Efficient synthesis of antifungal active 9-substituted-3-aryl-5H,13aH- quinolino[3,2-f][1,2,4]triazolo[4,3-b][1,2,4]triazepines in ionic liquids

Article abstract of DOI:10.1016/j.bmcl.2011.06.007

The title compounds, 9-substituted-3-aryl-5H,13aH-quinolino[3,2-f][1,2,4] triazolo[4,3-b][1,2,4]triazepines 8, are synthesized from 5-aryl-3,4-diamino-1, 2,4-triazoles 5 and 2-chloro-3-formylquinolines 7 in ionic liquid as solvent under microwave heating as well as using oil-bath heating at 80 °C. The products are obtained in the good to moderate yields and in high purity. These compounds have been screened for antifungal activity. The screening data indicate that the compounds 8a, 8b, 8c and 8d show excellent activity against Aspergillus niger 1000 μg concentration and Pencillium notatum species at 500 μg as well as 1000 μg concentrations whereas, these compounds show good to moderate activity against Aspergillus flavus and Rhizopus species at both the concentrations. Moreover, ionic liquid is found to be recyclable for at least three consecutive runs what makes the process cost-effective and economic that lead to the area of Green Chemistry as recyclability is one of the most important feature of Green Chemistry.

Full text of DOI:10.1016/j.bmcl.2011.06.007

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4919–4923
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Efficient synthesis of antifungal active 9-substituted-3-aryl-5H,
13aH-quinolino[3,2-f][1,2,4]triazolo[4,3-b][1,2,4]triazepines in ionic liquids
Monika Gupta
Department of Chemistry, University of Jammu, Jammu 180 006, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The title compounds, 9-substituted-3-aryl-5H,13aH-quinolino[3,2-f][1,2,4]triazolo[4,3-b][1,2,4]triaze-
pines 8, are synthesized from 5-aryl-3,4-diamino-1,2,4-triazoles 5 and 2-chloro-3-formylquinolines 7
in ionic liquid as solvent under microwave heating as well as using oil-bath heating at 80 °C. The products
are obtained in the good to moderate yields and in high purity. These compounds have been screened for
antifungal activity. The screening data indicate that the compounds 8a, 8b, 8c and 8d show excellent
Received 13 March 2011
Revised 11 May 2011
Accepted 2 June 2011
Available online 17 June 2011
activity against Aspergillus niger 1000
lg concentration and Pencillium notatum species at 500 lg as well
Keywords:
Quinoline
Triazolo
Triazepines
Room-temperature ionic liquid
Microwave irradiation
as 1000 g concentrations whereas, these compounds show good to moderate activity against Aspergillus
l
flavus and Rhizopus species at both the concentrations. Moreover, ionic liquid is found to be recyclable for
at least three consecutive runs what makes the process cost-effective and economic that lead to the area
of Green Chemistry as recyclability is one of the most important feature of Green Chemistry.
Ó 2011 Elsevier Ltd. All rights reserved.
Room-temperature ionic liquids1 are gaining academic and
industrial world wide attention,2 as these can be used to replace
the organic solvents in catalysis,3 synthesis,4,5 and separations.6
The unique properties of RTILs enable their use as alternative sol-
vents and may speed the introduction of potentially ‘green’ sol-
vents into sustainable industrial processes. Heterocyclic
compounds are highly essential to life as they play a vital role in
metabolism of all living cells. Many heterocyclic compounds con-
taining N, O and S show wide range of physiological activities.
Hence, they are claimed as potential biologically active com-
pounds. For instance, a number of pyrazole derivatives are associ-
ated with wide range of biological activities such as antifungal7
and antibacterial8. Triazole derivatives are known to possess anti-
fungal,9 antibacterial,10 anti-inflammatory,11 antimicrobial12,13
and antiasthamatic14,15 activities while thiadiazepine derivatives
have reported to exhibit wide range of biological activities such
as herbicidal, antimicrobial, antiinflammatory and analgesics.
Some recent examples16–22 have been reported in the literature
which show that antifungal active compounds occupy a unique po-
sition in pharmacological kingdom.
ture which are used as efficient catalysts and solvents in organic
synthesis.23–26 These ionic liquids have been found to be superior
to the classical solvents used for preparation of triazepines.27–30
Keeping in view the importance of reported ionic liquids, we have
tried to synthesize a new class of ionic liquids, that is, 1,3,5-trim-
ethylpyrazoliumtetrafluoroborate ionic liquid (10) (Scheme 4)
and are able to get 85% yield. In recent years, microwave activation
couple efficiently with solid supports and represent an environ-
ment-friendly methodology. Further, work-up procedure is simply
reduced to filtration followed by washing with water. Moreover,
products are obtained in a state of high purity. In this Letter, we re-
port the simple preparation of novel 1,3,5-trimethylpyrazolium
tetrafluoroborate (10) (Scheme 4) and its application in the synthe-
sis of antifungal active compounds 9-substituted-3-aryl-5H,13aH-
quinolino[3,2-f][1,2,4]triazolo[4,3-b][1,2,4]triazepines using ionic
liquid under microwave irradiation (Scheme 4). In this case, novel
1,3,5-trimethylpyrazoliumtetrafluoroborate (10) (Scheme 4) is
studied as solvent. Moreover, the novel 1,3,5-trimethylpyrazoli-
umtetrafluoroborate is found to be re-cyclable for at least three
runs without loss of much activity rendering the process more
economic.
To study the combined effect of these three heterocyclic moie-
ties in a single network, there is a continued interest in the synthe-
sis of 9-substituted-3-aryl-5H,13aH-quinolino[3,2-f][1,2,4]triazolo
4,3-b][1,2,4]triazepines 8. Various ionic liquids such as 1-butyl-
3-methyl imidazolium tetrafloroborate, imidazolium, pyridinium,
piperidinium and morpholinium have been reported in the litera-
The required precursor, 5-aryl-3,4-diamino-1,2,4-triazoles 5,31
were prepared from methyl benzoates 1 which were then con-
verted to aroyl hydrazides 232 on refluxing with hydrazine hydrate
in ethanol followed by conversion to aroyl thiosemicarbazides 333
on heating with potassium thiocyanate in aq HCl. Aroyl thiosemic-
arbazides were then converted to 2-amino-5-aryl-1,3,4-thiadiz-
oles34 4 which were then converted to 5-aryl-3,4-diamino-1,2,
4-triazoles 5 on refluxing with hydrazine hydrate in ethanol as
E-mail address: monika.gupta77@indiatimes.com
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.06.007

4920
M. Gupta / Bioorg. Med. Chem. Lett. 21 (2011) 4919–4923
O
C
CH3
NH
CH 3
KSCN
N2H4.H2
O
12 mL water
COOMe
NHNH2
BF4
HCl
+
HBF4
H3C
N
N
H3C
N
Room temperature
stirring
CH3
1
2
CH3
9
10
O
C
S
C
N
N
Conc.H 2SO4
Scheme 4.
NHNH
NH2
R
NH2
S
4
3
N
N
dences which support that displacement occurs via NH2–N– and
condensation occurs via –C–NH2.
N2 H4. H2
O
R
NH2
The reaction of 5-phenyl-3,4-diamino-1,2,4-triazole 5a with
2-chloro-3-formyl quinoline was tried in ionic liquid and isolated
8a in 70% yield. Similar reaction was also carried out with different
substrates under conventional conditions at 80 °C and was able to
isolate 58% yield. To check the generality of the reaction, this
procedure was also applied to other substrates and found good
to moderate yields. The results are summarised in Table 1. Thus,
this represents a rapid, mild, cost-effective and green procedure
for the synthesis of 9-substituted-3-aryl-5H,13aH-quinolino[3,2-
f][1,2,4]triazolo[4,3-b][1,2,4]triazepines.
In order to optimise the reaction conditions, different reactions
were tried with varying amount of 2-chloro-3-formylquinolines 7a
and 5-phenyl-3,4-diamino-1,2,4-triazole 5a which were selected
as test substrates. It was found that for 5 mmole of each of 5-phe-
nyl-3,4-diamino-1,2,4-triazole 5a, 2-chloro-3-formylquinoline 7a,
1 ml of ionic liquid was required under microwave heating and
as solvent under oil-bath heating to give maximum yield under
mild conditions. To select the optimum power level, reaction with
test substrates was carried out at different power levels from 80 to
900 W. It was found that 640 W was selected as the optimum
power level as far as yield and reaction times are concerned. At
low power level, the reaction remains incomplete whereas, at high
power level, low yields of products were obtained which may be
due to decomposition. Under oil-bath hating, 80 °C was selected
as the optimum reaction temperature.
N
NH2
5
Scheme 1. R = C6H5, 2-ClC6H4, 4-ClC6H4, CH2C6H5, (4-NO2)C6H4.
shown in Scheme 1, while 2-chloro-3-formyl quinolines 7,35 were
prepared by Vilsmeir Haack reaction of acetanilides/substituted
acetanilides 6 as illustrated in Scheme 2. The synthesized precur-
sors were then used for the synthesis of title compounds 8a–j in
the presence of ionic liquid under both microwave and oil-bath
heating.
It was found that ionic liquid has not yet been used for the con-
densation of 2-chloro-3-formyl quinolines 7 with 5-aryl-3,4-dia-
mino-1,2,4-triazoles
9-substituted-3-aryl-5H,13aH-quinolino[3,2-f][1,2,4]triazolo[4,3-
b][1,2,4]triazepines 8 which is outlined in Scheme 5. While carrying
out the reaction, it was found that the two amino groups were pres-
ent at 4 and 5-position of 5-aryl-3,4-diamino-1,2,4-triazole 5 but
the amino group at C-5 position was involved in tautomerisation
giving tautotmeric form as shown in Scheme 3. It was supported
by the fact that only –C–NH2 group can form Schiff’s base with
2-chloro-3-formyl quinolines 7 while H2N–N– group containing
compounds are analogues to hydrazino type compounds which
can displace chlorine easily of 2-chloro-3-formyl quinolines 7. So,
it was only the amino group at C-2 position of 5-aryl-3,4-diami-
no-1,2,4-triazole 5 which can form Schiff’s base with 2-chloro-3-
formyl quinolines 7 while N–NH2 of 5 cannot form Schiff’s base.
Moreover, in the resulting product 8, the H-atom at 5-position
(NH) can form hydrogen bond with all the ‘R’ groups present at
C-3 position. Free amino group can displace chlorine easily while
imino group cannot displace chlorine easily. These are the evi-
5
followed by cyclisation to afford
Some of the synthesized compounds were screened for anti-
fungal activity against Aspergillus flavus, Aspergillus niger, Rhizopus
species and Pencillium notatum species by paper disc technique
against two concentrations 500 lg/ml and 1000 lg/ml. The zone
of inhibition after 24 h of incubation at 28 2 °C was compared
with that of standard fluconazole. The screening data indicated
that the compounds 8a, 8b, 8c and 8d showed excellent activity
against A. niger 1000
l
g concentration and P. notatum species at
g concentrations whereas, these com-
500 g as well as 1000
l
l
pounds showed good to moderate activity against A. flavus and
Rhizopus species at both the concentrations as shown in Table 2.
The medium used for evaluation of antifungal activity was potato
dextrose agar-agar medium.
NHCOCH3
CHO
DMF/POCl3
Preparation of the medium: Potato dextrose agar-agar medium
was prepared as below:
R'
R'
N
Cl
Potato = 250 g
Dextrose = 10 g
Agar-agar = 20 g
6
7
Scheme 2. R = 4-CH3, 3-CH3, 4-OMe.
Distilled water = 100 ml
N
NH
N
N
Sliced potatoes were taken with 500 ml of distilled water in a
pan and boiled for half an hour till a spoon when placed on a slice
can pierce into it. Filter it while hot and broth was again taken in a
pan with rest of the distilled water. Dextrose dissolved in distilled
water and weighed agar-agar was added to the broth and heated it
to boil. The medium thus obtained was sterilized in pressure coo-
ker for 30 min and few drops of streptomycin were added to pre-
vent it from any bacterial contamination.
R
R
NH
NH2
N
N
NH2
H2 N
5
9
Scheme 3.

M. Gupta / Bioorg. Med. Chem. Lett. 21 (2011) 4919–4923
4921
N
N
R
N
CHO
CH
N
Ionic liquid
+
N
R'
R'
or
MW
R
NH2
N
N
N
Cl
N
NH
NH2
5
7
8
8a: R= C6H5 , R’= H
8b:R= (NO2)C6H4, R’= H
8c : R= 2-ClC6H4, R’= 3-CH3
8d:R= (4-NO2)C6H4, R’= 3-CH3
8e: R= 2-ClC6H4, R’= 4-OCH3
8f:R= CH2 C6H5 , R’= 4-CH3
8g: R= C6H5, R’= 4-CH3
8 h: R= 4-ClC6H4,R’= 4-OCH3
8 i: R= (4-NO2)C6H4 , R’= 4-OCH3
8j:R= (4-NO2)C6H4, R’= 4-CH3
Scheme 5. 8a: R = C6H5, R0 = H; 8b: R = (NO2)C6H4, R0 = H; 8c: R = 2-ClC6H4, R0 = 3-CH3; 8d: R = (4-NO2)C6H4, R0 = 3-CH3; 8e: R = 2-ClC6H4, R0 = 4-OCH3; 8f: R = CH2C6H5, R0 = 4-
CH3; 8g: R = C6H5, R0 = 4-CH3; 8h: R = 4-ClC6H4,R0 = 4-OCH3; 8i: R = (4-NO2)C6H4, R0 = 4-OCH3; 8j: R = (4-NO2)C6H4, R0 = 4-CH3.
Table 1
Physical data of synthesized compounds 9-substituted-3-aryl-5H,13aH-quinolino[3,2-f][1,2,4]triazolo[4,3-b][1,2,4]triazepines in ionic liquid
Compound
Microwave (MW)
Oil-bath heating at 8 °C (
D
)
Mp (°C)
Time (min)
Yield (%)
Time (h)
Yield (%)
8a
8b
8c
8d
8e
8f
8g
8h
8i
4
3
7
4
11
5
6.5
7.5
5
70a
21
12
20
10
20
26
23
20
9
58a
66b
65a
62a
70b
62a
65a
70a
76a
60a
160–162
210–212
172–174
204–206
220–222
210–212
214–216
215–217
138–140
190–192
78b
a
68
72a
80b
70a
78a
85a
80a
74a
8j
8
11
a
Products were purified by crystallisation from ethyl acetate.
Products were purified by passing through column of alumina and elution with ethyl acetate/petroleum ether.
b
Table 2
Antifungal activity of synthesized compounds 9-substituted-3-aryl-5H,13aH-quinolino[3,2-f][1,2,4]triazolo[4,3-b][1,2,4]triazepines
S. No.
Compd No. Concn (lg/ml)
Zone of inhibition in mm (%)
Aspergillus niger
Aspergillus flavus
500 1000
Rhizopus species
500 1000
Pencillium notatum species
500 1000
500
l
g
1000
lg
l
g
lg
lg
lg
lg
lg
1
2
3
4
8a
8b
8c
8d
39 (53.33)
22 (33.33)
24 (40.00)
34 (56.66)
42
43 (71.66)
38 (63.33)
43 (71.66)
40 (66.66)
48
32 (53.33)
36 (60.00)
42 (70.66)
43 (71.66)
35
45 (70.00)
36 (60.00)
32 (53.33)
49 (81.66)
42
30 (50.00)
25 (41.66)
28 (46.66)
20 (33.33)
38
30 (50.00)
26 (43.33)
32 (53.33)
30 (50.00)
42
44 (73.33)
43 (71.66)
44 (73.33)
48 (80.00)
52
54 (90.00)
52 (86.66)
42 (70.00)
42 (70.00)
54
Fluconazole
(70.00)
(80.00)
(58.33)
(70.00)
(63.33)
(70.00)
(86.66)
(90.00)
Procedure: Potato dextrose medium was prepared and sterilized
in pressure cooker for 30 min. Sterilized medium (15 ml) each was
pipetted out into flat petridishes. When it solidified 15 ml of warm
seeded medium was applied over it. The seeded agar was made by
cooling the medium to 40 °C and then adding spore suspension to
seeded medium. The spores were obtained from ten days culture of
A. niger, A. flavus, P. notatum species and Rhizopus species. Before
the solidification of agar, the plate was tilted to ensure that cover-
age should be even. These petridishes were then put into the
refrigerator upside down to prevent condensation of moisture.
the chilled seeded medium. The plates were then incubated for
24–72 h at 28 2 °C and inhibition of zone around each disc was
measured from the centre of the discs. The percentage zone of inhi-
bition was calculated by the formula:
I% ¼ C ꢀ T=C ꢁ 100
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 24 h, fluconazole
(500 lg/ml and 1000 lg/ml) was used as control standard.
Fungal infections have been reported to have dramatically in-
creased in the past decade, and these often occur as systemic infec-
tions or as coinfections with other diseases, such as AIDS or cancer,
or in patients who are immune compromised. In fact, candidiasis
has become the most common infection in AIDS and cancer
Two concentrations viz. 500 and 1000 lg/ml of the synthesized
compounds were prepared by dissolving the required quantity of
compounds in DMF. Sterilized Whatmann filter paper number
541 discs were prepared by cutting 6 mm diameter with a cork
borer and were spread individually with a needle and planted upon

4922
M. Gupta / Bioorg. Med. Chem. Lett. 21 (2011) 4919–4923
patients. Unfortunately, in addition to the limited number of anti-
fungal drugs currently available, fungal infections tend to rapidly
develop resistance to these drugs. For these reasons, fungal infec-
tions now show much higher mortality rates than bacterial infec-
tions. The rapid increase in fungal infections and the growing
number of new antifungal agents indicate an increasing need for
rapid and accurate methods for antifungal screening and suscepti-
bility testing. The National Committee for Clinical Laboratory Stan-
dards (NCCLS) recently approved a standardised method for
antifungal susceptibility testing, and proposed a method for testing
of filamentous fungi, based on a broth macrodilution method
(BMM). Subsequently, several modifications of these methods
were proposed. Most of these methods were developed for the
determination of MICs of agents against yeasts.
Experimental Section: General. All the melting points were deter-
mined on a Tempo melting point apparatus and are uncorrected.
1H NMR spectra were recorded on a Bruker DPX-200 NMR spec-
trometer (200 MHz) in CDCl3 + DMSO-d6 using tetramethylsilane
as an internal standard and IR spectra were recorded using KBr disc
on a Perkin–Elmer FTIR spectrophotometer. The mass spectral data
was obtained on a JEOL JMS-D 300 spectrometer. The elemental
analysis was performed on a simple CHNS-932 Analyser (Leco).
The reactions were carried out in domestic microwave oven LG-
MS-255R with maximum output power of 900 W and by using
pre-heated oil-bath.
General procedure for the synthesis of compounds 8a–j: Micro-
wave heating. A mixture of 5-phenyl-3,4-diamino-1,2,4-triazole 5
(5 mmol), 2-chloro-3-formylquinoline 7 (5 mmol), ionic liquid
(1 ml) was taken in a 50 ml borosil beaker and mixed properly
with the help of a glass rod (5 s). The mixture was then exposed
to microwave irradiation for an appropriate time (monitored by
TLC, shown in Table 1) followed by cooling time of 5 s each at
640 W. After the completion of reaction, petroleum ether was
added and it was found that ionic liquid settled at the bottom.
It was then decanted off. The crude product was purified either
by crystallisation from ethyl acetate or by passing through a col-
umn of alumina and elution with ethylacetate and petroleum
ether.
(aromatic C–H), 1642 (C@N), 1406 (C–N); 1H NMR (CDCl3 + DMSO-
d6): d 7.10–7.34 (m, 4H, Harom), 7.47–7.69 (m, 5H, Harom and s, 1H
buried N@CH), 8.01 (d, 1H, Harom), 8.35 (br s, 1H, Harom); 13CNMR
(CDCl3): d 166 (C-11a, 5a), 164 (C-12), 160 (C-3,14), 133 (C-11),
132 (C-9), 131 (C-8), 130 (C-10, 40), 129 (C-20, 60), 128(C-30, 50),
126 (C-7, 10), 121 (C-10a, 6a); ms: m/z (M+) 292.
Anal. Calcd for C18H12N6: C, 73.97; H, 4.10; N, 21.91. Found: C,
73.93; H, 4.06; N, 21. 87.
3-(40-Nitrophenyl)-5H,13aH-quinolino[3,2-f][1,2,4]triazolo[4,3-
b][1,2,4]triazepine 8b. This compound was obtained as brown col-
oured shining solid (through column), mp 210–212 °C; IR (KBr,
mmax in cmꢀ1): 3108 (NH), 3070 (aromatic C–H), 1638 (C@N),
1540 (NO2), 1430 (C–N); 1H NMR (CDCl3 + DMSO-d6): d 7.20 (m,
1H, Harom), 7.50–7.58 (m, 2H, Harom), 7.70–7.85 (m, 3H, Harom and
s, 1H buried N@CH), 8.02 (d, 1H, Harom), 8.20–8.31 (m, 2H, Harom),
8.55 (br s, 1H, NH); 13CNMR (CDCl3): d 166 (C-11a, 5a), 164 (C-
12), 160 (C-3,14), 134 (C-10, 40), 133 (C-11), 132 (C-9), 131 (C-8),
130 (C-20, 60), 129 (C-30, 50), 126 (C-7, 10), 121 (C-10a, 6a); ms:
m/z (M+) 353.
Anal. Calcd for C18H11N7O2: C, 61.18; H, 3.11; N, 26.62; O, 9.06.
Found: C, 61.14; H, 2.97; N, 26.58; O, 9.02.
9-(300-Methyl)-3-(20-chlorophenyl)-5H,13aH-quinoloino[3,2-
f][1,2,4]triazolo[4,3-b][1,2,4]triazepine 8c. This compound was ob-
tained as yellow shining solid (through column), mp172–174 °C;
IR (KBr, mmax in cmꢀ1): 3120 (NH), 3040 (aromatic C–H), 2825
(C–H), 1620 (C@N), 1424 (C–N), 748 (C–Cl); 1H NMR
(CDCl3 + DMSO-d6): d 2.30 (s, 3H, CH3), 7.12–7.36 (m, 4H, Harom),
7.45–7.58 (m, 3H, Harom), 7.69 (s, 1H, N@CH), 7.98 (d, 1H, Harom),
8.35 (br s, 1H, NH); 13CNMR (CDCl3): d 166 (C-11a, 5a), 164 (C-
12), 160 (C-3,14), 133 (C-11, 10, 40), 132 (C-9), 131 (C-8), 129 (C-
20, 60), 128 (C-30, 50), 126 (C-7, 10), 121 (C-10a, 6a), 30 (CH3); ms:
m/z (M+) 340.5.
Anal. Calcd for C19H13N6Cl: C, 66.96; H, 3.81; N, 18.79; Cl, 9.86.
Found: C, 66.92; H, 3.77; N, 18.72.
9-(300-Methyl)-3-(40-nitrophenyl)-5H,13aH-quinolino-
[3,2-f][1,2,4]triazolo[4,3-b][1,2,4]triazepine 8d. This compound was
obtained as brown coloured shining solid (ethyl acetate), mp
204–206 °C; IR (KBr, mmax in cmꢀ1): 3115 (NH), 3060 (aromatic
C–H), 2810 (C–H), 1510 (NO2), 1420 (C–N); 1H NMR
(CDCl3 + DMSO-d6): d 2.32 (s, 3H, CH3), 7.22 (m, 1H, Harom), 7.52–
7.68 (m, 1H, Harom and s, 1H buried N@CH), 7.72–7.82 (m, 3H, Har-
om), 8.16–8.28 (m, 2H, Harom), 8.35 (br s, 1H, NH); 13CNMR (CDCl3):
d 166 (C-11a, 5a), 164 (C-12), 160 (C-3, 14), 134 (C-10, 40), 133
(C-11), 132 (C-9), 131 (C-8), 130 (C-20, 60), 129 (C-30, 50), 126 (C-
7, 10), 121 (C-10a, 6a), 30 (CH3); ms: m/z (M+) 367.
The physical data of the synthesized compounds is given in
Table 1. The structures of the products were confirmed by IR, 1H
NMR, mass spectral data and elemental analysis.
Oil-bath heating. A mixture of 5-phenyl-3,4-diamino-1,2,4-tria-
zole 5 (5 mmol), 2-chloro-3-formylquinoline 7 (5 mmol), ionic
liquid (1 ml) was taken in a 50 ml in a round bottomed flask. The
reaction mixture was stirred in oil-bath at 80 °C for the appropriate
time (monitored by TLC, shown in Table 1). After the completion of
reaction, petroleum ether was added and it was found that ionic li-
quid settled at the bottom. It was then decanted off. The crude
product was purified either by crystallisation from ethyl acetate
or by passing through a column of alumina and elution with ethyl-
acetate and petroleum ether.
The physical data of the synthesized compounds is given in
Table 1. The structures of the products were confirmed by IR, 1H
NMR, mass spectral data and elemental analysis.
Recyclability of ionic liquid: 1,3,5-Trimethylpyrazolium tetrafluo-
roborate was found to be recyclable for at least three runs. The
reaction in case of entry 1 was carried out for three consecutive
runs (1st run: 70% after 4 min; 2nd run: 69% after 6 min.; 3rd
run: 67% after 9 min.) with the same ionic liquid. These results
demonstrated that there was no significant loss of activity of ionic
liquid as it was recyclable.
Anal. Calcd for C19H13N7O2: C, 62.12; H, 3.54; N, 25.61; O, 8.73.
Found: C, 61.98; H, 3.50; N, 25.50.
9-(400-Methoxy)-3-(20-chlorophenyl)-5H,13aH-quinolino
[3,2-f][1,2,4]triazolo[4,3-b][1,2,4]triazepine 8e. This compound was
obtained as yellow coloured shining solid (ethyl acetate), mp
220–222 °C; IR (KBr, mmax in cmꢀ1): 3120 (NH), 3080 (aromatic
C–H), 1628 (C@N), 1434 (C–N), 1225 (OCH3), 738 (C–Cl); 1H NMR
(CDCl3 + DMSO-d6): d 3.95 (s, 3H, OCH3), 7.15–7.34 (m, 4H, Harom),
7.42–7.60 (m, 3H, Harom), 7.60 (s, 1H, N@CH), 7.97 (d, 1H, Harom),
8.35 (br s, 1H, NH); 13CNMR (CDCl3): d 166 (C-11a, 5a), 164 (C-
12), 160 (C-3,14), 133 (C-11, 10, 40), 132 (C-9), 131 (C-8), 129 (C-
20, 60), 128 (C-30, 50), 126 (C-7, 10), 121 (C-10a, 6a), 60 (OCH3);
ms: m/z (M+) 356.5.
Anal. Calcd for C19H13N6OCl: C, 63.95; H, 3.64; N, 17.95; Cl, 9.42;
O, 4.91 Found: C, 63.91; H, 3.60; N, 17.91; O, 4.90.
9-(400-Methyl)-5-benzyl-3H,13aH-quinolino[3,2-f][1,2,4]triazol-
o[4,3-b][1,2,4]triazepine 8f. This compound was obtained as yellow
coloured shining solid (through column), mp 210–212 °C; IR (KBr,
Spectral data of the synthesized compounds 8a–j: 3-Phenyl-
5H,13aH-quinolino[3,2-f][1,2,4]triazolo[4,3-b][1,2,4]triazepine 8a. This
compound was obtained as orange coloured shining solid (ethyl
acetate), mp 160–162 °C; IR (KBr, mmax in cmꢀ1): 3100 (NH), 3040
m
max in cmꢀ1): 3120 (NH), 3030 (aromatic C–H), 1640 (C@N), 1421
(C–N); 1H NMR (CDCl3 + DMSO-d6): d 2.34 (s, 3H, CH3), 4.04 (s, 2H,

M. Gupta / Bioorg. Med. Chem. Lett. 21 (2011) 4919–4923
4923
Ar-CH2), 7.09–7.28 (m, 4H, Harom), 7.45–7.60 (m, 4H, Harom), 7.68 (s,
1H, N@CH), 8.01 (d, 1H, Harom), 8.35 (br s, 1H, NH); 13CNMR
(CDCl3): d 166 (C-11a, 5a), 164 (C-12), 160 (C-3, 14), 133 (C-11,
10, 40), 132 (C-9), 131 (C-8), 129 (C-20, 60), 128 (C-30, 50), 126 (C-7,
10), 121 (C-10a, 6a), 41 (CH2) 30(CH3); ms: m/z (M+) 340.
Anal. Calcd for C20H16N6: C, 70.58; H, 4.70; N, 24.70. Found: C,
70.52; H, 4.65; N, 24.78.
128 (C-30, 50), 126 (C-7, 10), 121 (C-10a, 6a), 30 (CH3); ms: m/z
(M+) 371.
Anal. Calcd for C19H13N7O2: C, 61.45; H, 3.50; N, 26.41; O, 8.64.
Found: C, 61.35; H, 3.42; N, 26.38; O, 8.60.
Acknowledgments
9-(400-Methyl)-5-phenyl-3H,13aH-quinolino-[3,2-f][1,2,4]triazol-
o[4,3-b][1,2,4]triazepine 8g. This compound was obtained as pale
yellow shining solid (ethyl acetate), mp 214–216 °C; IR (KBr, mmax
in cmꢀ1): 3110 (NH), 3022 (aromatic C–H),2810 (C–H), 1640
(C@N), 1406 (C–N); 1H NMR (CDCl3 + DMSO-d6): d 2.34 (s, 3H,
CH3), 7.11–7.34 (m, 4H, Harom), 7.43–7.65 (m, 4H, Harom), 7.70 (s,
The author, Monika Gupta, is thankful to Department of Science
and Technology, Ministry of Science and Technology, Govt. of India
(DST, New Delhi) for providing the funds in the research project
under Fast Track Proposal for Young Scientists (SERC Division)
allotted to her. I am also thankful to Sophisticated Analytical
Instrumentation Faculty Centre (SAIF) Panjab University, Chandi-
garh and IIIM Jammu for providing the spectral studies.
1H, N@CH), 8.02 (d, 1H, Harom), 8.31 (br s, 1H, Harom);
13CNMR
(CDCl3): d 166 (C-11a, 5a), 164 (C-12), 160 (C-3,14), 133 (C-11,
10, 40), 132 (C-9), 131 (C-8), 129 (C-20, 60), 128 (C-30, 50), 126 (C-7,
10), 121 (C-10a, 6a), 30 (CH3); ms: m/z (M+) 306.
References and notes
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9-(400-Methoxy)-5-(40-chlorophenyl)-3H,13aH-quinolino-
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[3,2-f][1,2,4]triazolo[4,3-b][1,2,4]triazepine 8h. This compound was
obtained as pale yellow shining solid (ethyl acetate), mp 215–
217 °C; IR (KBr, mmax in cmꢀ1); 3110 (NH), 3042 (aromatic C–H),
1612 (C@N), 1428 (C–N), 1275 (OCH3), 759 (C–Cl); 1H NMR
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7.39–7.57 (m, 4H, Harom), 7.70 (s, 1H, N@CH), 8.01 (d, 1H, Harom),
8.30 (br s, 1H, NH); 13CNMR (CDCl3): d 166 (C-11a, 5a), 164
(C-12), 160 (C-3, 14), 133 (C-11, 10, 40), 132 (C-9), 131 (C-8), 129
(C-20, 60), 128 (C-30, 50), 126 (C-7, 10), 121 (C-10a, 6a), 60 (OCH3);
ms: m/z (M+) 356.5.
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Cl, 9.95. Found: C, 63.90; H, 3.60; N, 17.90; O, 0.02.
9-(400-Methoxy)-5-(40-nitrophenyl)-3H,13aH-quinolino[3,2-
f][1,2,4]triazolo[4,3-b][1,2,4]triazepine 8i. This compound was ob-
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138–140 °C; IR (KBr, mmax in cmꢀ1): 3100 (NH), 3020 (aromatic
C–H), 1640 (C@N), 1442 (C–N), 1440 (NO2), 1275 (OCH3); 1H
NMR (CDCl3 + DMSO-d6): d 3.92 (s, 3H, OCH3), 7.22 (m, 1H, Harom),
7.60–7.72 (m, 1H, Harom and s, 1H buried N@CH), 7.75–7.86 (m, 3H,
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H
arom), 7.99 (d, 1H, Harom), 8.21–8.24 (m, 2H, Harom), 8.36 (br s, 1H,
Harom); 13CNMR (CDCl3): d 166 (C-11a, 5a), 164 (C-12), 160 (C-3,
14), 134 (C-10, 40), 133 (C-11), 132 (C-9), 131 (C-8), 129 (C-20, 60),
128 (C-30, 50), 126 (C-7, 10), 121 (C-10a, 6a), 60 (OCH3); ms: m/z
(M+) 387.
Anal. Calcd for C19H13O3N7: C, 58.91; H, 3.35; N, 25.32, O, 12.42.
Found: C,58.87; H,3.32; N, 25.31. O, 12.40.
9-(400-Methyl)-5-(40-nitrophenyl)-3H,13aH-quinolino-[3,2-
f][1,2,4]triazolo[4,3-b][1,2,4]triazepine 8j. This compound was
obtained as brown coloured shining solid (through column), mp
190–192 °C; IR (KBr, mmax in cmꢀ1); 3122 (NH), 3044 (aromatic
C–H), 1620 (C@N), 1470 (NO2), 1428 (C–N), 1H NMR
(CDCl3 + DMSO-d6): d 2.34 (s, 3H, CH3), 7.25 (m, 1H, Harom), 7.53–
7.69 (m, 1H, Harom and s, 1H buried N@CH), 7.712–7.85 (m, 3H, Har-
om), 8.01 (d,1H, Harom), 8.15–8.30 (m, 2H, Harom), 8.38 (br s, 1H,
NH); 13CNMR (CDCl3): d 166 (C-11a, 5a), 164 (C-12), 160 (C-3,
14), 134 (C-10, 40), 133 (C-11), 132 (C-9), 131 (C-8), 129 (C-20,60),