Synthesis, characterization, and in vitro microbial evaluation of some new 4H-chromene and quinoline derivatives of 1H-pyrazole

Article abstract of DOI:10.1002/jhet.1038

A new series of nine derivatives of 4H-pyrano[3,2-c]chromene and 12 derivatives of N-thiazolyl-4H-quinoline of 1H-pyrazole has been synthesized by one pot base catalyzed cyclocondensation reaction of 1H-pyrazole-4-carbaldehyde, malononitrile, and 4-hydroxy coumarin or β-enaminones, respectively. All the synthesized compounds were characterized by elemental analysis, FT-IR, ¹H NMR, ¹³C NMR spectral data and were further screened, against a panel of pathogenic strains of bacteria and fungi.

Full text of DOI:10.1002/jhet.1038

September 2012
Synthesis, Characterization, and In Vitro Microbial Evaluation
of Some New 4H‐Chromene and Quinoline Derivatives
of 1H‐Pyrazole
1169
*
Nilesh J. Thumar and Manish P. Patel
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar388120 Gujarat, India
*
E-mail: patelmanish1069@yahoo.com
Received September 10, 2010
DOI 10.1002/jhet.1038
Published online 26 October 2012 in Wiley Online Library (wileyonlinelibrary.com).
A new series of nine derivatives of 4H‐pyrano[3,2‐c]chromene and 12 derivatives of N‐thiazolyl‐4H‐
quinoline of 1H‐pyrazole has been synthesized by one pot base catalyzed cyclocondensation reaction of
1H‐pyrazole‐4‐carbaldehyde, malononitrile, and 4‐hydroxy coumarin or β‐enaminones, respectively. All
the synthesized compounds were characterized by elemental analysis, FT‐IR, 1H NMR, 13C NMR spectral
data and were further screened, against a panel of pathogenic strains of bacteria and fungi.
J. Heterocyclic Chem., 49, 1169 (2012).
INTRODUCTION
antiangiogenesis [22], anti‐parasitic [23], antiviral [24], and
also possesses analgesic and anxiolytic activity [25].
The 4H‐chromene nucleus is a fertile source of biologi-
cally important molecules possessing a wide spectrum of
pharmacological activities, such as antimicrobial [1], anti-
viral [2], mutagenicity [3], antiproliferative [4], sex phero-
mone [5], antitumor [6], cancer therapy [7], and central
nervous system activity [8]. Some of these compounds
are widely employed as cosmetics and pigments and as
potential biodegradable agrochemicals [9]. Moreover,
Quinoline represent an important class of compounds be-
ing the main components of molecules possessing a wide
spectrum of biological activities, such as antibacterial
[10], anticancer [11], antimalarial [12], antiplasmodial
[13], antiproliferative [14], antitumor [15], cytotoxic [16],
and intrinsic activity [17]. Therefore, the synthesis of 4H‐
chromene and ‐quinoline derivatives has attracted us with
strong interest.
Despite their importance from pharmacological, indus-
trial, and synthetic point of views, comparatively few stud-
ies on 4‐aryl‐4H‐pyrano[3,2‐c]chromene derivatives [26]
have been reported in the presence of piperidine, morpho-
line, K2CO3, diammonium hydrogen phosphate, H6
[P2W18O62]·18H2O, tetrabutylammonium bromide, and
water. Similarly, 1,4‐diaryl‐4H‐quinoline derivatives [27]
reported in the presence of piperidine, pyridine, DMAP,
TBAF, TEBAC, [bmim+][BF−4] and microwave irradia-
tion, wherein not a single reference has been found
for 4‐heteryl‐4H‐pyrano[3,2‐c]chromene or 1,4‐diheteryl‐
4H‐quinoline derivatives. In view of biological significance
of 4H‐chromene and ‐quinoline, a modification on the 4‐
position on 4H‐pyrano[3,2‐c]chromene by 1H‐pyrazole‐
4‐carbaldehydes and likewise modification on the 1 and
4‐position on 4H‐quinoline by thiazole and 1H‐pyrazole‐
4‐carbaldehydes, respectively may bring significant changes
in pharmacological activities and may provide new classes
of therapeutically active compounds, with this hope and as
In recent years, several 4 functionally substituted
N‐arylpyrazole derivatives identified as antimicrobial
[18–20], anti‐inflammatory (COX‐2 inhibitor and ulcero-
genic activity) [19], antitubercular [20], antitumor [21, 22],
© 2012 HeteroCorporation

1170
N. J. Thumar and M. P. Patel
Vol 49
Scheme 1. Synthetic pathway for the intermediates 1a‐c, 3a‐c, and 4a‐d.
part of our current studies in developing new antimicrobial
agents [27a, 27c, 28] containing 4H‐chromene, N‐aryl
(heteryl)‐4H‐quinoline, thiazole, and 1H‐pyrazole‐4‐carbal-
dehyde derivatives, we have prepared and report herein
4‐pyrazolyl‐4H‐chromene 5a‐i and N‐thiazolyl‐4‐pyrazo-
lyl‐4H‐quinoline 6a‐l derivatives via MCR approach i.e.,
one pot base catalyzed cyclocondensation reaction of 1H‐
pyrazole‐4‐carbaldehydes, malononitrile, and 4‐hydro-
xycoumarin or β‐thiazolylenaminone. The constitution
of all the products was characterized using elemental
analysis, FT‐IR, 1H NMR, and 13C NMR spectrometry
and were subjected to in vitro antimicrobial study against
eight human pathogens, of which three gram‐positive bac-
terial pathogens Streptococcus pneumoniae, Clostridium
tetani, Bacillus subtilis, three Gram‐negative bacterial
pathogens Salmonella typhi, Vibrio cholerae, Escherichia
coli and two fungal pathogens Aspergillus fumigatus and
Candida albicans, using broth microdilution MIC (Mini-
mum Inhibitory Concentration) method [29].
cyclocondensation reaction of 1‐aryl‐5‐chloro‐3‐methyl‐
1H‐pyrazole‐4‐carbaldehyde 1a‐c, malononitrile 2 and
4‐hydroxy‐6‐substituted‐2H‐chromen‐2‐one 3a‐c or 3‐(4‐
arylthiazol‐2‐ylamino)‐5,5‐disubstitutedcyclohex‐2‐enone
4a‐d. Solid phase reaction of 4‐substitutedacetophenone,
thiourea and iodine for 4 h at 120°C afford to give 2‐
amino‐4‐arylthiazole [30]. The required β‐enaminones
4a‐d were prepared [28a] by the reaction β‐diketone with
2‐amino‐4‐arylthiazole by refluxing in methanol in
presence of catalytic amount of acetic acid. Moreover,
Vilsmeier‐Haack reaction of 1‐aryl‐3‐methyl‐1H‐pyrazol‐
5(4H)‐one lead to chloroformylation to give required 1‐
aryl‐5‐chloro‐3‐methyl‐1H‐pyrazole‐4‐carbaldehyde 1a‐c
[31]. The 4‐hydroxy‐6‐substituted‐2H‐chromen‐2‐ones 3a‐c
[32] was prepared by solid phase reaction of malonic acid,
phenol and phosphorous oxychloride, and zinc chloride
(Scheme 1).
To obtain the title 4H‐chromene and ‐quinoline deriva-
tives 5a‐i and 6a‐l, according to literature survey, the reac-
tion was carried out in aqueous media under neutral
conditions but failed to proceed even on prolong refluxing.
The reaction was tried under microwave irradiation, but not
succeeded. The reaction proceeded under basic conditions
such as pyridine, morpholine, K2CO3, and DMAP, but re-
quired prolong refluxing and resulted only in poor yield.
Finally, upon refluxing the reaction mixture in ethanol for
6 h in the presence of piperidine as basic catalyst gave
RESULTS AND DISCUSSION
Chemistry. In continuation of our interest on
synthesizing biologically active heterocyclic derivatives
[27a, 27c, 28], we report herein series of 4‐pyrazolyl‐4H‐
chromene 5a‐i and N‐thiazolyl‐4‐pyrazolyl‐4H‐quinoline
6a‐l derivatives synthesized by one pot three component
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2012
Synthesis, Characterization, and In Vitro Microbial Evaluation of Some
New 4H‐Chromene and Quinoline Derivatives of 1H‐Pyrazole
1171
Scheme 2. Synthesis of various substituted 4H‐chromene 5a‐i and N‐thiazolylquinoline 6a‐l derivatives of 1H‐pyrazole.
moderate to good yield (58–78%) (Scheme 2). Hence,
these conditions were considered as the most optimized
conditions for the synthesis of title derivatives 4H‐chro-
mene and ‐quinoline derivatives 5a‐i and 6a‐l.
stands for methyl of pyrazole ring. Aromatic protons reso-
nate as multiplets appeared at around δ 7.31–8.05 ppm. 13
C
NMR of 5a‐i exhibited a signal around δ 12.51–12.63 and
27.32–27.42 ppm stands for methyl of pyrazole (pyz‐CH3)
and methine carbon (C4), respectively. All the aromatic
carbons showed signals around δ 101.28–158.94 ppm
and the distinctive peak around δ 160.00–160.10 ppm is
of carbonyl carbon (C5) confirms the structure 5a‐i. The
IR spectrum of compounds 5a‐i exhibited characteristic
absorption band around 3460–3260 cm−1 (asym. and
sym. str.) for amine, 2210–2190 cm−1 for cyanide (CN)
and 1705–1680 cm−1 for carbonyl (C O) group, respec-
tively supports the formation of 5a‐i.
A mechanism for the formation of the 4H‐chromene and
‐quinoline derivatives 5a‐i and 6a‐l is outlined in Scheme
3. The reaction occurs via an in situ initial formation of
the heterylidenenitrile, containing the electron‐poor C C
double bond, from the Knoevenagel condensation between
pyrazole‐4‐carbaldehyde and malononitrile by loss of
water molecules. Finally, Michael addition of 3 or 4 to
the initially formed unsaturated nitrile, i.e., nucleophilic
attack of hydroxyl moiety or enaminone to the cyano moi-
ety affords cyclized 4H‐chromene 5a‐i or 4H‐quinoline
derivatives 6a‐l.
Similarly, 1H NMR (DMSO‐d6) spectrum of 4H‐quinoline
derivatives 6a‐l exhibited a singlet around δ 4.56–4.64 for
methine and 5.94–6.10 ppm for amine, respectively. A
singlet around δ 2.31–2.38 ppm stands for methyl of
pyrazole ring. Aromatic protons resonate as multiplets
appeared at around δ 7.29–8.10 ppm and a deshielded singlet,
apart from aromatic multiplets, around δ 8.27–8.42 ppm
is of H5 of thiazole ring. 13C NMR of 6a‐l exhibited a
The structures of all the new compounds were estab-
1
lished by H NMR, 13C NMR, and FT‐IR spectrometry.
1H NMR (DMSO‐d6) spectrum of 4H‐chromene deriva-
tives 5a‐i exhibited a singlet around δ 4.52–4.64 for
methine (H4) and 7.28–7.46 ppm for amine protons
(NH2), respectively. A singlet around 2.21–2.28 ppm
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1172
N. J. Thumar and M. P. Patel
Vol 49
Scheme 3. Plausible mechanistic pathway for the 4H‐chromene 5a‐i and N‐thiazolylquinoline 6a‐l derivatives of 1H‐pyrazole.
signal around δ 12.82–13.04 and 25.01–29.72 ppm stands
for methyl of pyrazole (pyz‐CH3) and methine carbon
(C4), respectively. All the aromatic carbons showed sig-
nals around δ 111.67–166.18 ppm and the distinctive
peak around δ 195.51–196.48 ppm is of carbonyl carbon
(C5) confirms the structure 6a‐l. The IR spectrum of com-
pounds 6a‐l exhibited characteristic absorption band
around 3455–3320 cm−1 (asym. and sym. str.) for amine,
2210–2175 cm−1 for cyanide (CN) and 1695–1660 cm−1
for carbonyl (C O) group, respectively supports the for-
mation of 6a‐l.
Ciprofloxacin, Gentamicin, and Norfloxacin were used as
standard antibacterial drugs, whereas griseofulvin and
nystatin was used as standard antifungal drugs. DMSO
was used as diluents/vehicle to get desired concentration
of synthesized compounds and standard drugs to test
upon standard microbial strains. Serial dilutions were
prepared in primary and secondary screening. Each
compound and standard drugs were diluted obtaining
2000 μg mL−1 concentration, as a stock solution. In primary
screening 1000, 500, and 250 μg mL−1 concentrations of
the synthesized compounds were taken. The active
compounds found in this primary screening were further
diluted to obtain 200, 100, 62.5, 50, 25, 12.5, and 6.250
μg mL−1 concentrations for secondary screening to test in
a second set of dilution against all microorganisms. The
control tube containing no antibiotic is immediately sub
cultured [before inoculation] by spreading a loopful evenly
over a quarter of plate of medium suitable for the growth
of the test organism. The tubes are then put for
incubation at 37°C for 24 h for bacteria and 48 h for fungi.
The highest dilution (lowest concentration) preventing
appearance of turbidity is considered as minimal inhibitory
concentration (MIC, μg mL−1) 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. The result of this is much affected by
the size of the inoculum. The test mixture should contain
108 CFU mL−1 organisms. The protocols were summarized
in Table 1 as the minimal inhibitory concentration (MIC,
μg mL−1).
The obtained elemental analyses of 5a‐i and 6a‐l
values are in good agreement with theoretical data. The
structures of all new synthesized compounds were well
1
supported by H NMR, 13C NMR, and FT‐IR spectral
data and the molecular weight of compounds was con-
firmed by mass spectrometry. All spectroscopic data are
provided in the Experimental section. In addition, all
compounds were screened for their antibacterial and anti-
fungal activity.
Antimicrobial screening. The in vitro antimicrobial
activity of all the compounds and standard drugs were
assessed against three representative of Gram‐positive
bacteria viz. Streptococcus pneumoniae (MTCC 1936),
Clostridium tetani (MTCC 449), Bacillus subtilis (MTCC
441), three Gram‐negative bacteria viz. Salmonella
typhi (MTCC 98), Vibrio cholerae (MTCC 3906),
Escherichia coli (MTCC 443) and two fungi viz.
Aspergillus fumigatus (MTCC 3008) and Candida
albicans (MTCC 227) by the Broth Microdilution MIC
method recommended by National Committee for
Clinical Laboratory Standards (NCCLS). The strains
employed for the activity were procured from (MTCC—
micro type culture collection) Institute of Microbial
Technology, Chandigarh. Inoculum size for test strain
was adjusted to 108 CFU mL−1 (Colony Forming Unit
per milliliter) by comparing the turbidity (turbidimetric
method). 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. Ampicillin, Chloramphenicol,
The examination of the data (Table 1) reveals that major-
ity of the compounds showed antibacterial and antifungal
activity when compared with standard drugs ampicillin
and griseofulvin. Compounds 5d (R1 = H, R2 = Cl), 5e
(R1 = 3‐Cl, R2 = Cl), 6i (R1 = 4‐Me, R3 = F, R4 = H),
and 6j (R1 = H, R3 = F, R4 = Me) were found to be highly
potent against most of the employed strains to inhibit the
growth of organism. In particular, Against Gram‐positive
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2012
Synthesis, Characterization, and In Vitro Microbial Evaluation of Some
New 4H‐Chromene and Quinoline Derivatives of 1H‐Pyrazole
1173
Table 1
Antimicrobial activity of the compounds 5a‐i and 6a‐l.
Minimum inhibitory concentration (MIC, μg mL−1
Gram‐negative bacteria
)
Gram‐positive bacteria
C. t.
Fungi
S. p.
B. s.
S. t.
V. c.
E. c.
A. f.
C. a.
MTCC
(1936)
MTCC
(449)
MTCC
(441)
MTCC
(98)
MTCC
(3906)
MTCC
(443)
MTCC
(3008)
MTCC
(227)
Compds
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
6d
6e
6f
6g
500
500
250
500
150
500
500
1000
500
1000
100
100
200
500
500
100
500
200
500
500
500
100
50
500
250
500
200
100
250
250
250
250
250
500
250
250
500
100
500
200
1000
1000
250
500
250
50
500
250
500
250
62.5
500
500
250
250
1000
50
500
500
500
1000
150
500
100
100
100
1000
250
50
200
200
500
100
100
200
250
500
1000
500
200
500
100
500
200
250
500
100
100
500
500
100
50
500
250
200
250
200
500
500
250
200
250
1000
250
250
500
100
250
200
1000
1000
500
1000
100
50
500
250
500
100
150
250
500
1000
500
1000
500
100
500
500
500
100
500
50
100
1000
500
100
50
25
0.05
–
500
1000
>1000
>1000
100
500
500
250
500
100
500
1000
500
1000
500
1000
1000
>1000
>1000
500
1000
>1000
500
500
500
1000
1000
–
1000
>1000
500
1000
1000
>1000
>1000
500
500
>1000
500
>1000
>1000
1000
1000
–
6h
6i
6j
6k
6l
Ampi.
Chlora.
Cipro.
Genta.
Grise.
Nyst.
–
–
–
100
–
–
–
500
100
50
0.5
–
–
100
5
–
50
1
–
–
25
5
–
–
25
5
–
–
–
–
100
Ampi.: Ampicillin, Chlora.: Chloramphenicol, Cipro.: Ciprofloxacin, Genta.: Gentamicin, Grise.: Griseofulvin, Nyst.: Nystatin, S. p.: Streptococcus pneu-
moniae, 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.
pathogen S. pneumoniae, compounds 6b (R1 = 3‐Cl, R3 =
H, R4 = H), 6c (R1 = 4‐Me, R3 = H, R4 = H) and 6g (R1 =
H, R3 = F, R4 = H) were found to exhibit comparable activ-
ity, to ampicillin (MIC = 100 μg mL−1). The compounds
5d (R1 = H, R2 = Cl), 5e (R1 = 3‐Cl, R2 = Cl), 6f (R1 =
4‐Me, R3 = H, R4 = Me), and 6h (R1 = 3‐Cl, R3 = F,
R4 = H) found to be more efficient (MIC < 250 μg mL−1)
whereas, 5b (R1 = 3‐Cl, R2 = H), 5f (R1 = 4‐Me, R2 =
Cl), 5g (R1 = H, R2 = Me), 5h (R1 = 3‐Cl, R2 = Me), 5i
(R1 = 4‐Me, R2 = Me), 6a (R1 = H, R3 = H, R4 = H), 6c
(R1 = 4‐Me, R3 = H, R4 = H), 6d (R1 = H, R3 = H, R4 =
Me) and 6k (R1 = 3‐Cl, R3 = F, R4 = Me) was found
equally potent to ampicillin (MIC = 250 μg mL−1), toward
C. tetani. The compounds 5e (R1 = 3‐Cl, R2 = Cl), 6b
(R1 = 3‐Cl, R3 = H, R4 = H), 6g (R1 = H, R3 = F, R4 = H),
6i (R1 = 4‐Me, R3 = F, R4 = H), 6j (R1 = H, R3 = F, R4 = Me),
and 6k (R1 = 3‐Cl, R3 = F, R4 = Me) shows better activity
(MIC < 250 μg mL−1) where as, 5b (R1 = 3‐Cl, R2 = H),
5d (R1 = H, R2 = Cl), 5h (R1 = 3‐Cl, R2 = Me), and 5i
(R1 = 4‐Me, R2 = Me) found equally potent (MIC =
250 μg mL−1), to ampicillin, against B. subtilis. Toward
Gram‐negative strain S. typhi, compounds 5d (R1 = H,
R2 = Cl), 5e (R1 = 3‐Cl, R2 = Cl), 6d (R1 = H, R3 = H,
R4 = Me), 6i (R1 = 4‐Me, R3 = F, R4 = H), and 6j (R1 =
H, R3 = F, R4 = Me) were equally active to ampicillin
(MIC = 100 μg mL−1). The only Compound 6f (R1 = 4‐Me,
R3 = H, R4 = Me) found equipotent to ampicillin (MIC =
100 μg mL−1) against V. cholerae. The compound 6i
(R1 = 4‐Me, R3 = F, R4 = H) shows better (MIC < 100
μg mL−1) and 5d (R1 = H, R2 = Cl), 6c (R1 = 4‐Me,
R3 = H, R4 = H), 6g (R1 = H, R3 = F, R4 = H), and 6j
(R1 = H, R3 = F, R4 = Me) were found to exhibit compa-
rable activity to ampicillin (MIC = 100 μg mL−1) toward
E. coli.
Against fungal pathogen C. albicans, compound 5c (R1 =
4‐Me, R2 = H) and 5e (R1 = 3‐Cl, R2 = Cl) found better
Journal of Heterocyclic Chemistry
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N. J. Thumar and M. P. Patel
Vol 49
active (MIC < 500 μg mL−1) where as, 5a (R1 = H, R2 = H),
5b (R1 = 3‐Cl, R2 = H), 5d (R1 = H, R2 = Cl), 5g (R1 = H,
R2 = Me), 5i (R1 = 4‐Me, R2 = Me), 6e (R1 = 3‐Cl, R3 = H,
R4 = Me), 6h (R1 = 3‐Cl, R3 = F, R4 = H), 6i (R1 = 4‐Me,
R3 = F, R4 = H) and 6j (R1 = H, R3 = F, R4 = Me) were
found to be equipotent compared to the standard griseoful-
vin (MIC = 500 μg mL−1). None of the tested compounds
found to be potent against fungal strain, A. fumigatus, com-
pared to the standard drug griseofulvin. The remaining com-
pounds showed moderate to good activity to inhibit the
growth of bacterial pathogens and are all less effective than
standard drugs.
The investigation of the structure–activity relationship
of antibacterial screening revealed that the chloro substi-
tuted compounds (5b, 5d, 5e, 5f, 5h, 6h, 6k) gave better
results against C. tetani, B. subtilis, and E. coli. Similarly,
toward B. subtilis, compound (6b) containing chloro sub-
stituted phenyl ring in pyrazole were found to be most po-
tent. Moreover, compounds (5h, 5i, 6f, 6i, 6j, 6k) with
methyl substituted phenyl ring in pyrazole have exhibited
better activity against C. tetani and B. subtilis. Antifungal
evaluation results revealed none of the effect of the pres-
ence of particular group.
antimicrobials which can be of interest for further detailed
preclinical investigations.
EXPERIMENTAL
Phenyl hydrazine was distilled before used; all other reagents
were commercially available used without further purification.
Solvents used were of analytical grade. All melting points were
taken in open capillaries and are uncorrected. Thin‐layer chroma-
tography (TLC, on aluminum plates precoated with silica gel,
60
F
254
, 0.25 mm thickness) (Merck, Darmstadt, Germany) was
used for monitoring the progress of all reactions, purity, and ho-
mogeneity of the synthesized compounds; eluent‐toluene:ethyl
acetate = 7:3. UV radiation and/or iodine were used as the visual-
izing agents. Elemental analysis (% C, H, N) was carried out by
Perkin‐Elmer 2400 series‐II elemental analyzer (Perkin‐Elmer,
USA) and all compounds are within 0.4% of theory specified.
The IR spectra were recorded in KBr on a Perkin‐Elmer Spectrum
GX FT‐IR Spectrophotometer (Perkin‐Elmer, USA) and only the
characteristic peaks are reported in cm−1. 1H NMR and 13C NMR
spectra were recorded in DMSO‐d6 on a Bruker Avance 400F
(MHz) spectrometer (Bruker Scientific Corporation, Switzerland)
using solvent peak as internal standard at 400 and 100 MHz,
respectively. Chemical shifts are reported in parts per million
(ppm). Mass spectra were scanned on a Shimadzu LCMS 2010
spectrometer (Shimadzu, Tokyo, Japan). Required 1‐aryl‐5‐chloro‐
3‐methyl‐1H‐pyrazole‐4‐carbaldehyde 1a‐c was prepared, accord-
ing to literature procedure [31], by Vilsmeier–Haack reaction of
1‐aryl‐3‐methyl‐1H‐pyrazol‐5(4H)‐one lead to chloroformylation
to give 1‐aryl‐5‐chloro‐3‐methyl‐1H‐pyrazole‐4‐carbaldehyde 1a‐c
(Scheme 1). The 4‐hydroxycoumarin (4‐hydroxy‐6‐substituted‐
2H‐chromen‐2‐one) 3a‐c was synthesized, according to literature
method [32], by solid phase reaction of malonic acid, phenol and
phosphorous oxychloride, and zinc chloride (Scheme 1). Solid
phase reaction of 4‐substitutedacetophenone, thiourea, and io-
dine for 4 h at 120°C afford to give 2‐amino‐4‐arylthiazole
[30]. The 3‐(4‐Arylthiazol‐2‐ylamino)‐5,5‐disubstitutedcyclohex‐
2‐enone 4a‐d were synthesized by the reaction β‐diketone with
2‐amino‐4‐arylthiazole by refluxing in methanol in presence of
catalytic amount of acetic acid [28a].
General procedure. 2‐Amino‐4‐(5‐chloro‐3‐methyl‐1‐aryl‐
1H‐pyrazol‐4‐yl)‐9‐(un)substituted‐5‐oxo‐4,5‐dihydropyrano[3,2‐
c]chromene‐3‐carbonitrile (5a‐i). A mixture of appropriate
1H‐pyrazole‐4‐carbaldehyde 1a‐c (30 mmol), malononitrile 2
(30 mmol), and 2H‐chromen‐2‐ones 3a‐c (30 mmol) in ethanol
(20 mL) containing three drops of piperidine was slowly
heated and refluxed with stirring for 3–4 h. On completion of
reaction, monitored by TLC (ethyl acetate:toluene = 3:7), the
reaction mixture was cooled to room temperature and the solid
was collected by suction filtration and washed with mixture of
chloroform and methanol (1:1) to obtain the pure compounds
5a‐i. Physical, analytical and spectroscopic characterization
data of the compounds 5a‐i are given hereafter:
From antimicrobial screening results, it is interesting to
note that a minor alteration in the molecular configuration
of the investigated compounds may have a pronounced ef-
fect on antimicrobial activity.
CONCLUSION
A new series of substituted 4‐pyrazolyl‐pyrano[3,2‐c]
chromene 5a‐i and 4‐pyrazolyl‐N‐thiazolylquinoline 6a‐l
derivatives has been synthesized via MCR approach and
characterized through elemental and spectral analysis. This
synthetic strategy allows the construction of relatively
complicated nitrogen and oxygen containing fused hetero-
cyclic system as well as the introduction of various heteryl
substitutions into 1 and 4‐position of chromene and quino-
line system. It can be concluded from antimicrobial screen-
ing (Table 1), against panel of human pathogens, that most
of the synthesized chromene and quinoline derivatives was
found to be highly active, compared to the standard drugs,
against bacterial pathogens. Among them, many com-
pounds were found to be the most active against Bacillus
subtilis and Clostridium tetani compared to rest of the
employed species. Antifungal activity of the compounds
shows that most of the compounds found to be potent
against C. albicans compared to A. fumigatus. It is worth
mentioning that minor changes in molecular configuration
of these compounds profoundly influence the antimicrobial
activity. Further, synthetic work to intensify the potency of
these derivatives by changing molecular configuration is
in progress at our laboratory. The present study throws
light on the identification of this new structural class as
2‐Amino‐4‐(5‐chloro‐3‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)‐5‐
oxo‐4,5‐dihydropyrano[3,2‐c]chromene‐3‐carbonitrile (5a). This
compound was obtained as colorless solid, 980 mg (76 %), Mp
217–219 °C; IR (KBr): 3405 and 3290 (NH2), 2195 (CN), 1680
(CO); 1H NMR (400 MHz, DMSO‐d6): δ 2.28 (s, 3H, CH3),
4.53 (s, 1H, H4), 7.29 (s, 2H, NH2), 7.32–8.01 (m, 9H, aromatic
protons); 13C NMR (100 MHz, DMSO‐d6): 12.54 (CH3), 27.40
(C4), 55.35 (C3), 119.54 (CN), 102.10, 114.80, 117.99, 121.71,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2012
Synthesis, Characterization, and In Vitro Microbial Evaluation of Some
New 4H‐Chromene and Quinoline Derivatives of 1H‐Pyrazole
1175
1
123.78, 124.27, 125.62, 126.06, 130.13, 132.34, 133.45, 135.21,
148.43, 153.52, 155.64 (aromatic carbons), 158.83 (C2), 160.08
(C5); MS m/z: 430.7 [M]+, 432.7 [M+2]+; Anal. Calcd. for
C23H15ClN4O3: C, 64.12; H, 3.51; N, 8.23. Found: C, 63.90; H,
3.79; N, 7.96.
1695 (CO); H NMR (400 MHz, DMSO‐d6): δ 2.22 (s, 3H, pyz‐
CH3), 2.38 (tolyl‐CH3), 4.52 (s, 1H, H4), 7.42 (s, 2H, NH2),
7.45–7.95 (m, 7H, aromatic protons); 13C NMR (400 MHz,
DMSO‐d6): 12.62 (pyz‐CH3), 20.62 (tolyl‐CH3), 27.42 (C4),
55.33 (C3), 119.56 (CN), 103.82, 112.55, 115.02, 116.42,
117.58, 123.68, 125.62, 126.11, 128.79, 131.61, 133.20, 136.89,
149.06, 152.30, 154.25 (aromatic carbons), 158.82 (C2), 160.07
(C5); MS m/z: 478.8 [M]+, 480.8 [M+2]+; Anal. Calcd. for
C24H16Cl2N4O3: C, 60.14; H 3.36, N 11.69. Found: C, 59.87; H,
3.16; N, 11.91.
2‐Amino‐4‐(5‐chloro‐1‐(3‐chlorophenyl)‐3‐methyl‐1H‐pyrazol‐
4‐yl)‐5‐oxo‐4,5‐dihydropyrano[3,2‐c]chromene‐3‐carbonitrile
(5b). This compound was obtained as colorless solid, 960 mg
(69 %), Mp 256–258°C; IR (KBr): 3390 and 3320 (NH2),
2200 (CN), 1700 (CO); 1H NMR (400 MHz, DMSO‐d6): δ
2.25 (s, 3H, CH3), 4.62 (s, 1H, H4), 7.46 (s, 2H, NH2), 7.49–7.91
(m, 8H, aromatic protons); 13C NMR (100 MHz, DMSO‐d6):
12.56 (CH3), 27.32 (C4), 55.27 (C3), 119.59 (CN), 101.87,
113.10, 117.15, 118.96, 122.98, 123.52, 124.70, 125.25, 125.67,
128.48, 131.31, 133.55, 133.87, 139.17, 149.20, 152.62, 154.00
(aromatic carbons), 158.91 (C2), 160.00 (C5); MS m/z: 464.8
[M]+, 466.6 [M+2]+; Anal. Calcd. for C23H14Cl2N4O3: C, 59.37;
H, 3.03; N, 12.04. Found: C, 59.61; H, 2.83; N, 11.87.
2‐Amino‐4‐(5‐chloro‐3‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)‐9‐
methyl‐5‐oxo‐4,5‐dihydropyrano[3,2‐c]chromene‐3‐carbonitrile
(5g). This compound was obtained as colorless solid, 1040 mg
(78 %), Mp 230–232°C; IR (KBr): 3460 and 3310 (NH2), 2205
(CN), 1685 (CO); 1H NMR (400 MHz, DMSO‐d6): δ 2.26
(s, 3H, pyz‐CH3), 2.31 (Ar‐CH3), 4.63 (s, 1H, H4), 7.35 (s, 2H,
NH2), 7.39–7.90 (m, 8H, aromatic protons); 13C NMR (400
MHz, DMSO‐d6): 12.63 (pyz‐CH3), 20.73 (Ar‐CH3), 27.34
(C4), 55.62 (C3), 119.48 (CN), 102.52, 112.66, 114.08, 117.74,
123.73, 125.04, 126.51, 128.76, 130.22, 132.41, 135,14, 137.46,
149.81, 151.98, 154.27 (aromatic carbons), 158.94 (C2), 160.04
(C5); MS m/z: 444.7 [M]+, 446.7 [M+2]+; Anal. Calcd. for
C24H17ClN4O3: C, 64.80; H 3.85, N 12.59. Found: C, 65.18; H,
4.11; N, 12.38.
2‐Amino‐4‐(5‐chloro‐3‐methyl‐1‐p‐tolyl‐1H‐pyrazol‐4‐yl)‐5‐
oxo‐4,5‐dihydropyrano[3,2‐c]chromene‐3‐carbonitrile (5c). This
compound was obtained as colorless solid, 840 mg (63%), Mp
228–230°C; IR (KBr): 3415 and 3325 (NH2), 2190 (CN), 1690
1
(CO); H NMR (400 MHz, DMSO‐d6): δ 2.23 (s, 3H, pyz‐CH3),
2.34 (tolyl‐CH3), 4.64 (s, 1H, H4), 7.40 (s, 2H, NH2), 7.46–7.89
(m, 8H, aromatic protons); 13C NMR (100 MHz, DMSO‐d6):
12.57 (pyz‐CH3), 20.54 (tolyl‐CH3), 27.39 (C4), 55.24 (C3),
119.52 (CN), 101.28, 112.19, 114.23, 115.40, 117.65, 123.10,
125.28, 126.73, 127.15, 130.56, 132.83, 135.19, 148.00, 153.69,
155.49 (aromatic carbons), 158.82 (C2), 160.10 (C5); MS m/z:
444.9 [M]+, 446.8 [M+2]+; Anal. Calcd. for C24H17ClN4O3: C,
64.80; H, 3.85; N, 12.59. Found: C, 65.12; H, 4.05; N, 12.33.
2‐Amino‐9‐chloro‐4‐(5‐chloro‐3‐methyl‐1‐phenyl‐1H‐pyrazol‐
4‐yl)‐5‐oxo‐4,5‐dihydropyrano[3,2‐c]chromene‐3‐carbonitrile
(5d). This compound was obtained as pale yellow solid, 935 mg
(67%), Mp 254–256°C; IR (KBr): 3420 and 3305 (NH2), 2205
2‐Amino‐4‐(5‐chloro‐1‐(3‐chlorophenyl)‐3‐methyl‐1H‐pyrazol‐
4‐yl)‐9‐methyl‐5‐oxo‐4,5‐dihydropyrano[3,2‐c]chromene‐3‐
carbonitrile (5h). This compound was obtained as colorless solid,
875 mg (61%), Mp 210–212°C; IR (KBr): 3380 and 3280 (NH2),
1
2190 (CN), 1680 (CO); H NMR (400 MHz, DMSO‐d6): δ 2.25
(s, 3H, pyz‐CH3), 2.37 (Ar‐CH3), 4.64 (s, 1H, H4), 7.36 (s, 2H,
NH2), 7.40–7.88 (m, 7H, aromatic protons); 13C NMR (400
MHz, DMSO‐d6): 12.53 (pyz‐CH3), 20.89 (Ar‐CH3), 27.40 (C4),
55.56 (C3), 119.55 (CN), 103.96, 113.14, 114.43, 116.38,
119.88, 122.26, 124.54, 125.48, 127.71, 129.03, 132.78, 133.56,
135.68, 136.13, 148.83, 152.17, 154.07 (aromatic carbons),
158.85 (C2), 160.06 (C5); MS m/z: 478.6 [M]+, 480.5 [M+2]+;
Anal. Calcd. for C24H16Cl2N4O3: C, 60.14; H, 3.36; N, 11.69.
Found: C, 59.84; H, 3.59; N, 11.44.
2‐Amino‐4‐(5‐chloro‐3‐methyl‐1‐p‐tolyl‐1H‐pyrazol‐4‐yl)‐9‐
methyl‐5‐oxo‐4,5‐dihydropyrano[3,2‐c]chromene‐3‐carbonitrile
(5i). This compound was obtained as colorless solid, 990 mg
(72%), Mp 229–231°C; IR (KBr): 3420 and 3260 (NH2), 2200
1
(CN), 1690 (CO); H NMR (400 MHz, DMSO‐d6): δ 2.27 (s,
3H, CH3), 4.55 (s, 1H, H4), 7.36 (s, 2H, NH2), 7.41–7.93 (m,
8H, aromatic protons); 13C NMR (100 MHz, DMSO‐d6):
12.60 (CH3), 27.32 (C4), 55.41 (C3), 119.49 (CN), 101.69,
111.12, 114.09, 115.75, 116.85, 124.77, 125.45, 126.59,
129.00, 132.92, 134.63, 137.53, 148.84, 152.05, 155.25
(aromatic carbons), 158.81 (C2), 160.05 (C5); MS m/z: 464.6
[M]+, 466.6 [M+2]+; Anal. Calcd. for C23H14Cl2N4O3: C,
59.37; H, 3.03; N, 12.04. Found: C, 59.59; H, 2.87; N, 11.80.
2‐Amino‐9‐chloro‐4‐(5‐chloro‐1‐(3‐chlorophenyl)‐3‐methyl‐
1H‐pyrazol‐4‐yl )‐5‐oxo‐4,5‐dihydropyrano[3,2‐c]chromene‐3‐
carbonitrile (5e). This compound was obtained as pale yellow
solid, 1095 mg (73%), Mp 237–239°C; IR (KBr): 3390 and
3295 (NH2), 2190 (CN), 1705 (CO); 1H NMR (400 MHz,
DMSO‐d6): δ 2.24 (s, 3H, CH3), 4.57 (s, 1H, H4), 7.28 (s, 2H,
NH2), 7.35–8.05 (m, 7H, aromatic protons); 13C NMR (400
MHz, DMSO‐d6): 12.51 (CH3), 27.38 (C4), 55.57 (C3), 119.47
(CN), 102.18, 115.75, 117.29, 119.44, 122.94, 124.64, 125.01,
127.87, 128.24, 130.86, 131.16, 134.47, 136.69, 139.57,
149.72, 153.21, 154.12 (aromatic carbons), 158.92 (C2), 160.02
(C5); MS m/z: 500.5 [M]+, 502.5 [M+2]+; Anal. Calcd. for
C23H13Cl3N4O3: C, 55.28; H, 2.62; N, 11.21. Found: C, 54.95;
H, 2.82; N, 11.42.
1
(CN), 1695 (CO); H NMR (400 MHz, DMSO‐d6): δ 2.21 (s,
3H, pyz‐CH3), 2.35 (Ar‐CH3), 2.42 (tolyl‐CH3), 4.58 (s, 1H,
H4), 7.29 (s, 2H, NH2), 7.31–7.70 (m, 7H, aromatic protons);
13C NMR (400 MHz, DMSO‐d6): 12.51 (pyz‐CH3), 20.94 (Ar‐
CH3), 21.02 (tolyl‐CH3), 27.37 (C4), 55.62 (C3), 119.58 (CN),
101.81, 112.75, 116.86, 118.22, 122.45, 124.93, 125.31, 130.01,
132.77, 134.62, 135.75, 138.17, 148.26, 150.79, 153.89
(aromatic carbons), 158.84 (C2), 160.02 (C5); MS m/z: 458.9
[M]+, 460.8 [M+2]+; Anal. Calcd. for C25H19ClN4O3: C, 65.43;
H, 4.17; N, 12.21. Found: C, 65.68; H, 3.80; N, 11.99.
General procedure. 2‐Amino‐4‐(5‐chloro‐3‐methyl‐1‐aryl‐
1H‐pyrazol‐4‐yl)‐1‐(4‐arylthiazol‐2‐yl)‐7,7‐di(un)substituted‐5‐
oxo‐1,4,5,6,7,8‐hexahydroquinoline‐3‐carbonitrile (6a‐l). A mixture
of appropriate 1H‐pyrazole‐4‐carbaldehyde 1a‐c (30 mmol),
malononitrile 2 (30 mmol), and β‐enaminone 3a‐c (30 mmol)
in ethanol (20 mL) containing three drops of piperidine was
slowly heated and refluxed with stirring for 3–4 h. On
completion of reaction, monitored by TLC (ethyl acetate:
toluene = 3:7), the reaction mixture was cooled to room
temperature and the solid was collected by suction filtration
2‐Amino‐9‐chloro‐4‐(5‐chloro‐3‐methyl‐1‐p‐tolyl‐1H‐pyrazol‐
4‐yl)‐5‐oxo‐4,5‐dihydropyrano[3,2‐c]chromene‐3‐carbonitrile
(5f). This compound was obtained as pale yellow solid, 1020 mg
(71%), Mp >300°C; IR (KBr): 3385 and 3300 (NH2), 2210 (CN),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1176
N. J. Thumar and M. P. Patel
Vol 49
and washed with mixture of chloroform and methanol (1:1) to
obtain the pure compounds 6a‐l. Physical, analytical and
spectroscopic characterization data of the compounds 6a‐l are
given hereafter.
134.42, 137.10, 149.98, 152.18, 159.20, 158.56, 160.01, 162.90
(aromatic carbons), 196.20 (C5); MS m/z: 567.3 [M]+, 569.2 [M
+2]+; Anal. Calcd. for C31H27ClN6OS: C, 65.65; H, 4.80; N,
14.82. Found: C, 65.41; H, 5.03; N, 15.06.
2‐Amino‐4‐(5‐chloro‐3‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)‐5‐
oxo‐1‐(4‐phenylthiazol‐2‐yl)‐1,4,5,6,7,8‐hexahydroquinoline‐3‐
carbonitrile (6a). This compound was obtained as colorless
solid, 1210 mg (75 %), Mp 250–253°C; IR (KBr): 3455 and
3350 (NH2), 2205 (CN), 1685 (CO); 1H NMR (400 MHz,
DMSO‐d6): δ 1.84–2.27 (m, 6H, 3×CH2), 2.37 (s, 3H, CH3),
4.64 (s, 1H, H4), 5.97 (s, 2H, NH2), 7.34–7.94 (m, 10H,
aromatic protons), 8.27 (s, 1H, thiazole H5); 13C NMR (400
MHz, DMSO‐d6): 12.88 (CH3), 21.44 (C8), 25.14 (C4), 29.81
(C7), 36.28 (C6), 62.94 (C3), 120.03 (CN), 114.70, 115.61,
117.10, 122.80, 126.96, 127.49, 128.09, 131.38, 133.26,
136.28, 139.25, 149.08, 152.40, 158.29, 159.98, 162.18, 163.02
(aromatic carbons), 195.72 (C5); MS m/z: 539.3 [M]+, 541.2
[M+2]+; Anal. Calcd. for C29H23ClN6OS: C, 64.62; H, 4.30;
N, 15.59. Found: C, 64.41; H, 3.94; N, 15.76.
2‐Amino‐4‐(5‐chloro‐1‐(3‐chlorophenyl)‐3‐methyl‐1H‐
pyrazol‐4‐yl)‐7,7‐dimethyl‐5‐oxo‐1‐(4‐phenylthiazol‐2‐yl)‐1,4,5,6,7,8‐
hexahydroquinoline‐3‐carbonitrile (6e). This compound was
obtained as colorless solid, 1265 mg (70 %), Mp 238–241°C;
IR (KBr): 3440 and 3355 (NH2), 2180 (CN), 1685 (CO); 1H
NMR (400 MHz, DMSO‐d6): δ 0.90 (s, 3H, CH3), 0.97 (s, 3H,
CH3), 1.93–2.29 (m, 4H, 2×CH2), 2.34 (s, 3H, pyz‐CH3), 4.56
(s, 1H, H4), 5.94 (s, 2H, NH2), 7.29–7.92 (m, 9H, aromatic
protons), 8.37 (s, 1H, thiazole H5); 13C NMR (400 MHz,
DMSO‐d6): 12.97 (pyz‐CH3), 25.63, 26.98 (CH3), 28.47 (C4),
32.90 (C7), 40.49 (C8), 51.04 (C6), 63.87 (C3), 121.74 (CN),
111.81, 112.77, 115.59, 116.01, 118.46, 125.94, 126.91,
127.00, 128.29, 128.27, 131.34, 136.52, 137.81, 148.06,
152.30, 158.35, 158.13, 162.17, 163.14 (aromatic carbons),
196.39 (C5); MS m/z: 602.0 [M]+, 604.0 [M+2]+; Anal. Calcd.
for C31H26Cl2N6OS: C, 61.90; H, 4.36; N, 13.97. Found: C,
62.15; H, 4.19; N, 14.12.
2‐Amino‐4‐(5‐chloro‐3‐methyl‐1‐p‐tolyl‐1H‐pyrazol‐4‐yl)‐7,7‐
dimethyl‐5‐oxo‐1‐(4‐phenylthiazol‐2‐yl)‐1,4,5,6,7,8‐hexahydroquinoline‐
3‐carbonitrile (6f). This compound was obtained as colorless
solid, 1255 mg (72 %), Mp 263–265°C; IR (KBr): 3395 and
3340 (NH2), 2190 (CN), 1685 (CO); 1H NMR (400 MHz,
DMSO‐d6): δ 0.85 (s, 3H, CH3), 0.93 (s, 3H, CH3), (m, 4H,
2×CH2), 2.30 (s, 3H, tolyl‐CH3), 2.32 (s, 3H, pyz‐CH3), 4.60 (s,
1H, H4), 6.00 (s, 2H, NH2), 7.33–8.01 (m, 9H, aromatic
protons), 8.38 (s, 1H, thiazole H5); 13C NMR (400 MHz,
DMSO‐d6): 13.04 (pyz‐CH3), 21.02 (tolyl‐CH3), 26.06, 26.21
(CH3), 28.15 (C4), 32.41 (C7), 39.40 (C8), 50.66 (C6), 64.42
(C3), 120.82 (CN), 112.87, 114.51, 116.13, 125.89, 126.68,
127.07, 128.35, 129.43, 130.05, 132.45, 139.04, 149.89, 151.30,
157.12, 159.47, 161.02, 162.08 (aromatic carbons), 196.48 (C5);
MS m/z: 581.4 [M]+, 583.4 [M+2]+; Anal. Calcd. for
C32H29ClN6OS: C 66.14, H 5.03, N 14.46. Found: C 65.87, H
4.86, N 14.68.
2‐Amino‐4‐(5‐chloro‐3‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐
yl)‐1‐(4‐(4‐fluorophenyl)thiazol‐2‐yl)‐5‐oxo‐1,4,5,6,7,8‐
hexahydroquinoline‐3‐carbonitrile (6g). This compound was
obtained as colorless solid, 1135 mg (68 %), Mp 281–282°C;
IR (KBr): 3440 and 3375 (NH2), 2185 (CN), 1660 (CO); 1H
NMR (400 MHz, DMSO‐d6): δ 1.82–2.31 (m, 6H, 3×CH2),
2.38 (s, 3H, CH3), 4.61 (s, 1H, H4), 6.10 (s, 2H, NH2), 7.29–8.04
(m, 9H, aromatic protons), 8.42 (s, 1H, thiazole H5); 13C
NMR (400 MHz, DMSO‐d6): 12.85 (CH3), 20.22 (C8), 26.39
(C4), 28.02 (C7), 36.24 (C6), 62.11 (C3), 120.99 (CN),
112.43, 115.63, 118.80, 122.64, 124.01, 127.36, 128.88,
138.25, 142.11, 146.95, 152.76, 153.60, 154.23, 154.21,
157.61, 162.55, 163.15 (aromatic carbons), 195.83 (C5); MS m/z:
557.2 [M]+, 559.1 [M+2]+; Anal. Calcd. for C29H22ClFN6OS:
C, 62.53; H, 3.98; N, 15.09. Found: C, 62.72; H, 4.27; N,
14.83.
2‐Amino‐4‐(5‐chloro‐1‐(3‐chlorophenyl)‐3‐methyl‐1H‐
pyrazol‐4‐yl)‐1‐(4‐(4‐fluorophenyl)thiazol‐2‐yl)‐5‐oxo‐1,4,5,6,7,8‐
hexahydroquinoline‐3‐carbonitrile (6h). This compound was
obtained as colorless solid, 1295 mg (73 %), Mp 274–276°C;
IR (KBr): 3430 and 3355 (NH2), 2190 (CN), 1670 (CO); 1H
NMR (400 MHz, DMSO‐d6): δ 1.79–2.25 (m, 6H, 3×CH2),
2.35 (s, 3H, CH3), 4.57 (s, 1H, H4), 5.98 (s, 2H, NH2),
7.31–8.02 (m, 8H, aromatic protons), 8.39 (s, 1H, thiazole
2‐Amino‐4‐(5‐chloro‐1‐(3‐chlorophenyl)‐3‐methyl‐1H‐pyrazol‐
4‐yl)‐5‐oxo‐1‐(4‐phenylthiazol‐2‐yl)‐1,4,5,6,7,8‐hexahydroquinoline‐
3‐carbonitrile (6b). This compound was obtained as colorless
solid, 1170 mg (66%), Mp 254–257°C; IR (KBr): 3380 and 3355
1
(NH2), 2210 (CN), 1690 (CO); H NMR (400 MHz, DMSO‐d6):
δ 1.75–2.25 (m, 6H, 3×CH2), 2.36 (s, 3H, CH3), 4.59 (s, 1H,
H4), 6.04 (s, 2H, NH2), 7.35–8.02 (m, 9H, aromatic protons),
8.35 (s, 1H, thiazole H5); 13C NMR (400 MHz, DMSO‐d6):
12.83 (CH3), 20.16 (C8), 26.97 (C4), 29.03 (C7), 37.17 (C6),
60.25 (C3), 120.33 (CN), 116.58, 116.73, 116.86, 126.07,
127.12, 128.41, 129.37, 130.28, 130.42, 130.65, 131.19, 137.41,
139.57, 149.60, 150.17, 151.39, 157.71, 161.19, 163.22 (aromatic
carbons), 195.51 (C5); MS m/z: 574.0 [M]+, 576.0 [M+2]+; Anal.
Calcd. for C29H22Cl2N6OS: C, 60.73; H, 3.87; N, 14.65. Found:
C, 61.05; H, 4.03; N, 14.45.
2‐Amino‐4‐(5‐chloro‐3‐methyl‐1‐p‐tolyl‐1H‐pyrazol‐4‐yl)‐5‐
oxo‐1‐(4‐phenylthiazol‐2‐yl)‐1,4,5,6,7,8‐hexahydroquinoline‐3‐
carbonitrile (6c). This compound was obtained as colorless
solid, 960 mg (58%), Mp 244–246°C; IR (KBr): 3445 and 3370
(NH2), 2175 (CN), 1670 (CO); 1H NMR (400 MHz, DMSO‐
d6): δ 1.74–2.27 (m, 6H, 3×CH2), 2.35 (s, 3H, pyz‐CH3), 2.36
(s, 3H, tolyl‐CH3), 4.62 (s, 1H, H4), 6.01 (s, 2H, NH2), 7.32‐
7.99 (m, 9H, aromatic protons), 8.38 (s, 1H, thiazole H5); 13C
NMR (400 MHz, DMSO‐d6): 12.91 (pyz‐CH3), 20.46 (tolyl‐
CH3), 21.38 (C8), 25.01 (C4), 29.43 (C7), 37.32 (C6), 62.76
(C3), 120.95 (CN), 112.62, 113.78, 115.09, 117.79, 126.27,
127.72, 128.05, 128.99, 131.85, 134.82, 139.24, 148.40,
151.53, 157.11, 158.64, 160.97, 161.47 (aromatic carbons),
195.75 (C5); MS m/z: 553.5 [M]+, 555.5 [M+2]+; Anal. Calcd.
for C30H25ClN6OS: C, 65.15; H, 4.56; N, 15.20. Found: C,
64.94; H, 4.72; N, 14.96.
2‐Amino‐4‐(5‐chloro‐3‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐
yl)‐7,7‐dimethyl‐5‐oxo‐1‐(4‐phenylthiazol‐2‐yl)‐1,4,5,6,7,8‐
hexahydroquinoline‐3‐carbonitrile (6d). This compound was
obtained as colorless solid, 1105 mg (65%), Mp 229–231°C; IR
1
(KBr): 3395 and 3325 (NH2), 2195 (CN), 1670 (CO); H NMR
(400 MHz, DMSO‐d6): δ 0.94 (s, 3H, CH3), 1.01 (s, 3H, CH3),
1.92–2.34 (m, 4H, 2×CH2), 2.37 (s, 3H, pyz‐CH3), 4.62 (s, 1H,
H4), 6.02 (s, 2H, NH2), 7.35–8.07 (m, 10H, aromatic protons),
8.40 (s, 1H, thiazole H5); 13C NMR (400 MHz, DMSO‐d6):
12.93 (pyz‐CH3), 26.75, 27.36 (CH3), 28.12 (C4), 32.00 (C7),
40.08 (C8), 49.83 (C6), 64.31 (C3), 121.50 (CN), 112.20,
113.06, 116.59, 125.48, 126.85, 127.16, 128.72, 129.36, 131.73,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2012
Synthesis, Characterization, and In Vitro Microbial Evaluation of Some
New 4H‐Chromene and Quinoline Derivatives of 1H‐Pyrazole
1177
H5); 13C NMR (400 MHz, DMSO‐d6): 12.92 (CH3), 20.27
(C8), 26.09 (C4), 28.78 (C7), 36.89 (C6), 60.07 (C3),
120.15 (CN), 115.08, 116.31, 116.52, 118.69, 124.02,
127.55, 128.34, 129.23, 130.73, 139.84, 140.58, 147.13,
148.75, 150.16, 151.92, 152.44, 157.48, 161.73, 163.11
(aromatic carbons), 196.12 (C5); MS m/z: 591.9 [M]+, 593.7
[M+2]+; Anal. Calcd. for C29H21Cl2FN6OS: C, 58.89; H,
3.58; N, 14.21. Found: C, 59.20; H, 3.31; N, 13.99.
2‐Amino‐4‐(5‐chloro‐3‐methyl‐1‐p‐tolyl‐1H‐pyrazol‐4‐yl)‐1‐(4‐(4‐
fluorophenyl)thiazol‐2‐yl)‐5‐oxo‐1,4,5,6,7,8‐hexahydroquinoline‐
3‐carbonitrile (6i). This compound was obtained as colorless solid,
1295 mg (60%), Mp 259–261°C; IR (KBr): 3405 and 3320 (NH2),
2185 (CN), 1675 (CO); 1H NMR (400 MHz, DMSO‐d6): δ 1.96–2.25
(m, 6H, 3×CH2), 2.31 (s, 3H, pyz‐CH3), 2.35 (s, 3H, tolyl‐CH3),
4.56 (s, 1H, H4), 5.98 (s, 2H, NH2), 7.34–8.10 (m, 8H, aromatic
protons), 8.36 (s, 1H, thiazole H5); 13C NMR (400 MHz, DMSO‐
d6): 12.82 (pyz‐CH3), 21.34 (C8), 21.80 (tolyl‐CH3), 25.86 (C4),
28.99 (C7), 36.48 (C6), 59.33 (C3), 120.83 (CN), 112.06, 117.93,
118.03, 124.21, 126.46, 128.65, 129.12, 135.78, 140.51, 143.31,
147.86, 152.06, 155.87, 156.54, 158.03, 161.94, 163.15 (aromatic
carbons), 196.24 (C5); MS m/z: 571.5 [M]+, 573.5 [M+2]+; Anal.
Calcd. for C30H24ClFN6OS: C, 63.10; H, 4.24; N, 14.72. Found:
C, 62.80; H, 3.94; N, 15.08.
(s, 3H, tolyl‐CH3), 4.57 (s, 1H, H4), 5.95 (s, 2H, NH2), 7.29–7.90
(m, 8H, aromatic protons), 8.42 (s, 1H, thiazole H5); 13C NMR
(400 MHz, DMSO‐d6): 12.96 (pyz‐CH3), 21.77 (tolyl‐CH3),
25.26, 26.85 (CH3), 29.35 (C4), 32.13 (C7), 39.30 (C8), 52.93
(C6), 64.10 (C3), 121.07 (CN), 111.67, 113.54, 115.45, 119.04,
123.84, 124.24, 126.05, 140.26, 146.69, 147.88, 152.50, 153.10,
154.66, 155.37, 158.33, 163.56, 166.18 (aromatic carbons),
196.46 (C5); MS m/z: 599.6 [M]+, 601.5 [M+2]+; Anal. Calcd.
for C32H28ClFN6OS: C, 64.15; H, 4.71; N, 14.03. Found: C,
63.85; H, 5.04; N, 13.89.
Acknowledgments. The authors are thankful to Head, Department
of Chemistry, Sardar Patel University for providing 1H NMR, 13
C
NMR spectroscopy, and research facilities. They are also thankful
to Oxygen Bioresearch Pvt. Ltd., Ahmedabad, for providing mass
spectroscopy facilities, SICART, Vallabh Vidyanagar, for the FT‐
IR and elemental analysis and Dhanji P. Rajani, Microcare
Laboratory, Surat, for antimicrobial screening of the compounds
reported herein. One of the authors is grateful to UGC, New Delhi
for Research Fellowship in Sciences for Meritorious Students.
REFERENCES AND NOTES
2‐Amino‐4‐(5‐chloro‐3‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)‐1‐
(4‐(4‐fluorophenyl)thiazol‐2‐yl)‐7,7‐dimethyl‐5‐oxo‐1,4,5,6,7,8‐
hexahydroquinoline‐3‐carbonitrile (6j). This compound was
obtained as colorless solid, 1230 mg (70 %), Mp 281–283°C;
IR (KBr): 3430 and 3370 (NH2), 2200 (CN), 1695 (CO); 1H
NMR (400 MHz, DMSO‐d6): δ 0.95 (s, 3H, CH3), 1.04 (s, 3H,
CH3), 1.94–2.31 (m, 4H, 2×CH2), 2.33 (s, 3H, pyz‐CH3), 4.57
(s, 1H, H4), 6.07 (s, 2H, NH2), 7.36–8.05 (m, 9H, aromatic
protons), 8.39 (s, 1H, thiazole H5); 13C NMR (400 MHz,
DMSO‐d6): 13.03 (pyz‐CH3), 26.20, 27.05 (CH3), 28.91 (C4),
33.45 (C7), 41.84 (C8), 50.29 (C6), 62.32 (C3), 120.57 (CN),
113.19, 114.39, 118.44, 124.32, 126.93, 128.04, 129.14,
133.71, 144.53, 145.92, 153.49, 155.90, 157.76, 158.70, 158.91,
160.74, 164.62 (aromatic carbons), 195.95 (C5); MS m/z: 585.6
[M]+, 587.4 [M+2]+; Anal. Calcd. for C31H26ClFN6OS: C, 63.64;
H, 4.48; N, 14.36. Found: C, 63.82; H, 4.63; N, 14.11.
2‐Amino‐4‐(5‐chloro‐1‐(3‐chlorophenyl)‐3‐methyl‐1H‐pyrazol‐
4‐yl)‐1‐(4‐(4‐fluorophenyl)thiazol‐2‐yl)‐7,7‐dimethyl‐5‐oxo‐
1,4,5,6,7,8‐hexahydroquinoline‐3‐carbonitrile (6k). This compound
was obtained as colorless solid, 1245 mg (67%), Mp 269–270°C;
IR (KBr): 3415 and 3320 (NH2), 2205 (CN), 1680 (CO); 1H
NMR (400 MHz, DMSO‐d6): δ 0.85 (s, 3H, CH3), 0.94 (s, 3H,
CH3), 1.96–2.32 (m, 4H, 2×CH2), 2.38 (s, 3H, pyz‐CH3), 4.59
(s, 1H, H4), 6.03 (s, 2H, NH2), 7.31–8.05 (m, 8H, aromatic
protons), 8.37 (s, 1H, thiazole H5); 13C NMR (400 MHz,
DMSO‐d6): 12.85 (pyz‐CH3), 26.37, 27.73 (CH3), 29.72 (C4),
33.23 (C7), 41.69 (C8), 51.18 (C6), 60.19 (C3), 120.22 (CN),
112.21, 115.14, 118.32, 118.96, 123.67, 125.63, 128.66, 129.09,
134.56, 140.38, 142.97, 145.68, 150.75, 151.16, 152.77, 156.22,
159.79, 161.20, 163.67 (aromatic carbons), 195.72 (C5); MS m/z:
620.1 [M]+, 622.1 [M+2]+; Anal. Calcd. for C31H25Cl2FN6OS: C,
60.10; H, 4.07; N, 13.56. Found: C, 59.80; H, 3.88; N, 13.77.
2‐Amino‐4‐(5‐chloro‐3‐methyl‐1‐p‐tolyl‐1H‐pyrazol‐4‐yl)‐1‐
(4‐(4‐fluorophenyl)thiazol‐2‐yl)‐7,7‐dimethyl‐5‐oxo‐1,4,5,6,7,8‐
hexahydroquinoline‐3‐carbonitrile (6l). This compound was
obtained as colorless solid, 1115 mg (62 %), Mp 286–288°C;
IR (KBr): 3435 and 3360 (NH2), 2185 (CN), 1690 (CO); 1H
NMR (400 MHz, DMSO‐d6): δ 0.98 (s, 3H, CH3), 1.06 (s, 3H,
CH3), 1.92‐2.27 (m, 4H, 2×CH2), 2.32 (s, 3H, pyz‐CH3), 2.36
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