Microwave-assisted synthesis of novel 4H-chromene derivatives bearing phenoxypyrazole and their antimicrobial activity assessment

Article abstract of DOI:10.2298/JSC120102030S

A new series of 4H-chromene derivatives 4a-p bearing the 5-phenoxypyrazole nucleus were synthesized under microwave irradiation by the reaction of 5-phenoxypyrazole-4-carbaldehydes 1a-h, malononitrile 2 and compounds 1,3-cyclohexanedione and dimedone (3a

Full text of DOI:10.2298/JSC120102030S

J. Serb. Chem. Soc. 77 (9) 1165–1174 (2012)
JSCS–4341
UDC 547.56+547.772+546.76+542.913+
546.33–36:615.28–188
Original scientific paper
Microwave-assisted synthesis of novel 4H-chromene derivatives
bearing phenoxypyrazole and their antimicrobial
activity assessment
CHETAN B. SANGANI, NIMESH M. SHAH, MANISH P. PATEL
*
and RANJAN G. PATEL
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar-388120, Gujarat, India
(Received 2 January, revised 27 March 2012)
Abstract: A new series of 4H-chromene derivatives 4a–p bearing the 5-phe-
noxypyrazole nucleus were synthesized under microwave irradiation by the
reaction of 5-phenoxypyrazole-4-carbaldehydes 1a–h, malononitrile 2 and
compounds 1,3-cyclohexanedione and dimedone (3a and 3b, respectively) in
presence of NaOH as a basic catalyst. All the compounds were screened
against three Gram-positive bacteria (Streptococcus pneumoniae, Clostridium
tetani and Bacillus subtilis), three Gram-negative bacteria (Salmonella typhi,
Vibrio cholerae and Escherichia coli) and two fungi (Aspergillus fumigatus
and Candida albicans) using the broth microdilution minimum inhibitory con-
centration (MIC) method. The antimicrobial screening showed that the majo-
rity of the compounds were active against C. tetani and B subtilis as well as
against C. albicans when compared with standard drugs.
Keywords: phenoxypyrazole; 4H-chromene; multi-component reaction; micro-
wave irradiation; antimicrobial activity.
INTRODUCTION
The steadily increasing microbial resistance to existing first line drugs is a
serious problem in antimicrobial cure and necessitates continuing research into
1
new classes of antimicrobials. Moreover, the progression of drug-resistant strains
has contributed to the inefficiency of the straight antimicrobial therapy. This is-
sue has provoked enormous interest in antimicrobial research and it is strongly
believed that there is an urgent call for the development of new drugs with di-
vergent and unique structures and probably with an unusual mechanism of action
differing from that of existing first line drugs.
The chromene ring system is considered one of the most imperative hete-
rocycles in nature as it has the distinction of being the parent ring in countless
*Corresponding author. E-mail: patelranjanben@yahoo.com
doi: 10.2298/JSC120102030S
1165

1166
SANGANI et al.
derivatives of biological relevance. The current interest in 4H- and 2H-chromene
2
3
derivatives arises from their potential application as antimicrobial, anti-HIV,
4
5
6
7
8
antitubercular, antioxidant, anticancer, antitumor, cytotoxic agents, antidys-
lipidemic agent, antileishmanial, anti-inflammatory, anti-Helicobacter pylori
9
10
11
12
13
agent and TNF-α inhibitor. On the other hand, pyrazole derivatives are also
14–16
well-known for their biological properties, including antimicrobial,
anti-in-
15
16
flammatory (COX-2 inhibitor and ulcerogenic activity), antitubercular, anti-
tumor, anti-angiogenesis, antiparasitic, antiviral, analgesic and anxiolytic
17
18
19
20
21
activity.
Moreover, the most suitable protocol for the synthesis of functionalized or-
ganic compounds could be a multicomponent reaction (MCR) because the syn-
thesis could be performed without the isolation of the intermediates, without dis-
22
charging any functional groups and within short reaction time. . In addition, the
conventional procedures are not found to be satisfactory with regard to opera-
tional simplicity, effectiveness and yield. An alternative synthetic approach is
23
microwave irradiation. In recent years, microwave irradiation has been de-
monstrated not only to dramatically accelerate many organic reactions, but also
to improve yields and selectivity.
Thus, in view of biological significance of 4H-chromene, a modification on
the 4-position on pyrane by 5-phenoxypyrazole was undertaken to check whether
it may bring significant changes in the bioactivities of 4H-chromene derivatives.
As a part of current studies in developing new antimicrobial agents via combi-
24
nation of two therapeutically active moieties, the synthesis of 4H-chromene
derivatives 4a–p by MCR are reported herein.
1
All the compounds were characterized using elemental analysis, FT-IR, H-
13
-NMR and C-NMR spectroscopy, and the molecular weights of some selected
compounds were confirmed by mass spectroscopy. All compounds were screened
for in vitro antimicrobial activity against eight human pathogens, i.e., three
Gram-positive bacteria (Streptococcus pneumoniae, Clostridium tetani and Ba-
cillus subtilis), three Gram-negative bacteria (Salmonella typhi, Vibrio cholera
and Escherichia coli) and two fungal pathogens (Aspergillus fumigates and
Candida albicans) using the broth microdilution minimum inhibitory concen-
25
tration (MIC) method.
RESULTS AND DISCUSSION
Chemistry
The key intermediates, 3-methyl-5-aryloxy-1-aryl-1H-pyrazole-4-carbalde-
hydes 1a–h were prepared by refluxing 1-aryl-5-chloro-3-methyl-1H-pyrazole-4-
carbaldehyde and various phenols in the presence of anhydrous potassium car-
24a
bonate in dry dimethylformamide (DMF) for 3.5 h.
The required 1-aryl-5-

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 4H-CHROMENE
1167
-chloro-3-methyl-1H-pyrazole-4-carbaldehyde was prepared by the Vilsmeier–
26
–Haack reaction according to a literature procedure.
In the present study, 4H-chromene derivatives 4a–p were synthesized in
moderate to good yield, i.e., 68–90 %, by reaction of 1a–h, malononitrile 2 and
compounds 3a–b under microwave irradiation in the presence of NaOH as a
basic catalyst (Scheme 1).
Comp.
R1
R2
R3 Yielda, % Comp.
R1
R2
R3
Yielda, %
4a
4b
4c
4d
4e
4f
H
H
H
H
CH3
OCH3
Cl
H
H
H
H
H
H
H
H
78
90
84
69
80
84
72
64
4i
4j
4k
4l
4m
4n
4o
4p
H
H
H
H
CH3
OCH3
Cl
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
90
75
87
65
88
90
92
73
H
H
CH3
CH3
CH3
CH3
H
CH3
CH3
CH3
CH3
H
CH3
OCH3
Cl
CH3
OCH3
Cl
4g
4h
aAll yields are isolated yields
Scheme 1. Synthetic pathway for the synthesis of 4H-chromene derivatives
bearing the phenoxypyrazole core 4a–p.
In convenient electrochemical processes, organic basic catalysts, such as
piperidine and triethylamine, were used in the synthesis of many 4H-chromene
27
derivatives but in the present study, NaOH was used as the basic catalyst to
avoid the employment of hazardous organic bases. Furthermore, during attempts
to synthesize the title compounds by the conventional method, some shortco-
mings in this method were observed, such as longer reaction time, drastic reac-

1168
SANGANI et al.
tion conditions and poor yield. Consequently, to overcome these drawbacks, the
microwave irradiation method was used in the present study for the synthesis of
28
title compounds. In accordance with the mechanism suggested in literature, the
first step of this process may involve Knoevenagel condensation of the aldehyde
and malononitrile to gives heterylidenenitrile derivatives, which was followed by
Michael addition of 3a–b to the heterylidenenitrile to afford the title compounds
4a–p (Scheme 2).
Scheme 2. Plausible mechanistic pathway of the synthesis of 4H-chromene derivatives 4a–p.
The structures of all the newly synthesized compounds were confirmed by
1
13
FTIR, H-NMR, C-NMR and mass spectroscopy, and elemental analysis. The
physical, analytical and spectral data of all the synthesized compounds 4a–p are
given in the Supplementary material to this paper. The IR spectrum of title com-
pounds 4a–p revealed the presence of amino, cyano, carbonyl and ether groups
through the appearance of absorption bands at around 3370–3430, 3170–3350,
–1
1
2190–2220, 1630–1710 and 1190–1230 cm , respectively. Their H-NMR spec-
tra indicated the presence of a singlet in the range δ 4.12–4.38 ppm of the CH
proton and the disappearance of a singlet at δ 9.57–9.63 ppm of –CHO, which
clearly confirmed the cyclization of the Knoevenagel intermediates. Moreover,
multiplets in the range δ 6.59–7.55 ppm appeared for aromatic protons. In the
13
C-NMR spectral data of the title compounds 4a–p, most characteristic signal
around δ 24.50–25.25 ppm indicate the formation of the pyrane ring. The signal
at around δ 56.20–60.64 ppm is assigned to carbon attached to carbonitrile, while
signals around δ 110.20–164.50 and 196.10–196.35 ppm are attributed to all the

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 4H-CHROMENE
1169
aromatic and carbonyl carbons, respectively, of compounds 4a–p. The obtained
elemental analysis values are in good agreement with theoretical data. Further-
more, the molecular weight of selected compounds, i.e., 4c, 4i and 4o, were con-
firmed by mass spectral studies. The mass spectra of these compounds showed a
+
molecular ion peak [M+1] corresponding to the exact theoretical mass.
Biological evaluation
All the compounds were screened for their antibacterial and antifungal ac-
tivity and the results are presented in Table I, expressed in the form of MIC in μg
–1
mL .
TABLE I. Antimicrobial activity of compounds 4a–p (minimum inhibitory concentration
(MIC), µg mL-1); Bs.: B. subtilis; Ct.: C. tetani; Sp.: S. pneumoniae; Ec.: E. coli; St.: S. typhi;
Vc.: V. cholerae; Af.: A. fumigatus; Ca.: C. albicans; MTCC: microbial type culture collec-
tion; A: ampicillin; B: ciprofloxacin; C: norfloxacin; D: chloramphenicol; E: nystatin; F:
griseofulvin. “–“ represents “not tested”
Gram-positive bacteria
Bs. Ct. Sp.
MTCC MTCC MTCC MTCC MTCC MTCC MTCC MTCC
Gram-negative bacteria
Ec. St. Vc.
Fungal species
Af. Ca.
Compound
441
500
250
500
1000
250
500
500
500
250
500
500
250
500
62.5
500
250
250
50
449
500
500
500
100
200
200
250
200
500
100
250
200
500
100
100
250
250
100
50
1936
500
250
500
500
250
500
500
500
250
500
500
250
50
443
250
500
200
250
500
250
250
100
100
250
500
250
250
100
200
100
100
25
98
500
500
500
500
250
250
500
500
100
62.5
500
250
500
62.5
500
62.5
100
25
3906
500
100
500
200
200
200
100
250
250
250
200
200
500
200
200
250
100
25
3008
>1000 >1000
227
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
A
500
250
250
500
500
500
250
1000
1000
500
500
1000
500
250
100
250
500
200
250
500
1000
250
250
500
250
500
500
100
50
>1000 >1000
500
250
–
–
–
500
250
–
–
–
B
C
D
100
50
10
50
10
50
10
50
10
50
50
–
–
E
F
–
–
–
–
–
–
–
–
–
–
–
–
100
100
100
500
An examination of the data prescribed in Table I revealed that many of the
compounds were more potent or equipotent to the standard drugs against the
Gram-positive bacteria C. tetani and a few against S. pneumoniae and B. subtilis.

1170
SANGANI et al.
Against the Gram-positive bacteria B. subtilis, compound 4n (MIC = 62.5 μg
–1
mL ) was found to be more potent, whereas 4b, 4e, 4i, 4l, and 4p (MIC = 250
–1
–1
μg mL ) shows comparable activity to ampicillin (MIC = 250 μg mL ).
–1
Moreover, compound 4n (MIC = 62.5 µg mL ) was found to more active as
compared to norfloxacin (MIC = 100 µg mL ). Against C. tetani, compounds
4d, 4j, 4n and 4o (MIC = 100 μg/mL), and 4e, 4f, 4h and 4l (MIC = 200 μg mL )
were found to be more potent, whereas 4g, 4k and 4p (MIC = 250 μg mL )
showed comparable activity to ampicillin (MIC = 250 μg mL ), while com-
pounds 4d, 4j, 4n and 4o (MIC = 100 µg mL ) were equally potent as compared
to ciprofloxacin (MIC = 100 µg mL ). Against S. pneumoniae, compound 4m
(MIC = 50 μg mL ) showed comparable activity to chlormphenicol and cip-
–1
–1
–1
–1
–1
–1
–1
–1
rofloxacin (MIC = 50 µg mL ).
Towards the Gram-negative strain E. coli, compounds 4h, 4i, 4n and 4p
–1
(MIC = 100 μg mL ) showed comparable activity to ampicillin (MIC = 100 μg
–1
–1
mL ). Compounds 4j, 4n and 4p (MIC = 62.5 μg mL ) were more potent,
–1
whereas 4i (MIC = 100 μg mL ) showed comparable activity to ampicillin (MIC
= 100 μg mL ) towards S. typhi. Also the compounds 4b and 4g (MIC = 100
–1
μg/mL) show comparable activity, to ampicillin (MIC=100 μg/mL) towards V.
cholerae.
Comparison of the data for compounds 4a–d with those for 4e–h showed
that on replacement of H with CH , the poorly active compounds 4a, 4b and 4c
3
–1
(MIC = 500 μg mL against C. tetani) were converted to the highly potent 4e, 4f
and 4g, respectively, while the potency of compound 4d, where R = Cl, against
2
C. tetani decreased on introduction of CH at R . Against B. subtilis, comparing
3
1
compound 4f with 4n, it was observed that the poorly active compound 4f (MIC
–1
–1
= 500 μg mL ) led to the excellent activity of 4n (MIC = 62.5 μg mL ), com-
pared to the activity of ampicillin and norfloxacin. Similarly, against the Gram-
negative bacteria S. typhi, it was observed by comparing compound 4b with 4j
and 4f with 4n, that poorly active compounds were converted to highly active
–1
–1
ones (MIC = 62.5 μg mL ) as compared with ampicillin (MIC = 100 μg mL ),
i.e., the compound having a gem dimethyl group on the benzopyran ring showed
increased antibacterial activity.
Against fungal pathogen C. albicans, compounds 4d (MIC = 100 μg mL ),
4g (MIC = 200 μg mL ) 4c, 4e, 4h, 4k, 4l and 4p (MIC = 250 μg mL ) showed
good to excellent activity, whereas 4b, 4f, 4i, 4m and 4o (MIC = 500 μg mL )
were equipotent to griseofulvin (MIC = 500 μg mL ). Compound 4d (MIC =100
μg mL ) was found equipotent to nystatin towards C. albicans.
–1
–1
–1
–1
–1
–1
The remaining compounds showed moderate to good activity in the inhibi-
tion of the growth of bacterial pathogens and were all less effective than the
standard drugs. From the antimicrobial study of the title derivatives, it is inte-

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 4H-CHROMENE
1171
resting to note that a minor alteration in the molecular structure of the inves-
tigated compounds may have a pronounced effect on antimicrobial activity.
EXPERIMENTAL
Materials, instruments and methods
The required chemicals were obtained from S. D. Fine Chem Ltd., Vadodara, Gujarat,
India. 1,3-Cyclohexanedione and dimedone were obtained from Sigma-Aldrich. The solvents
were purified and dried before use. The microwave assisted reactions were conducted in a
“RAGA modified electromagnetic microwave system”, whereby the microwaves were gene-
rated by a magnetron at a frequency of 2450 MHz having adjustable output power levels, i.e.,
10 levels from 140 to 700 W and with an individual sensor for temperature control (fiber optic
was used as an individual sensor for temperature control). A reflux condenser was attached to
the reaction flask and the reactions were performed under constant stirring (thus avoiding the
risk of high pressure development). All melting points were taken in open capillaries and are
uncorrected. Thin-layer chromatography (TLC, on aluminium plates pre-coated with silica
gel, 60 F254, 0.25 mm thickness) (Merck, Darmstadt, Germany) was used for monitoring the
progress of all reactions, and the purity and homogeneity of the synthesized compounds. UV
radiation and/or iodine were used as the visualizing agents. Elemental analysis (% C, H, N)
was realized using a Perkin-Elmer 2400 Series-II elemental analyzer (Perkin-Elmer, USA)
and the results for all compounds were within ±0.4 % of the theoretical values. The IR spectra
were recorded in KBr on a Perkin-Elmer Spectrum GX FT-IR spectrophotometer (Perkin-
1
Elmer, USA) and only the characteristic peaks are reported in cm-1. The H-NMR and 13C-
-NMR spectra were recorded at 400 and 100 MHz, respectively, in DMSO-d6 on a Bruker
Avance 400F spectrometer (Bruker Scientific Corporation Ltd., Switzerland) using the solvent
peak as internal standard. Chemical shifts are reported in parts per million (ppm). Mass
spectra were scanned on a Shimadzu LCMS 2010 spectrometer.
Conventional synthesis of compounds 4a–p
Phenoxypyrazole-4-carbaldehyde 1a–h (10 mmol), malononitrile 2 (10 mmol) and 1,3-
-cyclohexanedione/dimedone 3a–b (10 mmol) were thoroughly mixed in ethanolic NaOH (5
mmol, 10 mL) and charged into a round bottom flask. Then the reaction mixture was refluxed
for 3–3.5 h. Completion of the reaction was monitored by TLC. The solid product 4a–p that
separated was filtered off, washed well with ethanol (10 mL), dried and crystallized from
chloroform to obtain the pure solid sample 4a–p.
Microwave-induced synthesis of compounds 4a–p
Phenoxypyrazole-4-carbaldehyde 1a–h (10 mmol), malononitrile 2 (10 mmol) and 1,3-
-cyclohexanedione/dimedone 3a–b (10 mmol) were thoroughly mixed in ethanolic NaOH (5
mmol, 10 mL) and irradiated in microwave oven at 350 W (50 % of the maximum output
power) for 140–170 s. After completion of the reaction (checked by TLC), the solution was
cooled to room temperature, the separated solid was filtered, washed well with ethanol (10
mL), dried and crystallized from chloroform to obtain the pure solid samples 4a–p.
CONCLUSIONS
A series of some new 4H-chromene derivatives 4a–p bearing the phenolxy-
pyrazole nuclei were synthesized through a facile one-pot multicomponent re-
action under microwave irradiation. This synthetic strategy allowed the construc-

1172
SANGANI et al.
tion of a relatively complicated nitrogen- and oxygen-containing heterocyclic
system, as well as the introduction of various aromatic and heteroaromatic sub-
stituents at the 4-position of pyrane. From the studied compounds, it was noticed
that the most effective antibacterial members had a methyl group on the N-phenyl
ring of the pyrazole moiety as well as a gem dimethyl group on the benzopyrane
ring with either Cl or methyl substituent on the O-phenyl ring of the pyrazole
moiety. The antifungal activity of the compounds shows that most of the com-
pounds were more potent against C. albicans than against A. fumigatus. It is
worth mentioning that minor changes in the molecular configuration of these
compounds profoundly influenced the activity. The present study throws light on
the identification of this new structural class as antimicrobials, which could be of
interest for further detailed preclinical investigations.
SUPPLEMENTARY MATERIAL
Analytical, physical and spectroscopic data of the synthesized compounds are available
electronically from http://www.shd.org.rs/JSCS/, or from the corresponding author on request.
Acknowledgements. The authors are thankful to Department of Chemistry, Sardar Patel
1
University, India, for providing the H-NMR and 13C-NMR spectroscopy and research fa-
cilities. Mr. C. B. Sangani is grateful to UGC, New Delhi for a Research Fellowship in Sci-
ences for Meritorious Students.
И З В О Д
СИНТЕЗА НОВИХ ДЕРИВАТА ФЕНОКСИПИРАЗИНИЛ-4H-ХРОМЕНА ПОД
УСЛОВИМА ЗРАЧЕЊА МИКРОТАЛАСИМА И ОДРЕЂИВАЊЕ ЊИХОВЕ
АНТИМИКРОБНЕ АКТИВНОСТИ
CHETAN B. SANGANI, NIMESH M. SHAH, MANISH P. PATEL и RANJAN G. PATEL
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar-388120, Gujarat, India
Нова серија деривата 4H-хромена 4a–p који садрже 5-феноксипиразол синтети-
сани су под условима озрачивања микроталасима, реакцијом 5-феноксипиразол-4-карб-
алдехида 1a–h, малононитрила 2 и једињења (1,3-циклохександион, димедон) 3a–b у
присуству NaOH или базних катализатора. Свим једињењима испитана је активност
према 3 врсте грам-позитивних бактерија (Streptococcus pneumoniae, Clostridium tetani и
Bacillus subtilis), 3 врсте грам-негативних (Salmonella typhi, Vibrio cholerae и Escherichia
coli) и две врсте гљива (Aspergillus fumigatus и Candida albicans) користећи поступке
одређивања МИК (минимална инхибиторна концентрација разблажењем). Током испи-
тивања антимикробне активности утврђено је да су једињења активна према C. tetani и B.
subtilis, као и према C. albicans у поређењу са вредностима стандардних лекова.
(Примљено 2. јануара, ревидирано 27. марта 2012)
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