Synthesis and characterization of novel benzo[d][1,3]dioxole gathered pyrazole derivatives and their antimicrobial evaluation

Article abstract of DOI:10.1007/s00044-014-0952-x

Benzo[d][1,3]dioxole gathered pyrazole derivatives (4a-i) were synthesized by the reaction of chalcones with phenyl hydrazine in presence of absolute alcohol as a solvent. Chalcones were prepared by the Claisen-Schmidt reaction between 1-(benzo[d][1,3]dioxol-5-yl)ethanone (2) and substituted aromatic aldehydes. The synthesized compounds were characterized by spectral and elemental analysis data. Furthermore, Benzo[ d][1,3]dioxole gathered pyrazole derivatives (4a-i) were evaluated for their in vitro antimicrobial activity. Among the newly synthesized compounds 4a, 4c, 4 g and 4 h showed the excellent antifungal activity and as well as 4a and 4d showed the excellent antibacterial activity when compared to other compounds. Springer Science+Business Media 2014.

Full text of DOI:10.1007/s00044-014-0952-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-014-0952-x
ORIGINAL RESEARCH
Synthesis and characterization of novel benzo[d][1,3]dioxole
gathered pyrazole derivatives and their antimicrobial evaluation
•
Basavaiah Umesha Yeriyur Basavaiah Basavaraju
Received: 20 September 2013 / Accepted: 11 February 2014
Ó Springer Science+Business Media New York 2014
Abstract Benzo[d][1,3]dioxole gathered pyrazole deriv-
atives (4a–i) were synthesized by the reaction of chalcones
with phenyl hydrazine in presence of absolute alcohol as a
solvent. Chalcones were prepared by the Claisen-Schmidt
reaction between 1-(benzo[d][1,3]dioxol-5-yl)ethanone (2)
and substituted aromatic aldehydes. The synthesized
compounds were characterized by spectral and elemental
analysis data. Furthermore, Benzo[d][1,3]dioxole gathered
pyrazole derivatives (4a–i) were evaluated for their in vitro
antimicrobial activity. Among the newly synthesized
compounds 4a, 4c, 4 g and 4 h showed the excellent
antifungal activity and as well as 4a and 4d showed the
excellent antibacterial activity when compared to other
compounds.
properties (Jiangli et al., 2011). The substituted pyrazoles and
their derivatives with different functional groups show
enhanced pharmacological activities. They are used as her-
bicides and pharmaceuticals (Pinka Patel and Patel, 2012).
Pyrazole, very important member of heterocyclic family has
5-memberedringsystemwithtwoadjacent nitrogenatomsare
well established in the literature for their remarkable biolog-
ical activity. From the literature survey it has been revealed
that pharmacological agents containing pyrozole moiety play
a very important role in medicinal chemistry (Vishnuvardan
Rao et al., 2011). Pyrazoles and benzo[d][1,3]dioxole are
being centre of attraction to many researcher because they
possess anti-microbial (Pimerova and Voronina, 2001), anti-
viral (Janus et al., 1999), anti-inflammatory (Nugent et al.,
1993), anti-tumor (Park et al., 2005), (Bouabdallah et al,
2006), anti-depressant (Bailey et al., 1985), anti-histaminic
(Mishra et al., 1998), anti-parasitic (Rathelot et al., 2002),
anti-arthritic (Diparsia et al., 1981), anti-hypertensive (Turan-
Zitouni et al., 2000), anti-cancer (Abbs et al., 2008), analgesic
(Basavaraja et al., 2008), herbicide (Xue et al., 2000), insec-
ticide and fungicide activities (Chu and Cutler, 1986).
Therefore, all these activities of pyrazole derivatives have
grabbedtheattentionoftheresearcherstosynthesizemoreand
more derivatives to study their biological activities. In the
present work such a versatile benzo[d][1,3]dioxole gathered
pyrazole derivatives are embedded with dioxole ring to
enhance their biological activity.
Keywords Chalcones ꢀ Ketone ꢀ Pyrazole derivatives ꢀ
Antimicrobial activity ꢀ Aldehydes
Introduction
In the recent years, a wide variety of heterocyclic compounds
are considered to be pharmacologically important molecules.
Benzo[d][1,3]dioxole which is used as a valuable starting
material for the synthesis of bioactive compounds. These
compounds constitute a major class of naturally occurring
compounds and interest in their chemistry continues unabated
because of their wide range of biological and therapeutic
Experimental
B. Umesha ꢀ Y. B. Basavaraju (&)
Department of Studies in Chemistry, University of Mysore,
Manasagangotri, Mysore 570 006, Karnataka, India
e-mail: basavaraju_yb@yahoo.co.in
Materials and methods
All reagents and chemicals were purchased from Merck
Chemicals used without further purification. Melting points
B. Umesha
e-mail: umesha.basaviah54@gmail.com
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Med Chem Res
were taken in open capillary tubes and are uncorrected.
TLC is performed with E. Merck precoated silica gel plates
(60F-254) with iodine as a developing agent. Acme, India
silica gel, 60–120 mesh for column chromatography is
used. IR spectra in KBr were recorded on Perkin-Elmer
H-2),7.45 (d, 1H, J = 5 Hz, H-20), 7.30–7.45 (m, 5H, H-30,
H-200, H-300, H-500, H-600), 6.02 (s, 2H, OCH2O), 2.53 (s, 3H,
SCH3); 13C NMR (CDCl3, 100 MHz) d = 196.5 (C, C-1),
154.1 (C, C-40), 149.5 (C, C-50), 145.3 (C, C-3), 138.9
(C, C-400), 131.2 (C, C-100), 128.9 (C, C-200, C-600), 126.3
(C, C-300, C-500), 123.5 (C, C-20), 122.9 (C, C-10), 121.1
(C, C-2), 108.8 (C, C-30), 107.5 (C, C-60), 101.6 (C, OCH2O),
14.5 (C, SCH3); MS (ESI) m/z: 298.10 (M?). Anal. Calcd. for
C17H14O3S: C, 68.44; H, 4.73. Found: C, 68.38; H, 4.70 %.
1
model 683 or 1310 spectrometers. H NMR (400 MHz)
and 13C NMR (100 MHz) spectra using trimethyl silane as
an internal reference were recorded on Bruker spectrome-
ter, Elemental analyses were performed on a Perkin-Elmer
2400. Mass spectra were obtained by Water-Q-TOF ultima
spectrometer. Micro analytical data were obtained by ele-
mental-Vario EL-III.
(E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-phenylprop-2-en-1-one
(3b) Light yellow solid (C2H5OH); m.p. 93–95 °C; IR
(KBr)vmax
: ;
3129–2965, 1639, 1543 cm-1 1H NMR
Synthesis
(CDCl3, 400 MHz): d = 8.03 (d, 1H, J = 7.0 Hz, H-3), 7.65
(s, 1H, H-60), 7.55 (d, 1H, J = 5.6 Hz, H-2), 7.51 (d, 1H,
J = 5 Hz, H-20), 7.42 (d, 1H, J = 5 Hz, H-30), 7.23–7.40
(m, 5H, H-200, H-300, H-400, H-500, H-600), 6.05 (s, 2H,
OCH2O); 13C NMR (CDCl3, 100 MHz) d = 194.9 (C, C-1),
154.3 (C, C-40), 149.5 (C, C-50), 145.6 (C, C-3), 135.4 (C, C-
100), 128.9 (C, C-300, C-500), 128.6 (C, C-200, C-600), 127.5 (C,
C-400), 123.6 (C, C-20), 122.9 (C, C-10), 122.9 (C, C-2), 108.3
(C, C-30), 107.4 (C, C-60), 101.9 (C, OCH2O); MS (ESI) m/z:
252.10 (M?). Anal. Calcd. for C16H12O3: C, 76.18; H, 4.79;
found: C, 76.15; H, 4.72 %.
Procedure for the synthesis of 1-(benzo[d][1,3]dioxol-5-
yl)ethanone (2)
Benzo[d][1,3]dioxole (1.22 g, 10 mmol) in acetic anhy-
dride (10 mL) containing fused zinc chloride (1.36 g,
10 mmol) as Friedel–crafts catalyst was stirred at room
temp for 12 h. After the usual workup a thick brown liquid
oily product was obtained in good yield and recrystallized
from ethanol.
1-(Benzo[d][1,3]dioxol-5-yl)ethanone (2) Dark brown
(E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(3,4,5-trimethoxyphenyl)
solid (C2H5OH); m.p. 85–87 °C; IR (KBr)vmax
:
prop-2-en-1-one (3c) Pale yellow solid (C2H5OH); m.p.
1675 cm-1; 1H NMR (CDCl3, 400 MHz): d = 7.47 (s, 1H,
H-60), 7.15 (d, 1H, J = 7 Hz, H-30), 7.32 (d, 1H, J = 5.2 Hz,
H-20) 6.05 (s, 2H, OCH2O), 2.58 (s, 3H, COCH3); 13C NMR
(CDCl3, 100 MHz) d = 197.5 (C, C-1), 153.6 (C, C-40),
148.5 (C, C-50), 130.4 (C, C-10), 122.5 (C, C-20), 110.1 (C,
C-60), 108.4 (C, C-30), 101.9 (C, OCH2O), 26.8 (CH3, C-2);
MS (ESI) m/z: 164.11 (M?). Anal. Calcd. for C9H8O3: C,
65.81; H, 4.91. Found: C, 65.88; H, 4.87 %.
114–116 °C; IR (KBr)vmax: 3121–2971, 1645, 1541 cm-1
;
1H NMR (CDCl3, 400 MHz): d = 8.09 (d, 1H, J = 7.3 Hz,
H-3), 7.63 (s, 1H, H-60), 7.51 (d, 1H, J = 5.4 Hz, H-2),
7.40–7.49 (dd, 2H, J = 5, 7 Hz, H-20, H-30), 7.16 (s,
2H, H-200, H-600), 6.10 (s, 2H, OCH2O), 3.77 (s, 9H, OCH3);
13C NMR (CDCl3, 100 MHz) d = 196.3 (C, C-1), 154.1
(C, C-40), 153.3 (C, C-300, C-500), 149.7 (C, C-50), 145.3 (C,
C-3), 138.7 (C, C-400), 126.1 (C, C-100), 123.3 (C, C-20),
122.5 (C, C-10), 121.5 (C, C-1), 108.2 (C, C-30), 107.6 (C,
C-60), 103.5 (C, C-200, C-600), 101.6 (C, OCH2O), 60.7 (C,
C-400, OCH3), 56.5 (C, H3CO–C-300, H3CO–C-500); MS
(ESI) m/z: 342.16 (M?). Anal. Calcd. for C19H18O6: C, 66.66;
H, 5.30. Found: C, 66.62; H, 5.27 %.
General procedure for the synthesis of substituted (E)-1-
(benzo[d][1,3]dioxol-5-yl)-3-phenylprop-2-en-1-one
(chalcones) (3a–i)
1-(Benzo[d][1,3]dioxol-5-yl)ethanone (2) (0.16 g, 1 mmol)
and substituted aromatic aldehydes (1 mmol) were stirred
in water (10 mL) and ethanol (5 mL) mixture in the pre-
sence of sodium hydroxide (0.08 g, 2 mmol) at 15–30 °C
for 4 h. The reaction mixture was kept overnight in an ice
bath. The precipitated products were filtered and recrys-
tallized from ethanol.
(E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(2-isopropylphenyl)
prop-2-en-1-one (3d) Light yellow solid (C2H5OH); m.p.
139–141 °C; IR (KBr)vmax: 3132–2963, 1651, 1535 cm-1
;
1H NMR (CDCl3, 400 MHz): d = 8.29 (d, 1H, J = 7.1 Hz,
H-3), 7.62 (s, 1H, H-60), 7.49 (d, 1H, J = 5.8 Hz, H-2),
7.42 (d, 1H, J = 5.1 Hz, H-20), 7.25–7.40 (m, 5H, H-30, H-
200, H-300, H-500, H-600), 6.04 (s, 2H, OCH2O), 2.82 (m,
6H, CH3), 1.17 (d, 1H, J = 6.1 Hz, CH3CH); 13C NMR
(CDCl3, 100 MHz) d = 196.0 (C, C-1), 154.8 (C, C-40),
149.6 (C, C-50), 145.2 (C, C-400), 141.3 (C, C-3), 133.3 (C,
C-100), 127.9 (C, C-200, C-600), 126.4 (C, C-300, C-500), 123.5
(C, C-20), 122.1 (C, C-10), 121.5(C, C-2), 108.6 (C, C-30),
(E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(4-(methylthio)phenyl)
prop-2-en-1-one (3a) Light yellow solid (C2H5OH); m.p.
101–103 °C; IR (KBr)vmax: 3125–2960, 1630, 1549 cm-1
;
1H NMR (CDCl3, 400 MHz): d = 8.10 (d, 1H, J = 7.2 Hz,
H-3), 7.59 (s, 1H, H-60), 7.57 (d, 1H, J = 5.8 Hz,
123

Med Chem Res
107.0 (C, C-60), 101.6 (C, OCH2O), 29.6 (CH, CHC2H6),
23.4 (C2H6, CHC2H6); MS (ESI) m/z: 294.15 (M?). Anal.
Calcd. for C19H18O3: C, 77.53; H, 6.16. Found: C, 77.51;
H, 6.11 %.
(E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(4-nitrophenyl)prop-2-
en-1-one (3h) Light yellow solid (C2H5OH); m.p. 108–
1
110 °C; IR (KBr)vmax: 3140–2926, 1640, 1543 cm-1; H
NMR (CDCl3, 400 MHz): d = 8.28 (d, 1H, J = 7.3 Hz,
H-3), 7.90–8.08 (dd, 2H, J = 5.3, 7.0 Hz, H-300, H-500), 7.81
(d, 1H, J = 5.1 Hz, H-2), 7.80 (s, 1H, H-60), 7.60–7.75
(dd, 2H, J = 5.0, 7.5 Hz, H-200, H-600), 7.42 (s, 1H, H-20),
7.21 (s, 1H, H-30), 6.08 (s, 2H, OCH2O); 13C NMR
(CDCl3, 100 MHz) d = 196.0 (C, C-1), 154.8 (C, C-40),
149.3 (C, C-50), 147.4 (C, C-400), 145.9 (C, C-3), 141.5 (C,
C-100), 129.3 (C, C-200, C-600), 123.6 (C, C-300, C-500), 123.1
(C, C-20), 122.8 (C, C-10), 121.4 (C, C-2), 108.7 (C, C-30),
107.5 (C, C-60), 101.4 (C, OCH2O); MS (ESI) m/z: 297.06
(M?). Anal. Calcd. for C16H11NO5: C, 64.65; H, 3.73; N,
4.66. Found: C, 64.61; H, 3.69; N, 4.70 %.
(E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-p-tolylprop-2-en-1-one
(3e) Dark yellow solid (C2H5OH); m.p. 133–135 °C; IR
(KBr)vmax
: ;
3120–2951, 1662, 1539 cm-1 1H NMR
(CDCl3, 400 MHz): d = 8.15 (d, 1H, J = 6.5 Hz, H-3),
7.66 (s, 1H, H-60), 7.53 (d, 1H, J = 6.0 Hz, H-20), 7.46 (d,
1H, J = 5.1 Hz, H-2), 7.21–7.38 (m, 5H, H-30, H-200, H-300,
H-500, H-600), 6.02 (s, 2H, OCH2O), 2.39 (s, 3H, CH3); 13C
NMR (CDCl3, 100 MHz) d = 196.9 (C, C-1), 154.3 (C, C-
40), 149.6 (C, C-50), 145.0 (C, C-3), 137.8 (C, C-400), 132.5
(C, C-100), 128.9 (C, C-300, C-500), 128.4 (C, C-200, C-600),
123.3 (C, C-20), 122.6 (C, C-10), 121.5 (C, C-2), 108.6 (C,
C-30), 107.3 (C, C-60), 101.3 (C, OCH2O), 21.6 (C, CH3);
MS (ESI) m/z: 266.05 (M?). Anal. Calcd. for C17H14O3: C,
76.68; H, 5.30. Found: C, 76.63; H, 5.28 %.
(E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(2-nitrophenyl)prop-2-
en-1-one (3i) Light yellow solid (C2H5OH); m.p. 144–
1
146 °C; IR (KBr)vmax: 3145–2920, 1652, 1529 cm-1; H
NMR (CDCl3, 400 MHz): d = 8.58 (d, 1H, J = 7.0 Hz,
H-3), 8.28 (d, 1H, J = 5.0 Hz, H-300), 7.72 (d, 1H, J =
5.2 Hz, H-2), 7.71 (s, 1H, H-60), 7.15–7.53 (m, 5H, H-20,
H-30, H-400, H-500, H-600), 6.03 (s, 2H, OCH2O); 13C NMR
(CDCl3, 100 MHz) d = 196.5 (C, C-1), 154.6 (C, C-40),
149.6 (C, C-50), 147.4 (C, C-200), 145.3 (C, C-2), 134.5 (C,
C-500), 128.4 (C, C-400), 127.6 (C, C-100, C-600), 123.6 (C, C-
300), 123.4 (C, C-20), 122.9 (C, C-10), 121.7 (C, C-2), 108.0
(C, C-30), 107.5 (C, C-60), 101.5 (C, OCH2O); MS (ESI) m/z:
297.20 (M?). Anal. Calcd. for C16H11NO5: C, 64.65; H,
3.73; N, 4.71. Found: C, 64.60; H, 3.68; N, 4.65 %.
(E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(3,4-dimethylphenyl)
prop-2-en-1-one (3f) Light yellow solid (C2H5OH); m.p.
121–123 °C; IR (KBr)vmax: 3127–2963, 1657, 1545 cm-1
;
1H NMR (CDCl3, 400 MHz): d = 8.13 (d, 1H, J =
6.2 Hz, H-3), 7.71 (s, 1H, H-60), 7.66 (d, 1H, J = 4.9 Hz,
H-2), 7.63 (s, 1H, H-20), 7.50 (s, 1H, H-30), 6.8 (m, 3H, H-
200, H-500, H-600), 6.06 (s, 2H, OCH2O), 2.37 (s, 6H, CH3);
13C NMR (CDCl3, 100 MHz) d = 196.3 (C, C-1), 154.8
(C, C-40), 149.5 (C, C-50), 145.6 (C, C-3), 136.6 (C, C-300),
136.1 (C, C-400), 132.1 (C, C-100), 132.0 (C, C-500), 131.6
(C, C-200), 125.6 (C, C-600), 123.9 (C, C-20), 122.7 (C, C-10),
121.3 (C, C-2), 108.6 (C, C-30), 107.4 (C, C-60), 101.6 (C,
OCH2O), 19.5 (C, H3C-300), 18.1 (C, H3C-400); MS (ESI) m/z:
280.05 (M?). Anal. Calcd. for C18H16O3: C, 77.12; H, 5.75.
Found: C, 77.07; H, 5.70 %.
General procedure for the synthesis of substituted
3-(benzo[d][1,3]dioxol-5-yl)-1,5-diphenyl-1H-pyrazole
(4a–i)
A mixture of benzodioxole chalcones (3a–i) (1 mmol) and
phenyl hydrazine (0.06 g, 1.2 mmol) in absolute ethanol
was refluxed for 3 h. The reaction mixture was cooled to
°C with ice cold water. The precipitate thus obtained was
filtered, washed with water and purified by recrystallization
from ethanol.
(E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(3,4-dimethoxyphenyl)
prop-2-en-1-one (3g) Dark yellow solid (C2H5OH); m.p.
138–140 °C; IR (KBr)vmax: 3137–2968, 1652, 1549 cm-1
;
1H NMR (CDCl3, 400 MHz): d = 8.09 (d, 1H, J = 6.7 Hz,
H-3), 7.75 (s, 1H, H-60), 7.68 (s, 1H, H-20), 7.55 (s, 1H,
H-30), 7.51 (d, 1H, J = 4.7 Hz, H-2), 6.98–7.42 (m, 3H, H-
200, H-500, H-600), 6.03 (s, 2H, OCH2O), 3.89 (s, 6H, OCH3);
13C NMR (CDCl3, 100 MHz) d = 193.5 (C, C-1), 154.6
(C, C-40), 149.7 (C, C-300), 149.2 (C, C-40), 149.1 (C, C-400),
145.3 (C, C-3), 127.8 (C, C-100), 123.5 (C, C-20), 122.9 (C,
C-10), 121.4 (C, C-2), 111.9 (C, C-500), 111.3 (C, C-200),
108.8 (C, C-30), 107.5 (C, C-50), 101.3 (C, OCH2O), 56.9
(C, H3CO-300, H3CO-400); MS (ESI) m/z: 312.06 (M?).
Anal. Calcd. for C18H16O5: C, 69.22; H, 5.16. Found: C,
69.17; H, 5.13 %.
3-(Benzo[d][1,3]dioxol-5-yl)-5-(4-(methylthio)phenyl)-1-
phenyl-1H-pyrazole (4a) Light brown solid (C2H5OH);
m.p. 150–152 °C; IR (KBr)vmax: 3267, 3140–2962 cm-1
;
1H NMR (CDCl3, 400 MHz): d = 7.65 (s, 1H, H-60), 7.53
(d, 1H, J = 7.0 Hz, H-20), 7.47–7.41 (m, 5H, H-30, H-200,
H-300, H-500, H-600), 7.35–7.21 (m, 5H, N-phenyl-H-6, H-7,
H-8, H-9, H-10, H-11), 7.05 (s, 1H, H-4), 6.10 (s, 2H,
OCH2O), 2.59 (s, 3H, SCH3); 13C NMR (CDCl3,
100 MHz) d = 151.6 (C, C-1), 149.5 (C, C-50), 148.9 (C,
C-40), 144.1 (C, C-5), 139.9 (C, C-6), 139.3 (C, C-400), 129.
7 (C, C-100), 129.5 (C, C-8, C-10), 128.5 (C, C-10), 127.5(C,
123

Med Chem Res
C-200, C-600), 127.1 (C, C-300, C-500), 126.9 (C, C-9), 124.8
(C, C-7, C-11), 120.4 (C, C-20), 108.7 (C, C-30), 106.5 (C,
C-60), 101.5 (C, OCH2O), 14.3 (C, SCH3); MS (ESI) m/z:
386.05 (M?). Anal. Calcd. for C23H18N2O2S: C, 71.48; H,
4.69; N, 7.25. Found: C, 71.42; H, 4.66; N, 7.22 %.
126.1 (C, C-200, C-600), 124.8 (C, C-7, C-11), 122.7 (C, C-20),
108.9 (C, C-30), 108.3 (C, C-60), 106.5 (C, C-4), 101.5 (C,
OCH2O), 28.8, (CH, CHC2H6), 23.9 (C2H6, CHC2H6); MS
(ESI) m/z: 382.10 (M?). Anal. Calcd. for C25H22N2O2: C,
78.51; H, 5.80; N, 7.32. Found: C, 78.50; H, 5.79; N,
7.30 %.
3-(Benzo[d][1,3]dioxol-5-yl)-1,5-diphenyl-1H-pyrazole (4b)
Dark brown solid (C2H5OH); m.p. 161–163 °C; IR
3-(Benzo[d][1,3]dioxol-5-yl)-1-phenyl-5-p-tolyl-1H-pyrazole
(KBr)vmax: 3282, 3129–2975 cm-1
;
1H NMR (CDCl3,
(4e) Light brown solid (C2H5OH); m.p. 166–168 °C; IR
400 MHz): d = 7.69 (s, 1H, H-60), 7.55 (d, 1H, J = 7.
3 Hz, H-20), 7.48, (d, 1H, J = 5.3 Hz, H-30), 7.41–7.20 (m,
5H, H-200, H-300, H-400, H-500, H-600), 7.20–7.12 (m, 5H,
N-phenyl-H-6, H-7, H-8, H-9, H-10, H-11), 7.09 (s, 1H, H-4),
6.15 (s, 2H, OCH2O); 13C NMR (CDCl3, 100 MHz) d =
151.5 (C, C-1), 149.6 (C, C-50), 148.9 (C, C-40), 144.5 (C,
C-5), 139.5 (C, C-6), 129.5 (C, C-100), 129.3 (C, C-8, C-10),
129.0 (C, C-300, C-500), 128.6 (C, C-400), 128.5 (C, C-10),
127.3 (C, C-200, C-600), 126.4 (C, C-9), 124.3 (C, C-7, C-
11), 120.5 (C, C-20), 108.5 (C, C-30), 108.1 (C, C-40), 106.6
(C, C-4), 101.3 (C, OCH2O); MS (ESI) m/z: 340.15 (M?).
Anal. Calcd. for C22H16N2O2: C, 77.63; H, 4.74; N, 8.23.
Found: C, 77.59; H, 4.71; N, 8.21 %.
(KBr)vmax: 3285, 3120–2970 cm-1 1H NMR (CDCl3,
;
400 MHz): d = 7.75 (s, 1H, H-60), 7.59–7.41 (d, 1H, J =
5.8 Hz, H-20), 7.36–7.15 (m, 5H, H-30, H-200, H-300, H-500,
H-600), 7.15-7.04 (m, 5H, N-phenyl-H-6, H-7, H-8, H-9, H-
10, H-11), 7.08 (s, 1H, H-4), 6.09 (s, 2H, OCH2O), 2.41 (m,
3H, CH3); 13C NMR (CDCl3, 100 MHz) d = 151.6 (C, C-
1), 149.3 (C, C-50), 148.7 (C, C-40), 144.5 (C, C-5), 139.9
(C, C-6), 131.5 (C, C-400), 130.4 (C, C-100), 129.6 (C, C-300,
C-500), 129.3 (C, C-8, C-10), 128.7 (C, C-10), 126.5 (C, C-
9), 125.3 (C, C-200, 600), 124.8 (C, C-7, C-11), 120.6 (C, C-
20), 108.8 (C, C-30), 108.5 (C, C-60), 106.3 (C, C-4), 101.7
(C, OCH2O), 21.5 (C, CH3); MS (ESI) m/z: 354.05 (M?).
Anal. Calcd. for C23H18N2O2: C, 77.95; H, 5.12; N, 7.90.
Found: C, 77.93; H, 5.10; N, 7.89 %.
3-(Benzo[d][1,3]dioxol-5-yl)-1-phenyl-5-(3,4,5-trimethoxy-
phenyl)-1H-pyrazole (4c) Dark brown solid (C2H5OH);
3-(Benzo[d][1,3]dioxol-5-yl)-5-(3,4-dimethylphenyl)-1-
m.p. 157–159 °C; IR (KBr)vmax: 3253, 3127–2987 cm-1
;
phenyl-1H-pyrazole (4f) Dark brown solid (C2H5OH);
1H NMR (CDCl3, 400 MHz): d = 7.68 (s, 1H, H-60), 7.51–
7.44 (dd, 2H, J = 7.7, J = 5.3 Hz, H-20, H-30), 7.25 (s, 2H,
H-200, 600), 7.22–7.09 (m, 5H, N-phenyl-H-6, H-7, H-8, H-9,
H-10, H-11), 7.07 (s, 1H, H-4), 6.10 (s, 2H, OCH2O), 3.87
(s, 9H, OCH3); 13C NMR (CDCl3, 100 MHz) d = 153.3
(C, C-300, C-500), 151.5 (C, C-1), 149.5 (C, C-50), 148.6 (C,
C-40), 144.6 (C, C-5), 139.1 (C, C-6), 139.0 (C, C-400), 129.5
(C, C-8, C-10), 128.5 (C, C-10), 127.9 (C, C-100), 126.7
(C, C-9), 124.7 (C, C-7), 120.8 (C, C-20), 108.7 (C, C-30),
108.2 (C, C-60), 106.6 (C, C-4), 101.6 (C, OCH2O), 100.9
(C, C-200, 600), 60.5, (C, C-400, OCH3), 56.4 (C, H3CO–C-300,
H3CO–C-500); MS (ESI) m/z: 430.05 (M?). Anal. Calcd. for
C25H22N2O5: C, 69.76; H, 5.15; N, 6.51. Found: C, 69.68;
H, 5.11; N, 6.49 %.
m.p. 172–174 °C; IR (KBr)vmax: 3280, 3125–2977 cm-1
;
1H NMR (CDCl3, 400 MHz): d = 7.65 (s, 1H, H-60), 7.61
(s, 1H, H-20), 7.53 (s, 1H, H-30), 7.35–7.25 (m, 3H, H-200,
H-500, H-600), 7.20–7.08 (m, 5H, N-phenyl-H-6, H-7, H-8,
H-9, H-10, H-11), 7.08 (s, 1H, H-4), 7.04 (s, 1H, H-4), 6.00
(s, 2H, OCH2O), 2.39 (m, 6H, CH3); 13C NMR (CDCl3,
100 MHz) d = 151.8 (C, C-1), 149.4 (C, C-50), 148.8 (C,
C-40), 144.5 (C, C-5), 139.5 (C, C-6), 137.6 (C, C-300), 136.
6 (C, C-400), 130.5 (C, C-200), 129.9 (C, C-100), 129.5 (C, C-
500), 129.1 (C, C-8, C-10), 128.5 (C, C-10), 126.4 (C, C-9),
124.9 (C, C-7, C-11), 122.5 (C, C-600), 120.3 (C, C-20), 108.
9 (C, C-30), 108.6 (C, C-60), 106.5 (C, C-4), 101.7 (C,
OCH2O), 19.8, (C, H3C-300), 18.2 (C, H3C-400); MS (ESI)
m/z: 368.11 (M?). Anal. Calcd. for C24H20N2O2: C, 78.24;
H, 5.47; N, 7.60. Found: C, 78.19; H, 5.43; N, 7.57 %.
3-(Benzo[d][1,3]dioxol-5-yl)-5-(2-isopropylphenyl)-1-phe-
nyl-1H-pyrazole (4d) Light brown solid (C2H5OH); m.p.
3-(Benzo[d][1,3]dioxol-5-yl)-5-(3,4-dimethoxyphenyl)-1-
176–178 °C; IR (KBr)vmax: 3291, 3122–2979 cm-1
;
1H
phenyl-1H-pyrazole (4g) Dark brown solid (C2H5OH);
NMR (CDCl3, 400 MHz): d = 7.65 (s, 1H, H-60), 7.60 (d,
1H, J = 5.3 Hz, H-20), 7.54–7.31 (m, 5H, H-30, H-200,
H-300, H-500, H-600), 7.24–7.10 (m, 5H, N-phenyl-H-6, H-7,
H-8, H-9, H-10, H-11), 7.05 (s, 1H, H-4), 6.05 (s, 2H,
OCH2O), 2.72 (m, 6H, CH3), 1.15 (d, 1H, J = 6.5 Hz,
CH3CH); 13C NMR (CDCl3, 100 MHz) d = 151.5 (C, C-
1), 149.3 (C, C-50), 148.7 (C, C-40), 146.9 (C, C-400), 144.5
(C, C-5), 139.9 (C, C-6), 131.5 (C, C-100), 129.6 (C, C-8,
C-10), 128.9 (C, C-10), 128.4 (C, C-300, C-500), 126.9 (C, C-9),
m.p. 197–199 °C; IR (KBr)vmax: 3288, 3135–2986 cm-1
;
1H NMR (CDCl3, 400 MHz): d = 7.69 (s, 1H, H-60), 7.61
(s, 1H, H-20), 7.52 (s, 1H, H-30), 7.45–7.32 (m, 3H, H-200,
H-500, H-600), 7.25–7.11 (m, 5H, N-phenyl-H-6, H-7, H-8,
H-9, H-10, H-11), 7.06 (s, 1H, H-4), 6.12 (s, 2H, OCH2O),
3.89 (m, 6H, OCH3); 13C NMR (CDCl3, 100 MHz) d =
151.9 (C, C-1), 150.6 (C, C-300), 149.8 (C, C-400), 149.5 (C,
C-50), 148.6 (C, C-40), 144.6 (C, C-5), 139.7 (C, C-6), 129.
8 (C, C-8, C-10), 128.6 (C, C-10), 126.7 (C, C-100), 126.6
123

Med Chem Res
(C, C-9), 124.6 (C, C-7, C-11), 120.8 (C, C-20), 110.5 (C,
C-500), 108.9 (C, C-30), 108.7 (C, C-60), 106.6 (C, C-4), 101.3
(C, OCH2O), 56.3 (C, H3CO-300, H3CO-400); MS (ESI) m/z:
400.10 (M?). Anal. Calcd. for C24H20N2O4: C, 71.99; H,
5.03; N, 7.00. Found: C, 71.96; H, 5.00; N, 6.93 %.
11 (s, 2H, OCH2O); 13C NMR (CDCl3, 100 MHz) d =
151.6 (C, C-1), 149.5 (C, C-50), 148.6 (C, C-40, C-200), 144.7
(C, C-5), 139.4 (C, C-6), 135.8 (C, C-500), 132.9 (C, C-600),
129.7 (C, C-400), 129.1 (C, C-8, C-10), 128.5 (C, C-10), 126.
8 (C, C-9), 125.6 (C, C-100), 124.2 (C, C-7, C-11), 124.0 (C,
C-300), 120.8 (C, C-20), 108.5 (C, C-30), 108.2 (C, C-60),
106.5 (C, C-4), 101.5 (C, OCH2O); MS (ESI) m/z: 385.30
(M?). Anal. Calcd. for C22H15N3O4: C, 68.57; H, 3.92; N,
10.90. Found: C, 68.53; H, 3.90; N, 10.88 %.
3-(Benzo[d][1,3]dioxol-5-yl)-5-(4-nitrophenyl)-1-phenyl-
1H-pyrazole (4h) Dark brown solid (C2H5OH); m.p.
;
1H
165–167 °C; IR (KBr)vmax: 3280, 3130–2990 cm-1
NMR (CDCl3, 400 MHz): d = 8.35-8.09 (dd, 2H, J = 7.1,
5.6 Hz, H-300, H-500), 7.94 (s, 1H, H-60), 7.85–7.61 (dd, 2H,
J = 7.3, 5.1 Hz, H-200, H-600), 7.51 (s, 1H, H-20), 7.43 (s,
1H, H-30) 7.39–7.21 (m, 3H, H-200, H-500, H-600), 7.15–7.05
(m, 5H, N-phenyl-H-6, H-7, H-8, H-9, H-10, H-11), 7.06
(s, 1H, H-4), 6.02 (s, 2H, OCH2O); 13C NMR (CDCl3,
100 MHz) d = 151.9 (C, C-1), 149.5 (C, C-50), 148.6 (C,
C-40), 147.5 (C, C-400), 144.8 (C, C-5), 139.9 (C, C-6), 139.
2 (C, C-100), 129.5 (C, C-8, C-10), 128.8 (C, C-10), 126.4
(C, C-9, C-200, C-600), 124.9 (C, C-7, C-10), 124.7 (C, C-300,
C-500), 120.7 (C, C-20), 108.6 (C, C-30), 108.2 (C, C-60),
106.5 (C, C-4), 101.5 (C, OCH2O); MS (ESI) m/z: 385.13
(M?). Anal. Calcd. for C22H15N3O4: C, 68.57; H, 3.92; N,
10.90. Found: C, 68.55; H, 3.89; N, 10.87 %.
Antimicrobial studies
Test microorganisms
Five microbial strains (four bacterial and one fungus) were
selected on the basis of their clinical importance in causing
diseases in humans. Staphylococcus aureus (MTCC 7443),
Bacillus subtilis (MTCC 121) (Gram-positive bacteria),
Escherichia coli (MTCC 7410) and Pseudomonas aeru-
ginosa (MTCC 7903) (Gram-negative) and Candida albi-
cans (MTCC 2827) were screened for evaluation of
antibacterial and antifungal activities of the newly syn-
thesized compounds.
3-(Benzo[d][1,3]dioxol-5-yl)-5-(2-nitrophenyl)-1-phenyl-
1H-pyrazole (4i) Light brown solid (C2H5OH); m.p.
;
1H
In vitro antibacterial activity
194–196 °C; IR (KBr)vmax: 3286, 3133–2998 cm-1
NMR (CDCl3, 400 MHz): d = 8.08 (d, 1H, J = 5.4 Hz,
H-300), 7.68 (s, 1H, H-60), 7.51–7.45 (m, 5H, H-20, H-30, H-
400, H-500, H-600), 7.34–7.19 (m, 5H, N-phenyl-H-6, H-7, H-
8, H-9, H-10, H-11), 7.06 (s, 1H, H-4), 7.09 (s, 1H, H-4), 6.
The antibacterial activities of the newly synthesized com-
pounds were evaluated by well plated method on Mueller–
Hinton Agar (Singh et al., 2009). All the microbial cultures
were adjusted to 0.5 McFarland standards, which is
O
H
O
6'
O
1
3
6'
3'
2"
5"
5'
4'
O
O
O
O
5'
4'
1"
O
O
Fused ZnCl2
Ac2O, rt, 12 h
1
3"
4"
R
1'
2'
2
1'
2'
2
NaOH, C2H5OH/H2O,
6
"
R
3'
-
rt, 3 4 h
(2)
(1)
(3a-i)
NHNH2
abs.C2H5OH
reflux
8
9
10
11
7
1
2
6
5
N
N
2"
1"
3"
4"
5'
4'
6'
1'
2'
O
3
4
6"
R
O
5"
3'
(4a-i)
Scheme 1 Reaction protocol for the synthesis of novel benzo[d][1,3]dioxole gathered pyrazole derivatives (4a–i)
123

Med Chem Res
Table 1 Chemical structure and yield of newly synthesized com-
pounds (4a–i)
Table 1 continued
Compound no.
Aldehydes
Yield (%)
69.3
Compound no.
Aldehydes
Yield (%)
81.3
4g
4h
4i
H
O
4a
H
O
H
OC
3
H
OC
3
H
SC
3
72.4
H
O2
N
O
4b
88.6
H
O
N
H
4c
74.9
H
O
O
O
31.4
O
O2
H
3CO
H
3
OC
H
OC
3
4d
65.7
H
Table 2 Antibacterial data of newly synthesized compounds (4a–i)
in MIC (mg/mL)
Compound no. E. coli P. aeruginosa B. subtilis S. aureus
Control
–
–
–
–
Gentamicin
1.00
0.25
1.00
2.00
0.25
2.00
1.50
1.50
1.00
1.50
1.00
1.50
1.00
1.50
2.00
1.50
1.50
1.00
0.50
1.00
0.25
1.00
–
1.50
1.00
1.00
0.50
1.50
1.50
1.50
1.00
0.25
0.50
4a
4b
4c
4d
4e
4f
4e
92.4
H
–
–
–
1.00
–
4g
4h
4i
1.50
–
4f
71.6
H
O
Bold values correspond to the most effective antibacterial agents
Concentration of tested compounds: 0.25, 0.50, 1.00, 1.50 and
2.00 mg/well
– No growth
visually comparable to a microbial suspension of approx-
imately 1.5 x108 cfu/mL. 20 mL of agar media was poured
into each Petri plate and plates were swabbed with 100 mL
inocula of the test microorganisms and kept for 15 min for
123

Med Chem Res
adsorption. Using sterile cork borer of 8 mm diameter,
wells were bored into the seeded agar plates and these were
loaded with a100 mL volume with different concentration
of 0.25, 0.50, 1.00, 1.50 and 2.00 mg/mL of each com-
pound reconstituted in the dimethylformamide (DMF). All
the plates were incubated at 37 °C for 24 h. Antimicrobial
activity of all the synthesized compounds was evaluated by
measuring the minimum inhibitory concentration (MIC)
against the test organisms with zone reader (Hi antibiotic
zone scale). The medium with DMF as solvent was used as
a negative control whereas media with Gentamycin (stan-
dard antibiotic) was used as positive control.
Table 3 Antifungal data of newly synthesized compounds (4a–i) in
MIC (mg/mL)
Compound no.
C. albicans
Control
–
Fluconazole
0.50
0.25
1.00
0.25
0.50
1.00
0.50
0.25
0.25
1.00
4a
4b
4c
4d
4e
4f
4g
4h
4i
In vitro antifungal activity
All the newly synthesized compounds were dissolved in
DMF and evaluated for their antifungal activity by well plate
method (MacLowry et al., 1970). The test mold was grown
on sabourauddextrose agar (SDA) at 25 °C for 7–8 days.
One week old culture of the mold was used as inoculums for
evaluating antifungal activity of chemical compounds. The
molten SDA (45 °C) was poisoned by the addition of
100 mL volume having different concentration of 0.25,
0.50, 1.00, 1.50 and 2.00 mg/mL of each compound
reconstituted in the DMF and poured into the sterile Petri
plates. The prepared SDA plates containing the test com-
pounds were inoculated with fungal plugs (8 mm diameter)
obtained from the actively growing margins of the fungal
plates. Plates were incubated at 25 °C for 7 days. The
medium with dimethylformamide (DMF) as solvent was
used as a negative control where as media with Fluconazole
(standard antifungal drug) were used as positive control.
Bold values correspond to the most effective antibacterial agents
Concentration of tested compounds: 0.25, 0.50, 1.00, 1.50 and
2.00 mg/well
– No growth
In the next step, the cyclocondensation of compound (3a–i)
with phenyl hydrazine in absolute ethanol obtained the
corresponding pyrazole derivatives (4a–i) (Amin et al.,
2010). The structures of the compounds (4a–i) were con-
1
firmed by IR, H NMR, 13C NMR, mass spectra and ele-
mental analysis data. The synthesized compounds were
also screened for their antibacterial and antifungal activi-
ties. The results are summarized in Tables 2 and 3.
Antimicrobial activity
The antibacterial activity of the pyrazole derivatives
revealed that some of the compounds showed good inhi-
bition against various tested microbial strains (Table 2).
Benzo[d][1,3]dioxole scaffold, compound (3a–i) possessed
least antibacterial and antifungal activity. Further, reaction
of phenyl hydrazine with chalcones gave pyrazole ring
accounted for the enhanced activities. The results indicated
that among the screened compounds 4a and 4d possessing
p-thiomethyl and p-isopropyl substituent present at the para
position of the 5-substituted phenyl ring showed excellent
activity against E. coli, 4c, 4 h, and 4i possessing 3,4,5-
trimethoxy, p-nitro and ortho-nitro substituent on the
5-substituted phenyl ring showed good activity against
P. aeruginosa and S. aureus, 4e, 4f and 4g possessing
p-methyl, 3,4-dimethyl and 3,4-dimethoxy substituent on
the 5-substituted phenyl ring showed considerable activity
against P. aeruginosa and S. aureus, 4b showed very less
activity against all screened bacteria and all the synthesized
compounds showed very least activity against B. subtilis at
different concentration of 0.25, 0.50, 1.00, 1.50 and
2.00 mg/mL compared to standard drug Gentamycin.
Results and discussion
Chemistry
The synthesis of novel benzo[d][1,3]dioxole gathered pyra-
zole derivatives have been carried out by chalcone route
(Scheme 1). 1-(Benzo[d][1,3]dioxol-5-yl)ethanone (2) was
prepared in excellent yield by the acylation of benzo
[d][1,3]dioxole (1) with acetic anhydride using fused zinc
chloride as catalyst (Kelly and Hart Well, 1954). In the
second step, base catalyzed claisen-schmid reaction of
1-(benzo[d][1,3]dioxol-5-yl)ethanone (2) with substituted
aromatic aldehydes (Table 1) in the presence of sodium
hydroxide in water–ethanol mixture afforded chalcones (3a–i)
(Furniss et al., 1989), (Basavaraju and Devaraju, 2002).
Generally, chalcones are considered to be useful inter-
mediates in several cyclisation reactions to produce het-
erocyclic compounds of diverse biological importance,
according to the reactants used and the reaction conditions.
123

Med Chem Res
Basavaraju YB, Devaraju (2002) Synthesis of analogues of podo-
phyllotoxin: tetralones as intermediates for the synthesis of
analogues of apopicropodophyllin. Indian J Heterocycl Chem
11:229–232
Bouabdallah I, M’barek LA, Zyad A, Ramadan A, Zidane I, Melhaoui
A (2006) Anticancer effect of three pyrazole derivatives. Nat
Prod Res 20:1024–1030
Newly synthesized compounds (4a–i) were also
screened for their antifungal activity against C. albicans
(Table 3). Among the tested compounds, compound 4a, 4c,
4g and 4h possessing p- thiomethyl, 3,4,5-trimethoxy, 3,4-
dimethoxy and p-nitro moiety on 5-substituted phenyl ring
at para position, accounted for the excellent antifungal
activity compared with standard drug fluconazole and as
well as other compounds, whereas compound 4d and 4f
having p-isopropyl and 3,4-dimethyl moiety on 5-substi-
tuted phenyl ring were equal to standard drug but 4e having
p-methyl substituent on the 5-substituted phenyl ring is
slightly less active than the standard drug. The remaining
compound 4b and 4i showed less activity compared to
standard drug against C. albicans.
Chu CK, Cutler SJ (1986) Chemistry and antiviral activities of
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DiParsia MT, Suarez C, Vitolo MJ, Marquez VE, Beyer B, Urbina C,
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solvent-free conditions. J Braz Chem Soc 22:1236–1240
Kelly MG, Hart Well JL (1954) The biological effects and chemical
composition of podophyllin. A review. Natl J Cancer Inst
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MacLowry JD, Jaqua JJ, Selepak ST (1970) Detailed methodology
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Patel P, Gor D, Patel PS (2012) Synthesis, characterization and
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Conclusion
In conclusion, the novel benzo[d][1,3]dioxole gathered
pyrazole derivatives (4a-i) were synthesized. The acylation
of benzo[d][1,3]dioxole with acetic anhydride using fused
zinc chloride as catalyst afforded 1-(benzo[d][1,3]dioxol-5-
yl)ethanone in good yield. Claisen-Schmidt reaction of
1-(benzo[d][1,3]dioxol-5-yl)ethanone with substituted aro-
matic aldehydes afforded respective chalcones (3a–i) in
high yield, which undergo further cyclocondensation with
phenyl hydrazine furnished benzo[d][1,3]dioxole gathered
substituted pyrazole derivatives (4a–i) in good yields. The
newly synthesized compounds (4a–i) were evaluated for
their in vitro antimicrobial activity, the compounds 4a, 4c,
4 g and 4 h showed the excellent antifungal activity and as
well as 4a and 4d showed the excellent antibacterial
activity compared to other compounds.
Acknowledgments The authors are thankful to Indian Institute of
Technology (IIT), Hyderabad for providing spectral data.
Pimerova EV, Voronina EV (2001) Antimicrobial activity of
pyrazoles and pyridazines obtained by interaction of 4-aryl-3-
arylhydrazono-2,4- dioxobutanoic acids and their esters with
hydrazines. Pharm Chem J 35:18–20
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