Applications of 2-arylhydrazononitriles in synthesis: Preparation of new indole containing 1,2,3-triazole, pyrazole and pyrazolo[1,5-a]pyrimidine derivatives and evaluation of their antimicrobial activities

Article abstract of DOI:10.1016/j.ejmech.2011.02.040

In this effort, 2-arylhdrazononitriles were used as key synthons for the preparation of wide variety of new, uniquely substituted heterocyclic substances. In addition, the results of biological evaluations demonstrate that members of the group prepared ha

Full text of DOI:10.1016/j.ejmech.2011.02.040

European Journal of Medicinal Chemistry 46 (2011) 1813e1820
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Applications of 2-arylhydrazononitriles in synthesis: Preparation of new indole
containing 1,2,3-triazole, pyrazole and pyrazolo[1,5-a]pyrimidine derivatives and
evaluation of their antimicrobial activities
,
a,
Haider Behbehani a , Hamada Mohamed Ibrahim b, Saad Makhseed a, Huda Mahmoud c
*
a Chemistry Department, Faculty of Science, Kuwait University, P.O. Box 5969, Safat 13060, Kuwait
b Chemistry Department, Faculty of Science, Fayoum University, Fayoum, Egypt
c Biology Department, Faculty of Science, Kuwait University, P.O. Box 5969, Safat 13060, Kuwait
a r t i c l e i n f o
a b s t r a c t
Article history:
In this effort, 2-arylhdrazononitriles were used as key synthons for the preparation of wide variety of
new, uniquely substituted heterocyclic substances. In addition, the results of biological evaluations
demonstrate that members of the group prepared have promising antimicrobial activities against Gram
negative bacteria, Gram positive bacteria and Yeast. In the synthetic sequences, 3-(1-methyl-1H-indol-3-
yl)-3-oxo-2-(phenylhydrazono)propanenitrile 2a and its 2-methyl derivative 2b were found to react with
hydroxylamine hydrochloride to yield the corresponding indolyl-5-amino-2-phenyl-1,2,3-triazoles 4a,b.
These amines react with cyanoacetic acid in presence of acetic anhydride either thermally or under
microwave irradiation conditions to yield the corresponding cyanoacetamides 5a,b, which condensed
readily with dimethylformamide dimethylacetal to yield the enaminonitriles 6a,b. Whereas heating of
6a,b with hydrazine hydrate affords compound 8, compound 12 is produced when these reactants are
subjected to microwave irradiation. We observed that the aminopyrazole 9 reacts with enaminal 13 to
yield 14 and that its reactions with enaminones 15 afford 17. Finally, compound 5 reacts with cinna-
maldehyde to yield the corresponding Schiff’s base 18 that does not undergo cyclization to form the
pyridine derivative 19. The activities of all new substances synthesized in this investigation were eval-
uated against a panel of microbial organisms. The results show that 4a, 4b, 5b and 9b display strong
antimicrobial activities against all of the tested organisms.
Received 28 October 2010
Received in revised form
13 February 2011
Accepted 15 February 2011
Available online 23 February 2011
Keywords:
Cyanoacetamides
5-Amino-1,2,3-triazole
Enaminonitrile
Pyridine-6-carbonitrile
Antimicrobial activity
Ó 2011 Elsevier Masson SAS. All rights reserved.
1. Introduction
synthesis and elucidate their biological activities. Below, we
describe the results of an investigation aimed at the preparation of
Owing to their interesting biological activities and medicinal
properties [1e7], indole derivatives have been targets of investi-
gations by several research groups [8e11]. Also, the 1,2,3-triazole
ring system has been the focus of numerous studies owing to its
importance in industrially interesting materials, such as dyes,
anticorrosive agents, photo stabilizers, photographic materials, and
agrochemicals [12]. Although the 1,2,3-triazole structural moiety
does not occur in nature, it may display biological activities and
there are numerous examples in the literature including anti-HIV
[13], anti-Gram positive bacterial [14,15], anti-allergic [16,17], anti-
these substances and an evaluation of their biological properties.
2. Result and discussion
2.1. Synthetic chemistry
We recently described an efficient synthesis of the cyanoacetyl-
indole derivative 1a that can be easily converted to the corre-
sponding hydrazone 2a [11], a potentially important synthon in
synthetic routes targeted at new aroyl-heteroaromatic substances.
In an extension of our previous effort leading to the synthesis of 2-
substituted-1,2,3-triazole-5-amines [11], we have utilized hydra-
zones 2a,b as precursors of new indolyl heteroaromatic substances.
The investigation aimed at this goal began with the reactions of
2a,b with hydroxylamine hydrochloride in the presence of sodium
acetate, promoted by heating in DMF solutions for 3 h or using
microwave irradiation for 60 s. Under these conditions,
convulsant [18], b-lactamase inhibitory [19], selective b3 adrenergic
receptor agonism [20], anti-tuberculosis [21] activities. The antici-
pated biological properties of interesting aroyltriazolylamines that
incorporate the indole moiety has encouraged us to explore their
* Corresponding author. Tel.: þ965 99063062; fax: þ965 24843891.
E-mail address: hbehbehani@hotmail.com (H. Behbehani).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.02.040

1814
H. Behbehani et al. / European Journal of Medicinal Chemistry 46 (2011) 1813e1820
condensation reactions occurred to produce the 2-aryl-1,2,3-tri-
Escherichia coli (Gram negative bacteria), Bacillus subtilis and
Staphylococcus aureus (Gram positive bacteria) and Candida albicans
(Yeast). An aliquot of 0.1 mL of each bacterial strain was spread on
nutrient agar while 0.1 mL of the yeast strain was spread on potato
dextrose agar (PDA). An Agar-Well diffusion test was performed in
each case, In these tests, 4 mm wells were produced by using
azole-5-amines 4a,b, as indicated by analysis of their 13C NMR
spectra which showed carbonyl carbon at d 180.34 and 183.35 ppm
respectively. It is believed that amidooximes 3 are initially formed
in these processes and that they undergo cyclization to generate
the corresponding 1,2,3-triazole-5-amines through a pathway that
has been described previously [11,22,23]. The formed 1,2,3-triazole-
5-amines 4a,b were then reacted with cyanoacetic acid in the
presence of acetic anhydride under either thermal or microwave
irradiation conditions. These reactions afford cyanoacetamides 5a,b
in excellent yields (Scheme 1).
The cyanoacetamides 5a,b react with dimethylformamide dime-
thylacetal (DMF-DMA) to yield the corresponding enamines 6a,b
(Scheme 2). Although these processes have the potential of
producing mixtures of the enamines stereoisomers 6 and 7, the fact
that only the E-isomers 6 are generated was demonstrated by using
NOE experiments that show that the vinyl protons in the enamine
moiety are located close to the amide NH. The enamines 6a,b react
with hydrazine hydrate in refluxing ethanol to yield the acyclic
hydrazine derivatives 8a,b that undergo cyclization to form the cor-
responding aminopyrazole 9a,b when stirred in refluxing pyridine.
In contrast, under microwave irradiation conditions enamines
6a,b react with hydrazine hydrate to afford the corresponding tri-
azolopyridone derivatives 12a,b. It is believed that upon microwave
irradiation the formed acyclic hydrazine derivatives 8a,b tauto-
merize to produce the hydrazones 11a,b that cyclize to generate
12a,b by way of condensation of their active methine moieties with
the internal indolyl carbonyl group. In addition,12a,b are formed by
stirring solutions of 5a,b in refluxing DMF containing anhydrous
sodium acetate (Scheme 2).
a sterile cork borer and each well was then inoculated with 100 mL
of each of the key substances in DMSO, resulting in a final
concentration of 1 mg mLꢀ1. Nutrient agar plates were incubated at
37 ꢁC for 24 h while the PDA plates were incubated at 25 ꢁC for 48 h.
The zones of inhibition around the wells were determined and the
averages based on triplicate measurements were recorded. Ampi-
cillin was used as the reference antibacterial agent.
3.2. Antimicrobial evaluation
The results of the antimicrobial activity evaluations, given in
Table 1, reveal that substances 4a, and 4b exhibit strong activities
against the tested organisms while compound 5b showed activity
only towards Gram negative bacteria and one of the Gram positive
bacterial strain (B. subtilis). Also, 9b displayed a broad spectrum
antibacterial profile only against Gram positive bacteria (B. subtilis).
In addition, the results displayed in Table
2 indicate that
compounds 5a, 12b, 17b and 17c have moderate growth inhibitory
activities against Gram positive bacteria (B. subtilis) as revealed by
the diameters of their inhibition zones. Among these substances,
12b and 17b show moderate growth inhibitory effects on E. coli
(Gram negative bacteria). Also 17c has moderate activity against
yeast. All of the substances listed in Table 3 exhibit weak antimi-
crobial activities against the Gram positive bacteria (B. subtilis).
The majority of the compounds containing 1,2,3-triazole, pyr-
azole and pyrazolo[1,5-a]- pyrimidine ring systems that incorpo-
rate an indole moiety had growth inhibitory activities against the
Gram positive bacteria B. subtilis but not necessary S. aureus. It
worth mentioning that the substances 4a,b, possessing a 1,2,3-tri-
azole ring appended to the C3 position of the indole nucleus via
a ketone linker showed a high antimicrobial activity but the cor-
responding substances 5a,b in which the triazole is changed to
a cyanoacetamide does not. In contrast, attachment of a pyrazole or
pyrazolo[1,5-a]pyrimidine to the triazole nucleus at position 4 via
a carboxamide linker, exemplified by compounds 9 and 17, unfor-
tunately leads to weak to medium antimicrobial activity except 9b
which displayed a broad spectrum antibacterial profile against
Gram positive bacteria (B. subtilis). Overall, the results showed that
four of the heterocycles prepared in this investigation exhibit
strong antimicrobial activities with significant inhibition zones
(ꢂ10 mm) against at least one of the tested organisms.
Pyrimidine rings can be inserted into 9a by reacting these
substances with 3-(dimethylamino)- acrolein 13. These processes
yield the corresponding pyrimidinopyrazole 14. In
a similar
manner, reactions of 9a,b with enaminones 15aec either thermally
or under microwave irradiation conditions yield the corresponding
pyrazolo[1,5-a]pyrimidines 17(Scheme 3).
A
strategy was explored to prepare pyridoneetriazoles.
Accordingly, condensation of cyanoamides 5a,b with cinnamalde-
hyde affords dienamides 18a,b. However, when treated under
a variety of condition designed to promote cyclization, 18a,b do not
react to form 19a,b (Scheme 4).
3. Pharmacology
3.1. Methodology
The antimicrobial activities of the compounds prepared in this
effort were evaluated using four test organisms, including
O
O
O
NH2
CN
CN
-
+
NH2OH.HCl/DMF
N
Ph N N Cl
N
anhyd. AcONa
or MW
OH
N
N
R
N
NH
Ph
R
N
NH
Ph
R
R'
R'
R'
2
1
3
O
O
R
H
N
CN
NH2
NCCH2CO2H
O
N
N
N
o
N
Ac O,
85 C
2
N
N
R
N
N
or MW
R'
R'
Ph
Ph
4
5
1, 2, 4, 5a, R = H, R' = Me
b, R = Me , R' = H
Scheme 1.

H. Behbehani et al. / European Journal of Medicinal Chemistry 46 (2011) 1813e1820
1815
NMe2
CN
O
H
N
O
N
N
O
H
N
N
N
CN
R
R'
DMF-DMA,
or MW
Ph
6
O
N
N
N
N
R
Me2N
R'
Ph
O
H
N
CN
5
O
N
N
N
N
R
5 - 12a, R = H, R' = Me
b, R = Me , R' = H
R'
Ph
7
O
O
NH2
O
NH2
R" HN
pyridine
CN
NH2NH2.H2O
R" HN
R" HN
6
N
NH
9
N
H
N
8
NH-NH2
10
O
NC
O
NH
CN
N
R" HN
R'
N
R
N
N-NH2
N
11
12
Ph
DMF, anhyd. AcONa
5a,b
O
R" =
N
N
N
N
R
R'
Ph
Scheme 2.
4. Conclusion
heterocyclic substances. In addition, the results of biological eval-
uations demonstrate that members from the prepared compounds
have promising antimicrobial activities against Gram negative
bacteria, Gram positive bacteria and Yeast.
In this effort, 2-arylhdrazononitriles were used as key synthons
for the preparation of a wide variety of new, uniquely substituted
O
CHO
N
R" HN
Me2N
N
N
14
13
O
NH2
R" HN
NH
O
N
9
O
H
N
NMe2
Ar
DMF/AcONa
R" HN
15
NH
Ar
N
O
R
16
O
R" =
N
N
N
N
O
R'
Ph
N
R = H, R' = Me
R = Me , R' = H
R" HN
,
Ar =
Ph,
N
N
N
S
Ar
17
Scheme 3.

1816
H. Behbehani et al. / European Journal of Medicinal Chemistry 46 (2011) 1813e1820
O
N
O
N
H
N
H
N
CHO
CN
N
CN
N
R'
R'
N
O
N
R
O
R
AcOH, AcONH4
or MW
N
N
18
Ph
Ph
5
Ph
O
N
5, 18, 19 a, R = H, R' = Me
b, R = Me , R' = H
N
N
CN
R'
O
N
R
N
19
Ph
Scheme 4.
5. Experimental section
(4.2 g, 30 mmol). The mixture was stirred at room temperature for
1 h and the resulting solid was collected by filtration, washed with
water and ethanol, and crystallized using the indicated solvent.
5.1. General remarks
All melting points are reported uncorrected. IR spectra were
recorded using KBr disks and a PerkineElmer System 2000 FT-IR
spectrophotometer.1H NMR (400 MHz) and 13C NMR (100 MHz)
spectra were recorded on a Bruker DPX 400, 400 MHz NMR spec-
trometer using CDCl3 or DMSO-d6 as solvents and TMS as an
internal standard. Chemical shifts are reported in ppm. Mass
spectra were measured using a high resolution GCMS (DFS) thermo
spectrometers with EI (70 EV). Microanalyses were performed on
a LECO CHNS-932 Elemental Analyzer. Reactions were conducted
under microwave irradiation in heavy-walled Pyrex tubes fitted
with PCS caps. Microwave heating was carried out with a single
mode cavity Explorer Microwave synthesizer (CEM Corporation,
NC, USA). 3-(1-methyl-1H-Indol-3-yl)-3-oxopropanenitrile 1a [24],
3-(2-methyl-1H-Indol-3-yl)-3-oxopropanenitrile 1b [24], 3-(1-
methyl-1H-indol-3-yl)-3-oxo-2-(phenylhydrazono) propanenitrile
2a [11] and (5-Amino-2-phenyl-2H-1,2,3-triazol-4-yl)(1-methy l-
1H-indol-3-yl)methanone 4a [11] were prepared by using literature
procedures.
5.2.1. 3-(1-Methyl-1H-indol-3-yl)-3-oxo-2-(phenylhydrazono)
propanenitrile (2a)
Recrystallized from a mixture of dioxane/DMF (1:1) as yellow
crystals, yield: 2.4 g (80%), mp 199 ꢁC; IR (KBr): /cmꢀ1 3225 (NH),
n
2207 (CN), 1684 (CO); 1H NMR (DMSO-d6):
d 3.92 (s, 3H, CH3),
7.14e7.57 (m, 8H, Ar-H), 8.29 (d, J ¼ 7.5 Hz, 1H, Ar-H), 8.40 (s, 1H,
indole H-2) and 11.97 ppm (br, 1H, hydrazone NH); 13C NMR
(DMSO-d6): d 34.45 (CH3), 111.72, 112.13, 112.79, 115.84 (CN), 117.32,
122.57, 123.37, 124.12, 125.31, 128.06, 130.55, 137.62, 139.71, 143.33
(Ar-C) and 180.46 (CO); MS (EI): m/z (%) 302 (Mþ, 45.7), 303
(Mþ þ 1, 14.6). Anal. Calcd for C18H14N4O (302.34): C, 71.51; H, 4.67;
N, 18.53. Found: C, 71.38; H, 4.58; N, 18.50.
5.2.2. 3-(2-Methyl-1H-indol-3-yl)-3-oxo-2-(phenylhydrazono)
propanenitrile (2b)
Recrystallized from a mixture of EtOH/dioxane (1:2) as yellow
crystals, yield: 2.6 g (85%), mp 223 ꢁC; IR (KBr): /cmꢀ1 3371, 3218
n
(2NH), 2200 (CN), 1667 (CO); 1H NMR (DMSO-d6):
d 2.56 (s, 3H,
CH3), 7.01e7.07 (m, 2H, Ar-H), 7.14 (t, J ¼ 8.0 Hz, 1H, Ar-H), 7.25 (t,
J ¼ 7.8 Hz, 2H, Ar-H), 7.35 (d, J ¼ 8.0 Hz, 2H, Ar-H), 7.41 (d, J ¼ 8.0 Hz,
1H, Ar-H), 7.77 (d, J ¼ 8.0 Hz, 1H, Ar-H), 11.95 (s, 1H, indole NH) and
5.2. General procedure for the preparation of 2a,b
12.03 ppm (s, 1H, hydrazone NH); 13C NMR (DMSO-d6):
d 14.60
A solution of the aryldiazonium salt (10 mmol) was prepared by
adding a solution of sodium nitrite (1.4 g dissolved in 10 mL water)
to a stirred solution of the arylamine hydrochloride (10 mmol in
6 mL, 6 M HCl) at 0 ꢁC. The resulting solution was then added to
a warm solution of 3-oxoalkanonitriles 1a,b (10 mmol) in ethanol/
dioxane mixture (30 mL each) containing sodium acetate trihydrate
(CH3), 111.11, 111.28, 112.10, 114.18, 115.59 (CN), 120.62, 120.86,
121.91, 124.29, 127.17, 129.31, 135.08, 142.24, 143.93 (Ar-C) and
183.08 (CO); MS (EI): m/z (%) 302 (Mþ, 14.5), 303 (Mþ þ 1, 4.8). Anal.
Calcd for C18H14N4O (302.34): C, 71.51; H, 4.67; N, 18.53. Found: C,
71.49; H, 4.73; N, 18.44.
Table 1
Table 2
Inhibition zone diameters of the tested substances that show strong antimicrobial
activities against the tested microorganisms.
Inhibition zone diameters of the tested substances that show moderate antimicro-
bial activities against the tested microorganisms.
Compound Inhibition zone diameter (Nearest mm)
no.
Compound Inhibition zone diameter (Nearest mm)
no.
E. coli
S. aureus
B. subtilis
C. albicans
Mean
E. coli Mean
S. aureus Mean B. subtilis Mean C. albicans Mean
Mean
Mean
Mean
(min-max) SD (min-max) SD (min-max) SD (min-max) SD
(min-max) SD (min-max) SD (min-max) SD (min-max) SD
5a
0
0
0
0
0
6 (4e8)
6 (2e10)
8 (6e10)
4 (2e6)
0
0
0
4a
4b
5b
9b
6.7 (4e10)
8.7 (8e10)
6.2 (4e8)
0
12.2 (9e17.5)
12 (10e14)
0
0
6 (6e6)
12 (10e14)
9.3 (8e10)
11.3 (8e14)
10.7 (8e14)
8.7 (6e10)
0
0
12b
17b
17c
4 (4-4)
5 (2e8)
0
5.7 (3e8)

H. Behbehani et al. / European Journal of Medicinal Chemistry 46 (2011) 1813e1820
1817
Table 3
added and the reaction mixtures were irradiated for further 10 s at
the same temperature. All of the reaction mixtures were cooled and
poured into cold water. The solid products 5a,b were collected by
filtration and crystallized from the indicated solvent.
Inhibition zone diameters of the tested substances that show week antimicrobial
activities against the tested microorganisms.
Compound Inhibition zone diameter (Nearest mm)
no.
E. coli Mean
S. aureus Mean B. subtilis Mean C. albicans Mean
(min-max) SD (min-max) SD (min-max) SD (min-max) SD
5.4.1. 2-Cyano-N-[5-(1-methyl-1H-indole-3-carbonyl)-2-phenyl-
2H-1,2,3-triazol-4-yl]acetamide (5a)
1a
1b
2a
2b
6a
6b
9a
12a
17a
17d
18a
18b
DMSO*
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
e
2 (0e4)
3.3 (2e4)
2.7 (2e4)
1.3 (0e2)
3.3 (2e6)
2.5 (2e3)
2.7 (2e4)
2 (2e2)
3.3 (2e5)
2.7 (2e4)
2.7 (2e4)
3 (1e5)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
e
Recrystallized from a mixture EtOH/DMF (3:1) as creamy white
crystals, yield: thermally (58%), by microwave (92%), mp 234 ꢁC; IR
(KBr):
(DMSO-d6):
n
/cmꢀ1 3303 (NH), 2252 (CN), 1691, 1601 (2CO); 1H NMR
d
3.99 (s, 3H, CH3), 4.16 (s, 2H, CH2), 7.31e7.38 (m, 2H, Ar-
H), 7.52 (t, J ¼ 7.2 Hz, 1H, Ar-H), 7.62e7.67 (m, 3H, Ar-H), 8.17 (d,
J ¼ 8.0 Hz, 2H, Ar-H), 8.36 (d, J ¼ 8.0 Hz,1H, Ar-H), 8.79 (s, 1H, indole
H-2) and 10.79 ppm (s, 1H, hydrazone NH); 13C NMR (DMSO-d6):
d
26.37 (CH2), 33.45 (CH3), 110.99,113.33,115.59 (CN),118.97,121.54,
122.77, 123.41, 126.60, 128.52, 129.83, 137.23, 137.68, 138.72, 140.43,
144.52,161.35 (Ar-C) and 178.80 ppm (CO); MS (EI): m/z (%) 384 (Mþ,
91.43), 385 (Mþ þ 1, 25.95). Anal. Calcd. for C21H16N6O2 (384.40): C,
65.62; H, 4.20; N, 21.86. Found: C, 65.55; H, 4.18; N, 21.92.
0
Ampicillin** 22 (22e22)
5 (5e5)
1 (1e1)
*DMSO (solvent) ¼ Dimethyl sulfoxide.
**Antibacterial drug, (e) not detected.
5.4.2. 2-Cyano-N-[5-(2-methyl-1H-indole-3-carbonyl)-2-phenyl-
2H-1,2,3-triazol-4-yl]acetamide (5b)
5.3. General method for the preparation of compounds 4a,b
Recrystallized from a mixture EtOH/DMF (3:1) as creamy white
crystals, yield: thermally (61%), by microwave (90%), mp 255 ꢁC; IR
Independent mixtures of arylhydrazononitriles 2a,b (10 mmol)
containing hydroxylamine hydrochloride (1 g, 15 mmol) and
anhydrous sodium acetate (2 g) in DMF (20 mL) were stirred at
reflux for 2 h or irradiated in a microwave reactor for 60 s at 120 ꢁC.
The reaction mixtures were cooled to rt and poured into ice cold
water. The formed solids were collected by filtration, washed with
water, and crystallized from the indicated solvent.
(KBr):
NMR (DMSO-d6):
n
/cmꢀ1 3426, 3332 (2NH), 2256 (CN), 1715, 1601 (2CO); 1H
d
2.45 (s, 3H, CH3), 4.03 (s, 2H, CH2), 7.10e7.20 (m,
2H, Ar-H), 7.43e7.47 (m, 2H, Ar-H) 7.58 (t, J ¼ 8.0 Hz, 2H, Ar-H), 7.77
(d, J ¼ 8.0 Hz,1H, Ar-H), 7.97 (d, J ¼ 7.6 Hz, 2H, Ar-H),11.23 (s,1H, NH)
and 12.10 ppm (s,1H, NH); 13C NMR (DMSO-d6):
d 14.46 (CH3), 26.00
(CH2), 111.38, 113.03, 115.48 (CN), 118.31, 120.41, 121.57, 122.30,
127.29, 128.21, 129.93, 135.05, 138.75, 140.53, 142.31, 145.90, 161.52
(Ar-C) and 181.59 ppm (CO); MS (EI): m/z (%) 384 (Mþ, 98.65), 385
(Mþ þ 1, 30.80). Anal. Calcd. for C21H16N6O2 (384.40): C, 65.62; H,
4.20; N, 21.86. Found: C, 65.66; H, 4.27; N, 21.79.
5.3.1. (5-Amino-2-phenyl-2H-1,2,3-triazol-4-yl)(1-methyl-1H-
indol-3-yl)methanone (4a)
Recrystallized from a mixture EtOH/DMF (1:1) as yellow crys-
tals, yield: thermally (79%), by microwave (91%); mp: 200e202 ꢁC;
IR (KBr):
4.01(s, 3H, CH3), 6.43 (s, 2H, NH2), 7.27e8.42 (m, 9H, Ar-H) and
8.95 ppm (s, 1H, indole H-2); 13C NMR (DMSO-d6):
33.38 (CH3),
n
/cmꢀ1 3454, 3342 (NH2), 1608 (CO); 1H NMR (DMSO-d6):
5.5. General method for the preparation of compounds 6a,b
d
d
Mixtures of 5a,b (3.84 g, 10 mmol), N,N-dimethylformamide
dimethylacetal (DMF-DMA) (1.2 mL,10 mmol) in DMF (20 mL) were
stirredat reflux for 2 h or irradiated in a microwaveovenat 120 ꢁC for
60 s. The reaction mixtures were cooled to room temperature and
poured into ice cold water containing a few drops from hydrochloric
acid. The formed solid products were collected by filtration, washed
with water then ethanol and crystallized from the indicated solvent.
110.76, 113.07, 118.28, 121.69, 122.36, 123.04, 126.89, 127.41, 129.62,
131.63, 136.93, 138.96, 139.12, 155.67 (Ar and triazole carbons) and
180.34 (CO); MS (EI): m/z (%) 317 (Mþ, 46.8), 318 (Mþ þ 1, 16.3).
Anal. Calcd for C18H15N5O (317.35): C, 68.13; H, 4.76; N, 22.07.
Found: C, 68.25; H, 4.72; N, 21.99.
5.3.2. (5-Amino-2-phenyl-2H-1,2,3-triazol-4-yl)(2-methyl-1H-
indol-3-yl)methanone (4b)
5.5.1. (E)-2-Cyano-3-(dimethylamino)-N-[5-(1-methyl-1H-indole-
3-carbonyl)-2-phenyl-2H-1,2,3-triazol-4-yl]acrylamide (6a)
Recrystallized from a mixture EtOH/DMF (1:1) as buff crystals,
Recrystallized from a mixture EtOH/H2O (2:1) as pale yellow
crystals, yield: thermally (80%), by microwave (94%); mp: 101 ꢁC; IR
n
/cmꢀ1 3464, 3330 (NH2), 3244 (NH), 1630 (CO); 1H NMR
yield: thermally (91%), by microwave (98%), mp 240 ꢁC; IR (KBr):
n/
(KBr):
(DMSO-d6):
cmꢀ1 3438 (NH), 2188 (CN), 1685, 1611 (2CO); 1H NMR (DMSO-d6):
3.27 (s, 3H, CH3), 3.33 (s, 3H, CH3), 4.01 (s, 3H, CH3), 7.30e7.37 (m,
d
2.66 (s, 3H, CH3), 6.38 (s, 2H, NH2), 7.09e7.17 (m, 2H,
Ar-H), 7.36 (t, J ¼ 7.6 Hz,1H, Ar-H), 7.41 (d, J ¼ 8.0 Hz,1H, Ar-H), 7.52 (t,
d
J ¼ 7.8 Hz, 2H, Ar-H),7.91e7.93 (m, 3H, Ar-H) and 11.94 ppm (s, 1H,
2H, Ar-H), 7.49 (t, J ¼ 7.2 Hz, 1H, Ar-H), 7.60e7.65 (m, 3H, Ar-H), 7.90
(s, 1H, olefinic CH), 8.20 (d, J ¼ 8.0 Hz, 2H, Ar-H), 8.37 (d, J ¼ 7.8 Hz,
1H, Ar-H) 8.97 (s, 1H, indole H-2) and 10.38 ppm (s, 1H, NH); 13C
indole NH); 13C NMR (DMSO-d6):
d 14.91 (CH3),111.15,113.08,117.75,
120.79, 120.85, 121.86, 127.16, 127.31, 129.73, 132.61, 135.00, 139.10,
143.66,155.60 (Ar and triazole carbons) and 183.35 (CO); MS (EI): m/
z (%) 317 (Mþ, 100), 318 (Mþ þ 1, 29.8). Anal. Calcd for C18H15N5O
(317.35): C, 68.13; H, 4.76; N, 22.07. Found: C, 68.08; H, 4.67; N, 22.15.
NMR (DMSO-d6):
d 33.54(CH3), 38.40(CH3), 47.31(CH3), 69.53(C-2),
111.00, 112.88(CN), 118.90, 119.12, 121.74, 122.81, 123.41, 126.70,
128.28, 129.76, 134.66, 137.11, 138.86, 140.28, 147.21, 157.14, 161.80
(Ar-C and olefinic C) and 179.92 (CO); MS (EI): m/z (%) 439 (Mþ,
38.24%), 440 (Mþ þ 1, 11.85%). Anal. Calcd for C24H21N7O2 (439.48):
C, 65.59; H, 4.82; N, 22.31. Found: C, 65.71; H, 4.85; N, 22.28.
5.4. General procedure for the preparation of 5a,b
Independent solutions of cyanoacetic acid (10 mmol) in Ac2O
(10 mL) were heated at 85 ꢁC for 5 min. To each was added either 4a
or 4b. Each solution was stirred at 85 ꢁC for 30 min Alternatively,
solutions of cyanoacetic acid (10 mmol) in Ac2O (10 mL) were
irradiated in a microwave oven at 80 ꢁC for 10 s. Then 4a,b were
5.5.2. (E)-2-Cyano-3-(dimethylamino)-N-[5-(2-methyl-1H-indole-
3-carbonyl)-2-phenyl-2H-1,2,3-triazol-4-yl]acrylamide (6b)
Recrystallized from a mixture EtOH/DMF (1:1) as pale brown
crystals, yield: thermally (90%), by microwave (98%), mp 231 ꢁC; IR

1818
H. Behbehani et al. / European Journal of Medicinal Chemistry 46 (2011) 1813e1820
(KBr):
NMR (DMSO-d6):
n
/cmꢀ1 3507, 3323 (2NH), 2189 (CN), 1685, 1610 (2CO); 1H
2.54 (s, 3H, CH3), 3.21 (s, 3H, CH3), 3.30 (s, 3H,
C
22H18N8O2 (426.44): C, 61.97; H, 4.25; N, 26.28; Found: C, 61.99; H,
d
4.19; N, 26.26.
CH3), 7.10e7.17 (m, 2H, Ar-H), 7.40e7.46 (m, 2H, Ar-H), 7.58 (t,
J ¼ 7.2 Hz, 2H, Ar-H), 7.82e7.85 (m, 2H, olefinic CH and Ar-H), 7.97 (d,
J ¼ 7.6 Hz, 2H, Ar-H), 10.12 (s, 1H, NH) and 12.04 ppm (s,1H, indole
5.7.2. 5-Amino-N-[5-(2-methyl-1H-indole-3-carbonyl)-2-phenyl-
2H-1,2,3-triazol-4-yl]-1H-pyrazole-4-carboxamide (9b)
NH); 13C NMR (DMSO-d6):
d
14.78(CH3), 38.23(CH3), 47.12(CH3),
Yield, 1.45 g (68%), mp 211 ꢁC; IR (KBr): /cmꢀ1 3422 (br), 3312,
n
69.91(C-2), 111.27, 112.99(CN), 118.18, 118.97, 120.66, 121.39, 122.20,
127.31, 127.95, 129.88, 135.03, 138.95, 139.14, 145.07, 145.61, 156.93,
163.19 (Ar-C and olefinic C) and 182.48 (CO); MS (EI): m/z (%) 439
(Mþ, 42.50%), 440 (Mþ þ 1, 12.73%). Anal. Calcd for C24H21N7O2
(439.48): C, 65.59; H, 4.82; N, 22.31. Found: C, 65.56; H, 4.79; N,
22.35.
3213, 3133 (NH2 and 3NH), 1660 (CO). 1H NMR (DMSO-d6):
d 2.45 (s,
3H, CH3), 5.86 (br, 2H, NH2), 7.09e7.18 (m, 2H, Ar-H), 7.40e7.45 (m,
2H, Ar-H), 7.58 (t, J ¼ 8.0 Hz, 2H, Ar-H), 7.78 (d, J ¼ 8.0 Hz, 1H, Ar-H),
7.98 (d, J ¼ 8.0 Hz, 2H, Ar-H), 8.05 (s, 1H, pyrazole H-3), 10.54 (s, 1H,
NH) 11.86 (s, 1H, NH) and 12.01 ppm (s, 1H, indole NH). 13C NMR
(DMSO-d6):
d 14.59 (CH3), 95.85, 111.25, 113.19 (CN), 118.02, 118.93,
120.44, 121.38, 122.11, 127.38, 127.80, 129.89, 134.97, 135.79, 138.92,
141.03, 143.46, 145.54, 162.20 and 182.07 ppm (Ar-C and CO); MS
(EI): m/z (%) 426 (Mþ, 44.0), 427 (Mþ þ 1, 12.5). Anal. Calcd. for
C22H18N8O2 (426.44): C, 61.97; H, 4.25; N, 26.28; Found: C, 62.03; H,
4.29; N, 26.34.
5.6. General method for the preparation of compounds 8a,b
Solutions of the enaminonitrile 6a,b (10 mmol) and hydrazine
hydrate (80%, 0.65 mL) in EtOH (50 mL) were stirred at reflux for
15 min and then cooled to room temperature. The formed solids
were separated by filtration then washed with EtOH to give creamy
white crystals.
5.8. General procedure for the preparation of 12a,b
Method A:
5.6.1. (E)-2-Cyano-3-hydrazinyl-N-[5-(1-methyl-1H-indole-3-
Solution of cyanoacetamides 5a,b (5 mmol) in DMF (20 mL)
containing anhydrous sodium acetate (2 g) were stirred at reflux for
3 h, cooled to rt and poured into ice cold water. The formed solids
were collected by filtration, washed with water and crystallized
from the indicated solvent.
carbonyl)-2-phenyl-2H-1,2,3-triazol-4-yl]acrylamide (8a)
Yield, 2.9 g (68%), mp 188e190 ꢁC; IR (KBr): /cmꢀ1 3365, 3306,
n
3286, 3257 (NH2 and 2NH), 2192 (CN), 1682, 1644 (CO). 1H NMR
(DMSO-d6): 4.02 (s, 3H, CH3), 5.35 (br, 2H, NH2), 7.31e9.02 (m,
11H, Ar-H, olefinic CH and indole H-2), 10.32 (br, 1H, NH) and
10.66 ppm (br, 1H, NH); 13C NMR (DMSO-d6):
33.49 (CH3), 79.14,
d
Method B:
d
Mixture of the enaminonitrile 6a,b (5 mmol) and hydrazine
hydrate (80%, 0.65 mL excess) in DMF (10 mL) were irradiated in
a microwave oven at 120 ꢁC for 90 s. Then the reaction mixtures
were cooled to room temperature and poured into ice cold water
containing few drops of HCl. The crude solids which formed were
collected by filtration, washed with water, and crystallized from the
indicated solvent.
110.96, 112.81 (CN), 118.86, 121.69, 122.77, 123.37, 126.65, 128.24,
129.72, 134.24, 134.70, 137.07, 138.82, 140.24, 147.45, 157.17, 162.34
and 179.91 ppm (Ar-C and CO); MS (EI): m/z (%) 426 (Mþ, 24.6), 427
(Mþ þ 1, 7.5). Anal. Calcd. for C22H18N8O2 (426.44): C, 61.97; H, 4.25;
N, 26.28; Found: C, 62.04; H, 4.29; N, 26.33.
5.6.2. (E)-2-Cyano-3-hydrazinyl-N-[5-(2-methyl-1H-indole-3-
carbonyl)-2-phenyl-2H-1,2,3-triazol-4-yl]acrylamide (8b)
5.8.1. 7-(1-Methyl-1H-indol-3-yl)-5-oxo-2-phenyl-4,5-dihydro-
2H-1,2,3-triazolo[4,5-b]pyridine-6-carbonitrile (12a)
Yield, 2.5 g (59%), mp 218e220 ꢁC; IR (KBr): /cmꢀ1 3437 (br),
n
3353, 3222, 3191 (NH2 and 3NH), 2222 (CN), 1683, 1649 (CO). 1H
NMR (DMSO-d6): 2.44 (s, 3H, CH3), 5.82 (br, 2H, NH2), 7.07e7.98
Recrystallized from a mixture EtOH/DMF (1:3) as yellow crys-
d
tals, yield, 1.40 g (78%), mp above 300 ꢁC; IR (KBr):
n
/cmꢀ1 3443
3.99 (s, 3H,
(m, 10H, Ar-H, olefinic CH and indole H-2), 10.52 (s, 1H, NH), 11.87
(br, 1H, NH) and 11.99 ppm (s, 1H, NH); MS (EI): m/z (%) 426 (Mþ,
12.5), 427 (Mþ þ 1, 3.9). Anal. Calcd. for C22H18N8O2 (426.44): C,
61.97; H, 4.25; N, 26.28; Found: C, 61.86; H, 4.34; N, 26.21.
(NH), 2218 (CN) and 1664 (CO). 1H NMR (DMSO-d6):
d
CH3), 7.25 (t, J ¼ 7.6 Hz, 1H, Ar-H), 7.34 (t, J ¼ 8.0 Hz, 1H, Ar-H), 7.48
(t, J ¼ 7.6 Hz, 1H, Ar-H), 7.58 (t, J ¼ 8.0 Hz, 2H, Ar-H), 7.64 (d,
J ¼ 8.0 Hz, 1H, Ar-H), 7.80 (d, J ¼ 8.0 Hz,1H, Ar-H), 8.02 (d, J ¼ 7.6 Hz,
2H, Ar-H), 8.35 (s, 1H, indole H-2) and 13.00 ppm (s, 1H, NH). 13C
5.7. General method for the preparation of compounds 9a,b
NMR (DMSO-d6): d 33.40 (CH3), 100.39, 105.85, 110.95, 117.12 (CN),
118.98, 120.90, 121.95, 122.77, 125.00, 128.97, 129.91, 130.65, 135.24,
137.31, 138.81, 145.53, 147.84 and 160.95 ppm (Ar-C and CO); MS
(EI): m/z (%) 366 (Mþ, 100), 367 (Mþ þ 1, 27.8). Anal. Calcd. for
C21H14N6O (366.39): C, 68.84; H, 3.85; N, 22.94; Found: C, 68.78; H,
3.89; N, 23.01.
Solutions of 8a,b (5 mmol) in pyridine (20 mL) were stirred at
reflux for 2 h and concentrated in vacuo to give a residues which
were triturated with EtOH to afford solids. Separation of the solids
by filtration gave a solid that was washed with EtOH and crystal-
lized from EtOH/DMF to give faint pink crystals.
5.8.2. 7-(2-Methyl-1H-indol-3-yl)-5-oxo-2-phenyl-4,5-dihydro-
2H-1,2,3-triazolo[4,5-b]pyridine-6-carbonitrile (12b)
5.7.1. 5-Amino-N-[5-(1-methyl-1H-indole-3-carbonyl)-2-phenyl-
2H-1,2,3-triazol-4-yl]-1H-pyrazole-4-carboxamide (9a)
Recrystallized from a mixture EtOH/DMF (1:3) as yellow crys-
Yield, 1.55 g (73%), mp 202 ꢁC; IR (KBr):
n
/cmꢀ1 3441, 3324, 3221,
tals, yield, 1.5 g (82%), mp 292 ꢁC; IR (KBr): /cmꢀ1 3422, 3384
n
3128 (NH2 and 2NH), 1669, 1621 (2CO). 1H NMR (DMSO-d6):
d
3.98
(2NH), 2222 (CN) and 1645 (CO). 1H NMR (DMSO-d6):
d 2.56 (s, 3H,
(s, 3H, CH3), 6.10 (br, 2H, NH2), 7.28e7.36 (m, 2H, Ar-H), 7.49 (t,
J ¼ 7.6 Hz, 1H, Ar-H), 7.59e7.66 (m, 3H, Ar-H), 7.90 (s, 1H, pyrazole
H-3), 8.18 (d, J ¼ 8.0 Hz, 2H, Ar-H), 8.36 (d, J ¼ 7.6 Hz, 1H, Ar-H), 8.76
(s, 1H, indole H-2), 10.37 (s, 1H, NH) and 12.01 ppm (s, 1H, NH). 13C
CH3), 7.09 (t, J ¼ 7.6 Hz, 1H, Ar-H), 7.18 (t, J ¼ 7.6 Hz, 1H, Ar-H),
7.40e7.57 (m, 5H, Ar-H), 7.96 (d, J ¼ 8.0 Hz, 2H, Ar-H), 12.01 (s, 1H,
NH) and 13.11 ppm (s, 1H, NH). 13C NMR (DMSO-d6):
d 13.91 (CH3),
104.25, 104.99, 111.26, 116.67 (CN), 118.89, 119.95, 120.06, 121.86,
126.41, 128.92, 129.90, 131.17, 135.65, 138.82, 138.99, 147.07, 147.83
and 160.74 ppm (Ar-C and CO); MS (EI): m/z (%) 366 (Mþ, 100), 367
(Mþ þ 1, 32.7). Anal. Calcd. for C21H14N6O (366.39): C, 68.84; H,
3.85; N, 22.94; Found: C, 68.91; H, 3.83; N, 22.87.
NMR (DMSO-d6):
d 33.42 (CH3), 95.85, 110.91, 113.61 (CN), 118.77,
121.73, 122.66, 123.34, 126.67, 128.20, 129.83, 137.21, 137.95, 138.92,
140.29,145.65,147.25,157.48,161.70 and 179.55 ppm (Ar-C and CO);
MS (EI): m/z (%) 426 (Mþ, 23.4), 427 (Mþ þ 1, 6.5). Anal. Calcd. for

H. Behbehani et al. / European Journal of Medicinal Chemistry 46 (2011) 1813e1820
1819
5.9. N-[5-(1-Methyl-1H-indole-3-carbonyl)-2-phenyl-2H-1,2,3-
5.10.3. N-[5-(1-Methyl-1H-indole-3-carbonyl)-2-phenyl-2H-1,2,3-
triazol-4-yl]pyrazolo[1,5-a]- pyrimidine-3-carboxamide (14)
triazol-4-yl]-7-(thiophen-2-yl) pyrazolo [1,5-a]pyrimidine-3-
carboxamide (17c)
A mixture of 9a (2.15 g, 5 mmol) and 3-(dimethylamino)acrolein
(0.5 g, 5 mmol) in pyridine (10 mL) was refluxed for 48 h or heated
in the microwave oven at the maximum power and 120 ꢁC for
2 min. Then, the solvent was removed under reduced pressure and
the remaining residue was triturated with MeOH to afford crystals,
which were then collected by filtration and recrystallized from
DMF as pale brown crystals. Yield: thermally (57%), by microwave
Recrystallized from DMF as yellow crystals, yield: thermally
(49%), by microwave (76%), mp 207 ꢁC; IR (KBr): /cmꢀ1 3433 (NH),
n
1682, 1606 (2CO); 1H NMR (DMSO-d6):
d 4.00 (s, 3H, CH3),
7.34e7.53 (m, 4H, Ar-H), 7.61e7.68 (m, 3H, Ar-H), 8.05 (d, J ¼ 4.4 Hz,
1H, H-6), 8.19e8.35 (m, 3H, Ar-H), 8.48e8.65 (m, 2H, Ar-H), 8.90 (s,
1H, pyrazole H-2), 8.99 (s, 1H, indole H-2), 9.04 (d, J ¼ 4.4 Hz, 1H, H-
5) and 11.71 ppm (s, 1H, NH). 13C NMR (DMSO-d6):
d 33.45 (CH3),
(89%), mp 234e236 ꢁC; IR (KBr):
n
/cmꢀ1 3420 (NH), 1683, 1615
104.39, 105.92, 110.83, 113.07, 118.91, 121.83, 122.63, 123.27, 126.78,
128.10, 128.23, 129.40, 129.70, 133.43, 135.28, 135.96, 137.07, 138.87,
139.95, 140.93, 146.20, 146.40, 146.63, 151.65, 157.99 and
179.39 ppm (Ar-C and CO); MS (EI): m/z (%) 544 (Mþ, 11.25), 545
(Mþ þ 1, 3.8). Anal. Calcd. for C29H20N8O2S (544.60): C, 63.96; H,
3.70; N, 20.58; Found: C, 64.03; H, 3.66; N, 20.50.
(2CO); 1H NMR (CDCl3):
d
3.93 (s, 3H, CH3), 7.09 (t, J ¼ 7.6 Hz, 1H, Ar-
H), 7.26e7.50 (m, 6H, Ar-H), 8.19 (d, J ¼ 7.6 Hz, 2H, Ar-H), 8.61e8.73
(m, 2H, Ar-H), 8.80 (s, 1H, Ar-H), 8.99 (s, 1H, indole H-2) and
11.84 ppm (s, 1H, NH). 13C NMR (CDCl3):
d 33.88 (CH3), 105.88,
109.48, 109.75, 114.31, 119.31, 122.87, 123.57, 127.50, 127.94, 129.26,
135.01, 136.27, 137.15, 139.04, 139.46, 145.97, 147.51, 147.86, 151.86,
157.11, 158.85 and 180.68 ppm (Ar-C and CO); MS (EI): m/z (%) 462
(Mþ, 75.6), 363 (Mþ þ 1, 23.9). Anal. Calcd. for C25H18N8O2 (462.47):
C, 64.93; H, 3.92; N, 24.23; Found: C, 64.87; H, 3.95; N, 24.19.
5.10.4. N-[5-(1-Methyl-1H-indole-3-carbonyl)-2-phenyl-2H-1,2,3-
triazol-4-yl]-7-(6-methylpyridin -2-yl)pyrazolo[1,5-a]pyrimidine-3-
carboxamide (17d)
Recrystallized from a mixture EtOH/DMF (1:3) as pale brown
crystals, yield: thermally (61%), by microwave (88%), mp
5.10. General procedure for the preparation of 17aed
260e262 ꢁC; IR (KBr):
(DMSO-d6): d 2.63(s, 3H, CH3), 4.03 (s, 3H, CH3), 7.32e7.35(m, 2H, Ar-
n
/cmꢀ1 3434 (NH), 1674, 1607 (2CO); 1H NMR
Mixtures of 9a,b (5 mmol) and enaminone 15aec (5 mmol) in
pyridine (20 mL) were stirred at reflux for 48 h or irradiated in
a microwave oven at the maximum power and 120 ꢁC for 2 min. The
reaction mixtures were cooled to room temperature and poured
into ice cold water then acidified with hydrochloric acid (2 N),
forming solids that were collected by filtration and washed with
water then MeOH and recrystallized from the indicated solvent.
H), 7.49e7.54 (m, 2H, Ar-H), 7.59e7.68 (m, 3H, Ar-H), 8.01e8.03(m,
2H, Ar-H), 8.25 (d, J ¼ 8.0 Hz, 2H, Ar-H), 8.49 (t, J ¼ 8 Hz, 1H, Ar-H),
8.81e8.85 (m, 2H, Ar-H), 8.98 (s, 1H, indole H-2), 9.16 (d, J ¼ 4.4 Hz,
1H, H-5) and 11.78 ppm (s, 1H, NH). 13C NMR (DMSO-d6):
d 24.21
(CH3), 33.49 (CH3), 104.53, 109.73, 110.87, 113.06, 118.93, 121.82,
122.67, 123.30, 123.70, 126.03, 126.82, 128.25, 129.73, 135.14, 137.08,
137.35, 138.88, 139.96, 145.11, 145.94, 146.40, 146.52, 146.98, 152.48,
157.91, 158.83 and 179.45 ppm (Ar-C and CO); MS (EI): m/z (%) 553
(Mþ,17.0), 554 (Mþ þ 1, 6.5). Anal. Calcd. for C31H23N9O2 (553.59): C,
67.26; H, 4.19; N, 22.77; Found: C, 67.18; H, 4.23; N, 22.84.
5.10.1. N-[5-(1-Methyl-1H-indole-3-carbonyl)-2-phenyl-2H-1,2,3-
triazol-4-yl]-7-phenyl pyrazolo [1,5-a]pyrimidine-3-carboxamide
(17a)
Recrystallized from a mixture of EtOH/DMF (1:4) as pink crys-
tals. Yield: thermally (63%), by microwave (90%), mp 186e188 ꢁC; IR
5.11. General procedure for the preparation of compounds 18a,b
(KBr): n d 3.95
/cmꢀ1 3423 (NH), 1685, 1611 (2CO); 1H NMR (CDCl3):
(s, 3H, CH3), 7.18 (d, J ¼ 4.6 Hz, 1H, H-6), 7.35e7.64 (m, 9H, Ar-H),
8.09e8.16 (m, 2H, Ar-H), 7.22(d, J ¼ 7.6 Hz, 2H, Ar-H), 8.67 (d,
J ¼ 7.6 Hz,1H, Ar-H), 8.75 (s, 1H, pyrazole H-2), 8.86 (s, 1H, indole H-
2), 9.04 (d, J ¼ 4.6 Hz, 1H, H-5) and 12.04 ppm (s, 1H, NH). 13C NMR
Mixtures of cyanoacetamides 5a,b (1.92 g, 5 mmol) and cinna-
maldehyde (0.66 g, 5 mmol) in AcOH (15 mL) containing ammo-
nium acetate (1 g) were stirred at reflux for 2 h or subjected to
microwave irradiation at 110 ꢁC for 50 s. The mixtures were cooled
to rt and poured into ice cold water. The formed solids were
collected by filtration, washed with water then ethanol, and crys-
tallized from a mixture EtOH/DMF (2:1) which gave yellow crystals.
(CDCl3):
d 33.76 (CH3), 105.60, 108.78, 109.59, 114.16, 119.11, 122.67,
122.76, 123.36, 127.39, 127.73, 128.78, 129.10, 129.44, 129.92, 131.65,
134.91, 136.98, 138.91, 139.30, 147.09, 147.23, 147.42, 148.04, 151.47,
159.00 and 180.44 ppm (Ar-C and CO); MS (EI): m/z (%) 538 (Mþ,
21.7), 539 (Mþþ1, 7.8). Anal. Calcd. for C31H22N8O2 (538.57): C,
69.14; H, 4.12; N, 20.81; Found: C, 69.22; H, 4.05; N, 20.95.
5.11.1. (2E,4E)-2-Cyano-N-[5-(1-methyl-1H-indole-3-carbonyl)-2-
phenyl-2H-1,2,3-triazol-4-yl]-5-phenylpenta-2,4-dienamide (18a)
Yield: thermally (77%), by microwave (88%); mp: 218e220 ꢁC; IR
5.10.2. N-[5-(2-Methyl-1H-indole-3-carbonyl)-2-phenyl-2H-1,2,3-
triazol-4-yl]-7-phenyl pyrazolo [1,5-a]pyrimidine-3-carboxamide
(17b)
(KBr):
n
/cmꢀ1 3432(NH), 2209 (CN), 1693, 1605 (2CO), 1555 (C]C);
1H NMR (DMSO-d6):
d
3.96 (s, 3H, CH3), 7.21e7.44 (m, 7H, Ar-H),
7.50 (d, J ¼ 6.6 Hz, 1H, CH]), 7.55e7.60 (m, 4H, Ar-H), 7.69 (t,
J ¼ 6.5 Hz,1H, CH]), 8.16e8.19 (m, 3H, Ar-H), 8.38 (d, J ¼ 6.6 Hz,1H,
CH]), 8.84 (s, 1H, indole H-2), and 10.98 ppm (s,1H, NH). MS (EI):
m/z (%) 498 (Mþ, 31.5), 499 (Mþ þ 1, 10.1). Anal. Calcd. for
C30H22N6O2 (498.55): C, 72.28; H, 4.45; N, 16.86; Found: C, 72.35; H,
4.52; N, 16.88.
Recrystallized from a mixture EtOH/DMF (1:3) as yellow crys-
tals. Yield: thermally (55%), by microwave (85%), mp 294 ꢁC; IR
(KBr):
d6):
n
/cmꢀ1 3430, 3232 (2NH), 1658, 1616 (2CO); 1H NMR (DMSO-
2.58 (s, 3H, CH3), 7.12e7.20 (m, 2H, Ar-H), 7.42e7.49 (m, 2H,
d
Ar-H), 7.55e7.67 (m, 6H, Ar-H), 7.89 (d, J ¼ 7.6 Hz, 1H, Ar-H), 8.05 (d,
J ¼ 8.0 Hz, 2H, Ar-H), 8.15 (d, J ¼ 7.6 Hz, 2H, Ar-H) 8.77 (s, 1H,
pyrazole H-2), 8.96 (d, J ¼ 4.4 Hz, 1H, H-5), 11.07 (s, 1H, NH) and
5.11.2. (2E,4E)-2-Cyano-N-[5-(2-methyl-1H-indole-3-carbonyl)-2-
phenyl-2H-1,2,3-triazol-4-yl]-5-phenylpenta-2,4-dienamide (18b)
Yield: thermally (82%), by microwave (91%); mp: 268 ꢁC; IR
12.08 ppm (s,1H, NH). 13C NMR (DMSO-d6):
d 14.80 (CH3), 104.01,
109.80, 111.26, 113.04, 118.35, 120.59, 121.39, 122.19, 127.29, 128.09,
128.60, 129.69, 129.82, 129.88, 131.67, 135.03, 138.69, 138.90, 144.21,
145.50, 146.13, 146.95, 147.58, 152.59, 158.48 and 182.09 ppm (Ar-C
and CO); MS (EI): m/z (%) 538 (Mþ, 18.3), 539 (Mþ þ 1, 6.0). Anal.
Calcd. for C31H22N8O2 (538.57): C, 69.14; H, 4.12; N, 20.81; Found: C,
69.12; H, 4.19; N, 20.75.
(KBr):
n
/cmꢀ1 3395, 3263 (2NH), 2209 (CN), 1677, 1606 (2CO); 1550
(C]C); 1H NMR (DMSO-d6):
d
2.48 (s, 3H, CH3), 7.11e7.28 (m, 3H,
Ar-H), 7.42e7.56 (m, 6H, Ar-H), 7.60 (t, J ¼ 8.0 Hz, 2H, Ar-H),
7.73e7.79 (m, 3H, Ar-H), 8.01 (d, J ¼ 8.0 Hz, 2H, Ar-H), 8.15 (d,
J ¼ 6.8 Hz, 1H, CH]), 11.33 (s, 1H, NH) and 12.10 ppm (s,1H, NH). 13C

1820
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d 14.63 (CH3), 106.29, 111.34, 112.95, 114.78 (CN),
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1e126.
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R.J. Reischer, C.W. Ford, G.E. Zurenko, J.C. Hamel, R.D. Schaadt, D. Stapert,
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118.29, 120.41, 121.52, 122.26, 122.91, 127.25, 128.21, 128.58, 129.20,
129.96, 131.04, 134.73, 135.03, 138.80, 140.79, 143.07, 145.86, 148.65,
153.22, 160.12 and 181.76 ppm (Ar-C and CO); MS (EI): m/z (%) 498
(Mþ, 68.6), 499 (Mþ þ 1, 21.0). Anal. Calcd. for C30H22N6O2 (498.55):
C, 72.28; H, 4.45; N, 16.86; Found: C,72.22; H, 4.48; N, 16.90.
Acknowledgments
Support of this work was provided by the University of Kuwait
through a research grant (SC03/07). The facilities of Analab/SAF
supported by the research grants GS01/01, GS01/05 and GS01/03
are gratefully acknowledged. The authors are grateful to Prof. Dr. M.
H. Elnagdi for his support and for reading the manuscript prior to
submission.
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