Piperidine mediated synthesis of N-heterocyclic chalcones and their antibacterial activity

Article abstract of DOI:10.1002/jhet.268

(Chemical Equation Presented) The chalcones 1-(2′-hydroxy-aryl)-3-(1- indol-3-yl)-prop-2-en-1-one (3) and 1-(2′-hydroxy-aryl)-3-(2- chloroquinolin-3-yl)-prop-2-en-1-one (6) were synthesised by piperidine mediated condensation of an ethanolic solution of a

Full text of DOI:10.1002/jhet.268

January 2010
Piperidine Mediated Synthesis of N-Heterocyclic Chalcones and
Their Antibacterial Activity
81
P. Venkatesan1* and S. Sumathi
School of Chemistry, Madurai Kamaraj University, Madurai, Tamil Nadu 625 021, India
1Present address: Department of Chemistry, Mahendra Institute of Technology, India 637 503
*E-mail: venkatesanps@yahoo.co.in
Received May 28, 2009
DOI 10.1002/jhet.268
Published online 29 December 2009 in Wiley InterScience (www.interscience.wiley.com).
The chalcones 1-(20-hydroxy-aryl)-3-(1-indol-3-yl)-prop-2-en-1-one (3) and 1-(20-hydroxy-aryl)-3-(2-chlor-
oquinolin-3-yl)-prop-2-en-1-one (6) were synthesised by piperidine mediated condensation of an ethanolic
solution of an o-hydroxyacetophenone (1) with corresponding heteroaryl-3-carboxaldehyde. The structures
have been established on the basis of elemental (C, H, N) analysis, UV, IR, H NMR spectral data. The
1
compounds 3 and 6 were screened for antimicrobial activities against a variety of bacterial agents.
J. Heterocyclic Chem., 47, 81 (2010).
INTRODUCTION
RESULTS AND DISCUSSION
Chalcones are well known naturally occurring pig-
ments which serve as valuable intermediate in organic
synthesis of flavonoid compounds [1]. It has found sig-
nificant role in pharmaceutical effects [2] including anti-
oncogenic, antiinflammatory, antiulcerative, analgesic,
antiviral, antimalarial and antibacterial activities. Chlor-
oquinoline [3] and indole [4] compounds are known to
exhibit variety of antimicrobial activity. Also, it has
been reported that chalcone having quinoline moiety is
an intermediate for the synthesis of chloroquinoline cya-
nopyridines and cyanopyrans derivatives [5].
The syntheses of 1-(20-hydroxy-aryl)-3-(1-indol-3-yl)-
prop-2-en-1-one (3) and 1-(20-hydroxyaryl)-3-(2-chloro-
quinolin-3-yl)-prop-2-en-1-one (6) was carried out by
condensation of an ethanolic solution of an o-hydroxya-
cetophenone (1) in the presence of piperidine with
indole-3-carboxaldehyde (2) and with 2-chloroquinolin-
3-carboxaldehyde (5) as shown in Scheme 1.
The compounds 3 and 6 gave violet colouration with
alcoholic FeCl3 test indicating the presence of chelated
hydroxyl group in it. Also, gave positive test for presence
of elements such as N and Cl in corresponding chalcone
by sodium fusion extraction test. When using AlCl3-HCl as
shift reagents, bathochromic shift about 40 nm at band-I
was observed in UV spectral studies of products 3 and 6
due to presence of chelated hydroxyl group. IR spectra of
compounds 3 revealed the presence of ANH absorption
bands in the region of 3228–3098 cmꢀ1, in addition to two
characteristic signals about 1630 cmꢀ1 for the unsaturated
keto group and 3043–3444 cmꢀ1 for hydroxyl groups. Sim-
ilarly, IR spectrum of compounds 6 showed absorption at
3436–3431 cmꢀ1, 1654–1621 cmꢀ1, 1446–1432 cmꢀ1 and
744–756 cmꢀ1 for presence of AOH, AC¼¼O, AC¼¼NA,
In the Claisen-Schemidt condensation of Chalcone
synthesis, 20-hydroxy functional group may cyclise to
the corresponding flavanones under higher concentration
of alkali. Also, side reactions such as multiple condensa-
tions, polymerizations, and rearrangements are common.
These undesirable side reaction decreases the yields of
the target adduct and render their purification difficult
[6]. So, it was planned to use a weaker base like piperi-
dine instead of using strong base to enhance the better
yields.
In present communication, we report piperidine medi-
ated synthesis of N-heterocyclic chalcones 3 and 6 from
indole-3-carboxaldehyde and 2-chloroquinoline-3-car-
boxaldehyde respectively. The structures of the com-
pound 3 and 6 have been established on the basis of ele-
1
ACl groups, respectively. The H NMR spectra gave two
doublet centred about d 7.6 and d 8.2 with coupling con-
stant about J ¼ 15 Hz were assigned to the trans olefinic
1
proton at Ca and Cb position. The entire H NMR spectral
1
mental (C, H, N) analysis, UV, IR, H NMR spectral
data and they were screened for antibacterial activities.
data were given in the experimental part and the values
were in accordance with the title compounds 3 and 6.
C
V
2009 HeteroCorporation

82
P. Venkatesan and S. Sumathi
Vol 47
Scheme 1
Silica Gel-G and spotting was done using iodine or UV light.
UV spectra were taken in Perkin-Elmer 402 UV-Vis spectro-
photometer. IR spectra were recorded in Perkin-Elmer 577 IR
spectrophotometer. 1H NMR spectra were conducted on
Bruker (300 MHz) spectrometer in CDCl3 with tetramethylsi-
lane as the internal standard. The chemical shifts are reported
in ppm scale. The compound (2) was obtained from SISCO
research laboratories and used as such. The compound (5) was
prepared adopting the published procedure with the same melt-
ing point at 150ꢁC [8].
Antibacterial activities. The antibacterial activity of
the compounds 3 and 6 have been evaluated using filter
paper disc diffusion method [7] at a concentration of 100
lg/disc against human pathogenic bacteria such as Staphy-
lococcus aureus (Gþ), Shigella dysenteriae (Gꢀ) and Sal-
monella typhi (Gꢀ). Kanamycin (30 lg/disc) was used as
standard for comparing the activity. Each sample was
used in triplicates for the determination of antibacterial ac-
tivity. The diameter of observed inhibition zone of 3 and
6 were measured (in mm) and they are given in Table 1.
By visualizing the antibacterial data, it could be
observed that most of the compound shows significant
activity. The compound 3e, 6a, 6e showed excellent ac-
tivity for all the three test microorganisms. However,
compounds 3d, 6c are inactive against S. aureus and
compounds 3d, 6b are inactive for S. dysenteriae. Simi-
larly compounds 3b, 6d are inactive against S. typhi.
The preliminary result confirms the importance of chlor-
oquinone nucleus and indole nucleus with respect to
antibacterial activity.
General procedure for synthesis of 1-(20-hydroxy-aryl)-3-
(1-indol-3-yl)-prop-2-en-1-one (3). To a mixture of o-hydrox-
yacetophenone (0.01 mol) and indole-3-carboxaldehyde (0.01
mol) in ethanol (50 mL), piperidine (1 mL) was added and
refluxed. After the completion of reaction, which was moni-
tored by TLC, ethanol was distilled off and residue was poured
on ice water (100 mL). It was kept overnight in the refrigera-
tor. The resulting solid was collected by filtration, washed
with distilled water and crystallized from methanol to give
corresponding chalcone 3.
Synthesis of 1-(20-hydroxy-40-methoxyphenyl)-3-(1-indol-3-
yl)-prop-2-en-1-one (3a). Yellow solid (0.75 g, 25.6%); mp.
196ꢁC; kmax (CHCl3, nm): 274, 396; ir (KBr, cmꢀ1):
3374(mOH), 3225(m
NH), 1625(mC¼¼O); 1H NMR (300 MHz,
>
CDCl3): d 13.90 (s, 1H, 20-OH), 6.54 (d, 1H, 30-H), 3.87 (s,
3H, 40-OCH3), 6.44 (d, 1H, 50-H), 7.96 (d, 1H, 60-H), 7.81 (d,
1H, CaH, J ¼ 15.3 Hz), 8.18 (d, 1H, CbH, J ¼ 15.3 Hz), 8.61
(s, 1H, > NH), 7.66 (d, 1H, 2-H), 8.04 (d, 1H, 4-H), 7.33 (m,
2H, 5- and 6-H), 7.46 (m, 1H, 7-H); Anal. Calcd for
EXPERIMENTAL
Melting point determinations were made in open capillaries
and were uncorrected. TLC was carried out using Merck brand
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010
Piperidine Mediated Synthesis of N-Heterocyclic Chalcones and Their
Antibacterial Activity
83
Table 1
Antibacterial activity of compound 3 and 6.
Diameter of zone inhibition (mm)
S. dysenteriae
R
Compound
S. aureus
S. typhi
3a
3b
3c
3d
3e
6a
6b
18 6 0.7
12 6 0.9
10 6 0.7
–
19 6 1.1
18 6 0.8
16 6 0.9
–
21 6 0.6
–
15 6 0.7
12 6 1.1
24 6 2.1
22 6 0.5
14 6 0.7
11 6 0.7
–
a: R2 ¼ OCH3; R1, R3, R4 ¼ H
b: R3 ¼ OCH3; R1, R2, R4 ¼ H
c: R1, R2 ¼ OCH3; R3, R4 ¼ H
d: R1, R2, R4 ¼ OCH3; R3 ¼ H
e: R2, R4 ¼ OCH3; R1, R3 ¼ H
28 6 1.2
26 6 2.3
23 6 1.8
–
20 6 1.3
22 6 0.9
29 6 2.1
27 6 1.1
26 6 1.2
–
6c
6d
13 6 0.5
22 6 0.9
24 6 0.5
31 6 1.8
6e
Kanamycin
22 6 0.8
28 6 1.6
C18H15NO3 (293.32): C, 73.71; H, 5.15; N, 4.78. Found: C,
73.52; H, 5.14; N, 4.71.
Synthesis of 1-(20-hydroxy-50-methoxyphenyl)-3-(1-indol-3-
yl)-prop-2-en-1-one (3b). Yellow solid (0.9 g, 30.7%); mp.
120ꢁC; kmax (CHCl3, nm): 258, 344; ir (KBr, cmꢀ1):
for C19H17NO4 (323.34): C, 70.58; H, 5.30; N, 4.33. Found:
C, 70.41; H, 5.29; N, 4.29.
General procedure for synthesis of 1-(20-hydroxy-aryl)-3-
(2-chloroquinolin-3-yl)-prop-2-en-1-one (6). To a mixture of
o-hydroxyacetophenone (0.01 mol) and 2-chloroquinoline-3-
carboxaldehyde (0.01 mol) in ethanol (50 mL), piperidine
(1 mL) was added and refluxed. After the completion of reac-
tion, which was monitored by TLC, ethanol was distilled off
and residue was poured on ice water (100 mL). It was kept
overnight in the refrigerator. The resulting solid was collected
by filtration, washed with distilled water and crystallized from
methanol to give corresponding chalcone 6.
3444(mOH), 3166(m
NH), 1633(mC¼¼O); 1H NMR (300 MHz,
>
CDCl3): d 12.80 (s, 1H, 20-OH), 6.97 (d, 1H, 30-H), 7.11 (d,
1H, 40-H), 3.87 (s, 3H, 50-OCH3), 7.97 (s, 1H, 60-H), 7.85 (d,
1H, CaH, J ¼ 15.3 Hz), 8.22 (d, 1H, CbH, J ¼ 15.3 Hz), 8.61
(s, 1H, > NH), 7.54 (d, 1H, 2-H), 8.04 (d, 1H, 4-H), 7.34 (m,
2H, 5- and 6-H), 7.46 (m, 1H, 7-H); Anal. Calcd for
C18H15NO3 (293.32): C, 73.71; H, 5.15; N, 4.78. Found: C,
73.73; H, 5.16; N, 4.72.
Synthesis of 1-(20-hydroxy-40-methoxyphenyl)-3-(2-chloro-
quinolin-3-yl)-prop-2-en-1-one (6a). Yellow solid (1.32 g,
38.9%); mp. 226ꢁC; kmax (CHCl3, nm): 269, 361; ir (KBr,
cmꢀ1): 3432(mOH), 1633(mC¼¼O), 1432(mAC¼¼NA), 748(mCl); 1H
NMR (300 MHz, CDCl3): d 13.10 (s, 1H, 20-OH), 6.48 (s, 1H,
30-H), 3.75 (s, 3H, 40-OCH3), 6.42 (d, 1H, 50-H), 7.92 (d, 1H,
60-H), 7.56 (d, 1H, CaH, J ¼ 15.2 Hz), 7.83 (d, 1H, CbH, J ¼
15.2 Hz), 8.06 (s, 1H, 4-H), 7.72 (d, 1H, 5-H), 7.48 (m, 2H, 6-
and 7-H), 7.61 (m, 1H, 8-H); Anal. Calcd for C19H14ClNO3
(339.77): C, 67.16; H, 4.15; N, 4.12. Found: C, 67.27; H,
4.12; N, 4.17.
Synthesis of 1-(20-hydroxy-50-methoxyphenyl)-3-(2-chloro-
quinolin-3-yl)-prop-2-en-1-one (6b). Yellow solid (0.83 g,
24.5%); mp. 216ꢁC; kmax (CHCl3, nm): 258, 331; ir (KBr,
cmꢀ1): 3434(mOH), 1654(mC¼¼O), 1434(mAC¼¼NA), 750(mCl); 1H
NMR (300 MHz, CDCl3): d 12.80 (s, 1H, 20-OH), 6.97 (d, 1H,
30-H), 7.18 (d, 1H, 40-H), 3.76 (s, 3H, 50-OCH3), 7.98 (s, 1H,
60-H), 7.66 (d, 1H, CaH, J ¼ 15.1 Hz), 8.11 (d, 1H, CbH, J ¼
15.1 Hz), 8.06 (s, 1H, 4-H), 7.74 (d, 1H, 5-H), 7.58 (m, 2H, 6-
and 7-H), 7.90 (m, 1H, 8-H); Anal. Calcd for C19H14ClNO3
(339.77): C, 67.16; H, 4.15; N, 4.12. Found: C, 66.99; H,
4.16; N, 4.11.
Synthesis of 1-(20-hydroxy-30,40-dimethoxyphenyl)-3-(1-
indol-3-yl)-prop-2-en-1-one (3c). Yellow solid (1.32 g,
40.8%); mp. 124ꢁC; kmax (CHCl3, nm): 268, 345; ir (KBr,
cmꢀ1): 3438(mOH), 3228(m > NH), 1627(mC¼¼O); 1H NMR (300
MHz, CDCl3): d 13.6 (s, 1H, 20-OH), 3.94 (s, 3H, 30-OCH3),
3.96 (s, 3H, 40-OCH3), 6.57 (d, 1H, 50-H), 7.98 (d, H, 60-H),
7.82 (d, 1H, CaH, J ¼ 15.3 Hz), 8.15 (d, 1H, CbH, J ¼ 15.3
Hz), 8.70 (s, 1H, > NH), 7.61 (s, 1H, 2-H), 8.04 (d, 1H, 4-H),
8.34 (m, 2H, 5- and 6-H), 7.49 (d, 1H, 7 H); Anal. Calcd for
C19H17NO4 (323.34): C, 70.58; H, 5.30; N, 4.33. Found: C,
70.36; H, 5.28; N, 4.35.
Synthesis of 1-(2-hydroxy-30,40,60-trimethoxyphenyl)-3-(1-
indol-3-yl)-prop-2-en-1-one (3d). Yellow solid (0.84 g,
23.8%); mp. 202ꢁC; kmax (CHCl3, nm): 296, 402; ir (KBr,
cmꢀ1): 3143(mOH), 3098(m > NH), 1637(mC¼¼O); 1H NMR (300
MHz, CDCl3): d 12.2 (s, 1H, 20-OH), 3.8 (s, 9H, 30-, 40- and
60-OCH3), 7.19 (s, 1H, 50-H), 7.89 (d, 1H, CaH, J ¼ 15.3 Hz),
8.19 (d, 1H, CbH, J ¼ 15.3 Hz), 9.9 (s, 1H, > NH), 7.61 (s,
1H, 2-H), 7.99 (s, 1H, 4-H), 7.29 (m, 2H, 5- and 6-H), 7.47
(d, 1H, 7-H); Anal. Calcd for C20H19NO5 (353.37): C, 67.98;
H, 5.42; N, 3.96. Found: C, 67.91; H, 5.41; N, 3.89.
Synthesis of 1-(2-hydroxy-40,60-dimethoxyphenyl)-3-(1-
indol-3-yl)-prop-2-en-1-one (3e). Yellow solid (1.46 g,
45.2%); mp. 198ꢁC; kmax (CHCl3, nm): 281, 396; ir (KBr,
cmꢀ1): 3410(mOH), 3230(m > NH), 1610(mC¼¼O); 1H NMR (300
MHz, CDCl3): d 14.05 (s, 1H, 20-OH), 6.01 (d, 1H, 30-H), 3.82
(s, 3H, 40-OCH3), 6.13 (s, 1H, 50-H), 3.88 (s, 3H, 60-OCH3),
7.74 (d, 1H, CaH, J ¼ 15.3 Hz), 8.15 (d, 1H, CbH, J ¼ 15.3
Hz), 8.99 (s, 1H, > NH), 7.48 (d, 1H, 2-H), 8.12 (m, 1H, 4-
H), 7.33 (m, 2H, 5- and 6-H), 7.40 (d, 1H, 7-H); Anal. Calcd
Synthesis of 1-(20-hydroxy-30,40-dimethoxyphenyl)-3-(2-
chloroquinolin-3-yl)-prop-2-en-1-one (6c). Yellow solid (1.48
g, 40%); mp. 216ꢁC; kmax (CHCl3, nm): 267, 349; ir (KBr,
cmꢀ1): 3434(mOH), 1654(mC¼¼O), 1446(mAC¼¼NA), 750(mCl); 1H
NMR (300 MHz, CDCl3): d 13.6 (s, 1H, 20-OH), 3.86 (s, 3H,
30-OCH3), 3.82 (s, 3H, 40-OCH3), 6.61 (d, 1H, 50-H), 7.52 (d,
1H, 60-H), 7.88 (d, 1H, CaH, J ¼ 15.2 Hz), 8.18 (d, 1H, CbH,
J ¼ 15.2 Hz), 8.10 (s, 1H, 4-H), 7.68 (d, 1H, 5-H), 7.62 (m,
2H, 6- and 7-H), 7.94 (d, 1H, 8-H); Anal. Calcd for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

84
P. Venkatesan and S. Sumathi
Vol 47
C20H16ClNO4 (369.79): C, 64.96; H, 4.36; N, 3.79. Found: C,
64.79; H, 4.35; N, 3.75.
bated at 37ꢁC for 18 h to allow maximum growth of the
organisms. Then, the antimicrobial activity of the test agents
was determined by measuring the diameter of zone of inhibi-
tion expressed in mm. The experiment was carried out in
triplicate.
Synthesis of 1-(2-hydroxy-30,40,60-trimethoxyphenyl)-3-(2-
chloroquinolin-3-yl)-prop-2-en-1-one (6d). Yellow solid (0.86
g, 21.5%); mp. 216ꢁC; kmax (CHCl3, nm): 265, 383; ir (KBr,
cmꢀ1): 3432(mOH), 1633(mC¼¼O), 1432(mAC¼¼NA), 746(mCl); 1H
NMR (300 MHz, CDCl3): d 12.2 (s, 1H, 20-OH), 3.86 (s, 9H,
30-, 40- and 60-OCH3), 7.12 (s, 1H, 50-H), 7.69 (d, 1H, CaH, J
¼ 15.3 Hz), 8.18 (d, 1H, CbH, J ¼ 15.3 Hz), 8.09 (s, 1H, 4-
H), 7.32 (d, 1H, 5-H), 7.44 (m, 2H, 6- and 7-H), 7.92 (d, 1H,
8-H); Anal. Calcd for C21H18ClNO5 (399.82): C, 63.08; H,
4.54; N, 3.50. Found: C, 62.88; H, 4.56; N, 3.51.
Acknowledgment. The authors thank Dr. R.Gandhidasan (Pro-
fessor in Chemistry, Madurai Kamaraj University) for providing
the lab facilities to carry out this research work.
Synthesis of 1-(2-hydroxy-40,60-dimethoxyphenyl)-3-(2-
chloroquinolin-3-yl)-prop-2-en-1-one (6e). Yellow solid (1.36
g, 36.8%); mp. 216ꢁC; kmax (CHCl3, nm): 270, 345; ir (KBr,
cmꢀ1): 3431(mOH), 1621(mC¼¼O), 1436(mAC¼¼NA), 756(mCl); 1H
NMR (300 MHz, CDCl3): d 14.05 (s, 1H, 20-OH), 6.54 (s, 1H,
30-H), 3.76 (s, 3H, 40-OCH3), 6.18 (d, 1H, 50-H), 3.82 (s, 3H,
60-OCH3), 7.72 (d, 1H, CaH, J ¼ 15.2 Hz), 8.21 (d, 1H, CbH,
J ¼ 15.2 Hz), 8.09 (s, 1H, 4-H), 7.58 (d, 1H, 5-H), 7.42 (m,
2H, 6- and 7-H), 7.86 (m, 1H, 8-H); Anal. Calcd for
C20H16ClNO4 (369.79): C, 64.96; H, 4.36; N, 3.79. Found: C,
64.76; H, 4.34; N, 3.75.
Antibacterial activities. The antibacterial activity of the
compounds 3 and 6 have been evaluated using filter paper disc
diffusion method [7] at a concentration of 100 lg/disc against
human pathogenic bacteria such as Staphylococcus aureus
(Gþ), Shigella dysenteriae (Gꢀ), and Salmonella typhi (Gꢀ).
Kanamycin (30 lg/disc) was used as standard for comparing
the activity. Each sample was prepared with dimethyl sulfox-
ide (DMSO) to the concentration of 100 lg/mL. Dried and
sterilized filter paper discs (6 mm in diameter) were impreg-
nated with test solution using micropipette and the residual
solvents were completely evaporated. Discs containing the test
materials were placed on nutrient agar medium uniformly
seeded with the test microorganisms. Standard disc of kanamy-
cin (30 lg/disc) and blank discs were used as positive and
negative control, respectively. These plates were then kept at
low temperature (4ꢁC) for 24 h to allow maximum diffusion
of test materials and kanamycin. The plates were then incu-
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet