Microwave-assisted synthesis of new spiro[indoline-3,4'-quinoline] derivatives via a one-pot multicomponent reaction

Article abstract of DOI:10.1080/00397910802527714

A simple and efficient synthesis of spiro[indoline-3,4'-quinoline] derivatives by a one-pot reaction of isatin, malononitrile, and enaminone under microwave irradiation was investigated. This protocol has the advantages of short reaction time, high yields

Full text of DOI:10.1080/00397910802527714

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Microwave-Assisted Synthesis
of New Spiro[indoline-3,4′-
quinoline] Derivatives via
a One-Pot Multicomponent
Reaction
Song-Lei Zhu a b , Kai Zhao a , Xiao-Ming Su a & Shun-
Jun Ji a
a Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry and Chemical
Engineering, Suzhou (Soochow) University, Suzhou,
China
b Department of Chemistry, Xuzhou Medical College,
Xuzhou, China
Published online: 19 Mar 2009.
To cite this article: Song-Lei Zhu , Kai Zhao , Xiao-Ming Su & Shun-Jun Ji (2009):
Microwave-Assisted Synthesis of New Spiro[indoline-3,4′-quinoline] Derivatives via
a One-Pot Multicomponent Reaction, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 39:8, 1355-1366
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Synthetic Communications1, 39: 1355–1366, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802527714
Microwave-Assisted Synthesis of New
Spiro[indoline-3,40-quinoline] Derivatives via a
One-Pot Multicomponent Reaction
Song-Lei Zhu,1,2 Kai Zhao,1 Xiao-Ming Su,1 and Shun-Jun Ji1
1Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry and Chemical Engineering,
Suzhou (Soochow) University, Suzhou, China
2Department of Chemistry, Xuzhou Medical College, Xuzhou, China
Abstract: A simple and efficient synthesis of spiro[indoline-3,40-quinoline]
derivatives by a one-pot reaction of isatin, malononitrile, and enaminone under
microwave irradiation was investigated. This protocol has the advantages of short
reaction time, high yields of products, broad substrate scope, and easy workup
procedure.
Keywords: Microwave irradiation, multicomponent reactions, spiro[indoline-3,40-
quinoline]
Multicomponent reactions (MCRs), in which multiple reactions are
combined into one synthetic operation, have been used extensively in
synthetic chemistry.[1] Such reactions offer a wide range of possibilities for
the efficient construction of highly complex molecules in a single procedural
step, thus avoiding complicated purification operations and allowing savings
of both solvents and reagents.[2] Organic reactions accelerated by microwave
irradiation (MWI) have also attracted considerable attention over past years
for the rapid and efficient synthesis of a variety of organic compounds.[3]
Received June 5, 2008.
Address correspondence to Shun-Jun Ji, Key Laboratory of Organic Synthesis
of Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou
(Soochow) University, Suzhou 215123, China. E-mail: chemjsj@suda.edu.cn
1355

1356
S.-L. Zhu et al.
These technologies are particularly useful for the creation of diverse chemi-
cal libraries of druglike molecules for biological screening.[4]
Isatins (1H-indole-2,3-diones) are synthetically versatile substrates
that are utilized for the synthesis of a large variety of heterocyclic
compounds.[5] A number of spiro compounds derived from isatin are
important pharmacophores and exhibit promising biological activities
such as analgesic, fungicidal, antidepressant, antitumor, and antibiotic
activities.[6,7] Likewise, polysubstituted quinoline, an important hetero-
cyclic molecule, has also been reported for use in the pharmaceutical
industry and possesses a broad spectrum of biological potency including
antiasthmatic, anti-inflammatory, and antimalarial activities.[8] There-
fore, the diverse biological activities reported for isatin and polysubsti-
tuted quinoline encouraged us to synthesize some new heterocyclic
derivatives incorporating these moieties, which may lead to enhanced
bioactivity.
Recently, Abdel-Rahman et al. have reported the synthesis and
evaluation of some new spiro indoline-based heterocycles as potentially
active antimicrobial agents by the reaction of isatin, malononitrile or ethyl
cyanoacetate, and oxazolone derivatives.[7a] Dandia et al. have developed a
microwave-assisted, one-pot, three-component, regioselective cyclocon-
densation of isatin, 3-amino-1,2,4-triazole or 2-aminobenzimidazole and
thioacids to afford of a series of novel spiro[indole-thiazolidinones].[7b]
In our previous work,[9] we synthesized a series of indole derivatives, which
have shown some potential biological activities, under different conditions.
In this article, we investigated a simple and facile protocol for the synthesis
of a series of new spiro[indoline-3,40-quinoline] derivatives.
The target compounds 20-amino-10-aryl-2,50-dioxo-50,60,70,80-tetra-
hydro-10H-spiro[indoline-3,40-quinoline]-30-carbonitrile 4 were synthesi-
zed by one-pot reactions of isatins 1, malononitrile 2, and enaminones 3
under MWI (Scheme 1).
Choosing an appropriate solvent is of crucial importance for a
successful MW-assisted synthesis. In our initial study, various reaction
conditions including solvent and temperature were tested in the
one-pot, three-component synthesis of 4a under MW irradiation.
Among different polar solvents, such as ethanol, acetic acid, glycol,
Scheme 1. Synthesis of 4 by reaction of isatins, malonitrile, and enaminones.

New Spiro[indoline-3,40-quinoline] Derivatives
1357
Table 1. Optimization of reaction conditions of compound 4aa
Entry
Solventb
T (ꢀC)
Time (min)
Yieldc (%)
1
2
3
4
5
6
7
8
H2O
80
80
80
80
80
60
70
90
15
8
Trace
78
50
42
57
65
72
76
EtOH
HOAc
DMF
Glycol
EtOH
EtOH
EtOH
10
10
10
10
9
8
aThe reaction was carried out under MWI at the power of 150 W.
bThe amount of solvent was 2 mL.
cIsolated yields.
dimethylformamide (DMF), and water, the best yield was found when
ethanol was employed. The most suitable temperature should be 80 ꢀC.
The results are summarized in Table 1.
Moreover, when 4a was synthesized under both MWI and classical
heating at 80 ꢀC, we found that MWI efficiently promoted the reaction
and led to both a dramatic reduction of the reaction time, from 6 h to
8 min, and a remarkable increase in yield from 50% to 78%.
To expand the scope of the present method, different substituted
isatins and enaminones containing either electron-withdrawing or
electron-donating groups were applied in this reaction. From Table 2,
it can be seen that the method works with a wide variety of substrates,
and a series of spiro[indoline-3,40-quinoline] derivatives 4 were obtained
in good yields under the same reaction conditions.
The products were characterized by melting point, infrared (IR),
1H NMR, and high-resolution mass spectrometry (HRMS) spectral data.
Furthermore, the structure of 4 g was further confirmed by x-ray diffrac-
tion (XRD) analysis (Fig. 1). Crystallographic data for the structure of
4 g reported in this article have been deposited at the Cambridge Crystal-
lographic Data Centre with No. CCDC-680112.
The proposed mechanism for the synthesis of spiro derivative 4 is
described in Scheme 2. The process represents a typical cascade reaction
in which the isatin 1 first condenses with malononitrile 2 to afford
isatylidene malononitrile 5. This step was regarded as a fast Knoevenagel
condensation. Then, 5 is attacked via Michael addition with enaminone 3
to give the intermediate 6 and followed by the intramolecular cyclization
to form the desired product 4.
Evidence supporting this proposed mechanism was provided by the
observation that when 5 and 3a were subjected to the same conditions,

1358
S.-L. Zhu et al.
Table 2. Synthesis of compound 4 under MWI
Entry
R1
R2
R3
R4
Time (min) Yielda (%) M.p (ꢀC)
4a
4b
4c
4d
4e
4f
H
H
H
H
H
H
H
CH3 C6H5
8
7
7
8
7
10
9
10
9
78
76
75
77
85
66
81
70
72
67
82
75
77
80
75
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
H
H
H
H
H
H
H
H
CH3 4-ClC6H4
CH3 4-CH3C6H4
CH3 4-OCH3C6H4
CH3 4-BrC6H4
CH3 1-Naphthyl
CH3 4-ClC6H4
CH3 4-ClC6H5
CH3 4-CH3C6H4
4g
4h
4i
ꢁCH3
ꢁCH2Ph
ꢁCH2Ph
4j
H
H
H
H
H
H
4-Br CH3 4-OCH3C6H4 10
6-Br CH3 4-ClC6H4
6-Br CH3 4-CH3C6H4
H
H
H
4k
4l
8
8
9
9
9
4m
4n
4o
H
H
H
4-ClC6H4
4-BrC6H4
4-OCH3C6H4
aIsolated yields.
the expected product 4a was obtained in a yield similar to that obtained
in the one-pot reaction (Scheme 3).
In conclusion, we have developed a facile, one-pot, three-component
reaction involving isatins, malononitrile, and enaminones for the synthe-
sis of a series of spirooxindoles derivatives under MWI. Particularly
valuable features of this method include broad substrate scope, shorter
reaction time, high yields of the products, and straightforward procedure,
which make it a useful and attractive process for the synthesis of these
important compounds.
EXPERIMENTAL
Melting points were recorded on an Electrothermal digital melting-point
apparatus and are uncorrected. IR spectra were recorded on a Nicolet
1
FT-IR500 spectrophotometer using KBr optics. H NMR spectra were
recorded on a Varian Mercury 400-MHz spectrometer using dimethyl
sulfoxide (DMSO)-d6 as solvent and tetramethylsilane (TMS) as internal
standard. HRMS were obtained using GCT-TOF instrument. X-ray
diffraction data were made on a Rigaku Mercury CCD area detector with
graphite monochromated Mo-Ka radiation. CHN analyses were
recorded on a Carlo-Erba EA1110 CNNO-S analyzer.

New Spiro[indoline-3,40-quinoline] Derivatives
1359
Figure 1. X-ray crystal structure of 4 g.
Scheme 2. Plausible mechanism for the reaction of isatin and malononitrile with
enaminones.

1360
S.-L. Zhu et al.
Scheme 3. Synthesis of 4a by the reaction of isatylidene malononitrile with
enaminone.
Typical Experimental Procedure: Preparation of Compounds 4
The reaction was performed in a monomodal Emrys Creator from
Personal Chemistry, Uppsala, Sweden. In a 10-mL Emrys reaction vial,
isatin 1 (1 mmol), malononitrile 2 (1 mmol), enaminone 3 (1 mmol),
and ethanol (2 mL) were mixed and then capped. The mixture was irra-
diated at 80ꢀC and the maximum power of 150 W for the given time.
Upon completion, monitored by thin-layer chromatography (TLC), the
reaction mixture was allowed to cool to room temperature and then
poured into cold water (100 mL). The solid product was filtered and
washed with EtOH (95%). The product was purified by recrystallization
from EtOH–DMF (1:1) to afford 4a–4o.
Data
20-Amino-70,70-dimethyl-2,50-dioxo-10-phenyl-50,60,70,80-tetrahydro-10H-
spiro[indoline-3,40-quinoline]-30-carbonitrile (4a)
White solid; mp > 300ꢀC; IR (KBr): n 3442, 3334, 3218, 2184, 1715, 1643,
1551, 1366, 1258, 1049, 733 cmꢁ1 1H NMR (400 MHz, DMSO-d6):
;
d 10.17 (br s, 1H, NH), 7.58–7.63 (m, 3H, Ar-H), 7.46–7.48 (m, 2H,
Ar-H), 7.16 (d, J ¼ 7.2 Hz, 1H, Ar-H), 7.12 (t, J ¼ 7.6 Hz, 1H, Ar-H),
6.91 (t, J ¼ 7.6 Hz, 1H, Ar-H), 6.76 (d, J ¼ 7.6 Hz, 1H, Ar-H), 5.30
(s, 2H, NH2), 2.07–2.14 (m, 2H, CH2), 1.80–1.95 (m, 2H, CH2), 0.88
(s, 3H, CH3), 0.82 (s, 3H, CH3). HRMS found: m=z 410.1738 (Mþ);
calcd. for C25H22N4O2: M, 410.1743. Anal. calcd. for C25H22N4O2:
C, 73.15; H, 5.40; N, 13.65. Found: C, 73.27; H, 5.27; N, 13.72.
20-Amino-10-(4-chlorophenyl)-70,70-dimethyl-2,50-dioxo-50,60,70,80-
tetrahydro-10H-spiro[indoline-3,40-quinoline]-30-carbonitrile (4b)
Yellow solid; mp > 300ꢀC; IR (KBr): n 3457, 3334, 3218, 2191, 1721,
1644, 1566, 1489, 1366, 1188, 1049, 756 cmꢁ1 1H NMR (400 MHz,
;

New Spiro[indoline-3,40-quinoline] Derivatives
1361
DMSO-d6): d 10.21 (br s, 1H, NH), 7.56 (d, J ¼ 8.4 Hz, 2H, Ar-H),
7.45–7.53 (m, 2H, Ar-H), 7.17 (d, J ¼ 7.2 Hz, 1H, Ar-H), 7.11
(t, J ¼ 7.6 Hz, 1H, Ar-H), 6.89 (t, J ¼ 7.6 Hz, 1H, Ar-H), 6.75
(d, J ¼ 7.6 Hz, 1H, Ar-H), 5.55 (s, 2H, NH2), 2.07–2.16 (m, 2H, CH2),
1.79–1.93 (m, 2H, CH2), 0.89 (s, 3H, CH3), 0.81 (s, 3H, CH3). HRMS
found: m=z 444.1342 (Mþ); calcd. for C25H21ClN4O2: M, 444.1353. Anal.
calcd. for C25H21ClN4O2: C, 67.49; H, 4.76; N, 12.59. Found: C, 67.38;
H, 4.67; N, 12.65.
20-Amino-70,70-dimethyl-2,50-dioxo-10-p-tolyl-50,60,70,80-tetrahydro-10H-
spiro[indoline-3,40-quinoline]-30-carbonitrile (4c)
White solid; mp > 300ꢀC; n 3434, 3318, 3218, 2191, 1721, 1643, 1559,
1366, 1258, 1196, 1048, 748 cmꢁ1 1H NMR (400 MHz, DMSO-d6):
;
d 10.16 (br s, 1H, NH), 7.41 (d, J ¼ 8.0 Hz, 2H, Ar-H), 7.30–7.41
(m, 2H, Ar-H), 7.09–7.15 (m, 2H, Ar-H), 6.90 (t, J ¼ 7.2 Hz, 1H,
Ar-H), 6.75 (d, J ¼ 7.6 Hz, 1H, Ar-H), 5.27 (s, 2H, NH2), 2.41 (s, 3H,
CH3), 2.06–2.14 (m, 2H, CH2), 1.82–1.94 (m, 2H, CH2), 0.88 (s, 3H,
CH3), 0.82 (s, 3H, CH3). HRMS found: m=z 424.1892 (Mþ); calcd. for
C26H24N4O2: M, 424.1899. Anal. calcd. for C26H24N4O2: C, 73.56;
H, 5.70; N, 13.20. Found C, 73.62; H, 5.77; N, 13.12.
20-Amino-10-(4-methoxyphenyl)-70,70-dimethyl-2,50-dioxo-50,60,70,80-
tetrahydro-10H-spiro[indoline-3,40-quinoline]-30-carbonitrile (4d)
White solid; mp > 300ꢀC; IR (KBr): n 3435, 3337, 3218, 2184, 1716, 1643,
1592, 1470, 1361, 1195, 1051, 725 cmꢁ1; 1H NMR (400 MHz, DMSO-d6):
d 10.20 (br s, 1H, NH), 7.32–7.41 (m, 2H, Ar-H), 7.09–7.16 (m, 4H,
Ar-H), 6.89 (t, J ¼ 7.2 Hz, 1H, Ar-H), 6.75 (d, J ¼ 7.2 Hz, 1H, Ar-H),
5.37 (s, 2H, NH2), 3.84 (s, 3H, OCH3), 2.06–2.15 (m, 2H, CH2), 1.82–
1.93 (m, 2H, CH2), 0.88 (s, 3H, CH3), 0.81 (s, 3H, CH3). HRMS found:
m=z 440.1860 (Mþ); calcd. for C26H24N4O3: M, 440.1848. Anal. calcd.
for C26H24N4O3: C, 70.89; H, 5.49; N, 12.72. Found: C, 70.80; H, 5.56;
N, 12.78.
20-Amino-10-(4-bromophenyl)-70,70-dimethyl-2,50-dioxo-50,60,70,80-
tetrahydro-10H-spiro[indoline-3,40-quinoline]-30-carbonitrile (4e)
Yellow solid; mp > 300ꢀC; IR (KBr): n 3417, 3340, 3291, 2190, 1745,
1657, 1485, 1364, 1261, 1193, 1012, 751 cmꢁ1 1H NMR (400 MHz,
;
DMSO-d6): d 10.21 (br s, 1H, NH), 7.78 (d, J ¼ 8.8 Hz, 2H, Ar-H),

1362
S.-L. Zhu et al.
7.40–7.48 (m, 2H, Ar-H), 7.17 (d, J ¼ 7.6 Hz, 1H, Ar-H), 7.11
(t, J ¼ 7.6 Hz, 1H, Ar-H), 6.89 (t, J ¼ 7.6 Hz, 1H, Ar-H), 6.75
(d, J ¼ 7.6 Hz, 1H, Ar-H), 5.56 (s, 2H, NH2), 2.07–2.15 (m, 2H, CH2),
1.79-1.93 (m, 2H, CH2), 0.88 (s, 3H, CH3), 0.81 (s, 3H, CH3). HRMS
found: m=z 488.0843 (Mþ); calcd. for C25H21BrN4O2: M, 488.0848. Anal.
calcd. for C25H21BrN4O2: C, 61.36; H, 4.33; N, 11.45. Found: C, 61.43;
H, 4.40; N, 11.52.
20-Amino-70,70-dimethyl-10-(naphthalen-1-yl)-2,50-dioxo-50,60,70,80-
tetrahydro-10H-spiro[indoline-3,40-quinoline]-30-carbonitrile (4f)
White solid; mp > 300ꢀC; IR (KBr): n 3446, 3334, 3221, 2182, 1728, 1661,
1
1557, 1418, 1242, 1192, 1054, 920, 805, 726 cmꢁ1; H NMR (400 MHz,
DMSO-d6): d 10.28 (br s, 1H, NH), 8.11–8.18 (m, 2H, Ar-H), 7.89–
7.94 (m, 2H, Ar-H), 7.67–7.75 (m, 3H, Ar-H), 7.20 (d, J ¼ 9.6 Hz, 1H,
Ar-H), 7.14 (t, J ¼ 8.8 Hz, 1H, Ar-H), 6.93 (t, J ¼ 10.0 Hz, 1H, Ar-H),
6.79 (d, J ¼ 9.6 Hz, 1H, Ar-H), 5.47 (s, 2H, NH2), 2.12 (d, J ¼ 23.2 Hz,
1H, CH2), 1.99 (s, 2H, CH2), 1.55 (d, J ¼ 22.8 Hz, 1H, CH2), 0.79
(s, 3H, CH3), 0.69 (s, 3H, CH3). HRMS found: m=z 460.1882 (Mþ);
calcd. for C29H24N4O2: M, 460.1899. Anal. calcd. for C29H24N4O2:
C, 75.63; H, 5.25; N, 12.17. Found: C, 75.53; H, 5.30; N, 12.25.
20-Amino-10-(4-chlorophenyl)-1,70,70-trimethyl-2,50-dioxo-50,60,70,80-
tetrahydro-10H-spiro[indoline-3,40-quinoline]-30-carbonitrile (4g)
White solid; mp > 300ꢀC; IR (KBr): n 3463, 3312, 2190, 1716, 1650, 1568,
1
1491, 1364, 1090, 1018, 915, 753 cmꢁ1; H NMR (400 MHz, DMSO-d6):
d 7.65 (d, J ¼ 8.4 Hz, 2H, Ar-H), 7.51–7.54 (m, 2H, Ar-H), 7.23
(t, J ¼ 8.0 Hz, 2H, Ar-H), 6.93–6.70 (m, 2H, Ar-H), 5.55 (s, 2H, NH2),
3.13 (s, 3H, ꢁNCH3), 2.05–2.17 (m, 2H, CH2), 1.81–1.93 (m, 2H,
CH2), 0.89 (s, 3H, CH3), 0.81 (s, 3H, CH3). HRMS found: m=z
458.1501 (Mþ); calcd. for C25H23ClN4O2: M, 458.1510. Anal. calcd. for
C25H23ClN4O2: C, 68.04; H, 5.05; N, 12.21. Found: C, 68.13; H, 5.12;
N, 12.30.
20-Amino-1-benzyl-10-(4-chlorophenyl)-70,70-dimethyl-2,50-dioxo-
50,60,70,80-tetrahydro-10H-spiro[indoline-3,40-quinoline]-30-carbonitrile (4h)
White solid; mp > 300ꢀC; IR (KBr): n 3454, 3365, 2182, 1703, 1644, 1556,
1487, 1362, 1259, 1094, 917, 850, 755 cmꢁ1; 1H NMR (400 MHz, DMSO-
d6): d 7.67 (d, J ¼ 11.6 Hz, 2H, Ar-H), 7.55 (d, J ¼ 9.2 Hz, 4H, Ar-H),

New Spiro[indoline-3,40-quinoline] Derivatives
1363
7.25–7.33 (m, 4H, Ar-H), 7.10 (t, J ¼ 10.4 Hz, 1H, Ar-H), 6.97
(t, J ¼ 9.6 Hz, 1H, Ar-H), 6.61 (d, J ¼ 10.4 Hz, 1H, Ar-H), 5.67 (s, 2H,
NH2), 4.83–4.96 (m, 2H, CH2), 2.11–2.22 (m, 2H, CH2), 1.81–1.98
(m, 2H, CH2), 0.90 (s, 3H, CH3), 0.82 (s, 3H, CH3). HRMS found:
m=z 534.1831 (Mþ); calcd. for C32H27ClN4O2: M, 534.1823. Anal. calcd.
for C32H27ClN4O2: C, 71.83; H, 5.09; N, 10.47. Found: C, 71.76; H, 5.17;
N, 10.35.
20-Amino-1-benzyl-70,70-dimethyl-2,50-dioxo-10-p-tolyl-50,60,70,80-
tetrahydro-10H-spiro[indoline-3,40-quinoline]-30-carbonitrile (4i)
White solid; mp > 300ꢀC; IR (KBr): n 3441, 3330, 2183, 1716, 1644, 1559,
1486, 1362, 1259, 1185, 1052, 917, 751 cmꢁ1 1H NMR (400 MHz,
;
DMSO-d6): d 7.55 (d, J ¼ 7.6 Hz, 2H, Ar-H), 7.35–7.43 (m, 4H, Ar-H),
7.31 (t, J ¼ 7.2 Hz, 2H, Ar-H), 7.25 (d, J ¼ 7.6 Hz, 2H, Ar-H), 7.09
(t, J ¼ 7.6 Hz, 1H, Ar-H), 6.97 (t, J ¼ 7.6 Hz, 1H, Ar-H), 6.61
(d, J ¼ 8.0 Hz, 1H, Ar-H), 5.37 (s, 2H, NH2), 4.85–4.95 (m, 2H, CH2),
2.42 (s, 3H, CH3), 2.11–2.19 (m, 2H, CH2), 1.86–1.98 (m, 2H, CH2), 0.90
(s, 3H, CH3), 0.83 (s, 3H, CH3). HRMS found: m=z 514.2391 (Mþ);
calcd. for C33H30N4O2: M, 514.2369. Anal. calcd. for C33H30N4O2:
C, 77.02; H, 5.88; N, 10.89. Found: C, 77.12; H, 5.79; N, 10.95.
20-Amino-4-bromo-10-(4-methoxyphenyl)-70,70-dimethyl-2,50-dioxo-
50,60,70,80-tetrahydro-10H-spiro[indoline-3,40-quinoline]-30-carbonitrile (4j)
Yellow solid; mp > 300ꢀC; IR (KBr): n 3457, 3334, 3218, 2184, 1721,
1643, 1512, 1443, 1366, 1250, 1180, 1049, 910, 764 cmꢁ1 1H NMR
;
(400 MHz, DMSO-d6): d 10.47 (br s, 1H, NH), 7.34–7.36 (m, 1H,
Ar-H), 7.26–7.29 (m, 1H, Ar-H), 7.06–7.13 (m, 4H, Ar-H), 6.78–6.80
(m, 1H, Ar-H), 5.48 (s, 2H, NH2), 3.83 (s, 3H, OCH3), 2.07–2.17 (m,
2H, CH2), 1.77–1.95 (m, 2H, CH2), 0.89 (s, 3H, CH3), 0.86 (s, 3H,
CH3). HRMS found: m=z 518.0954 (Mþ); calcd. for C26H23BrN4O3:
M, 518.0930. Anal. calcd. for C26H23BrN4O3: C, 60.12; H, 4.46; N,
10.79. Found: C, 60.18; H, 4.51; N, 10.85.
20-Amino-6-bromo-10-(4-chlorophenyl)-70,70-dimethyl-2,50-dioxo-
50,60,70,80-tetrahydro-10H-spiro[indoline-3,40-quinoline]-30-carbonitrile (4k)
Yellow solid; mp > 300ꢀC; IR (KBr): n 3462, 3328, 3210, 2186, 1721,
1644, 1560, 1470, 1362, 1261, 1049, 782 cmꢁ1 1H NMR (400 MHz,
;
DMSO-d6): d 10.40 (br s, 1H, NH), 7.59–7.61 (m, 3H, Ar-H), 7.42–7.54

1364
S.-L. Zhu et al.
(m, 2H, Ar-H), 7.08–7.17 (m, 2H, Ar-H), 6.90 (s, 1H, Ar-H), 5.47 (s, 2H,
NH2), 2.07–2.12 (m, 2H, CH2), 1.78–1.96 (m, 2H, CH2), 0.86 (s, 3H,
CH3), 0.80 (s, 3H, CH3). HRMS found: m=z 522.0448 (Mþ); calcd. for
C25H20BrClN4O2: M, 522.0458. Anal. calcd. for C25H20BrClN4O2:
C, 57.32; H, 3.85; N, 10.70. Found: C, 57.28; H, 3.91; N, 10.78.
20-Amino-6-bromo-70,70-dimethyl-2,50-dioxo-10-p-tolyl-50,60,70,80-
tetrahydro-10H-spiro[indoline-3,40-quinoline]-30-carbonitrile (4l)
Yellow solid; mp > 300ꢀC; IR (KBr): n 3442, 3323, 3217, 2183, 1729,
1645, 1555, 1477, 1362, 1317, 1258, 1052, 919, 747 cmꢁ1 1H NMR
;
(400 MHz, DMSO-d6): d 10.33 (br s, 1H, NH), 7.40–7.42 (m, 3H,
Ar-H), 7.27–7.34 (m, 2H, Ar-H), 7.07–7.14 (m, 2H, Ar-H), 6.90 (s, 1H,
Ar-H), 5.36 (s, 2H, NH2), 2.41 (s, 3H, CH3), 2.06–2.12 (m, 2H, CH2),
1.83–1.95 (m, 2H, CH2), 0.88 (s, 3H, CH3), 0.82 (s, 3H, CH3). HRMS
found: m=z 502.1022 (Mþ); calcd. for C26H23BrN4O2: M, 502.1004. Anal.
calcd. for C26H23BrN4O2: C, 62.03; H, 4.61; N, 11.13. Found: C, 62.13;
H, 4.52; N, 11.21.
20-Amino-10-(4-chlorophenyl)-2,50-dioxo-50,60,70,80-tetrahydro-10H-
spiro[indoline-3,40-quinoline]-30-carbonitrile (4m)
Light yellow solid; mp > 300ꢀC; IR (KBr): n 3442, 3334, 2190, 1719,
1655, 1561, 1491, 1357, 1200, 1087, 1008, 743 cmꢁ1
;
1H NMR
(400 MHz, DMSO-d6): d 10.21 (br s, 1H, NH), 7.64 (d, J ¼ 8.8 Hz, 2H,
Ar-H), 7.50–7.54 (m, 2H, Ar-H), 7.18 (d, J ¼ 7.2 Hz, 1H, Ar-H), 7.11
(t, J ¼ 7.2 Hz, 1H, Ar-H), 6.89 (t, J ¼ 7.6 Hz, 1H, Ar-H), 6.74 (d,
J ¼ 7.6 Hz, 1H, Ar-H), 5.57 (s, 2H, NH2), 2.11–2.17 (m, 2H, CH2),
1.95–2.07 (m, 2H, CH2), 1.68–1.77 (m, 2H, CH2). HRMS found: m=z
416.1024 (Mþ); calcd. for C23H17ClN4O2: M, 416.1040. Anal. calcd. for
C23H17ClN4O2: C, 66.27; H, 4.11; N, 13.44. Found: C, 66.38; H, 4.20;
N, 13.27.
20-Amino-10-(4-bromophenyl)-2,50-dioxo-50,60,70,80-tetrahydro-10H-
spiro[indoline-3,40-quinoline]-30-carbonitrile (4n)
Yellow solid; mp > 300ꢀC; IR (KBr): n 3446, 3337, 3288, 2190, 1718,
1653, 1560, 1488, 1357, 1302, 1200, 1013, 743 cmꢁ1
;
1H NMR
(400 MHz, DMSO-d6): d 10.16 (br s, 1H, NH), 7.77 (d, J ¼ 8.4 Hz, 2H,
Ar-H), 7.45 (d, J ¼ 8.0 Hz, 2H, Ar-H), 7.17 (d, J ¼ 7.2 Hz, 1H, Ar-H),
7.11 (t, J ¼ 7.6 Hz, 1H, Ar-H), 6.89 (t, J ¼ 7.2 Hz, 1H, Ar-H), 6.74

New Spiro[indoline-3,40-quinoline] Derivatives
1365
(d, J ¼ 7.6 Hz, 1H, Ar-H), 5.48 (s, 2H, NH2), 1.96–2.18 (m, 4H, CH2),
1.62–1.80 (m, 2H, CH2). HRMS found: m=z 460.0523 (Mþ); calcd. for
C23H17BrN4O2: M, 460.0535. Anal. calcd. for C23H17BrN4O2: C, 59.88;
H, 3.71; N, 12.15. Found: C, 59.98; H, 3.79; N, 12.23.
20-Amino-10-(4-methoxyphenyl)-2,50-dioxo-50,60,70,80-tetrahydro-10H-
spiro[indoline-3,40-quinoline]-30-carbonitrile (4o)
White solid; mp > 300ꢀC; IR (KBr): n 3469, 3327, 3206, 2179, 1637, 1510,
1421, 1359, 1252, 1195, 1009, 952, 755 cmꢁ1 1H NMR (400 MHz,
;
DMSO-d6): d 10.15 (br s, 1H, NH), 7.36–7.41 (m, 2H, Ar-H), 7.09–
7.17 (m, 4H, Ar-H), 6.89 (t, J ¼ 7.6 Hz, 1H, Ar-H), 6.74 (d, J ¼ 7.6 Hz,
1H, Ar-H), 5.31 (s, 2H, NH2), 3.84 (s, 3H, OCH3), 1.99–2.19 (m, 4H,
CH2), 1.69–1.79 (m, 2H, CH2). HRMS found: m=z 412.1536 (Mþ); calcd.
for C24H20N4O3: M, 412.1535. Anal. calcd. for C24H20N4O3: C, 69.89;
H, 4.89; N, 13.58. Found: C, 69.75; H, 4.79; N, 13.65.
Preparation of Compound 5
A mixture of isatin 1 (2 mmol) and malononitrile 2 (2 mmol) in absolute
ethanol (5 mL) was irritated for 2 min at a maximum power of 100 W and
80 ꢀC. Upon completion, monitored by TLC, the reaction mixture was
allowed to cool to room temperature and washed with EtOH (95%) to
give pure deep red product 5.
2-Oxo-(3H)-indol-3-ylidene Malononitrile (5)
Mp 239–240 ꢀC (lit.[6c] 239 ꢀC).
ACKNOWLEDGMENTS
This work was partially supported by the Key Laboratory of Organic
Synthesis of Jiangsu Province at Suzhou University (No. S8109108),
the Natural Science Foundation of Jiangsu Province (No. BK2006048),
and the National Science Foundation of China (Nos. 20472062
and 20672079), Nature Science Key Basic Research of Jiangsu Province
for Higher Education (Nos. 06KJA15007 and 05KJB150116), Jiangsu
Provincial Key Laboratory of Fine Petrochemical Technology
(No. KF0402), and a research grant from the Innovation Project for
Graduate Students of Jiangsu Province.

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S.-L. Zhu et al.
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