Synthesis and biological evaluation of quinolines, thiazolo[3,2-a]pyrimidines, thiadiazolo[3,2-a]pyrimidines and triazolo[3,4-b][1,3,4]thiadiazepines as antimicrobial agents

Article abstract of DOI:10.1007/s00044-016-1540-z

Series of quinolines, thiazolo[3,2-a]pyrimidines, thiadiazolo[3,2-a]pyrimidines and triazolo[3,4-b][1,3,4]thiadiazepines were synthesized by the reaction of amino compound, aromatic aldehyde and malononitrile/ethyl cyanoacetate, using 2-[5-(4-methoxypheny

Full text of DOI:10.1007/s00044-016-1540-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2016) 25:951–969
DOI 10.1007/s00044-016-1540-z
ORIGINAL RESEARCH
Synthesis and biological evaluation of quinolines, thiazolo
[3,2-a]pyrimidines, thiadiazolo[3,2-a]pyrimidines and triazolo
[3,4-b][1,3,4]thiadiazepines as antimicrobial agents
Seema Sahi1 Satya Paul1
•
Received: 29 January 2015 / Accepted: 16 February 2016 / Published online: 3 March 2016
Ó Springer Science+Business Media New York 2016
Abstract Series of quinolines, thiazolo[3,2-a]pyrimidi-
nes, thiadiazolo[3,2-a]pyrimidines and triazolo[3,4-
b][1,3,4]thiadiazepines were synthesized by the reaction of
amino compound, aromatic aldehyde and malononitrile/
ethyl cyanoacetate, using 2-[5-(4-methoxyphenyl)-4H-
1,2,4-triazol-3-ylthio]acetic acid as an organocatalyst in
water–ethanol mixture. Synthesized compounds were
evaluated for in vitro antibacterial and antifungal activities
against three fungal and five bacterial strains. Some of them
exhibited good activity in comparison with the standard
fluconazole and streptomycin such as compound 16h has
shown best antifungal activity with MIC value of 60 lg/mL
against A. niger and 12g exhibited best antibacterial activity
with MIC value of 50 lg/mL against E. coli.
from a biological and industrial point of view as well as to
the understanding of life processes and the efforts to
improve the quality of life. These are present in a wide
variety of drugs, most vitamins and many natural products.
Also, they have been frequently found as a key structural
unit in synthetic pharmaceuticals and agrochemicals.
Specifically, nitrogen-containing heterocycles are of wide
interest because of their diverse biological activity and
clinical applications. They are remarkably effective com-
pounds both with respect to their inhibitory activity and
with respect to their favourable selectivity ratio (Molina
et al., 2000).
The efficacy of several heterocyclic active ingredients is
based on the fact that heterocycle is acting as a prodrug,
itself being not efficacious against the target enzyme or
organism but delivering the intrinsically active compound
by UV light, heat, moisture or a metabolic transformation
(Lamberth and Dinges, 2012). Biological importance of
fused heterocycles as antimicrobial agents has led to a
considerable amount of synthetic work in the field of
heterocyclic fused ring systems. For example, quinoline,
thiazolo-pyrimidine, thiadiazolo-pyrimidine and triazolo-
thiadiazepine derivatives are known to possess antifungal
(Dandia et al., 2006), anticancer (Holla et al., 2002),
antibacterial (Bekhit et al., 2003), anti-inflammatory (Alam
et al., 2010), antiparkinson (Abd et al., 2008), tuberculo-
therapeutic (Vangapandu et al., 2004), anti-HIV (Tabarrini
et al., 2008) and antimicrobial (Pattan et al., 2012) activ-
ities. Looking at the importance of heterocycles, it was
thought that it would be worthwhile to design and syn-
thesize some new nitrogen-containing heterocyclic com-
pounds and screen them for potential biological activities.
In multicomponent approaches, complex products and
biologically active molecules are synthesized from readily
available starting materials in environmentally benign
Keywords Quinolines Á Thiazolo[3,2-a]pyrimidines Á
Thiadiazolo[3,2-a]pyrimidines Á
Triazolo[3,4-b][1,3,4]thiadiazepines Á
3-Triazolylthioacetic acid Á Organocatalyst
Introduction
For more than a century, heterocyclic compounds have
constituted one of the largest areas of research in organic
chemistry. They contributed to the development of society
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-016-1540-z) contains supplementary
material, which is available to authorized users.
& Satya Paul
paul7@rediffmail.com
1
Department of Chemistry, University of Jammu,
Jammu 180006, India
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Med Chem Res (2016) 25:951–969
solvents, in a single-step process using catalyst. Recent
advances in the application of organocatalyst have pro-
vided efficient synthesis of a wide range of bioactive
molecules. Organocatalysed reactions represent an attrac-
tive alternative to metal-catalysed processes notably
because of their lower cost and benign environmental
impact in comparison with organometallic catalysis. Also,
application of organocatalysts in organic transformations
due to their unique characteristics has enormously been
considered. Some important organocatalysts (Fig. 1) used
in organic synthesis include proline (Nezhad et al., 2012),
cinchona alkaloids (Tian et al., 2004), chiral amino sul-
phonamide (Kano et al., 2009), 3-ethylbenzothiazolium
bromide (Matsumoto et al., 1985), L-pipecolic acid (Kumar
and Maurya, 2008) and adenine (Goswami and Dass,
2009). Although examples of organocatalysis have been
intermittently reported in the literature for decades, it was
only recently realized that it represents a fundamental
concept, the development of which could provide catalysts
for a wide array of important organic transformations,
which relies on neither transition metals nor enzymes (Lu
et al., 2008). In contrast to many transition metal catalysts,
most organocatalysts are stable to air and water, easily
handled experimentally, relatively non-toxic and readily
separated from the crude reaction mixture.
trapping via Pictet–Spengler cyclization. The multicom-
ponent Mannich reaction (Guillena et al., 2007) of amine
derivative, non-enolizable aldehyde and enolizable car-
bonyl compound using proline as a catalyst in the presence
of NaBH4 has also been reported.
Quinolines, thiazolo-pyrimidines, thiadiazolo-pyrimidi-
nes and triazolo-thiadiazepines exhibit various biological
activities such as antibacterial, anticancer, antifungal and
antitumor. Due to these useful pharmacophoric properties,
they have extensively been studied. In the view point of
synthetic chemistry, multicomponent synthesis is known as
an important strategy to extend the structural diversity of
these heterocyclic compounds (Guillena et al., 2007). In
this regard, the development of new multicomponent pro-
tocols for the synthesis of heterocycles has attracted con-
siderable interest in recent years (Majumder et al., 2013).
A green and efficient one-pot process to synthesize 5-aryl-
pyrimido[4,5-b]quinoline-diones, via three-component
reaction involving anilines, aldehydes and barbituric acids
using L-proline as catalyst in aqueous medium, has been
reported (Nezhad et al., 2012). 4-Arylquinolines were
synthesized by the reaction of 2-aminobenzophenones and
ketones in the presence of conc. H2SO4 under microwave
irradiation (Agrawal and Joshipura, 2005). Thiazolo[3,2-
a]pyrimidines were synthesized by one-pot multicompo-
nent reaction of aromatic aldehydes, ethylacetoacetates and
4-(4-bromophenyl)-1,3-thiazol-2-amines in the presence of
silica gel under microwave irradiation (Bansal et al., 2013).
One-pot synthesis of 5H-[1,3,4]thiadiazolo[3,2-a]pyrim-
idine-6-carboxylates has been reported by the reaction of
aldehydes, 2-aminothiadiazoles and ethyl acetoacetates
under microwave irradiation in acetic acid (Zhao et al.
2014). [1,2,4]Triazolo[3,4-b][1,3,4]thiadiazepines were
synthesized by the condensation of ethyl 2-arylhydrazono-
3-oxo-butyrates with 4-amino-3-(4-hydroxyphenyl)-5-
mercapto-1,2,4- triazoles in acetic acid (Rajput, 2013).
In this paper, we have synthesized 2-[5-aryl-4H-1,2,4-
triazol-3-ylthio]acetic acids as organocatalysts possessing
different aryl groups with a view to select the most active
catalyst. Among various catalysts, 2-[5-(4-methoxyphenyl)-
4H-1,2,4-triazol-3-ylthio]acetic acid was found to be the
most active, which has been used for the one-pot synthesis
of 2-amino-4-aryl-3,6-disubstituted quinolines, 7-amino-
3,5-bis(aryl)-6-substituted-8aH-thiazolo[3,2-a]pyrimidines,
7-amino-5-aryl-2-(4-methoxyphenyl)-6-substituted-8aH-[1,
3,4]thiadiazolo[3,2-a]pyrimidines and 6-amino-8-aryl-3-
methyl-7-substituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepines
by the reaction of amino compound, aldehyde, malononi-
trile/ethyl cyanoacetate in refluxing EtOH/H2O mixture.
Some of these synthesized compounds have been screened
for antifungal and antibacterial activity.
Organocatalyst-catalysed MCRs and the use of envi-
ronmentally benign solvents and reagents are particularly
attractive, because they incorporate many of the green
chemistry principles (Cordova, 2003). The multicomponent
reaction of malononitrile, aldehyde and 4-hydroxy-
coumarin has been reported in the presence of imidazole as
an organocatalyst, provided very interesting molecular
diversity (Khan et al., 2014). Organocatalytic enantiose-
lective multicomponent synthesis of pyrrolopiperazines
(Du et al., 2014) was obtained under catalytic iminium
activation through a reaction sequence involving an enan-
tioselective Michael addition followed by an iminium ion
NHSO2CF3
AcO
NH
N
COOH
N
H
H
N
Proline
Cinchona alkaloids
Chiral amino sulphonamide
NH
Et
N
HO
N
NH2
Br
O
HN
N
N
S
3-Ethylbenzo-
thiazolium bromide
L-Pipecolic acid
Adenine
Fig. 1 Some organocatalysts used in organic synthesis
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Med Chem Res (2016) 25:951–969
953
2-[5-(4-methoxyphenyl)-4H-1,2,4-triazol-3-ylthio]acetic acid
(A) as an organocatalyst at 100 °C in C2H5OH-H2O mix-
ture (5 mL). It was found that after 15 h at 100 °C, the
reaction was still incomplete. Hence, the reactions were
carried out under microwave irradiation.
Results and discussion
Synthesis of 2-[5-aryl-4H-1,2,4-triazol-3-ylthio]
acetic acids [organocatalysts]
In order to select the appropriate organocatalyst, we have
prepared organocatalysts possessing different aryl groups
in the triazole ring, so as to study the effect of substituent
on the catalytic activity. 2-[5-Aryl-4H-1,2,4-triazol-3-
ylthio] acetic acids were prepared by the reaction of 5-aryl-
4H-1,2,4-triazole-3-thiols (1 mmol) with chloroacetic acid
(0.940 g, 1 mmol) in 30 % aq. NaOH (5 mL) at 100 °C
under microwave irradiation (200 W) followed by acidifi-
cation with conc. HCl.
One-pot synthesis of 2-amino-4-aryl-3,6-
disubstituted quinolines
Quinoline derivatives have aroused great interest due to
their extremely versatile small framework, could be easily
synthesized at low cost on a large scale and have well-
known biochemical properties that make them suit-
able pharmacophore structures (Tabarrini et al., 2008). So,
1
N
2
N
N N
2'
ClCH2COOH
5
3'
4'
1'
6'
SH
SCH2COOH
3
N
H
4
N
R
H
NaOH(aq), MW,
100 oC
R
5'
The catalytic activities of 2-(5-aryl-4H-1,2,4-triazol-3-
ylthio)acetic acids as homogeneous catalysts were studied
for the one-pot multicomponent synthesis of 2-amino-4-
aryl-3,6-disubstituted quinolines, under microwave irradi-
ation in EtOH/water at 100 °C. In order to select the
in this part of study, we decided to investigate the three-
component reaction of anilines, aldehydes and malononi-
trile or ethyl cyanoacetate using A as catalyst in ethanol–
water mixture at 100 °C. The resulting products, 2-amino-
4-aryl-3,6-disubstituted quinolines were obtained in good
yield. To determine the scope of the designed protocol, a
number of commercially available aldehydes and aromatic
amines were chosen, and the results are summarized in
Table 2.
appropriate
organocatalyst,
4-bromobenzaldehyde,
malononitrile and 4-bromoaniline were selected as the test
substrates, and the reaction was carried out using 2-[5-(4-
methoxyphenyl)-4H-1,2,4-triazol-3-ylthio]acetic
acid,
2-(5-phenyl-4H-1,2,4-triazol-3-ylthio)acetic acid and 2-[5-
(4-nitrophenyl)-4H-1,2,4-triazol-3-ylthio]acetic acid in
EtOH/water at 100 °C under microwave irradiation
(200 W). The results are presented in Table 1, which
indicated that out of various catalysts, 2-[5-(4-methox-
yphenyl)-4H-1,2,4-triazol-3-ylthio]acetic acid exhibited
the highest activity.
Synthesis of 7-amino-3,5-bis(aryl)-6-substituted-
8aH-thiazolo[3,2-a]pyrimidines
In the past decade, lot of work has been devoted to thiazolo-
pyrimidines, as they possess remarkable pharmacological
properties, and their potential value as therapeutic compo-
nents for antimicrobial agents has also been studied (Abd
et al., 2008). Keeping in view the importance of thiazolo-
pyrimidines, we decided to investigate the reaction of
Reaction of 4-bromobenzaldehyde (0.185 g, 1 mmol),
malononitrile (0.66 g, 1 mmol) and 4-bromoaniline
(0.172 g, 1 mmol) was also performed thermally using
Table 1 Effect of organocatalysts on the one-pot synthesis of 2-amino-4-aryl-3,6-disubstituted quinolines under microwave irradiation (200 W)
in EtOH/water at 100°C
Entry
Catalyst
Time (h)
Yield (%)a
1
2
3
2-[5-(4-Methoxyphenyl)-4H-1,2,4-triazol-3-ylthio]acetic acid (A)
2-(5-Phenyl-4H-1,2,4-triazol-3-ylthio)acetic acid (B)
1
91
70
60
1.5
2
2-[5-(4-Chlorophenyl)-4H-1,2,4-triazol-3-ylthio]acetic acid (C)
The most active catalyst (A) selected out of the three catalysts (A, B, C) for carrying out the reactions are highlighted in bold
Reaction conditions: Aniline (1 mmol), aldehyde (1 mmol), malononitrile (1 mmol) and catalyst (0.066 g, 25 mol%) were taken in 10 mL
microwave reaction tube, and C2H5OH–H2O mixture (5 mL) was added and stirred at 100 °C in a microwave synthesizer (200 W)
a
Isolated yield
123

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Med Chem Res (2016) 25:951–969
Table 2 Three-component one-pot synthesis of 2-amino-4-aryl-3,6-disubstituted quinolines
R'
4'
5'
3'
NH2
CHO
A,
6'
2'
1'
4
Ethanol-H2O,
NC
X
5
8
10
6
R
X
MW, 100 oC
3
7
9
2
N
NH2
R
R'
1
3
1
2
4
NO2
Br
NO2
Cl
N
Cl
CN
Br
CN
NH2
Cl
CN
Cl
CN
N
NH2
N
NH2
NH2
N
4a: 1.5 h, 89%
4b: 1.2 h, 92%
4c: 1.4 h, 91%
4d: 1 h, 89%
Cl
Br
NO2
Br
Br
CN
Br
CN
NH2
Cl
COOC2H5
NH2
Cl
COOC2H5
NH2
N
NH2
N
N
N
4e: 1.1 h, 90%
4f: 1.2 h, 92%
4g: 1.5 h, 89%
4h: 1.3 h, 92%
Cl
Cl
NO2
Br
Cl
COOC2H5
Br
COOC2H5
NH2
Br
COOC2H5
NH2
Br
COOC2H5
NH2
N
NH2
N
N
N
4i: 1.4 h, 91%
4j: 1 h, 91%
4k: 1.1 h, 89%
4l: 1.2 h, 93%
Reaction conditions: Aniline (1 mmol), aldehyde (1 mmol), malononitrile/ethyl cyanoacetate (1 mmol) and catalyst A (0.066 g, 25 mol%) were
taken in a vial (10 mL), and C2H5OH–H2O mixture (2:3, 5 mL) was added and stirred at 100 °C in a microwave synthesizer (200 W). Yield
refers to isolated yield
2-aminothiazoles, aldehydes and malononitrile or ethyl
cyanoacetate using A as catalyst in ethanol–water mixture at
100 °C, leading to the formation of 7-amino-3,5-bis(aryl)-6-
substituted-8aH-thiazolo[3,2-a]pyrimidines. To determine
the scope of the developed protocol, different aldehydes,
2-amino-4-arylthiazoles and malononitrile or ethyl
cyanoacetate were condensed under the optimized condi-
tions, and the results are summarized in Table 3.
aldehyde and malononitrile in the presence of A (Fig. 2).
Organocatalyst A reacts with aldehyde to give interme-
diate I, which on reaction with active methylene com-
pound gave intermediate II. Intermediate II lose A to
generate intermediate III, which again combines with
A to give intermediate IV. Intermediate IV on reaction
with 2-aminothiazole gave intermediate V, which subse-
quently undergoes an intramolecular cyclization to yield
the desired product and organocatalyst A is regenerated
back.
Following mechanism has been proposed for the three-
component reaction between 2-amino-4-arylthiazole,
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Med Chem Res (2016) 25:951–969
955
Table 3 Three-component reaction of 2-aminothiazoles, aldehydes and active methylene compound using 3-triazolylthioacetic acid as catalyst
R
4"
5"
CHO
3"
R
5'
4'
2"
R'
6'
6"
6
NC
X
A,
1"
N
5
4
Ethanol-H2O,
MW, 100 oC
X
3
3'
1'
N
2'
NH2
S
R'
7
2
9
H2N
N
S
8
1
5
7
6
8
Cl
N
Br
Cl
Cl
NC
Cl
NO2
NC
NC
H2N
N
N
N
H2N
S
H2N
N
S
N
S
8a: 1.5 h, 88%
8b: 1.25 h, 86%
8c: 1.3 h, 89%
Br
Cl
Br
Cl
Cl
NO2
OCH3
C2H5OOC
C2H5OOC
N
NC
N
N
H2N
N
S
H2N
N
S
H2N
N
S
8d: 1.5 h, 85%
8e: 1.25 h, 87%
8f: 1.5 h, 89%
Cl
Br
NO2
C2H5OOC
NO2
C2H5OOC
H2N
N
N
N
S
H2N
N
S
8g: 1.25 h, 88%
8h: 1.5 h, 87%
Reaction conditions: 2-Aminothiazole (1 mmol), aldehyde (1 mmol), malononitrile/ethyl cyanoacetate (1 mmol) and catalyst A (0.066 g,
25 mol%) were taken in a vial (10 mL) and EtOH–H2O mixture (2:3, 5 mL) was added and stirred at 100 °C in a microwave synthesizer
(200 W). Yield refers to isolated yield
Synthesis of 7-amino-5-aryl-2-(4-methoxyphenyl)-6-
substituted-8aH-[1,3,4]thiadiazolo[3,2-a]pyrimidines
we have extended our work for the one-pot synthesis of
thiadiazolo-pyrimidine derivatives by the three-component
reaction between 2-amino-4-(4-methoxyphenyl)thiadia-
zole, aromatic aldehydes and malononitrile or ethyl
cyanoacetate using A as catalyst in ethanol–water mixture
at 100 °C. To demonstrate the versatility of the developed
protocol, various substituted aldehydes and 2-amino-4-
arylthiadiazoles were condensed with malononitrile or
ethyl cyanoacetate under the optimized reaction conditions,
and excellent results were obtained (Table 4).
Thiadiazolo-pyrimidine motif plays an important role in
the medicinal chemistry because it possess promising
anticancer, antioxidant, antimicrobial, antitubercular,
antiparkinsonian, anti-inflammatory, analgesic and anti-
HIV activities (Shekhar et al., 2011). Since these systems
serve as useful synthetic intermediates and are the
promising candidates for the development of new drugs,
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Med Chem Res (2016) 25:951–969
Fig. 2 Proposed mechanism for
the one-pot three-component
synthesis of thiazolo[3,2-a]
pyrimidines using A as catalyst
HO
O
NH2
N
NC
N
N
Ar
H3CO
SCH2COOH
N
H
A
R
N
S
Ar
R'
OOCH2CS
N
Ar
Ar'
CN
N
OCH3
N
N
I
S
NH2
NH2
OCH3
NC CN
N
HOOCH2CS
R'
N
N
NC
V
N
Ar
CN
NH2
S
OCH3
N
OOCH2CS
H3CO
N
N
N
N
II
N
SCH2CH3OO
H2N
CN
NC
IV
NC
Ar
H
N
OCH3
HOOCH2CS
Ar
H
N
N
N
III
OCH3
HOOCH2CS
N
N
Synthesis of 6-amino-8-aryl-3-methyl-7-substituted-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepines
used were Aspergillus niger, Aspergillus Flavus and Pen-
cillium Species. The screening data indicated that these
compounds showed good activity against tested micro-or-
ganism strains. Compounds 12d and 16h exhibited com-
parable activity with standard Fluconazole against A. niger
and A. flavus, whereas compounds 4d, 4k, 12g and 12i also
showed good activity. Antifungal activity was determined
by measuring the diameter of the inhibition zone. The
results of the studies are given in Table 6.
A number of triazoles fused to thiadiazepines are incor-
porated into a wide variety of therapeutically important
compounds possessing a broad spectrum of biological
activities (Holla et al., 2002), particularly antiviral activity
and cytotoxicity in various viral test systems. So, we
decided to extend the same reaction conditions for the
synthesis of s-triazolo[3,4-b][1,3,4]thiadiazepine deriva-
tives by replacing 2-amino-4-arylthiadiazole with mercapto
amino triazole, keeping all other substrates same, in the
presence of A in ethanol–water mixture at 100 °C. The
reaction worked efficiently for different aldehydes, and
products (16a–h) were obtained in good yield (Table 5).
Experimental
Preparation of the medium
Potato dextrose agar–agar medium was prepared following
the already reported method (Liu et al., 2002) with slight
modification.
Antimicrobial activity
Potato = 250 g; Dextrose = 10 g; Agar–agar = 20 g;
Distilled water = 1000 mL.
Heterocyclic compounds exhibit a broad spectrum of bio-
logical activities. Keeping in view the biological impor-
tance of condensed heterocycles, some of the synthesized
compounds were evaluated for the antifungal and
antibacterial activity.
Sliced potatoes (250 g) were boiled in distilled water
(1000 mL) for half an hour and filtered while hot. Dextrose
(10 g) and agar–agar (20 g) were added to the above fil-
trate and further heated for 30 min. Petri dishes must be
completely sterilized before they are used for growing
fungi. Warm potato dextrose agar solution was poured into
the petri dish just enough to form a layer over the bottom of
the dish. Quickly petri dish was covered to prevent any
airborne bacteria from contamination during the experi-
ment. Petri dishes were kept aside for 30 min to 1 h, until
Antifungal activity
Fungicidal activities of some of the synthesized com-
pounds were studied on potato dextrose agar (PDA) med-
ium using plate dilution method. Micro-organism strains
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Med Chem Res (2016) 25:951–969
957
Table 4 One-pot synthesis of 7-amino-5-aryl-2-(4-methoxyphenyl)-6-substituted-8aH-[1,3,4]thiadiazolo[3,2-a]pyrimidines via cyclization of
thiadiazole, aldehyde and active methylene compound
R
4"
5"
6"
3"
2"
CHO
A,
1"
N
N
Ethanol-H2O,
5
4
NC
X
X
N
N3
6
NH2
MW, 100 oC
6'
S
1'
2'
H3CO
5'
4'
OCH3
9
7
2
H2N
N
S
8
R'
1
3'
11
9
10
12
Cl
Br
ORGANOCATALYST
NC
ORGANOCATALYST
NC
H2N
NC
N
N
N
N
N
N
H2N
OCH3
N
S
N
S
H2N
N
S
OCH3
OCH3
12a: 1.5 h, 92%
12b: 1.5 h, 86%
12c: 1.3 h, 87%
NO2
CH3
Cl
ORGANOCATALYST
ORGANOCATALYST
NC
ORGANOCATALYST
NC
C2H5OOC
H2N
N
N
N
N
N
N
H2N
N
S
N
S
H2N
N
S
OCH3
OCH3
OCH3
12d: 1.5 h, 88%
12e: 1.25 h, 85%
12f: 1.3 h, 89%
Br
NO2
C2H5OOC
C2H5OOC
H2N
C2H5OOC
H2N
N
N
N
N
N
N
H2N
N
S
N
S
N
S
OCH3
OCH3
12i: 1.3 h, 88%OCH
3
12g: 1.5 h, 90%
12h: 1.25 h, 86%
CH3
C2H5OOC
H2N
N
N
N
S
OCH3
12 j: 1.5h, 86%
Reaction conditions: 2-Aminothiadiazole (1 mmol), aldehyde (1 mmol), malononitrile/ethyl cyanoacetate (1 mmol) and catalyst A (0.066 g,
25 mol%) were taken in a vial (10 mL), and EtOH–H2O mixture (2:3, 5 mL) was added and stirred at 100 °C in a microwave synthesizer
(200 W). Yield refers to isolated yield
the agar solution was cooled and hardened followed by
storing in the refrigerator.
A. Flavus and P. Species) was spread on a 48-h-old culture
grown on potato dextrose agar (PDA) medium. After 15 min,
punch into the agar surface with sterile cork borer of size
6 mm and scoop out the punch part of agar. Three such cups
were made into each petri dish. Two concentrations viz. 500
and 1000 lg/mL of the synthesized compounds in DMSO
were added into two cups, respectively, and other one was
Procedure
Antifungal activity assay was carried out by agar well diffu-
sion method. 0.1 mL of test fungal spore suspension (A. niger,
123

958
Med Chem Res (2016) 25:951–969
Table 5 Synthesis of 6-amino-8-aryl-3-methyl-7-substituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepines via three-component reaction of
4-amino-3-methyl-5-mercapto-1,2,4-triazole, aromatic aldehyde and active methylene compound
1
N
2
5'
CHO
6'
9
N
10
4'
R'
S
A,
N
N
3
8
Ethanol-H2O,
NC
X
4N
5N
1'
H3C
H3C
SH
3'
N
2'
MW, 100 oC
7
X
6
NH2
R'
NH2
13
14
15
16
N
N
N
N
N
N
N
N
N
S
Br
H3C
S
Cl
S
H3C
H3C
N
N
N
CN
CN
CN
NH2
NH2
NH2
16a: 1.5 h, 86%
16b: 1.5 h, 87%
16c: 1.25 h, 86%
N
N
N
N
N
S
N
N
NO2
H3C
Br
Cl
H3C
S
S
N
N
N
H3C
N
N
CN
COOC2H5
COOC2H5
NH2
NH2
NH2
16d: 1 h, 88%
16e: 1.3 h, 90%
16f: 1.5 h, 88%
N
N
N
N
NO2
S
S
N
N
N
N
H3C
H3C
COOC2H5
COOC2H5
NH2
NH2
16g: 1.5h, 89%
16h: 1.5h, 87%
Reaction conditions: 4-Amino-3-methyl-5-mercapto-1,2,4-triazole (1 mmol), aldehyde (1 mmol), malononitrile/ethyl cyanoacetate (1 mmol)
and catalyst A (0.066 g, 25 mol%) were taken in a vial (10 mL), and C2H5OH-H2O mixture (2:3, 5 mL) was added and stirred at 100 °C in a
microwave synthesizer. Yield refers to isolated yield
filled with pure DMSO. The plates were then incubated for
48 h at 28 2 °C, and inhibition zone around each disc was
measured from the centre of the discs. Each experiment was
done in triplicate to get an average result.
screened for their antibacterial activity against E. coli, B.
subtilus, P. aeruginosa, K. pneumonia and E. faciolus bac-
terial strains by disc diffusion method (Cruickshank et al.,
1975). The compounds 12g and 12i showed comparable
activity with drug streptomycin, whereas compounds 8g, 12a,
12d, 16a, 16b and 16h also showed good activity. The results
of the studies are presented in Table 8. Antibacterial activity
was determined by measuring the diameter of the inhibition
zone. The medium used for evaluationof antibacterial activity
was nutrient agar medium.
Minimum inhibition concentration (MIC) is the lowest
antimicrobial concentration that will inhibit the visible growth
of micro-organism after overnight incubation. MIC is studied
in agar dilution method. MIC of some of the compounds is
given in Table 7. Compound 16h has shown best antifungal
activity with MIC value of 60 lg/mL against A. niger.
Antibacterial activity
Experimental
Five different species of bacteria are used in the study to
explore the effectiveness of the synthesized compounds. The
bacteria chosen for the study are both gram positive and gram
negative, and all bacteria Genera have significant interaction
with humans. Some of the synthesized compounds were
Preparation of the medium
Nutrient agar medium was prepared by the following
procedure:
123

Med Chem Res (2016) 25:951–969
959
Table 6 Antifungal activity of quinolines, thiazolo[3,2-a]pyrimidines, thiadiazolo[3,2-a]pyrimidines and triazolo[3,4-b][1,3,4]thiadiazepines
Entry
Zone of inhibition (%)
A. niger
A. Flavus
500
P. Species
500
500
1000
1000
1000 (lg/mL)
Control
4b
0
20
24
22
25
08
09
18
05
25
20
22
18
24
20
23
28
44
0
27
32
27
31
12
15
27
11
33
28
30
26
32
27
30
37
49
0
30
31
28
27
12
07
21
09
32
35
31
30
29
34
32
33
35
0
37
39
32
34
20
17
30
14
41
44
40
31
38
41
41
44
43
0
10
07
12
09
28
32
16
28
10
06
09
07
09
10
12
06
52
0
15
12
19
17
37
41
22
37
15
09
10
09
14
15
19
09
45
4d
4h
4k
8c
8d
8f
8 g
12a
12d
12g
12i
16a
16b
16f
16h
Fluconazole
The percentage zone of inhibition was calculated by the formula
where I = inhibition, C = diameter of zone of micro-organisms in check, and T = diameter of the disc
The zone of inhibition was measured after 48 h; fluconazole (500 and 1000 lg/mL) was used as control standard
Table 7 Minimum inhibition concentration (MIC, lg/mL) of com-
pounds having good antifungal activity
Nutrient agar = 50 g;
Distilled water = 300 mL
Compounds
A. niger
A. Flavus
P. Species
In a 500-mL beaker, nutrient agar (50 g) was added in hot
water (300 mL) and stirred in a microwave oven until agar
powder was completely dissolved and a clear solution was
obtained. Petri dishes must be completely sterilized before
they are used for growing bacteria. Warm potato dextrose
agar solution was poured into the bottom half of the petri dish
just enough to form a layer over the bottom of the dish.
Quickly petri dish was covered to prevent any airborne bac-
teria from contamination during the experiment. Petri dishes
were kept aside for 30 min to 1 h, until the agar solution was
cooled and hardened followed by storing in the refrigerator.
4d
100
108
110
85
85
120
100
100
70
90
100
90
4 k
12 g
12i
125
105
8
16 h
60
Fluconazole
15
11
dissolving the required quantity of compounds in DMSO
were added into two cups, respectively, and other one is filled
with pure DMSO. The plates were then incubated for 48 h at
37 2 °C, and inhibition zone around each disc was mea-
sured from the centre of the discs. Each experiment was done
in triplicate to get an average result. The percentage zone of
inhibition was calculated by the formula:
Procedure
Antibacterial activity assay was carried out by agar disc dif-
fusion method. 0.1 mL of testbacterial suspension (E. coli, B.
subtilus, P. aeruginosa, K. pneumonia and E. faciolus) was
spread on a 48-h-old culture of nutrient agar. After 15 min,
punch into the agar surface with sterile cork borer of size
6 mm and scoop out the punch part of agar. Three such cups
were made into each petri dish. Two concentrations viz. 500
and 1000 lg/mL of the synthesized compounds prepared by
C À T
I% ¼
 100
C
where I = inhibition, C = diameter of zone of micro-or-
ganisms in check, and T = diameter of the disc.The zone
of inhibition was measured after 48 h; streptomycin (500
and 1000 lg/mL) was used as control standard.
123

960
Med Chem Res (2016) 25:951–969
Table 8 Antibacterial activity of quinolines, thiazolo[3,2-a]pyrimidines, thiadiazolo[3,2-a]pyrimidines and triazolo[3,4-b][1,3,4]thiadiazepines
Entry
Zone of inhibition (%)
E. coli
B. subtilus
500
P. aeruginosa
K. pneumonia
E. faciolus
500
500
1000
1000
500
1000
500
1000
1000 (lg/mL)
Control
0
09
08
10
13
18
20
19
20
24
26
29
27
26
29
26
30
13
0
13
15
17
19
27
31
29
30
30
34
40
38
33
30
29
31
44
0
14
10
11
16
22
19
20
22
14
11
14
16
21
19
24
21
14
0
20
18
18
23
30
34
36
35
21
24
21
27
29
25
32
30
20
0
16
18
20
19
09
07
10
12
18
16
15
16
18
23
26
21
16
0
25
30
31
26
15
13
18
20
25
23
27
29
25
30
31
32
25
0
12
16
18
14
23
21
24
24
30
32
30
32
18
19
20
17
12
0
25
30
29
28
35
30
33
29
41
44
38
40
28
29
31
27
25
0
18
21
22
20
11
13
10
08
19
19
21
20
20
21
24
26
18
0
29
34
34
27
23
22
19
09
29
30
29
27
28
30
36
38
29
4b
4d
4 h
4 k
8c
8d
8f
8 g
12a
12d
12g
12i
16a
16b
16f
16 h
Streptomycin
Esquire 3000 Bruker Daltonics spectrometer. IR spectra
were recorded on a PerkinElmer FTIR spectrophotometer.
All the reactions were performed using CEM discover
microwave synthesizer and were monitored by TLC using
0.25-mm silica gel plates. All melting points were taken on
Perfit melting point apparatus and are uncorrected. All
other reagents and solvents were purified after receiving
from commercial suppliers.
Conclusions
In summary, we have synthesized quinolines, thiazolo[3,2-
a]pyrimidines, thiadiazolo[3,2-a]pyrimidines and tria-
zolo[3,4-b][1,3,4]thiadiazepines by the three-component
coupling of anilines/2-aminothiazoles/2-aminothiadiazoles/
4-aminotriazoles, aldehydes and malononitrile/ethyl
cyanoacetate using 2-[5-(4-methoxyphenyl)-4H-1,2,4-tria-
zole-3-ylthio]acetic acid (A) as organocatalyst. A variety
of these compounds were produced in a single step with
good to excellent yields. Some of the synthesized com-
pounds showed good antifungal and antibacterial activities.
Minimum inhibition concentration (MIC) of some of the
compounds is given in Table 9. Compound 12g exhibited
best antibacterial activity with MIC value of 50 lg/mL
against E. coli.
Synthesis of 2-[5-(4-methoxyphenyl)-4H-1,2,4-
triazol-3-ylthio]acetic acid (A)
White crystalline solid (water) (This compound was pre-
pared by the reaction of 5-(4-methoxyphenyl)-4H-1,2,4-
triazole-3-thiol (1.035 g, 0.005 mol) and chloroacetic acid
(0.940 g, 0.1 mol) in 30 % NaOH solution (5 mL) at
100 °C in a microwave synthesizer (200 W) for 15 min.
The reaction was cooled to room temperature using cooling
system built in a microwave synthesizer followed by
acidification with conc. HCl.) 2-[5-(4-Methoxyphenyl-4H-
1,2,4-triazol-3-ylthio] acetic acid was separated out as
white crystalline solid, which was filtered and dried
(0.89 g, 86 %); M.p. 180 °C; IR (Vmax cm-1, KBr): 3373,
2924, 1713, 1369 and 1290; 1H NMR (acetone-d6,
400 MHz): d = 3.33 (3H, s, OCH3), 3.88 (1H, s, NH,
Experimental
General
1H NMR spectra were recorded on a Bruker Avance III
spectrometer (400 MHz) using TMS as an internal standard
and 13C NMR spectra at 100 MHz. The coupling constants
(J) are given in Hz. Mass spectra were recorded on ESI-
123

Med Chem Res (2016) 25:951–969
961
Table 9 Minimum inhibition concentration (MIC, lg/mL) of compounds having good antibacterial activity
Compounds
E. coli
B. subtilus
P. aeruginosa
K. pneumonia
E. faciolus
8 g
60
55
58
40
50
56
52
68
4
80
65
70
55
43
75
83
80
16
85
90
85
45
75
85
68
85
6
90
95
90
60
88
64
85
90
2
100
90
12a
12d
110
40
12 g
12i
70
16a
100
105
92
16b
16 h
Streptomycin
12
H-30, H-50, H-60); 13C NMR (100 MHz, CDCl3): d = 113.8
(C, C-3), 115.6 (C, C-10, CN), 121.6 (C, C-5), 130.1 (C,
C-7), 131.6 (C, C-8), 131.9 (C, C-6), 132.0 (C, C-10), 132.4
(C, C-30, C-50), 133.1 (C, C-20, C-60), 146.2 (C, C-40), 151.7
(C, C-9), 163.7 (C, C-4) and 171.3 (C, C-2); MS (ESI): 325
(M?).
exchangeable with D2O), 4.92 (2H, s, CH2), 7.03–7.05 (2H,
d, H-30, H-50), 8.00–8.02 (2H, d, H-20, H-60); 13C NMR
(Acetone-d6, 100 MHz): d 33.2 (S-CH2-CO), 54.6 (OCH3),
113.3 (C-30, C-50) 122.7 (C-10), 131.25 (C-20, C-60), 159.2
(C-3, C-5), 163.7 (C-40), 168.4(C=O); MS (ESI): 266
(M ? 1), 248 (M-17), 220 (M-45).
2-Amino-6-chloro-4-(4-bromophenyl)quinoline-3-carboni-
trile (4b) Light brown crystalline solid (EtOH) (This
compound was prepared from 4-chloroaniline (1 mmol),
4-bromobenzaldehyde (1 mmol) and malononitrile
(1 mmol) using catalyst A (0.066 g, 25 mol%) in EtOH–
H2O mixture (2:3, 5 mL) at 100 °C in a microwave syn-
thesizer. The product was obtained as light brown crys-
talline solid); M.p. 152–153 °C; IR (KBr) tmax 3373, 3034,
Representative procedure for the one-pot synthesis
of quinolines, thiazolo[3,2-a]pyrimidines,
thiadiazolo[3,2-a]pyrimidines and triazolo[3,4-
b][1,3,4]thiadiazepines
In a typical experimental procedure, amino compound
(1 mmol), aromatic aldehyde (1 mmol), malononitrile/
ethyl cyanoacetate (1 mmol) and catalyst A (0.066 g,
25 mol%) were taken in a vial (10 mL), and EtOH–H2O
mixture (2:3, 5 mL) was added, and the reaction mixture
was stirred at 100 °C in a microwave synthesizer (200 W)
until all reactants were consumed (monitored by TLC).
After completion of the reaction, product was extracted
with ethyl acetate (3 9 10 mL) and organic layer was
dried over anhydrous sodium sulphate. Finally, the product
was obtained after removal of the solvent under reduced
pressure followed by crystallization from ethanol.
2225, 1151 cm-1
;
1H NMR (400 MHz, Acetone):
d = 3.92 (2H, s, NH2, exchangeable with D2O), 7.26–7.28
(2H, d, J = 8 Hz, H-20, H-60), 7.58–7.62 (3H, m, H-5, H-7,
H-8), 8.01–8.03 (2H, d, J = 8 Hz, H-30, H-50); 13C NMR
(100 MHz, Acetone): d = 113.6 (C, C-3), 118.6 (C, C-10,
CN), 123.0 (C, C-5, C-40), 128.9 (C, C-8), 130.3 (C, C-20,
C-60), 131.6 (C, C-7, C-30, C-50), 132.2 (C, C-6), 136.9 (C,
C-10), 150.9 (C, C-9), 159.9 (C, C-4) and 165.8 (C, C-2);
MS (ESI): 359 (M?).
2-Amino-6-chloro-4-(4-chlorophenyl)quinoline-3-carboni-
1
The structures of the products were confirmed by H
NMR, 13C NMR, FTIR and mass spectral data.
trile (4c) White crystalline solid (EtOH) (This compound
was
prepared
from
4-chloroaniline
(1 mmol),
4-chlorobenzaldehyde (1 mmol) and malononitrile
(1 mmol) using catalyst A (0.066 g, 25 mol%) in EtOH–
H2O mixture (2:3, 5 mL) at 100 °C in a microwave syn-
thesizer. The product was obtained as white crystalline
solid); M.p. 85–86 °C; IR (KBr) tmax 3358, 3064, 2232,
1130 cm-1; 1H NMR (400 MHz, MeOD): d = 3.89 (2H, s,
NH2, exchangeable with D2O), 7.00–7.02 (2H, d,
J = 8 Hz, H-30, H-50), 7.78–7.92 (2H, m, H-7, H-8),
7.99–8.01 (2H, d, J = 8 Hz, H-20, H-60), 8.22 (1H, s, H-5);
13C NMR (100 MHz, MeOD): d = 113.3 (C, C-3), 116.1
(C, C-10, CN), 122.7 (C, C-5), 131.4 (C, C-6, C-40), 131.8
2-Amino-6-chloro-4-(4-nitrophenyl)quinoline-3-carbonitrile
(4a) Pale yellow crystalline solid (EtOH) (This com-
pound was prepared from 4-chloroaniline (1 mmol), 4-ni-
trobenzaldehyde (1 mmol) and malononitrile (1 mmol)
using catalyst A (0.066 g, 25 mol%) in EtOH–H2O mix-
ture (2:3, 5 mL) at 100 °C in a microwave synthesizer. The
product was obtained as pale yellow crystalline solid); M.p.
239–240/240–245 °C (Nezhad et al., 2012); IR (KBr) tmax
3374, 3099, 2226, 1096 cm-1
;
1H NMR (400 MHz,
CDCl3): d = 3.91 (2H, s, NH2, exchangeable with D2O),
7.53–7.89 (3H, m, H-5, H-7, H-8), 8.07–8.11 (4H, m, H-20,
123

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Med Chem Res (2016) 25:951–969
(C, C-30, C-50), 132.5 (C, C-8, C-20, C-60), 132.6 (C, C-7,
C-10), 159.1 (C, C-9), 163.4(C, C-4) and 170.7 (C, C-2);
MS (ESI): 314 (M?).
C-10), 145.1 (C, C-9), 160.6 (C, C-4) and 174.2 (C, C-2);
MS (ESI): 359 (M?).
Ethyl 2-amino-6-chloro-4-(4-nitrophenyl)quinoline-3-car-
boxylate (4g) Creamish white crystalline solid (EtOH)
(This compound was prepared from 4-chloroaniline
(1 mmol), 4-nitrobenzaldehyde (1 mmol) and ethyl
2-Amino-6-bromo-4-(4-nitrophenyl)quinoline-3-carbonitrile
(4d) Yellow crystalline solid (EtOH) (This compound
was prepared from 4-bromoaniline (1 mmol), 4-nitroben-
zaldehyde (1 mmol) and malononitrile (1 mmol) using
catalyst A (0.066 g, 25 mol%) in EtOH–H2O mixture (2:3,
5 mL) at 100 °C in a microwave synthesizer. The product
was obtained as yellow crystalline solid); M.p. 174–176/
175–176 °C (Nezhad et al., 2012); IR (KBr) tmax 3373,
cyanoacetate (1 mmol) using catalyst
A
(0.066 g,
25 mol%) in EtOH–H2O mixture (2:3, 5 mL) at 100 °C in
a microwave synthesizer. The product was obtained as
creamish white crystalline solid); M.p. 162–163 °C; IR
1
(KBr) tmax 3356, 3062, 2889, 1683, 1103 cm-1; H NMR
3070, 2225, 1095 cm-1
;
1H NMR (400 MHz, MeOD):
(400 MHz, Acetone): d = 1.35–1.39 (3H, t, J = 8 Hz,
CH2CH3), 3.90 (2H, s, NH2, exchangeable with D2O),
4.35–4.41 (2H, q, CH2CH3), 7.02–7.04 (2H, d, J = 8 Hz,
H-7, H-8), 7.67–7.69 (2H, d, J = 8 Hz, H-20, H-60),
7.99–8.14 (2H, m, H-30, H-50), 8.38 (1H, s, H-5); 13C NMR
(100 MHz, acetone): d = 14.3 (CH3, O–CH2CH3), 54.7
(CH2, O–CH2CH3), 113.6 (C, C-3), 115.2 (C, C-10), 129.3
(C, C-8, C-20, C-60), 131.6 (C, C-30, C-50), 131.9 (C, C-6),
132.2 (C, C-7), 133.4 (C, C-5), 142.7 (C, C-10), 149.1 (C,
C-40), 152.8 (C, C-9), 155.8 (C, C-4), 166.3 (C, C=O) and
170.9 (C, C-2); MS (ESI): 372 (M?).
d = 3.89 (2H, s, NH2, exchangeable with D2O), 7.00–7.02
(2H, d, J = 8 Hz, H-20, H-60), 7.63–7.65 (2H, d, J = 8 Hz,
H-7, H-8), 7.99–8.01 (2H, d, J = 8 Hz, H-30, H-50), 8.24
(1H, s, H-5); 13C NMR (100 MHz, MeOD): d = 113.3 (C,
C-3), 115.2 (C, C-10, CN), 122.4 (C, C-6, C-30, C-50),
129.4 (C, C-8), 131.4 (C, C-5), 131.8 (C, C-7, C-20, C-60),
139.7 (C, C-10), 147.9 (C, C-40), 151.14 (C, C-9), 159.8 (C,
C-4) and 174.4 (C, C-2); MS (ESI): 369 (M?).
2-Amino-6-bromo-4-(4-bromophenyl)quinoline-3-carboni-
trile (4e) Pale yellow crystalline solid (EtOH) (This
compound was prepared from 4-bromoaniline (1 mmol),
4-bromobenzaldehyde (1 mmol) and malononitrile
(1 mmol) using catalyst A (0.066 g, 25 mol%) in EtOH–
H2O mixture (2:3, 5 mL) at 100 °C in a microwave syn-
thesizer. The product was obtained as pale yellow crys-
talline solid); M.p. 142–143 °C; IR (KBr) tmax 3359, 3111,
Ethyl
2-amino-6-chloro-4-(4-bromophenyl)quinoline-3-
carboxylate (4h) Creamish white crystalline solid (EtOH)
(This compound was prepared from 4-chloroaniline
(1 mmol), 4-bromobenzaldehyde (1 mmol) and ethyl
cyanoacetate (1 mmol) using catalyst
A
(0.066 g,
25 mol%) in EtOH–H2O mixture (2:3, 5 mL) at 100 °C in
a microwave synthesizer. The product was obtained as
creamish white crystalline solid); M.p. 115–116 °C; IR
1
2253, 1081 cm-1; H NMR (400 MHz, CDCl3): d = 3.88
(2H, s, NH2, exchangeable with D2O), 7.52–7.54 (2H, d,
J = 8 Hz, H-20, H-60), 7.77 (1H, s, H-5), 7.85–7.89 (4H, m,
H-7, H-8, H-30, H-50); 13C NMR (100 MHz, CDCl3):
d = 112.4 (C, C-3), 113.5 (C, C-10, CN), 127.7 (C, C-5,
C-40), 129.3 (C, C-6, C-20, C-60), 130.1 (C, C-30, C-50)
131.9 (C, C-8), 132.0 (C, C-7), 141.1 (C, C-10), 150.6 (C,
C-9), 158.37 (C, C-4) and 176.9 (C, C-2); MS (ESI): 403
(M?).
1
(KBr) tmax 3373, 3096, 2943, 1686, 1101 cm-1; H NMR
(400 MHz, Acetone): d = 1.35–1.39 (3H, t, J = 8 Hz,
CH2CH3), 3.90 (2H, s, NH2, exchangeable with D2O),
4.36–4.41 (2H, q, CH2CH3), 7.03–7.05 (2H, d, J = 8 Hz,
H-20, H-60), 7.25–7.27 (2H, d, J = 8 Hz, H-7, H-8),
7.59–8.03 (3H, m, H-5, H-30, H-50); 13C NMR (100 MHz,
acetone): d = 13.51 (CH3, O–CH2CH3), 54.9 (CH2, O–
CH2CH3), 113.7 (C, C-3), 115.4 (C, C-10), 123.0 (C, C-5,
C-40), 129.8 (C, C-6, C-20, C-60), 130.5 (C, C-8), 132.2 (C,
C-30, C-50), 132.5 (C, C-7, C-10), 159.9 (C, C-9), 161.8 (C,
C-4), 166.5 (C, C=O) and 172.2 (C, C-2); MS (ESI): 406
(M?).
2-Amino-6-bromo-4-(4-chlorophenyl)quinoline-3-carboni-
trile (4f) White crystalline solid (EtOH) (This compound
(1 mmol),
was
prepared
from
4-bromoaniline
4-chlorobenzaldehyde (1 mmol) and malononitrile
(1 mmol) using catalyst A (0.066 g, 25 mol%) in EtOH–
H2O mixture (2:3, 5 mL) at 100 °C in a microwave syn-
thesizer. The product was obtained as white crystalline
solid); M.p. 152–153 °C; IR (KBr) tmax 3374, 3068, 2226,
1096 cm-1; 1H NMR (400 MHz, MeOD): d = 3.89 (2H, s,
NH2, exchangeable with D2O), 7.41–8.01 (6H, m, H-7,
H-8, H-20, H-30, H-50, H-60), 8.25 (1H, s, H-5); 13C NMR
(100 MHz, MeOD): d = 113.3 (C, C-3), 115.2 (C, C-10,
CN), 128.4 (C, C-6, C-20, C-60), 129.1 (C, C-8, C-30, C-50),
130.4 (C, C-5), 131.2 (C, C-40), 131.5 (C, C-7), 134.0 (C,
Ethyl
2-amino-6-chloro-4-(4-chlorophenyl)quinoline-3-
carboxylate (4i) Creamish white crystalline solid (EtOH)
(This compound was prepared from 4-chloroaniline
(1 mmol), 4-chlorobenzaldehyde (1 mmol) and ethyl
cyanoacetate (1 mmol) using catalyst
A
(0.066 g,
25 mol%) in EtOH–H2O mixture (2:3, 5 mL) at 100 °C in
a microwave synthesizer. The product was obtained as
creamish white crystalline solid); M.p. 164–165 °C; IR
1
(KBr) tmax 3362, 3084, 2983, 1695, 1089 cm-1; H NMR
123

Med Chem Res (2016) 25:951–969
963
(400 MHz, Acetone): d = 1.18–1.22 (3H, t, J = 8 Hz,
CH2CH3), 3.90 (2H, s, NH2, exchangeable with D2O),
4.36–4.41 (2H, q, CH2CH3), 7.57–7.59 (2H, d, J = 8 Hz,
H-20, H-60), 7.67–7.69 (2H, d, J = 8 Hz, H-30, H-50),
8.00–8.15 (3H, m, H-5, H-7, H-8); 13C NMR (100 MHz,
acetone): d = 13.6 (CH3, O–CH2CH3), 54.7 (CH2, O–
CH2CH3), 113.8 (C, C-3), 115.8 (C, C-10), 122.7 (C, C-5),
128.6 (C, C-20, C-60), 129.2 (C, C-8, C-30, C-50), 130.6 (C,
C-6), 131.2 (C, C-6), 132.3 (C, C-40), 138.6 (C, C-10),
153.1 (C, C-9), 163.1 (C, C-4), 166.2 (C, C=O) and 169.3
(C, C-2); MS (ESI): 361 (M?).
compound was prepared from 4-bromoaniline (1 mmol),
4-chlorobenzaldehyde (1 mmol) and ethyl cyanoacetate
(1 mmol) using catalyst A (0.066 g, 25 mol%) in EtOH–
H2O mixture (2:3, 5 mL) at 100 °C in a microwave syn-
thesizer. The product was obtained as yellow crystalline
solid); M.p. 132–133 °C; IR (KBr) tmax 3373, 3096, 2943,
1686, 1101 cm-1
;
1H NMR (400 MHz, acetone):
d = 1.36–1.40 (3H, t, J = 8 Hz, CH2CH3), 3.91 (2H, s,
NH2, exchangeable with D2O), 4.36–4.42 (2H, q, CH2
CH3), 7.04–7.06 (2H, d, J = 8 Hz, H-20, H-60), 7.68–7.70
(2H, d, J = 8 Hz, H-30, H-50), 8.00–8.15 (3H, m, H-5, H-7,
H-8); 13C NMR (100 MHz, acetone): d = 14.1 (CH3, O–
CH2CH3), 55.1 (CH2, O–CH2CH3), 114.0 (C, C-3), 115.2
(C, C-10), 130.7 (C, C-6, C-20, C-60), 131.4 (C, C-30, C-50),
132.2 (C, C-5), 133.2 (C, C-8), 133.6 (C, C-7), 134.7 (C,
C-40), 146.0 (C, C-10), 147.8 (C, C-9), 163.1 (C, C-4),
165.9 (C, C=O) and 172.9 (C, C-2); MS (ESI): 406 (M?).
Ethyl 2-amino-6-bromo-4-(4-nitrophenyl)quinoline-3-car-
boxylate (4j) Yellow crystalline solid (EtOH) (This
compound was prepared from 4-bromoaniline (1 mmol),
4-nitrobenzaldehyde (1 mmol) and ethyl cyanoacetate
(1 mmol) using catalyst A (0.066 g, 25 mol%) in EtOH–
H2O mixture (2:3, 5 mL) at 100 °C in a microwave syn-
thesizer. The product was obtained as yellow crystalline
solid); M.p. 157–159 °C; IR (KBr) tmax 3354, 3079, 2967,
7-Amino-3,5-bis(4-chlorophenyl)-8aH-thiazolo[3,2-a]pyrim-
idine-6-carbonitrile (8a) Pale yellow crystalline solid
(EtOH) (This compound was prepared from 4-(4-
chlorophenyl)thiazole-2-amine (1 mmol), 4-chloroben-
zaldehyde (1 mmol) and malononitrile (1 mmol) using
catalyst A (0.066 g, 25 mol%) in EtOH–H2O mixture (2:3,
5 mL) at 100 °C in a microwave synthesizer. The product
was obtained as pale yellow crystalline solid); M.p.
162–163 °C; IR (KBr) tmax 3356, 3069, 2226, 1109,
1694, 1103 cm-1
;
1H NMR (400 MHz, Acetone):
d = 1.29–1.33 (3H, t, J = 8 Hz, CH2CH3), 3.83 (2H, s,
NH2, exchangeable with D2O), 4.30–4.35 (2H, q, CH2
CH3), 7.47–7.50 (2H, d, J = 12 Hz, H-20, H-60), 7.59–7.61
(2H, d, J = 8 Hz, H-7, H-8), 7.92–8.04 (3H, m, H-5, H-30,
H-50); 13C NMR (100 MHz, acetone): d = 14.2 (CH3, O–
CH2CH3), 54.9 (CH2, O–CH2CH3), 113.6 (C, C-3), 115.9
(C, C-10), 122.7 (C, C-30, C-50), 129.2 (C, C-20, C-60),
130.5 (C, C-5), 131.4 (C, C-6), 131.6 (C, C-8), 131.9 (C,
C-7), 131.9 (C, C-40), 150.3 (C, C-10, C-9), 163.2 (C, C-4),
166.5 (C, C=O) and 172.2 (C, C-2); MS (ESI): 416 (M?).
1
613 cm-1; H NMR (400 MHz, acetone): d = 3.9 (2H, s,
NH2, exchangeable with D2O), 5.85 (1H, s, –S–CH=C),
7.03–7.05 (4H, d, J = 8 Hz, H-20, H-60 H-200, H-600),
7.97–8.02 (4H, m, H-30, H-50 H-300, H-500), 8.28 (1H, s, –S–
CH–N=); 13C NMR (100 MHz, acetone): d = 55.0 (C,
C-6), 60.0 (C, C-9), 98.3 (C, C-2), 113.6 (C, CN), 116.7 (C,
C-3), 122.8 (C, C-200, C-600), 125.3 (C, C-20, C-60), 125.6,
129.9 (C, C-300, C-500), 130.2 (C, C-10, C-100), 130.8 (C,
C-30, C-50), 131.6 (C, C-40, C-400), 163.5 (C, C-5) and 166.5
(C, C-7); MS (ESI): 373 (M?).
Ethyl
2-amino-6-bromo-4-(4-bromophenyl)quinoline-3-
carboxylate (4k) Yellow crystalline solid (EtOH) (This
compound was prepared from 4-bromoaniline (1 mmol),
4-bromobenzaldehyde (1 mmol) and ethyl cyanoacetate
(1 mmol) using catalyst A (0.066 g, 25 mol%) in EtOH–
H2O mixture (2:3, 5 mL) at 100 °C in a microwave syn-
thesizer. The product was obtained as yellow crystalline
solid); M.p. 100–101 °C; IR (KBr) tmax 3373, 3096, 2943,
7-Amino-5-(4-bromophenyl)-3-(4-chlorophenyl)8aH-thiazolo
[3,2-a]pyrimidine-6-carbonitrile (8b) Pale yellow crys-
talline solid (EtOH) (This compound was prepared from
4-(4-chlorophenyl)thiazole-2-amine (1 mmol), 4-bro-
mobenzaldehyde (1 mmol) and malononitrile (1 mmol)
using catalyst A (0.066 g, 25 mol%) in EtOH–H2O mix-
ture (2:3, 5 mL) at 100 °C in a microwave synthesizer. The
product was obtained as pale yellow crystalline solid); M.p.
172–174 °C; IR (KBr) tmax 3373, 3092, 2225, 1107,
615 cm-1; 1H NMR (400 MHz, acetone): d = 3.81 (2H, s,
NH2, exchangeable with D2O), 5.64 (1H, s, –S–CH=C),
6.95–6.97 (2H, d, J = 8 Hz, H-20, H-60), 7.46–7.48 (2H, d,
J = 8 Hz, H-30, H-50), 7.89–7.92 (2H, d, J = 12 Hz, H-200,
H-600), 7.93–7.95 (2H, d, J = 8 Hz, H-300, H-500), 8.28 (1H,
s, –S–CH–N=); 13C NMR (100 MHz, acetone): d = 54.8
(C, C-6), 59.4 (C, C-9), 87.7 (C, C-2), 113.3 (C, CN), 115.6
1686, 1101 cm-1
;
1H NMR (400 MHz, acetone):
d = 1.36–1.39 (3H, t, J = 8 Hz, CH2CH3), 3.90 (2H, s,
NH2, exchangeable with D2O), 4.36–4.42 (2H, q, CH2
CH3), 7.03–7.05 (2H, d, J = 8 Hz, H-20, H-60), 7.32–7.75
(2H, m, H-7, H-8), 7.93–8.03 (3H, m, H-5, H-30, H-50); 13C
NMR (100 MHz, acetone): d = 14.3 (CH3, O–CH2CH3),
55.0 (CH2, O–CH2CH3), 113.4 (C, C-3), 116.1 (C, C-10),
129.6 (C, C-20, C-60), 131.2 (C, C-5), 132.2 (C, C-6, C-40),
132.6 (C, C-30, C-50), 134.4 (C, C-8), 135.6 (C, C-7), 142.9
(C, C-10), 151.1 (C, C-9), 164.0 (C, C-4), 166.3 (C, C=O)
and 171.4 (C, C-2); MS (ESI): 450 (M?).
Ethyl
2-amino-6-bromo-4-(4-chlorophenyl)quinoline-3-
carboxylate (4l) Yellow crystalline solid (EtOH) (This
123

964
Med Chem Res (2016) 25:951–969
(C, C-3), 125.3 (C,0 C-20, C-60), 127.8 (C, 00C-200, C-600),
128.9 (C, C-30, C-5 ), 131.0 (C, C-300, C-5 ), 132.9 (C,
C-40), 135.4 (C, C-400), 137.6 (C, C-10, C-100), 163.6 (C,
C-5) and 166.5 (C, C-7); MS (ESI): 417 (M?).
product was obtained as pale yellow crystalline solid); M.p.
100–101 °C; IR (KBr) tmax 3369, 3097, 2945, 1686, 1096,
1
614 cm-1; H NMR (400 MHz, acetone): d = 1.35–1.39
(3H, t, J = 8 Hz, CH2CH3), 3.9 (2H, s, NH2, exchangeable
with D2O), 4.35–4.41 (2H, q, CH2CH3), 6.53 (1H, s, –S–
CH=C), 7.02–7.04 (2H, d, J = 8 Hz, H-20, H-60),
7.66–7.68 (2H, d, J = 8 Hz, H-200, H-600), 7.99–8.01 (2H,
d, J = 8 Hz, H-300, H-500), 8.12–8.14 (2H, d, J = 8 Hz,
H-30, H-50), 8.37 (1H, s, –S–CH–N=); 13C NMR
(100 MHz, acetone): d = 13.4 (CH3, O–CH2CH3), 55.0
(CH2, O–CH2CH3), 59.8 (C, C-9), 62.5 (C, C-6), 113.6 (C,
C-2), 115.9 (C, C-3), 122.9 (C, C-30, C-50, C-300, C-500),
129.5 (C, C-200, C-600), 130.8 (C, C-20, C-60), 131.6 (C,
C-100), 132.2 (C, C-10), 132.4 (C, C-400), 132.6 (C, C-40),
153.2 (C, C-5), 163.5 (C, C-7) and 166.6 (C, C=O); MS
(ESI): 420 (M?).
7-Amino-5-(4-chlorophenyl)-3-(4-nitrophenyl)-8aH-thiazolo
[3,2-a]pyrimidine-6-carbonitrile (8c) Pale yellow crys-
talline solid (EtOH) (This compound was prepared from
4-(4-nitrophenyl)thiazole-2-amine (1 mmol), 4-chloroben-
zaldehyde (1 mmol) and malononitrile (1 mmol) using
catalyst A (0.066 g, 25 mol%) in EtOH–H2O mixture (2:3,
5 mL) at 100 °C in a microwave synthesizer. The product
was obtained as pale yellow crystalline solid); M.p.
155–156 °C; IR (KBr) tmax 3369, 3090, 2228, 1103,
1
612 cm-1; H NMR (400 MHz, acetone): d = 3.9 (2H, s,
NH2, exchangeable with D2O), 5.87 (1H, s, –S–CH=C),
7.03–7.05 (4H, d, J = 8 Hz, H-200, H-600), 7.56–7.58 (2H,
d, J = 8 Hz, H-300, H-500), 7.99–8.06 (4H, m, H-20, H-30,
H-50, H-60), 8.37 (1H, s, –S–CH–N=); 13C NMR
(100 MHz, acetone): d = 55.0 (C, C-6), 59.3 (C, C-9),
99.4 (C, C-2), 113.6 (C, CN), 116.8 (C, C-3), 122.9 (C,
C-30, C-50), 128.7 (C, C-300, C-500), 131.3 (C, C-200, C-600),
131.6 (C, C-100), 132.1 (C, C-20, C-60), 135.0 (C, C-400),
138.6 (C, C-10), 142.6 (C, C-40), 163.5 (C, C-5) and 166.6
(C, C-7); MS (ESI): 383 (M?).
Ethyl
7-amino-5-(4-bromophenyl)-3-(4-chlorophenyl)-
8aH-thiazolo[3,2-a]pyrimidine-6-carboxylate (8f) Pale
yellow crystalline solid (EtOH) (This compound was pre-
pared from 4-(4-chlorophenyl)thiazole-2-amine (1 mmol),
4-bromobenzaldehyde (1 mmol) and ethyl cyanoacetate
(1 mmol) using catalyst A (0.066 g, 25 mol%) in EtOH–
H2O mixture (2:3, 5 mL) at 100 °C in a microwave syn-
thesizer. The product was obtained as pale yellow crys-
talline solid); M.p. 152–153 °C; IR (KBr) tmax 3374, 3088,
1
2951, 1690, 1102, 617 cm-1; H NMR (400 MHz, ace-
7-Amino-5-(4-bromophenyl)-3-(4-nitrophenyl)-8aH-thiazolo
[3,2-a]pyrimidine-6-carbonitrile (8d) Pale yellow crys-
talline solid (EtOH) (This compound was prepared from
4-(4-nitrophenyl)thiazole-2-amine (1 mmol), 4-bromoben-
zaldehyde (1 mmol) and malononitrile (1 mmol) using
catalyst A (0.066 g, 25 mol%) in EtOH–H2O mixture (2:3,
5 mL) at 100 °C in a microwave synthesizer. The product
was obtained as pale yellow crystalline solid); M.p.
152–153 °C; IR (KBr) tmax 3371, 3096, 2226, 1101,
613 cm-1; 1H NMR (400 MHz, acetone): d = 3.90 (2H, s,
NH2, exchangeable with D2O), 4.86 (1H, s, –S–CH=C),
7.03–7.05 (2H, d, J = 8 Hz, H-200, H-600), 7.99–8.07 (4H,
m, H-300, H-500, H-20, H-60), 8.41–8.43 (2H, d, J = 8 Hz,
H-30, H-50), 8.88 (1H, s, –S–CH–N=); 13C NMR
(100 MHz, acetone): d = 55.0 (C, C-6), 59.8 (C, C-9),
98.4 (C, C-2), 113.2 (C, CN), 116.3 (C, C-3), 122.8 (C,
C-30, C-50), 125.5 (C, C-400), 127.4 (C, C-200, C-600), 130.6
(C, C-20, C-60), 131.6 (C, C-300, C-500), 133.3 (C, C-100),
134.9 (C, C-10), 143.7 (C, C-40), 163.5 (C, C-5) and 166.5
(C, C-7); MS (ESI): 428 (M?).
tone): d = 1.35–1.39 (3H, t, J = 8 Hz, CH2CH3), 3.9 (2H,
s, NH2, exchangeable with D2O), 4.36–4.41 (2H, q, CH2
CH3), 6.1 (1H, s, –S–CH=C), 6.75–6.77 (2H, d, J = 8 Hz,
H-20, H-60), 7.03–7.05 (2H, d, J = 8 Hz, H-200, H-600),
7.35–7.37 (2H, d, J = 8 Hz, H-30, H-50), 7.54–7.56 (2H, d,
J = 8 Hz, H-300, H-500), 8.37 (1H, s, –S–CH–N=); 13C
NMR (100 MHz, acetone): d = 14.9 (CH3, O–CH2CH3),
55.0 (CH2, O–CH2CH3), 58.6 (C, C-9), 82.9 (C, C-6),
112.6 (C, C-2), 113.6 (C, C-3), 122.9 (C, C-30, C-50), 125.3
(C, C-300, C-500), 130.3 (C, C-20, C-60), 131.3 (C, C-40, C-200,
C-600), 131.6 (C, C-100) 132.2 (C, C-10, C-400), 159.4 (C,
C-5), 163.5 (C, C-7), 166.6 (C, C=O); MS (ESI): 464 (M?).
Ethyl 7-amino-5-(4-chlorophenyl)-3-(4-nitrophenyl)-8aH-
thiazolo[3,2-a]pyrimidine-6-carboxylate (8g) Pale yel-
low crystalline solid (EtOH) (This compound was prepared
from
4-(4-nitrophenyl)thiazole-2-amine
(1 mmol),
4-chlorobenzaldehyde (1 mmol) and ethyl cyanoacetate
(1 mmol) using catalyst A (0.066 g, 25 mol%) in EtOH–
H2O mixture (2:3, 5 mL) at 100 °C in a microwave syn-
thesizer. The product was obtained as pale yellow crys-
talline solid); M.p. 124–125 °C; IR (KBr) tmax 3386, 3095,
Ethyl 7-amino-3,5-bis(4-chlorophenyl)-8aH-thiazolo[3,2-
a]pyrimidine-6-carboxylate (8e) Pale yellow crystalline
solid (EtOH) (This compound was prepared from 4-(4-
chlorophenyl)thiazole-2-amine (1 mmol), 4-chloroben-
zaldehyde (1 mmol) and ethyl cyanoacetate (1 mmol)
using catalyst A (0.066 g, 25 mol%) in EtOH–H2O mix-
ture (2:3, 5 mL) at 100 °C in a microwave synthesizer. The
1
2952, 1688, 1098, 611 cm-1; H NMR (400 MHz, ace-
tone): d = 1.36–1.39 (3H, t, J = 8 Hz, CH2CH3), 3.9 (2H,
s, NH2, exchangeable with D2O), 4.36–4.41 (2H, q, CH2
CH3), 6.07 (1H, s, –S–CH=C), 6.75–6.77 (2H, d, J = 8 Hz,
H-200, H-600), 7.03–7.05 (2H, d, J = 8 Hz, H-20, H-60),
123

Med Chem Res (2016) 25:951–969
965
7.56–7.58 (2H, d, J = 8 Hz, H-300, H-500), 7.67–7.69 (2H,
d, J = 8 Hz, H-30, H-50), 8.35 (1H, s, –S–CH–N=); 13C
NMR (100 MHz, acetone): d = 13.5 (CH3, O–CH2CH3),
54.9 (CH2, O–CH2CH3), 62.5 (C, C-9), 95.38 (C, C-6),
112.6 (C, C-2), 113.6 (C, C-3), 126.0 (C, C-30, C-50), 128.7
(C, C-20, C-60), 129.5 (C, C-300, C-500), 131.3 (C, C-100),
131.6 (C, C-200, C-400, C-600), 132.4 (C, C-10), 137.4 (C,
C-40), 142.07 (C, C-5), 163.5 (C, C-7), 166.5 (C, C=O); MS
(ESI): 430 (M?).
7-Amino-5-(4-bromophenyl)-2-(4-methoxyphenyl)-8aH-
[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carbonitrile (12b)
Pale yellow crystalline (EtOH) (This compound was pre-
pared from 5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-amine
(1 mmol), 4-bromobenzaldehyde (1 mmol) and malononi-
trile (1 mmol) using catalyst A (0.066 g, 25 mol%) in
EtOH–H2O mixture (2:3, 5 mL) at 100 °C in a microwave
synthesizer. The product was obtained as pale yellow
crystalline solid); M.p. 142–143 °C; IR (KBr) tmax 3391,
3036, 2226, 1109, 616 cm-1
;
1H NMR (400 MHz,
Ethyl 7-amino-5-(4-bromophenyl)-3-(4-nitrophenyl)-8aH-
MeOD): d = 3.88 (5H, s, OCH3, NH2), 6.99–7.01 (2H, d,
J = 8 Hz, H-20, H-60), 7.76–7.78 (2H, d, J = 8 Hz, H-200,
H-600), 7.88–7.90 (2H, d, J = 8 Hz, H-30, H-50), 7.98–8.00
(2H, d, J = 8 Hz, H-300, H-500), 8.19 (1H, s, –S–CH–N);
13C NMR (100 MHz, MeOD): d = 54.6 (C, OCH3), 73.9
(C, C-6), 82.1 (C, C-9), 113.3 (C, CN), 122.7 (C, C-10,
C-30, C-50), 128.3 (C, C-200, C-600), 130.3 (C, C-20, C-60),
131.4 (C, C-300, C-500), 131.8 (C, C-400), 132.5 (C, C-100),
143.9 (C, C-2), 159.2 (C, C-40), 163.7 (C, C-5) and 168.4
(C, C-7); MS (ESI): 439 (M?).
thiazolo[3,2-a]pyrimidine-6-carboxylate
(8h) Yellow
crystalline solid (EtOH) (This compound was prepared
from 4-(4-nitrophenyl)thiazole-2-amine (1 mmol), 4-bro-
mobenzaldehyde (1 mmol) and ethyl cyanoacetate
(1 mmol) using catalyst A (0.066 g, 25 mol%) in EtOH–
H2O mixture (2:3, 5 mL) at 100 °C in a microwave syn-
thesizer. The product was obtained as yellow crystalline
solid); M.p. 170–171 °C; IR (KBr) tmax 3371, 3097, 2950,
1692, 1103, 615 cm-1 1H NMR (400 MHz, acetone):
;
d = 1.30–134 (3H, t, J = 8 Hz, CH2CH3), 3.9 (2H, s,
NH2, exchangeable with D2O), 4.35–4.41 (2H, q, CH2
CH3), 5.23 (1H, s, –S–CH=C), 7.03–7.05 (2H, d, J = 8 Hz,
H-200, H-600), 7.70–7.72 (2H, d, J = 8 Hz, H-20, H-60),
7.99–8.01 (2H, d, J = 8 Hz, H-30, H-50), 8.06–8.08 (2H, d,
J = 8 Hz, H-300, H-500), 8.37 (1H, s, –S–CH–N=); 13C
NMR (100 MHz, acetone): d = 13.3 (CH3, O–CH2CH3),
54.9 (CH2, O–CH2CH3), 59.9 (C, C-9), 92.9 (C, C-6),
112.3 (C, C-2), 113.3 (C, C-3), 123.2 (C, C-30, C-50), 124.2
(C, C-400), 125.9 (C, C-200, C-600), 128.0 (C, C-20, C-60),
130.0 (C, C-300, C-500), 131.7 (C, C-100), 132.4 (C, C-10),
143.7 (C, C-40), 154.9 (C, C-5), 163.3 (C, C-7) and 166.7
(C, C=O); MS (ESI): 475 (M?).
7-Amino-2-(4-methoxyphenyl)-5-phenyl-8aH-[1,3,4]thiadi-
azolo[3,2-a]pyrimidine-6-carbonitrile
(12c) Creamish
white crystalline solid (EtOH) (This compound was pre-
pared from 5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-amine
(1 mmol), benzaldehyde (1 mmol) and malononitrile
(1 mmol) using catalyst A (0.066 g, 25 mol%) in EtOH–
H2O mixture (2:3, 5 mL) at 100 °C in a microwave syn-
thesizer. The product was obtained as creamish white
crystalline solid); M.p. 145–146 °C; IR (KBr) tmax 3389,
3042, 2225, 1107, 614 cm-1
;
1H NMR (400 MHz,
MeOD): d = 3.88 (5H, s, OCH3, NH2), 6.99–7.01 (2H, d,
J = 8 Hz, H-20, H-60), 7.57–7.68 (5H, m, H-200, H-300,
H-400, H-500, H-600), 7.98–8.00 (2H, d, J = 8 Hz, H-30,
H-50), 8.22 (1H, s, –S–CH–N); 13C NMR (100 MHz,
MeOD): d = 54.6 (C, OCH3), 77.5 (C, C-6), 82.2 (C, C-9),
113.6 (C, CN), 122.7 (C, C-10, C-30, C-50), 129.1 (C, C-200,
C-600), 130.4 (C, C-20, C-60), 131.4 (C, C-300, C-400, C-500),
134.0 (C, C-100), 141.7 (C, C-2), 160.6 (C, C-40), 163.7 (C,
C-5) and 168.4 (C, C-7); MS (ESI): 360 (M?).
7-Amino-5-(4-chlorophenyl)-2-(4-methoxyphenyl)-8aH-
[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carbonitrile (12a)
Pale yellow crystalline (EtOH) (This compound was pre-
pared from 5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-amine
(1 mmol), 4-chloro benzaldehyde (1 mmol) and malonon-
itrile (1 mmol) using catalyst A (0.066 g, 25 mol%) in
EtOH–H2O mixture (2:3, 5 mL) at 100 °C in a microwave
synthesizer. The product was obtained as pale yellow
crystalline solid); M.p. 169–170 °C; IR (KBr) tmax 3390,
7-Amino-2-(4-methoxyphenyl)-5-(4-nitrophenyl)-8aH-[1,3,4]
thiadiazolo[3,2-a]pyrimidine-6-carbonitrile (12d) Pale
yellow crystalline (EtOH) (This compound was prepared
3035, 2223, 1111, 615 cm-1
;
1H NMR (400 MHz,
MeOD): i = 3.89 (5H, s, OCH3, NH2), 7.00–7.02 (2H, d,
J = 8 Hz, H-20, H-60), 7.58–7.60 (2H, d, J = 8 Hz, H-200,
H-600), 7.98–8.00 (2H, d, J = 8 Hz, H-300, H-500), 8.14–8.16
(2H, d, J = 8 Hz, H-30, H-50), 8.45 (1H, s, –S–CH–N); 13C
NMR (100 MHz, MeOD): d = 54.6 (C, OCH3), 77.4 (C,
C-6), 86.9 (C, C-9), 113.3 (C, CN), 122.3 (C, C-30, C-50),
122.6 (C, C-10), 124.5 (C, C-200, C-600), 127.9 (C, C-300,
C-500), 128.8 (C, C-20, C-60), 131.4 (C, C-100 C-400), 139.2
(C, C-2), 162.8 (C, C-40), 163.7 (C, C-5) and 168.4 (C,
C-7); MS (ESI): 395 (M?).
from
5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-amine
(1 mmol), 4-nitrobenzaldehyde (1 mmol) and malononi-
trile (1 mmol) using catalyst A (0.066 g, 25 mol%) in
EtOH–H2O mixture (2:3, 5 mL) at 100 °C in a microwave
synthesizer. The product was obtained as pale yellow
crystalline solid); M.p. 155–156 °C; IR (KBr) tmax 3392,
3033, 2222, 1113, 612 cm-1
;
1H NMR (400 MHz,
MeOD): d = 3.89 (5H, s, OCH3, NH2), 7.00–7.02 (2H, d,
J = 8 Hz, H-20, H-60), 7.42–7.44 (2H, d, J = 8 Hz, H-200,
H-600), 7.91–7.93 (2H, d, J = 8 Hz, H-30, H-50), 7.99–8.01
123

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Med Chem Res (2016) 25:951–969
(2H, d, J = 8 Hz, H-300, H-500), 8.17 (1H, s, –S–CH–N);
13C NMR (100 MHz, MeOD): d = 55.2 (C, OCH3), 71.3
(C, C-6), 81.5 (C, C-9), 113.6 (C, CN), 123.8 (C, C-010 0,
C-30, C-50), 128.6 (C, C-300, C-500), 129.9 (C, C-200, C-6 ),
130.7 (C, C-20, C-60), 131.8 (C, C-100), 133.2 (C, C-400),
140.2 (C, C-2), 161.7 (C, C-40), 163.8 (C, C-5), 165.3 (C,
C-7); MS (ESI): 405 (M?).
compound was prepared from 5-(4-methoxyphenyl)-1,3,4-
thiadiazol-2-amine
(1 mmol),
4-bromobenzaldehyde
(1 mmol) and ethyl cyanoacetate (1 mmol) using catalyst
A (0.066 g, 25 mol%) in EtOH–H2O mixture (2:3, 5 mL)
at 100 °C in a microwave synthesizer. The product was
obtained as creamish white crystalline solid); M.p.
184–185 °C; IR (KBr) tmax 3388, 3040, 2932, 1689, 1113,
1
614 cm-1; H NMR (400 MHz, Acetone): d = 1.36–1.39
7-Amino-5-(4-methylphenyl)-2-(4-methoxyphenyl)-8aH-[1,3,4]
thiadiazolo[3,2-a]pyrimidine-6-carbonitrile (12e) Yellow
crystalline solid (EtOH) (This compound was prepared from
5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-amine (1 mmol),
4-methylbenzaldehyde (1 mmol) and malononitrile
(1 mmol) using catalyst A (0.066 g, 25 mol%) in EtOH–
H2O mixture (2:3, 5 mL) at 100 °C in a microwave syn-
thesizer. The product was obtained as yellow crystalline
solid); M.p. 112–115 °C; IR (KBr) tmax 3387, 3036, 2221,
(3H, t, J = 8 Hz, CH2CH3), 3.90 (5H, s, OCH3, NH2),
4.36–4.41 (2H, q, CH2CH3), 7.03–7.05 (2H, d, J = 8 Hz,
H-20, H-60), 7.56–7.58 (2H, d, J = 8 Hz, H-200, H-600),
8.00–8.02 (2H, d, J = 8 Hz, H-300, H-500), 8.05–8.07 (2H,
d, J = 8 Hz, H-30, H-50), 8.37 (1H, s, –S–CH–N); 13C
NMR (100 MHz, Acetone): d = 13.9 (CH3, O–CH2CH3),
54.9 (CH2, O–CH2CH3), 61.9 (C, OCH3), 75.3 (C, C-6),
82.7 (C, C-9), 122.8 (C, C-30, C-50), 123.1 (C-10), 128.7 (C,
C-300, C-500), 131.2 (C, C-200, C-600), 131.6 (C, C20, C-60,
C-400), 132.7 (C, C-100), 142.3 (C, C-2), 163.5 (C, C-40, C-5,
C-7) and 166.4 (C, C=O); MS (ESI): 486 (M?).
1
1108, 616 cm-1; H NMR (400 MHz, MeOD): d = 1.31
(3H, s, CH3), 3.88 (5H, s, OCH3, NH2), 7.00–7.02 (2H, d,
J = 8 Hz, H-20, H-60), 7.56–7.64 (4H, m, H-200, H-300, H-500,
H-600), 7.98–8.00 (2H, d, J = 8 Hz, H-30, H-50), 8.23 (1H, s,
–S–CH–N); 13C NMR (100 MHz, MeOD): d = 25.5 (C,
CH3), 54.5 (C, OCH3), 74.8 (C, C-6), 80.3 (C, C-9), 112.9
(C, CN), 122.9 (C, C-10, C-30, C-50), 129.2 (C, C-200, C-600),
129.6 (C, C-300, C-500), 129.9 (C, C-20, C-60), 131.4 (C,
C-100), 131.7 (C, C-400), 142.1 (C, C-2), 158.9 (C, C-40),
163.8 (C, C-5) and 168.5 (C, C-7); MS (ESI): 374 (M?).
Ethyl 7-amino-2-(4-methoxyphenyl)-5-phenyl-8aH-[1,3,4]
thiadiazolo[3,2-a]pyrimidine-6-carboxylate (12h) Creamish
white crystalline solid (EtOH) (This compound was pre-
pared from 5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-amine
(1 mmol), benzaldehyde (1 mmol) and ethyl cyanoacetate
(1 mmol) using catalyst A (0.066 g, 25 mol%) in EtOH–
H2O mixture (2:3, 5 mL) at 100 °C in a microwave syn-
thesizer. The product was obtained as creamish white
crystalline solid); M.p. 177–180 °C; IR (KBr) tmax 3390,
Ethyl 7-amino-5-(4-chlorophenyl)-2-(4-methoxyphenyl)-
8aH-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylate (12f)
Creamish white crystalline solid (EtOH) (This compound
was prepared from 5-(4-methoxyphenyl)-1,3,4-thiadiazol-
2-amine (1 mmol), 4-chlorobenzaldehyde (1 mmol) and
ethyl cyanoacetate (1 mmol) using catalyst A (0.066 g,
25 mol%) in EtOH–H2O mixture (2:3, 5 mL) at 100 °C in
a microwave synthesizer. The product was obtained as
creamish white crystalline solid); M.p. 182–185 °C; IR
1
3040, 2930, 1690, 1105, 616 cm-1; H NMR (400 MHz,
Acetone): d = 1.35–1.39 (3H, t, J = 8 Hz, CH2CH3), 3.90
(5H, s, OCH3, NH2), 4.35–4.40 (2H, q, CH2CH3),
7.03–7.06 (2H, d, J = 8 Hz, H-20, H-60), 7.44–7.46 (2H, d,
J = 8 Hz, H-200, H-600), 8.00–8.04 (5H, m, H-30, H-50,
H-300, H-400, H-500), 8.33 (1H, s, –S–CH–N); 13C NMR
(100 MHz, Acetone): d = 13.5 (CH3, O–CH2CH3), 55.0
(CH2, O–CH2CH3), 62.2 (C, OCH3), 76.5 (C, C-6), 82.4
(C, C-9), 122.8 (C, C-10, C-30, C-50), 128.5 (C, C-300, C-400,
C-500), 129.9 (C, C-200, C-600), 131.1 (C, C-100) 131.6 (C,
C-20, C-60), 144.9 (C, C-2), 154.5 (C, C-40), 163.5 (C, C-5,
C-7) and 166.4 (C, C=O); MS (ESI): 407 (M?).
1
(KBr) tmax 3384, 3038, 2929, 1686, 1110, 613 cm-1; H
NMR (400 MHz, Acetone): d = 1.31–1.35 (3H, t,
J = 8 Hz, CH2CH3), 3.90 (5H, s, OCH3, NH2), 4.04–4.08
(2H, q, CH2CH3), 7.03–7.05 (2H, d, J = 8 Hz, H-20, H-60),
7.71–7.73 (2H, d, J = 8 Hz, H-200, H-600), 8.00–8.02 (2H,
d, J = 8 Hz, H-300, H-500), 8.06–8.08 (2H, d, J = 8 Hz,
H-30, H-50), 8.38 (1H, s, –S–CH–N); 13C NMR (100 MHz,
Acetone): d = 14.1 (CH3, O–CH2CH3), 54.9 (CH2, O–
CH2CH3), 59.4 (C, OCH3), 74.4 (C, C-6), 83.1 (C, C-9),
123.2 (C, C-10, C-30, C-50), 129.3 (C, C-300, C-500), 129.7 (C,
C-400), 129.9 (C, C-200, C-600), 131.6 (C, C20, C-60), 132.2
(C, C-100), 139.7 (C, C-2), 159.4 (C, C-40), 162.7(C, C-5,
C-7), 165.8 (C, C=O); MS (ESI): 442 (M?).
Ethyl 7-amino-2-(4-methoxyphenyl)-5(4-nitrophenyl)-8aH-
[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylate
(12i)
Pale yellow crystalline solid (EtOH) (This compound was
prepared from 5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-
amine (1 mmol), 4-nitrobenzaldehyde (1 mmol) and ethyl
cyanoacetate (1 mmol) using catalyst
A
(0.066 g,
25 mol%) in EtOH–H2O mixture (2:3, 5 mL) at 100 °C in
a microwave synthesizer. The product was obtained as pale
yellow crystalline solid); M.p. 164–165 °C; IR (KBr) tmax
3384, 3042, 2934, 1688, 1110, 615 cm-1 1H NMR
;
Ethyl 7-amino-5-(4-bromophenyl)-2-(4-methoxyphenyl)-
8aH-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylate
(12g) Creamish white crystalline solid (EtOH) (This
(400 MHz, acetone): d = 1.36–1.40 (3H, t, J = 8 Hz,
CH2CH3), 3.90 (5H, s, OCH3, NH2), 4.36–4.41 (2H, q,
123

Med Chem Res (2016) 25:951–969
967
CH2CH3), 7.03–7.05 (4H, m, H-20, H-60), 7.63–7.65 (2H, d,
J = 8 Hz, H-200, H-600), 8.00–8.02 (2H, d, J = 8 Hz, H-30,
H-50), 8.11–8.13 (2H, d, J = 8 Hz, H-300, H-500), 8.38 (1H,
s, –S–CH–N); 13C NMR (100 MHz, acetone): d = 13.7
(CH3, O–CH2CH3), 54.7 (CH2, O–CH2CH3), 62.1 (C,
OCH3), 74.1 (C, C-6), 78.7 (C, C-9), 128.1 (C, C-10, C-30,
C-50), 129.0 (C, C-300, C-500), 130.2 (C, C-400), 130.5 (C,
C-20, C-60), 131.1 (C, C-200, C-600), 131.3 (C, C-100), 140.7
(C, C-2), 154.8 (C, C-40), 163.4 (C, C-5, C-7) and 166.1 (C,
C=O); MS (ESI): 452 (M?).
6-Amino-8-(4-bromophenyl)-3-methyl-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazepine-7-carbonitrile (16b) Light brown
crystalline solid (EtOH) (This compound was prepared
from 5-methyl-4H-1,2,4-triazol-3-amine (1 mmol), 4-bro-
mobenzaldehyde (1 mmol) and malononitrile (1 mmol)
using catalyst A (0.066 g, 25 mol%) in EtOH–H2O mix-
ture (2:3, 5 mL) at 100 °C in a microwave synthesizer. The
product was obtained as light brown crystalline solid); IR
(KBr) tmax 3375, 3066, 2950, 2252, 1101, 615 cm-1; M.p.
1
132–133 °C; H NMR (400 MHz, MeOD): d = 2.21 (3H,
s, CH3), 3.90 (2H, s, NH2, exchangeable with D2O),
7.03–7.05 (2H, d, J = 8 Hz, H-20, H-60), 7.98–8.00 (2H, d,
J = 8 Hz, H-30, H-50); 13C NMR (100 MHz, MeOD):
d = 12.6 (C, CH3), 54.7 (C, C-7), 113.4 (C, CN), 129.3 (C,
C-30, C-50), 129.9 (C, C-40), 130.3 (C, C-20, C-60), 131.4 (C,
C-10), 160.2 (C, C-3), 160.6 (C, C-6), 166.2 (C, C-8) and
168.0 (C, C-10); MS (ESI): 361 (M?).
Ethyl 7-amino-5-(4-methylphenyl)-2-(4-methoxyphenyl)-
8aH-[1,3,4]thiadiazol[3,2-a]
pyrimidine-6-carboxylate
(12j) Pale yellow crystalline solid (EtOH) (This com-
pound was prepared from 5-(4-methoxyphenyl)-1,3,4-
thiadiazol-2-amine
(1 mmol),
4-methylbenzaldehyde
(1 mmol) and ethyl cyanoacetate (1 mmol) using catalyst
A (0.066 g, 25 mol%) in EtOH–H2O mixture (2:3, 5 mL)
at 100 °C in a microwave synthesizer. The product was
obtained as pale yellow crystalline solid); M.p.
162–163 °C; IR (KBr) tmax 3388, 3037, 2927, 1687, 1110,
6-Amino-3-methyl-8-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazepine-7-carbonitrile (16c) Brown crystalline
solid (EtOH) (This compound was prepared from
5-methyl-4H-1,2,4-triazol-3-amine (1 mmol), benzalde-
hyde (1 mmol) and malononitrile (1 mmol) using catalyst
A (0.066 g, 25 mol%) in EtOH–H2O mixture (2:3, 5 mL)
at 100 °C in a microwave synthesizer. The product was
obtained as brown crystalline solid); M.p. 152–153 °C; IR
1
613 cm-1; H NMR (400 MHz, acetone): d = 1.32–1.35
(3H, t, J = 8 Hz, CH2CH3), 1.99 (3H, s, CH3), 3.86 (2H, s,
NH2, exchangeable with D2O), 3.92 (3H, s, OCH3),
4.32–4.38 (2H, q, C2H5), 6.99–7.01 (2H, d, J = 8 Hz,
H-20, H-60), 7.62–7.64 (2H, d, J = 8 Hz, H-300, H-500),
7.95–7.97 (2H, d, J = 8 Hz, H-200, H-600), 8.06–8.08 (2H,
d, J = 8 Hz, H-30, H-50), 8.35 (1H, s, –S–CH–N); 13C
NMR (100 MHz, acetone): d = 15.5 (CH3, O–CH2CH3),
23.6 (CH3), 55.0 (CH2, O–CH2CH3), 62.2 (C, OCH3), 74.2
(C, C-6), 83.700(C, C-9), 123.0 (C, C-10, C-30, C-50), 129.1
(C, C-300, C-5 ), 130.1 (C, C-400), 130.5 (C, C-20, C-60),
131.2 (C, C-200, C-600), 131.9 (C, C-100), 144.5 (C, C-2),
153.1 (C, C-40), 163.6 (C, C-5, C-7) and 166.7 (C, C=O);
MS (ESI): 421 (M?).
1
(KBr) tmax 3375, 3064, 2949, 2253, 1099, 615 cm-1; H
NMR (400 MHz, Acetone): d = 2.08 (3H, s, CH3), 3.90
(2H, s, NH2, exchangeable with D2O), 7.03–7.05(2H, d,
J = 8 Hz, H-20, H-60),7.77–8.02 (3H, m, H-30, H-40, H-50);
13C NMR (100 MHz, acetone): d = 9.7 (C, CH3), 54.9 (C,
C-7), 113.6 (C, CN), 128.3 (C, C-30, C-50), 130.4 (C, C-40),
131.4 (C, C-20, C-60), 134.1 (C, C-10), 160.8 (C, C-3), 161.2
(C, C-6), 163.2 (C, C-8) and 166.3 (C, C-10); MS (ESI):
282 (M?).
6-Amino-8-(4-chlorophenyl)-3-methyl-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazepine-7-carbonitrile (16a) Yellow crys-
talline solid (EtOH) (This compound was prepared from
5-methyl-4H-1,2,4-triazol-3-amine (1 mmol), 4-chloroben-
zaldehyde (1 mmol) and malononitrile (1 mmol) using
catalyst A (0.066 g, 25 mol%) in EtOH–H2O mixture (2:3,
5 mL) at 100 °C in a microwave synthesizer. The product
was obtained as yellow crystalline solid); M.p. 164–165 °C;
IR (KBr) tmax 3374, 3067, 2948, 2255, 1097, 617 cm-1; 1H
NMR (400 MHz, MeOD): d = 2.22 (3H, s, CH3), 3.90 (2H,
s, NH2, exchangeable with D2O), 7.02–7.04 (2H, d,
J = 8 Hz, H-20, H-60), 7.98–8.00 (2H, d, J = 8 Hz, H-30,
H-50); 13C NMR (100 MHz, MeOD): d = 11.7 (C, CH3),
54.2 (C, C-7), 113.3 (C, CN), 129.0 (C, C-30, C-50), 130.4
(C, C-20, C-60), 131.2 (C, C-40), 131.8 (C, C-10), 160.6 (C,
C-3), 163.9 (C, C-6), 164.2 (C, C-8) and 168.3 (C, C-10);
MS (ESI): 317 (M?).
6-Amino-3-methyl-8-(4-nitrophenyl)-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazepine-7-carbonitrile (16d) Light brown
crystalline solid (EtOH) (This compound was prepared
from 5-methyl-4H-1,2,4-triazol-3-amine (1 mmol), 4-ni-
trobenzaldehyde (1 mmol) and malononitrile (1 mmol)
using catalyst A (0.066 g, 25 mol%) in EtOH–H2O mix-
ture (2:3, 5 mL) at 100 °C in a microwave synthesizer. The
product was obtained as light brown crystalline solid); M.p.
130–131 °C; IR (KBr) tmax 3377, 3066, 2945, 2256, 1099,
614 cm-1; 1H NMR (400 MHz, acetone): d = 2.04 (3H, s,
CH3), 3.90 (2H, s, NH2, exchangeable with D2O),
7.95–8.07 (4H, m, H-20, H-30, H-50, H-60); 13C NMR
(100 MHz, acetone): d = 10.0 (C, CH3), 54.9 (C, C-7),
113.2 (C, CN), 127.7 (C, C-30, C-50), 131.5 (C, C-40), 132.1
(C, C-20, C-60), 133.2 (C, C-10), 162.0 (C, C-3), 163.3 (C,
C-6), 163.7 (C, C-8) and 167.0 (C, C-10); MS (ESI): 327
(M?).
123

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Ethyl 6-amino-8-(4-chlorophenyl)-3-methyl-[1,2,4]triazolo
[3,4-b][1,3,4]thiadiazepine-7-carboxylate (16e) Creamish
white crystalline solid (EtOH) (This compound was pre-
pared from 5-methyl-4H-1,2,4-triazol-3-amine (1 mmol),
4-chlorobenzaldehyde (1 mmol) and ethyl cyanoacetate
(1 mmol) using catalyst A (0.066 g, 25 mol%) in EtOH–
H2O mixture (2:3, 5 mL) at 100 °C in a microwave syn-
thesizer. The product was obtained as creamish white
crystalline solid); M.p. 142–143 °C; IR (KBr) tmax 3375,
O–CH2CH3), 55.0 (CH2, O–CH2CH3), 113.6 (C, C-7),
128.5 (C, C-30, C-40, C-50), 131.3 (C, C-20, C-60), 132.4 (C,
C-10), 153.2 (C, C-3), 159.5 (C, C-6), 162.6 (C, C-8) 163.2
(C, C-10) and 166.4 (C, C=O); MS (ESI): 329 (M?).
Ethyl 6-amino-3-methyl-8-(4-nitrophenyl)-[1,2,4]triazolo
[3,4-b][1,3,4]thiadiazepine-7-carboxylate (16h) Creamish
white crystalline solid (EtOH) (This compound was pre-
pared from 5-methyl-4H-1,2,4-triazol-3-amine (1 mmol),
4-nitrobenzaldehyde (1 mmol) and ethyl cyanoacetate
(1 mmol) using catalyst A (0.066 g, 25 mol%) in EtOH–
H2O mixture (2:3, 5 mL) at 100 °C in a microwave syn-
thesizer. The product was obtained as creamish white
crystalline solid); M.p. 142–143 °C; IR (KBr) tmax 3374,
1
3069, 2948, 1684, 1099, 617 cm-1; H NMR (400 MHz,
acetone): d = 1.14–1.18 (3H, t, J = 8 Hz, CH2CH3), 2.0
(3H, s, CH3), 3.83 (2H, s, NH2, exchangeable with D2O),
4.00–4.06 (2H, q, CH2CH3), 6.98–7.00 (2H, d, J = 8 Hz,
H-20, H-60), 7.92–7.94 (2H, d, J = 8 Hz, H-30, H-50); 13C
NMR (100 MHz, acetone): d = 10.1 (C, CH3), 13.5 (CH3,
O–CH2CH3), 54.7 (C, C-7), 113.5 (CH3, O–CH2CH3),
129.4 (C, C-30, C-50), 129.9 (C, C-40), 131.4 (C, C-10),
132.2 (C, C-20, C-60), 159.5 (C, C-3), 162.4 (C, C-6, C-8),
163.2 (C, C-10) and 166.9 (C, C=O); MS (ESI): 364 (M?).
1
3072, 2946, 1687, 1097, 613 cm-1; H NMR (400 MHz,
Acetone): d = 1.26–1.29 (3H, t, J = 8 Hz, CH2CH3), 2.11
(3H, s, CH3), 3.79 (2H, s, NH2, exchangeable with D2O),
4.26–4.32 (2H, q, CH2CH3), 7.79–7.81 (2H, d, J = 8 Hz,
H-20, H-60), 7.87–7.90 (2H, d, J = 8 Hz, H-30, H-50); 13C
NMR (100 MHz, acetone): d = 9.2 (C, CH3), 18.3 (CH3,
O–CH2CH3), 54.9 (CH2, O–CH2CH3), 113.5 (C, C-7),
129.6 (C, C-30, C-50), 130.6(C, C-20, C-60), 130.9 (C, C-40),
132.3 (C, C-10), 159.6 (C, C-3), 162.6 (C, C-6), 163.7 (C,
C-8), 165.7 (C, C-10) and 166.4 (C, C=O); MS (ESI): 374
(M?).
Ethyl 6-amino-8-(4-bromophenyl)-3-methyl-[1,2,4]triazolo
[3,4-b][1,3,4]thiadiazepine-7-carboxylate (16f) Creamish
white crystalline solid (EtOH) (This compound was pre-
pared from 5-methyl-4H-1,2,4-triazol-3-amine (1 mmol),
4-bromobenzaldehyde (1 mmol) and ethyl cyanoacetate
(1 mmol) using catalyst A (0.066 g, 25 mol%) in EtOH–
H2O mixture (2:3, 5 mL) at 100 °C in a microwave syn-
thesizer. The product was obtained as creamish white
crystalline solid); M.p. 122–123 °C; IR (KBr) tmax 3373,
Supplementary Material
1
3070, 2952, 1682, 1103, 615 cm-1; H NMR (400 MHz,
Supplementary material provides spectral data (1H, 13C and
D2O) of compounds.
MeOD): d = 1.25–128 (3H, t, J = 8 Hz, CH2CH3), 2.19
(3H, s, CH3), 3.89 (2H, s, NH2, exchangeable with D2O),
4.10–4.15 (2H, q, CH2CH3), 7.01–7.03 (2H, d, J = 8 Hz,
H-20, H-60), 7.98–8.00 (2H, d, J = 8 Hz, H-30, H-50); 13C
NMR (100 MHz, MeOD): d = 10.8 (C, CH3), 16.9 (CH3,
O–CH2CH3), 53.7 (C, C-7), 113.5 (CH3, O–CH2CH3),
131.1 (C, C-30, C-50), 131.5 (C, C-40), 131.9 (C, C-20, C-60),
133.1 (C, C-10), 154.8 (C, C-3), 156.6 (C, C-6, C-8), 159.2
(C, C-10) and 163.6 (C, C=O); MS (ESI): 408 (M?).
Acknowledgments We gratefully acknowledge the Department of
Science and Technology, Government of India for NMR spectrometer
(Bruker Avance III, 400 MHz) under PURSE program to the
University of Jammu, and IIIM, Jammu for mass spectral data. We
also gratefully acknowledge the UGC, New Delhi, for PerkinElmer
FTIR spectrophotometer under SAP.
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