Eco-friendly synthesis and antimicrobial activities of substituted-5-(1H- indol-3-yl)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione derivatives

Article abstract of DOI:10.1007/s00044-013-0728-8

l-Tyrosine is an efficient catalyst for the condensation of substituted indole-3-aldehydes 1(a-d), N-methyl indole-3-aldehydes 4(a-d), and N-ethyl indole-3-aldehydes 6(a-d) with meldrum's acid (2) containing a cyclic active methylene group to produce 3(a-d), 5(a-d), and 7(a-d), respectively, in water at room temperature for 30 min. The antimicrobial activities of 3(a-d), 5(a-d), and 7(a-d) have been studied.

Full text of DOI:10.1007/s00044-013-0728-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:1569–1580
DOI 10.1007/s00044-013-0728-8
ORIGINAL RESEARCH
Eco-friendly synthesis and antimicrobial activities
of substituted-5-(1H-indol-3-yl)methylene)-2,2-dimethyl-
1,3-dioxane-4,6-dione derivatives
•
G. Thirupathi M. Venkatanarayana
•
•
P. K. Dubey Y. Bharathi Kumari
Received: 7 May 2013 / Accepted: 14 August 2013 / Published online: 4 September 2013
Ó Springer Science+Business Media New York 2013
Abstract L-Tyrosine is an efficient catalyst for the con-
densation of substituted indole-3-aldehydes 1(a–d), N-
methyl indole-3-aldehydes 4(a–d), and N-ethyl indole-3-
aldehydes 6(a–d) with meldrum’s acid (2) containing a
cyclic active methylene group to produce 3(a–d), 5(a–d),
and 7(a–d), respectively, in water at room temperature for
30 min. The antimicrobial activities of 3(a–d), 5(a–d), and
7(a–d) have been studied.
ethylenediamine, potassium fluroiodide, primary, and sec-
ondary amines, and their corresponding ammonium salts,
Lewis acids (Prajapati et al., 1996; Rao and Ratnam, 1991;
Narsaiah and Nagaiah, 2003), zeolite (Martins et al., 2008;
Tran et al., 2011; Reddy and Verma, 1997), and ionic
liquids (Formentin et al., 2004; Hu et al., 2004; Santamarta
et al., 1978) have also been added to the existing list of
substances that assisted Knoevenagel condensation in
organic synthesis.
Keywords Anti-bacterial activities Á
Anti-fungal activities Á Indole-3-aldehyde Á
Meldrum’s acid Á L-Tyrosine Á Water
Knoevenagel condensation of Meldrum’s acid and
aldehydes gives rise to substrates for a variety of reactions
(Mc Nab, 1978). They are used in cycloaddition reactions
(Kraus and Krolski, 1986), 1,4-conjugate addition reac-
tions, preparation of mono alkyl Meldrum’s acid deriva-
tives (Huang and Xie, 1986), and preparation of deuterated
carboxylic acid derivatives (Kadam et al., 1999). These
derivatives are also used in the preparation of ketenes by a,
b-pyrolysis (Brown et al., 1974), which are then used for
preparation of different compounds such as cyclobutadiene
derivatives (Brown and McMullen, 1974), a, b-unsaturated
esters (Nakamura et al., 2004), and a, b-unsaturated amides
(Thorat et al., 1987; Rao and Venkataratnam, 1993) .
Earlier in 1986, Jones et al. reported (Miroslav et al.,
2009) the reaction of meldrum’s acid with indole-3-car-
boxaldehyde under flash vacuum pyrolysis to yield the
Knoevenagel derivative of 5-((1H-indol-3-yl)methylene)-
2,2-dimethyl-1,3-dioxane-4,6-dione with 61 % yield. This
method is more time-consuming and not very good for the
preparation of large amounts of these products; moreover,
it is a very good intermediate for the preparation of anti-
cancer drugs (Tara and Gordon, 2001). L-Tyrosine is
known to be an efficient, bi-functional, zwitterionic, and
eco-friendly catalyst. It is available in both the enantio-
meric, (S)-Tyrosine and (R)-Tyrosine, forms. The two
functional groups of Tyrosine enable it to act both as an
Introduction
The carbon–carbon bond formation reaction is the most
important reaction in organic synthesis (Jones, 1967;
Knoevenagel, 1898; Tietze and Beifuss, 1991; Freeman,
1980). The Knoevenagel condensation is one such reaction
which facilitates C–C double bond formation and has been
widely used in synthesis of alkenes of biological signifi-
cance (Zidar et al., 2010; Ibrahim et al., 2011; Oguchi
et al., 2000; Malamas et al., 2000; Murugan et al., 2009).
These reactions are usually catalyzed by bases (Desai et al.,
2004; Fildes et al., 2001; Texier-Boullet and Foucod, 1982;
Cabello et al., 1984; Yadav et al., 2004; Yang et al., 2006;
Narsaiah et al., 2004; Rodriguez et al., 1999) such as
G. Thirupathi (&) Á M. Venkatanarayana Á
P. K. Dubey Á Y. Bharathi Kumari
Department of Chemistry, College of Engineering Hyderabad,
Jawaharlal Nehru Technological University Hyderabad,
Kukatpally, Hyderabad, A.P 500085, India
e-mail: thiru.g607@gmail.com
123

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Med Chem Res (2014) 23:1569–1580
acid as well as a base catalyst in chemical condensation
reactions.
The above reactions of 1(a–d), 4(a–d), and 6(a–d) with
meldrum’s acid were attempted in the presence of various
amino acids like valine, glycine, alanine, and Lysine, but
there was not much progress in the reactions as seen by
TLC examination of crude reaction mixtures. In the pres-
ence of phenyl alanine in water at room temperature, there
was a little bit of progress, but the reaction was not com-
pleted for 20 h.
Results and discussion
Treatment of substituted indole-3-carboxaldehydes 1(a–d),
its N-methyl derivatives 4(a–d), and N-ethyl derivatives
6(a–d), each with meldrum’s acid containing cyclic active
methylene group (2), in water at room temperature for
30 min resulted in the corresponding Knoevenagel prod-
ucts 3(a–d), 5(a–d), and 7(a–d) in excellent yields
(94–97 %) (Scheme 1; Table 1). L-Tyrosine is used as an
eco-friendly and efficient catalyst to induce the reaction.
Structures of all the products have been assigned based on
spectral and analytical data.
The above reactions of substituted indole-3-aldehydes
1(a–d), 4(a–d), and 6(a–d) with meldrum’s acid containing
cyclic active methylene group were attempted in the
presence of L-proline and L-tryptophan; low yields were
obtained for 4 h in water at room temperature.
Treatment of substituted indole-3-carboxaldehydes 1(a–
d), its N-methyl derivative 4(a–d), and N-ethyl derivative
6(a–d), each with meldrum’s acid containing cyclic active
methylene group (2), was attempted in the presence of
various bases like NaOH and KOH, which were too strong
to result in more by-products. Low yield was obtained and
a 12-h reaction time is needed using K2CO3, ammonium
acetate, piperidine, and triethylamine as the catalyst for
condensation of substituted indole-3-aldehydes 1(a–d),
4(a–d), and 6(a–d) with meldrum’s acids containing cyclic
active methylene group (2) in water at room temperature.
From Table 1, it is shown that the condensation of
substituted indole-3-aldehydes 1(a–d), 4(a–d), and 6(a–
d) with electron-withdrawing groups such as –NO2 and –Br
at the 5th position with meldrum’s acid containing cyclic
In the absence of L-tyrosine, the reaction did not proceed
even after refluxing the reactants in water for 24 h. The use
of L-tyrosine as a catalyst helps to complete the reaction in
30 min. Thus, L-tyrosine has been found to be an efficient
and eco-friendly catalyst for the Knoevenagel condensation
reaction of indole-3-carboxyaldehyde (1) and its N-methyl
derivative 4(a–d) and N-ethyl derivative 6(a–d), each with
meldrum’s acid containing cyclic active methylene group
(2).The use of L-tyrosine as a catalyst helps to avoid the use
of environmentally unfavorable organic solvents as the
reaction medium.
Scheme 1 Condensation of
indole-3-aldehyde with
meldrum’s acid in the presence
of L-Tyrosine in aqueous
medium and alkylation under
solvent-free condition using
alkylating agents
O
O
O
H
O
O
R
O
O
O
L-tyrosine/ 30 min
Water/ r.t.
H2O
+
+
N
O
N
CH3
4
CH3
2
5
DMS / Na2CO3
20min / Physical grinding
/
DMS / Na2CO3
15min / Physical grinding
/
R
O
O
O
H
O
O
R
L-tyrosine/ 30 min
Water/ r.t.
H2O
+
+
O
N
O
O
O
H
N
H
1
3
2
DES / Na2CO3
/
20 min / Physical grinding
DES / Na2CO3
/
15min / Physical grinding
O
O
O
H
R
O
O
O
L-tyrosine/ 30 min
Water/ r.t.
H2O
+
+
O
N
O
O
N
C2H5
C2H5
2
6
7
R= H, NO2 ,Br,OCH3
123

Med Chem Res (2014) 23:1569–1580
1571
Table 1 Synthesis substituted-
S. no.
Reactants
Product
Time (min)
Yield (%)
M.P. °C
5-(1H-indol-3-yl)methylene)-
2,2-dimethyl-1,3-dioxane-4,6-
dione derivatives using L-
Tyrosine as eco-friendly
catalyst in water at room
temperature and alkylation
under solvent-free condition
using alkylating agents
1
1a (R=H)
2
3a (R=H)
10
12
9
95
94
96
97
93
91
92
94
93
91
92
94
93
91
92
94
93
91
92
94
241–243
255
2
1b (R=OMe)
1c (R=Br)
1d (R=NO2)
4a (R=H)
2
3b (R=OMe)
3c (R=Br)
3
2
251–253
241
4
2
3d (R=NO2)
5a (R=H)
9
5
2
11
14
13
13
11
14
13
13
20
23
21
20
20
23
21
20
218–221
198–200
265
6
4b (R=OMe)
4c (R=Br)
4d (R=NO2)
6a (R=H)
2
5b (R=OMe)
5c (R=Br)
7
2
8
2
5d (R=NO2)
7a (R=H)
215
9
2
203–205
140–142
198–200
151–153
218–221
198–200
265
10
11
12
13
14
15
16
17
18
19
20
6b (R=OMe)
6c (R=Br)
6d (R=NO2)
3a (R=H)
2
7b (R=OMe)
7c (R=Br)
2
2
7d (R=NO2)
5a (R=H)
DMS
DMS
DMS
DMS
DES
DES
DES
DES
3b (R=OMe)
3c (R=Br)
3d (R=NO2)
3a (R=H)
5b (R=OMe)
5c (R=Br)
5d (R=NO2)
7a (R=H)
215
203–205
140–142
198–200
151–153
3b (R=OMe)
3c (R=Br)
3d (R=)
7b (R=OMe)
7c (R=Br)
7d (R=NO2)
active methylene compounds can be carried out in rela-
tively shorter time and higher yield than with electron-
donating group such as –OCH3 in water at room
temperature.
condition, under the grindstone method at room temperature
for 20 min resulted in 5(a–d) and 7(a–d), respectively, in
excellent yields 91–94 % (Scheme 1). The compounds 5(a–
d) and 7(a–d) could also be synthesized in an alternative
manner. The compounds 4(a–d) and 6(a–d) were obtained
from 1(a–d) by alkylation with DMS and DES each, in the
presence of Na2CO3 as the base in solvent-free condition
under the grindstone method at room temperature.
This method was very facile and convenient for the
preparation of large amounts of Knoevenagel adducts with
high yields in less time. L-tyrosine acted as the base to
induce the reaction. The use of L-tyrosine as a catalyst
helps to avoid the use of environmentally unfavorable
organic solvents (DMF, C6H6, DMSO, CHCl3, CH3CN,
etc.) as the reaction medium. The L-tyrosine was readily
reactive in water at room temperature compared to solvents
such as methanol, ethanol, DMF, C6H6, etc.; that is why the
yield was also very high when the reaction was carried out
in water at room temperature.
A comparative study of the progress of condensation
reactions 1(a–d), 4(a–d), and 6(a–d) with 2 was carried out
in different solvents containing L-tyrosine as the catalyst
and the result is summarized in Table 2.
A plausible mechanism for the formation of 3 from 1
and 2 in the presence of L-tyrosine as the catalyst is shown
In some cases, yields were very high when the nucleo-
phile was very active such as 5-nitroindole-3-carbox-
aldehyde, N-methyl-5-nitroindole-3-carboxaldehyde, and
N-ethyl-5-nitroindole-3-carboxaldehyde.
Table 2 Progress of reaction in different solvent media
Entry
Solvent
Time (h)
Temp (°C)
Yield
1.
2.
3.
4.
5.
L-Tyrosine/water
L-Tyrosine/EtOH
L-Tyrosine/Benzene
L-Tyrosine/DMSO
1
r.t.
r.t.
r.t.
r.t.
94–97
74–76
42–46
36–40
NIL
However, 5-methoxy indole-3-carboxaldehyde, N-methyl-
5-methoxyindole-3-carboxy aldehyde, N-ethyl-5-methox-
yindole-3-carboxaldehyde,5-bromoindole-3-carboxaldehyde,
N-methyl-5-bromo indole-3-carboxy aldehyde, and N-ethyl-
5-bromoindole-3-carboxaldehyde underwent condensation
very easily with meldrum’s acid in the presence of L-tyrosine
in water at room temperature.
2-5
8
10
24
Without catalyst
in water
r.t./reflux at
100 °C
6.
7.
8.
L-Tyrosine/DMF
L-Tyrosine/CH3CN
L-Tyrosine/CHCl3
7
r.t.
r.t.
r.t.
26–28
18–20
NIL
12
18
Treatment of 3(a–d) independently with DMS and DES
each, in the presence of Na2CO3 as the base in solvent-free
123

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Med Chem Res (2014) 23:1569–1580
Scheme 2 Plausible
O
O
mechanism for the formation of
3 from 1 and 2 in the presence
of L-Tyrosine in water at room
temperature
O
OH
NH3
NH2
HO
HO
HO
Xb
Xa
Xb
O
O
O
O
O
O
O
OH
+
H
O
O
+
NH3
H
O
O
HO
NH3
XC
2
2I
O
H
R
H
O
R
OH
OH
O
OH
H2N
Xa
+
HO
+
NH2
H
N
H
N
HO
H
1I
Xc
1
O
O
O
H
O
O
O
H
R
R
H
O
O
O
O
H2O
+
R
HO
OH
+
H2O
H
O
N
N
O
H
N
H
H
3
2I
1I
1II
in Scheme 2. The reaction mechanism is supported by the
literature reference (Darvatkar et al., 2006; Thirupathi
et al., 2012a, b, c; Venkatanarayana and Dubey, 2012) .
In the mechanism shown in Scheme 2, L-tyrosine, in its
zwitterionic form (Xb), abstracts a proton from meldrum’s
acid containing cyclic active methylene group (2) forming
the carbanion of meldrum’s acid (2I), which then attacks
the protonated indole-3-aldehydes (1I) forming the corre-
sponding intermediate (1II) that loses water to form the end
product 3, which on alkylation results in the title com-
pounds 5 and 7.
very good activity against Staphylococcus aureus and
Bacillus subtilis. 3(a–d) compounds tested were found to
have more anti-bacterial activities compared with 5(a–
d) and 7(a–d) against K. pneumoniae, E. coli, S. aureus,
and B. subtilis.
3(a–d) compounds have NH functional groups due to
having more anti-bacterial activities compared with 5(a–
d) and 7(a–d). 5(a-d) and 7(a–d) compounds have N-
alkylated functional groups due to having less anti-bacte-
rial activities compared with 3(a–d).
3(a–d), 5(a–d), and 7(a–d) compounds tested were
found to have very good anti-fungal activity against Rhi-
zoctonia solani and Fusarium oxysporum. However, they
were found to have good activity against Aspergillus niger
and A. flavus.
Conclusions
In summary, L-tyrosine has been employed as an efficient,
eco-friendly catalyst for the preparation of substituted-5-
(1H-indol-3-yl methylene)-2,2-dimethyl-[1,3]dioxane-4,6-
dione derivatives by the knoevenagel reaction in water at
room temperature. This method is applicable to a wide
range of indole-3-carboxyldehydes, including N-sub-
stituted-indole-3-carboxyaldehydes. The attractive features
of this procedure are the mild reaction conditions, high
conversions, operational simplicity, and inexpensive and
ready availability of the catalyst, all of which make it a
useful and attractive strategy for the preparation of
3(a–d) compounds tested were found to have more anti-
fungal activities compared with 5(a–d) and 7(a–d) against
R. solani, F. oxysporum, A. niger, and A. flavus.
3(a–d) compounds have NH functional groups due to
having more anti-fungal activities compared with 5(a–
d) and 7(a–d).
5(a–d) and 7(a–d) compounds have N-alkylated func-
tional groups due to having less anti-fungal activities
compared with 3(a–d).
substituted-5-(1H-indol-3-yl
methylene)-2,2-dimethyl-
Experimental
[1,3]dioxane-4,6-dione derivatives in water at room tem-
perature. 3(a–d), 5(a–d), and 7(a–d) compounds tested
were found to have excellent anti-bacterial activity against
Klebsiella pneumoniae and Escherichia coli and also had
Melting points were measured in open capillary tubes and
are uncorrected. TLC was done on plates coated with silica
gel-G, and spotting was done using iodine or a UV lamp.
123

Med Chem Res (2014) 23:1569–1580
1573
1
IR spectra were recorded using FT-IR in KBr phase. H
NMR spectra and 13C NMR spectra were recorded at
400 MHz. The compounds are known and products were
identified by spectral and melting-point comparisons with
the authentic samples.
was poured at the rate of 15 ml into each petri dish
(90 mm). After solidification of the medium, small por-
tions of the mycelium of each fungus were spread carefully
over the center of each PDA plate with the help of steril-
ized needles. Thus, each fungus was transferred to a
number of PDA plates, which were then incubated at
(25 2) °C and ready for use after 5 days of incubation.
PDA plates were prepared by the pour plate method. The
activity of the compounds, freshly seeded with the test
organisms with sterile forceps, was tested by the agar well
diffusion method. A control ager well was also prepared on
the test plates to compare the effect of the test samples and
to nullify the effect of the solvent. The plates were then
kept in a refrigerator at 4 °C for 24 h so that the materials
had sufficient time to diffuse over a considerable area of
the plates. After this, the plates were incubated at 37 °C for
72 h. N,N-Dimethyl formamide (DMF) was used as solvent
to prepare the desired solutions of the compounds and also
to maintain proper control. The diameter (mm) of the zone
of inhibition around each agar well was measured and
results are recorded in Tables 4, 5, and 6.
Biological evaluation
Anti-bacterial activity
All the compounds, substituted-5-(1H-indol-3-yl methy-
lene)-2,2-dimethyl-[1,3]di oxane-4,6-dione derivatives 3(a–
d), 5(a–d), and 7(a–d), were screened for their anti-bacterial
activities (Ravichandran et al., 2011) against gram-positive
bacteria such as B. subtilis and S. aureus (ATCC6538) and
also against gram-negative bacteria such as K. pneumonia,
and E. coli (ATCC8739) bacterial strains (Kaspady et al.,
2010) at concentrations of 50, 100, 200, 300, and 500 lg/ml.
Streptomycin was used as a reference standard. Petri plates
and necessary glassware were sterilized in a hot air oven at
190 °C for 45 min. The mueller hinton agar and saline
(0.82 % Nacl) media were sterilized in an autoclave
(121 °C, 15 psi, 20 min). Inoculum was prepared in sterile
saline (0.82 % Nacl) and the optical density of all pathogens
was adjusted to 0.10 at 625 nm on a chemito spectra scan UV
2600 spectrophotometer that is equivalent to 0.5 Mc Farland
standards (Frankel et al., 1970). The mueller hinton agar
plates were prepared by the pour plate method. The activity
of the compounds was tested by the agar well diffusion
method. All the bacterial cells were cultured in mueller
hinton agar plates and the compounds to be tested were
dissolved in N,N-dimethylformamide (DMF), soaked in agar
well, and the Petri plates incubated at 37 °C for 24 h. The
diameter (mm) of the zone of inhibition around each agar
disk was measured and results are recorded in Table 3. 3(a–
d), 5(a–d), and 7(a–d) compounds tested were found to have
excellent anti-bacterial activity against K. pneumoniae and
E. coli. However, they were found to have very good activity
against S. aureus and B. subtilis. 3(a–d) compounds tested
were found to have more anti-bacterial activities compared
with 5(a–d) and 7(a–d) against K. pneumoniae, E. coli, S.
aureus, and B. subtilis.
3(a–d), 5(a–d), and 7(a–d) compounds tested were
found to have very good anti-fungal activity against R.
solani and F. oxysporum. However, they were found to
have good activity against A. niger and A. flavus.
3(a–d) compounds tested were found to have more anti-
fungal activities compared with 5(a–d) and 7(a–d) against
R. solani, F. oxysporum, A. niger, and A. flavus.
General procedure for the preparation of 3 from 1
A mixture of 1 (10 mmol), meldrum’s acid 2 (10 mmol), L-
tyrosine (2 mmol) ,and water (25 ml) was stirred at room
temperature for a specified period of time (Table 1). After
completion of the reaction (as shown by TLC checking),
the mixture was poured onto ice-cold water (50 ml). The
separated solid was filtered, washed with water (100 ml),
and dried to obtain crude product 3. The product was then
recrystallized from ethyl acetate to afford pure 3.
General procedure for the preparation of 5 from 3
Anti-fungal activity
A mixture of 3 (10 mmol), DES (10 mmol), and Na2CO3
was physically ground in solvent-free condition under the
grindstone method at room temperature for a specified
period of time (Table 1). After completion of the reaction
(as shown by TLC checking), the mixture was poured onto
ice-cold water (50 ml).The separated solid was filtered,
washed with water (100 ml), and dried to obtain crude 5.
The product was then recrystallized from ethyl acetate to
afford pure 5.
All the compounds synthesized 3(a–d), 5(a–d), and 7(a–
d) were screened for anti-fungal activity (Kaspady et al.,
2010; Navneet et al., 2012) against R. solani, F. oxyspo-
rum, A. niger, and A. flavus at concentrations of 50, 100,
200, 300, and 500 lg/ml. Mycostatin was used as a refer-
ence standard. Potato dextrose agar (PDA) was used as the
basal medium for test fungi. The glass petri dishes used
were sterilized. Sterilized melted PDA medium (*45 °C)
123

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Med Chem Res (2014) 23:1569–1580
Table 3 Anti-bacterial activity of 3(a–d), 5(a–d), and 7(a–d) against Klebsiella pneumonia, Escherichia coli, Staphylococcus aureus, and
Bacillus subtilis
S. no.
Compound no.
Types of bacteria
Zone of inhibition in mm for concentration of
50 lg/ml
100 lg/ml
200 lg/ml
300 lg/ml
500 lg/ml
1
3a
Klebsiella pneumonia
Escherichia coli
11
10
8
16
15
12
11
16
15
12
9
20
18
16
14
20
17
15
11
20
16
15
13
20
17
15
13
18
16
14
12
18
15
13
11
18
14
13
11
18
16
14
12
18
16
14
11
15
13
11
10
14
13
11
11
25
22
20
17
25
22
18
14
25
23
19
17
25
22
18
16
23
20
18
15
23
20
16
14
23
21
17
15
23
20
18
15
23
20
18
14
20
16
14
13
21
17
15
15
33
32
27
25
34
33
28
22
34
32
27
25
34
33
28
24
31
30
25
23
32
31
26
22
32
30
25
23
31
30
25
23
31
30
25
22
31
26
22
21
30
25
23
23
Staphylococcus aureus
Bacillus subtilis
6
2
3b
3c
3d
5a
5b
5c
5d
7a
7b
7c
Klebsiella pneumonia
Escherichia coli
11
10
8
Staphylococcus aureus
Bacillus subtilis
4
3
Klebsiella pneumonia
Escherichia coli
11
10.4
8
16
15.5
12
11.5
16
15
12
11
14
13
10
9
Staphylococcus aureus
Bacillus subtilis
7
4
Klebsiella pneumonia
Escherichia coli
11
10
8
Staphylococcus aureus
Bacillus subtilis
6
5
Klebsiella pneumonia
Escherichia coli
9
8
Staphylococcus aureus
Bacillus subtilis
6
4
6
Klebsiella pneumonia
Escherichia coli
9
14
13
10
9
8
Staphylococcus aureus
Bacillus subtilis
6
4
7
Klebsiella pneumonia
Escherichia coli
9
14
13.5
10
9.5
14
13
10
9
8.4
6
Staphylococcus aureus
Bacillus subtilis
5
8
Klebsiella pneumonia
Escherichia coli
9
8
Staphylococcus aureus
Bacillus subtilis
6
4
9
Klebsiella pneumonia
Escherichia coli
9
14
13
10
9
8
Staphylococcus aureus
Bacillus subtilis
6
4
10
11
Klebsiella pneumonia
Escherichia coli
8
13
10
9
6
Staphylococcus aureus
Bacillus subtilis
4
4
8
Klebsiella pneumonia
Escherichia coli
8.4
6
13.4
10
9.5
9.5
Staphylococcus aureus
Bacillus subtilis
5
5
123

Med Chem Res (2014) 23:1569–1580
1575
Table 3 continued
S. no.
Compound no.
Types of bacteria
Zone of inhibition in mm for concentration of
50 lg/ml
100 lg/ml
200 lg/ml
300 lg/ml
500 lg/ml
12
7d
Klebsiella pneumonia
Escherichia coli
9
8
14
13
10
9
18
15
13
11
24
23
19
17
23
20
16
14
28
26
22
20
32
31
26
22
37
36
31
28
Staphylococcus aureus
Bacillus subtilis
6
4
13
Streptomycin
Klebsiella pneumonia
Escherichia coli
13
12
10
9
18
17
15
14
Staphylococcus aureus
Bacillus subtilis
5-((5-Bromo-1H-indol-3-yl)methylene)-2, 2-di-methyl-
General procedure for the preparation of 7 from 3
1,3-dioxane-4,6-dione (3c)
A mixture of 3 (10 mmol), DES (10 mmol), and Na2CO3
was physically ground in solvent-free condition under the
grindstone method at room temperature for a specified
period of time (Table 1). After completion of the reaction
(as shown by TLC checking), the mixture was poured onto
ice-cold water (50 ml). The separated solid was filtered,
washed with water (100 ml), and dried to obtain crude 7.
The product was then recrystallized from ethyl acetate to
afford pure 7.
Yellow solid; Yield = 3.36 g (96 %); m.p.: 251–253 °C;
IR(KBr) : 3,142 cm-1(very NH), 1,731 cm-1(broad very
strong CO) and 1,679 cm-1 (very strong CO).1H NMR
(DMSO-d6/TMS): d 1.69 (s, 6H, 2CH3) 7.44–7.57 (m, 3H,
aryl proton of the indole ring), 8.66 (s, 1H, a-proton of the
indole ring), 9.27 (s, 1H vinylic proton of the indole ring);
12.93 (br, s, 1H, D2O-exchangeble NH proton); 13C spec-
trum (DMSO-d6/TMS): d 27.12, 103.12, 103.93, 112.12,
116.12, 117.14, 123.12, 124.91, 130.8, 138.12, 146.12,
153.12, 159.12; MS : m/z = 351 (M?1).
5-((1H-indol-3-yl)methylene)-2,2-dimethyl-1,3-
dioxane-4,6-dione (3a)
5-((5-Nitro-1H-indol-3-yl)methylene)-2,2-dimeth-yl-
Yellow solid; Yield = 2.57 g (95 %); m.p.: 241–243 °C;
1,3-dioxane-4,6-dione (3d)
IR (KBr): 3,191 cm-1 (very broad, NH), 1,733 cm-1 (very
1
strong, CO) and 1,684 cm-1 (very strong, CO); H NMR
Yellow solid; Yield = 3.065 g (97 %); m.p.: 241 °C;
IR(KBr): 3,144 cm-1 (very broad, NH) 1,732 cm-1 (sharp,
strong, CO), 1,678 cm-1 (very strong, CO); 1H NMR
(DMSO-d6/TMS): d 1.61 (s, 6H, 2CH3), 7.7–8.1 (m, 3H
aryl protons of the indole ring), 8.84 (s, 1H, a-proton of the
indole ring), 9.38 (s, 1H, vinylic proton of the indole ring),
12.8 (br, s, 1H, NH proton); 13C spectrum (DMSO-d6/
TMS): d 27.38, 103.12, 104.1, 111.12, 113.6, 119, 122.3,
124.1, 128.12, 134.14, 142, 148.12, 160.4; MS : m/z = 317
(M?1).
(DMSO-d6/TMS): d 1.7 (s, 6H, 2CH3), 7.3–7.9 (m, 4H,
aryl protons of the indole ring), 8.8 (s, 1H, a-proton of the
indole ring), 9.3–9.4 (s, 1H, vinylic proton of the indole
ring), 12.8–12.9 (br, s, 1H, NH proton); 13C spectrum
(DMSO-d6/TMS): d 27.2, 103.44, 103.86, 111.74, 113.78,
118, 123.46, 124.44, 129.30, 134, 140, 146.58, 159.4; MS:
m/z = 272 (M?1).
5-((5-methoxy-1H-indol-3-yl)methylene)-2,2-di-
methyl-1,3-dioxane-4,6-dione (3b)
2,2-Dimethyl-5-((1-methyl-1H-indol-3-yl)methyl-ene)-
Yellow solid; Yield = 2.82 g (94 %); m.p.: 255 °C;
IR(KBr): 3,171 cm-1 (very broad, NH), 1,727 cm-1(very
1,3-dioxane-4,6-dione (5a)
1
strong, CO–) and 1,676 cm-1(very strong, CO); H NMR
Yellow solid; Yield = 2.65 g (93 %); m.p.: 218–221 °C;
IR (KBr): 1,700 cm-1 (very strong, CO) and 1,679 cm-1
(very strong, CO); 1H NMR (DMSO-d6/TMS): d 1.69 (s,
6H, 2CH3), 4.01 (s, 3H, N CH3), 7.36–7.91 (m, 4H aryl
protons of the indole ring), 8.68 (s, 1H, a-proton of the
indole ring), 9.30 (s, 1H, vinylic proton of the indole ring);
13C spectrum (DMSO-d6/TMS): d 27.41,44.3, 103.51,
(DMSO-d6/TMS): d 1.72 (s, 6H, 2CH3), 3.83 (s, 3H,
OCH3), 6.9–7.49 (m, 3H, aryl protons of the indole ring),
8.7 (s, 1H, a-proton of the indole ring), 9.24 (s, 1H, vinylic
proton of the indole ring), 12.77 (br, s, 1H, NH proton); 13
C
spectrum (DMSO-d6/TMS): d 27.81, 54.21, 102.98,
104.23, 112.40, 117.28, 119.1, 120.71, 124.12, 128.48,
132.10, 147, 151, 159.8; MS : m/z = 302 (M?1).
123

1576
Med Chem Res (2014) 23:1569–1580
Table 4 Anti-fungal activity of 3(a–d), 5(a–d), and 7(a–d) against Rhizoctonia solani, Fusarium oxysporum, Aspergillus niger, and Aspergillus
flavus
S. no.
Compound no.
Types of fungi
Zone of inhibition in mm for concentration of
50 lg/ml
100 lg/ml
200 lg/ml
300 lg/ml
500 lg/ml
1
3a
Rhizoctonia solani
Fusarium oxysporum
Aspergillus niger
Aspergillus flavus
Rhizoctonia solani
Fusarium oxysporum
Aspergillus niger
Aspergillus flavus
Rhizoctonia solani
Fusarium oxysporum
Aspergillus niger
Aspergillus flavus
Rhizoctonia solani
Fusarium oxysporum
Aspergillus niger
Aspergillus flavus
Rhizoctonia solani
Fusarium oxysporum
Aspergillus niger
Aspergillus flavus
Rhizoctonia solani
Fusarium oxysporum
Aspergillus niger
Aspergillus flavus
Rhizoctonia solani
Fusarium oxysporum
Aspergillus niger
Aspergillus flavus
Rhizoctonia solani
Fusarium oxysporum
Aspergillus niger
Aspergillus flavus
Rhizoctonia solani
Fusarium oxysporum
Aspergillus niger
Aspergillus flavus
Rhizoctonia solani
Fusarium oxysporum
Aspergillus niger
Aspergillus flavus
Rhizoctonia solani
Fusarium oxysporum
Aspergillus niger
Aspergillus flavus
10
10
7
15
14
11
10
15
15
12
9
19
17
15
13
19
18
15
12
19
17
15
13
19
17
15
13
16
16
14
12
16
16
14
12
16
16
14
12
16
16
14
12
16
16
14
12
16
16
14
12
16
16
14
12
24
21
19
17
24
24
14
13
24
21
19
17
24
21
19
17
21
21
18
15
21
21
18
15
21
21
18
15
21
21
18
15
21
21
18
15
21
21
18
15
21
21
18
15
32
31
26
24
31
30
24
22
32
31
26
24
32
31
26
24
29
29
25
23
29
29
25
23
29
29
25
23
29
29
25
23
29
29
25
23
29
29
25
23
29
29
25
23
5
2
3b
3c
3d
5a
5b
5c
5d
7a
7b
7c
10
10
7
5
3
10
10
7
15
14
11
10
15
14
11
10
12
12
10
9
5
4
10
10
7
5
5
7
7
6
4
6
7
12
12
10
9
7
6
4
7
7
12
12
10
9
7
6
4
8
7
12
12
10
9
7
6
4
9
7
12
12
10
9
7
6
4
10
11
7
12
12
10
9
7
6
4
7
12
12
10
9
7
6
4
123

Med Chem Res (2014) 23:1569–1580
1577
Table 4 continued
S. no.
Compound no.
Types of fungi
Zone of inhibition in mm for concentration of
50 lg/ml
100 lg/ml
200 lg/ml
300 lg/ml
500 lg/ml
12
7d
Rhizoctonia solani
Fusarium oxysporum
Aspergillus niger
Aspergillus flavus
Rhizoctonia solani
Fusarium oxysporum
Aspergillus niger
Aspergillus flavus
7
7
12
12
10
9
16
16
14
12
22
21
16.6
16
21
21
18
15
30
29
23
22
29
29
25
23
38
37
34
32
6
4
13
Mycostanin
16
15
11.2
11
20
18
14
13
Table 5 Anti-bacterial activity of 3(a–d), 5(a–d), and 7(a–d) against Klebsiella pneumonia, Escherichia coli, Staphylococcus aureus, and
Bacillus subtilis in minimum inhibitory concentration (MIC) in lg/ml
S. no. Compound no. Types of bacteria and minimum inhibitory concentration (MIC) in lg/ml
Klebsiella pneumonia (MIC) Escherichia coli (MIC) Staphylococcus aureus (MIC) Bacillus subtilis (MIC)
1
3a (R=H)
10
10
10
10
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
5
10
10
10
10
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
5
20
20
20
20
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
10
20
20
20
20
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
20
2
3b (R=OMe)
3c (R=Br)
3
4
3d (R=NO2)
5a (R=H)
5
6
5b (R=OMe)
5c (R=Br)
7
8
5d (R=NO2)
7a (R=H)
9
10
11
12
13
14
15
16
17
18
19
20
21
7b (R=OMe)
7c (R=Br)
7d (R=NO2)
5a (R=H)
5b (R=OMe)
5c (R=Br)
5d (R=NO2)
7a (R=H)
7b (R=OMe)
7c (R=Br)
7d (R=NO2)
Streptomycin
104.61, 111.12, 119.12, 122.9, 123.14, 126.39, 134.12,
1,664 cm-1 (very strong, CO). 1H NMR (DMSO-d6/TMS):
d 1.68 (s, 6H, 2CH3), 3.45 (s, 3H, –OCH3), 3.96 (s, 3H, N
CH3), 6.9–7.58 (m, 3H aryl protons of the indole ring), 8.65
(s, 1H, a-proton of the indole ring), 9.23 (s, 1H, vinylic
proton of the indole ring); 13C spectrum (DMSO-d6/TMS):
d 27.36, 45.2, 53.11, 103.18, 104.23, 111.60, 118.18,
121.8, 123.9, 127.48, 132.4, 146.4, 150, 159.7; MS : m/
z = 316 (M?1).
136.12, 142.1, 150.21, 160.2; MS : m/z = 286 (M?1).
5-((5-Methoxy-1-methyl-1H-indol-3-yl)methyle-ne)-
2,2-dimethyl-1,3dioxane-4,6-dione (5b)
Light orange color solid; Yield = 2.866 g (91 %); m.p.:
198–200 °C; IR (KBr): 1,743 cm-1 (very strong, CO) and
123

1578
Med Chem Res (2014) 23:1569–1580
Table 6 Anti-fungal activity of 3(a–d), 5(a–d), and 7(a–d) against Rhizoctonia solani, Fusarium oxysporum, Aspergillus niger, and Aspergillus
flavus in minimum inhibitory concentration (MIC) in lg/ml
S. no.
Compound no.
Types of fungi and minimum inhibitory concentration (MIC) in lg/ml
Rhizoctonia solani (MIC)
Fusarium oxysporum (MIC)
Aspergillus niger (MIC)
Aspergillus flavus (MIC)
1
3a (R=H)
25
25
25
25
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
15
25
25
25
25
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
15
30
30
30
30
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
20
35
35
35
35
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
20
2
3b (R=OMe)
3c (R=Br)
3
4
3d (R=NO2)
5a (R=H)
5
6
5b (R=OMe)
5c (R=Br)
7
8
5d (R=NO2)
7a (R=H)
9
10
11
12
13
14
15
16
17
18
19
20
21
7b (R=OMe)
7c (R=Br)
7d (R=NO2)
5a (R=H)
5b (R=OMe)
5c (R=Br)
5d (R=NO2)
7a (R=H)
7b (R=OMe)
7c (R=Br)
7d (R=NO2)
Mycostanin
5-((5-Bromo-1-methyl-1H-indol-3-yl)methylene)-2,2-
104.1, 111.12, 113.6, 119, 122.3, 124.1, 128.12, 134.14,
dimethyl-1,3-dioxane-4,6-dione (5c)
142, 148.12, 159.9; MS : m/z = 331 (M?1).
Yellow solid; Yield = 3.34 g (92 %); m.p.: 265 °C; IR
(KBr): 1,708 cm-1 (very strong CO) and 1,622 cm-1 (very
strong, CO); 1H NMR (DMSO-d6./TMS): d1.67 (s, 6H,
2CH3), 4.21 (s, 3H, N CH3), 6.9–7.5 (m, 3H aryl protons of
the indole ring), 8.47 (s, 1H, a-proton of the indole ring),
8.54 (s, 1H, vinylic proton of the indole ring); 13C spectrum
(DMSO-d6/TMS): d 27.4, 45.4, 103.55, 104.13, 111.12,
117.1, 119.4, 122.34, 124.32, 130.8, 136.12, 144.1,
151.12,160; MS : m/z = 365 (M?1).
2,2-Dimethyl-5-((1-ethyl-1H-indol-3-yl)methyl-
ene)1,3-dioxane-4,6-dione (7a)
Yellow solid; Yield = 2.78 g (93 %); m.p.: 203–205 °C;
IR (KBr):1,711 cm-1 (Very strong, CO), 1,689 cm-1(Very
strong, CO);1H NMR (DMSO-d6/TMS): d 1.53 (t, 3H,
CH3), 1.66 (s, 6H, 2CH3), 4.03 (q, 2H, CH2), 7.33–7.82 (m,
4H aryl protons of the indole ring), 8.61 (s, 1H, a-proton of
the indole ring), 9.34 (s, 1H, vinylic proton of the indole
ring); 13C spectrum (DMSO-d6/TMS): d 14.7, 27.2, 44.5,
103, 110, 111, 113, 120.1, 121, 122, 127, 136.6, 138.2,
148.2, 161. MS : m/z = 300 (M?1).
5-((5-Nitro-1-methyl-1H-indol-3-yl)methylene)-2,2-
dimethyl-1,3-dioxane-4,6-dione (5d)
Yellow solid; Yield = 3.10 g (94 %); m.p.: 215 °C; IR
(KBr): 1,722 cm-1 (very strong, CO) and 1,672 cm-1
(very strong, CO); 1H NMR (DMSO-d6/TMS): d 1.71 (s,
6H, 2CH3), 4.20 (s, 3H, N CH3), 7.6–8.0 (m, 3H aryl
protons of the indole ring), 8.74 (s, 1H, a-proton of the
indole ring), 9.28 (s, 1H, vinylic proton of the indole ring);
13C spectrum (DMSO-d6/TMS): d 27.38, 47.2, 103.12,
5-((5-Methoxy-1-ethyl-1H-indol-3-yl)methylene)-2,2-
dimethyl-1,3-dioxane-4,6-dione (7b)
Yellow solid; Yield = 2.99 g (91 %); m.p: 140–142 °C;
IR(KBr): 1,718 cm-1 (very strong, CO) and 1,661 cm-1
1
(very strong, CO); H NMR (DMSO-d6/TMS): d 1.54 (t,
3H, CH3), 1.67 (s, 6H, 2CH3), 3.62 (s, 3H, O CH3), 4.15 (q,
123

Med Chem Res (2014) 23:1569–1580
1579
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heterogeneous basic catalyst Knovenagel reaction with out
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Formentin P, Garcia H, Leyva A (2004) Assessment of the suitability
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laboratory methods and diagnosis: textbook on a laboratory
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J Brazilian Chem Soc 22:1130–1139
2H, CH2), 7.21–7.98 (m, 3H aryl protons of the indole
ring), 8.61 (s, 1H, a-proton of the indole ring), 9.28 (s, 1H,
vinylic proton of the indole ring); 13C spectrum (DMSO-
d6/TMS): d 14.6, 27.3, 43.4, 56.5, 102, 103.5, 110.1, 111,
113, 120.8, 126.3, 128.4, 152, 153.3, 161.1; MS : m/
z = 330 (M?1).
5-((5-Bromo-1-ethyl-1H-indol-3-yl)methylene)-2,2-
dimethyl-1,3-dioxane-4,6-dione (7c)
Yellow solid; Yield = 3.477 g (92 %); m.p: 198–200 °C;
IR(KBr): 1,703 cm-1 (very strong, CO) and 1,691 cm-1
1
(very strong, CO); H NMR (DMSO-d6/TMS): d 1.51 (t,
3H, CH3), 1.68 (s, 6H, 2CH3), 4.23 (q, 2H, CH2), 7.32–8.03
(m, 3H aryl protons of the indole ring), 8.12 (s, 1H, a-
proton of the indole ring), 8.87 (s, 1H, vinylic proton of the
indole ring); 13C spectrum (DMSO-d6/TMS): d 14.21, 27.8,
44.1, 104.5, 109.5, 113.2, 117.0, 120.5, 121, 121.8, 128.5,
134.5, 135.5, 150, 160.2; MS : m/z = 379 (M?1).
Jones G (1967) The Knovenagel condensation reaction in organic
reactions, vol 15. Wiley, New York, pp 204–599
5-((5-Nitro-1-ethyl-1H-indol-3-yl)methylene)-2,2-
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Kraus GA, Krolski ME (1986) Synthesis of a precursor to quassim-
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inhibitors of protein tyrosine phosphatase with antihyperglyce-
mic properties. J Med Chem 43:995–1010
dimethyl-1,3-dioxane-4,6-dione (7d)
Yellow solid; Yield = 3.233 g (94 %); m.p.: 151–153 °C;
IR(KBr): 1,709 cm-1 (very strong, CO) and
1
1,691 cm-1(very strong, CO); H NMR (DMSO-d6/TMS):
d 1.56 (t, 3H, CH3), 1.71 (s, 6H, 2CH3), 4.65 (q, 2H, N
CH2), 7.87–8.34 (m, 3H aryl protons of the indole ring),
8.23 (s, 1H, a-proton of the indole ring), 8.54 (s, 1H,
vinylic proton of the indole ring); 13C spectrum (DMSO-
d6/TMS): d 14.5, 27.38, 47.2, 103.12, 104.1, 111.12, 113.6,
119, 122.3, 124.1, 128.12, 134.14, 142, 150.9, 160; MS : m/
z = 345 (M?1).
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Acknowledgments The authors are grateful to the Jawaharlal
Nehru Technological University, Hyderabad, for providing financial
support and to the principal of the JNTUH College of Engineering,
Hyderabad, for providing facilities to carry out the work.
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and in vivo antidiabetic activity of novel dispiropyrrolidines
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