Solvent-free, one-pot synthesis and biological evaluation of some new dipyrazolo [3,4-b:4′,3′-e]pyranylquinolones and their precursors

Article abstract of DOI:10.1007/s00044-013-0608-2

One-pot synthesis of 24 new compounds, belonging to three families; dipyrazolo[3,4-b:4′,3′-e]pyranylquinolones 7a-h and its precursors (pyrazolonylidene)methylquinolones 5a-h and 4,4′-[(quinolinyl)methylene] bispyrazols 6a-h, 8 from each, has been achieve

Full text of DOI:10.1007/s00044-013-0608-2

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0608-2
ORIGINAL RESEARCH
Solvent-free, one-pot synthesis and biological evaluation
of some new dipyrazolo [3,4-b:40,30-e]pyranylquinolones
and their precursors
•
Narsidas J. Parmar Bhavesh R. Pansuriya
•
•
Bhagyashri D. Parmar Hitesh A. Barad
Received: 7 January 2013 / Accepted: 2 May 2013
Ó Springer Science+Business Media New York 2013
Abstract One-pot synthesis of 24 new compounds,
belonging to three families; dipyrazolo[3,4-b:40,30-e]pyra-
nylquinolones 7a–h and its precursors (pyrazolonylidene)
methylquinolones 5a–h and 4,40-[(quinolinyl)methylene]bi-
spyrazols 6a–h, 8 from each, has been achieved in the pres-
ence of catalyst tetrabutylammonium hydrogen sulfate
(TBA–HS) in solvent-free conditions. In addition to assuring
chromatography-free product isolation, this method had also
allowed the reaction to proceed in a regio-selective manner
provided the temperature and amount of pyrazolone are var-
ied. At 100 °C, while 1:1 mixture of aldehyde 3 and pyrazo-
lone 4 underwent Knoevenagel condensation, same reactants
taken in ratio of 1:2 mainly domino/Knoevenagel–Michael
reaction. At 120 °C, however, the domino/Knoevenagel–
Michael-adducts converted into cyclized product, highlight-
ing a new domino/Knoevenagel–Michael-cyclization syn-
thetic sequence. The structure of all heterocycles has been
confirmed by mass, IR and NMR spectral data. Based on 2D
NMR NOESY experiment, it was also confirmed that the
formation of only ‘Z’ configuration of Knoevenagel alkene
took place in the transformation. All are good antitubercular
agents as they were found to be active against M. tuberculosis
H37RV, in addition to being found active against three Gram-
positive (Streptococcus pneumoniae, Clostridium tetani,
Bacillus subtilis) and three Gram-negative (Salmonella typhi,
Vibrio cholerae, Escherichia coli) bacteria, respectively.
Keywords Knoevenagel–Michael ꢀ
Tetrabutyl ammonium hydrogen sulfate ꢀ
3-Methyl-1-phenyl-5-pyrazolone ꢀ Bis-Pyrazole ꢀ
N-Allyl quinolone
Introduction
Pyrazolone is a subunit of many biologically active com-
pounds (McDonald et al., 2006; El-Nagdi et al., 1987).
Drugs incorporating this unit have been a continuous
source of known anti-anxiety (DeWald et al., 1977), anti-
inflammatory, antipyretic, analgesic (El-Hawash Soad
et al., 2006), anti-depressant (Bailey et al., 1985), anti-
convulsant (Abdel–Aziz et al., 2009) and hypnotic agents
(Sugiura et al., 1977). For example, 4,40-(arylmethyl-
ene)bis(1H-pyrazol-5-ols) have remarkable anti-inflamma-
tory, antipyretic (Behr et al., 1967), gastric secretion
stimulatory (Rosiere et al., 1951), antibacterial (Mahajan
et al., 1991), and antifilarial activities (Chauhan et al.,
1993). Several fungicides (Singh and Singh, 1991), pesti-
cides (Londershausen, 1996), insecticides (Lube, 1970),
dyestuffs (Garnovskii et al., 2004), and chelating and
extracting reagents used for different metal ions are
potential candidates (Parmar and Teraiya, 2009; Parmar
et al., 2010, 2011a). Tendency of bis-pyrazole to coordi-
nate many metal ions via its 5-ol oxygen has played sig-
nificant role in metal extraction studies (Parmar and
Teraiya, 2009; Parmar et al., 2010).
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-013-0608-2) contains supplementary
material, which is available to authorized users.
Condensed pyrazoles, on the other hand, are equally
significant (Baraldi et al., 2012; Verheijen et al., 2009).
Many pyrano[2,3-c]pyrazoles are known in this group (EL-
Nagdi et al., 1990; Kuo et al., 1984). In recent past, fused
azoles have also emerged as intensive research topic (EL-
Nagdi et al., 1990; Kuo et al., 1984; Koyama and Umezawa,
N. J. Parmar (&) ꢀ B. R. Pansuriya ꢀ B. D. Parmar ꢀ
H. A. Barad
Department of Chemistry, Sardar Patel University, Vallabh
Vidyanagar, Dist. Anand 388120, Gujarat, India
e-mail: njpchemdeptspu@yahoo.co.in
123

Med Chem Res
1965; Elmoghayar et al., 1984; Anderson and Jones, 1984).
Finally, bis-pyrazolopyrans and their analogues have
revealed an excellent activity against pest des petits rumi-
nant virus (PPRV) (Sujatha et al., 2009), a useful biological
application.
Quinolone-incorporated heterocycles (Uchida et al.,
1985; Hong et al., 2001; Parmar et al., 2012a), as new
molecular templates, are anticipated to have promising
pharmaceutical activities especially antioxidant and anti-
cancer (Hong et al., 2001; Parmar et al., 2012a, b, c; Faber
and Kappe, 1984; Chen et al., 2004; Ukrainets et al., 1993).
Both 3,4-double bond and 2-oxo functionalities in 2-quin-
olone unit are well known for hydroxyl radical scavenging
properties (Uchida et al., 1985). Rebamipide, for example,
is effective antioxidant as well as antiulcer agent (Hong
et al., 2001). Alkylation in general and allylation in par-
ticular improves affinity of resulted heterocycles towards
the cholecystokinin (CCK2) receptor that has been
involved in many pathological situations (Lattmann et al.,
2002).Those which include anxiety (Bain and Candillis,
2000) and panic (Tullio et al., 2000) particularly, are rel-
evant targets to therapeutic interventions. Considering the
biological significance of quinoline-based compounds and
a part of our ongoing interest (Parmar et al., 2011b, 2012a,
b; c), it was therefore planned to prepare some new
pyrazolonylidenemethylquinolones 5a–h, 4,40-[(quinoline-
3-yl)methylene]bis(1H-pyrazol-5-ols) 6a–h, and dipyraz-
olo[3,4-b:40,30-e]pyranylquinolones 7a–h.
Knoevenagel adducts arylidenepyrazolones formed in
the first step transform into bis-pyrazoles via Michael
addition reaction (Singh and Singh, 1984; Singh and Singh,
1991; Londershausen, 1996). Conventionally, their syn-
theses take a longer reaction time in refluxing water or
other refluxing solvents like ethanol or benzene, in addition
to affording moderate yields. Product isolation step is also
tedious part of conventional methods (Gunasekaran et al.,
2011; Tale et al., 2011; Yao et al., 2007). One-pot Knoe-
venagel–Michael addition of aldehyde with 2 equivalents
of 3H-pyrazol-3-ones in tandem is another approach
(Sujatha et al., 2009; Pavlov et al., 1998; Buzykin and
Lonshchakova, 1971; Wang et al., 2005; Elinson et al.,
2008; Niknam et al., 2010). In piperidine, however, yields
were in the 15–30 % range (Singh and Singh, 1984).
Improved protocols seemed to be in water or ethanol in the
presence of electrolyte NaBr (Elinson et al., 2008), sur-
factant sodium dodecyl sulfate (SDS) (5 mol %) (Wang
et al., 2005), Lewis acid ceric ammonium nitrate (CAN)
(Sujatha et al., 2009) or [Cu(3,4-tmtppa)](MeSO4)4
(Sobhani et al., 2009) and recyclable catalyst silica-bonded
S-sulfonic acid (SBSSA) (Niknam et al., 2010). Other
method utilized acetic acid and ETBA (Shi et al., 2005). Li
et al. (1995, 1997).utilized a solid-state for the synthesis of
4,40-(arylmethylene)bis(1H-pyrazol-5-ols) Bai et al. (2004)
reported catalyst-free microwave irradiation. As Brønsted
acid, ionic liquid 1-methylimidazolium hydrogen sulfate
[HMIM]HSO4 though promotes reaction it takes a longer
reaction time (Zang et al., 2011). In spite of vast literature
reports, however, no tetrabutylammonium hydrogen sulfate
(TBA–HS) has been tried and explored in the strategy.
Moreover, several aldehydes (Sujatha et al., 2009; Pavlov
et al., 1998; Buzykin and Lonshchakova, 1971; Wang
et al., 2005; Elinson et al., 2008; Niknam et al., 2010;
Ballini et al., 2003; Macquarrie et al., 2003) have been
tried, but no insoluble quinoline-3-carbaldehydes. Insolu-
ble aldehyde is thus limitation of reported protocols along
with other issues like yields, reaction time, high tempera-
ture and tedious workup procedure (Sujatha et al., 2009;
Pavlov et al., 1998; Buzykin and Lonshchakova, 1971;
Wang et al., 2005; Elinson et al., 2008; Niknam et al.,
2010; Li et al., 1995, 1997; Shi et al., 2005; Sobhani et al.,
2009; Niknam et al., 2010). Use of solid catalysts envi-
ronmentally is of a great interest in chemistry and industry
as they offer them simplicity in handling, safety of dis-
posal, and less industrial corrosion (Michail et al., 2011;
Fan et al., 2006). The reactive centers because of highly
mobility have an advantage of being recyclable, too.
Results and discussion
Chemistry
First, we treated quinolines 2a–b obtained (from acetani-
lides 1a–b) via Vilsmeier–Haack reaction with 70 % acetic
acid (Scheme 1). Second, the quinolone obtained was
treated with allyl bromide in the presence of potassium
carbonate suspended in DMF (dimethylformamide) (Par-
mar et al., 2012a). Finally, N-allyl-2-quinolone-3-carbal-
dehyde 3 thus obtained was heated with corresponding
pyrazolone 4 taken in varied amounts in the presence of
20 mol % tetrabutyl ammonium hydrogensulftae (TBA–
HS) under solvent-free conditions. At 100 °C, while 1:1
mixture of reactants (3 and 4 each in 1.12 mmol) results in
(pyrazolonylidene)methylquinolones 5a–h formation via
Knoevenagel condensation, their 1:2 mixture (4 in 2.24
mmol and 3 in 1.12 mmol) in 4,40-[(quinoline-3-yl)methy-
lene]bis(1H-pyrazol-5-ols) 6a–h formation via Knoevena-
gel–Michael reaction (Scheme 2). On heating the reaction
mass containing Knoevenagel–Michael products further at
120 °C, cyclization of the products 6a–h was observed,
highlighting a new tandem Knoevenagel–Michael-cycliza-
tion route to dipyrazolo [3,4-b:40,30-e]pyranylquinolones
7a–h products. The protocol had advantageously employed
no chromatography for product separation, and the workup
procedure used was very simple. In our early work, TBA–
HS has been successfully used to promote domino/
123

Med Chem Res
Knoevenagel-hetero-Diels–Alder reaction in refluxing
xylene (Parmar et al., 2011b, 2012b). Investigating further,
we in present work described the application of this PTC
catalyst in solvent-free environment too, highlighting a
new greener approach to access heterocycles (Table 1;
Scheme 2).
The structure of all newly synthesized compounds 5a–h,
1
6a–h and 7a–h was confirmed by mass, IR, H NMR and
13C NMR spectral data. In the IR of all, the band at around
1,640 cm-1 can be assigned to amide linkage of quinolone
moiety. At a small distance, the second band at around
1,673 cm-1 in all Knoevenagel-adducts 5 is assigned to
pyrazolone moiety. Formation of all new families of
compounds; 5, 6 and 7, can be asserted from the spectral
data. In Michael-adduct 6a, broad bands that appeared in
the region around 3,418 cm-1 confirm the presence of
pyrazolol (enol form) moieties. In 1H NMR, the singlet at d
2.40 in 5a, at 2.35 in 6a and at 2.29 in 7a confirms the
presence of methyl protons at pyrazole ring. A complete
shift of singlet arylidine CH proton from d 8.19 in 5a to d
5.16 a little bit higher in 6a indicate the formation of
Michael-adduct 6a from Knoevenagel alkene 5a. The same
could also be traced out from 13C NMR which evidenced
the complete transformation of alkene sp2 CH (appeared in
the aromatic region d 120–150 of 5a) into sp3 CH
(appeared at d 29.44 in 6a). In the same way, the cycli-
zation of Michael-adduct could also be evidenced from
observing the disappearance of peaks d 12.56 and d 14.29
of 6a (assigned to hydroxyl groups) in 7a. Further, a
The mechanism of the entire domino reaction begins
with the formation of reactive species tetrabutylammonium
pyrazolonate. With quinolone-3-carbaldehyde, it formed
Z-Knoevenagel alkene 5 at 100 °C. Consuming second
molecule of pyrazolone, this Knoevenagel-adduct 5 then
transformed into Michael-adducts 6. Finally, in the influ-
ence of TBA–HS, compound 6 gave cyclized products 7 at
120 °C (Scheme 3).
The recyclability of the catalyst was also tested, con-
firmed and established by re-using the recovered catalyst,
at least four times without the significant loss of its activity
(Fig. 1). To recover the catalyst, the reaction mass, after
being dissolved in methanol, was first poured into ice cold
water to precipitate the product. The solid products were
then isolated through ordinary filtration. Heating the filtrate
in vacuum at 70 °C evaporated the fluid aqueous-organic
mixture and gave residues of TBA–HS in 6 h.
Table 1 Synthesis of Knoevenagel-adducts pyrazolonylidenemethylquinolones 5a–h, Michael-adducts 4,40-[(quinoline-3-yl) methylene]bis(1H-
pyrazol-5-ols) 6a–h, and cyclized products dipyrazolo[3,4-b: 40,30-e]pyranylquinolones 7a–h
Entry
Compounds
R1
R2
Time
Yield %
1
5a
5b
5c
5d
5e
5f
H
Ph
20 min
25 min
20 min
25 min
20 min
25 min
30 min
20 min
2.0 h
90
87
91
88
91
89
90
93
92
91
93
94
92
91
93
92
89
85
88
87
89
86
85
88
2
H
2-Cl Ph
3-Cl Ph
2,5-Cl2 Ph
Ph
3
H
4
H
5
Cl
Cl
Cl
Cl
H
6
2-Cl Ph
3-Cl Ph
2,5-Cl2 Ph
Ph
7
5g
5h
6a
6b
6c
6d
6e
6f
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
H
2-Cl Ph
3-Cl Ph
2,5-Cl2 Ph
Ph
1.5 h
H
2.0 h
H
1.5 h
Cl
Cl
Cl
Cl
H
2.0 h
2-Cl Ph
3-Cl Ph
2,5-Cl2 Ph
Ph
2.0 h
6g
6h
7a
7b
7c
7d
7e
7f
2.0 h
1.5 h
1.5 h
H
2-Cl Ph
3-Cl Ph
2,5-Cl2 Ph
Ph
2.0 h
H
1.5 h
H
1.5 h
Cl
Cl
Cl
Cl
1.5 h
2-Cl Ph
3-Cl Ph
2,5-Cl2 Ph
2.0 h
7g
7h
2.0 h
1.5 h
123

Med Chem Res
CHO
O
CHO
Cl
(ii)
(i)
R1
N
R1
NHCOCH3
R1
N
(iii)
3a-b
1a-b
2a-b
R1 = H, Cl
Scheme 1 Synthesis of N-allyl-2-quinolone-3-carbaldehyde. Reagents and conditions: (i) DMF, POCl3, 75–80 °C, 8 h; (ii) 70 % AcOH, reflux,
4 h; (iii) allyl bromide, K2CO3, DMF, 12 h, RT
Scheme 2 Knoevenagel–
Michael–cyclization reaction.
Reagents and conditions:
(i) 20 % TBA–HS, solvent-free
100 °C; (ii) 5 % SLS, water,
reflux; (iii) 20 % TBA–HS,
solvent-free, 120 °C
R1
4a-d
N
2 equi. of
O
CHO
O
N
N
R2
O
R1
N
(i) or (ii)
N
N
3a-b
N
N
R2
R2
OH
HO
6a-h
4, (i)
100 º C
(iii)
120 º C
R1
O
C2
N
N
4, (iii)
N
N
C5'
R2
120 º C
O
O
R1
5a-h
N
N
N
N
O
R2
R2
7a-h
R1 = H, Cl R2 = Ph, 2-Cl Ph, 3-Cl Ph, 2,5-Cl2Ph
multiplet at d 6.03, a doublet at d 5.01 (J = 2.0), and two
doublets; one at 5.17 with J = 17.2 and second at d 5.29
with J = 10.4 confirm the presence of allyl protons in 5a.
The same can be concluded from 13C NMR wherein both
CH2 gave characteristic peaks; one at d 45.44 and second at
d 117.50.
confirming the Z configuration. Correlation of neither
alkene sp2 CH (d 8.14) nor pyrazolone methyl protons with
that of quinoline nitrogen ring too rules out the possibility
of E-configuration. The proposed structure of 5e has been
depicted as Fig. 2.
Besides above, the 2D NMR NOESY spectrum was also
taken to assign E or Z configuration to Knoevenagel alkene
5e generated from the N-allyl-2-quinolone-3-carbaldehydes
3b and pyrazolone 4a. As could be seen from the NOESY,
it showed the apparent correlation between pyrazolone
methyl (d 2.40) protons and that of alkene sp2 CH,
Antimicrobial activity
The in vitro antimicrobial activity of all the compounds
were determined against three Gram-positive Streptococ-
cus pneumoniae (MTCC 1936), Clostridium tetani (MTCC
123

Med Chem Res
CHO
3
R1
N
O
Bu4N
O
H2SO4
O
N
N
R1
N
O
R2
H
N
H
O
N
O
N
R2
4
H2SO4
N
R2
Bu4N HSO4
R1
R1
Bu4N HSO4
N
N
R1
C2
O
O
O
C5'
R2
N
N
N
N
N
O
O
N
N
O
NBu4
R2
R2
5
N
N
N
R2
N
7
N
N
R2
R2
O
HO
NBu4
H2SO4
-Bu4NHSO4
R1
R1
N
N
O
O
N
N
N
N
N
N
N
R2
N
R2
OH
HO
R2
R2
OH
O
6
Scheme 3 Plausible mechanism for TBA–HS catalyzed Knoevenagel–Michael-cyclization reaction
123

Med Chem Res
2,000 lg/mL concentration, as a stock solution. By further
progressive dilutions with the test medium, the required
concentrations were obtained for primary and secondary
screening. In primary screening 1,000, 500, and 250 lg/mL
concentrations of the compounds were taken. The active
compounds found in this primary screening were further
diluted to obtain 200, 100, 62.5 lg/mL concentrations for
secondary screening to test in a second set of dilution
against all microorganisms. Briefly, the control tube con-
taining no antibiotic is immediately subcultured (before
inoculation) by spreading a loopful evenly over a quarter of
plate of medium suitable for the growth of the test organ-
ism. The tubes are then put for incubation at 37 °C for 24 h
for bacteria and 48 h for fungi. Growth or a lack of growth
in the tubes containing the antimicrobial agent was deter-
mined by comparison with the growth control, indicated by
turbidity. The lowest concentration that completely inhib-
ited visible growth of the organism was recorded as the
minimum inhibitory concentration (MIC, lg/mL), i.e., the
amount of growth from the control tube before incubation
(which represents the original inoculum) is compared. A
set of tubes containing only seeded broth and the solvent
controls were maintained under identical conditions so as
to make sure that the solvent had no influence on strain
growth. All bioassays were repeated at least three times
and the calculated error margin value was 2 lg/mL.
Protocols are summarized in Table 2 as the minimum
inhibitory concentration (MIC, lg/mL).
Screening results showed that all Knoevenagel-adducts
5a–h, Michael-adducts 6a–h, and corresponding cyclized
products dipyrazolo[3,4-b:40,30-e]pyranylquinolones 7a–h
are possessing good antibacterial activity against three
Gram-positive (Streptococcus pneumoniae, Clostridium
tetani, Bacillus subtilis) and three Gram-negative (Salmo-
nella typhi, Vibrio cholerae, Escherichia coli) bacteria, in
comparison to their antifungal activity against two fungus
Aspergillus fumigatus and Candida albicans. The results
are expressed in minimum inhibition concentration (MIC)
measured in lg/mL (Table 2). More than 80 % of the
total compounds tested are active against each type of
Gram-positive and Gram-negative bacteria with a MIC in
the range 250–50, except the ones against Salmonella
typhi bacteria. Here, the highest 95.8 % of total screened
candidates were potent particularly against type of these
bacteria. Analyzing in terms of MIC, it was further
inferred that majority have MIC equal to 200. Those with
lowest MIC (50–62.5 lg/mL) include; 7d against Gram-
positive Streptococcus pneumoniae bacteria, and 5g and
7a against Gram-negative Escherichia coli bacteria,
resembling the standard drug chloramphenicol. Addition-
ally, compounds 5g and 7d are much closer to standard
ciprofloxacin in terms of their potency against former type
bacteria.
Fig. 1 Recyclability of catalyst TBA–HS
CH3
O
H
C2
N
N
N
C5'
O
H
Cl
H
Fig. 2 Characteristic NOESY of 5e
449), Bacillus subtilis (MTCC 441), three Gram-negative
Salmonella typhi (MTCC 98), Vibrio cholerae (MTCC
3906), Escherichia coli (MTCC 443) bacteria and two
Aspergillus fumigatus (MTCC 3008), Candida albicans
(MTCC 227) fungi by the broth microdilution MIC (min-
imum inhibitory concentration) (Shadomy and Pfaller MA
1991) method according to NCCLS (National Committee
for Clinical Laboratory Standards). (NCCLS, 2000) Strains
employed for the activity were procured from [MTCC
(Micro Type Culture Collection)] Institute of Microbial
Technology, Chandigarh. Mueller–Hinton broth was used
as nutrient medium to grow and dilute the compound
suspension for the test bacteria and Sabouraud Dextrose
Broth used for fungal nutrition. Bacterial strains were
primarily inoculated into Mueller–Hinton agar and, after
overnight growth, a number of colonies were directly
suspended in saline solution until the turbidity matched the
turbidity of the McFarland standard (approximately 108
CFU/mL), i.e., inoculum size for test strain was adjusted to
108 CFU/mL (colony forming unit) per milliliter well by
comparing the turbidity (turbidimetric method). Similarly,
fungi were inoculated on Sabouraud Dextrose Broth; the
procedures of inoculum standardization were also similar.
DMSO was used as diluents/vehicle to get desired con-
centration of compounds to test upon standard microbial
strains, i.e., the compounds were dissolved in DMSO and
the solutions were diluted with a culture medium. Each
compound and standard drugs were diluted obtaining
123

Med Chem Res
Table 2 Antibacterial and antifungal test results (MIC)
Compounds
Gram-positive bacteria
Gram-negative bacteria
Fungi
S.p.
MTCC 1936
C.t.
MTCC 449
B.s.
MTCC 441
S.t.
MTCC 98
V.c.
MTCC 3906
E.c.
MTCC 443
A.f.
MTCC 3008
C.a.
MTCC 227
5a
5b
5c
150
250
200
250
100
500
200
250
500
125
250
200
250
250
100
250
100
500
250
50
500
500
100
250
250
500
100
100
100
250
200
100
200
100
200
500
100
250
200
250
100
100
250
250
250
50
200
250
250
100
100
500
500
200
500
200
250
125
250
125
200
250
500
200
250
200
200
250
500
200
250
100
50
100
200
200
100
250
250
62.5
100
200
100
200
200
500
200
200
100
62.5
200
250
100
200
250
200
200
100
10
250
100
200
200
200
500
200
125
500
500
200
100
200
200
250
250
125
100
200
500
200
200
500
250
100
10
62.5
500
250
250
250
500
100
100
250
200
500
250
500
200
250
100
250
500
250
250
100
200
100
200
100
10
[250
[250
[250
[250
[250
[250
[250
[250
[250
[250
[250
[250
[250
[250
[250
[250
[250
[250
[250
[250
[250
[250
[250
[250
–
[250
[250
[250
[250
[250
[250
[250
250
5d
5e
5f
5g
5h
6a
6b
6c
[250
[250
[250
[250
[250
250
6d
6e
6f
6g
6h
7a
7b
7c
[250
[250
[250
[250
[250
[250
[250
250
7d
7e
250
200
500
200
100
10
7f
7g
7h
[A]
[B]
[C]
[D]
[E]
[F]
[250
[250
–
–
–
50
50
50
50
50
–
–
50
100
–
50
25
25
25
–
–
–
–
–
–
–
100
500
–
–
–
–
–
–
100
100
Bold numbers indicate relatively good activities, which are close to standards
MIC is minimum inhibitory concentration in lg/mL as average of triplicate results, all with standard deviation 2 lg/mL
S.p. Streptococcus pneumoniae, C.t. Clostridium tetani, B.s. Bacillus subtilis, S.t. Salmonella typhi, V.c. Vibrio cholerae, E.c. Escherichia coli,
A.f. Aspergillus fumigatus, C.a. Candida albicans, [A] ampicillin, [B] norfloxacin, [C] chloramphenicol, [D] ciprofloxacin, [E] griseofulvin, [F]
nystatin
Antitubercular activity
screening was conducted at 250 lg/ml against
bacilli per tube). These tubes were then incubated at 37 °C.
Growth of bacilli was seen after 12, 22, and finally 28 days
incubation. Tubes having the compounds were compared
with control tubes where medium alone was incubated with
M. tuberculosis H37Rv. The standard strain M. tubercu-
losis H37Rv was tested with known drugs; isoniazide,
fluconazole and miconazole. The screening test results are
summarized as % inhibition relative to standard drugs.
All the compounds were also screened against
M. Tuberculosis H37RV bacteria. The screening test results
were obtained and examined running L.J. method (NCCLS,
A
M. tuberculosis H37Rv following a Lowenstein–Jensen
(L-J) MIC method. Compounds were added to liquid L-J
medium and then media were sterilized by inspissations
method. A culture of M. tuberculosis H37Rv grown on L-J
medium was harvested in 0.85 % saline in bijou bottles.
DMSO was used as vehicle to get a desired concentration.
These tubes were then incubated at 37 °C for 24 h fol-
lowed by streaking of M. tuberculosis H37Rv (5 9 104
123

Med Chem Res
Shimadzu LCMS-2010 spectrometer. Elemental analysis (%
C, H, N) was carried out by Perkin-Elmer 2400 series-II
elemental analyzer (Perkin-Elmer, USA). TLC was per-
formed on Merck 60 F254 precoated silica plates, spots were
detected either by UV (254 nm, 366 nm) or dipping into a
permanganate [KMnO4 (3 g), K2CO3 (20 g), NaOH (5 mL,
5 % in H2O), H2O (300 mL)] or an anisaldehyde solution
[3 % p-methoxybenzaldehyde and 1 % H2SO4 in MeOH] or
2,4 dinitro phenyl hydrazine solution [2,4-DNP (12 g), conc.
H2SO4 (6 mL), water (8 mL), EtOH (20 mL)] followed by
heating.
Table 3 Antitubercular test results
Compounds
Growth of
inhibitiona (%)
Compounds
Growth of
inhibitiona (%)
5a
5b
5c
5d
5e
5f
92
86
27
46
35
91
44
26
88
80
65
39
87
6f
23
74
51
39
43
62
18
46
71
30
28
99
6g
6h
7a
7b
7c
5g
5h
6a
6b
6c
6d
6e
7d
7e
7f
Synthesis of N-allylquinolone-3-carbaldehyde 3a–b
(Parmar et al., 2012a)
7g
7h
Standardb
Synthesis of quinoline 2a–b
POCl3 (9 ml, 98.28 mmol) was added drop wise to DMF
(2.7 ml, 34.65 mmol) whilst maintaining the temperature
at 0–5 °C. The mixture was stirred for about 5 min.
Acetanilide 1a–b (10.37 mmol) was then added and the
resulting solution heated for 8 h at 75–80 °C. The reaction
mixture was cooled to room temperature and then poured
into crushed ice with stirring. A pale yellow precipitate
appeared immediately and was filtered and washed with
water and then dried.
Bold numbers indicate relatively good activities, which are close to
standards
a
A concentration 250 lg/mL of each was used against M. Tuber-
culosis H37RV bacteria, and standard deviation (SD) of measuring %
growth inhibition thrice was in the 2–5 % range
b
Standard antimicrobials used were: isoniazide (0.2 lg/mL), fluco-
nazole ([256 lg/mL) and miconazole ([256 lg/mL)
2009). Test results are shown in Table 3. Here, 250 lg/mL
of each compound was tested. From the test results, it
divulges that compounds 5a and 5f are good in antituber-
cular activity as their percent growth inhibitions showed 91
and 92 %, respectively. For others 5b, 6a and 6e, the per-
cent growth inhibition lies in the 86–88 % range, indicating
that they are less potent than the former ones. Nevertheless,
these results when analyzed in terms of concentration are
very close to the ones that standard drugs like fluconazole
([256 lg/mL) and miconazole ([256 lg/mL) reveal.
Synthesis of quinolone
A suspension of aldehyde 2a–b (1 mmol) in 70 % acetic
acid (10 ml) was heated under reflux for 4–6 h. The
complication of the reaction was checked by TLC. Up on
cooling the reaction mixture, a solid product precipitated
out which was filtered, washed well with water, dried and
purified by recrystallisation from DMF.
Synthesis of N-allylquinolone 3a–b
Experimental
Allyl bromide (1.5 equiv.) and potassium carbonate (1.5
equiv.) were added to quinolones (1 mmol) in DMF (5 ml)
and the reaction mixture was stirred at room temperature
for 3–4 h. After completion (checked by TLC) the reaction
mixture was poured into ice-cooled water (25 ml) where-
upon a solid product precipitated out, which was filtered,
washed well with water, dried and purified by recrystalli-
sation from 70 % aqueous ethanol.
All solvents and reagents were used as supplied from com-
mercial sources. The recorded melting points are uncor-
rected. IR spectra were recorded in KBr on Shimadzu FT-IR
8401 spectrometer and are reported in wave numbers
(cm-1). 1H NMR and 13C NMR spectra were recorded on a
Bruker Avance 400 spectrometer operating at 400 MHz for
1H NMR and 100 MHz for 13C NMR as solutions in CDCl3,
unless otherwise indicated. Chemical shifts are reported as
parts per million (ppm, d) and referenced to the residual
protic solvent. Coupling constants are reported in Hertz (Hz).
Splitting patterns are designated as s, singlet; d, doublet; t,
triplet; q, quartet; br, broad; m, multiplet. The degree of
substitution (C, CH, CH2, and CH3) was determined by the
DEPT-135 method. The ESI mass spectra were measured on
General procedure for the synthesis of Knoevenagel-
adducts pyrazolonylidenemethylquinolones 5a–h
N-Allyl quinolone 3a–b (1.12 mmol), pyrazolone 4a–d
(1.12 mmol, 1 eq.) and TBA–HS (20 mol %) were well
mixed in a round-bottom flask and heated to 100 °C for
123

Med Chem Res
(ethyl acetate/n-hexane 3:7); IR (mmax, cm-1): 3,063, 2,920,
2,852, 1,686, 1,640, 1,599, 1,497, 1,365, 1,231, 1,154,
1,062, 993, 790, 758, 723, 699; 1H NMR (400 MHz,
CDCl3): d 2.40 (s, 3 H, CH3), 5.02 (d, J = 1.6 Hz, 2H,
CH2), 5.17 (d, J = 17.2 Hz, 1H, one of =CH2), 5.29 (d,
J = 10.4 Hz, 1H, the other of =CH2), 6.01 (m, 1H, CH),
7.24–7.80 (m, 8H, Ar–H), 8.26 (s, 1H, –CH=) 10.30 (s, 1H,
Ar–H); 13C NMR (100 MHz, CDCl3): 13.30 (CH3), 45.45
(CH2), 114.82, 117.51 (=CH2), 120.38, 123.02, 123.65,
127.50, 127.56, 129.23, 129.76, 130.54, 131.16, 131.91,
132.26, 133.39, 135.04, 140.95, 141.26, 146.19,
20–35 min with constant stirring. After completion of the
reaction as confirmed by TLC (ethyl acetate/n-hexane 3:7),
reaction mass was cooled to room temperature, solid resi-
due was obtained, which was crystallized from methanol to
give the pure product 5.
General procedure for the synthesis of Michael-adducts
4,40-[(quinoline-3-yl)methylene]bis(1H-pyrazol-5-ols)
6a–h
N-Allyl quinolone 3a–b (1.12 mmol), pyrazolone 4a–d
(2.24 mmol, 2 eq.) and TBA–HS (20 mol %) were well
mixed in a round-bottom flask and heated to 100 °C for
1.5–2.0 h with constant stirring. After completion of the
reaction as checked by TLC (ethyl acetate/n-hexane
9.5:0.5), reaction mass was cooled to room temperature,
solid residue was crystallized from methanol to give the
product in pure form.
0
151.57(arom.), 161.32 (C2=O), 163.01 (C5 =O); ESI–MS:
m/z: 404.1 (M?H)?, Anal Calcd for C23H18ClN3O2: C,
68.40; H, 4.49; N, 10.40; Found: C, 68.67; H, 4.65; N,
10.13.
1-Allyl-3-{(Z)-[1-(3-chlorophenyl)-3-methyl-1,5-dihydro-4H-
pyrazol-5-one-4-ylidene]methyl}quinolin-2(1H)-one 5c Red
solid, yield 91 %, 431 mg, mp 180–182 °C; Rf = 0.55
(ethyl acetate/n-hexane 3:7); IR (mmax, cm-1): 3,059, 2,928,
2,867, 1,688, 1,645, 1,593, 1,492, 1,368, 1,238, 1,153, 1,064,
General procedure for the synthesis of cyclized
products dipyrazolo[3,4-b:40,30-e]pyranylquinolones
7a–h
1
990, 821, 788, 757, 674; H NMR (400 MHz, CDCl3): d
2.38 (s, 3 H, CH3), 4.99 (d, J = 2.0 Hz, 2H, CH2), 5.16 (d,
J = 16.8 Hz, 1H, one of =CH2), 5.24 (d, J = 10.0 Hz, 1H,
the other of =CH2), 6.00 (m, 1H, CH), 7.14–7.89 (m, 8H,
Ar–H), 8.20 (s, 1H, –CH=), 10.31 (s, 1H, Ar–H); 13C NMR
(100 MHz, CDCl3): 14.23 (CH3), 46.02 (CH2), 115.63,
116.98 (=CH2), 117.78, 120.52, 121.06, 122.15, 123.21,
123.87, 128.32, 129.11, 132.18, 133.46, 133.82, 135.32,
137.67, 139.04, 140.56, 147.13, 151.78 (arom.), 162.31
N-Allyl quinolone 3a–b (1.12 mmol), pyrazolone 4a–d
(2.24 mmol, 2 eq.) and TBA–HS (20 mol %) were well
mixed in a round-bottom flask and heated to 120 °C for
1.5–2.0 h with constant stirring. After completion of the
reaction as checked by TLC (ethyl acetate/n-hexane
9.5:0.5), reaction mass was cooled to room temperature,
gave solid residue, which was crystallized from methanol
to give the pure product.
?
0
(C2=O), 163.54 (C5 =O); ESI–MS: m/z: 404.1 (M?H) ,
Anal Calcd for C23H18ClN3O2: C, 68.40; H, 4.49; N, 10.40;
Found: C, 68.60; H, 4.73; N, 10.69.
1-Allyl-3-[(Z)-(3-methyl-1-phenyl-1,5-dihydro-4H-pyrazol-
5-one-4-ylidene)methyl]quinolin-2(1H)-one 5a Orange
solid, yield 90 %, 390 mg, mp 182–184 °C; Rf = 0.42
(ethyl acetate/n-hexane 3:7); IR (mmax, cm-1): 3,043, 2,919,
2,857, 1,673, 1,644, 1,597, 1,361, 1,495, 1,236, 1,149,
1,109, 1,022, 992, 780, 754, 691, 671; 1H NMR (400 MHz,
CDCl3): d 2.40 (s, 3 H, CH3), 5.01 (d, J = 2.0 Hz, 2H,
CH2), 5.17 (d, J = 17.2 Hz, 1H, one of =CH2), 5.29 (d,
J = 10.4 Hz, 1H, the other of =CH2), 6.03 (m, 1H, CH),
7.20–7.98 (m, 9H, Ar–H), 8.19 (s, 1H, –CH=), 10.30 (s,
1H, Ar–H); 13C NMR (100 MHz, CDCl3): 13.23 (CH3),
45.44 (CH2), 114.78, 117.50 (=CH2), 119.21, 120.31,
122.94, 123.57, 124.98, 128.76, 128.82, 131.20, 131.89,
133.32, 138.29, 140.54, 140.87, 146.04, 151.29 (arom.),
1-Allyl-3-{(Z)-[1-(2,5-dichlorophenyl)-3-methyl-1,5-dihydro-
4H-pyrazol-5-one-4-ylidene]methyl}quinolin-2(1H)-one 5d
Orange solid, yield 88 %, 452 mg, mp 202–204 °C;
Rf = 0.57 (ethyl acetate/n-hexane 3:7); IR (mmax, cm-1):
3,063, 2,924, 2,856, 1,685, 1,646, 1,596, 1,496, 1,364,
1
1,232, 1,152, 1,062, 993, 793, 784, 759, 684; H NMR
(400 MHz, CDCl3): d 2.36 (s, 3 H, CH3), 5.04 (d,
J = 1.6 Hz, 2H, CH2), 5.14 (d, J = 16.8 Hz, 1H, one of
=CH2), 5.23 (d, J = 10.4 Hz, 1H, the other of =CH2), 6.03
(m, 1H, CH), 7.12-8.12 (m, 7H, Ar–H), 8.23 (s, 1H,
–CH=), 10.34 (s, 1H, Ar–H); 13C NMR (100 MHz,
CDCl3): 13.45 (CH3), 44.49 (CH2), 116.01, 117.67 (=CH2),
120.21, 123.27, 124.38, 127.36, 130.45, 130.83, 131.32,
131.83, 132.61, 133.42, 134.48, 135.49, 136.21, 140.42,
141.69, 145.23, 152.26 (arom.), 161.61 (C2=O), 163.32
0
161.24 (C2=O), 162.27 (C5 =O); ESI–MS: m/z: 370.2
(M?H)?, Anal Calcd for C23H19N3O2: C, 74.78; H, 5.18;
N, 11.37; Found: C, 74.64; H, 5.32; N, 11.55.
?
0
(C5 =O); ESI–MS: m/z: 438.1 (M?H) , Anal Calcd for
C23H17Cl2N3O2: C, 63.03; H, 3.91; N, 9.59; Found: C,
63.31; H, 3.72; N, 9.77.
1-Allyl-3-{(Z)-[1-(2-chlorophenyl)-3-methyl-1,5-dihydro-4H-pyr-
azol-5-one-4-ylidene]methyl}quinolin-2(1H)-one 5b Orange
solid, yield 87 %, 412 mg, mp 178–180 °C; Rf = 0.40
123

Med Chem Res
1-Allyl-7-chloro-3-[(Z)-(3-methyl-1-phenyl-1,5-dihydro-4H-
pyrazol-5-one-4-ylidene)methyl]quinolin-2(1H)-one 5e Red
solid, yield 91 %, 410 mg, mp 208–211 °C; Rf = 0.53
(ethyl acetate/n-hexane 3:7); IR (mmax, cm-1): 3,057, 2,921,
2,862, 1,680, 1,646, 1,599, 1,368, 1,490, 1,231, 1,138, 1,101,
1,031, 996, 790, 768, 682, 656; 1H NMR (400 MHz,
CDCl3): d 2.40 (s, 3 H, CH3), 4.97 (d, J = 4.4 Hz, 2H,
CH2), 5.18 (d, J = 17.2 Hz, 1H, one of =CH2), 5.33 (d,
J = 10.4 Hz, 1H, the other of =CH2), 6.01 (m, 1H, CH),
7.21–7.96 (m, 8H, Ar–H), 8.14 (s, 1H, –CH=), 10.29 (s, 1H,
Ar–H); 13C NMR (100 MHz, CDCl3): 13.62 (CH3), 45.43
(CH2), 116.62, 117.42 (=CH2), 119.21, 120.43, 123.01,
124.86, 125.34, 127.56, 128.64, 128.82, 133.56, 136.32,
138.24, 140.27, 140.62,0 146.41, 151.45 (arom.), 161.63
(C2=O), 162.72 (C5 =O); ESI–MS: m/z: 404.1
(M?H)?,Anal Calcd for C23H18ClN3O2: C, 68.40; H, 4.49;
N, 10.40; Found: C, 68.63; H, 4.76; N, 10.22.
for C23H17Cl2N3O2: C, 63.03; H, 3.91; N, 9.59; Found: C,
62.87; H, 4.13; N, 9.76.
1-Allyl-7-chloro-3-{(Z)-[1-(2,5-dichlorophenyl)-3-methyl-1,5-
dihydro-4H-pyrazol-5-one-4-ylidene]methyl}quinolin-2(1H)-
one 5h Orange solid, yield 93 %, 492 mg, mp 170–
172 °C; Rf = 0.75 (ethyl acetate/n-hexane 3:7); IR (mmax
,
cm-1): 3,071, 2,928, 2,863, 1,688, 1,641, 1,590, 1,486,
1
1,361, 1,229, 1,159, 1,067, 991, 821, 788, 765, 664; H
NMR (400 MHz, CDCl3): d 2.46 (s, 3 H, CH3), 5.08 (d,
J = 2.0 Hz, 2H, CH2), 5.17 (d, J = 17.2 Hz, 1H, one of
=CH2), 5.32 (d, J = 10.4 Hz, 1H, the other of =CH2), 6.06
(m, 1H, CH), 7.02–7.90 (m, 6H, Ar–H), 8.14 (s, 1H,
–CH=), 10.32 (s, 1H, Ar–H); 13C NMR (100 MHz,
CDCl3): 13.14 (CH3), 46.01 (CH2), 116.76, 117.50 (=CH2),
120.89, 123.56, 124.52, 127.43, 127.23, 128.42, 129.71,
130.23, 131.12, 133.11, 134.67, 135.45, 136.91, 138.13,
140.46, 144.79, 146.12, 152.02 (arom.), 160.93 (C2=O),
?
0
162.45 (C5 =O); ESI–MS: m/z: 472.1 (M?H) ,Anal Calcd
for C23H16Cl3N3O2: C, 58.43; H, 3.41; N, 8.89; Found: C,
58.76; H, 3.33; N, 9.01.
1-Allyl-7-chloro-3-{(Z)-[1-(2-chlorophenyl)-3-methyl-1,5-dihy-
dro-4H-pyrazol-5-one-4-ylidene]methyl}quinolin-2(1H)-one
5f Orange solid, yield 89 %, 437 mg, mp 226–228 °C;
Rf = 0.44 (ethyl acetate/n-hexane 3:7); IR (mmax, cm-1):
3,053, 2,916, 2,851, 1,687, 1,651, 1,587, 1,485, 1,358, 1,229,
1,159, 1,061, 995, 812, 768, 716, 681; 1H NMR (400 MHz,
CDCl3): d 2.40 (s, 3 H, CH3), 4.98 (d, J = 4.4 Hz, 2H, CH2),
5.17 (d, J = 17.2 Hz, 1H, one of =CH2), 5.32 (d,
J = 10.8 Hz, 1H, the otherof =CH2), 6.01 (m, 1H, CH), 7.23-
7.72 (m, 7H, Ar–H), 8.21 (s, 1H, –CH=), 10.28 (s, 1H, Ar–H);
13C NMR (100 MHz, CDCl3): 13.59 (CH3), 44.86 (CH2),
116.12, 117.51 (=CH2), 121.41, 123.46, 123.35, 127.32,
127.64, 128.53, 130.66, 131.36, 131.84, 132.65, 133.43,
135.21, 136.76, 140.68, 141.32, 146.27, 151.47 (arom.),
4,40-[(1-Allyl-quinolin-2-one)methylene]bis(3-methyl-1-phenyl-
1H-pyrazol-5-ol) 6a White solid, yield 92 %, 585 mg, mp
198–200 °C; Rf = 0.45 (ethyl acetate/n-hexane 9.5:0.5); IR
(mmax, cm-1): 3,418, 3,073, 2,921, 1,639, 1,596, 1,415,
1,296, 1,023, 875, 795, 754, 689; 1H NMR (400 MHz,
DMSO-d6): d 2.35 (s, 6H, 2 CH3), 4.93 (d, J = 2.0 Hz, 2H,
CH2), 4.97 (d, J = 17.2 Hz, 1H, one of =CH2), 5.12 (d,
J = 10.4 Hz, 1H, the other of =CH2), 5.16 (s, 1H, CH), 5.93
(m, 1H, CH), 7.19–8.03 (m, 15H, Ar–H), 12.56 (s, 1H, OH),
14.29 (s, 1H, OH); 13C NMR (100 MHz, DMSO-d6): 12.29
(CH3), 29.44 (CH), 44.67 (CH2), 115.21, 116.96 (=CH2),
120.27, 121.20, 122.48, 126.06, 128.32, 129.30, 129.35,
130.31, 130.87, 132.44, 133.13, 135.58, 138.27, 147.08,
153.43 (arom.), 160.99 (C=O); ESI–MS: m/z: 544.2
(M?H)?, Anal Calcd for C33H29N5O3: C, 72.91; H, 5.38; N,
12.88; Found: C, 73.21; H, 5.57; N, 12.62.
0
161.43 (C2=O), 162.79 (C5 =O); ESI–MS: m/z: 438.1
(M?H)?, Anal Calcd for C23H17Cl2N3O2: C, 63.03; H, 3.91;
N, 9.59; Found: C, 63.21; H, 4.09; N, 9.70.
1-Allyl-7-chloro-3-{(Z)-[1-(3-chlorophenyl)-3-methyl-1,5-dihy-
dro-4H-pyrazol-5-one-4-ylidene]methyl}quinolin-2(1H)-
one 5g Orange solid, yield 90 %, 441 mg, mp 196–
4,40-[(1-Allyl-quinolin-2-one)methylene]bis[3-methyl-1-(2-
chlorophenyl)-1H-pyrazol-5-ol] 6b White solid, yield
91 %, 653 mg, mp 180–182 °C; Rf = 0.44 (ethyl acetate/
n-hexane 9.5:0.5); IR (mmax, cm-1): 3,410, 3,079, 2,921,
198 °C; Rf = 0.49 (ethyl acetate/n-hexane 3:7); IR (mmax
,
cm-1): 3,064, 2,912, 2,869, 1,679, 1,649, 1,586, 1,493,
1
1,366, 1,227, 1,156, 1,054, 990, 816, 778, 721, 693; H
1
1,642, 1,596, 1,420, 1,300, 1,067, 883, 744, 657; H NMR
NMR (400 MHz, CDCl3): d 2.37 (s, 3H, CH3), 4.95 (d,
J = 4.4 Hz, 2H, CH2), 5.17 (d, J = 17.2 Hz, 1H, one of
=CH2), 5.31 (d, J = 10.4 Hz, 1H, the other of =CH2), 6.00
(m, 1H, CH), 7.15-8.05 (m, 7H, Ar–H), 8.35 (s, 1H,
–CH=), 10.22 (s, 1H, Ar–H); 13C NMR (100 MHz,
CDCl3): 13.65 (CH3), 45.13 (CH2), 116.23, 117.20 (=CH2),
117.87, 121.21, 121.87, 122.45, 123.37, 123.76, 127.56,
127.76, 128.56, 132.84, 133.34, 135.78, 136.67, 137.23,
138.12, 140.34, 146.54, 151.65 (arom.), 161.03 (C2=O),
(400 MHz, DMSO-d6): d 2.32 (s, 6H, 2 CH3), 4.93 (m, 3H,
CH2 and one of =CH2), 5.11 (m, 2H, the other of =CH2 and
CH), 5.92 (m, 1H, CH), 7.19-7.92 (m, 13H, Ar–H), 12.59
(s, 1H, OH), 14.09 (s, 1H, OH); 13C NMR (100 MHz,
DMSO-d6): 12.43 (CH3), 29.45 (CH), 44.71 (CH2), 115.31,
116.59 (=CH2), 119.73, 122.72, 127.43, 128.96, 129.46,
130.65, 130.69, 130.88, 131.76, 132.38, 132.86, 133.39,
134.75, 138.63, 140.95, 146.94, 153.21(arom.), 161.78
(C=O); ESI–MS: m/z: 611.2 (M?H)?, Anal Calcd for
?
0
162.13 (C5 =O); ESI–MS: m/z: 438.1 (M?H) ,Anal Calcd
123

Med Chem Res
C33H27Cl2N5O3: C, 64.71; H, 4.44; N, 11.43; Found: C,
64.86; H, 4.60; N, 11.64.
(M?H)?, Anal Calcd for C33H28ClN5O3: C, 68.57; H, 4.88;
N, 12.12; Found: C, 68.71; H, 4.71; N, 12.31.
4,40-[(1-Allyl-quinolin-2-one)methylene]bis[3-methyl-1-(3-
chlorophenyl)-1H-pyrazol-5-ol]6c White solid, yield
93 %, 667 mg, mp 184–186 °C; Rf = 0.54 (ethyl acetate/
n-hexane 9.5:0.5); IR (mmax, cm-1): 3,421, 3,069, 2,924,
4,40-[(1-Allyl-7-chloroquinolin-2-one)methylene]bis[3-methyl-
1-(2-chlorophenyl)-1H-pyrazol-5-ol] 6f White solid, yield
91 %, 658 mg, mp 192–194 °C; Rf = 0.48 (ethyl acetate/
n-hexane 9.5:0.5); IR (mmax, cm-1): 3,421, 3,068, 2,922,
1
1
1,642, 1,592, 1,423, 1,291, 1,058, 881, 798, 768, 692; H
1,637, 1,597, 1,411, 1,293, 1,025, 893, 821, 758, 690; H
NMR (400 MHz, DMSO-d6): d 2.34 (s, 6H, 2 CH3), 4.95
(d, J = 2.0 Hz, 2H, CH2), 5.05 (d, J = 17.2 Hz, 1H, one of
=CH2), 5.16 (d, J = 10.0 Hz, 1H, the other of =CH2), 5.19
(s, 1H, CH), 6.00 (m, 1H, CH), 7.09-8.17 (m, 13H, Ar–H),
12.45 (s, 1H, OH), 14.21 (s, 1H, OH); 13C NMR
(100 MHz, DMSO-d6): 13.43 (CH3), 30.35 (CH), 44.77
(CH2), 115.12, 117.56 (=CH2), 119.18, 120.21, 121.67,
127.53, 128.46, 129.28, 130.49, 131.29, 131.84, 133.37,
135.41, 135.87, 137.23, 138.58, 141.39, 147.42, 152.17
(arom.), 161.34 (C = O); ESI–MS: m/z: 611.2 (M?H)?,
Anal Calcd for C33H27Cl2N5O3: C, 64.71; H, 4.44; N,
11.43; Found: C, 64.40; H, 4.14; N, 11.60.
NMR (400 MHz, DMSO-d6): d 2.33 (s, 6H, 2 CH3), 4.89
(m, 3H, CH2 and one of =CH2), 5.11 (d, J = 10.4 Hz,
1H, the other of =CH2), 5.14 (s, 1H, CH), 5.92 (m, 1H,
CH), 7.26–7.95 (m, 12H, Ar–H), 12.57 (s, 1H, OH), 14.11
(s, 1H, OH); 13C NMR (100 MHz, DMSO-d6): 13.05
(CH3), 29.23 (CH), 45.03 (CH2), 116.71, 117.65 (=CH2),
118.94, 122.54, 127.57, 128.85, 129.67, 130.65, 131.04,
131.56, 132.21, 132.89, 133.45, 135.68, 136.57, 138.56,
140.45, 147.32, 153.33 (arom.), 161.36 (C=O); ESI–MS:
m/z: 646.1 (M?H)?, Anal Calcd for C33H26Cl3N5O3: C,
61.26; H, 4.05; N, 10.83; Found: C, 61.07; H, 4.23; N,
10.69.
4,40-[(1-Allyl-quinolin-2-one)methylene]bis[3-methyl-1-(2,5-
dichlorophenyl)-1H-pyrazol-5-ol] 6d White solid, yield
94 %, 751 mg, mp 202–204 °C; Rf = 0.68 (ethyl acetate/
n-hexane 9.5:0.5); IR (mmax, cm-1): 3,416, 3,071, 2,918,
4,40-[(1-Allyl-7-chloroquinolin-2-one)methylene]bis[3-methyl-
1-(3-chlorophenyl)-1H-pyrazol-5-ol] 6g White solid, yield
93 %, 673 mg, mp 202–204 °C; Rf = 0.57 (ethyl acetate/
n-hexane 9.5:0.5); IR (mmax, cm-1): 3,419, 3,071, 2,921,
1
1
1,639, 1,598, 1,421, 1,296, 1,063, 894, 787, 753, 667; H
1,636, 1,595, 1,412, 1,292, 1,026, 897, 825, 769, 672; H
NMR (400 MHz, DMSO-d6): d 2.37 (s, 6H, 2 CH3), 4.96 (m,
3H, CH2 and one of =CH2), 5.17 (m, 2H, the other of =CH2
and CH), 5.96 (m, 1H, CH), 7.17–8.12 (m, 11H, Ar–H),
12.67 (s, 1H, OH), 14.21 (s, 1H, OH); 13C NMR (100 MHz,
DMSO-d6): 13.94 (CH3), 29.66 (CH), 45.13 (CH2), 115.82,
117.23 (=CH2), 118.61, 126.08, 127.62, 128.26, 129.15,
129.56, 130.13, 130.85, 131.59, 132.94, 133.72, 135.12,
136.18, 138.72, 141.62, 147.29, 151.91 (arom.), 162.15
(C=O); ESI–MS: m/z: 680.1 (M?H)?, Anal Calcd for
C33H25Cl4N5O3: C, 58.17; H, 3.70; N, 10.28; Found: C,
58.01; H, 3.92; N, 10.54.
NMR (400 MHz, DMSO-d6): d 2.31 (s, 6H, 2 CH3), 4.95
(d, J = 2.0 Hz, 2H, CH2), 5.01 (d, J = 16.8 Hz, 1H, one of
=CH2), 5.14 (d, J = 10.0 Hz, 1H, the other of =CH2), 5.17
(s, 1H, CH), 5.92 (m, 1H, CH), 7.12-8.07 (m, 12H, Ar–H),
12.59 (s, 1H, OH), 14.34 (s, 1H, OH); 13C NMR
(100 MHz, DMSO-d6): 12.39 (CH3), 30.43 (CH), 45.67
(CH2), 116.43, 117.67 (=CH2), 118.56, 119.98, 122.54,
127.69, 128.56, 130.04, 131.67, 132.79, 133.67, 134.78,
135.57, 136.89, 137.09, 138.43, 140.21, 147.11, 153.59
(arom.), 161.20 (C=O); ESI–MS: m/z: 646.1 (M?H)?,
Anal Calcd for C33H26Cl3N5O3: C, 61.26; H, 4.05; N,
10.83; Found: C, 61.56; H, 4.28; N, 11.03.
4,40-[(1-Allyl-7-chloroquinolin-2-one)methylene]bis(3-methyl-
1-phenyl-1H-pyrazol-5-ol) 6e White solid, yield 92 %,
592 mg, mp 218–220 °C; Rf = 0.55 (ethyl acetate/n-hexane
9.5:0.5); IR (mmax, cm-1): 3,412, 3,061, 2,927, 1,631, 1,591,
1,417, 1,288, 1,021, 881, 828, 765, 665; 1H NMR (400 MHz,
DMSO-d6): d 2.32 (s, 6H, 2 CH3), 4.90 (d, J = 2.0 Hz, 2H,
CH2), 4.99 (d, J = 17.6 Hz, 1H, one of =CH2), 5.12 (d,
J = 10.0 Hz, 1H, the other of =CH2), 5.13 (s, 1H, CH), 5.92
(m, 1H, CH), 7.13–7.98 (m, 14H, Ar–H), 12.51 (s, 1H, OH),
14.23 (s, 1H, OH); 13C NMR (100 MHz, DMSO-d6): 12.16
(CH3), 29.27 (CH), 44.44 (CH2), 116.23, 117.12 (=CH2),
120.25, 121.78, 122.23, 126.56, 128.08, 128.81, 129.67,
130.34, 131.56, 133.54, 135.62, 136.04, 138.64, 147.18,
152.05 (arom.), 161.19 (C=O); ESI–MS: m/z: 578.2
4,40-[(1-Allyl-7-chloroquinolin-2-one)methylene]bis[3-methyl-
1-(2,5-dichlorophenyl)-1H-pyrazol-5-ol] 6h White solid,
yield 92 %, 737 mg, mp 198–200 °C; Rf = 0.78 (ethyl
acetate/n-hexane 9.5:0.5); IR (mmax, cm-1): 3,418, 3,066,
2,921, 1,633, 1,594, 1,423, 1,287, 1,018, 893, 819, 792,
1
656; H NMR (400 MHz, DMSO-d6): d 2.35 (s, 6H, 2
CH3), 4.97 (d, J = 2.0 Hz, 2H, CH2), 5.04 (d,
J = 17.2 Hz, 1H, one of =CH2), 5.18 (d, J = 10.4 Hz, 1H,
the other of =CH2), 5.19 (s, 1H, CH), 5.96 (m, 1H, CH),
7.18–8.23 (m, 10H, Ar–H), 12.56 (s, 1H, OH), 14.32 (s,
1H, OH); 13C NMR (100 MHz, DMSO-d6): 14.01 (CH3),
30.29 (CH), 46.48 (CH2), 116.23, 117.78 (=CH2), 119.62,
126.67, 127.45, 128.87, 129.45, 130.48, 130.93, 132.89,
123

Med Chem Res
133.65, 133.94, 135.73, 136.64, 137.03, 138.23, 141.54,
147.62, 152.28 (arom.), 162.04 (C=O); ESI–MS: m/z:
714.1 (M?H)?, Anal Calcd for C33H24Cl5N5O3: C, 55.37;
H, 3.38; N, 9.78; Found: C, 55.04; H, 3.13; N, 9.97.
ESI–MS: m/z: 593.1 (M?H)?, Anal Calcd for
C33H25Cl2N5O2: C, 66.67; H, 4.24; N, 11.78; Found: C,
66.65; H, 4.04; N, 11.63.
1-Allyl-3-(3,5-dimethyl-1,7-bis(2,5-dichlorophenyl)-1,4-dihy-
dro-1H-dipyrazolo[3,4-b:4030-e]pyran-4-yl)quinoline-2-one
7d White solid, yield 87 %, 677 mg, mp 252–254 °C;
Rf = 0.72 (ethyl acetate/n-hexane 9.5:0.5); IR (mmax, cm-1):
3,062, 2,925, 1,632, 1,584, 1,501, 1,324, 1,020, 991, 782,
678; 1H NMR (400 MHz, DMSO-d6): d 2.32 (s, 6H, 2 CH3),
4.93 (d, J = 2.0 Hz, 2H, CH2), 4.95 (d, J = 17.2 Hz, 1H,
one of =CH2), 5.11 (s, 1H, CH), 5.15 (d, J = 10.4 Hz, 1H,
the other of =CH2), 5.95 (m, 1H, CH), 7.22-8.04 (m, 11H,
Ar–H); 13C NMR (100 MHz, DMSO-d6): 13.54 (CH3),
28.02 (CH), 44.97 (CH2), 113.24, 117.79 (=CH2), 118.65,
126.56, 128.14, 128.84, 129.65, 130.16, 130.78, 131.57,
132.07, 132.89, 133.94, 135.34, 136.81, 139.23, 141.75,
147.64, 151.01 (arom.), 161.63 (C=O); ESI–MS: m/z: 662.1
(M?H)?, Anal Calcd for C33H23Cl4N5O2: C, 59.75; H,
3.49; N, 10.56; Found: C, 59.73; H, 3.30; N, 10.36.
1-Allyl-3-(3,5-dimethyl-1,7-diphenyl-1,4-dihydro-1H-dipy-
razolo[3,4-b:4030-e]pyran-4-yl)quinoline-2-one 7a White
solid, yield 87 %, 536 mg, mp 244–246 °C; Rf = 0.56
(ethyl acetate/n-hexane 9.5:0.5); IR (mmax, cm-1): 3,061,
2,925, 1,631, 1,582, 1,492, 1,307, 1,026, 987, 792, 723,
1
692; H NMR (400 MHz, DMSO-d6): d 2.29 (s, 6H, 2
CH3), 4.94 (d, J = 1.6 Hz, 2H, CH2), 4.96 (d,
J = 17.6 Hz, 1H, one of =CH2), 5.11 (s, 1H, CH), 5.16 (d,
J = 10.8 Hz, 1H, the other of =CH2), 5.97 (m, 1H, CH),
7.17-8.00 (m, 15H, Ar–H); 13C NMR (100 MHz, DMSO-
d6): 13.24 (CH3), 27.89 (CH), 44.30 (CH2), 113.21.37,
117.42 (=CH2), 120.51, 121.72, 122.58, 126.31, 128.37,
129.17, 129.59, 130.65, 130.74, 132.77, 133.63, 135.52,
138.92, 147.48, 149.85 (arom.), 162.12 (C=O); ESI–MS:
m/z: 526.2 (M?H)?,Anal Calcd for C33H27N5O2: C, 75.41;
H, 5.18; N, 13.32; Found: C, 75.64; H, 5.47; N, 13.04.
1-Allyl-7-chloro-3-(3,5-dimethyl-1,7-diphenyl-1,4-dihydro-
1H-dipyrazolo[3,4-b:4030-e]pyran-4-yl)quinoline-2-one 7e
White solid, yield 89 %, 557 mg, mp 236–238 °C;
1-Allyl-3-(3,5-dimethyl-1,7-bis(2-chlorophenyl)-1,4-dihydro-
1H-dipyrazolo[3,4-b:4030-e]pyran-4-yl)quinoline-2-one 7b
White solid, yield 85 %, 592 mg, mp 236–238 °C;
Rf = 0.62 (ethyl acetate/n-hexane 9.5:0.5); IR (mmax
,
cm-1): 3,062, 2,926, 1,637, 1,582, 1,496, 1,309, 1,021,
1
989, 829, 757, 667; H NMR (400 MHz, DMSO-d6): d
Rf = 0.54 (ethyl acetate/n-hexane 9.5:0.5); IR (mmax
,
2.33 (s, 6H, 2 CH3), 4.93 (m, 3H, CH2 and one of =CH2),
5.11 (s, 1H, CH), 5.14 (d, J = 12.0 Hz, 1H, the other of
=CH2), 5.91 (m, 1H, CH), 7.24–8.01 (m, 14H, Ar–H); 13C
NMR (100 MHz, DMSO-d6): 13.65 (CH3), 27.86 (CH),
45.17 (CH2), 112.69, 118.02 (=CH2), 120.05, 121.64,
122.54, 125.92, 128.34, 128.95, 129.34, 130.49, 131.75,
133.27, 136.11, 136.88, 138.79, 147.42, 150.06 (arom.),
161.37 (C=O); ESI–MS: m/z: 560.2 (M?H)?, Anal Calcd
for C33H26ClN5O2: C, 70.77; H, 4.68; N, 12.50; Found: C,
70.98; H, 4.82; N, 12.75.
cm-1): 3,066, 2,921, 1,634, 1,579, 1,496, 1,313, 1,024,
1
982, 790, 749, 688; H NMR (400 MHz, DMSO-d6): d
2.33 (s, 6H, 2 CH3), 4.91 (m, 3H, CH2 and one of =CH2),
5.11 (m, 2H, the other of =CH2 and CH), 5.94 (m, 1H, CH),
7.21–7.97 (m, 13H, Ar–H); 13C NMR (100 MHz, DMSO-
d6): 12.32 (CH3), 27.54 (CH), 44.51 (CH2), 112.31, 116.59
(=CH2), 119.99, 122.55, 127.94, 128.34, 128.95, 130.28,
130.49, 130.77, 131.03, 132.00, 132.73, 133.11, 135.55,
138.31, 140.39, 147.06, 153.25 (arom.), 161.62 (C=O);
ESI–MS: m/z: 593.1 (M?H)?,Anal Calcd for
C33H25Cl2N5O2: C, 66.67; H, 4.24; N, 11.78; Found: C,
66.33; H, 4.56; N, 12.01.
1-Allyl-7-chloro-3-(3,5-dimethyl-1,7-bis(2-chlorophenyl)-1,4-
dihydro-1H-dipyrazolo[3,4-b:4030-e]pyran-4-yl)quinoline-2-
one 7f White solid, yield 86 %, 605 mg, mp 256–258 °C;
Rf = 0.56 (ethyl acetate/n-hexane 9.5:0.5); IR (mmax
,
1-Allyl-3-(3,5-dimethyl-1,7-bis(3-chlorophenyl)-1,4-dihydro-
1H-dipyrazolo[3,4-b:4030-e]pyran-4-yl)quinoline-2-one 7c
White solid, yield 88 %, 613 mg, mp 240–242 °C;
cm-1): 3,063, 2,931, 1,641, 1,586, 1,486, 1,325, 1,029,
1
991, 824, 792, 657; H NMR (400 MHz, DMSO-d6): d
2.33 (s, 6H, 2 CH3), 4.90 (d, J = 2.0 Hz, 2H, CH2), 4.99
(d, J = 17.6 Hz, 1H, one of =CH2), 5.12 (m, 2H, the other
of =CH2 and CH), 5.93 (m, 1H, CH), 7.21–7.99 (m, 12H,
Ar–H); 13C NMR (100 MHz, DMSO-d6): 12.93 (CH3),
28.21 (CH), 44.23 (CH2), 113.17, 117.72 (=CH2), 119.12,
122.42, 127.31, 128.64, 129.93, 130.42, 131.32, 131.28,
132.75, 132.81, 133.39, 135.59, 136.26, 138.91, 140.81,
147.16, 149.62 (arom.), 161.63 (C=O); ESI–MS: m/z:
628.1 (M?H)?, Anal Calcd for C33H24Cl3N5O2: C, 63.02;
H, 3.85; N, 11.14; Found: C, 63.28; H, 3.56; N, 10.84.
Rf = 0.61 (ethyl acetate/n-hexane 9.5:0.5); IR (mmax
,
cm-1): 3,071, 2,928, 1,633, 1,586, 1,491, 1,321, 1,019,
1
978, 791, 761, 663; H NMR (400 MHz, DMSO-d6): d
2.33 (s, 6H, 2 CH3), 4.94 (m, 3H, CH2 and one of =CH2),
5.14 (m, 2H, the other of =CH2 and CH), 5.94 (m, 1H, CH),
7.18–7.95 (m, 13H, Ar–H), 13C NMR (100 MHz, DMSO-
d6): 13.84 (CH3), 28.10 (CH), 44.61 (CH2), 112.53, 117.83
(=CH2), 118.58, 119.93, 121.47, 127.95, 128.42, 129.65,
130.13, 131.23, 131.69, 133.75, 135.37, 135.80, 137.60,
138.53, 141.31, 147.75, 150.11 (arom.), 161.27 (C=O);
123

Med Chem Res
1-Allyl-7-chloro-3-(3,5-dimethyl-1,7-bis(3-chlorophenyl)-1,4-
dihydro-1H-dipyrazolo[3,4-b:4030-e]pyran-4-yl)quinoline-2-
one 7g White solid, yield 85 %, 709 mg, mp 236–238 °C;
compounds possess antibacterial and antitubercular activi-
ties. Specifically, 7d resembles standard drug ciprofloxacin
in terms of its potency against Streptococcus pneumoniae
bacteria. Compounds 5a and 5f on the other hand are very
close to standard fluconazole ([256 lg/mL) and mico-
nazole ([256 lg/mL) in their antitubercular activity,
showing percent growth inhibitions in the 91–92 % range.
Rf = 0.62 (ethyl acetate/n-hexane 9.5:0.5); IR (mmax
,
cm-1): 3,072, 2,928, 1,641, 1,584, 1,487, 1,301, 1,019,
1
992, 827, 772, 676; H NMR (400 MHz, DMSO-d6): d
2.33 (s, 6H, 2 CH3), 4.93 (m, 3H, CH2 and one of =CH2),
5.09 (s, 1H, CH), 5.13 (d, J = 10.8 Hz, 1H, the other of
=CH2), 5.91 (m, 1H, CH), 7.23–7.99 (m, 12H, Ar–H); 13C
NMR (100 MHz, DMSO-d6): 12.56 (CH3), 28.31(CH),
44.38 (CH2), 113.32, 117.59 (=CH2), 118.46, 119.32,
122.63, 127.36, 128.92, 130.36, 131.39, 132.46, 133.63,
134.27, 135.47, 136.73, 137.32, 138.64, 140.63, 147.55,
150.14 (arom.), 161.48 (C=O); ESI–MS: m/z: 628.1
(M?H)?, Anal Calcd for C33H24Cl3N5O2: C, 63.02; H,
3.85; N, 11.14; Found: C, 63.34; H, 4.03; N, 11.34.
Acknowledgments We sincerely express our thanks to the Head,
Department of Chemistry, S.P. University for providing necessary
research facilities. Authors B. R. P., B. D. P. and H.A.B. acknowledge
financial supports from the UGC under the UGC RFSMS Scheme. We
also acknowledge the help rendered by Nutan Dye Chem, Surat.
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1,4-dihydro-1H-dipyrazolo[3,4-b:4030-e]pyran-4-yl)quinoline-
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1
1,026, 991, 828, 786, 665; H NMR (400 MHz, DMSO-
d6): d 2.31 (s, 6H, 2 CH3), 4.96 (d, J = 1.6 Hz, 2H, CH2),
5.04 (d, J = 17.6 Hz, 1H, one of =CH2), 5.10 (s, 1H, CH),
5.18 (d, J = 10.4 Hz, 1H, the other of =CH2), 5.94 (m, 1H,
CH), 7.21-8.30 (m, 10H, Ar–H); 13C NMR (100 MHz,
DMSO-d6): 13.58 (CH3), 27.91 (CH), 45.38 (CH2), 112.78,
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56.96; H, 3.34; N, 9.81.
Conclusions
In conclusion, we have developed a new recyclable TBA–
HS catalyzed one-pot procedure for quinolylmethelene-
bispyrazoles via a tandem Knoevenagel–Michael reaction
under solvent-free conditions. Main advantage of the
method is that chromatography was not used to isolate the
desired product. Temperature- and stoichiometry-con-
trolled nature of the products is other interesting part.
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adducts at 100 °C, doubling the amount of one of the
reactants pyrazolone with aldehyde resulted into formation
of Knoevenagel–Michael-adducts. Heating the mixture at
120 °C, however, resulted in the cyclization of Michael-
adducts and gave dipyrazolopyranylquinolines. Biological
screening tests results revealed that all newly synthesized
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123

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