Simple, fast and efficient synthesis of β-keto esters from the esters of heteroaryl compounds, its antimicrobial study and cytotoxicity towards various cancer cell lines

Article abstract of DOI:10.1016/j.bmcl.2012.04.008

A series of β-keto esters were synthesized from heteroaryl esters and ethyl acetate using LiHMDS as base at -50 to -30 °C. The increase in yields of cross condensed product were observed and the percentage of self condensed product was reduced drastically by applying the suitable base (LiHMDS), solvent and the minimum amount of ethyl acetate. All these β-keto esters were characterized using ¹H NMR, ¹³C NMR and mass spectral data. A plausible mechanism is also depicted to prove the formation of trans-esterified products. All the synthesized compounds were subjected to test for their cytotoxicity towards various cancer cell lines and also tested for their antimicrobial activity towards various bacterial and fungal strains and some of them were found to have promising activity.

Full text of DOI:10.1016/j.bmcl.2012.04.008

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4193–4197
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Simple, fast and efficient synthesis of b-keto esters from the esters
of heteroaryl compounds, its antimicrobial study and cytotoxicity
towards various cancer cell lines
R. Venkat Ragavan a, V. Vijayakumar a, , K. Rajesh a, B. Palakshi Reddy a, S. Karthikeyan b,
⇑
N. Suchetha Kumari c
a Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632 014, India
b Industrial Biotechnology Division, School of Bio Sciences & Technology, VIT University, Vellore 632 014, India
c Department of Biochemistry, K.S. Hegde Medical Academy, Deralakatte 574 162, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of b-keto esters were synthesized from heteroaryl esters and ethyl acetate using LiHMDS as base
at À50 to À30 °C. The increase in yields of cross condensed product were observed and the percentage of
self condensed product was reduced drastically by applying the suitable base (LiHMDS), solvent and the
minimum amount of ethyl acetate. All these b-keto esters were characterized using 1H NMR, 13C NMR and
mass spectral data. A plausible mechanism is also depicted to prove the formation of trans-esterified
products. All the synthesized compounds were subjected to test for their cytotoxicity towards various
cancer cell lines and also tested for their antimicrobial activity towards various bacterial and fungal
strains and some of them were found to have promising activity.
Received 27 October 2011
Revised 22 March 2012
Accepted 3 April 2012
Available online 13 April 2012
Keywords:
Heteroaryl esters
b-Keto esters
LiHMDS
Ó 2012 Elsevier Ltd. All rights reserved.
trans-Esterification
Cytotoxic studies
Many hetero cyclic compounds such as pyrazolones, pyrimi-
dines, thiazoles, oxazoles and isooxazoles were prepared tradition-
ally from their corresponding b-keto esters. There are methods to
synthesize b-keto esters from esters1,2, aldehydes3, but these
methods have main limitation in varying the substituents. A num-
ber of methods such as acylation of enolates of malonates4,5, acyl-
large quantity of ethyl acetate, excess of strong base (sodium eth-
oxide, tert-butoxide, NaH) and refluxing conditions with longer
time under the usual reaction conditions. Apart from that these
transformations suffer by large quantity of by products (formed
by the self condensation of ethyl acetate in particular) and require
tedious work up procedures to remove the same. b-Keto esters of
N-protected amino acids were efficiently prepared by treating
the corresponding esters with the enolate of tert-butyl acetate
(prepared using LDA in THF) at À50 to À78 °C.19 Reactions of these
b-keto-tert-butyl esters in the preparation of pyrazolones, pyrimi-
dones, isooxazolones with hydrazines, amidines and hydroxyl-
amine respectively, always suffers by the steric effect of
tert-butyl group. b-Keto methyl (or) ethyl esters are the most pre-
ferred esters for these transformations.
Unfortunately the existing methods do not produce the b-keto
ester of heteroaryls from the heteroaryl esters in good yield. In
most of the cases we did not get the product when we tried to syn-
thesize b-keto esters of some heteroaryl esters by applying the
existing methods. Reactivity of the esters mainly depends upon
the electrophilicity. Electrophilicity of the heterocyclic esters will
change drastically by changing the substituents. So it is not easy
to avoid the self-condensed product. The importance of these es-
ters, led us to develop a simple method to synthesize b-keto ethyl
esters of heteroaryls in good yield by changing the base, reagent,
equivalence of base reagent and reaction conditions.
ation of meldrum’s acid6–9
,
mixed malonate esters10,11 and
bistrimethylsilylmalonate12,13, often, a chelating effect has been
employed to lock the enolate anion of malonate using lithium
and magnesium salts14,15
, however these methods suffer by
inconsistent yield in case of aliphatic acylation. The synthesis of
b-keto esters from ketones like caboxylation of ketone enolates16,17
using carbon dioxide and carbon monoxide sources in the presence
of palladium or transition metal catalysts. The most general and
simple method to synthesize b-keto esters in these days is the
reaction of dimethyl or ethyl carbonate with ketone in the pres-
ence of strong base also suffers by long reaction time, inconsistent
yield and use of excess reagent.
Ohta et al.18 synthesized b-keto esters by treating the esters
with the enolate of ethyl acetate (or) tert-butyl acetate in the
refluxing conditions but these transformations also require the
⇑
Corresponding author. Tel.: +91 416 220 2535; fax: +91 416 224 3092.
E-mail address: kvpsvijayakumar@gmail.com (V. Vijayakumar).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.04.008

4194
R. Venkat Ragavan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4193–4197
O
To overcome the difficulties present in the synthesis of b-keto
esters of heteroaryl esters as the continuation of our interest to-
wards the synthesis of b-keto esters and pyrazolones20–30, we at-
tempted the synthesis of 1–21 from their corresponding
heteroaryl esters and ethyl acetate using Scheme 1. Then the yield
of cross condensed product was optimized with reference to the
compound 8 by changing the equivalence of base, solvents, ethyl
acetate and the results are summarized in Table 1.
O
O
O
O
O
+
O
Ar
O
O
Ar
O
LiHMDS
THF
1-21
[Self condensed
product]
[Cross condensed
desired product]
Scheme 1. Efficient synthesis of b-keto esters of heteroaryl compounds 1–21.
Our initial attempt with 1 equiv of LiHMDS as base was disap-
pointing and produced only 18% of product. Reaction with 3 equiv
of LDA and 3 equiv of ethyl acetate gave the moderate yield. When
the reaction was carried out with hydrocarbon solvent like toluene
and LiHMDS as base, yield got improved to 78%. Reaction using
NaH gave only 9% yield. Other bases NaOMe and tert-BuOK did
not give the product at all. Finally a reaction with 3.5 equiv of
LiHMDS and 7 equiv of ethyl acetate at À50 to À30 °C produced
the better yield. By applying the suitable base, solvent and the min-
imum amount of ethyl acetate we have increased the yields of the
cross condensed product and the percentage of self condensed
product was reduced drastically. After finding the optimized
Table 1
Effect of solvent and base on the yield of 8
Base
Ethylacetate Solvent Temp
Yield
(%)
(equiv)
LiHMDS (1.0 M THF) (1 equiv)
LDA (1.0 M THF) (3 equiv)
LiHMDS (3 equiv)
3
3
7
THF
THF
À78 °C
À78 °C
18
56
78
9
0
0
Toluene À78 °C
NaH (2 equiv)
NaOMe (2 equiv)
KOtBu (3 equiv)
LiHMDS (1.0 M THF) (3.5 equiv)
50
75
10
7
THF
THF
THF
THF
À78 °C
Reflux
25 °C
À50 to À30 °C 94
Table 2
Synthesis of b-keto esters by cross-Claisen condensation
Compd
Ester
Product
Yield (%)
94
COOC2H5
COCH2COOC2H5
1
N
N
COOC2H5
N
COCH2COOC2H5
N
Br
S
2
3
97
Br
S
S
COOC2H5
COCH2COOC2H5
S
91
88
Cl
N
Cl
N
N
N
N
N
COOC2H5
N
N
COCH2COOC2H5
4
5
N
COOC2H5
N
COCH2COOC2H5
COCH2COOC2H5
a
0
COOC2H5
a
6
7
0
COOC2H5
N
COCH2COOC2H5
N
85
N
COOC2H5
N
COCH2COOC2H5
8
9
83
72
Cl
N
Cl
N
COOC2H5
COCH2COOC2H5
N
N
N
N
COCH2COOC2H5
COCH2COOC2H5
COOC2H5
10
11
66
92
N
N
COOC2H5
N
N
COOC2H5
COCH2COOC2H5
N
12
87
N

R. Venkat Ragavan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4193–4197
4195
Table 2 (continued)
Compd
Ester
Product
Yield (%)
COOCH3
COCH2COOC2H5
13
56
N
N
Boc
Boc
COOC2H5
COCH2COOC2H5
N
N
14
15
85
76
N
N
N
N
N
COCH2COOC2H5
CH2CH2OCH3
COCH2COOC2H5
COOC2H5
N
CH2CH2OCH3
COOCH3
16
17
0a
H3CO
N
OCH3
H3CO
N
OCH3
COOCH3
COCH2COOC2H5
0a
N
N
COOC2H5
N
COCH(CH3)COOC2H5
N
18
19
89
84
N
N
COOC2H5
N
N
COCH(CH3)COOC2H5
COOCH3
COCH2COOC2H5
20
0a
N
N
Cbz
Cbz
21
78
N
COOC2H5
N
COCH2COOC2H5
a
Percentage of products in crude LC–MS.
condition, the same methodology has been applied to synthesis
various b-keto esters (1–21) using different heterocyclic esters to
prove the generality of the reaction (Table 2). All these b-keto es-
ters (1–21) were characterized through 1H NMR, 13C NMR and
LC–MS spectral data. The experimental results clearly reveal that
heterocyclic esters with even lower to moderate electrophilicity
undergoes the condensation smoothly without unwanted by-prod-
ucts to the greater extent. Esters of different heterocyclic com-
pounds (quinoline, isoquinoline, benzo-thiazole, thiazole,
pyridine, pyrazine, pyrimidine, imidazole, indole) were converted
in to the corresponding b-keto esters in good yield. In the case of
16 and 17 the unexpected and interesting trans-esterification
was observed instead of desired b-keto esters.
Table 3
Antibacterial activity of the newly synthesized compounds (zone of inhibition in mm,
MIC in mg/mL given in parenthesis, standard = ciprofloxacin)
Compd
S. aureus
E. coli
P. aeruginosa
K. pneumonia
2
7
8
9
21 (6.25)
22 (6.25)
23 (6.25)
16 (12.5)
22 (6.25)
23 (6.25)
22 (6.25)
19 (6.25)
24 (6.25)
19 (12.5)
24 (6.25)
32 (6.25)
22 (6.25)
20 (6.25)
21 (6.25)
22 (12.5)
22 (6.25)
28 (6.25)
23 (6.25)
22 (6.25)
20 (6.25)
23 (12.5)
23 (6.25)
23 (6.25)
14
Standard
This may be due to the weaker electrophilicity of the ester. Pres-
ence of two methoxy groups in 16 decreases the electrophilicity of
the esters by donating the electrons. In case of 17 the electron
donating nature of N-ethyl group increases the electron density
in the molecule, causes the complete trans-esterification in this
particular case. In case of 13 and 20, we observed unexpected
deprotection of the Boc and Cbz groups. In compound 13 the Boc
group was partially deprotected and produced the Boc-cleaved
starting material and the desired product in 56% yield, whereas
in the case of 20 the Cbz group was completely cleaved and gave
the Cbz-cleaved starting material. Cleavage of the Boc and Cbz
groups were observed within 10 min. This may be due to the labile
nature of the protecting groups particularly in indole systems. In
Table 4
Antifungal activities of the newly synthesized compounds
Compd
Trichophyton
Penicillium
A. flavus
A. fumigates
2
7
8
9
17 (12.5)
17 (12.5)
25 (6.25)
23 (6.25)
18 (12.5)
27 (3.125)
17 (12.5)
18 (12.5)
24 (6.25)
25 (6.25)
17 (12.5)
23 (6.25)
19 (12.5)
15 (12.5)
22 (6.25)
27 (6.25)
22 (12.5)
27 (3.125)
18 (12.5)
18 (12.5)
26 (6.25)
23 (6.25)
25 (12.5)
26 (6.25)
14
Standard
Zone of inhibition in mm, MIC in mg/mL given in parenthesis,
standard = ciclopiroxolamine.

4196
R. Venkat Ragavan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4193–4197
Table 5
Cytotoxic activity of the cross condensed b-keto esters (1–21)
Compd Screening concentration in H460 (non-small cell lung
HCT116 (colon
cancer)
ACHN (renal
cancer)
Calu1 (lung
cancer)
Panc-1 (pancreatic
cancer)
lM
cancer)
1
2
3
4
5
7
8
9
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
20
14
24
20
13
34
34
17
14
19
10
39
20
14
19
87
36
71
73
28
39
48
30
20
26
40
29
11
30
39
33
23
28
24
90
21
78
74
20
31
37
34
15
30
30
30
30
30
31
30
10
21
25
93
25
71
73
23
19
32
16
12
30
31
21
30
30
12
20
17
24
20
94
22
88
71
26
27
29
27
35
35
14
23
35
35
10
23
37
26
30
97
27
74
79
10
11
12
13
14
15
18
19
21
Std 1
Std 2
10
Flavopiridol (1000 nM)
Gemcitabine (1000 nM)
only the compounds with good inhibition results given in Table 3).
Compound 9 was moderately active against all the stains and the
b-keto esters of heterocyclic compounds shown a good bacterial
activity in particular b-keto esters of benzothiazole, isoquinoline,
pyrazine are equipotent or even higher than the standard used in
some cases. Pyrimidine 2-b-keto ester is moderately active. From
the impressive results of the biological activity further conversion
of these b-keto esters into the heterocyclic compounds are
required.
Similarly all these newly synthesized b-keto esters were
screened for their antifungal activity against Aspergillus flavus
(NCIM No. 524), Aspergillus fumigates (NCIM No. 902), Penicillium
marneffei (recultured) and Trichophyton mentagrophytes (recul-
tured) in DMSO by the serial plate dilution method.34,35 Antifungal
activity was determined by measuring the inhibition zone and
compared with the standard ciclopiroxolamine (though all the
compounds are subjected to the study only the compounds with
good inhibition results given in Table 4). Among the tested com-
pounds, compounds 8 and 9 are highly active against all the stains
tested. Compounds 2, 7 and 14 were moderately active against all
the stains.
Table 6
Cytotoxic activity of the cross condensed b-keto ester 19 at varying concentrations
and its IC50 M)
(
l
Concn (
lM)
H460
HCT116
ACHN
Calu1
Panc-1
MCF10A
0.01
0.03
0.1
0.3
1
3
10
30
IC50 (lM)
3.6
6.7
9.4
À23.4
À28.9
19.0
27.9
46.2
51.6
67.4
82.3
3.0
1.5
2.9
6.7
9.4
22.8
60.8
85.3
99.2
2.8
8.3
À15.2
À14.1
À9.5
À6.8
6.3
24.0
39.1
82.8
21.2
18.8
26.9
32.3
44.8
92.2
100.0
100.0
1.3
10.0
13.6
15.9
29.2
67.8
92.1
100.0
2.9
14.2
38.6
44.6
55.0
100.0
100.0
3
these cases (13 and 20), trans-esterified products were not ob-
served even in trace amount.
We have investigated newly synthesized b-keto esters for their
antibacterial activity against Escherichia coli (ATTC-25922), Staphy-
lococcus aureus (ATTC-25923), Pseudomonas aeruginosa (ATTC-
27853), and Klebsiella pneumonia (recultured) bacterial strains by
the disc diffusion method.31–33 Among the tested compounds,
compounds 2, 7, 8 and 14 are highly active against all the bacterial
stains tested (though all the compounds are subjected to the study,
The fungicidal activity of b-keto esters of heterocyclic com-
pounds are very good, in particular b-keto esters of isoquinoline
Figure 1. Effect of compound 19 on proliferation of different cell lines.

R. Venkat Ragavan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4193–4197
4197
and pyrazine are equipotent or even higher than the standard used.
Supplementary data
Benzothiazole and 2-pyrimidine b-keto esters were moderately ac-
tive. Because of the good fungicidal activity further conversion of
these b-keto esters into the heterocyclic compounds are required.
All the synthesized compounds 1–21 have been subjected to
WST-1 cytotoxicity assay. A panel of five cancer cells representing
multiple cancers of clinical relevance were obtained from ATCC
(American Type Culture Collection), namely; ACHN (human renal
cell carcinoma), Panc-1 (human pancreatic adenocarcinoma),
H460 (human non-small cell lung carcinoma), Calu-1 (human lung
carcinoma) and HCT-116 (human colon cancer). Cells were main-
tained in DMEM (Dulbecco’s modified Eagle’s medium) medium
containing 10% heat inactivated Fetal Bovine Serum and kept in
humidified 5% CO2 incubator at 37 °C. Logarithmically growing
cells were plated at a density of 5 Â 103 cells/well in a 96-well tis-
sue culture grade micro-plate and allowed to recover overnight.
The cells were challenged with varying concentration of com-
pounds for 48 h. Control cells received standard media containing
dimethylsulfoxide vehicle at a concentration of 0.2%. After 48 h of
incubation, cell toxicity was determined by CCK-8 (Cell Counting
Kit-8) reagent (Dojindo Molecular Technologies, Inc. Maryland, Ja-
pan); (WST-1 [2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-
(2,4-disulfo phenyl)]-2H-tetrazolium, monosodium salt assay). In
Supplementary data (the experimental data along the spectral
evidence) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.bmcl.2012.04.008.
References and notes
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accordance with the manufacturer’s instructions36
, 5 lL/well
CCK-8 reagent was added and plates were incubated for 2 h. Cyto-
toxicity of all the compounds have been determined by measuring
the absorbance on Tecan Sapphire multi-fluorescence micro-plate
reader (Tecan, Germany, GmbH (Gesellschaft mit beschränkter
Haftung; English: company with limited liability) at a wavelength
of 450 nm corrected to 650 nm and normalized to controls. Each
independent experiment was performed thrice and tabulated in
Table 5. The compound 19 was found to be inhibitive against all
these cell lines and hence its % cytotoxicity for various concentra-
tions has been observed (Table 6). By plotting these values (Fig. 1)
the IC50 value for cancer cell lines has been found as 3, 1.3, 3, 2.8,
2.9 and 21.2 lM for H460, HCT116, ACHN, Calu-1, Panc-1 and
MCF10A cancer cell lines respectively. The study reveals the prom-
ising activity of 19 towards the above mentioned cancer cell lines
and further investigations are in need.
In summary simple, fast and an efficient method has been
developed to synthesis b-keto esters from their corresponding het-
eroaryl esters in mild conditions using LiHMDS as a base. All these
compounds have been subjected to WTS-1 cytotoxicity assay and
antimicrobial screening; compounds 19 and 8 have been found
to be the promising candidates for anti cancer activity and micro-
bial agent respectively and hence further attention of these com-
pounds are in need.
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Acknowledgments
Authors are grateful to Syngene International Pvt. Ltd, Bengal-
uru for providing spectral facilities. Authors are thankful to the
VIT management for their generous support and facilities.