
CN
CN
Ph
CN
MeI
NH2NH2
CN
N
S K
NHPh
Ph
N
N
SMe
Ph
N
O
12
O
NHPh
Ph
15
4a,b
CN
O
CN
Ph
CN
O
H
N
NC
O
N
CN
Ph
Ph
NH2
Ph
N
N
N
S
Ph
NHPh
N
N
16
NH
HN
N
13
Ph
H2N
Ph
CN
NH
Ar
- H2O
CN
- PhNH2
CN
N
N
Ph
N
Ph
Ph
NC
O
NHPh
O
CN
18
CN
Ph
Ph
N
N
S
Ph
Ph
N
N
N
N
O
N
N
HN
N
NHPh
17
Ar
14
14a: Ar = C6H5
14b: Ar = p-CH3C6H4
Scheme 2
n
max cm-1 2228 (C≡N), 1700 (C=O); 1H NMR (DMSO-d6) d 4.07 (s,
4-Cyano-a-oxo-N,1,5-triphenyl-1H-pyrazole-3-ethanehy-drazonoyl
bromide (4a): Yield (65%); m.p. 176–178°C; IR (KBr) nmax cm-1
6H, 2CH3), 5.91 (s, 2H, CH2), 7.33–7.50 (m, 10H, ArHs); 13C NMR
(DMSO-d6) d 64.8, 86.5, 112.8, 125.7, 125.9, 126.0, 128.9, 129.3,
129.6, 130.6, 137.8, 148.3, 150.4, 189.9. Anal. for C20H18BrN3SO
Calcd C, 56.08; H, 4.24; N, 9.81; S, 7.49. Found: C, 56.20; H, 4.35;
N, 9.8; S, 7.31%.
1
3209 (NH), 2237 (C≡N), 1651 (C=O), 1543 (C=N) cm–1; H NMR
(CDCl3) d 7.11–7.40 (m, 15H, ArH), 8.80 (br.s, 1H, NH); m/z 470
(M+). C24H16BrN5O Calcd. C, 61.29; H, 4.43; N, 14.89. Found: C,
61.33; H, 4.56; N, 14.92%.
4-Cyano-a-oxo-1,5-diphenyl-N-aryl-1H-pyrazol-3-ethane-hydrazonoyl
bromides 4a,b: To a solution of the sulfonium bromide 2 (12.85 g,
30 mmol) in ethanol (50 mL) was added sodium acetate trihydrate
(5 g) and the reaction mixture was cooled at 0°C then treated with
the appropriate arene diazonium chloride (30 mmol) with stirring
over a period of 30 min. After the addition was complete, the reaction
mixture was stirred for further 3 h at 0–5°C and left to stand in an
ice box for 12 h then diluted with water. The solid that precipitated
was filtered off, washed with water and dried. Recrystallisation from
acetic acid afforded the corresponding hydrozonoyl bromides 4a,b in
65 and 70% yields, respectively.
4-Cyano-a-oxo-N-(4-tolyl)-1,5-diphenyl-1H-pyrazole-3-ethane-
hydrazonoyl bromide (4b): Yield (10.16 g, 70%); m.p. 220–222°C;
1
IR (KBr) nmax cm-1 3237 (NH), 2230 (C≡N), 1651 (C=O). H NMR
(CDCl3) d 2.23 (s, 3H, CH3), 7.01–7.32 (m, 14H, ArHs), 8.71 (s, br,
1H, NH); m/z 484 (M+). Anal. for C25H18BrN5O Calcd C, 61.99; H,
3.75; N, 14.46. Found: C, 62.11; H, 3.84; N, 14.37%.
Reaction of the hydrazonoyl bromides 4a,b with the active methylenes
5, 8 and 10
The appropriate active methylene compound (acetylacetone 5a,
dibenzoylmethane 5b, benzoylacetonitrile 8 or cyanoacetylpyrazole 10)
H
Ph
Ph
Ph
N
NH2
CN
CN
O
N
N
N
Ph
N
N
N
Br
HN
N
1
22
Scheme 3

JOURNAL OF CHEMICAL RESEARCH 2009 633
1
(2 mmol) was added to an ethanolic sodium ethoxide solution [prepared
from sodium metal (46 mg, 2 mmol) and absolute ethanol (20 mL)] with
stirring. After stirring for 15 min, the appropriate hydrazonoyl bromide
4a,b (2 mmol) was added portion-wise to the resulting solution over a
period of 30 min. and the reaction mixture was left to stir for further
12 h at room temperature. The solid product that formed was filtered
off, washed with water and dried. Recrystallisation from ethanol/DMF
mixture afforded the pyrazole derivatives 6a,b, 6c,d, 9a,b, and 11a,b,
respectively in 70–95% yields.
3-(4-Acetyl-1-phenyl-5-methyl-1H-pyrazol-3-carbonyl)-1,5-diphenyl-
1H-pyrazole-4-carbonitrile (6a): Yield (0.67 g, 71%); m.p. 198–
199°C; IR (KBr) nmax cm-1 2230 (C≡N), 1682, 1651 (2C=O).
1H NMR (DMSO-d6) d 2.45 (s, 3H, CH3), 3.31 (s, 3H, CH3), 7.34–
7.62 (m, 15H, ArHs); m/z 471 (M+). Anal. for C29H21N5O2 Calcd C,
73.87; H, 4.49; N, 14.85. Found: C, 73.90; H, 4.30; N, 14.98%.
3-(4-Acetyl-5-methyl-1-(p-tolyl)-1H-pyrazol-3-carbonyl)-1,5-
diphenyl-1H-pyrazole-4-carbonitrile (6b): Yield (0.73 g, 75%);
m.p. 204–206°C; IR (KBr) nmax cm-1 2229 (C≡N), 1685, 1650
(2C=O). 1H NMR (DMSO-d6) d 2.38 (s, 3H, CH3), 2.42 (s, 3H, CH3),
2.47 (s, 3H, CH3), 7.40–7.48 (m, 14H, ArHs); m/z 485 (M+). Anal. for
C30H23N5O2 Calcd C, 74.21; H, 4.77; N, 14.42. Found: C, 74.05; H,
4.82; N, 14.58%.
IR (KBr) nmax cm-1 2230 (C≡N); H NMR (DMSO-d6) d 7.01–7.39
(m, 6H, ArHs), 7.45–7.52 (m, 19H, ArHs); m/z 591 (M+). Anal.
for C39H25N7: Calcd C, 79.17; H, 4.26; N, 16.57. Found: C, 80.01;
H, 4.33; N, 16.79%.
7-(4-Cyano-1,5-diphenyl-1H-pyrazol-3-yl)-3,4-diphenyl-2-
(p-tolyl)-2H-pyrazolo[3,4-d]pyridazine (7d): Yield (0.57 g, 95%);
m.p. > 300°C; IR (KBr) nmax cm-1 2230 (C≡N); H NMR (DMSO-
1
d6) d 2.30 (s, 3H, CH3), 7.07–7.52 (m, 24H, ArHs); m/z 605 (M+).
Anal. for C40H27N7: Calcd C, 79.32 H, 4.49 N, 16.19. Found: C, 79.4;
H, 4.5; N, 16.05%.
Synthesis of 1,3,4-thiadiazole derivatives 14a,b
To a stirred solution of potassium hydroxide (0.11 g, 2 mmol) in
dimethylformamide (20 mL) was added the cyanoacetylpyrazole 10
(0.6 g, 2 mmol). After stirring for 30 minutes, phenyl isothiocyanate
(0.27 g, 2 mmol) was added to the resulting mixture. Stirring was
continued for 6 h, then the appropriate hydrazonoyl bromide 4
(2 mmol) was added. The mixture was stirred for further 12 h at room
temperature. The solid product was filtered off, washed with ethanol
and recrystallised from DMF to afford the corresponding 1,3,4-
thiadiazole derivatives 14a,b.
5-(4-Cyano-1,5-diphenyl-1H-pyrazole-3-carbonyl)-2-(4-cyano-
1,5-diphenyl-1H-pyrazole-3-carbonyl)-3-phenylcyanomethylene-
2,3-dihydro[1,3,4]thiadiazole (14a): Yield (1.11 g, 75%); m.p.
290–292°C; IR (KBr) nmax cm-1 2235, 2205 (C≡N), 1674 (C=O);
1H NMR (DMSO-d6) d 7.27–7.80 (m, ArHs); m/z 743 (M+). Anal. for
C44H25N9O2S Calcd C, 71.05; H, 3.39; N, 16.95; S, 4.31. Found: C,
71.23; H, 3.41; N, 17.01; S, 4.43%.
5-(4-Cyano-1,5-diphenyl-1H-pyrazole-3-carbonyl)-2-(4-cyano-
1,5-diphenyl-1H-pyrazole-3-carbonyl)-3-(p-tolyl)cyanomethylene-
2,3-dihydro[1,3,4]thiadiazole (14b): Yield (1.2 g, 79%); m.p. 286–
288°C; IR (KBr) nmax cm-1 2235, 2208 (3 C≡N), 1678 (2 C=O).
1H NMR (DMSO-d6) d 2.99 (s, 3H, CH3), 7.15–7.67 (m, 24H, ArHs);
m/z 757 (M+). Anal. for C45H 27N9O2S: Calcd C, 71.32; H, 3.59; N,
16.63; S, 4.23. Found: C, 71.40; H, 3.68; N, 16.52; S, 4.19%.
3-(4-Benzoyl-1,5-diphenyl-1H-pyrazole-3-carbonyl)-1,5-diphenyl-
1H-pyrazole-4-carbonitrile (6c): Yield (1.01 g, 85%); m.p. 232–
234°C; IR (KBr) nmax cm-1 2230 (C≡N), 1690, 1651 (2C=O).
1H NMR (DMSO-d6) d 7.17–7.66 (m, ArHs); m/z 595 (M+). Anal. for
C39H25N5O2: Calcd C, 78.64; H, 4.23; N, 11.76. Found: C, 78.77; H,
4.41; N, 11.60%.
3-(4-Benzoyl-1-(p-tolyl)-5-phenyl-1H-pyrazole-3-carbonyl)-1,5-
diphenyl-1H-pyrazole-4-carbonitrile (6d): Yield (1.15 g, 95%);
m.p. 240–242°C; IR (KBr) nmax cm-1 2237 (C≡N), 1690, 1659
1
(2C=O); H NMR (DMSO-d6) d 2.32 (s, 3H, CH3), 7.17–7.65 (m,
24H, ArHs); m/z 609 (M+). Anal. for C40H27N5O2 Calcd C, 78.80; H,
4.46; N, 11.49. Found: C, 78.92; H, 4.52; N, 11.36%.
3-(4-Cyano-1,5-diphenyl-1H-pyrazole-3-carbonyl)-1,5-diphenyl-
1H-pyrazole-4-carbonitrile (9a): Yield (0.74 g, 72%); m.p. 260–262°C;
1
IR (KBr) nmax cm-1 2230 (2C≡N), 1655 (C=O); H NMR (DMSO)
2-(2-Cyano-3-methylthio-3-phenylaminoacryloyl)-1,5-diphenyl-1H-
pyrazole-4-carbonitrile (15)
d 7.23–7.51 (m, ArH); m/z 516 (M+). Anal. for C33H20N6O Calcd C,
76.73; H, 3.90; N, 16.27. Found: C, 76.86; H, 4.14; N, 16.44%.
3-(4-Cyano-1-(p-tolyl)-5-phenyl-1H-pyrazole-3-carbonyl)-1,5-
diphenyl-1H-pyrazole-4-carbonitrile (9b): Yield (0.8 g, 76%);
m.p. 270–272°C; IR (KBr) nmax cm-1 2228 (2C≡N), 1659 (C=O);
1H NMR (DMSO) d 2.32 (s, 3H, CH3), 7.25–7.53 (m, 19H, ArH);
m/z 530 (M+). Anal. for C34H22N6O Calcd C, 76.97; H, 4.18; N,
15.84. Found: C, 77.01; H, 4.33; N, 15.94%.
To a stirred solution of potassium hydroxide (0.56 g, 10 mmol) in
dimethylformamide(30mL),cyanoacetylpyrazole10(3.12g,10mmol)
was added. After stirring for 30 min, phenyl isothiocyanate (1.35 g,
10 mmol) was added to the resulting mixture and stirring was
continued for 2 h at room temperature. To the resulting mixture,
methyl iodide (1.41 g, 10 mmol) was added and the mixture was left
to stir for further 6 h till all the starting materials were completely
consumed. The precipitated solid was filtered off, washed with water,
dried and finally recrystallised from ethanol to afford 3.95 g of 15
(86% yield); m.p. 210–212°C; IR (KBr) nmax cm-1 3340 (NH), 2230,
2199 (2 C≡N), 1710 (C=O); 1H NMR (DMSO-d6) d 2.25 (s, 3H,
SCH3), 7.27–7.33 (m, 15H, ArH), 13.71 (br.s, 1H, D2O-exchangeable,
NH); m/z 461 (M+). Anal. for C27H19N5OS Calcd. C, 70.26; H, 4.15;
N, 15.17; S, 6.95. Found: C, 70.39; H, 4.04; N, 15.35; S, 7.18%.
3'-(4-Cyano-1,5-diphenyl-1H-pyrazole-3-carbonyl)-1,5,1'-
triphenyl-1H,1'H-3,5'-bipyrazolyl-4,4'-dicarbonitrile (11a): Yield
(0.92 g, 72%); m.p. 293–295°C. IR: nmax cm-1 2231, 2222 (3≡N),
1
1643 (C=O). H NMR (DMSO-d6) d 7.33–7.53 (m, ArHs); m/z 683
(M+). Anal. for C43H25N9O Calcd C, 75.54; H, 3.69; N, 18.44. Found:
C, 75.43; H, 3.84; N, 18.66%.
3'-(4-Cyano-1,5-diphenyl-1H-pyrazole-3-carbonyl)-1,5-diphenyl-
1'-(p-tolyl)-1H,1'H-[3,5']bipyrazolyl-4,4'-dicarbonitrile (11b): Yield
(0.99 g, 71%); m.p. 265–267°C; IR (KBr) nmax cm-1 2230, 2223
(2 C≡N), 1659 (C=O); 1H NMR (DMSO-d6) d 2.38 (s, 3H, CH3),
7.29-7.52 (m, 24H, ArHs); m/z 697 (M+). Anal. for C44H27N9O: Calcd
C, 75.74; H, 3.90; N, 18.07. Found: C, 75.82; H, 4.01; N, 18.25%.
Synthesis of 1,5-diphenyl-5'-phenylamino-1H,2'H-3,3'-bipyrazol-
4,4'-dicarbonitrile (17)
To a solution of 15 (0.92 g, 2 mmol) in ethanol (20 mL), hydrazine
hydrate (80%, 0.2 mL) was added. The mixture was refluxed for
4 h, then allowed to cool to room temperature. The solid product
that formed was filtered off, washed with ethanol and dried.
Recrystallisation from ethanol/DMF mixture afforded 0.74 g of
17 (87% yield); m.p. 278–280°C; IR (KBr) nmax cm-1 3294, 3240
(2 NH), 2232, 2222 (2 C≡N); 1H NMR (DMSO-d6) d 7.39–7.51 (m,
15H, ArH), 9.24 (br.s, 1H, D2O-exchangeable, NH), 9.67 (br.s, 1H,
D2O-exchangeable, NH); m/z 427 (M+). Anal. for C26H17N7 Calcd C,
73.05; H, 4.01; N, 22.94. Found: C, 72.90; H, 4.28; N, 23.22%.
Synthesis of pyrazolo[3,4-d]pyridazine derivatives 7a–d.
A mixture of the appropriate pyrazole derivative 6a–d (1 mmol) and
hydrazine hydrate (0.4 mL, 80%), in ethanol (20 mL) was refluxed for
1 h, then allowed to cool. The solid product that formed was collected
by filtration, washed with water, dried and finally recrystallised from
ethanol/DMF mixture to afford the pyrazolo[3,4-d]-pyridazines 7a–
d, respectively in 75-97% yields.
7-(4-Cyano-1,5-diphenyl-1H-pyrazol-3-yl)-3,4-dimethyl-2-phenyl-
2H-pyrazolo[3,4-d]-pyridazine (7a): Yield (0.35 g, 76%); m.p. 275–
1
277°C. IR: nmax cm-1 2230 (C≡N). H NMR (DMSO-d6) d 2.80 (s,
Synthesis of 1'-acetyl-1,5-diphenyl-1H,1'H[3,5']bipyrazolyl-4,4'-
dicarbonitriles 20
3H, CH3), 2.98 (s, 3H, CH3), 7.40–7.69 (m, 15H, ArHs); m/z 467
(M+). Anal. for C29H21N7 Calcd C, 74.50; H, 4.53; N, 20.97. Found:
C, 74.71; H, 4.43; N, 21.07%.
General procedure: To an ethanolic sodium ethoxide solution
[prepared by dissolving sodium metal (0.046 g, 2 mmol) in absolute
ethanol (20 mL)] was added cyanoacetylpyrazole 10 (0.62 g, 2 mmol)
with stirring. To the resulting solution, the appropriate hydrazonoyl
chloride 19a,b (2 mmol) was added portionwise with stirring over
a period of 30 min. The reaction mixture was left to stir for further
12 h at room temperature. The resulting solid product was filtered
off, washed with water, dried and finally recrystallisation from
DMF/ethanol mixture (1:1) to afford the corresponding bipyrazole
derivatives 20a,b in good yields.
7-(4-Cyano-1,5-diphenyl-1H-pyrazol-3-yl)-3,4-dimethyl-2-
(p-tolyl)-2H-pyrazolo[3,4-d] pyridazine (7b): Yield (79%); m.p. 297–
299°C; IR (KBr) nmax cm-1 2230 (C≡N); 1H NMR (DMSO-d6) d 2.78
(s, 3H, CH3), 2.97 (s, 3H, CH3), 3.28 (s, 3H, CH3), 7.43–7.56 (m,
14H, ArHs); m/z 481 (M+). Anal. for C30H23N7 Calcd C, 74.83; H,
4.81; N, 20.36. Found: C, 75.04; H, 4.73; N, 20.59%.
7-(4-Cyano-1,5-diphenyl-1H-pyrazol-3-yl)-2,3,4-triphenyl-2H-
pyrazolo[3,4-d]pyridazine (7c): Yield (0.53 g, 90%); m.p. > 300°C;

634 JOURNAL OF CHEMICAL RESEARCH 2009
3
4
5
6
7
8
9
F. Manna, F. Chimenti, A. Bolasco, M.L. Cenicola and M.D. Amico, Eur.
J. Med. Chem. Chim. Ther., 1992, 27, 633.
O. Bruno, A. Ranise, F. Bondavalli, P. Schenone, M. D'Amico,
A. Filippelli, W. Felippelli and S. Rossi, Farmaco, 1993, 48, 949.
A.M. Cuadro, J. Elguero and P. Navarro, Chem. Pharm. Bull., 1985, 33,
2535.
Ethyl 4-cyano-5-(4-cyano-1,5-diphenyl-1H-pyrazol-3-yl)-1-phenyl-
1H-pyrazol-3-carboxylate (20a): Yield (65%); m.p. 221–223°C;
IR(KBr)nmax cm-1 2233,2185(2C≡N),1720(C=O);1HNMR(DMSO-
d6) d 1.36 (t, 3H, CH3, J = 7.2 Hz), 4.44 (q, 2H, CH2, J = 7.2 Hz),
7.23–7.31 (m, 3H, ArH), 7.32-7.56 (m, 12H, ArH); 13C NMR
(DMSO) d 13.4, 61.8, 93.9, 96.5, 111.3, 111.5, 125.1, 125.2, 128.8,
129.1, 129.3, 129.7, 130.5, 137.4, 139.1, 139.4, 144.6, 146.6, 146.8,
149.3, 158.8; m/z 484 (M+). Anal. for C29H20N6O2 Calcd C, 71.89; H,
4.16; N, 17.35. Found: C, 71.65; H, 4.03; N, 17.12%.
Ethyl 4-cyano-5-(4-cyano-1,5-diphenyl-1H-pyrazol-3-yl)-1-(p-tolyl)-
1H-pyrazole-3-carboxylate (20b): Yield (66%); m.p. 208–210°C;
IR (KBr) nmax cm-1 2235, 2189 (2 C≡N), 1743 (C=O); 1H NMR
(DMSO-d6) d 1.35 (t, 3H, CH2CH3, J = 7.2 Hz), 2.38 (s, 3H, CH3),
4.44 (q, 2H, CH2CH3, J = 7.2 Hz), 7.25–7.50 (m, 14H, ArH); m/z
498 (M+). Anal. for C30H22N6O2 Calcd C, 72.28; H, 4.45; N, 16.86.
Found: C, 72.49; H, 4.33; N, 16.78%.
K.M. Dawood, H. Abdel-Gawad E.A. Ragab, M. Ellithey and
H.A. Mohamed, Bioorg. Med. Chem., 2006, 14, 3672.
S. Schenone, O. Bruno, A. Ranise, F. Bondavalli, W. Filippelli, G. Falcone,
L. Giordano and M.R. Vitelli, Bioorg. Med. Chem., 2001, 9, 2149.
M.A. Ilies, B. Masereel, S. Rolin, A. Scozzafava, G. Campeanu,
V. Cimpeanu and C.T. Supuran, Bioorg. Med. Chem., 2004, 12, 2717.
H.N. Dogan, A. Duran, S. Rollas, G. Sener, M.K. Uysal and D. Gulen,
Bioorg. Med. Chem., 2002, 10, 2893.
10 S. Sharma, F. Athar, M.R. Maurya and A. Azam, Eur. J. Med. Chem.,
2005, 40, 1414.
11 A.A. Fadda, E. Abdel-Latif and R.E. El-Mekawy, Eur. J. Med. Chem.,
2009, 44, 1250.
12 A.D. Pillai, P.D. Rathod, F.P. Xavier, H. Padh, V. Sudarsanam and
K.K. Vasu, Bioorg. Med. Chem., 2005, 13, 6685.
13 P.R. Kumar, S Raju, P.S. Goud, M Sailaja, M.R. Sarma, G. Om Reddy,
M.P. Kumar, V.V.R.M.K. Reddy, T Suresh and P. Hegde, Bioorg. Med.
Chem., 2004, 12, 1221.
14 A.S. Shawali and M.A. Abdalla, Adv. Heterocycl. Chem., 1995, 63, 277.
15 K.M. Dawood, E.A. Ragab and S.N. Mohamed, Z. Naturforschung,, 2009,
64B, 43.
16 N.A. Kheder, E.S. Darwish and K.M. Dawood, Heterocycles, 2009, 78,
177.
17 A.M. Farag, A.S. Mayhoub, S.E. Barakat and A.H. Bayomi, Bioorg. Med.
Chem., 2008, 16, 881.
Reaction of bromoacetylpyrazole 1 with 2-aminobenzimidazole
A mixture of 3-bromoacetylpyrazole 1 (0.73 g, 2 mmol) and
2-aminobenzimidazole (0.29 g, 2.2 mmol) in ethanol (20 mL) was
refluxed for 3 h, then allowed to cool. The solid that formed was
filtered off, washed with water and dried. Recrystallisation from
dimethylformamide afforded 2-(4-cyano-1,5-diphenyl-1H-pyrazol-
3-yl)-1H-imidazo[1,2-a]benzimidazole (22). Yield (76%); m.p. 270–
272°C; IR (KBr) nmax cm-1 3387 (NH), 2230 (C≡N); 1H NMR
(DMSO-d6) d 6.0 (s, 1H, pyrazole-CH), 7.27–7.67 (m, 13H, ArHs),
8.0 (d, 1H, ArH, J = 7.8 Hz), 8.43 (br.s, 1H, NH); m/z 400 (M+). Anal.
for C25H16N6 Calcd C, 74.99; H, 4.03; N, 20.99. Found: C, 75.14; H,
3.88; N, 20.80%.
18 A.M. Farag, A.S. Mayhoub, S.E. Barakat and A.H. Bayomi, Bioorg. Med.
Chem., 2008, 16, 4569.
19 K.M. Dawood and M.A. Raslan, J. Heterocycl. Chem., 2008, 45, 137.
20 K.M. Dawood, H. Abdel-Gawad, M. Ellithey, H.A. Mohamed and
B. Hegazi, Arch. Pharm. Chem. Life Sci., 2006, 339, 133.
21 K.M. Dawood, J. Heterocycl. Chem., 2005, 42, 221.
22 K.M. Dawood, Tetrahedron, 2005, 61, 5229.
23 K.M. Dawood, E.A. Ragab and A.M. Farag, J. Chem. Res., 2003, (S) 685
(M) 1151.
Received 31 July 2009; accepted 10 September 2009
Paper 09/0716 doi: 10.3184/030823409X12528547964044
Published online: 9 October 2009
24 K.M. Dawood, A.M. Farag and E.A. Ragab, J. Chin. Chem. Soc., 2004,
51, 853.
25 Z.E. Kandeel, K.M. Dawood, E.A. Ragab and A.M. Farag. Heteroatom
Chem., 2002, 13, 248.
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