Synthesis and characterization of ethyl 7-acetyl-2-substituted 3-(substituted benzoyl)indolizine-1-carboxylates for in vitro anticancer activity

Article abstract of DOI:10.14233/ajchem.2016.19582

Efficient synthesis of a series of novel indolizines (2a-r) has been achieved by reaction between 4-acetyl-1-[2-(substituted phenyl)-2-oxoethyl]pyridin-1-ium bromide and substituted alkynes in presence of anhydrous potassium carbonate in dimethyl formamid

Full text of DOI:10.14233/ajchem.2016.19582

Asian Journal of Chemistry; Vol. 28, No. 5 (2016), 1043-1048
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2016.19582
Synthesis and Characterization of Ethyl 7-Acetyl-2-substituted 3-(substituted
benzoyl)indolizine-1-carboxylates for in vitro Anticancer Activity
1
,2
1,3,*
4,*
C. SANDEEP , BASAVARAJ PADMASHALI
, KATHARIGATTA N. VENUGOPALA ,
5
6
4
RASHMI S. KULKARNI , RASHMI VENUGOPALA and BHARTI ODHAV
1
2
3
4
5
6
Department of Chemistry, Sahyadri Science College (Autonomous), Shimoga-577 203, India
Institute for Stem Cell Biology and Regenerative Medicine, NCBS, TIFR, GKVK, Bellary Road, Bangalore-560 065, India
Department of Studies and Research in Chemistry, School of Basic Sciences, Rani Channamma University, Belagavi-591 156, India
Department of Biotechnology and Food Technology, Durban University of Technology, Durban-4001, South Africa
Department of Chemistry, Jain University, Bangalore-560 019, India
Department of Public Health Medicine, University of KwaZulu-Natal, Howard College Campus, Durban-4001, South Africa
*
Corresponding authors: Tel. +27 31 3736887; Fax: +27 86 2423534; E-mail: basavarajpadmashali@yahoo.com; katharigattav@dut.ac.za
Received: 25 August 2015; Accepted: 17 November 2015; Published online: 30 January 2016; AJC-17744
Efficient synthesis of a series of novel indolizines (2a-r) has been achieved by reaction between 4-acetyl-1-[2-(substituted phenyl)-2-
oxoethyl]pyridin-1-ium bromide and substituted alkynes in presence of anhydrous potassium carbonate in dimethyl formamide medium.
The title compounds have been characterized by spectroscopic techniques and elemental analysis. Selected compounds 2b, 2h, 2i, 2q and
2r have been screened for in vitro anticancer activity using adriamycin as positive control and it was found that compounds 2b, 2q and 2r
have shown significant anticancer activity.
Keywords: Anticancer, Characterization, Indolizine analogues, Synthesis.
[
16], etc. On the other hand, synthetic indolizine derivatives
have been reported as calcium channel blockers [17], phos-
pholipaseA2 inhibitors [18], histamine H -receptors antagonist
[19] and 5-HT -receptors antagonists [20]. Besides this,
INTRODUCTION
Indolizines are heteroaromatic compounds containing
3
condensed five and six membered rings with bridging nitrogen.
They are isoelectronic with indole and represent a group
of heterocyclic compounds structurally related to purines.
Indolizine skeletons with different degrees of unsaturation are
present in wide variety of natural and unnatural azacyclic
compounds. Most of the naturally occurring indolizines have
been isolated from species of genus dendrobates (poison-arrow
frogs) [1,2]; monomorium (ants) [3]; dendrobium (orchids)
3
indolizines are also associated with pharmacological properties
such as anti-inflammatory (cyclooxygenase inhibitors) [21,22],
anti-tumour (alkylating agents) [23,24], oral hypoglycaemic
[25] and CNS activities [26,27].
Because of unexceptional potential of these indolizines,
noteworthy advances on their synthesis and biological evalua-
tion have gone unreported. A careful look at the indolizine
framework would logically suggest that one step or one-pot
simultaneously tandem construction of the N-C bond and C-C
bond on to six membered nitrogen heterocycles (piperidine/
pyridine), in an appropriately organized manner using a suitable
reagent would lead to the formation of the desired azabicyclo-
(4.3.0)nonane frame work [28-32].
[
4]; tylophora [5] and the leguminosae family (plants).
Indolizine alkaloids display broad spectrum of biological
activities. Polyhydroxylated indolizine alkaloids are excellent
inhibitors of biologically important pathways. These include
the binding and processing of glycoproteins [6], potent
glycosidase inhibitor activities [7,8], activity against AIDS
[
1
9,10] as well as against other important pathologies [11]. The
-azabicyclo[4,3,0]nonane (indolizine) framework occupies
Typical molecular constructions of indolizines fall into
three classes. (a) Condensation reactions of a 2-alkylpyridine
with acid anhydrides (Scholta reaction) [33] or α-haloketones
(Tschitschibabin reaction) [34-36]. (b) Reaction of an α-
unsubstituted pyridine with a three carbon fragment such as
an acyl or aryl substituted allyl halides or esters [37] and methyl
a special place in heterocyclic systems due to the presence of
this structural assembly in a number of natural products of
biological importance such as tabersonine [12], (-)-strychnine
[13], (+)-vinblastine [14], (-)-monomorine [15], (-)-gephyrotoxin

1
044 Sandeep et al.
Asian J. Chem.
propiolates. (c) Reaction of pyridinium N-methylides generated
from pyridinium salts under K CO [38,39], pyridine and carbenes
40] or N-trimethylsilylmethylpyridinium triflates under
MHz, DMSO-d
Hz, 2H), 8.20-8.16 (m, 2H), 7.54 (t, J =8.8 Hz, 2H), 6.58 (s,
2H), 2.79 (s, 3H). LC-MS (ESI, Positive): m/z 258 [M+H] .
6
): δ 9.22 (d, J = 6.8 Hz, 2H), 8.64 (d, J = 7.2
2
3
+
[
fluoride ion [41] with acetylenes or reaction of pyridinium N-
methylides with ethylene in the presence of an oxidant [42].
Keeping these observations in mind and in continuation
of our research on pharmacologically active heterocyclic
compounds [43,44] and polymorphism [45,46], herewith we
undertake synthesis and characterization of ethyl 7-acetyl-3-
Anal. calcd. for C15
Found; C, 53.03; H, 3.81; N, 4.05 %.
4-Acetyl-1-[2-(4-chlorophenyl)-2-oxoethyl]pyridi-
niumbromide (1c): Light yellow solid.Yield 98 %. H NMR
(400 MHz, DMSO-d ): δ 9.19 (d, J= 7 Hz, 2H),8.64 (d, J= 4
Hz, 2H),8.10 (d, J= 7.4 Hz, 2H),7.78 (d, J= 7.2 Hz, 2H),6.55
(s, 2H), 2.79 (s, 3H). LC-MS (ESI, Positive): m/z 274 [M+H] .
H
13BrFNO : C, 53.27; H, 3.87; N, 4.14 %.
2
1
6
+
(4-substituted benzoyl)-2-substituted indolizine-1-carboxylate
(
2a-r, Scheme-I) for in vitro anticancer properties.
Anal. calcd. for C15
. Found; C, 50.70; H, 3.59; N, 3.90 %.
4-Acetyl-1-[2-(4-bromophenyl)-2-oxoethyl]pyridini-
H
13BrClNO
2
: C, 50.80; H, 3.69; N, 3.95;
%
O
CH3
1
H
3
C
umbromide (1d): Yellow solid. Yield 99 %. H NMR (400
CH
2
O
O
O
MHz, DMSO-d ): δ 9.19 (d, J = 7.2 Hz, 2H), 8.63 (d, J = 7.0
6
+
N
–
O
CH
3
Br
CH3
Hz, 2H), 8.01 (d, J = 7.2 Hz, 2H), 7.91 (d, J = 8 Hz, 2H), 6.54
R2
O
+
COOC H
N
(s, 2H), 2.78 (s, 3H). LC-MS (ESI, Positive): m/z 318 [M+H] .
2
5
(ii)
(
i)
+
R
2
Anal. calcd. for C15
Found; C, 45.01; H, 3.18, N, 3.46 %.
-Acetyl-1-[2-(4-cyanophenyl)-2-oxoethyl]pyridi-
H13Br
2
NO
2
: C, 45.14; H, 3.28; N, 3.51 %.
O
N
4
R1
R1
1
niumbromide (1e): Light brown solid. Yield 99 %. H NMR
400 MHz, DMSO-d ): δ 9.15 (d, J = 7.2 Hz, 2H), 8.61 (d, J =
.0 Hz, 2H), 7.99 (d, J = 7.2 Hz, 2H), 7.87 (d, J = 8 Hz, 2H),
.49 (s, 2H), 2.73 (s, 3H). LC-MS (ESI, Positive): m/z 265
1a-f
2a-r
R1 = H, F, Cl, Br, CN, CH
R2 = H, CH , C H , COOC H
5
(
6
3
7
6
3
2
5
2
Scheme-I: Reagents and conditions: (i) 4-substitued phenacyl bromide,
acetone, 5 h, stir; (ii) K CO , DMF, 0.5 h stir at room temperature
+
[
M+H] . Anal. calcd. for C16
H
13BrN
2
O
2
: C, 55.67; H, 3.80; N,
.12; %. Found; C, 55.55; H, 3.77; N, 8.07 %.
-Acetyl-1-(2-oxo-2-p-tolylethyl)pyridiniumbromide
2
3
8
4
EXPERIMENTAL
1
(
1f): Yellow solid. Yield 98 %. H NMR (400 MHz, DMSO-
Commercially available chemicals were procured from
Sigma Aldrich. Hot-air dried glass wares were used to carry
out reactions under nitrogen atmosphere using dry solvents.
Monitoring of chemical reactions was done on analytical thin
layer chromatography (TLC) with Merck 60 F-254 silica-gel
d ): δ 9.22 (d, J = 7.2 Hz, 2H), 8.63 (d, J = 7.0 Hz, 2H), 7.98
6
(d, J = 7.2 Hz, 2H), 7.49 (d, J = 6.9 Hz, 2H), 6.56 (s, 2H), 2.79
+
(s, 3H), 2.46 (s, 3H). LC-MS (ESI, Positive): m/z 254 [M+H] .
Anal. calcd. for C16
H
16BrNO : C, 57.50; H, 4.83; N, 4.19 %.
2
Found; C, 57.30; H, 4.81; N, 4.15 %.
1
13
plates. NMR spectra ( H and C) were recorded at ambient
temperature using CDCl , DMSO-d as a solvent on 400 MHz
General procedure for the synthesis of ethyl 7-acetyl-
3-(4-substituted benzoyl)-2-substituted indolizine-1-carbo-
xylate: To a solution of 4-acetyl-1-[2-(4-substituted phenyl)-
2-oxoethyl]pyridinium bromide (0.0156 mol), in dry dimethyl
3
6
Bruker-spectrometer using tetramethylsilane (TMS) as internal
standard. Chemical shifts were showed in ppm (δ) and were
referenced with TMS. LC-MS analysis was performed on
Agilent LC-1200 series coupled with 6140 single quad mass
spectro-meter with ESI +ve and –ve mode, MS range from
formamide, substituted ethyl propiolate (0.0156 mol), K
2
CO
3
(0.0156 mol, 2.15 g) was added and the reaction mixture was
stirred at room temperature for 0.5 h. Completion of the reaction
was monitored on TLC. After completion of the reaction,
thesolvent was evaporated under reduced pressure and diluted
with ethyl acetate. Organic layer was washed with water, brine
and dried with sodium sulphate. The crude compounds were
purified by column chromatography using 30 % n-hexane in
ethyl acetate to afford the title compound 2a-2r and physical
constants are tabulated in Table-1.
1
00-2000. IR spectra were recorded using KBr pellets on
Brucker alpha FT-IR spectrometer. Perkin Elmer CHNS
analyser was used for elemental analyses.
General procedure for the synthesis of 4-acetyl-1-(2-
(4-substituted phenyl)-2-oxoethyl)pyridinium bromide (1a-
1
f): To a stirred solution of 4-acetylpyridine (0.1 mol, 12.1 g)
in dry acetone (60 mL), substituted phenacyl bromide (0.1
mol) was added and stirred at room temperature for 5 h. The
reaction completion was monitored on TLC, product formed
was filtered and dried under vacuum to afford compounds 1a-f.
Ethyl 7-acetyl-3-benzoylindolizine-1-carboxylate (2a):
-1
Yellow fluffy crystalline; IR (KBr, νmax, cm ): 1685, 1626,
1
1597, 1575. H NMR (400 MHz, CDCl ): δ 9.92 (d, J = 7.2Hz,
3
4
-Acetyl-1-(2-oxo-2-phenylethyl)pyridiniumbromide
1H), 8.99 (s, 1H), 7.87-7.84 (m, 3H), 7.63-7.53 (m, 4H), 4.42
(q, J = 7.2Hz, 2H), 2.73 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H). C
1
13
(
1a): White solid. Yield 99 %. H NMR (400 MHz, DMSO-
d
8
2
6
): δ 9.15 (d, J = 8 Hz, 2H), 8.60 (d, J = 6.8 Hz, 2H), 8.07-
NMR (400 MHz, CDCl ): δ 195.82, 185.94, 163.72, 139.31,
3
.04 (m, 2H), 7.81-7.77 (m, 1H), 7.68-7.64 (m, 2H), 6.53 (s,
138.32, 134.24, 131.97, 129.06, 128.85, 128.74, 128.52,
+
H), 2.76 (s, 3H). LC-MS (ESI, Positive) m/z 240 [M+H] .
123.82, 121.05, 112.49, 109.38, 60.49, 26.17, 14.48. LC-MS
+
Anal. calcd. for C15
Found: C, 56.09; H, 4.39; N, 4.30 %.
-Acetyl-1-[2-(4-fluorophenyl)-2-oxoethyl]pyridi-
H14BrNO
2
: C, 56.27; H, 4.41; N, 4.37 %.
(ESI, Positive): m/z 336 [M+H] . Anal. calcd. for C20
H
17NO :
4
C 71.63, H 5.11, N 4.18 %. Found: C 71.72, H 5.21, N 4.11 %.
4
Diethyl 7-acetyl-3-benzoylindolizine-1,2-dicarboxylate
1
-1
niumbromide (1b): White solid. Yield 98 %. H NMR (400
(2b): Yellow crystalline compound; IR (KBr, νmax, cm ): 1650,

Vol. 28, No. 5 (2016) Synthesis and Characterization of Ethyl 7-Acetyl-2-substituted 3-(substituted benzoyl)indolizine-1-carboxylates 1045
TABLE-1
PHYSICO-CHEMICAL CONSTANTS OF ETHYL 7-ACETYL-3-(4-SUBSTITUTED
BENZOYL)-2-SUBSTITUTED INDOLIZINE-1-CARBOXYLATE ANALOGUES (2a-r)
1
2
a,b
c
Compound
m.f.
m.w.
335
407
353
367
381
425
369
383
441
413
427
485
374
388
432
349
363
421
R
R
Yield (%)
78
m.p. (°C)
118-119
144-145
155-156
121-122
102-103
169-170
161-162
133-134
188-189
154-155
142-143
185-186
146-147
116-117
171-172
151-152
109-110
cLogP
2a
C
20
C
23
C
20
C
21
C
22
C
23
C
20
C
21
C
23
C
20
C
21
C
23
C
22
C
23
C
24
C
21
C
22
C
24
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
17NO
21NO
16NO
18NO
20NO
20NO
16NO
18NO
20NO
16NO
18NO
20NO
4
H
H
F
F
F
H
COOC
H
CH
H
COOC
H
CH
COOC
H
CH
COOC
CH
H
COOC
H
CH
COOC
1.5990
2.1814
2.8312
4.4772
5.0062
3.4512
3.4012
5.0472
4.0212
3.5512
5.1972
4.1712
3.8200
4.3490
2.7843
3.1840
4.8300
3.8061
2
b
6
2
H
5
73
75
70
68
71
79
73
75
70
65
71
72
71
69
61
55
2c
4
F
F
F
F
Cl
Cl
Cl
Br
Br
Br
2
d
4
3
2e
4
C
2
5
2f
6
F
2
H
5
2g
4
Cl
Cl
Cl
Br
Br
Br
CN
CN
CN
2
h
4
3
2i
6
2
H
5
2j
4
2
k
4
3
2l
6
2
H
5
2
m
18
20
20
N
2
O
O
O
4
4
6
3
2
2
2
2
n
o
p
q
N
2
C
2
5
N
2
H
2
5
19NO
21NO
23NO
CH
CH
CH
4
3
4
3
3
2r
6
3
2
H
5
65
178-179
a
b
c
All of the products were characterized by spectral and physical data; Yields after purification by column chromatography; cLogP was calculated
using ChemBioDraw Ultra 13.0v.
1
1
7
2
3
605, 1591, 1569. H NMR (400 MHz, CDCl
3
): δ 9.33 (d, J =
7.2 Hz, 1H), 7.15 (t, J = 8.4 Hz, 2H), 4.39 (q, J = 7.2 Hz, 2H),
3.78 (q, J = 7.2 Hz, 2H), 2.71 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H),
.2 Hz, 1H), 8.83 (s, 1H), 7.70-7.64 (m, 4H), 7.54-7.50 (m,
H), 4.31 (q, J = 7.2 Hz, 2H), 3.62 (q, J = 7.2 Hz, 2H), 2.70 (s,
H), 1.29 (t, J = 7.2 Hz, 3H), 1.01 (t, J = 7.2 Hz, 3H). LC-MS
ESI, Positive): m/z 408[M+H] . Anal. calcd. for C23
1.09 (t, J = 7.2 Hz, 3H). LC-MS (ESI, Positive): m/z 426
+
[M+H] . Anal. calcd. for C23
H
20FNO : C 64.94, H 4.74, N 3.29
6
+
(
H21NO
6
:
%. Found: C 64.78, H 4.69, N 3.19 %.
C 67.80, H 5.20, N 3.44 %. Found: C 66.93, H 5.27, N3.17 %.
Ethyl 7-acetyl-3-(4-chlorobenzoyl)indolizine-1-carbo-
-1
Ethyl 7-acetyl-3-(4-fluorobenzoyl)indolizine-1-carbo-
xylate (2g): Light green solid; (KBr, νmax, cm ): 1695, 1680,
-1
1
xylate (2c): Yellow solid; IR (KBr, νmax, cm ): 1675, 1625,
1618, 1591. H NMR (400 MHz, CDCl ): δ 9.86 (d, J = 7.2
3
1
1
8
586. H NMR (400 MHz, CDCl
3
): δ 9.86 (d, J = 7.2 Hz, 1H),
Hz, 1H), 8.98 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.65 (s, 1H),
7.61 (d, J = 7.2 Hz, 1H), 7.51 (d, J = 8.4, 2H), 4.41 (q, J = 7.2
.99 (s, 1H), 7.90-7.83 (m, 2H), 7.83 (s, 1H), 7.62 (d, J = 7.2
Hz, 1H), 7.23 (t, J = 8.4 Hz, 2H), 4.42 (q, J = 7.2 Hz, 2H),
.73 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H). LC-MS (ESI, Positive):
Hz, 2H), 2.72 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H). LC-MS (ESI,
+
2
Positive): m/z 370 [M+H] . Anal. calcd. for C20
H
16ClNO : C
4
+
m/z 354 [M+H] . Anal. calcd. for C20
H16FNO
4
: C 67.98, H
64.96, H 4.36, N 3.79 %. Found: C 64.82, H 4.01, N 3.69 %.
Ethyl 7-acetyl-3-(4-chlorobenzoyl)-2-methylindolizine-
1-carboxylate (2h): Light yellow crystalline compound; IR
4
.56, N 3.96 %. Found: C 67.81, H 4.31, N 3.71 %.
Ethyl 7-acetyl-3-(4-fluorobenzoyl)-2-methylindolizine-
-1
1
1
ν
9
-carboxylate (2d): Yellow crystalline compound; IR (KBr,
(KBr, νmax, cm ): 1681, 1608, 1589. H NMR (400 MHz,
CDCl ): δ 9.98 (d, J = 7.2 Hz, 1H), 8.99 (s, 1H), 7.57 (d, J = 6.4
Hz, 1H), 7.50-7.37 (m, 4H), 4.42 (q, J = 7.2 Hz, 2H), 2.71 (s,
-1
1
max, cm ): 1665, 1635, 1575. H NMR (400 MHz, CDCl
3
): δ
3
.01 (d, J = 8 Hz, 1H), 8.89 (s, 1H), 7.80-7.74 (m, 2H), 7.40
13
(d, J = 7 Hz, 1H), 7.18 (t, J = 8.4Hz, 2H), 4.45 (q, J = 7.2 Hz,
3H), 2.15 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H). C NMR (400 MHz,
CDCl
2
H), 2.69 (s, 3H), 2.24 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H). LC-MS
3
): δ 195.87, 185.08, 164.46, 140.55, 140.20, 138.55,
+
(ESI, Positive): m/z 368[M+H] . Anal. calcd. for C21
H18FNO
4
:
134.47, 131.24, 130.92, 130.28 128.50, 128.41, 127.44, 123.80,
C 68.66, H 4.94, N 3.81 %. Found; C 68.46, H 4.74, N 3.68 %.
120.74, 112.26, 109.18, 60.29, 26.17, 14.41, 12.84. LC-MS
+
Ethyl 7-acetyl-2-ethyl-3-(4-fluorobenzoyl)indolizine-1-
(ESI, Positive): m/z 384 [M+H] .Anal. calcd. for C21
H
18ClNO :
4
-1
carboxylate (2e): Dark yellow solid; IR (KBr, νmax, cm ):
C 65.71, H 4.73, N 3.65 %. Found: C 65.46, H 4.81, N 3.47 %.
Diethyl 7-acetyl-3-(4-chlorobenzoyl)indolizine-1,2-
dicarboxylate (2i): Yellow crystalline compound; IR (KBr,
1
1
8
1
695, 1645, 1600. H NMR (400 MHz, CDCl ): δ 9.01 (d, J =
3
Hz, 1H), 8.90 (s, 1H), 7.79-7.76 (m, 2H), 7.42 (d, J = 7 Hz,
H), 7.18 (t, J = 8.4 Hz, 2H), 4.45 (q, J = 7.2 Hz, 2H), 2.78 (q,
-
1
1
ν
max, cm ): 1708, 1682, 1614, 1590. H NMR (400 MHz,
J = 7.2 Hz, 2H), 2.69 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H), 1.04 (t,
CDCl ): δ 9.45 (d, J = 7.6 Hz, 1H), 8.98 (s, 1H), 7.67 (d, J =
3
+
J = 7.2 Hz, 3H). LC-MS (ESI, Positive): m/z 382[M+H] .Anal.
8.4 Hz, 2H), 7.60 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 8.4Hz, 2H),
4.37 (q, J = 7.2 Hz, 2H), 3.75 (q, J = 7.2 Hz, 2H), 2.71 (s, 3H),
calcd. for C22
8.92, H 5.12, N 3.51 %.
Diethyl 7-acetyl-3-(4-fluorobenzoyl)indolizine-1,2-
H20FNO
4
: C 69.28, H 5.29, N 3.67 %. Found: C
6
1.37 (t, J = 7.2 Hz, 3H), 1.09 (t, J = 7.2 Hz, 3H). LC-MS (ESI,
+
Positive): m/z 442 [M+H] . Anal. calcd. for C23
H
20ClNO : C
6
-1
dicarboxylate (2f): Yellow solid; IR (KBr, νmax, cm ): 1732,
62.52, H 4.56, N 3.17 %. Found: C 62.69, H 4.39, N 3.01 %.
1
1
(
708, 1681, 1616, 1596. H NMR (400 MHz, CDCl
3
): δ 9.41
Ethyl 7-acetyl-3-(4-bromobenzoyl)indolizine-1-carbo-
-1
d, J = 7 Hz, 1H), 8.99 (s, 1H), 7.79-7.76 (m, 2H), 7.60 (d, J =
xylate (2j): Yellow solid; IR (KBr, νmax, cm ): 1701, 1687,

1
046 Sandeep et al.
Asian J. Chem.
1
1
1
6
7
1
1
1
622, 1586. H NMR (400 MHz, CDCl
3
): δ 9.87 (d, J = 8 Hz,
Hz, 1H), 8.97 (s, 1H), 7.85 (s, 1H), 7.75 (d, J = 8 Hz, 2H),
7.58 (d, J = 7.2 Hz, 1H), 7.33 (d, J = 7.2 Hz, 2H), 4.41 (q, J =
7.2 Hz, 2H), 2.71 (s, 3H), 2.47 (s, 3H), 1.42 (t, J = 7.2 Hz,
H), 8.98 (s, 1H), 7.81 (s, 1H), 7.73-7.68 (m, 4H), 7.62 (d, J =
.2 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 2.73 (s, 3H), 1.44 (t, J =
1
3
+
.2 Hz, 3H). C NMR (400 MHz, CDCl
3
): δ 195.72, 184.58,
3H). LC-MS (ESI, Positive): m/z 350 [M+H] . Anal. calcd.
63.58, 138.50, 138.03, 134.43, 131.82, 130.56, 128.72,
28.62, 126.86, 123.43, 121.02, 112.67, 109.55, 60.56, 26.17,
4.48. LC-MS (ESI, Positive): m/z 414 [M+H] . Anal. calcd.
16BrNO : C 57.99, H 3.89, N 3.38 %. Found: C 57.92,
H 3.92, N 3.31 %.
for C21
H
19NO
4
: C 72.19, H 5.48, N 4.01 %. Found: C 71.98, H
5.41, N 4.11 %.
Ethyl 7-acetyl-2-methyl-3-(4-methylbenzoyl)indolizine-
1-carboxylate (2q): Yellow crystalline compound; IR (KBr,
+
for C20
H
4
-
1
1
νmax, cm ):1697, 1683, 1625. H NMR (400 MHz, CDCl ): δ
3
Ethyl 7-acetyl-3-(4-bromobenzoyl)-2-methylindolizine-
9.19 (d, J = 7.2 Hz, 1H), 8.95 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H),
7.43 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 4.43 (q, J =
7.2 Hz, 2H), 2.69 (s, 3H), 2.46 (s, 3H), 2.29 (s, 3H), 1.46 (t, J
-1
1
1
1
2
3
-carboxylate (2k): Yellow solid; IR (KBr, νmax, cm ): 1681,
1
606, 1583. H NMR (400 MHz, CDCl ): δ 9.30 (d, J = 7 Hz,
3
+
H), 8.97 (s, 1H), 7.65 (d, J = 10.4 Hz, 2H), 7.60 (d, J = 9 Hz,
H), 7.47 (d, J = 7.2 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 2.70 (s,
= 7.2 Hz, 3H). LC-MS (ESI, Positive): m/z 364 [M+H] .Anal.
calcd. for C22
H
21NO : C 72.71, H 5.82, N 3.85 %. Found: C
4
13
H), 2.28 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H). C NMR (400
): δ 195.89, 186.78, 164.54, 139.00, 137.84,
37.41, 133.69, 132.02, 130.60, 127.53, 127.34, 123.85,
21.12, 111.62, 108.55, 60.24, 26.09, 15.00, 14.45. LC-MS
72.63, H 5.88, N 3.76 %.
MHz, CDCl
3
Diethyl 7-acetyl-3-(4-methylbenzoyl)indolizine-1,2-
dicarboxylate (2r): Yellow crystalline compound; IR (KBr,
1
1
(
-
1
1
ν
max, cm ): 1705, 1685, 1625, 1610. H NMR (400 MHz,
+
ESI, Positive): m/z 428 [M+H] .Anal. calcd. for C21
H
18BrNO
4
:
CDCl ): δ 9.37 (d, J = 7.2 Hz, 1H), 8.97 (s, 1H), 7.65 (d, J =
3
C 58.89, H 4.24, N 3.27 %. Found: C 58.91, H 4.01, N 3.09 %.
Diethyl 7-acetyl-3-(4-bromobenzoyl)indolizine-1,2-
dicarboxylate (2l): Dark brown crystalline compound; IR
8.0 Hz, 2H), 7.57 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H),
4.38 (q, J = 7.2 Hz, 2H), 3.72 (q, J = 7.2 Hz, 2H), 2.71 (s, 3H),
2.43 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H), 1.05 (t, J = 7.2 Hz, 3H).
-1
1
+
(
KBr, νmax, cm ): 1710, 1672, 1630, 1585. H NMR (400 MHz,
CDCl ): δ 9.31 (d, J = 7 Hz, 1H), 8.80 (s, 1H), 7.72 (d, J = 8.4
Hz, 2H), 7.64 (d, J = 4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 4.29
LC-MS (ESI, Positive): m/z 422 [M+H] . Anal. calcd. for
3
C
24
H
23NO
6
: C 68.40, H 5.50, N 3.32 %. Found: C 68.29, H
5.42, N 3.49 %.
Anticancer activity: Selected test compounds 2b, 2h, 2i,
(
(
q, J = 7.2 Hz, 2H), 3.65 (q, J = 7.2 Hz, 2H), 2.68 (s, 3H), 1.27
t, J = 7.2 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H). LC-MS (ESI,
2q and 2r have been screened for in vitro anticancer activity
against human cervix cancer cell line SiHa at 10, 20, 40 and
80 µg/mL concentration using sulforhodamine B assay accor-
ding to reported literature [47,48]. The results are tabulated in
Table-2.
+
Positive): m/z 486 [M+H] . Anal. calcd. for C23
H
20BrNO : C
6
56.80, H 4.15, N 2.88 %. Found: C 56.87, H 4.01, N 2.79 %.
Ethyl 7-acetyl-3-(4-cyanobenzoyl)-2-methylindolizine-
-
1
1
1
7
-carboxylate (2m): Yellow solid; IR (KBr, νmax, cm ): 2231,
1
707, 1684, 1624. H NMR (400 MHz, CDCl
3
): δ 9.47 (d, J =
.2 Hz, 1H), 8.98 (s, 1H), 7.83-7.78 (m, 4H), 7.52 (d, J = 7.2
TABLE-2
in vitro ANTICANCER ACTIVITY OF TEST
COMPOUNDS 2b, 2h, 2i, 2q AND 2r AGAINST
HUMAN CERVIX CANCER CELL LINE SiHa
Hz, 1H), 4.45 (q, J = 7.2 Hz, 2H), 2.71 (s, 3H), 2.22 (s, 3H),
.46 (t, J = 7.2 Hz, 3H). LC-MS (ESI, Positive): m/z 375
1
+
[
M+H] . Anal. calcd. for C22
H
18
N
2
4
O : C 70.58, H 4.85, N
a
Cell growth inhibition (%) at concentration (µg/mL)
7
.48 %. Found: C 70.39, H 4.91, N 7.69 %.
Compound
10
20
40
80
Ethyl 7-acetyl-3-(4-cyanobenzoyl)-2-ethylindolizine-1-
2
2
2
2q
2r
b
h
i
91.0
100.0
100.0
100.0
100.0
-67.4
-42.5
97.1
100.0
100.0
-30.9
-70.0
-53.9
86.9
96.1
-9.4
-41.4
-73.1
-63.1
81.9
94.2
-22.4
-54.8
-74.1
-1
carboxylate (2n): Light yellow solid; IR (KBr, νmax, cm ):
1
2
(
235, 1725, 1675, 1630. H NMR (400 MHz, CDCl
3
): δ 9.02
d, J = 7 Hz, 1H), 8.94 (s, 1H), 7.81-7.55 (m, 5H), 7.42 (d, J =
7.2Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H), 2.75 (q, I = 7.2 Hz, 2H),
ADR
2
.63 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H).
a
+
Average values of tested compounds with the reference adriamycin
ADR) as a reference positive control drug.
LC-MS (ESI, Positive): m/z 389 [M+H] . Anal. calcd. for
(
C
23
H
20
N
2
O : C 71.12, H 5.19, N 7.21 %. Found: C 70.92, H
4
5.22, N 7.04 %.
Diethyl 7-acetyl-3-(4-cyanobenzoyl)indolizine-1,2-
RESULTS AND DISCUSSION
The general route to obtain the title compounds 2a-r is
-1
dicarboxylate (2o): Yellow solid; IR (KBr, νmax, cm ): 2227,
1
1
(
=
2
3
732, 1688, 1620, 1599. H NMR (400 MHz, CDCl
d, J = 7.2 Hz, 1H), 9.01 (s, 1H), 7.80-7.74 (m, 4H), 7.59 (d, J
7.2 Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H),3.78 (q, J = 7.2 Hz,
3
): δ 9.50
illustrated in Scheme-I. Compounds 1a-f as intermediates were
prepared by stirring 4-acetylpyridine with substituted phenacyl
bromides separately in the presence of acetone medium at room
temperature as shown in Scheme-I. The completion of reaction
was monitored on thin layer chromatography (TLC), the solid
deposited was filtered, dried under vacuum and recrystallized
using ethanol as solvent. The yields of 1a-f obtained were up
to 98-99 % and characterization was achieved by proton NMR,
LC-MS and elemental analysis.
H), 2.70 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H), 1.08 (t, J = 7.2 Hz,
+
H). LC-MS (ESI, Positive): m/z [M+H] : 433. Anal. calcd.
for C24
H
20
N
2
O : C 66.66, H 4.66, N 6.48 %. Found: C 66.79,
6
H 4.79, N, 6.51 %.
Ethyl 7-acetyl-3-(4-methylbenzoyl)indolizine-1-
-1
carboxylate (2p): Yellow solid; IR (KBr, νmax, cm ): 1700,
1
1
690, 1615. H NMR (400 MHz, CDCl ): δ 9.86 (d, J = 7.2
3

Vol. 28, No. 5 (2016) Synthesis and Characterization of Ethyl 7-Acetyl-2-substituted 3-(substituted benzoyl)indolizine-1-carboxylates 1047
Substituted indolizine compounds 2a-r have been
synthesized by the reaction between 4-acetyl-1-[2-(substituted
phenyl)-2-oxoethyl]pyridin-1-ium bromide and substituted
alkynes in presence of anhydrous potassium carbonate in
dimethyl formamide medium as depicted in Scheme-I. The
reaction completion was observed on TLC and all the products
have been achieved within 0.5 h with constant stirring. Column
chromatography was used to purify products using 60-120
mesh silica gel using 30 % n-hexane in ethyl acetate as a solvent
and the yield was found to be 54-79 %. The title compounds
have been characterized by IR, NMR, LC-MS and elemental
analysis. cLogP of the compounds was calculated using
ChemBioDraw Ultra 13.0v and found to be in the range of
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1
1
1
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4
[
1
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