Synthesis and antimicrobial activity of some new pyrazoles, fused pyrazolo[3,4-d]-pyrimidine and 1,2-dihydroimidazo-[2,1-c][1,2,4]triazin-6-one derivatives

Article abstract of DOI:10.3390/molecules16086549

A novel series of 7,7-diphenyl-1,2-dihydroimidazo[2,1-c][1,2,4]triazin- 6(7H)- one 6a-h, were easily prepared via reactions of novel 2-hydrazinyl-4,4-diphenyl-1Himidazol- 5(4H)-one (2) with hydrazonoyl halides 3a-h. In addition, we also examined the react

Full text of DOI:10.3390/molecules16086549

Molecules 2011, 16, 6549-6560; doi:10.3390/molecules16086549
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Antimicrobial Activity of Some New Pyrazoles,
Fused Pyrazolo[3,4-d]-pyrimidine and
1,2-Dihydroimidazo-[2,1-c][1,2,4]triazin-6-one Derivatives
Sobhi Mohamed Gomha * and Huwaida M.E. Hassaneen
Department of Chemistry, Faculty of Science, University of Cairo, Giza 12613, Egypt;
E-Mail: huwaidahassaneen@hotmail.com (H.M.E.H.)
* Author to whom correspondence should be addressed; E-Mail: s.m.gomha@hotmail.com.
Received: 6 July 2011; in revised form: 25 July 2011 / Accepted: 28 July 2011 /
Published: 4 August 2011
Abstract: A novel series of 7,7-diphenyl-1,2-dihydroimidazo[2,1-c][1,2,4]triazin-6(7H)-
one 6a–h, were easily prepared via reactions of novel 2-hydrazinyl-4,4-diphenyl-1H-
imidazol-5(4H)-one (2) with hydrazonoyl halides 3a–h. In addition, we also examined the
reaction of compound 2 with commercially available active methylene compounds to
afford new pyrazoles containing an imidazolone moiety, expected to be biologically active.
The structures of the synthesized compounds were assigned on the basis of elemental
analysis, IR, 1H-NMR and mass spectral data. The antifungal and antibacterial activities of
the newly synthesized compounds were evaluated.
Keywords: 2-hydrazinyl-5-imidazolone; hydrazonoyl halides; imidazo[2,1-c][1,2,4]triazinone;
pyrazolo[3,4-d]pyrimidinone; pyrazoles; antimicrobial activity
1. Introduction
Imidazoles are reported to have broad biological activities [1-4]. On the other hand, over the past
two decades; pyrazole-containing compounds have received considerable attention owing to their
diverse chemotherapeutic potential, including antineoplastic activities. Our literature survey revealed that
some pyrazoles have been implemented as antileukemic [5,6], antitumor [7,8] and anti-proliferative [9]
agents, in addition to their capability to exert remarkable anticancer effects through inhibiting different
types of enzymes that play important roles in cell division [10]. Moreover, they have emerged as

Molecules 2011, 16
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analgesic and anti-inflammatory drugs [11,12]. The synthesis of pyrazolo[3,4-d]-pyrimidine derivatives
has also received significant attention in recent years because of their wide range of biological and
pharmaceutical properties such as antitumor and antileukemia activity [13], anti-mycobacterial [14]
and antidiabetic [15-17] agents, kinase [18,19] and phosphodiesterase [20] inhibitors, and also for their
valuable antiangiogenic [21], fungicidal [22], cytotoxic [23] antitubercular [24], antimicrobial [25],
potent antiproliferative agent [26] and anthelmintic [27] activities. In view of the above mentioned
findings and as continuation of our effort [28-31] to identify new candidates that may be of value in
designing new, potent, selective and less toxic antimicrobial agents, we report in the present work the
synthesis of some new pyrazoles, pyrazolo[3,4-d]pyrimidine- and imidazo[2,1-c][1,2,4]triazinone
derivatives starting from 2-hydrazinyl-4,4-diphenyl-1H-imidazol-5(4H)-one in order to investigate
their antimicrobial activity.
2. Results and Discussion
The required starting material 2-hydrazinyl-4,4-diphenyl-1H-imidazol-5(4H)-one (2) was prepared
by reacting 5,5-diphenyl-2-thioxoimidazolidin-4-one (1) [32] with hydrazine hydrate in EtOH under
reflux for 25 h (Scheme 1). The structure of 2 was elucidated on the basis of spectroscopic data and
microanalysis. For example, its mass spectrum showed the correct molecular ion peak as a base peak.
The IR spectrum of revealed typical absorption bands at 3440, 3324, 3228, 3166, 1724 cm−1 assignable
to NH2, 2NH, and C=O moieties, respectively. The 1H-NMR spectrum showed a characteristic singlet
signal at δ 2.10, assigned to the NH2 group.
Scheme 1. Synthesis of 3,4-disubstituted 7,7-diphenyl-1,2-dihydroimidazo[2,1-c]-
[1,2,4]triazin-6(7H)-ones 6a–h.
X
H
N
H
N
H
O
O
O
R
O
N
RCO
NNHAr
NH2NH2 \ EtOH
NHNH2
NHNH
3a-h
S
Ph
Ph
Ph
Ph
Ph
NNHAr
N
N
N
TEA / dioxane
Ph
H
4
2
1
HO
H
N
R
O
O
R
N=N-Ar
N
NHNH
Ph
Ph
- H2O
Ph
Ph
N=N-Ar
N
NH
X
N
N
H
5
6a-h
H
N
N
6a: R = CH3, Ar = C6H5, X = Cl
NH
6b: R = CH3, Ar = 4-CH3C6H4, X = Cl
6c: R = CH3, Ar = 4-ClC6H4, X = Cl
O
N
R = CH , Ar = 4-CH OC H , X = Cl
N=N-Ar
6d:
3
3
6 4
: R = CH , Ar = 4-NO C H , X = Cl
6e
6f
3
2
6
4
R
Ph
: R = Ph, Ar = C H , X = Br
Ph
6
5
:
6g R = Ph, Ar = 4-CH3C6H4, X = Br
6h: R = Ph, Ar = 4-ClC6H4, X = Br
7a-h

Molecules 2011, 16
6551
Reaction of 2 with hydrazonoyl halides 3a–h was carried in EtOH in the presence of triethylamine
(TEA) and gave the corresponding substituted 7,7-diphenyl-3-(phenyldiazenyl)-1,2-dihydroimidazo[2,1-c]
[1,2,4]triazin-6(7H)-ones 6a–h rather than the isomeric 4-substituted-6,6-diphenyl-3-(phenyldiazenyl)-
1,2-dihydroimidazo[2,1-c][1,2,4]triazin-7(6H)-ones 7a–h (Scheme 1).
The structural elucidation of compounds 6a–h was based on spectral evidence and microanalytical
data. The mass spectra of them showed the molecular ion peaks at the expected m/z values. Their IR
spectra indicated the disappearance of the NH2 group, and revealed in each case a C=O band in the
region 1734–1710 cm−1 and two bands at 3430–3220 cm−1 assignable to 2NH groups. Also, their 1H-NMR
spectra showed the presence of two signals for two NH groups at δ = 8.28–8.41 and 9.28–9.36 ppm.
13
These two signals disappeared upon exchange with deuterium oxide. The C-NMR spectrum of 6a,
taken as an example for the series of compounds 6, revealed a signal for the C=O group at δ = 166.7 ppm.
This chemical shift value suggested that the N-1 near C=O is sp3 hybridized nitrogen atom pyrrole
type, similar to that of compounds of type A (δ 164–167) and different from the sp2 hybridized
nitrogen that of their isomers having structure B (δ 170–175) ppm (Figure 1). Based on the above
finding we conclude that the isolated products have structures 6 and not the isomeric structure 7.
Figure 1. Comparison of C=O shifts with an N-atom in different bonding states next to C=O.
170 -175
166.7
O
O
164 -167
N
N=NPh
R
O
N
6
Ph
Ph
N
R
NH
N
X
N
N
R
X
H
N
R
A
B
Finally, the suggestion that the site of cyclization of the intermediates 4 involves N-1 to give 6 is
consistent with literature reports [33]. Our study was extended to the reaction of 2 with a variety of
active methylene compounds, namely acetyl acetone (8), ethyl acetoacetate (9), diethyl malonate (10)
and malononitrile (11) in order to synthesize compounds 12–15, respectively (Scheme 2). These
compounds have a pyrazole moiety and were anticipated to be biologically active. The structures of 12–15
were confirmed on the basis of spectroscopic data and elemental analyses (see Experimental section).
In addition, reaction of the hydrazine derivative 2 with acetophenone (16) gave the hydrazone 19,
which was converted further into the 1-(imidazol-2-yl) pyrazole-4-carbaldehyde 20 by treatment with
Vilsmeier-Haack reagent (prepared by dropwise addition of phosphorus oxychloride in ice cooled
1
DMF) [34]. The structure of the isolated aldehyde was confirmed on the basis of MS, IR, H-NMR
spectra and elemental analysis. For example, the IR spectrum revealed absorption bands at 1681, 1724,
1
3166 cm−1 corresponding to 2 C=O and NH groups, respectively. The H-NMR spectra showed the
presence of the NH and aldehyde groups at δ = 9.33, 9.88 ppm, respectively (Scheme 3). We also
examined the reaction of 2 with ethoxymethylenemalononitrile (17). The isolated product was
identified as the pyrazole derivative 21 on the basis of its elemental analysis and spectral data (Scheme 3).
For example, the IR spectra of compounds 21 showed vCN and vCO near 2240 and 1724 cm−1,
respectively (see Experimental section). The reaction of carbonitrile 21 with formic acid gave the

Molecules 2011, 16
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corresponding 1-imidazol-2-yl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one 22. The lack of vCN in the IR
spectrum of the isolated product supported the formation of structure 22 (Scheme 3).
Scheme 2. The reactivity of 2-hydrazino-4,4-diphenyl-1H-imidazol-5(4H)-one (2) towards
active methylene reagents.
H
N
H
N
H
N
O
O
CH2(COOEt)2
10
CH3COCH2COCH3
8
Me
N
O
N
Ph
Ph
N
Ph
Ph
N
AcOH, Reflux
AcOH, Reflux
N
H
N
O
O
Me
14
12
NHNH2
Ph
Ph
N
H
Me
N
N
O
CH3COCH2COOEt
9
2
H
N
CH2(CN)2
11
NH2
N
O
N
Ph
Ph
N
N
Ph
Ph
AcOH, Reflux
O
AcOH, Reflux
N
13
NH2
15
Scheme 3. Synthesis of pyrazole derivatives from 2-hydrazino-4,4-diphenyl-1H-imidazol-
5(4H)-one (2).
O
O
PhCOCH3
16
Me
NH
CHO
Ph
Ph
NH
Ph
Ph
DMF-POCl3
N
N
Ph
N
N
N
H
Ph
N
EtOH / AcOH
20
19
O
CN
NH
H
N
N
N
EtOCH=C(CN)2
O
NH2
N
N
17
NHNH2
Formic acid
N
Ph
Ph
HN
O
EtOH
N
N
HN
N
2
Ph
Ph
O
Ph
Ph
21
22
PhCOCH=CHPh
Ph
O
N
18
NH
HA
HB
Ph
Ph
EtOH / Piperidine
N
N
Ph
HX
23
Furthermore, 1-(1H-pyrazol-1-yl)-1H-imidazol-5(4H)-one 23, was prepared by reaction of 2 with
chalcone 18 (Scheme 3). The structure of 23 was established based on its spectral data. The IR
1
spectrum showed strong bands at 1722, 3169 cm−1 for C=O and NH, respectively. Also, the H-NMR
spectra of 23 revealed no signal assignable to the NH2 group, while it revealed the presence of three
characteristic signals due to the diasterotopic H atoms of a CH2 group coupled with H atom (Hx) next
to it (HA, HB and HX). The HA proton which is cis to HX resonates upfield at δ 2.91 ppm as doublet of
doublets (dd, J = 17.2 and 6.5 Hz), while HB which is trans to HX resonates downfield at δ 4.14 ppm

Molecules 2011, 16
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(dd, J = 17.3 and 12.6 Hz). HX appeared as double of doublet at δ of 5.98 (dd, J = 12.8 and 6.5 Hz)
(see Experimental section).
Antimicrobial Activity
The compounds were tested for their activities against Gram +ve bacteria (Staphylcoccus aureus)
and Gram –ve bacteria (Escherichia coli), in addition to the pathogenic fungi Aspergillus flavus and
Candida albicans. The antimicrobial screening results were measured by the average diameter of the
inhibition zones, expressed in mm, and are depicted in Table 1. The results showed that, all the tested
compounds displayed significant activities against E. coli and S. aureus, while, only compounds 6c, 6h
and 20 were moderately active against A. flavus and C. albicans. However, the activities of the tested
compounds are much less than those of standard antifungal and antibacterial agents used.
Table 1. Antimicrobial activity of the tested compounds.
Inhibition zone diameter (mm/mg sample)
Sample No.
Fungus
C. albicans
E. coli
(G−)
22
21
14
15
18
24
16
18
12
18
14
S. aureus
(G+)
16
20
16
13
15
12
19
14
18
22
23
30
--
A. flavus
6a
6c
6f
--
10
--
9
--
--
--
--
11
--
--
--
18
--
15
--
13
--
--
--
--
14
--
--
6h
12
13
14
15
20
22
23
Tetracycline 30
Amphotricine --
--
21
* The concentration of the solution 20.0 mg/mL was tested; E. coli: Esherichia coli; G−: Gram
negative bacteria; S. aureus: Staphylococcus aureus; G+: Gram positive bacteria; A. flavus:
Aspergillus flavus; C. albicans: Candida albicans.
3. Experimental
3.1. General
All melting points were measured on Electrothermal IA 9000 series digital melting point apparatus.
The IR spectra were recorded in potassium bromide discs on a Pye Unicam SP 3300 or Shimadzu FT
IR 8101 PC infrared spectrophotometers. The NMR spectra were recorded at 270 MHz on a Varian
1
13
Mercury VX-300 NMR spectrometer. H-NMR (300 MHz) and C-NMR (75.46 MHz) were run in
deuterated chloroform (CDCl3) or dimethylsulphoxide (DMSO-d6). Chemical shifts were related to
those of the solvent. Mass spectra were recorded on a Shimadzu GCMS-QP1000 EX mass
spectrometer at 70 eV. Elemental analyses and the biological evaluation of the products were carried

Molecules 2011, 16
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out at the Microanalytical Centre of Cairo University, Giza, Egypt. All reactions were followed by
TLC (Silica gel, Aluminum Sheets 60 F254, Merck). Hydrazonoyl chlorides 3a–g [35,36] were
prepared as reported in the literature.
3.2. 2-Hydrazinyl-4,4-diphenyl-1H-imidazol-5(4H)-one (2)
To 2-thioxoimidazolidin-4-one 1 (1.0 g, 4 mmol) in dry EtOH (10 mL) was added hydrazine
hydrate (80%, 2 mL). The reaction mixture was kept under reflux for 25 h, and then cooled. The solid
which precipitated was filtered off and crystallized from DMF to give 2 in 70% yield, m.p. 354 °C; MS
m/z (%): 266 (M+, 70), 248 (45), 165 (42), 104 (35), 77 (100), 66 (33); IR (KBr): v 3440, 3324 (NH2),
1
3228, 3166 (2NH), 1724 (CO) cm−1; H-NMR (CDCl3): δ 2.10 (s, 2H, NH2), 3.57 (s, 1H, NH),
7.34–8.23 (m, 10H, Ar–H), 9.34 (s, 1H, NH); Anal. Calcd. for C15H14N4O (266.12): C, 67.65; H, 5.30;
N, 21.04%. Found: C, 67.3; H, 5.32; N, 21.21%.
3.3. 3,4-Disubstituted 7,7-diphenyl-1,2-dihydroimidazo[2,1-c][1,2,4]triazin-6(7H)-ones 6a–h
General procedure: To 2 (2.68 g, 10 mmol) and the appropriate hydrazonoyl halides 3a–h (10 mmol)
in dioxane (50 mL) was added triethylamine (1.4 mL, 10 mmol) at room temperature. The reaction
mixture was heated under reflux until all the starting material was consumed (6–10 h, monitored by
TLC). The solvent was evaporated and the residue was triturated with MeOH. The formed solid was
filtered and recrystallized from DMF to give compounds 6a–h.
4-Methyl-7,7-diphenyl-3-(phenyldiazenyl)-1,2-dihydroimidazo[2,1-c][1,2,4]triazin-6(7H)-one
(6a).
Yield 82%; red crystals (from EtOH); m.p. 152 °C; IR (KBr): v 1724 (C=O), 3425, 3259 (2NH) cm−1;
1H-NMR (DMSO-d6): δ 2.53 (s, 3H, CH3), 6.98–7.52 (m, 15H, Ar–H), 8.31 (s, 1H, NH), 9.36 (s, 1H,
13
NH); MS m/z (%): 408 (M+, 6), 248 (13), 206 (29), 165 (20), 91 (30), 77 (100), 51 (53); C-NMR
(DMSO-d6) δ ppm: 166.7 (C=O), 158.6 (C=N), 147.3, 139.8, 139.6, 133.8, 132.4, 132.1, 130.9, 130.8,
127.8, 127.1, 124.7, 121.9 (Ar–C) 118.6, 114.3 (C=C), 71.3 (Ph2C), 8.4 (CH3); Anal. Calcd for
C24H20N6O (408.17): C, 70.57; H, 4,94; N, 20.58%. Found: C, 70.54; H, 4.88; N, 20.50%.
4-Methyl-7,7-diphenyl-3-(p-tolyldiazenyl)-1,2-dihydroimidazo[2,1-c][1,2,4]triazin-6(7H)-one
(6b).
Yield 80%, red crystals (from EtOH), m.p. 164 °C; IR (KBr): v 1724 (C=O), 3425, 3257 (2NH) cm−1;
1H-NMR (DMSO-d6): δ 2.25 (s, 3H, CH3), 2.52 (s, 3H, CH3), 6.96–7.48 (m, 10H, Ar–H), 7.54 (d,
J = 7.2 Hz, 2H, Ar–H), 8.14 (d, J = 7.2 Hz, 2H, Ar–H), 8.31 (s, 1H, NH), 9.30 (s, 1H, NH); MS m/z
(%): 422 (M+, 6), 341 (72), 299 (11), 165 (66), 91 (85), 77 (100), 52 (30); Anal. Calcd for C25H22N6O
(422.19): C, 70.07; H, 5.25; N, 19.89%. Found: C, 70.04; H, 5.22; N, 19.74%.
3-[(4-Chlorophenyl)diazeny]-4-methyl-7,7-diphenyl-1,2-dihydroimidazo[2,1-c][1,2,4]triazin-6(7H)-one
(6c). Yield 85%, red crystals (from EtOH), m.p. 136 °C; IR (KBr): v 1722 C=O), 3423, 3254 (2NH)
cm−1; 1H-NMR (DMSO-d6): δ 2.53 (s, 3H, CH3), 6.99–7.53 (m, 10H, Ar–H), 7.58 (d, J = 8.4 Hz, 2H,
Ar–H), 8.22 (d, J = 8.4 Hz, 2H, Ar–H), 8.28 (s, 1H, NH), 9.30 (s, 1H, NH); MS m/z (%): 442 (M+, 26),
401 (32), 360 (19), 165 (57), 91 (13), 77 (100), 51 (60); Anal. Calcd for C24H19ClN6O (442.13): C,
65.08; H, 4.32; N, 18.97%. Found: C, 65.04; H, 4.30; N, 18.74%.

Molecules 2011, 16
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3-[(4-Methoxyphenyl)diazeny]-4-methyl-7,7-diphenyl-1,2-dihydroimidazo[2,1-c][1,2,4]triazin-6(7H)-
one (6d). Yield 79%, red crystals (from EtOH), m.p. 122 °C; IR (KBr): v 1724 (C=O), 3422, 3253
(2NH) cm−1; 1H-NMR (DMSO-d6): δ 2.51 (s, 3H, CH3), δ 3.36 (s, 3H, CH3), 6.97–7.52 (m, 10H, Ar–H),
7.58 (d, J = 8.0 Hz, 2H, Ar–H), 8.21 (d, J = 8.0 Hz, 2H, Ar–H), 8.28 (s, 1H, NH), 9.32 (s, 1H, NH);
MS m/z (%): 439 (M+, 14), 338 (28), 208 (27), 165 (100), 91 (42), 77 (100), 51 (30). Anal. Calcd for
C25H22N6O2 (438.18): C, 68.48; H, 5.06; N, 19.17%. Found: C, 68.44; H, 5.02; N, 19.12%.
4-Methyl-3-[(4-nitrophenyl)diazenyl]-7,7-diphenyl-1,2-dihydroimidazo[2,1-c][1,2,4]triazin-6(7H)-one
(6e). Yield 77%, red crystals (from EtOH), m.p. 146 °C; IR (KBr): v 1723 (C=O), 3425, 3255 (2NH)
1
cm−1; H-NMR (DMSO-d6): δ 2.5 (s, 3H, CH3), 6.97–7.55 (m, 10H, Ar–H), 7.58 (d, J = 7.2 Hz, 2H,
Ar–H), 8.24 (d, J = 7.2 Hz, 2H, Ar–H), 8.29 (s, 1H, NH), 9.36 (s, 1H, NH); MS m/z (%): 453 (M+, 15),
372 (40), 248 (23), 180 (100), 165 (32), 104 (68), 77 (76), 51 (49); Anal. Calcd for C24H19N7O3
(453.15): C, 63.57; H, 4.22; N, 21.62%. Found: C, 63.54; H, 4.20; N, 21.58%.
4,7,7-Triphenyl-3-(phenyldiazenyl)-1,2-dihydroimidazo[2,1-c][1,2,4]triazin-6(7H)-one (6f). Yield
80%, red crystals (from EtOH), m.p. 118 °C; IR (KBr): v 1732 (C=O), 3425, 3264 (2NH) cm−1;
1H-NMR (DMSO-d6): δ 6.91–7.59 (m, 20H, Ar–H), 8.41 (s, 1H, NH), 9.28 (s, 1H, NH); MS m/z (%):
13
470 (M+, 11), 326 (21), 297 (31), 165 (74), 91 (38), 76 (100), 52 (44); C-NMR (DMSO-d6) δ ppm:
166.7 (C=O), 158.2 (C=N), 147.1, 140.4, 139.3, 139.2, 133.8, 133.2, 133.0, 132.1, 130.9, 130.8, 127.8,
127.1, 124.7, 124.3, 121.1, 120.9 (Ar–C) 118, 114 (C=C), 71.3 (Ph2C); Anal. Calcd for C29H22N6O
(470.19): C, 74.03; H, 4.71; N, 17.86%. Found: C, 70.04; H, 4.58; N, 17.63%.
4,7,7-Triphenyl-3-(p-tolyldiazenyl)-1,2-dihydroimidazo[2,1-c][1,2,4]triazin-6(7H)-one (6g). Yield
78%, red crystals (from EtOH), m.p. 124 °C; IR (KBr): v 1730 (C=O), 3425, 3266 (2NH) cm−1.
1H-NMR (DMSO-d6): δ 2.27 (s, 3H, CH3), 6.94–7.55 (m, 15H, Ar–H), 7.57 (d, J = 7.2 Hz, 2H, Ar–H),
8.20 (d, J = 7.2 Hz, 2H, Ar–H), 8.40 (s, 1H, NH), 9.28 (s, 1H, NH); MS m/z (%): 484 (M+, 18), 329
(26), 284 (18), 165 (57), 91 (32), 76 (100), 52 (54); Anal. Calcd for C30H24N6O (484.20): C, 74.63; H,
4.99; N, 17.34%. Found: C, 74.71; H, 4.87; N, 17.21%.
3-[(4-Chlorophenyl)diazenyl]-4,7,7-triphenyl-1,2-dihydroimidazo[2,1-c][1,2,4]triazin-6(7H)-one (6h).
Yield 81%, red crystals (from EtOH), m.p. 142 °C; IR (KBr): v 1732 (C=O), 3424, 3246 (2NH) cm−1;
1H-NMR (DMSO-d6): δ 6.94–7.55 (m, 15H, Ar–H), 7.64 (d, J = 8.1 Hz, 2H, Ar–H), 8.24 (d, J = 8.1 Hz,
2H, Ar–H), 8.41 (s, 1H, NH), 9.31 (s, 1H, NH); MS m/z (%): 504 (M+, 18), 326 (25), 165 (100), 91
(41), 77 (65), 52 (37); Anal. Calcd for C29H21Cl N6O (504.15): C, 68.98; H, 4.19; N, 16.64%. Found:
C, 68.90; H, 4.11; N, 16.60%.
3.4. Reaction of 2 with Active Methylene Compounds
General procedure: A mixture of compound 2 (1.34 g, 5 mmol) and active methylene compound
(5 mmol) in glacial acetic acid (20 mL) was refluxed for 6 h. After cooling, the precipitate was
collected by filtration and crystallized from the appropriate solvent to afford compounds 12–15.
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-4,4-diphenyl-1H-imidazol-5(4H)-one (12). Yield 80%, Pale yellow
1
solid (from EtOH), m.p. 220 °C; IR (KBr): v 1724 (C=O), 3166 (NH) cm−1; H-NMR (DMSO-d6):

Molecules 2011, 16
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δ 2.32 (s, 3H, CH3), 2.49 (s, 3H, CH3), 6.08 (s, 1H, pyrazolyl–H), 7.12–7.98 (m, 10H, Ar–H), 9.33 (s,
1H, NH); MS m/z (%): 330 (M+, 30), 223 (41), 180 (100), 104 (51), 77 (53), 51 (49); Anal. Calcd for
C20H18ClN4O (330.15): C, 72.71; H, 5.49; N, 16.96%. Found: C, 72.68; H, 5.44; N, 16.86%.
3-Methyl-1-(5-oxo-4,4-diphenyl-4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazol-5(4H)-one (13). Yield 82%,
Pale yellow micro-crystals (from EtOH), m.p. 266 °C; IR (KBr): v 1678, 1690, 1720 (3C=O), 3169
(NH) cm−1; 1H-NMR (DMSO-d6): δ 2.41 (s, 3H, CH3), 3.52 (s, 2H, CH2), 7.12–7.96 (m, 10H, Ar–H),
9.33 (s, 1H, NH); MS m/z (%): 332 (M+, 22), 223 (41), 180 (100), 104 (47), 77 (33), 51 (58); Anal.
Calcd for C19H16Cl N4O2 (332.13): C, 68.66; H, 4.85; N, 16.86%. Found: C, 68.85; H, 4.79; N, 16.61%.
1-(4-Oxo-4,4-diphenyl-4,5-dihydro-1H-imidazol-2-yl)pyrazolidine-3,5-dione (14). Yield 74%, yellow
crystals (from EtOH-dioxane), m.p.292 °C; IR (KBr): v 1679, 1690, 1724 (3C=O), 3166, 3210 (2NH)
1
cm−1; H-NMR (DMSO-d6): δ 4.82 (s, 2H, CH2), 7.12–7.98 (m, 10H, Ar–H), 9.33 (s, 1H, NH), 10.64
(s, 1H, NH); MS m/z (%): 334 (M+, 23), 223 (31), 180 (64), 104 (33), 77 (100), 51 (42); Anal. Calcd
for C18H14N4O3 (334.11): C, 64.66; H, 4.22; N, 16.76%. Found: C, 64.54; H, 4.12; N, 16.69%.
2-(3,5-Diamino-1H-pyrazol-1-yl)-4,4-diphenyl-1H-imidazol-5(4H)-one (15). Yield 80%, Pale yellow
solid (from EtOH), m.p. 312 °C; IR (KBr): v 1722 (C=O), 3166 (NH), 3212–3360 (2NH2) cm−1;
1H-NMR (DMSO-d6): δ 6.01 (s, 1H, pyrazolyl–H), 6.34–6.48 (s, 4H, 2NH2), 7.12–7.98 (m, 10H, Ar–H),
9.33 (s, 1H, NH); MS m/z (%): 332 (M+, 30), 223 (41), 180 (100), 104 (51), 77 (53), 51 (49); Anal.
Calcd for C18H16N6O (332.14): C, 65.05; H, 4.85; N, 25.29%. Found: C, 65.10; H, 4.68; N, 25.21%.
Synthesis of 4,4-diphenyl-2-(2-(1-phenylethylidene)hydrazinyl)-1H-imidazol-5(4H)-one (19). A
mixture of 2 (2.68 g, 10 mmol) and acetophenone 16 (1.20 g, 10 mmol) in 20 mL absolute ethanol was
refluxed in water bath for 4 h in presence of glacial acetic acid (1 mL). The product obtained after
cooling was crystallized from absolute ethanol. Yield 80%, yellow crystals (from EtOH), m.p. 148 °C;
IR (KBr): v 1722 (C=O), 3166, 3340 (2NH) cm−1; 1H-NMR (DMSO-d6): δ 2.58 (s, 3H, CH3), 7.12–7.98
(m, 15H, Ar–H), 9.33 (s, 1H, NH), 11.60 (s, 1H, NH); MS m/z (%): 368 (M+, 23), 248 (44), 167 (37),
104 (49), 77 (75), 60 (100); Anal. Calcd for C23H20ON4O (368.16): C, 74.98; H, 5.74; N, 15.21%.
Found: C, 74.11; H, 5.67; N, 15.14%.
Synthesis
of
1-(5-oxo-4,4-diphenyl-4,5-dihydro-1H-imidazol-2-yl)-3-phenyl-1H-pyrazole-4-carb-
aldehyde (20). Dimethylformamide (2.19 g, 30 mmol) was cooled to below 5 °C and POCl3 (4.59 g,
30 mmole) was added dropwise under stirring for 30 min, to this mixture (2.68 g, 10 mmol) of
compound 2 was added. The resulting mixture was refluxed for 2 h on water-bath. The precipitate
obtained by pouring into ice-cold water was collected by filtration and recrystallized from absolute
ethanol. Yield 80%, yellow crystals (from EtOH-dioxane), m.p. 294 °C; IR (KBr): v 1681, 1724
1
(2C=O), 3166 (NH) cm−1; H-NMR (DMSO-d6): δ 7.12–7.98 (m, 16H, Ar–H and 1H, pyrazolyl–H),
9.33 (s, 1H, NH), 9.88 (s, 1H, CHO); MS m/z (%): 406 (M+, 24), 248 (44), 182 (100), 104 (98), 77
(90), 51 (66); Anal. Calcd for C25H18N4O2 (406.14): C, 73.88; H, 4.46; N, 13.78%. Found: C, 73.95; H,
4.22; N, 13.72%.

Molecules 2011, 16
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Synthesis of 5-amino-1-(5-oxo-4,4-diphenyl-4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazole-4-carbonitrile
(21). A mixture of 2 (2.64 g, 10 mmol) and ethoxymethylenemalononitrile 17 (1.22 g, 10 mmol) in
absolute ethanol (50 mL) was heated under reflux for 30 min. The solvent was evaporated under
vacuum and the residual solid was crystallized from EtOH to give 21. Yield 80%, yellow solid,
1
m.p. 228 °C; IR (KBr): v 1724 (C=O), 2240 (CN), 3168 (NH), 3294, 3382 (NH2) cm−1; H-NMR
(DMSO-d6): δ 6.68 (s, 2H, NH2), 7.12–7.98 (m, 11H, Ar–H and 1H, pyrazolyl–H), 9.33 (s, 1H, NH);
MS m/z (%): 343 (M++1, 5), 342 (M+, 14), 234 (39), 165 (68), 104 (65), 77 (100), 51 (71); Anal. Calcd
for C19H14 N6O (342.12): C, 66.66; H, 4.12; N, 24.55%. Found: C, 66.40; H, 4.12; N, 24.43%.
Synthesis of 1-(5-oxo-4,4-diphenyl-4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(7H)-
one (22). Compound 21 (10 mmol) in formic acid (20 mL, 85%) was refluxed for 3 h, cooled, poured
onto ice-water to give a precipitate, which was filtered off, dried and recrystallized from EtOH to
afford 22. Yield 80%, yellow crystals (from EtOH-dioxane), mp 284 °C; IR (KBr): v 1671, 1723
1
(2C=O), 3166, 3280 (2NH) cm−1; H-NMR (DMSO-d6): δ 7.12–7.98 (m, 12H, Ar–H and 2H,
pyrazolyl–H and pyrimidine–H), 9.33 (s, 1H, NH), 11.83 (s, 1H, NH); MS m/z (%): 470 (M+, 28), 323
(26), 208 (21), 165 (49), 93 (14), 77 (100); Anal. Calcd for C20H14N6O2 (370.12): C, 64.86; H, 3.81; N,
22.69%. Found: C, 64.60; H, 3.88; N, 22.60%.
Synthesis of 2-(3,5-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)-4,4-diphenyl-1H-imidazol-5(4H)-one (23).
A mixture of compound 2 (0.271 g, 1 mmol) and 3-(phenyl)-1-phenylprop-2-en-1-one (18, 0.238 g,
1 mmol) in acetic acid (20 mL) was refluxed for 7 h. Excess of solvent was removed under reduced
pressure and the reaction mixture was added to crushed ice. The product separated was filtered,
washed with water, dried and recrystallized from DMF. Yield 80%, yellow crystals (from EtOH-dioxane),
1
m.p.141 °C; IR (KBr): v 1722 (C=O), 3169 (NH) cm−1; H-NMR (DMSO-d6): δ 2.91 (dd, 1H, HA,
J = 17.2, 6.5 Hz), 4.14 (dd, 1H, HB, J = 17.3, 12.6 Hz), 5.98 (dd, 1H, HX, J = 12.8, 6.5 Hz), 7.12–7.98
(m, 20H, Ar–H), 9.35 (s, 1H, NH); MS m/z (%): 456 (M+, 10), 357 (12), 248 (46), 181 (73), 104 (93),
77 (76), 51 (66); Anal. Calcd for C30H24N4O (456.20): C, 78.92; H, 5.30; N, 12.27%. Found: C, 78.84;
H, 5.34; N, 12.22%.
3.5. Preliminary Antimicrobial Screening
A selection of the prepared compounds (namely 6a, 6c, 6f, 6h, 12, 13, 14, 15, 20, 22 and 23) were
screened for their antibacterial activity (in nutrient agar broth) and antifungal activity (in Dox’s
medium and Saboured’s agar) by the agar diffusion method [37,38] at a concentration 20 mg/mL using
DMSO as solvent and blank.
4. Conclusions
We have established a new and efficient synthesis of a novel series of 7,7-diphenyl-1,2-
dihydroimidazo[2,1-c][1,2,4]triazin-6(7H)-ones. We could also extend this technique to the synthesis
of new pyrazole containing imidazolone moieties. The antifungal and antibacterial activities of the
newly synthesized compounds were evaluated.

Molecules 2011, 16
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Sample Availability: Samples of the compounds 2–23 are available from the authors.
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