Synthesis and antimicrobial screening of pyrano[3,2-c]chromene derivatives of 1H-pyrazoles

Article abstract of DOI:10.2478/s11532-011-0041-7

A new series of twenty four derivatives of pyrano[3,2-c]chromene IVa-x bearing 1H-pyrazole were synthesized by a one pot, base-catalyzed cyclocondensation reaction of 1H-pyrazole-4-carbaldehyde Ia-l, malononitrile II and 4-hydroxycoumarin IIIa-b. All the synthesized compounds were characterized by elemental analysis, FT-IR, ¹H NMR and ¹³C NMR spectral data. All the synthesized compounds were screened against six bacterial pathogens, namely B. subtilis, C. tetani, S. pneumoniae, S. typhi, V. cholerae, E. coli and for antifungal activity against two fungal pathogens, A. fumigatus and C. albicans using the broth microdilution MIC method. Some of the compounds were found to be equipotent or more potent than commercial drugs against most of employed strains, as evident from the screening data. Versita Sp. z o.o.

Full text of DOI:10.2478/s11532-011-0041-7

Cent. Eur. J. Chem. • 9(4) • 2011 • 635-647
DOI: 10.2478/s11532-011-0041-7
Central European Journal of Chemistry
Synthesis and antimicrobial screening
of pyrano[3,2-c]chromene derivatives
of 1H-pyrazoles
Research Article
Chetan B. Sangani, Divyesh C. Mungra, Manish P. Patel, Ranjan G. Patel*
Department of Chemistry, Sardar Patel University,
Vallabh Vidyanagar-388120, Gujarat, India
Received 20 January 2011; Accepted 10 March 2011
Abstract:
A new series of twenty four derivatives of pyrano[3,2-c]chromene IVa-x bearing 1H-pyrazole were synthesized by a one pot,
base-catalyzed cyclocondensation reaction of 1H-pyrazole-4-carbaldehyde Ia-l, malononitrile II and 4-hydroxycoumarin IIIa-b.
All the synthesized compounds were characterized by elemental analysis, FT-IR, 1H NMR and 13C NMR spectral data.
All the synthesized compounds were screened against six bacterial pathogens, namely B. subtilis, C. tetani, S. pneumoniae, S. typhi,
V. cholerae, E. coli and for antifungal activity against two fungal pathogens, A. fumigatus and C. albicans using the broth microdilution
MIC method. Some of the compounds were found to be equipotent or more potent than commercial drugs against most of employed
strains, as evident from the screening data.
Keywords: Chromene • MCR • Pyrazole-4-carbaldehyde • Antimicrobial activity
© Versita Sp. z o.o.
1. Introduction
the 4H-pyrano[3,2-c]chromene nucleus is
a fertile
source of biologically important molecules possessing
a wide spectrum of pharmacological activities, such
as antimicrobial [11], antiviral [12], mutagenicity [13],
antiproliferative [14], sex pheromone [15], antitumor [16],
cancer therapy [17] and central nervous system activity
[18].
The steadily increasing microbial resistance to existing
first drugs is a serious problem in antimicrobial cure
and necessitates continuing research into new classes
of antimicrobials [1]. Moreover, the progression of drug-
resistant strains has contributed to the inefficiency of
antimicrobial therapy. This has led to enormous interest
in antibacterial research, and we strongly believe that
there is an urgent call for development of new drugs
with diverse and unique structures and with novel
mechanisms of action from that of existing first line
drugs. Consequently, this area of research is significant
and attracts much attention of an increasing number of
medicinal chemists.
Recently, we have been particularly interested
in the synthesis of N-arylpyrazole and 4H-chromene
incorporating structures for antimicrobial evaluation
[2] on the premise that N-arylpyrazole is a chemically
useful synthon bearing diverse biological activities like
antimicrobial [3-5], anti-inflammatory (COX-2 inhibitor
and ulcerogenic activity) [4], antitubercular [5], antitumor
[6,7], antiangiogenesis [7], anti-parasitic [8], antiviral
[9], analgesic and anxiolytic activity [10]. Moreover,
Despite their importance from pharmacological and
synthetic point of views, comparatively few modified
methods for the preparation of 4-aryl-4H-pyrano[3,2-c]
chromene derivatives [19] have been reported using
piperidine, morpholine, K2CO3, diammonium hydrogen
phosphate, H6[P2W18O62]•18H2O, tetrabutylammonium
bromide or water using various aromatic/heterocyclic
aldehydes, wherein not a single reference have been
found where 3-methyl-5-aryloxy-1-aryl-1H-pyrazole-
4-carbaldehyde is used. Thus, in view of the biological
significance of 4H-chromene, a modification of the
4-position on 4H-pyrano[3,2-c]chromene by 3-methyl-
5-phenoxy-1-phenyl-1H-pyrazole is undertaken to
check whether it may bring significant changes in the
bioactivities of 4H-chromene derivatives. As a part of our
current studies in developing new antimicrobial agents
via combination of two therapeutically active moieties
* E-mail: patelranjanben@yahoo.com
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Synthesis and antimicrobial screening
of pyrano[3,2-c]chromene derivatives of 1H-pyrazoles
[20], we have prepared and report herein pyrano[3,2-c]
chromene IVa-x derivatives via MCR approach. The
identity of all the products was confirmed using elemental
analysis, FT-IR, 1H NMR and 13C NMR spectrometry. The
compounds were subjected to an in vitro antimicrobial
screening against a representative panel of eight human
pathogens, of which three Gram-positive bacterial
pathogens Streptococcus pneumoniae, Clostridium
tetani, Bacillus subtilis, three Gram-negative bacterial
pathogensSalmonellatyphi,Vibriocholerae,Escherichia
coli and two fungal pathogens Aspergillus fumigatus
and Candida albicans, using broth microdilution MIC
(Minimum Inhibitory Concentration) method [21].
2.3. General procedure for the synthesis
of 3-methyl-5-aryloxy-1-aryl-1H-pyrazole-
4-carbaldehyde(Ia-l)
3-Methyl-5-aryloxy-1-aryl-1H-pyrazole-4-carbaldehydes
Ia-l were prepared, according to literature procedure
[23], by nucleophilic reaction of 1-Aryl-5-chloro-3-methyl-
1H-pyrazole-4-carbaldehyde and the respective phenol
in presence of basic catalyst (K2CO3) (Scheme 1).
2.4.
General procedure for the synthesis
of 4-hydroxy-6-substituted-2H-chromen-
2-one(IIIa-b)
4-Hydroxy-6-(substituted)-2H-chromen-2-one
was
synthesized, according to literature procedure [24] by
the solid phase reaction of malonic acid and phenol
in phosphorous oxychloride in the presence of zinc
chloride (Scheme 1).
2. Experimental Procedure
2.1. Chemistry
Solvents used were of analytical grade. Phenyl
hydrazine was distilled before used; all other reagents
were commercially available and used without further
purification.Allmeltingpointsweretakeninopencapillaries
and are uncorrected. Thin-layer chromatography (TLC,
2.5.
General procedure for the synthesis
of 2-amino-9-(un)substituted-4-(5-(4-
(un)substitutedaryloxy)-1-(3/4-(un)
substitutedaryl)-3-methyl-1H-pyrazol-
4-yl)-5-oxo-4,5-dihydropyrano[3,2-c]
chromene-3-carbonitrile(IVa-x)
on aluminium plates precoated with silica gel, 60F254
,
0.25 mm thickness) (Merck, Darmstadt, Germany)
was used for monitoring the progress of all reactions,
purity and homogeneity of the synthesized compounds;
eluent-hexane:ethyl acetale 6:4. UV radiation and/or
iodine were used as the visualizing agents. Elemental
analysis (% C, H, N) was carried out by a Perkin-Elmer
2400 series-II elemental analyzer (Perkin-Elmer, USA)
and all compounds were within ±0.4% of calculation.
The IR spectra were recorded in KBr on a Perkin-Elmer
Spectrum GX FT-IR Spectrophotometer (Perkin-Elmer,
USA), and only the characteristic peaks were reported
in cm-1. 1H-NMR and 13C-NMR spectra were recorded in
DMSO- d6 on a BrukerAvance 400F (MHz) spectrometer
(Bruker Scientific Corporation Ltd., Switzerland)
using solvent peak as internal standard at 400 MHz
and 100 MHz respectively. Chemical shifts were reported
in parts per million (ppm). Mass spectra were scanned
on a Shimadzu LCMS 2010 spectrometer (Shimadzu,
Tokyo, Japan).
Amixtureoftheappropriate1H-pyrazole-4-carbaldehyde
Ia-l (30 mmol), malononitrile II (30 mmol) and 4-hydroxy
coumarin IIIa-b (30 mmol) in ethanol (20 mL) containing a
catalytic amount of piperidine was stirred and refluxed for
1-1.5 h. Upon completion of the reaction as determined
by TLC (ethyl acetate:hexane::1:1), the reaction mixture
was cooled to room temperature. The solid separated
was filtered and washed with ethanol to obtain the pure
compoundsIVa-x. Physical, analyticalandspectroscopic
characterization data of the synthesized compounds Ia-l
and IVa-x are given below:
2.6. Spectral data of compounds Ia-l and IVa-x
3-Methyl-5-phenoxy-1-phenyl-1H-pyrazole-4-
carbaldehyde (Ia): Yield: 92%; m.p.: 115-116 °C; IR
(KBr, ν, cm-1): 2995 (ArC-H str.), 1695 (-C=O str.), 1200
(C-O-C ether str.); 1H NMR (400 MHz, DMSO-d6) δH
(ppm): 2.57 (s, 3H, CH3), 7.03-7.62 (m, 10H, Ar-H), 9.62
(S, 1H, CHO). 13C NMR (100 MHz, DMSO-d6) δC (ppm):
14.56 (Ar-CH3), 108.92, 116.21, 122.81, 124.65, 128.01,
129.24, 130.25, 136.90, 150.83, 152.52, 157.04 (Ar-C),
2.2. General procedure for the synthesis
of 1-aryl-5-chloro-3-methyl-1H-pyrazole-
4-carbaldehyde
1-Aryl-5-chloro-3-methyl-1H-pyrazole-4-carbaldehydes 183.09 (C=O); Anal. Calcd. for C17H14N2O2 (279.31 gm/
were prepared, according to literature procedure [22], by mole): C, 73.37; H, 5.07; N, 10.07%. Found: C, 73.43;
Vilsmeier-Haack reaction of 3-methyl-1-aryl-1H-pyrazol- H, 5.22; N, 10.13%.
5(4H)-one (Scheme 1).
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C. B. Sangani et al.
3-Methyl-5-(4-methylphenoxy)-1-phenyl-1H- (-C=O str.), 1210 (C-O-C ether str.); 1H NMR (400 MHz,
pyrazole-4-carbaldehyde (Ib): Yield: 82%; m.p.: DMSO-d6) δH (ppm): 2.27 (s, 3H, CH3), 2.42 (s, 3H,
124-126 °C; IR (KBr, ν, cm-1): 3005 (ArC-H str.), 1715 CH3), 7.01-7.70 (m, 9H, Ar-H), 9.62 (S, 1H, CHO). 13C
(-C=O str.), 1205 (C-O-C ether str.); 1H NMR (400 MHz, NMR (100 MHz, DMSO-d6) δC (ppm): 14.19, 20.79 (Ar-
DMSO-d6) δH (ppm): 1.98 (s, 3H, CH3), 2.42 (s, 3H, CH3), 108.87, 116.32, 122.45, 124.55, 128.23, 129.34,
CH3), 7.08-7.67 (m, 9H, Ar-H), 9.60 (S, 1H, CHO). 13C 130.67, 136.88, 150.87, 152.61, 157.06 (Ar-C), 184.25
NMR (100 MHz, DMSO-d6) δC (ppm): 14.35, 20.43 (Ar- (C=O); Anal. Calcd. for C18H16N2O2 (292.33 gm/mole):
CH3), 108.77, 116.33, 123.02, 124.44, 127.97, 129.25, C, 73.95; H, 5.52; N, 9.58%. Found: C, 74.14; H, 5.36;
130.63, 137.01, 150.78, 152.64, 157.06 (Ar-C), 182.27 N, 9.64%.
(C=O); Anal. Calcd. for C18H16N2O2 (292.33 gm/mole):
C, 73.95; H, 5.52; N, 9.58%. Found: C, 74.05; H, 5.45; methylphenyl)-1H-pyrazole-4-carbaldehyde
N, 9.37%.
Yield: 93%; m.p.: 127-128 °C; IR (KBr, ν, cm-1): 2955
3 - M e t h y l - 5 - ( 4 - m e t h y l p h e n o x y ) - 1 - ( 4 -
(If):
3-Methyl-5-(4-chlorophenoxy)-1-phenyl-1H- (ArC-H str.), 1730 (-C=O str.), 1205 (C-O-C ether str.);
pyrazole-4-carbaldehyde (Ic): Yield: 88%; m.p.: 118- 1H NMR (400 MHz, DMSO-d6) δH (ppm): 2.10 (s, 3H,
119 °C; IR (KBr, ν, cm-1): 2975 (ArC-H str.), 1690 (-C=O CH3), 2.35 (s, 3H, CH3), 2.38 (s, 3H, CH3), 7.09-7.72
str.), 1200 (C-O-C ether str.);1H NMR (400 MHz, DMSO- (m, 8H, Ar-H), 9.60 (S, 1H, CHO). 13C NMR (100 MHz,
d6) δH (ppm): 2.18 (s, 3H, CH3), 6.95-7.52 (m, 9H, Ar-H), DMSO-d6) δC (ppm): 14.60, 20.28, 20.80 (Ar-CH3),
9.57 (S, 1H, CHO). 13C NMR (100 MHz, DMSO-d6) δC 108.99, 115.93, 122.81, 124.67, 128.08, 129.87, 131.03,
(ppm): 14.08 (Ar-CH3), 108.90, 116.33, 122.67, 124.42, 137.05, 150.64, 152.67, 157.13 (Ar-C), 184.45 (C=O);
128.03, 129.54, 130.33, 137.05, 150.73, 152.58, 157.09 Anal. Calcd. for C19H18N2O2 (306.36 gm/mole): C, 74.49;
(Ar-C), 182.01 (C=O); Anal. Calcd. for C17H13ClN2O2 H, 5.92; N, 9.14%. Found: C, 74.52; H, 6.16; N, 9.01%.
(312.75 gm/mole): C, 65.29; H, 4.19; N, 8.96%. Found:
C, 65.38; H, 4.27; N, 9.15%.
3 - M e t h y l - 5 - ( 4 - c h l o r o p h e n o x y ) - 1 - ( 4 -
methylphenyl)-1H-pyrazole-4-carbaldehyde (Ig):
3-Methyl-5-(4-methoxyphenoxy)-1-phenyl-1H- Yield: 85%; m.p.: 110-111 °C; IR (KBr, ν, cm-1): 3010
pyrazole-4-carbaldehyde (Id): Yield: 95%; m.p.: 148- (ArC-H str.), 1715 (-C=O str.), 1210 (C-O-C ether str.);
150 °C; IR (KBr, ν, cm-1): 3020 (ArC-H str.), 1720 (-C=O 1H NMR (400 MHz, DMSO-d6) δH (ppm): 2.19 (s, 3H,
str.), 1195 (C-O-C ether str.);1H NMR (400 MHz, DMSO- CH3), 2.40 (s, 3H, CH3), 7.03-7.63 (m, 8H, Ar-H), 9.59
d6) δH (ppm): 1.82 (s, 3H, CH3), 3.37 (s, 3H, OCH3), (S, 1H, CHO). 13C NMR (100 MHz, DMSO-d6) δC (ppm):
6.92-7.54 (m, 9H, Ar-H), 9.58 (S, 1H, CHO). 13C NMR 14.40, 20.82 (Ar-CH3), 108.66, 116.86, 122.67, 124.34,
(100 MHz, DMSO-d6) δC (ppm): 14.37 (Ar-CH3), 54.15 128.22, 129.44, 130.65, 137.17, 151.05, 153.02, 157.01
(Ar-OCH3), 108.88, 116.33, 122.87, 124.84, 128.09, (Ar-C), 183.92 (C=O); Anal. Calcd. for C18H15ClN2O2
129.33, 130.26, 137.03, 151.03, 152.55, 157.09 (Ar-C), (326.78 gm/mole): C, 66.16; H, 4.63; N, 8.57%. Found:
183.88 (C=O); Anal. Calcd. for C18H16N2O3 (308.33 gm/ C, 66.35; H, 4.43; N, 8.33%.
mole): C, 70.12; H, 5.23; N, 9.09%. Found: C, 70.27; H,
5.18; N, 8.93%.
3-Methyl-5-(4-methoxyphenoxy)-1-(4-
methylphenyl)-1H-pyrazole-4-carbaldehyde (Ih):
3-Methyl-5-phenoxy-1-(4-methylphenyl)-1H- Yield: 79%; m.p.: 147-148 °C; IR (KBr, ν, cm-1): 2990
pyrazole-4-carbaldehyde (Ie): Yield: 78%; m.p.: (ArC-H str.), 1695 (-C=O str.), 1210 (C-O-C ether str.);
132-134 °C; IR (KBr, ν, cm-1): 3025 (ArC-H str.), 1705 1H NMR (400 MHz, DMSO-d6) δH (ppm): 2.30 (s, 3H,
Scheme 1. Synthetic pathway for the compounds Ia-l and IIIa-b.
637

Synthesis and antimicrobial screening
of pyrano[3,2-c]chromene derivatives of 1H-pyrazoles
CH3), 2.34 (s, 3H, CH3), 3.42 (s, 3H, OCH3), 6.94-7.65 (C=O); Anal. Calcd. for C18H15ClN2O3 (342.78 gm/mole):
(m, 8H, Ar-H), 9.63 (S, 1H, CHO). 13C NMR (100 MHz, C, 63.07; H, 4.41; N, 8.17%. Found: C, 63.28; H, 4.13;
DMSO-d6) δC (ppm): 14.22, 20.80 (Ar-CH3), 54.85 (Ar- N, 8.28%.
OCH3), 108.97, 116.90, 123.05, 124.52, 128.14, 129.29,
2-Amino-4-(3-methyl-5-phenoxy-1-phenyl-
130.41, 137.04, 150.57, 152.88, 157.15 (Ar-C), 183.07 1H-pyrazol-4-yl)-5-oxo-4,5-dihydropyrano[3,2-c]
(C=O); Anal. Calcd. for C19H18N2O3 (322.36 gm/mole): chromene-3-carbonitrile (IVa): Yield: 80%; m.p.: 250-
C, 70.79; H, 5.63; N, 8.69%. Found: C, 70.94; H, 5.44; 251 °C; IR (KBr, ν, cm-1): 3380 & 3170 (asym. & sym.
N, 8.78%.
str. of -NH2), 2205 (-C≡N str.), 1700 (-C=O str.);1H NMR
3-Methyl-5-phenoxy-1-(3-chlorophenyl)-1H- (400 MHz, DMSO-d6) δH (ppm): 1.88 (s, 3H, CH3), 4.42
pyrazole-4-carbaldehyde (Ii): Yield: 77%; m.p.: 153- (s, 1H, H4), 6.38-7.54 (m, 16H, NH2+Ar-H). 13C NMR
155 °C; IR (KBr, ν, cm-1): 3015 (ArC-H str.), 1700 (-C=O (100 MHz, DMSO-d6) δC (ppm): 13.07 (Ar-CH3), 26.50
str.), 1195 (C-O-C ether str.);1H NMR (400 MHz, DMSO- (C4), 56.16 (C-CN), 103.08, 110.21, 112.48, 114.25,
d6) δH (ppm): 2.45 (s, 3H, CH3), 6.90-7.68 (m, 9H, Ar-H), 116.86, 119.57, 120.94, 122.55, 124.40, 126.95, 129.31,
9.56 (S, 1H, CHO). 13C NMR (100 MHz, DMSO-d6) δC 130.21, 132.18, 132.88, 137.86, 146.03, 148.39, 152.16,
(ppm): 14.18 (Ar-CH3), 108.88, 116.33, 119.22, 121.99, 153.43, 153.89, 158.48 (Ar-C), 160.11 (C=O); Anal.
123.89, 127.84, 129.42, 130.25, 137.03, 142.57, 150.81, Calcd. for C29H20N4O4 (488.49 gm/mole): C, 71.30; H,
151.92, 157.07 (Ar-C), 183.14 (C=O); Anal. Calcd. for 4.13; N, 11.47%. Found: C, 71.52; H, 4.36; N, 11.22%.
C17H13ClN2O2 (312.75 gm/mole): C, 65.29; H, 4.19; N,
8.96%. Found: C, 65.40; H, 4.05; N, 9.16%.
2 - A m i n o - 4 - ( 3 - m e t h y l - 1 - p h e n y l - 5 - ( 4 -
methylphenoxy)-1H-pyrazol-4-yl)-5-oxo-4,5-
3-Methyl-5-(4-methylphenyloxy)-1-(3- dihydropyrano[3,2-c]chromene-3-carbonitrile (IVb):
chlorophenyl)-1H-pyrazole-4-carbaldehyde
(Ij): Yield: 78%; m.p.: 230-223 °C; IR (KBr, ν, cm-1): 3450
Yield: 90%; m.p.: 160-162 °C; IR (KBr, ν, cm-1): 2965 & 3150 (asym. & sym. str. of -NH2), 2200 (-C≡N str.),
1
(ArC-H str.), 1710 (-C=O str.), 1200 (C-O-C ether str.); 1680 (-C=O str.); H NMR (400 MHz, DMSO-d6) δH
1H NMR (400 MHz, DMSO-d6) δH (ppm): 2.33 (s, 3H, (ppm): 1.76 (s, 3H, CH3), 2.39 (s, 3H, CH3), 4.43 (s, 1H,
CH3), 2.36 (s, 3H, CH3), 7.10-7.55 (m, 8H, Ar-H), 9.64 H4), 6.30-7.52 (m, 15H, NH2+Ar-H). 13C NMR (100 MHz,
(S, 1H, CHO). 13C NMR (100 MHz, DMSO-d6) δC (ppm): DMSO-d6) δC (ppm): 13.06, 20.23 (Ar-CH3), 26.54 (C4),
14.27, 20.29 (Ar-CH3), 108.95, 116.55, 119.13, 122.87, 56.11 (C-CN), 102.29, 110.48, 112.69, 113.69, 116.56,
124.43, 128.11, 129.24, 130.37, 136.88, 142.12, 151.04, 119.97, 121.54, 122.70, 124.50, 127.05, 129.65, 130.11,
152.02, 157.10 (Ar-C), 182.33 (C=O); Anal. Calcd. for 132.16, 132.78, 138.06, 145.83, 148.19, 152.26, 153.43,
C18H15ClN2O2 (326.78 gm/mole): C, 66.16; H, 4.63; N, 153.80, 158.58 (Ar-C), 160.07 (C=O); Anal. Calcd. for
8.57%. Found: C, 66.39; H, 4.29; N, 8.41%.
3 - M e t h y l - 5 - ( 4 - c h l o r o p h e n o x y ) - 1 - ( 3 - 11.15%. Found: C, 71.52; H, 4.36; N, 10.98%.
chlorophenyl)-1H-pyrazole-4-carbaldehyde (Ik):
Yield: 87%; m.p.: 142-144 °C; IR (KBr, ν, cm-1): 3015
C30H22N4O4 (502.52 gm/mole): C, 71.70; H, 4.41; N,
2 - A m i n o - 4 - ( 5 - ( 4 - c h l o r o p h e n o x y ) - 3 -
(ArC-H str.), 1685 (-C=O str.), 1215 (C-O-C ether str.); methyl-1-phenyl-1H-pyrazol-4-yl)-5-oxo-4,5-
1H NMR (400 MHz, DMSO-d6) δH (ppm): 2.37 (s, 3H, dihydropyrano[3,2-c]chromene-3-carbonitrile (IVc):
CH3), 7.03-7.61 (m, 8H, Ar-H), 9.61 (S, 1H, CHO). 13C Yield: 75%; m.p.: 208-210 °C; IR (KBr, ν, cm-1): 3400
NMR (100 MHz, DMSO-d6) δC (ppm): 14.12 (Ar-CH3), & 3200 (asym. & sym. str. of -NH2), 2180 (-C≡N str.),
1
108.88, 116.33, 119.47, 122.67, 124.61, 128.22, 129.63, 1710 (-C=O str.); H NMR (400 MHz, DMSO-d6) δH
130.48, 136.96, 142,27, 150.97, 153.01, 157.07 (Ar-C), (ppm): 2.10 (s, 3H, CH3), 4.40 (s, 1H, H4), 6.40-7.59
183.67 (C=O); Anal. Calcd. for C17H12Cl2N2O2 (347.20 (m, 15H, NH2+Ar-H). 13C NMR (100 MHz, DMSO-d6)
gm/mole): C, 58.81; H, 3.48; N, 8.07%. Found: C, 59.07; δC (ppm): 13.05 (Ar-CH3) 26.52 (C4), 55.90 (C-CN),
H, 3.71; N, 7.93%.
3-Methyl-5-(4-methoxyphenoxy)-1-(3- 122.38, 123.51, 126.15, 128.55, 131.01, 132.26, 132.88,
chlorophenyl)-1H-pyrazole-4-carbaldehyde (Il): 137.26, 144.85, 148.09, 152.14, 153.43, 154.21, 158.52
102.17, 110.34, 112.47, 113.86, 115.56, 119.77, 120.34,
Yield: 80%; m.p.: 131-132 °C; IR (KBr, ν, cm-1): 2985 (Ar-C), 160.17 (C=O); Anal. Calcd. for C29H19ClN4O4
(ArC-H str.), 1725 (-C=O str.), 1210 (C-O-C ether str.); (522.94 gm/mole): C, 66.61; H, 3.66; N, 10.71%. Found:
1H NMR (400 MHz, DMSO-d6) δH (ppm): 2.20 (s, 3H, C, 66.70; H, 3.46; N, 10.98%.
CH3), 3.41 (s, 3H, OCH3), 7.02-7.62 (m, 8H, Ar-H),
2 - A m i n o - 4 - ( 5 - ( 4 - m e t h o x y p h e n o x y ) - 3 -
9.60 (S, 1H, CHO). 13C NMR (100 MHz, DMSO-d6) methyl-1-phenyl-1H-pyrazol-4-yl)-5-oxo-4,5-
δC (ppm): 14.42 (Ar-CH3), 54.40 (Ar-OCH3), 108.72, dihydropyrano[3,2-c]chromene-3-carbonitrile (IVd):
116.24, 118.97, 123.99, 124.69, 127.94, 129.31, 131.55, Yield: 77%; m.p.: 262-263 °C; IR (KBr, ν, cm-1): 3340
137.23, 141.98, 150.74, 152.88, 157.05 (Ar-C), 184.02 & 3150 (asym. & sym. str. of -NH2), 2190 (-C≡N str.),
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1
1680 (-C=O str.); H NMR (400 MHz, DMSO-d6) δH 132.17, 132.88, 138.36, 145.82, 147.29, 152.66, 153.44,
(ppm): 1.96 (s, 3H, CH3), 3.39 (s, 3H, OCH3), 4.45 (s, 153.21, 158.39 (Ar-C), 160.13 (C=O); Anal. Calcd. for
1H, H4), 6.38-7.55 (m, 15H, NH2+Ar-H). 13C NMR (100 C30H21ClN4O4 (536.97 gm/mole): C, 67.10; H, 3.94; N,
MHz, DMSO-d6) δC (ppm): 13.02 (Ar-CH3), 26.58 (C4), 10.43%. Found: C, 67.40; H, 3.76; N, 10.25%.
54.30 (Ar-OCH3), 55.85 (C-CN), 103.48, 111.08, 112.19,
2-Amino-4-(5-(4-methoxyphenoxy)-3-methyl-
113.66, 115.86, 118.99, 121.44, 122.66, 124.59, 126.95, 1-(4-methylphenyl)-1H-pyrazol-4-yl)-5-oxo-4,5-
128.61, 130.31, 132.16, 132.88, 138.02, 144.83, dihydropyrano[3,2-c]chromene-3-carbonitrile (IVh):
147.49, 152.22, 153.44, 154.13, 158.61 (Ar-C), 160.15 Yield: 65%; m.p.: 274-275 °C; IR (KBr, ν, cm-1): 3375 &
(C=O); Anal. Calcd. for C30H22N4O5 (518.52 gm/mole): 3210 (asym. & sym. str. of -NH2), 2195 (-C≡N str.), 1730
C, 69.49; H, 4.28; N, 10.81%. Found: C, 69.61; H, 4.36; (-C=O str.);1H NMR (400 MHz, DMSO-d6) δH (ppm): 2.32
N, 10.97%.
(s, 3H, CH3), 2.37 (s, 3H, CH3), 3.43 (s, 3H, OCH3), 4.47
2-Amino-4-(3-methyl-5-phenoxy-1-(4- (s, 1H, H4), 6.33-7.58 (m, 14H, NH2+Ar-H). 13C NMR
methylphenyl)-1H-pyrazol-4-yl)-5-oxo-4,5- (100 MHz, DMSO-d6) δC (ppm): 13.02, 20.75 (Ar-CH3),
dihydropyrano[3,2-c]chromene-3-carbonitrile (IVe): 26.53 (C4), 55.01 (Ar-OCH3), 56.17 (C-CN), 102.36,
Yield: 68%; m.p.: 221-222 °C; IR (KBr, ν, cm-1): 3420 110.12, 111.06, 113.33, 116.16, 119.72, 121.31, 121.98,
& 3195 (asym. & sym. str. of -NH2), 2210 (-C≡N str.), 123.51, 127.21, 128.95, 130.18, 132.36, 132.88, 137.56,
1
1715 (-C=O str.); H NMR (400 MHz, DMSO-d6) δH 144.33, 147.29, 152.36, 153.52, 154.35, 158.56 (Ar-C),
(ppm): 2.15 (s, 3H, CH3), 2.37 (s, 3H, CH3), 4.43 (s, 1H, 160.03 (C=O); Anal. Calcd. for C31H24N4O5 (532.17 gm/
H4), 6.42-7.59 (m, 15H, NH2+Ar-H). 13C NMR (100 MHz, mole): C, 69.92; H, 4.54; N, 10.52%. Found: C, 70.12;
DMSO-d6) δC (ppm): 13.09, 20.85 (Ar-CH3), 26.55 (C4), H, 4.33; N, 10.59%.
56.03 (C-CN), 103.59, 110.98, 111.96, 113.68, 116.55,
2-Amino-4-(1-(3-chlorophenyl)-3-methyl-
119.07, 120.94, 122.77, 124.55, 127.04, 129.15, 130.21, 5 - p h e n o x y - 1 H - p y r a z o l - 4 - y l ) - 5 - o x o - 4 , 5 -
131.76, 132.75, 138.16, 145.23, 148.49, 152.28, 153.43, dihydropyrano[3,2-c]chromene-3-carbonitrile (IVi):
153.88, 158.59 (Ar-C), 160.05 (C=O); Anal. Calcd. for Yield: 72%; m.p.: 225-227 °C; IR (KBr, ν, cm-1): 3345
C30H22N4O4 (502.52 gm/mole): C, 71.70; H, 4.41; N, & 3180 (asym. & sym. str. of -NH2), 2190 (-C≡N str.),
1
11.15%. Found: C, 71.55; H, 4.56; N, 10.99%.
1695 (-C=O str.); H NMR (400 MHz, DMSO-d6) δH
2-Amino-4-(3-methyl-1-(4-methylphenyl)-5- (ppm): 2.40 (s, 3H, CH3), 4.45 (s, 1H, H4), 6.46-7.54
(4-methylphenoxy)-1H-pyrazol-4-yl)-5-oxo-4,5- (m, 15H, NH2+Ar-H). 13C NMR (100 MHz, DMSO-d6)
dihydropyrano[3,2-c]chromene-3-carbonitrile (IVf): δC (ppm): 13.05 (Ar-CH3), 26.46 (C4), 55.98 (C-CN),
Yield: 65%; m.p.: 257-259 °C; IR (KBr, ν, cm-1): 3415 & 103.20, 111.02, 112.57, 115.81, 116.68, 119.70, 119.84,
3145 (asym. & sym. str. of -NH2), 2185 (-C≡N str.), 1725 121.16, 122.59, 124.80, 126.99, 127.53, 129.88, 131.46,
(-C=O str.);1H NMR (400 MHz, DMSO-d6) δH (ppm): 1.92 133.20, 134.05, 138.90, 145.44, 148.33, 151.20, 152.21,
(s, 3H, CH3), 2.37 (s, 3H, CH3), 2.37 (s, 3H, CH3), 4.47 154.57, 157.96 (Ar-C), 160.09 (C=O); Anal. Calcd. for
(s, 1H, H4), 6.38-7.50 (m, 14H, NH2+Ar-H). 13C NMR C29H19ClN4O4 (522.94 gm/mole): C, 66.61; H, 3.66; N,
(100 MHz, DMSO-d6) δC (ppm): 13.03, 20.21, 20.82 10.71%. Found: C, 66.39; H, 3.73; N, 10.83%.
(Ar-CH3), 26.51 (C4), 56.09 (C-CN), 102.99, 111.38,
2-Amino-4-(1-(3-chlorophenyl)-3-methyl-5-
112.45, 114.28, 115.76, 119.33, 121.83, 121.96, 123.51, (4-methylphenoxy)-1H-pyrazol-4-yl)-5-oxo-4,5-
127.15, 129.32, 130.11, 132.23, 132.80, 138.34, 145.82, dihydropyrano[3,2-c]chromene-3-carbonitrile (IVj):
148.48, 152.27, 153.15, 153.43, 158.44 (Ar-C), 160.11 Yield: 65%; m.p.: 245-247 °C; IR (KBr, ν, cm-1): 3445
(C=O); Anal. Calcd. for C31H24N4O4 (516.55 gm/mole): & 3205 (asym. & sym. str. of -NH2), 2185 (-C≡N str.),
1
C, 72.08; H, 4.68; N, 10.85%. Found: C, 72.32; H, 4.46; 1700 (-C=O str.); H NMR (400 MHz, DMSO-d6) δH
N, 10.66%.
(ppm): 2.32 (s, 3H, CH3), 2.34 (s, 3H, CH3), 4.40 (s,
2-Amino-4-(5-(4-chlorophenoxy)-3-methyl- 1H, H4), 6.41-7.49 (m, 14H, NH2+Ar-H). 13C NMR (100
1-(4-methylphenyl)-1H-pyrazol-4-yl)-5-oxo-4,5- MHz, DMSO-d6) δC (ppm): 13.08, 20.25 (Ar-CH3), 26.51
dihydropyrano[3,2-c]chromene-3-carbonitrile (IVg): (C4), 55.92 (C-CN), 102.49, 110.38, 112.07, 114.87,
Yield: 62%; m.p.: 215-216 °C; IR (KBr, ν, cm-1): 3395 117.08, 119.36, 119.85, 120.56, 121.99, 124.30, 126.03,
& 3195 (asym. & sym. str. of -NH2), 2200 (-C≡N str.), 127.55, 129.17, 130.66, 133.28, 134.48, 138.70, 144.40,
1
1690 (-C=O str.); H NMR (400 MHz, DMSO-d6) δH 146.92, 151.28, 152.77, 154.47, 158.51 (Ar-C), 160.14
(ppm): 2.28 (s, 3H, CH3), 2.36 (s, 3H, CH3), 4.49 (s, 1H, (C=O); Anal. Calcd. for C30H21ClN4O4 (536.97 gm/mole):
H4), 6.42-7.45 (m, 14H, NH2+Ar-H). 13C NMR (100 MHz, C, 67.10; H, 3.94; N, 10.43%. Found: C, 67.35; H, 4.09;
DMSO-d6) δC (ppm): 13.07, 20.79 (Ar-CH3), 26.49 (C4), N, 10.22%.
56.19 (C-CN), 102.89, 110.84, 112.44, 112.99, 116.26,
2-Amino-4-(5-(4-chlorophenoxy)-1-(3-
119.43, 120.57, 121.84, 124.34, 126.15, 129.03, 130.41, chlorophenyl)-3-methyl-1H-pyrazol-4-yl)-5-oxo-4,5-
639

Synthesis and antimicrobial screening
of pyrano[3,2-c]chromene derivatives of 1H-pyrazoles
dihydropyrano[3,2-c]chromene-3-carbonitrile (IVk): 13C NMR (100 MHz, DMSO-d6) δC (ppm): 13.04, 20.22,
Yield: 63%; m.p.: 238-240 °C; IR (KBr, ν, cm-1): 3400 20.85 (Ar-CH3), 26.55 (C4), 56.14 (C-CN), 103.45,
& 3200 (asym. & sym. str. of -NH2), 2200 (-C≡N str.), 111.52, 112.97, 114.33, 114.92, 116.68, 118.73, 121.35,
1
1710 (-C=O str.); H NMR (400 MHz, DMSO-d6) δH 122.88, 126.13, 128.42, 133.78, 134.12, 137.76, 146.17,
(ppm): 2.39 (s, 3H, CH3), 4.45 (s, 1H, H4), 6.48-7.58 148.25, 149.72, 151.34, 153.01, 154.75, 158.40 (Ar-C),
(m, 14H, NH2+Ar-H). 13C NMR (100 MHz, DMSO-d6) 160.17 (C=O); Anal. Calcd. for C31H24N4O4 (516.55 gm/
δC (ppm): 13.05 (Ar-CH3), 26.47 (C4), 55.83 (C-CN), mole): C, 72.08; H, 4.68; N, 10.85%. Found: C, 72.37;
102.19, 111.35, 112.57, 115.81, 116.68, 119.70, 119.84, H, 4.40; N, 10.60%.
121.16, 122.59, 124.80, 126.99, 127.53, 129.88, 131.46,
2-Amino-4-(5-(4-chlorophenoxy)-3-methyl-
133.20, 134.05, 138.90, 145.44, 148.96, 152.20, 153.57, 1-phenyl-1H-pyrazol-4-yl)-9-methyl-5-oxo-4,5-
154.42, 158.61 (Ar-C), 160.01 (C=O); Anal. Calcd. for dihydropyrano[3,2-c]chromene-3-carbonitrile (IVo):
C29H18Cl2N4O4 (557.38 gm/mole): C, 62.49; H, 3.26; N, Yield: 69%; m.p.: 218-220 °C; IR (KBr, ν, cm-1): 3375
10.05%. Found: C, 62.34; H, 3.09; N, 9.88%; MS m/z: & 3200 (asym. & sym. str. of -NH2), 2210 (-C≡N str.),
1
558.6 [M+1]+.
1705 (-C=O str.); H NMR (400 MHz, DMSO-d6) δH
2 - A m i n o - 4 - ( 1 - ( 3 - c h l o r o p h e n y l ) - 5 - ( 4 - (ppm): 2.05 (s, 3H, CH3), 2.38 (s, 3H, CH3), 4.40 (s, 1H,
methoxyphenoxy)-3-methyl-1H-pyrazol-4-yl)-5-oxo- C4), 6.47-7.53 (m, 14H, NH2+Ar-H). 13C NMR (100 MHz,
4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile DMSO-d6) δC (ppm): 13.01, 20.97 (Ar-CH3), 26.49 (C4),
(IVl): Yield: 69%; m.p.: 277-279 °C; IR (KBr, ν, cm-1): 56.01 (C-CN), 102.01, 110.92, 112.33, 113.87, 114.54,
3385 & 3180 (asym. & sym. str. of -NH2), 2210 (-C≡N 116.21, 119.02, 121.45, 123.08, 127.02, 129.53, 133.61,
str.), 1690 (-C=O str.); 1H NMR (400 MHz, DMSO-d6) δH 133.71, 138.12, 146.12, 148.75, 149.83, 150.68, 152.25,
(ppm): 2.23 (s, 3H, CH3), 3.40 (s, 3H, OCH3), 4.47 (s, 153.95, 158.32 (Ar-C), 160.16 (C=O); Anal. Calcd. for
1H, H4), 6.44-7.51 (m, 14H, NH2+Ar-H). 13C NMR (100 C30H21ClN4O4 (536.97 gm/mole): C, 67.10; H, 3.94; N,
MHz, DMSO-d6) δC (ppm): 13.07 (Ar-CH3), 26.52 (C4), 10.43%. Found: C, 67.32; H, 4.15; N, 10.61%.
53.70 (Ar-OCH3), 55.93 (C-CN), 103.66, 111.93, 112.14,
2-Amino-4-(5-(4-methoxyphenoxy)-3-methyl-
115.77, 117.05, 119.34, 119.96, 121.34, 122.41, 124.47, 1-phenyl-1H-pyrazol-4-yl)-9-methyl-5-oxo-4,5-
125.92, 127.31, 129.07, 131.33, 132.89, 134.13, 138.16, dihydropyrano[3,2-c]chromene-3-carbonitrile (IVp):
143.99, 147.06, 151.97, 153.49, 154.63, 158.37 (Ar-C), Yield: 72%; m.p.: 271-273 °C; IR (KBr, ν, cm-1): 3430 &
160.06 (C=O); Anal. Calcd. for C30H21ClN4O5 (552.96 3165 (asym. & sym. str. of -NH2), 2200 (-C≡N str.), 1725
gm/mole): C, 65.16; H, 3.83; N, 10.13%. Found: C, (-C=O str.);1H NMR (400 MHz, DMSO-d6) δH (ppm): 2.36
65.35; H, 4.09; N, 9.91%.
(s, 3H, CH3), 2.37 (s, 3H, CH3), 3.37 (s, 3H, OCH3), 4.41
2 - A m i n o - 4 - ( 3 - m e t h y l - 5 - p h e n o x y - 1 - (s, 1H, H4), 6.35-7.54 (m, 14H, NH2+Ar-H). 13C NMR
phenyl-1H-pyrazol-4-yl)-9-methyl-5-oxo-4,5- (100 MHz, DMSO-d6) δC (ppm): 13.08, 20.92 (Ar-CH3),
dihydropyrano[3,2-c]chromene-3-carbonitrile (IVm): 26.57 (C4), 55.29 (Ar-OCH3), 56.04 (C-CN), 102.23,
Yield: 73%; m.p.: 254-256 °C; IR (KBr, ν, cm-1): 3395 & 110.39, 112.47, 114.62, 114.77, 116.32, 119.99, 121.54,
3195 (asym. & sym. str. of -NH2), 2196 (-C≡N str.), 1700 122.27, 127.03, 129.66, 133.65, 133.87, 138.12, 146.09,
(-C=O str.); 1H NMR (400 MHz, DMSO-d6) δH (ppm): 148.13, 149.68, 150.45, 153.39, 154.90, 158.63 (Ar-C),
2.35 (s, 3H, CH3), 2.36 (s, 3H, CH3), 4.41 (s, 1H, H4), 160.20 (C=O); Anal. Calcd. for C31H24N4O5 (532.55 gm/
6.36-7.40 (m, 15H, NH2+Ar-H). 13C NMR (100 MHz, mole): C, 69.92; H, 4.54; N, 10.52%. Found: C, 70.18;
DMSO-d6) δC (ppm): 13.08, 20.90 (Ar-CH3), 26.54 (C4), H, 4.29; N, 10.68%.
56.04 (C-CN), 102.72, 110.87, 112.18, 114.13, 114.99,
2-Amino-4-(3-methyl-5-phenoxy-1-(4-
116.01, 118.15, 120.62, 122.38, 127.45, 130.33, 133.01, methylphenyl)-1H-pyrazol-4-yl)-9-methyl-5-oxo-4,5-
133.52, 136.92, 145.72, 147.23, 149.27, 150.72, 152.58, dihydropyrano[3,2-c]chromene-3-carbonitrile (IVq):
155.38, 158.45 (Ar-C), 160.12 (C=O); Anal. Calcd. for Yield: 68%; m.p.: 211-213 °C; IR (KBr, ν, cm-1): 3400 &
C30H22N4O4 (502.52 gm/mole): C, 71.70; H, 4.41; N, 3100 (asym. & sym. str. of -NH2), 2190 (-C≡N str.), 1730
11.15%. Found: C, 71.95; H, 4.55; N, 10.97%.
(-C=O str.);1H NMR (400 MHz, DMSO-d6) δH (ppm): 2.20
2 - A m i n o - 4 - ( 3 - m e t h y l - 1 - p h e n y l - 5 - ( 4 - (s, 3H, CH3), 2.35 (s, 3H, CH3), 2.36 (s, 3H, CH3), 4.40
methylphenoxy)-1H-pyrazol-4-yl)-9-methyl-5-oxo- (s, 1H, H4), 6.42-7.40 (m, 14H, NH2+Ar-H). 13C NMR
4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile (100 MHz, DMSO-d6) δC (ppm): 13.04, 20.83, 20.88
(IVn): Yield: 74%; m.p.: 242-243 °C; IR (KBr, ν, cm-1): (Ar-CH3), 26.52 (C4), 56.14 (C-CN), 102.27, 110.34,
3355 & 3175 (asym. & sym. str. of -NH2), 2205 (-C≡N 112.51, 114.08, 116.41, 119.97, 121.64, 122.21, 122.85,
str.), 1715 (-C=O str.); 1H NMR (400 MHz, DMSO-d6) δH 129.69, 130.05, 133.65, 133.91, 135.68, 136.50, 145.38,
(ppm): 1.99 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.37 (s, 3H, 147.71, 150.44, 153.45, 156.02, 158.60 (Ar-C), 160.15
CH3), 4.46 (s, 1H, H4), 6.45-7.59 (m, 14H, NH2+Ar-H). (C=O); Anal. Calcd. for C31H24N4O4 (516.55 gm/mole):
640

C. B. Sangani et al.
C, 72.08; H, 4.68; N, 10.85%. Found: C, 72.33; H, 4.47; dihydropyrano[3,2-c]chromene-3-carbonitrile (IVu):
N, 10.68%; MS m/z: 517.2 [M+1]+.
Yield: 72%; m.p.: 235-236 °C; IR (KBr, ν, cm-1): 3395
2-Amino-4-(3-methyl-1-(4-methylphenyl)-5-(4- & 3140 (asym. & sym. str. of -NH2), 2205 (-C≡N str.),
1
methylphenoxy)-1H-pyrazol-4-yl)-9-methyl-5-oxo- 1695 (-C=O str.); H NMR (400 MHz, DMSO-d6) δH
4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile (ppm): 2.34 (s, 3H, CH3), 2.37 (s, 3H, CH3), 4.45 (s,
(IVr): Yield: 67%; m.p.: 269-270 °C; IR (KBr, ν, cm-1): 1H, H4), 6.46-7.55 (m, 14H, NH2+Ar-H). 13C NMR (100
3385 & 3190 (asym. & sym. str. of -NH2), 2180 (-C≡N MHz, DMSO-d6) δC (ppm): 13.06, 21.01 (Ar-CH3), 26.48
str.), 1690 (-C=O str.); 1H NMR (400 MHz, DMSO-d6) (C4), 55.89 (C-CN), 102.62, 111.12, 112.62, 115.72,
δH (ppm): 2.10 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.36 (s, 117.04, 119.19, 119.64, 121.29, 122.32, 124.91, 126.85,
3H, CH3), 2.36 (s, 3H, CH3), 4.48 (s, 1H, H4), 6.44-7.49 127.14, 129.67, 131.31, 133.48, 134.56, 138.78, 144.32,
(m, 13H, NH2+Ar-H). 13C NMR (100 MHz, DMSO-d6) δC 148.13, 152.38, 153.28, 154.31, 158.44 (Ar-C), 160.07
(ppm): 13.05, 20.24, 20.85, 20.99 (Ar-CH3), 26.57 (C4), (C=O); Anal. Calcd. for C30H21ClN4O4 (536.97 gm/mole):
56.18 (C-CN), 102.39, 110.38, 112.03, 113.91, 117.21, C, 67.10; H, 3.94; N, 10.43%. Found: C, 67.27; H, 4.15;
119.42, 121.19, 122.13, 122.83, 128.28, 130.19, 132.72, N, 10.62%.
133.42, 135.12, 136.54, 144.78, 147.79, 150.21, 154.03,
2-Amino-4-(1-(3-chlorophenyl)-3-methyl-5-(4-
156.14, 158.62 (Ar-C), 160.19 (C=O); Anal. Calcd. for methylphenoxy)-1H-pyrazol-4-yl)-9-methyl-5-oxo-
C32H26N4O4 (530.57 gm/mole): C, 72.44; H, 4.94; N, 4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile
10.56%. Found: C, 72.18; H, 4.73; N, 10.76%.
(IVv): Yield: 71%; m.p.: 248-249 °C; IR (KBr, ν, cm-1):
2-Amino-4-(5-(4-chlorophenoxy)-3-methyl-1-(4- 3410 & 3160 (asym. & sym. str. of -NH2), 2180 (-C≡N
methylphenyl)-1H-pyrazol-4-yl)-9-methyl-5-oxo-4,5- str.), 1700 (-C=O str.); 1H NMR (400 MHz, DMSO-d6) δH
dihydropyrano[3,2-c]chromene-3-carbonitrile (IVs): (ppm): 2.16 (s, 3H, CH3), 2.38 (s, 3H, CH3), 2.38 (s, 3H,
Yield: 74%; m.p.: 229-230 °C; IR (KBr, ν, cm-1): 3365 & CH3), 4.41 (s, 1H, H4), 6.41-7.59 (m, 13H, NH2+Ar-H).
3170 (asym. & sym. str. of -NH2), 2210 (-C≡N str.), 1710 13C NMR (100 MHz, DMSO-d6) δC (ppm): 13.08, 20.27,
(-C=O str.);1H NMR (400 MHz, DMSO-d6) δH (ppm): 1.92 20.95 (Ar-CH3), 26.54 (C4), 55.97 (C-CN), 103.02,
(s, 3H, CH3), 2.34 (s, 3H, CH3), 2.35 (s, 3H, CH3), 4.49 110.92, 112.72, 115.37, 116.91, 118.94, 119.72, 121.47,
(s, 1H, H4), 6.32-7.49 (m, 13H, NH2+Ar-H). 13C NMR 122.62, 124.77, 126.84, 127.42, 129.57, 131.14,
(100 MHz, DMSO-d6) δC (ppm): 13.07, 20.77, 20.89 (Ar- 133.37, 134.18, 138.75, 145.32, 148.62, 152.11, 153.48,
CH3), 26.51 (C4), 56.13 (C-CN), 102.31, 110.65, 112.13, 154.31, 158.38 (Ar-C), 160.02 (C=O); Anal. Calcd. for
114.13, 116.32, 118.42, 121.38, 122.19, 122.87, 128.32, C31H23ClN4O4 (550.99 gm/mole): C, 67.57; H, 4.21; N,
130.02, 133.46, 133.74, 134.18, 136.44, 144.98, 146.11, 10.17%. Found: C, 67.35; H, 4.09; N, 9.92%.
151.14, 153.33, 156.35, 158.29 (Ar-C), 160.18 (C=O);
2-Amino-4-(5-(4-chlorophenoxy)-1-(3-
Anal. Calcd. for C31H23ClN4O4 (550.99 gm/mole): C, chlorophenyl)-3-methyl-1H-pyrazol-4-yl)-9-methyl-
67.57; H, 4.21; N, 10.17%. Found: C, 67.78; H, 4.45; 5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-
N, 10.35%.
carbonitrile (IVw): Yield: 79%; m.p.: 266-268 °C; IR
2-Amino-4-(5-(4-methoxyphenoxy)-3-methyl-1- (KBr, ν, cm-1): 3435 & 3205 (asym. & sym. str. of -NH2),
(4-methylphenyl)-1H-pyrazol-4-yl)-9-methyl-5-oxo- 2195 (-C≡N str.), 1690 (-C=O str.); 1H NMR (400 MHz,
4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile DMSO-d6) δH (ppm): 2.03 (s, 3H, CH3), 2.38 (s, 3H,
(IVt): Yield: 62%; m.p.: 283-285 °C; IR (KBr, ν, cm-1): CH3), 4.43 (s, 1H, H4), 6.42-7.60 (m, 13H, NH2+Ar-H).
3450 & 3155 (asym. & sym. str. of -NH2), 2200 (-C≡N 13C NMR (100 MHz, DMSO-d6) δC (ppm): 13.03, 21.05
str.), 1680 (-C=O str.); 1H NMR (400 MHz, DMSO-d6) (Ar-CH3), 26.55 (C4), 56.15 (C-CN), 102.37, 111.42,
δH (ppm): 2.17 (s, 3H, CH3), 2.35 (s, 3H, CH3), 2.36 (s, 112.71, 114.92, 116.32, 119.62, 119.79, 120.97, 122.31,
3H, CH3), 3.36 (s, 3H, OCH3), 4.44 (s, 1H, H4), 6.40- 124.62, 126.87, 127.62, 129.94, 131.21, 133.91, 134.17,
7.50 (m, 13H, NH2+Ar-H). 13C NMR (100 MHz, DMSO- 138.49, 144.33, 148.30, 152.35, 153.31, 154.52, 158.34
d6) δC (ppm): 13.01, 20.86, 20.96 Ar-CH3), 26.45 (C4), (Ar-C), 160.12 (C=O); Anal. Calcd. for C30H20Cl2N4O4
53.90 (Ar-OCH3), 56.19 (C-CN), 103.03, 111.12, 112.78, (571.41 gm/mole): C, 63.06; H, 3.53; N, 9.81%. Found:
114.66, 117.41, 119.45, 121.37, 122.46, 122.92, 129.21, C, 62.85; H, 3.79; N, 9.92%.
130.18, 132.31, 133.43, 135.13, 136.88, 145.19,
2 - A m i n o - 4 - ( 1 - ( 3 - c h l o r o p h e n y l ) - 5 - ( 4 -
147.83, 150.40, 153.03, 156.23, 158.55 (Ar-C), 160.14 methoxyphenoxy)-3-methyl-1H-pyrazol-4-yl)-9-
(C=O); Anal. Calcd. for C32H26N4O5 (546.57 gm/mole): methyl-5-oxo-4,5-dihydropyrano[3,2-c]chromene-
C, 70.32; H, 4.79; N, 10.25%. Found: C, 70.48; H, 4.55; 3-carbonitrile (IVx): Yield: 68%; m.p.: 280-281 °C; IR
N, 10.54%.
(KBr, ν, cm-1): 3370 & 3180 (asym. & sym. str. of -NH2),
2-Amino-4-(1-(3-chlorophenyl)-3-methyl-5- 2200 (-C≡N str.), 1720 (-C=O str.); 1H NMR (400 MHz,
phenoxy-1H-pyrazol-4-yl)-9-methyl-5-oxo-4,5- DMSO-d6) δH (ppm): 2.33 (s, 3H, CH3), 2.36 (s, 3H,
641

Synthesis and antimicrobial screening
of pyrano[3,2-c]chromene derivatives of 1H-pyrazoles
Scheme 2. Synthetic Pathway for the title compounds 4H-pyrano[3,2-c]chromene derivatives of 1H-pyrazole IVa-x.
Scheme 3. Plausible mechanistic pathway for the title compounds 4H-pyrano[3,2-c]chromene derivatives of 1H-pyrazole IVa-x.
642

C. B. Sangani et al.
CH3), 3.45 (s, 3H, OCH3), 4.42 (s, 1H, H4), 6.38-7.53 concentration) preventing appearance of turbidity is
(m, 13H, NH2+Ar-H). 13C NMR (100 MHz, DMSO-d6) δC considered as minimal inhibitory concentration (MIC,
(ppm): 13.08, 20.86 (Ar-CH3), 26.55 (C4), 55.20 (Ar- μg mL−1) i.e. the amount of growth from the control
OCH3), 55.16 (C-CN), 103.02, 111.91, 112.53, 115.42, tube before incubation (which represents the original
117.01, 119.82, 119.99, 121.50, 122.31, 124.72, 126.99, inoculum) is compared. A set of tubes containing only
127.53, 129.81, 131.53, 133.18, 134.17, 138.90, 145.32, seeded broth and the solvent controls were maintained
148.93, 152.23, 153.71, 154.35, 158.46 (Ar-C), 160.06 under identical conditions so as to make sure that the
(C=O); Anal. Calcd. for C31H23ClN4O5 (566.99 gm/mole): solvent had no influence on strain growth. The result of
C, 65.67; H, 4.09; N, 9.88%. Found: C, 65.35; H, 4.23; this is much affected by the size of the inoculum. The
N, 9.92%.
test mixture should contain 108 CFU mL-1 organisms.
The protocols are summarized in Table 1 as the minimal
inhibitory concentration (MIC, μg mL-1).
2.7. Antimicrobial Activity
The in vitro antimicrobial activity of all the synthesized
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-negativebacteriaviz.Salmonellatyphi(MTCC98),
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 the National
Committee for Clinical Laboratory Standards (NCCLS)
[21].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 CFUmL-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. Sabouraud Dextrose Broth was
used for fungal nutrition. Ampicillin, Chloramphenicol,
Ciprofloxacin, Gentamicin and Norfloxacin were used
as standard antibacterial drugs, whereas griseofulvin
and nystatin were used as standard antifungal drugs.
DMSO was used as a diluent / vehicle to obtain the
desired concentration of synthesized compounds and
standard drugs to test upon standard microbial strains.
Serial dilutions were prepared in primary and secondary
screenings. Each synthesized compound and standard
drug was 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 drugs
were used. The active synthesized compounds found in
this primary screening were further diluted to obtain 200,
100, 62.5 and 50 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 subcultured [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
3. Results and Discussion
In continuation of our interest on synthesizing biologically
potent antimicrobials [20], we report herein a new
series of dihydropyrano[3,2-c]chromene derivatives
IVa-x via a one pot, three component, base-catalyzed
cyclocondensation reaction of 3-methyl-5-aryloxy-1-
ary-1H-lpyrazole-4-carbaldehyde Ia-l, malononitrile II
and 4-hydroxycoumarin IIIa-b in ethanol. The required
starting material, 1-aryl-5-chloro-3-methyl-1H-pyrazole-
4-carbaldehydes were prepared by Vilsmeier-Haack
reaction
of
3-methyl-1-aryl-1H-pyrazol-5(4H)-one,
which leads to chloroformylation to afford 1-aryl-5-
chloro-3-methyl-1H-pyrazole-4-carbaldehyde according
to literature procedure [22]. 1-Aryl-5-chloro-3-methyl-
1H-pyrazole-4-carbaldehyde undergoes a nucleophilic
substitution reaction with the respective phenol at
refluxing temperature for 4 h in the presence of a base
catalyst (K2CO3) in DMF to yield the desired 3-methyl-
5-aryloxy-1-aryl-1H-pyrazole-4-carbaldehyde
Ia-l
(Scheme 1) [23]. 4-Hydroxycoumarin (4-hydroxy-
6-substituted-2H-chromen-2-one) was synthesized
according to literature method by the solid phase reaction
of malonic acid and phenol in phosphorous oxychloride
in the presence of zinc chloride (Scheme 1) [24].
To obtain the title pyrano[3,2-c]chromene derivatives
of 1H-pyrazole, according to literature procedure, the
reaction was carried out in aqueous media and under
neutral conditions but failed to proceed even with
prolonged refluxing. The reaction was also attempted
under microwave irradiation but was not successful.
The reaction proceeded in acetonitrile, methanol,
benzene or DMF in the presence of morpholine or
K2CO3, but required prolonged refluxing and resulted
only in poor yield. Finally, refluxing the reaction mixture
in ethanol for 1-1.5 h in the presence of piperidine as a
basic catalyst gave moderate to good yield (62–80%)
(Scheme 2). Hence, these conditions were considered
as the most optimized conditions for the synthesis of the
title derivatives.
643

Synthesis and antimicrobial screening
of pyrano[3,2-c]chromene derivatives of 1H-pyrazoles
Table 1. Antibacterial and antifungal activity of compounds IVa-x.
Minimum Inhibitory Concentration (MIC, μg mL-1
)
Gram-positive bacteria
Gram-negative bacteria
Fungi
S.P.
C.T.
B.S.
S.T.
V.C.
E.C.
A.F.
C.A.
Compds
MTCC
1936
MTCC
449
MTCC
441
MTCC
98
MTCC
3906
MTCC
443
MTCC
3008
MTCC
227
IVa
IVb
IVc
IVd
IVe
IVf
250
200
250
250
100
100
200
200
200
250
250
200
500
62.5
100
250
500
1000
200
500
500
100
500
500
500
500
100
500
100
200
250
100
500
200
250
200
250
200
250
500
150
100
500
200
500
250
500
200
100
250
100
100
500
200
250
250
200
250
200
500
250
200
100
200
1000
1000
100
500
200
500
100
200
500
200
200
200
250
200
100
250
100
62.5
200
250
500
100
100
250
100
500
500
1000
>1000
500
250
1000
>1000
500
>1000
>1000
>1000
250
>1000
>1000
>1000
250
IVg
IVh
IVi
500
500
IVj
500
250
IVk
IVl
500
1000
500
1000
1000
500
IVm
IVn
IVo
IVp
500
250
>1000
>1000
200
200
500
250
200
100
250
250
250
100
50
100
200
500
200
250
500
100
250
200
250
50
500
250
250
500
100
100
250
200
250
250
50
250
200
250
200
100
250
200
200
200
100
50
200
200
100
250
250
250
250
200
250
100
50
500
100
200
62.5
200
100
200
200
100
100
50
1000
>1000
500
250
500
250
500
500
500
-
1000
>1000
500
250
250
100
250
500
500
-
IVq
IVr
IVs
IVt
IVu
IVv
IVw
IVx
Ampicillin
Chlormphenicol
Ciprofloxacin
Gentamycin
Griseofulvin
Nystatin
-
-
50
100
5
50
25
25
25
-
-
0.5
-
1
5
5
0.05
-
-
-
-
-
-
-
100
100
500
100
-
-
-
-
-
-
B.S.: Bacillus subtilis; C.T.: Clostridium tetani; S.P.: Streptococcus pneumoniae; E.C.: Escherichia coli; S.T.: Salmonella typhi; V.C.: Vibrio cholerae; A.F.:
Aspergillus fumigatus; C.A.: Candida albicans
A mechanism for the formation of the chromene singlet around δ 1.75-2.40 ppm stands for methyl of the
derivatives IVa-x is outlined in Scheme 3. The reaction pyrazole ring. 13C-NMR of IVa-x exhibited distinctive
may proceed via an in situ initial formation of the signals around δ 13.01-13.10 and δ 26.40-26.60 ppm
hetarylidenenitrile, containing the electron-poor C=C stands for methyl of pyrazole ring and C4 of the pyran
double bond, from a Knoevenagel condensation. Finally, ring respectively. All the aromatic carbons of IVa-x
Michael addition of 3 to the initially formed unsaturated showed signals around δ 102.15–158.70 ppm in the
nitrile, i.e., nucleophilic attack of hydroxyl moiety to the 13C-NMR spectra. Moreover, distinctive signals around
cyano olefins afforded cyclized pyrano[3,2-c]chromene δ 55.50-56.60 and δ 160.01-160.15 ppm represent the
derivatives IVa-x.
C-CN and carbonyl carbon respectively. The IR spectrum
The structures of all the newly synthesized of compound IVa-x exhibited characteristic absorption
compounds were established by 1H-NMR, 13C-NMR bands around 3450-3140 cm-1 and 2210-2180 cm-1
and FT-IR spectral data, and the molecular weight of are inidicative of the (asym. & sym. str.) –NH2 and
some selected compounds were confirmed by mass -CN functional groups, respectively. The characteristic
1
spectrometry. H-NMR (DMSO-d6) spectrum of IVa-x absorption band of carbonyl carbon is found around
exhibited a singlet peak around δ 4.40-4.50 stands 1730-1680cm-1 supportstheformationofpyranderivative
for H4 of the pyran ring. Amine and aromatic protons IVa-x. Further, the structure of selected compounds IVk
of IVa-x resonate as multiplets at δ 6.30–7.60 ppm. A and IVq were confirmed by its mass spectral studies.
644

C. B. Sangani et al.
The mass spectra detected the expected molecular (R1= CH3, R2= CH3, R3= CH3) (MIC = 100 μg mL-1) found
ion signals corresponding to respective molecular equipotent to Ampicillin (MIC = 100 μg mL-1) against V.
formula of synthesized compounds. Similarly, all these cholerae. The compound IVg (R1= CH3, R2=Cl, R3=H)
compounds were characterized on the basis of above and IVs (R1= CH3, R2=Cl, R3= CH3) (MIC < 100 μg mL-1)
spectral studies. All spectroscopic and physicochemical shows better and IVd (R1=H, R2= OCH3, R3=H), IVf
data have been given in experimental section. All the (R1= CH3, R2= CH3, R3=H), IVk (R1=Cl, R2=Cl, R3=H),
compounds were screened for their antibacterial and IVl (R1=Cl, R2= OCH3, R3=H), IVn (R1=H, R2= CH3, R3=
antifungal activity and results are shown in the form of CH3), IVq (R1= CH3, R2=H, R3= CH3), IVu (R1=Cl, R2=H,
MIC μg mL-1.
R3= CH3) and IVx (R1=Cl, R2= OCH3, R3= CH3) (MIC =
100 μg mL-1) were found to exhibit comparable activity
to Ampicillin (MIC = 100 μg mL-1) towards E. coli.
3.1. Antibacterial screening
The examination of the data (Table 1) reveals that
most of the compounds showed excellent antibacterial 3.2. Antifungal screening
and antifungal activity when compared with standard Against fungal pathogen C. albicans, compound IVa
drugs Ampicillin and Griseofulvin respectively. Against (R1=R2=R3=H), IVh (R1= CH3, R2= OCH3, R3=H), IVj
Gram-positive bacteria S. pneumoniae, compounds (R1=Cl, R2= CH3, R3=H), IVn (R1=H, R2= CH3, R3=
IVn (R1=H, R2=CH3, R3=CH3) (MIC = 62.5 μg mL-1) was CH3), IVs (R1= CH3, R2=Cl, R3= CH3), IVt (R1= CH3, R2=
found to be more potent whereas, IVe (R1=CH3, R2=H, OCH3, R3= CH3), IVu (R1=Cl, R2=H, R3= CH3) and IVv
R3=H), IVf (R1=CH3, R2=CH3, R3=H), IVo (R1=H, R2=Cl, (R1=Cl, R2= CH3, R3= CH3) (MIC < 500 μg mL-1) found
R3=CH3) and IVu (R1=Cl, R2=H, R3=CH3) (MIC = 100 better activity whereas, IVd (R1=H, R2= OCH3, R3=H),
μg mL-1) shows comparable activity, to Ampicillin (MIC IVi (R1=Cl, R2=H, R3=H), IVl (R1=Cl, R2= OCH3, R3=H),
= 100 μg mL-1). The compounds IVd (R1=H, R2=OCH3, IVm (R1=H, R2=H, R3= CH3), IVr (R1= CH3, R2= CH3,
R3=H), IVg (R1=CH3, R2=Cl, R3=H), IVl (R1=Cl, R2=OCH3, R3= CH3), IVw (R1=Cl, R2=Cl, R3= CH3) and IVx (R1=Cl,
R3=H), IVn (R1=H, R2=CH3, R3=CH3), IVo (R1=H, R2=Cl, R2= OCH3, R3= CH3) (MIC = 500 μg mL-1) were found to
R3=CH3), IVp (R1=H, R2=OCH3, R3=CH3), IVq (R1=CH3, be equipotent compared to Griseofulvin (MIC = 500 μg
R2=H, R3=CH3), IVs (R1=CH3, R2=Cl, R3=CH3), IVv mL-1). The remaining compounds showed moderate to
(R1=Cl, R2=CH3, R3=CH3) and IVx (R1=Cl, R2=OCH3, good activity to inhibit the growth of bacterial pathogens
R3=CH3) (MIC < 250 μg mL-1) found to be more efficient and are all less effective than standard drugs. From
whereas, IVa (R1=R2=R3=H), IVt (R1=CH3, R2=OCH3, the antimicrobial study of the title derivatives, it is
R3=CH3) and IVw (R1=Cl, R2=Cl, R3=CH3) (MIC = 250 interesting to note that a minor alteration in the molecular
μg mL-1) were found equally potent to Ampicillin (MIC configuration of the investigated compounds may have
= 250 μg mL-1), towards C. tetani. The compounds IVb a pronounced effect on antimicrobial activity.
(R1=H, R2=CH3, R3=H), IVd (R1=H, R2=OCH3, R3=H),
IVf (R1=CH3, R2=CH3, R3=H), IVh (R1=CH3, R2=OCH3,
R3=H), IVk (R1=Cl, R2=Cl, R3=H), IVl (R1=Cl, R2=OCH3, 4. Conclusions
R3=H), IVn (R1=H, R2= CH3, R3=CH3), IVt (R1=CH3,
R2=OCH3, R3=CH3), IVu (R1=Cl, R2=H, R3=CH3) and Anew series of substituted pyrano[3,2-c]chromene IVa-x
IVw (R1=Cl, R2=Cl, R3=CH3) (MIC < 250 μg mL-1) shows derivatives have been synthesized via MCR approach.
better activity whereas, IVa (R1=R2=R3=H), IVe (R1=CH3, This synthetic strategy allows the construction of
R2=H, R3=H), IVg (R1=CH3, R2=Cl, R3=H), IVi (R1=Cl, relatively complicated nitrogen and oxygen containing
R2=H, R3=H), IVq (R1=CH3, R2=H, R3=CH3), IVr (R1=CH3, fused heterocyclic systems, as well as the introduction
R2= CH3, R3= CH3), IVv (R1=Cl, R2=CH3, R3=CH3) and of various (hetero)aromatic substitutents onto the
IVx (R1=Cl, R2=OCH3, R3= CH3) (MIC = 250 μg mL-1) 4-position of the chromene system. It can be concluded
found equally potent, to Ampicillin (MIC = 250 μg mL-1), from antimicrobial screening (Table 1) that compound
against B. subtilis. Towards Gram-negative strain S. Ivn, which bears two methyl groups, is the most efficient
typhi, compounds IVd (R1=H, R2=OCH3, R3=H), IVf antimicrobial amongst all the synthesized derivatives.
(R1=CH3, R2=CH3, R3=H), IVg (R1=CH3, R2=Cl, R3=H) Antifungal activity of the compounds shows that most of
and IVt (R1=CH3, R2=OCH3, R3=CH3) (MIC = 100 μg the compounds wre found to be more potent against C.
mL-1) were equally active to Ampicillin (MIC = 100 μg albicanscomparedtoA. fumigatus. Itisworthmentioning
mL-1). The Compounds 4c (R1=H, R2=Cl, R3=H), IVg that minor changes in the molecular configuration of
(R1=CH3, R2=Cl, R3=H), IVk (R1=Cl, R2=Cl, R3=H) and IVr these compounds profoundly influences the activity.
645

Synthesis and antimicrobial screening
of pyrano[3,2-c]chromene derivatives of 1H-pyrazoles
(SICART), Vallabh Vidyanagar for elemental analysis.
Oxygen Healthcare Research Pvt. Ltd., Ahmadabad
for providing mass spectrometry facilities and Dhanji
P. Rajani, Microcare Laboratory, Surat for antimicrobial
screening of the compounds reported herein. Chetan B.
Sangani is grateful to UGC, New Delhi for a Research
Fellowship in Sciences for Meritorious Students.
Acknowledgements
The authors are thankful to Department of Chemistry,
Sardar Patel University for providing research
facilities. We are also thankful to Vaibhav Analytical
Laboratory, Ahmedabad for the FT-IR and Sophisticated
InstrumentationCentreforAppliedResearchandTraining
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