Ionic Liquid Mediated Green Synthesis of Spirooxindoles from N-methyl Quinolones and Their Anti Bacterial Activity

Article abstract of DOI:10.1002/jhet.2821

Three-component reaction involving condensation of 1-methyl quinoline-2,4(1H,3H)-dione 1, isatins 2(a–e), and malononitrile/cyanoacetic ester 3(a–b) in the task-specific ionic liquid [DBU][Ac] (1,8-diazabicyclo[5.4.0]-undec-7-en-8-ium acetate) leading to the spirooxindole derivatives 4(a–j) is described. This approach is affords the products in high yields without use of column chromatography and resulting compounds were evaluated for antibacterial activity against both gram positive and gram negative bacteria (Staphylococcus aureus, Escherichia coli, Bacillus cereus, Bacillus subtilis, Salmonella typhimurium, and Klebsiella pneumonia). Among the all compounds, four compounds, that is, 4b, 4e, 4f, 4g, 4j exhibited moderate activity against all the strains as compared with the standard used.

Full text of DOI:10.1002/jhet.2821

Month 2017 Ionic Liquid Mediated Green Synthesis of Spirooxindoles from N-methyl
Quinolones and Their Anti Bacterial Activity
a
a,b
a
a
a
*
*
Ch. Venkata Ramana Reddy, B. Rama Devi, and P.K. Dubey
Raja S. Bhupathi, Bandi Madhu,
aDepartment of Chemistry, Jawaharlal Nehru Technological University Hyderabad College of Engineering, Kukatpally,
Hyderabad, Telangana 500 085, India
bJawaharlal Nehru Technological University, Kakinada, Andhra Pradesh, India
*
E-mail: madhubandi2@gmail.com; rs.bhupathi@gmail.com
Additional Supporting Information may be found in the online version of this article.
Received July 15, 2016
DOI 10.1002/jhet.2821
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
Three-component reaction involving condensation of 1-methyl quinoline-2,4(1H,3H)-dione 1, isatins
2(a–e), and malononitrile/cyanoacetic ester 3(a–b) in the task-specific ionic liquid [DBU][Ac] (1,8-
diazabicyclo[5.4.0]-undec-7-en-8-ium acetate) leading to the spirooxindole derivatives 4(a–j) is described.
This approach is affords the products in high yields without use of column chromatography and resulting
compounds were evaluated for antibacterial activity against both gram positive and gram negative bacteria
(Staphylococcus aureus, Escherichia coli, Bacillus cereus, Bacillus subtilis, Salmonella typhimurium, and
Klebsiella pneumonia). Among the all compounds, four compounds, that is, 4b, 4e, 4f, 4g, 4j exhibited
moderate activity against all the strains as compared with the standard used.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
spirooxindoles under solvent free conditions by using
microwave method and Shaghyegh et al. [17] reported
quinolone substituted spirooxindoles from one-pot
method under ultrasonic conditions. The need to reduce
the amount of toxic waste and by product formation from
chemical process is increasing in the designing process of
synthetic methods.
The spirooxindole system, probably most well-known
heterocycle, a common and important feature of a variety
of natural products [1] and medicinal agents. Spiro
compounds represent an important class of naturally
occurring substances characterized by highly pronounced
biological properties [2]. The spirooxindole system is a
core structure of many pharmacological agents and
natural alkaloids such as gelsemine [3], horsfiline [4],
mitraphylline [5], spirotryprotatins [6] A, B, and others
[7]. Especially spirooxindoles acts as antibacterial [8],
anti-viral [9], and anti-fungal agents [10]. These are the
great interest in modern organic, medicinal and natural
product chemistry. In this connection, spirooxindoles
with diverse pharmacological activities have gained much
interest because of its well-defined three dimensional
stereo-architecture [11]. Because of the presence of
conformational restrictions of spirooxindoles and
spirocarbon causes structural rigidity that triggers the
biological activities [12], that is, NITD 609 [13] used in
malarial treatment and MI77301 [14] used for cancer
therapy. Recently, Zhu et al. [15] reported three
component Triethylbenzylammonium Chloride (TEBA)
catalyzed syntheses of spirooxindoles in aqueous
medium. And Shanthi et al. [16] reported InCl3 mediated
One of the most promising approaches is using ionic
liquids as reaction media. Ionic liquids are the salts of
organic heterocyclic cations and inorganic anions. They
exist in liquid state at ambient temperatures; hence, the
reactions in the presence of ionic liquids need no
additional solvent. Ionic liquids have attracted much
attention because of their mild reaction conditions, short
© 2017 Wiley Periodicals, Inc.

R. S. Bhupathi, B. Madhu, C. V. R. Reddy, B. R. Devi, and P. K. Dubey
Vol 000
reaction times and better yield, solvating ability, and easy
recyclability. Various reactions have been reported
recently using ionic liquids as a catalyst, reaction media,
as rate enhancers, and in peptide synthesis [18].
liquid [DBU] [Ac] could be recycled four times without
considerable loss of activity.
In order to demonstrate the scope of these conditions,
several examples were studied and are summarized in
Table 2. In all cases, the three-component reaction
proceeded smoothly to give the corresponding
spirooxindoles in high yields. As shown in the Table 2, it
was found that this method works with a wide variety of
substrates.
RESULTS AND DISCUSSION
A mixture of 1-methylquinoline-2,4(1H,3H)-dione 1,
isatin 2(a–e), malononitrile or ethyl cyanoacetate 3(a–b)
were stirred at 100°C for 20 min in DBU acetate. After
processing, the product 20-amino-60-methyl-2,50-dioxo-
50,60-dihydrospiro[indoline-3,40-pyrano[3,2-c]quinoline]-30-
carbonitrile 4(a–j) was isolated and characterized by IR,
1HNMR,13C–NMR, and mass spectral data. (For details
please see the Experimental Section). When the reaction
was carried out in the absence of DBU acetate by
refluxing the reactants in ethanol for 2–3 h, no progress in
the product formation was observed by periodic thin-layer
chromatography (TLC) analysis of the reaction mixture.
Initially a mixture of 1-methylquinoline-2,4(1H,3H)-
dione 1, isatin 2a, malononitrile 3a, and was stirred with
5 mL of [DBU] [Ac] at room temperature. TLC showed
no formation of the product. Therefore, the same mixture
was heated at 100°C for 20 min to accomplish the
reaction. After workup, spirooxindole was the only
product isolated in high yield. We noticed that reducing
the quantity of [DBU] [Ac] (3 mL) did not affect the
yields. However, when the multi component reaction was
carried out independently with DBU free base as catalyst
in ethanol solution, the reaction was found to be very
sluggish as observed by TLC, leading to the poor yields
of the final product on processing the reaction mixture
after 3 h (Scheme 1).
The synthesis of spirooxindoles could also be achieved
in two different methods in a tandem fashion (Scheme 2).
Thus, a mixture of 2a, 3a, and DBU acetate was stirred
at 100°C for 20 min. The reaction was monitored by
TLC. After the completion of the reaction, as shown by
disappearance of one of the reactants, to the resulting
mixture, 1 was added and the resulting mixture stirred at
100°C for further 20 min. At the end of this period, the
mixture was processed to obtain 4a as final product.
Similarly, a mixture of 2a, 1, and DBU acetate was
stirred at 100°C for 20 min. The reaction was monitored
by TLC. After the completion of reaction, as shown by
disappearance of one of the reactants to the resulting
mixture, 3a was added and the whole mixture stirred at
RT for further 20 min. At the end of this period, the
mixture was processed to obtain the final 4a.
Mechanism I.
The catalyst/reaction medium plays a vital role in
determining the success of the reaction in terms of rate
and yields. Various ionic liquids such as [bmim]Br,
[bmim]AlCl4, [bmim]SbF6, [bmim]PF6,[DBU][Lac] and
DBU were screened, apart from DBU acetate, for the
synthesis of spirooxindoles. Among these ionic liquids,
DBU acetate proved to be the most effective as far as
completion of reaction in short time and yields are
concerned (Table 1). As shown in the Chart 1, the ionic
Plausible mechanism for the formation of spirooxindoles 4
(a–j):. Two possible mechanisms have been proposed for
the formation of 4 from 1, 2(a–e) and 3(a,b).
Scheme 1. Synthesis of 4(a–j) from 1, 2(a–e), and 3(a–b).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Green Synthesis of Spirooxindoles and Their Anti Bacterial Activity
Table 1
Ionic liquids screened for the synthesis of spirooxindoles.
Entry
Ionic liquid used
[bmim]Br
[bmim]AlCl4
[bmim]SbF6
[bmim]PF6
[DBU][AC]
[DBU][Lac]
DBU
Time (min) of reaction
Temp (°C)
Yield (%) of product 4a
1
2
3
4
5
6
7
90
90
90
90
20
30
40
100
100
100
100
100
100
100
32
55
45
50
92
75
30
Bold symbols indicates [DBU][AC] gave high yield than other ionic liquids.
Chart 1. Reaction of 1, 2a, and 3a in DBU acetate at 100oC for 20 min. [Color figure can be viewed at wileyonlinelibrary.com]
Table 2
Synthesis of spirooxindole derivatives 4(a–j) from 1, 2 and 3.
S.No
Isatin (2)
2a(R = H)
2b (R = F)
2c (R = Cl)
2d (R = Br)
2e (R = I)
2a (R = H)
2b (R = F)
2c (R = Cl)
2d (R = Br)
2e (R = I)
Active methylene (3)
Product
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
3a (X = CN)
3a (X = CN)
3a (X = CN)
3a (X = CN)
4a
4b
4c
4d
4e
4f
4g
4h
4i
15
18
20
17
20
18
20
20
20
20
92
88
85
90
94
90
87
88
86
90
3a (X = CN)
3b (X = COOC2H5)
3b (X = COOC2H5)
3b (X = COOC2H5)
3b (X = COOC2H5)
3b (X = COOC2H5)
10
4j
Scheme 2. Alternate synthesis of Spirooxindoles.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. S. Bhupathi, B. Madhu, C. V. R. Reddy, B. R. Devi, and P. K. Dubey
Vol 000
In the first mechanism proposed, the reaction involves a
Knoevenagel condensation catalyzed by DBU acetate
between isatin 2 and active methylene group of the cyano
derivative 3a to yield an α, β-unsaturated nitrile
intermediate 6. The latter is then attacked by the
carbanion of the 1-methylquinoline-2,4(1H,3H)-dione
compound 11in the form of Michael addition followed by
containing 1.5 × 108 cfu mLꢀ1. Wells of 6.0 mm
diameter were prepared in the media plates by using a
cork borer and the synthesized compounds dissolved
in 15% DMSO at a dosage range of 250 μg/disc, was
performed in order to evaluate the inhibitory potency
of the compounds against seven pathogenic bacterial
strains namely Staphylococcus aureus, Escherichia
coli, Bacillus cereus, Bacillus subtilis, Salmonella
typhimurium, and Klebsiella pneumonia. Out of all the
spirooxindole derivatives four compounds, that is, 4b,
4e, 4f, 4g, 4j exhibited moderate activity against all the
tested strains with zone of inhibition between 10 and
16 mm and minimum inhibitory concentration value in
the range of 75–170 μg/mL when compared with the
standard gentamicin, all the results were summarized in
Table 7.
a
keto-enol tautomerization to furnish the enol
intermediate X. Nucleophilic addition of the hydroxyl
group of intermediate X to the cyano moiety afforded
imine intermediate XI, which undergoes enolisation to
yield the final product 4.
Mechanism II.
EXPERIMENTAL
Melting points were determined in open capillary tubes
and are uncorrected. The progress of the reaction was
monitored by TLC performed on silica gel G coated
Merck plastic sheets and spots were observed by
exposure to iodine vapor or UV light. IR spectra were
recorded by using KBr disc on a Perkin-Elmer 240c
analyzer. 1H NMR spectra were recorded on Brucker
DPX-400 at 400 MHz (chemical shifts in δ, ppm) and
Mass spectra on an Agilent liquid chromatography–mass
spectrometry instrument giving only M+ values in Q + 1
mode.
General procedure for synthesis of spirooxindoles 4(a–j).
A mixture of 1(1 mmol), 2a–e (1 mmol), 3a or 3b
(1 mmol) respectively in DBU acetate (3 mL) was stirred
at 100°C for 20 min. To the resulting oily reaction
mixture was added 5 mL of ethanol to force out the crude
product from the polar ionic liquid reaction medium.
Then the precipitated product was filtered and washed
with cold ethanol to afford the pure products. The
collected ionic liquid along with ethanol as filtrate in the
filtration flask was evaporated to remove ethanol and the
obtained ionic liquid was reused for subsequent reactions.
In the second mechanism, the acetate ion abstracts the
proton from the active methylene group of 1 to afford
carbanion species 1I, which attacks the protonated
carbonyl group of the isatin to result in a C–C bond
intermediate. Loss of water molecule gives the α,
β-unsaturated diketo intermediate 5. The latter is then
attacked by the carbanion of the 3 to afford Y, which
undergoes intramolecular nucleophilic attack by hydroxyl
group on the cyano afforded imine intermediate Y1,
which undergoes enolisation to yield the final product 4.
(Table 3–6).
ANTIBACTERIAL ASSAY
Table 3
The antibacterial activity of all the synthesized
spirooxindole derivatives 4(a–j) was determined using
the well disc diffusion method [19] against different
gram positive and gram negative microbial strains, which
were produced from the Microbial Culture Collection
Department of Chemistry, JNTU-Hyderabad, India. The
clinical strains were seeded on the surface of the media
Petri plates, containing Muller-Hinton agar with 0.1 mL
of prepared microbial suspensions, which individually
Synthesis of 5 (a–e) from 2(a–e) and 1.
Product
5(a–e)
Time
(min)
Yield
(%)
S. No
Isatin (2)
1
2
3
4
5
2a (R = H)
2b (R = F)
2c (R = Cl)
2d (R = Br)
2e (R = I)
5a
5b
5c
5d
5e
20
22
20
20
20
87
81
83
83
85
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Green Synthesis of Spirooxindoles and Their Anti Bacterial Activity
Table 4
Synthesis of 6(a–j) from 2(a–e) and 3(a, b).
S. No
Isatin (2)
Active methylene (3)
Product 6(a–j)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
2a (R = H)
2b (R = F)
2c (R = Cl)
2d (R = Br)
2e (R = I)
2a (R = H)
2b (R = F)
2c (R = Cl)
2d (R = Br)
2e (R = I)
3a (X = CN)
3a (X = CN)
3a (X = CN)
3a (X = CN)
6a
6b
6c
6d
6e
6f
6g
6h
6i
20
23
21
20
20
20
24
22
20
21
89
80
81
81
83
87
79
82
82
84
3a (X = CN)
3b (X = COOC2H5)
3b (X = COOC2H5)
3b (X = COOC2H5)
3b (X = COOC2H5)
3b (X = COOC2H5)
10
6j
Table 5
Synthesis of 4(a–j) from 5(a–e) and 3(a, b).
S. No
5(a–e)
3 (a–b)
Product
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
5a(R = H)
5b (R = F)
5c (R = Cl)
5d (R = Br)
5e (R = I)
5a (R = H)
5b (R = F)
5c (R = Cl)
5d (R = Br)
5e (R = I)
3a (X = CN)
3a (X = CN)
3a (X = CN)
3a (X = CN)
4a
4b
4c
4d
4e
4f
4g
4h
4i
14
20
18
18
17
16
20
18
20
19
90
86
86
88
87
89
85
87
87
89
3a (X = CN)
3b (X = COOC2H5)
3b (X = COOC2H5)
3b (X = COOC2H5)
3b (X = COOC2H5)
3b (X = COOC2H5)
10
4j
To compensate for the loss of some acetic acid during the
work up procedure, an amount acetic acid (2 mL) was
Table 6
Synthesis of 4(a–j) from 6(a–j) and 1.
added after each run. A volume of DBU (2 mL) was
added to the ionic liquid filtrate after three runs.
S. No
6(a–j)
Product
Time (min)
Yield (%)
4a (R = H, X = CN): 20-amino-60-methyl-2,50-dioxo-50,60-
1
2
3
4
5
6
7
8
9
10
6a
6b
6c
6d
6e
6f
6g
6h
6i
4a
4b
4c
4d
4e
4f
4g
4h
4i
16
21
20
18
16
18
22
20
20
19
87
81
85
86
87
80
85
86
87
87
dihydrospiro[indoline
carbonitrile.
3,40pyrano
[3,2-c]quinoline]-30-
Yield: 92%; MP: >300°C; IR (KBr):
3499, 3326 (unequal doublet, asymmetric, and symmetric
stretchings of ꢀNH2), 2190 (sharp, medium, ꢀCN),
1
1720, 1674 cmꢀ1 (ꢀCO-group, broad); H-NMR(DMSO
d6/TMS): δ 3.47 (s, 3H, ꢀNCH3), 6.80 (s, 2H, ꢀNH2),
6.85–8.06 (m, 7H, Ar-H), 10.51 (s, 1H, ꢀNH, D2O
exchangeable). 13C-NMR (DMSO d6/TMS): δ 29.1, 48.1,
6j
4j
Table 7
Zone of inhibition of active compounds 4b, 4e, 4f, 4g, 4j against pathogenic bacterial test strains using gentamicin as positive control.
S. NO
Test compounds
B. cereus
B. subtilis
S. aureus
E. coli
K. pneumoniae
S. typhimurium
P. aeruginosa
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
0.00
12.66
10.00
10.00
13.67
13.67
13.68
0.00
0.00
12.02
10.00
10.00
11.65
11.34
13.04
0.00
0.00
13.35
0.00
0.00
11.31
0.00
0.00
11.00
10.00
10.00
11.02
11.00
12.38
0.00
0.00
11.01
0.00
0.00
11.67
0.00
0.00
0.00
0.00
0.00
13.68
14.32
13.00
0.00
11.35
10.69
12.38
0.00
11.34
11.04
12.68
0.00
14.66
13.36
13.67
0.00
9
10
11
4i
4j
10.00
14.00
30.34
10.00
13.38
30.69
0.00
14.37
30.02
0.00
13.32
30.23
10.00
13.10
29.34
0.00
13.37
30.00
0.00
15.62
29.37
Gentamicin
Bold text indicates high activity than other derivatives.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. S. Bhupathi, B. Madhu, C. V. R. Reddy, B. R. Devi, and P. K. Dubey
Vol 000
57.2, 106.4, 109.1, 112.2, 114.9, 117.3, 121.6, 122.3,
123.3, 128.2, 132.1, 134.2, 138.6, 142.4, 151.4, 158.7,
158.8, 177.7; m/z (M++1): 371. Anal. Calcd for
C21H14N4O3 (370.12): C, 68.50; H, 3.81; N, 15.13%
Found: C, 68.54; H, 3.85; N, 15.17%.
ꢀNH2), 6.85–7.64 (m, 7H, Ar-H), 10.09 (s, 1H, ꢀNH,
D2O exchangeable). 13C-NMR (DMSO d6/TMS): δ 29.3,
48.2, 57.9, 106.2, 109.4, 112.8, 114.7, 117.2, 121.1,
122.8, 123.2, 128.2, 132.1, 134.4, 138.2, 142.8, 151.2,
158.2, 158.5, 177.2; m/z (M++1): 497. Anal. Calcd for
C21H13IN4O3 (496.04): C, 50.83; H, 2.64; N, 11.29; I,
25.57% Found: C, 50.87; H, 2.61; N, 11.24; I, 25.55%.
4b (R = F, X = CN): 20-amino-5-fluoro-60-methyl-2,50-dioxo-
50,60-dihydrospiro[indoline
3,40-pyrano[3,2-c]quinoline]-30-
4f (R = H, X = COOC2H5): ethyl 20-amino-60-methyl-2,50-
dioxo-50,60-dihydrospiro[indoline-3,40-pyrano[3,2-c]quinoline]-
30-carboxylate. Yield: 92%; MP: >300°C; IR (KBr): 3374,
carbonitrile.
Yield: 88%; Time: 8 min; MP: >300°C;
IR (KBr): 3482, 3332 (unequal doublet, asymmetric, and
symmetric stretchings of ꢀNH2), 2182 (sharp, medium,
ꢀCN), 1722, 1672 cmꢀ1 (ꢀCO-group, broad); 1H-
NMR(DMSO d6/TMS): δ 2.78 (s, 3H, ꢀNCH3), 6.86
(s,2H, ꢀNH2), 6.75–7.60 (m, 7H,Ar-H), 10.15 (s, 1H,
ꢀNH, D2O exchangeable).13C-NMR (DMSO d6/TMS): δ
29.3, 48.4, 57.1, 106.6, 109.3, 112.6, 114.8, 117.4,
121.3, 122.6, 123.6, 128.4, 132.0, 134.5, 138.8, 142.2,
151.1, 158.3, 158.9, 177.3; m/z (M++1): 389. Anal. Calcd
for C21H13FN4O3 (388.12): C, 64.95; H, 3.37; N, 14.43;
F, 4.89% Found: C, 64.98; H, 3.33; N, 14.48; F, 4.84%.
3253 (unequal doublet, asymmetric, and symmetric
stretchings of ꢀNH2), 2199 (sharp, medium, ꢀCN), 1698,
1
1656, 1630 cmꢀ1 (ꢀCO-group, broad); H-NMR (DMSO
d6/TMS): δ 0.82 (t, 3H, CH3), 3.7 (s, 3H, ꢀNCH3), 4.43 (q,
2H, ꢀCH2), 6.6 (s, 2H, ꢀNH2), 6.76–8.1 (m, 7H, Ar-H),
10.22 (s, 1H, ꢀNH, D2O exchangeable). 13C-NMR (DMSO
d6/TMS): δ 13.1, 29.1, 47.9, 58.9, 76.0, 108.0, 109.0, 112.2,
114.7, 120.5, 122.1, 122.5, 127.3, 132.0, 135.5, 138.4,
144.6, 150.2, 158.6, 159.1, 167.5, 179.6; m/z (M++1): 418.
Anal. Calcd for C23H19N3O5 (417.21): C, 66.18; H, 4.59, N,
10.47% Found: C, 66.15; H, 4.56, N, 10.44%.
4c (R = Cl, X = CN): 20-amino-5-chloro-60-methyl-2,50-
dioxo-50,60-dihydrospiro[indoline-3,40-pyrano[3,2-c]quinoline]-
30-carbonitrile. Yield: 85%; Time: 10 min; MP: >280°C;
4g (R = F, X = COOC2H5): ethyl 20-amino-5-fluoro-60-
methyl-2,50-dioxo-50,6’dihydrospiro [indoline-3,40-pyrano[3,2-
IR (KBr): 3489, 3336 (unequal doublet, asymmetric, and
symmetric stretchings of ꢀNH2), 2229 (sharp, medium,
ꢀCN), 1721, 1672 cmꢀ1 (ꢀCO-group, broad); 1H-
NMR(DMSO d6/TMS): δ 2.65 (s, 3H, ꢀNCH3), 6.91 (s,
2H, ꢀNH2), 7.05–7.59 (m, 7H,Ar-H), 10.23 (s, 1H,
ꢀNH, D2O exchangeable).13C-NMR (DMSO d6/TMS): δ
29.4, 48.5, 57.4, 106.9, 109.3, 112.7, 114.3, 117.2, 121.7,
122.8, 123.2, 128.1, 132.8, 134.2, 138.3, 142.1, 151.7,
158.0, 158.2, 177.1; m/z (M++1): 405. Anal. Calcd for
C21H13ClN4O3 (404.21): C, 62.31; H, 3.24; N, 13.84; Cl,
8.76% Found: C, 62.34; H, 3.20; N, 13.88; Cl, 8.72%.
c]quinoline]-30-carboxylate.
Yield: 87%; Time: 7 min;
MP: 184–186°C; IR (KBr): 3380, 3246 (unequal doublet,
asymmetric, and symmetric stretchings of ꢀNH2), 2187
(sharp, medium, ꢀCN), 1687, 1664, 1654 cmꢀ1 (ꢀCO-
1
group, broad); H-NMR (DMSO d6/TMS): δ 0.98 (t, 3H,
CH3), 3.8(s, 3H, ꢀNCH3), 4.56 (q, 2H, ꢀCH2), 6.7 (s, 2H,
ꢀNH2), 6.79–8.3 (m, 7H, Ar-H), 10.24 (s, 1H, ꢀNH, D2O
exchangeable). 13C-NMR (DMSO d6/TMS): δ 13.1, 29.1,
47.9, 58.9, 76.0, 108.0, 109.0, 112.2, 114.7, 120.5, 122.1,
122.5, 127.3, 132.0, 135.5, 138.4, 144.6, 150.2, 158.6,
159.1, 167.5, 179.6; m/z (M++1): 436. Anal. Calcd for
C23H18 FN3O5 (433.01): C, 63.45; H, 4.17; N, 9.65; F,
4.36% Found: C, 63.49; H, 4.13; N, 9.69; F, 4.32%.
4d (R = Br, X = CN): 20-amino-5-bromo-60-methyl-2,50-
dioxo-50,60-dihydrospiro[indoline-3,40-pyrano[3,2-c]quinoline]-
30-carbonitrile. Yield: 90%; Time: 7 min; MP: >300°C;
4h (R = Cl, X = COOC2H5): ethyl 20-amino-5-chloro-60-
IR (KBr): 3487, 3322 (unequal doublet, asymmetric, and
symmetric stretchings of ꢀNH2), 2180 (sharp, medium,
ꢀCN), 1719, 1670 cmꢀ1 (ꢀCO-group, broad); 1H-
NMR(DMSO d6/TMS): δ 2.70 (s, 3H, ꢀNCH3), 7.02 (s,
2H, ꢀNH2), 6.95–7.70 (m, 7H, Ar-H), 10.12 (s, 1H,
ꢀNH, D2O exchangeable). 13C-NMR (DMSO d6/TMS):
δ 29.1, 48.9, 57.7, 106.0, 109.6, 112.9, 114.2, 117.8,
121.9, 122.2, 123.9, 128.9, 132.9, 134.1, 138.3, 142.9,
151.0, 158.1, 158.7, 177.8; m/z (M++1): 449. Anal.
Calcd for C21H13BrN4O3 (448.02): C, 56.14; H, 2.92; N,
12.47; Br, 17.79% Found: C, 56.18; H, 2.96; N, 12.43;
Br, 17.73%.
methyl-2,50-dioxo-50,6’dihydrospiro [indoline-3,40-pyrano[3,2-
c]quinoline]-30-carboxylate.
Yield: 88%; Time: 8 min;
MP: 268–70°C; IR (KBr): 3372, 3250 (unequal doublet,
asymmetric, and symmetric stretchings of ꢀNH2), 2197
(sharp, medium, ꢀCN), 1697, 1650, 1628 cmꢀ1 (ꢀCO-
1
group, broad); H-NMR (DMSO d6/TMS): δ 0.96 (t, 3H,
CH3), 3.4(s, 3H, ꢀNCH3), 4.65 (q, 2H, ꢀCH2), 6.4 (s,
2H, ꢀNH2), 6.99–8.5 (m, 7H, Ar-H), 10.28 (s, 1H,
ꢀNH, D2O exchangeable). 13C-NMR (DMSO d6/TMS):
δ 13.4, 29.4, 47.5, 58.6, 76.4, 108.3, 109.2, 112.5, 114.5,
120.6, 122.8, 122.3, 127.6, 132.2, 135.7, 138.2, 144.2,
150.5, 158.7, 159.5, 167.2, 179.3; m/z (M++1): 452.
Anal. Calcd for C23H18ClN3O5 (451.31): C, 61.14; H,
4.02; N, 9.30; Cl, 7.85% Found: C, 61.19; H, 4.05; N,
9.34; Cl, 7.88%.
4e (R = I, X = CN): 20-amino-5-iodo-60-methyl-2,50-dioxo-
50,60-dihydrospiro[indoline-3,40-pyrano[3,2-c]quinoline]-30-
carbonitrile. Yield: 94%; Time: 10 min; MP: >300°C; IR
(KBr): 3479, 3198 (unequal doublet, asymmetric, and
4i (R = Br, X = COOC2H5): ethyl 20-amino-5-bromo-60-
symmetric stretchings of ꢀNH2), 2205 (sharp, medium,
1
ꢀCN), 1720, 1673 cmꢀ1 (ꢀCO-group, broad); H-NMR
methyl-2,50-dioxo-50,6’dihydrospiro [indoline-3,40-pyrano[3,2-
(DMSO d6/TMS): δ 2.65 (s, 3H, ꢀNCH3), 6.96 (s, 2H,
c]quinoline]-30-carboxylate.
Yield: 86%; Time: 8 min;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Green Synthesis of Spirooxindoles and Their Anti Bacterial Activity
MP: 284–86°C; IR (KBr): 3379, 3258 (unequal doublet,
asymmetric, and symmetric stretchings of ꢀNH2), 2220
(sharp, medium, ꢀCN), 1701, 1660, 1631 cmꢀ1 (ꢀCO-
exhibited moderate activity against all the tested strains
with standard gentamicin.
1
group, broad); H-NMR (DMSO d6/TMS): δ 0.93 (t, 3H,
Acknowledgments. The authors are indebted to the authorities
of Jawaharlal Nehru Technological University Hyderabad for
providing laboratory facilities.
CH3) 3.7 (s, 3H, ꢀNCH3), 4.35 (q, 2H, ꢀCH2), 6.6 (s,
2H, ꢀNH2), 6.94–8.8 (m, 7H, Ar-H), 10.48 (s, 1H,
ꢀNH, D2O exchangeable). 13C-NMR (DMSO d6/TMS):
δ 13.5, 29.3, 47.7, 58.4, 76.7, 108.2, 109.6, 112.1, 114.3,
120.7, 122.2, 122.1, 127.3, 132.0, 135.2, 138.8, 144.6,
150.3, 158.1, 159.9, 167.3, 179.5; m/z (M++1): 496.
Anal. Calcd for C23H18BrN3O5 (495.13): C, 55.66; H,
3.66; N, 8.47; Br, 16.10% Found: C, 55.69; H, 3.62; N,
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4j (R = I, X = COOC2H5): ethyl-20-amino-5-iodo-60-methyl-
2,50-dioxo-50,6’dihydrospiro[indoline-3,40-pyrano[3,2-c]quino
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22°C; IR (KBr): 3389, 3268 (unequal doublet,
asymmetric, and symmetric stretchings of ꢀNH2), 2202
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1
group, broad); H-NMR (DMSO d6/TMS): δ 0.96 (t, 3H,
CH3) 3.4 (s, 3H-NCH3), 4.55 (q, 2H, ꢀCH2) 6.7 (s, 2H,
ꢀNH2),6.73–8.6 (m, 7H, Ar-H), 10.36 (s, 1H, ꢀNH,
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122.3, 122.3, 127.7, 132.8, 135.7, 138.7, 144.5, 150.1,
158.6, 159.3, 167.8, 179.6; m/z (M++1): 544. Anal. Calcd
for C23H18IN3O5 (543.01): C, 50.84; H, 3.34; N, 7.73; I,
23.36% Found: C, 50.88; H, 3.39; N, 7.77; I, 23.32%.
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CONCLUSION
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We have developed green and efficient method for
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The main advantages of this reaction is provides high
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet