Domino reactions of vinyl malononitriles with 3-phenacylideneoxindoles for efficient synthesis of functionalized spirocyclic oxindoles

Article abstract of DOI:10.1021/co500006c

The reactions of vinyl malononitriles with 3-phenacylideneoxindoles in ethanol in the presence of DBU as base resulted in the functionalized spirocyclic oxindoles through the domino Michael addition and intramolecular nucleophilic addition to cyano group.

Full text of DOI:10.1021/co500006c

Research Article
pubs.acs.org/acscombsci
Domino Reactions of Vinyl Malononitriles with
3‑Phenacylideneoxindoles for Efficient Synthesis of Functionalized
Spirocyclic Oxindoles
Ya-Jing Xie, Jing Sun, and Chao-Guo Yan*
College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou 225002, China
S
* Supporting Information
ABSTRACT: The reactions of vinyl malononitriles with 3-
phenacylideneoxindoles in ethanol in the presence of DBU as
base resulted in the functionalized spirocyclic oxindoles
through the domino Michael addition and intramolecular
nucleophilic addition to cyano group. On the other hand, the
similar reaction in the presence of piperidine as base afforded
1
the simple Michael addition products in good yields. The stereochemistry of the spirooxindoles was established with H NMR
data and single crystal structures.
KEYWORDS: spirooxindole, vinyl malononitrile, domino reaction, Michael addition, cycloaddition
find out that the base appears to be a crucial factor for the
reaction. No reaction was observed when pyridine was used as
base. When piperidine was used as base, the reaction gave the
simple Michael addition product at room temperature.
Prolonging the reaction time or heating the reaction mixture
affords the expected cyclized product 3a in 83% yield. The
reaction also proceeded smoothly to afford a mixture of
products when triethylamine, diethylamine was used as the
base. When DBU was used, the reaction was complete in less
than half an hour at room temperature affording the spirocyclic
oxindole 3a in 89% yields. Thus, DBU was chosen as the best
base for the reaction of various vinyl malononitriles with 3-
phenacyclidedenoxindoles. The results are summarized in
Table 1. It can be seen that the reactions usually gave the
functionalized spiro[indoline-3,2′-naphthalenes] 3a−3e and
spiro[benzo[7]annulene-2,3′-indolines] 3f−3h in satisfactory
yields. It should be pointed out that very pure products are
obtained only by filtration of the resulting precipitates and
washing with a little ethanol. There was not need for further
purification.
To demonstrate the utility and generality of this reaction, a
one-pot domino reaction procedure was developed for the
reactions containing 4-alkylpiperidinones. First, an ethanol
solution of N-methylpiperidinone and malononitrile in the
presence of piperidine was heated for five minutes. Then 3-
phenacylidineoxindole was added and the resulting mixture was
refluxed for about one hour. The expected functionalized
spiro[indoline-3,7′-isoquinolines] 4a−4e were obtained in
satisfactory yields (Table 2, entries 1−5). By using this one-
pot domino reaction procedure, the reactions containing N-
1. INTRODUCTION
In recent years, spirocyclic 2-oxindoles have drawn tremendous
interests in synthetic and medicinal chemistry because they
occur in many natural products and have been reported to have
various types of bioactivity.1,2 Isatin and its C-3 derivatives are
the most employed starting materials in the architecture of
various spirocyclic 2-oxindoles.3,4 In this respect, 3-methylene-
2-oxindoles are one of the most important reagents because of
their easy synthesis and versatile reactivity.5 They have been
used as active electron-deficient alkenes in many synthetic
reactions, such as 1,3-dipolar cycloaddition, Diels−Alder
reaction, Michael addition and versatile multicomponent
reactions for the design of the fused cyclic and spirocyclic
frameworks.6−10 In recent years, we have developed several
efficient procedures for the synthesis spirocyclic oxindoles by
using 3-phenacylideneoxindoles as key substrates.11−13 In
continuation of our interest on the construction of complex
spirooxindole skeletons with domino reaction, herein we wish
to report the domino reactions of vinyl malononitriles with 3-
phenacylideneoxindoles for the efficient synthesis of a series of
the functionalized spiro[indoline-3,2′-naphthalene], spiro-
[benzo[7]annulene-2,3′-indoline], and spiro[indoline-3,7′-iso-
quinoline] derivatives.
2. RESULTS AND DISCUSSION
Since the γ-C−H of vinyl malononitriles are easily deuterated in
the presence of organic bases, they can act as versatile, direct
vinylogous donors in Michael addition reactions and behave as
good hydride acceptors in conjugate reduction reactions.14−16
According to the previously reported reaction of vinyl
malononitrile with isatylidene malononitirle,17 the reaction of
equimolecular cyclohexylidene malononitrile (1a) and 3-
phenacylideneoxindole (2a) in ethanol was carried out with
different base catalysts at room temperature. It is interesting to
Received: January 15, 2014
Revised: February 15, 2014
Published: February 20, 2014
© 2014 American Chemical Society
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ACS Combinatorial Science
Research Article
a
Table 1. Synthesis of Spirocyclic Oxindoles 3a−3h
yield
b
entry compd
R
R′
Bn
Bn
Ar
R″
n
(%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
F
p-CH3C6H4
p-CH3C6H4
H
1
1
1
1
1
2
2
2
89
74
85
92
83
80
82
87
Cl
H
F
n-C4H9 p-CH3OC6H4 t-Bu
H
Bn
Bn
p-CH3OC6H4 t-Bu
H
p-ClC6H4
t-Bu
H
CH3
H
n-C4H9 p-ClC6H4
3g
3h
Bn
Bn
p-ClC6H4
p-ClC6H4
H
Figure 1. Molecular structure of compound 3a.
CH3
H
a
Reaction condition: 3-phenacylidieneoxindole (1.0 mmol), vinyl
malononitrile (1.0 mmol), DBU (0.1 mmol) in ethanol (10.0 mL), rt,
b
30 min. Isolated yield.
benzylpiperidinone also afforded the corresponding spiro-
[indoline-3,7′-isoquinolines] 4f−4e in high yields (Table 2,
entries 6−10).
The structures of the above obtained spirocyclic oxindoles
3a−3h and 4a−4j were characterized by spectroscopic
methods. The single crystal structures of 3a (Figure 1), 3d
(Figure 2), 3h and 4e were successfully determined by X-ray
1
diffraction method. H NMR spectra of 3a−3h and 4a−4j
usually display one set of absorptions for the characteristic
groups in each spirooxindole, which indicated there is only one
stereoisomer. In the molecular structures of 3a, 3h, and 4e, the
phenyl group of oxindole moiety and the benzoyl group exist in
a cis-configuration. Furthermore, the benzoyl group also exists
in trans-position to the methylene unit of the annulated cycle.
Figure 2. Molecular structure of compound 3d.
a
Table 2. Synthesis Spiro[indoline-3,7′-isoquinolines] 4a−4j
b
entry
compd
R
R′
Ar
R″
yield (%)
1
2
3
4
5
6
7
8
9
10
4a
4b
4c
4d
4e
4f
H
H
F
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
p-CH3C6H4
p-ClC6H4
CH3
CH3
CH3
CH3
CH3
Bn
83
96
92
88
89
92
95
94
93
90
p-CH3OC6H4
C6H5
Cl
Cl
H
F
p-CH3C6H4
p-CH3OC6H4
C6H5
4g
4h
4i
Bn
F
p-CH3OC6H4
p-CH3OC6H4
p-CH3C6H4
Bn
Cl
Cl
Bn
4j
Bn
a
Reaction condition: piperdinone (1.0 mmol), malononitrile (1.0 mmol), piperidine (0.1 mmol) in ethanol (15.0 mL), reflux, 5 min. 3-
b
phenacylidieneoxindole (1.0 mmol), reflux, one hour. Isolated yield.
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Research Article
But it is clear to see that the phenyl group of oxindole moiety
and the benzoyl are in trans-configuration in molecular
structure of 3d. Thus, the single crystal structures of the four
compounds demonstrate that two kinds of stereoisomers exist
in the prepared spiro compounds, which also reveals that it is
difficult to elucidate the stereochemistry of these complex
piperidine as base gave a complicated mixture of products.
When 4-dimethylaminopyridine was used as the base, the
simple adducts 5g−5l were obtained in very high yields (Table
4). On the other hand, the trying to produce cycloaddition
products continuously failed despite many attempts. The
simple Michael adduct 5a−5l in ethanol in the presence of
DBU did not afford the cyclized product. The single crystal
structure of the compound 5i was determined by X-ray
diffraction method.
On the basis of the above experimental results, together with
the related reports of the vinyl malononitrile,14 a plausible
mechanism for the formation of the spirooxindoles is illustrated
in Scheme 1 by using N-methylpiperidinone as an example. At
first, the base catalyzed condensation of N-methylpiperidinone
with malononitrile afforded the vinyl malononitrile 1. Second, a
carbanium (A) is generated by deprotonation of vinyl
malononitrile 1 with base, which in turn attacked the exocyclic
carbon atom of the 3-phenacyclideneoxindole to give a new
carbanium intermediate (B). Then the intramolecular addition
of carbanion to one cyano group resulted in the cyclized
product with a imino group (C). At last, the spirocyclic
oxindole 4 was formed by imino-enamine tautomerization.
Depending on the reaction conditions and structures of the
substrates, the sequential reactions can stop at the middle step
to give the separated product. The simple Michael addition
product can be separated in case of using weak base or carrying
out the reaction at room temeprature. In the proposed reaction
mechanism, it is clear to be seen that each reaction step is
thermodynamically controlled reaction and a mixture of the
diastereoisomers is formed in this domino reaction.
1
spirocyclic oxindoles with H NMR spectra.
It has been mentioned above that the piperidine promoted
reaction of vinyl malononitrile with 3-phenacyclideneoxindole
can afford the simple Michael addition product at room
temperature. Thus, we also extended this strategy to the
reactions of p-tert-butylcyclohexylidene malononitrile and
cycloheptylidene malononitrile. The simple Michael addition
products 5a−5f were successfully prepared in good yields
(Table 3). This reaction not only provides an efficient
a
Table 3. Synthesis of the Michael Addition Products 5a−5f
yield
b
entry compd
R
R′
Ar
R″
n
(%)
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
Cl
H
F
n-C4H9
Bn
p-CH3OC6H4
p-CH3OC6H4
p-CH3C6H4
p-CH3C6H4
p-CH3OC6H4
p-CH3C6H4
H
1
1
1
1
2
2
81
85
88
87
78
90
t-Bu
t-Bu
t-Bu
H
Bn
Cl
H
H
Bn
CONCLUSION
■
Bn
In conclusion, we systematically investigated the domino
reactions of 3-phenacyclideneoxindole with a series of vinyl
malononitriles and successfully developed an efficient protocol
for the synthesis of novel functionalized spirocyclic oxindoles.
Significantly, the stereochemistry of the reaction was clearly
elucidated mainly by determination of seven single crystal
structures. The reaction mechanism is also rationally proposed
on the basis of capture of the reaction intermediates. The
advantages of the reactions are using readily available starting
materials, mild reaction conditions, short reaction times,
operational simplicity by avoiding column chromatography
and good to high yields. The potential uses of the reaction in
synthetic and medicinal chemistry may be significant.
n-C4H9
H
a
Reaction condition: 3-phenacylidieneoxindole (1.0 mmol), vinyl
malononitrile (1.0 mmol), piperidine (0.1 mmol) in ethanol (10.0
b
mL), rt, one hour. Isolated yield.
procedure for the preparation of functionalized 3-substituted
oxindoles, but also provides practical facts for the reaction
mechanism for the formation of spirocyclic oxindoles. The
single crystal structures of the compounds 5a (Figure 3) and 5e
were determined by X-ray diffraction method.
The acyclic vinyl malononitrile displayed different reactivity
to the above used cyclic vinyl malononitriles in the reaction.
Under similar conditions, treatment of 2-(1-p-tolylethylidene)-
malononitrile with 3-phenacyldieneoxindoles in ethanol with
EXPERIMENTAL PROCEDURES
■
General Procedure for the Synthesis of Spirocyclic
Oxindoles 3a−3h. A mixture of vinyl malononitrile (1.0
mmol) and 3-phenacylideneoxindole (1.0 mmol) and DBU
(0.1 mmol) in ethanol (10.0 mL) was stirred at room
temperature for about 20−30 min. The resulting precipitate
was collected by filtration and washed with cold alcohol to give
the pure product for analysis.
3′-Amino-1-benzyl-5-fluoro-1′-(4-methylbenzoyl)-2-oxo-
6′,7′,8′,8a′-tetrahydro-1′H-spiro[indoline-3,2′-naphthalene]-
4′-carbonitrile 3a: white solid, 89%, 0.460 g, mp 213.6−214.0
°C; 1H NMR (600 MHz, DMSO-d6) δ 7.77 (d, J = 7.8 Hz, 2H,
ArH), 7.30 (d, J = 7.8 Hz, 2H, ArH), 7.27 (d, J = 7.8 Hz, 1H,
ArH), 7.11−7.07 (m, 2H, ArH), 6.94 (t, J = 7.2 Hz, 2H, ArH),
6.71−6.68 (m, 3H, ArH), 6.17 (s, 2H, NH2), 5.64 (s, 1H, CH),
4.94 (d, J = 16.2 Hz, 1H, CH), 4.25 (d, J = 15.6 Hz, 1H, CH),
Figure 3. Molecular structure of compound 5a.
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Research Article
a
Table 4. Synthesis of the Michael addition products 5g−5j
b
entry
compd
R
R′
Bn
R″
Ar
yield (%)
1
2
3
4
5
6
5g
5h
5i
Cl
F
CH3
CH3
CH3
CH3
Cl
p-CH3C6H4
p-CH3C6H4
p-ClC6H4
92
90
89
86
85
88
Bn
H
Cl
Cl
H
Bn
5j
n-C4H9
Bn
p-CH3C6H4
p-CH3C6H4
p-CH3OC6H4
5k
5l
Bn
OCH3
a
b
Reaction condition: 3-phenacylidieneoxindole (1.0 mmol), vinyl malononitrile (1.0 mmol), DMAP (1.0 mmol) in ethanol (10.0 mL), rt, 30 min.
Isolated yield.
117.0, 110.9, 95.3, 86.9, 53.8, 53.2, 44.6, 33.0, 27.9, 25.3, 21.7,
21.6; IR (KBr) υ 3456, 3330, 3235, 3070, 2928, 2862, 2824,
2206, 1709, 1669, 1627, 1607, 1570, 1489, 1456, 1429, 1397,
1336, 1272, 1208, 1178, 1124, 1082, 1030, 991, 913, 848, 810,
776 cm−1; MS (m/z) HRMS (ESI) Calcd for C33H28ClN3NaO2
([M + Na]+) 556.1762; Found 556.1756.
Scheme 1. Formation Mechanism for the Spirocyclic
Oxindoles
3′-Amino-7′-tert-butyl-1-butyl-5-fluoro-1′-(4-methoxy-
benzoyl)-2-oxo-6′,7′,8′,8a′-tetrahydro-1′H-spiro[indoline-
3,2′-naphthalene]-4′-carbonitrile 3c: white solid, 85%, 0.472
1
g, mp 228.1−230.5 °C; H NMR (600 MHz, DMSO-d6) δ:
7.81 (d, J = 9.0 Hz, 2H, ArH), 7.41 (dd, J1 = 8.2 Hz, J2 = 2.0
Hz, 1H, ArH), 6.96−6.92 (m, 1H, ArH), 6.90 (d, J = 8.4 Hz,
2H, ArH), 6.88−6.86 (m, 1H, ArH), 5.60 (brs, 1H, CH), 5.57
(s, 2H, NH2), 4.40 (d, J = 12.0 Hz, 1H, CH), 3.79 (s, 3H,
OCH3), 3.68−3.64 (m, 1H, CH), 3.57−3.52 (m, 1H, CH),
3.39 (t, J = 11.4 Hz, 1H, CH), 2.91 (d, J = 18.0 Hz, 1H, CH),
1.91−1.86 (m, 1H, CH), 1.63−1.58 (m, 2H, CH2), 1.40−1.34
(m, 2H, CH2), 1.30−1.24 (m, 2H, CH2), 0.95 (t, J = 7.2 Hz,
3H, CH3), 0.74−0.68 (m, 1H, CH), 0.66 (s, 9H, CH3); 13C
NMR (150 MHz, DMSO-d6) δ 197.9, 173.8, 163.3, 158.8,
157.2, 153.7, 140.5, 131.4, 130.7, 130.4, 128.4 (d, J = 8.2 Hz),
117.9, 116.6, 115.6 (d, J = 23.5 Hz), 113.7, 112.6 (d, J = 25.2
Hz), 109.7 (d, J = 7.7 Hz), 80.7, 55.4, 53.7, 51.7, 43.1, 33.5,
31.8, 28.9, 28.7, 26.6, 26.5, 19.6, 13.8; IR (KBr) υ 3685, 3469,
3352, 3236, 2958, 2907, 2871, 2202, 1705, 1667, 1624, 1600,
1574, 1494, 1452, 1421, 1398, 1354, 1268, 1207, 1177, 1139,
1090, 1028, 987, 845, 819, 803 cm−1; MS (m/z) HRMS (ESI)
Calcd for C34H38FN3NaO3 ([M + Na]+) 578.2789; Found
578.2782.
4.18 (d, J = 12.0 Hz, 1H, CH), 2.93 (brs, 1H, CH), 2.37 (s, 3H,
CH3), 2.20−2.12 (m, 2H, CH2), 1.67−1.65 (m, 1H, CH),
1.50−1.47 (m, 1H, CH), 1.36−1.34 (m, 1H, CH), 1.06−1.01
(m, 1H, CH); 13C NMR (150 MHz, DMSO-d6) δ 197.0, 174.1,
153.3, 144.6, 139.3, 135.2, 134.5, 130.2, 129.4, 128.7, 128.2,
127.0, 126.9, 117.6, 117.1, 114.9, 114.8, 112.7, 112.5, 110.4,
110.3, 79.9, 55.3, 49.9, 44.1, 34.1, 27.0, 24.8, 21.3, 21.1, 18.5; IR
(KBr) υ 3460, 3320, 3234, 3078, 2948, 2887, 2203, 1708, 1667,
1607, 1572, 1498, 1433, 1396, 1350, 1201, 1177, 1131, 1087,
1030, 985, 845, 818, 792 cm−1; MS (m/z) HRMS (ESI) Calcd
for C33H29FN3O2 ([M + H]+) 518.2238; Found 518.2242.
3′-Amino-1-benzyl-5-chloro-1′-(4-methylbenzoyl)-2-oxo-
6′,7′,8′,8a′-tetrahydro-1′H-spiro[indoline-3,2′-naphthalene]-
4′-carbonitrile 3b: white solid, 74%, 0.394 g, mp 118.1−118.4
°C; 1H NMR (600 MHz, DMSO-d6) δ 7.78 (s, 2H, ArH), 7.67
(s, 1H, ArH), 7.45 (brs, 2H, ArH), 7.35 (brs, 2H, ArH), 7.28−
7.21 (m, 3H, ArH), 7.09 (s, 1H, ArH), 6.61 (s, 1H, ArH), 5.75
(s, 2H, NH2), 5.61 (s, 1H, CH), 4.96 (brs, 1H, CH), 4.77 (brs,
1H, CH), 4.54 (brs, 1H, CH), 3.42 (brs, 1H, CH), 2.30 (s, 3H,
CH3), 2.17−2.11 (m, 2H, CH2), 1.68 (s, 1H, CH), 1.36 (brs,
1H, CH), 1.25 (brs, 1H, CH), 0.98 (brs, 1H, CH); 13C NMR
(150 MHz, CDCl3) δ 199.2, 177.4, 150.1, 144.8, 142.5, 135.3,
130.1, 129.4, 128.9, 128.2, 128.1, 127.9, 127.5, 124.2, 121.8,
3′-Amino-1-benzyl-7′-tert-butyl-1′-(4-methoxybenzoyl)-2-
oxo-6′,7′,8′,8a′-tetrahydro-1′H-spiro[indoline-3,2′-naphtha-
lene]-4′-carbonitrile 3d: white solid, 92%, 0.525 g, mp 232.2−
1
233.9 °C; H NMR (600 MHz, DMSO-d6) δ 7.85 (d, J = 9.0
Hz, 2H, ArH), 7.48−7.45 (m, 3H, ArH), 7.35 (t, J = 7.8 Hz,
2H, ArH), 7.29−7.27 (m, 1H, ArH), 7.04 (t, J = 7.8 Hz, 1H,
ArH), 6.89 (d, J = 8.4 Hz, 2H, ArH), 6.81 (t, J = 7.8 Hz, 1H,
ArH), 6.62 (d, J = 8.4 Hz, 1H, ArH), 5.63 (s, 1H, CH), 5.47 (s,
2H, NH2), 4.97 (d, J = 15.6 Hz, 1H, CH), 4.79 (d, J = 16.2 Hz,
1H, CH), 4.48 (d, J = 12.0 Hz, 1H, CH), 3.78 (s, 3H, OCH3),
3.48−3.45 (m, 1H, CH), 2.21 (d, J = 18.0 Hz, 1H, CH), 1.93−
1.88 (m, 1H, CH), 1.32−1.26 (m, 2H, CH2), 0.77 (q, J = 12.0
Hz, 1H, CH2), 0.66 (s, 9H, CH3); 13C NMR (150 MHz,
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DMSO-d6) δ 198.4, 174.5, 163.3, 154.1, 143.8, 136.2, 131.4,
130.7, 130.6, 129.3, 128.4, 127.2, 126.7, 124.6, 122.2, 117.9,
116.8, 113.7, 109.4, 81.0, 55.4, 53.6, 51.7, 43.6, 43.1, 33.8, 31.8,
28.7, 26.6, 26.5; IR (KBr) υ 3656, 3464, 3347, 3237, 3194,
3057, 2948, 2903, 2203, 1707, 1666, 1625, 1598, 1573, 1509,
1489, 1467, 1420, 1398, 1350, 1327, 1267, 1249, 1205, 1174,
1110, 1077, 1027, 981, 846, 803 cm−1; MS (m/z) HRMS (ESI)
Calcd for C37H37N3NaO3 ([M + Na]+) 594.2727; Found
594.2724.
DMSO-d6) δ 197.4, 73.1, 155.9, 142.8, 139.2, 136.7, 135.5,
130.8, 128.7, 128.2, 127.1, 127.0, 124.3, 122.6, 121.0, 118.3,
109.5, 79.4, 56.1, 55.1, 50.0, 43.9, 32.7, 30.5, 27.9, 25.4, 18.5; IR
(KBr) υ 3457, 3326, 3225, 3059, 2921, 2846, 2201, 1708, 1676,
1649, 1609, 1588, 1483, 1462, 1437, 1400, 1356, 1295, 1236,
1201, 1176, 1087, 1041, 1006, 986, 928, 882, 850, 833, 811, 781
cm−1; MS (m/z) HRMS (ESI) Calcd for C33H29ClN3O2 ([M +
H]+) 534.1943; Found 534.1931.
3-Amino-1′-benzyl-1-(4-chlorobenzoyl)-5′-methyl-2′-oxo-
1,6,7,8,9,9a-hexahydrospiro[benzo[7]annulene-2,3′-indo-
line]-4-carbonitrile 3h: white solid, 87%, 0.476 g, mp 224.3−
3′-Amino-1-benzyl-7′-tert-butyl-1′-(4-chlorobenzoyl)-2-
oxo-6′,7′,8′,8a′-tetrahydro-1′H-spiro[indoline-3,2′-naphtha-
lene]-4′-carbonitrile 3e: white solid, 83%, 0.477 g, mp 164.8−
1
226.1 °C; H NMR (600 MHz, DMSO-d6) δ 7.95 (d, J = 8.4
1
165.3 °C; H NMR (600 MHz, DMSO-d6) δ 7.85 (d, J = 6.6
Hz, 2H, ArH), 7.55 (d, J = 8.4 Hz, 2H, ArH), 7.16−7.14 (m,
1H, ArH), 7.08−7.04 (m, 3H, ArH), 6.97 (s, 1H, ArH), 6.78
(d, J = 7.8 Hz, 2H, ArH), 6.69 (d, J = 7.8 Hz, 1H, ArH), 6.20 (s,
2H, NH2), 5.86 (t, J = 6.0 Hz, 1H, CH), 4.89 (d, J = 16.2 Hz,
1H, CH), 4.43 (d, J = 12.0 Hz, 1H, CH), 4.26 (d, J = 16.2 Hz,
1H, CH), 3.15 (t, J = 10.8 Hz, 1H, CH), 2.35−2.31 (m, 1H,
CH), 2.27 (s, 3H, CH3), 2.25−2.20 (m, 1H, CH), 1.75−1.73
(m, 1H, CH), 1.69−1.68 (m, 1H, CH), 1.53−1.47 (m, 1H,
CH), 1.39−1.33 (m, 1H, CH), 1.28−1.25 (m, 1H, CH), 1.19
(d, J = 13.2 Hz, 1H, CH); 13C NMR (150 MHz, DMSO-d6) δ
197.4, 172.9, 156.0, 140.5, 139.1, 136.8, 135.6, 135.5, 131.4,
130.8, 129.0, 128.7, 128.2, 127.1, 127.0, 124.8, 120.8, 118.4,
109.3, 79.2, 55.1, 50.0, 43.9, 32.7, 30.4, 27.8, 25.4, 20.9, 14.1; IR
(KBr) υ 3731, 3454, 3329, 3240, 3030, 2919, 2848, 2207, 1708,
1673, 1650, 1616, 1588, 1490, 1454, 1436, 1400, 1347, 1283,
1250, 1231, 1197, 1137, 1090, 1042, 1012, 987, 951, 849, 836,
808, 771 cm−1; MS (m/z) HRMS (ESI) Calcd for
C34H31ClN3O2 ([M + H]+) 548.2099; Found 548.2085.
General Procedure for the Synthesis of Spirocyclic
Oxindoles 4a−4j. A mixture of N-methyl or N-benzylpiperdi-
none (1.0 mmol), malononitrile (1.0 mmol), and piperidine
(0.1 mmol) in ethanol (15.0 mL) was refluxed for 5 min. Then
3-phenacylideneoxindole (1.0 mmol) was added, and the
mixture was refluxed for about one hour. After it was cooled,
the resulting precipitate was collected by filtration and washed
with cold alcohol to give the pure product for analysis.
6′-Amino-1-benzyl-2′-methyl-8′-(4-methylbenzoyl)-2-oxo-
2′,3′,8′,8a′-tetrahydro-1′H-spiro[indoline-3,7′-isoquinoline]-
5′-carbonitrile 4a: yellow solid, 83%, 0.427 g, mp 118.1−118.4
°C; 1H NMR (600 MHz, DMSO-d6) δ 7.75 (d, J = 7.8 Hz, 2H,
ArH), 7.49 (d, J = 7.2 Hz, 1H, ArH), 7.46 (d, J = 7.2 Hz, 2H,
ArH), 7.35 (t, J = 7.8 Hz, 2H, ArH), 7.29−7.27 (m, 1H, ArH),
7.17 (d, J = 8.4 Hz, 2H, ArH), 7.04 (t, J = 7.8 Hz, 1H, ArH),
6.80 (t, J = 7.2 Hz, 1H, ArH), 6.63 (d, J = 7.8 Hz, 1H, ArH),
5.68 (s, 2H, NH2), 5.53−5.52 (m, 1H, CH), 4.98 (d, J = 15.6
Hz, 1H, CH), 4.78 (d, J = 16.2 Hz, 1H, CH), 4.53 (d, J = 12.6
Hz, 1H, CH), 3.77−3.73 (m, 1H, CH), 3.30 (brs, 1H, CH),
2.68 (d, J = 18.0 Hz, 1H, CH), 2.29 (s, 3H, CH3), 2.22 (dd, J1 =
10.2 Hz, J2 = 4.4 Hz, 1H, CH), 2.08 (s, 3H, CH3), 1.76 (t, J =
10.2 Hz, 1H, CH); 13C NMR (150 MHz, DMSO-d6) δ 199.3,
174.7, 155.1, 144.7, 144.2, 136.7, 135.1, 130.5, 129.9, 129.8,
129.7, 129.1, 128.9, 127.8, 127.7, 127.6, 125.2, 122.8, 118.0,
109.9, 55.6, 55.3, 54.8, 54.0, 49.8, 44.1, 33.4, 21.5; IR (KBr) υ
3424, 3317, 3204, 2944, 2849, 2780, 2209, 1713, 1678, 1638,
1608, 1587, 1488, 1423, 1398, 1352, 1279, 1258, 1190, 1171,
1085, 985, 936, 846, 815, 796, 755 cm−1; MS (m/z) HRMS
(ESI) Calcd for C33H31N4O2 ([M + H]+) 515.2442; Found
515.2424.
Hz, 2H, ArH), 7.55 (d, J = 6.0 Hz, 2H, ArH), 7.36 (d, J = 6.0
Hz, 1H, ArH), 7.25 (brs, 1H, ArH), 7.12−7.08 (m, 2H, ArH),
6.99 (brs, 2H, ArH), 6.79 (d, J = 6.0 Hz, 1H, ArH), 6.73 (d, J =
4.2 Hz, 2H, ArH), 6.18 (s, 2H, NH2), 5.65 (s, 1H, CH), 4.90
(d, J = 16.2 Hz, 1H, CH), 4.29 (d, J = 15.0 Hz, 1H, CH), 4.18
(d, J = 10.8 Hz, 1H, CH), 2.97 (brs, 1H, CH), 2.20 (d, J = 14.4
Hz, 1H, CH), 1.96−1.91 (m, 1H, CH), 1.38−1.33 (m, 2H,
CH2), 0.83−0.80 (m, 1H, CH), 0.69 (s, 9H, CH3); 13C NMR
(150 MHz, CDCl3) δ 197.1, 174.8, 151.1, 142.3, 140.3, 135.9,
134.9, 130.0, 129.5, 129.0, 128.8, 126.6, 127.8, 127.3, 125.6,
123.5, 122.4, 116.8, 109.7, 86.1, 55.6, 51.2, 44.3, 43.7, 35.6,
32.3, 28.8, 27.7, 27.2, 27.0; IR (KBr) υ 3419, 3327, 3230, 3060,
2925, 2852, 2235, 1701, 1655, 1580, 1484, 1453, 1429, 1367,
1300, 1287, 1202, 1173, 1027, 1003, 990, 919, 826, 764 cm−1;
MS (m/z) HRMS (ESI) Calcd for C36H34ClN3NaO2 ([M +
Na]+) 598.2232; Found 598.2228.
3-Amino-1′-butyl-1-(4-chlorobenzoyl)-5′-methyl-2′-oxo-
1,6,7,8,9,9a-hexahydrospiro[benzo[7]annulene-2,3′-indo-
line]-4-carbonitrile 3f: white solid, 80%, 0.513 g, mp 222.7−
1
223.9 °C; H NMR (600 MHz, DMSO-d6) δ 7.88 (d, J = 8.4
Hz, 2H, ArH), 7.54 (d, J = 7.8 Hz, 2H, ArH), 7.11 (d, J = 7.8
Hz, 1H, ArH), 6.92 (s, 1H, ArH), 6.84 (d, J = 7.8 Hz, 1H,
ArH), 6.01 (s, 2H, NH2), 5.84 (s, 1H, CH), 4.31 (d, J = 12.0
Hz, 1H, CH), 3.51−3.46 (m, 1H, CH), 3.17−3.14 (m, 1H,
CH), 3.08−3.04 (m, 1H, CH), 2.29 (s, 3H, CH3), 1.72−1.70
(m, 2H, CH2), 1.55−1.49 (m, 1H, CH), 1.41−1.35 (m, 1H,
CH), 1.31−1.27 (m, 1H, CH), 1.16 (d, J = 13.2 Hz, 1H, CH),
0.98−0.94 (m, 1H, CH), 0.91−0.87 (m, 2H, CH2), 0.74−0.70
(m, 1H, CH), 0.61 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (150
MHz, DMSO-d6) δ 197.0, 172.4, 155.5, 140.8, 139.0, 136.6,
135.6, 131.0, 129.1, 128.6, 128.5, 124.8, 120.7, 118.4, 108.8,
79.5, 55.0, 50.6, 37.7, 32.9, 30.2, 28.6, 27.8, 25.4, 20.9, 19.3,
13.5; IR (KBr) υ 3461, 3330, 3241, 3031, 2957, 2916, 2853,
2207, 1710, 1675, 1650, 1618, 1587, 1491, 1441, 1400, 1400,
1283, 1254, 1234, 1203, 1093, 1041, 1012, 990, 931, 849, 803,
769, 751 cm−1; MS (m/z) HRMS (ESI) Calcd for
C31H32ClN3NaO2 ([M + Na]+) 536.2075; Found 536.2076.
3-Amino-1′-benzyl-1-(4-chlorobenzoyl)-2′-oxo-
1,6,7,8,9,9a-hexahydrospiro[benzo[7]annulene-2,3′-indo-
line]-4-carbonitrile 3g: white solid, 82%, 0.437 g, mp 234.6−
1
236.2 °C; H NMR (600 MHz, DMSO-d6) δ 7.95 (d, J = 8.4
Hz, 2H, ArH), 7.55 (d, J = 8.4 Hz, 2H, ArH), 7.24 (t, J = 7.8
Hz, 1H, ArH), 7.18−7.15 (m, 2H, ArH), 7.09−7.06 (m, 3H,
ArH), 6.82−6.79 (m, 3H, ArH), 6.23 (s, 2H, NH2), 5.86 (t, J =
6.0 Hz, 1H, CH), 4.91 (d, J = 15.6 Hz, 1H, CH), 4.45 (d, J =
12.0 Hz, 1H, CH), 4.29 (d, J = 16.2 Hz, 1H, CH), 3.14 (t, J =
10.2 Hz, 1H, CH), 2.35−2.30 (m, 1H, CH), 2.25−2.20 (m, 1H,
CH), 1.76−1.74 (m, 1H, CH), 1.68−1.67 (m, 1H, CH), 1.53−
1.47 (m, 1H, CH), 1.37−1.31 (m, 1H, CH), 1.27−1.23 (m, 1H,
CH), 1.19 (d, J = 10.2 Hz, 1H, CH); 13C NMR (150 MHz,
6′-Amino-1-benzyl-8′-(4-chlorobenzoyl)-2′-methyl-2-oxo-
2′,3′,8′,8a′-tetrahydro-1′H-spiro[indoline-3,7′-isoquinoline]-
5′-carbonitrile 4b: yellow solid, 96%, 0.513 g, mp 190.3−192.1
275
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ACS Combinatorial Science
Research Article
°C; 1H NMR (600 MHz, DMSO-d6) δ 7.83 (d, J = 8.4 Hz, 2H,
ArH), 7.47−7.42 (m, 5H, ArH), 7.36 (t, J = 7.8 Hz, 2H, ArH),
7.29 (t, J = 7.2 Hz, 1H, ArH), 7.04 (t, J = 7.2 Hz, 1H, ArH),
6.80 (t, J = 7.8 Hz, 1H, ArH), 6.65 (d, J = 7.8 Hz, 1H, ArH),
5.73 (s, 2H, NH2), 5.54−5.53 (m, 1H, CH), 4.97 (d, J = 16.2
Hz, 1H, CH), 4.77 (d, J = 15.6 Hz, 1H, CH), 4.57 (d, J = 12.0
Hz, 1H, CH), 3.75 (brs, 1H, CH), 3.38 (m, 1H, CH), 2.70 (d, J
= 16.8 Hz, 1H, CH), 2.25 (dd, J1 = 10.2 Hz, J2 = 4.8 Hz, 1H,
CH), 2.10 (s, 3H, CH3), 1.78 (t, J = 10.2 Hz, 1H, CH); 13C
NMR (150 MHz, DMSO-d6) δ 198.7, 174.0, 154.3, 143.6,
138.8, 136.1, 135.6, 130.1, 129.7, 129.5, 128.7, 128.4, 127.3,
126.1, 124.8, 122.4, 117.6, 114.1, 109.5, 79.9, 55.0, 54.4, 53.5,
49.4, 45.2, 43.6, 32.9; IR (KBr) υ 3460, 3327, 3234, 3061, 2940,
2779, 2205, 1716, 1676, 1637, 1609, 1586, 1489, 1468, 1400,
1380, 1352, 1282, 1239, 1202, 1177, 1091, 982, 848, 794, 754
cm−1; MS (m/z) HRMS (ESI) Calcd for C32H28ClN4O2 ([M +
H]+) 535.1895. Found 535.1906.
(d, J = 8.4 Hz, 2H, ArH), 7.34−7.30 (m, 4H, ArH), 7.11 (t, J =
7.2 Hz, 1H, ArH), 6.95 (t, J = 7.8 Hz, 2H, ArH), 6.74 (d, J = 7.8
Hz, 1H, ArH), 6.66 (d, J = 7.8 Hz, 2H, ArH), 6.40 (s, 2H,
NH2), 5.57 (s, 1H, CH), 4.93 (d, J = 16.2 Hz, 1H, CH), 4.37 (t,
J = 4.8 Hz, 1H, CH), 4.25−4.19 (m, 2H, CH), 3.37 (brs, 1H,
CH), 2.71 (d, J = 17.4 Hz, 1H, CH), 2.37 (s, 3H, CH3), 2.29
(dd, J1 = 10.1 Hz, J2 = 4.2 Hz, 1H, CH), 2.11 (s, 3H, CH3),
1.79 (t, J = 10.2 Hz, 1H, CH); 13C NMR (150 MHz, DMSO-
d6) δ 196.2, 173.7, 153.8, 145.1, 142.0, 135.0, 133.8, 131.1,
129.5, 128.8, 128.7, 128.4, 128.2, 127.1, 126.9, 126.5, 124.4,
117.3, 111.2, 78.6, 56.0, 55.0, 54.2, 47.4, 44.9, 44.2, 34.6, 21.1,
18.5; IR (KBr) υ 3462, 3317, 3202, 2956, 2922, 2858, 2785,
2207, 1714, 1668, 1639, 1607, 1586, 1481, 1428, 1396, 1331,
1280, 1258, 1188, 1169, 1123, 1080, 1050, 983, 934, 887, 854,
837, 815, 777, 755 cm−1; MS (m/z) HRMS (ESI) Calcd for
C33H30ClN4O2 ([M + H]+) 549.2052; Found 549.2069.
6′-Amino-1,2′-dibenzyl-8′-(4-methoxybenzoyl)-2-oxo-
2′,3′,8′,8a′-tetrahydro-1′H-spiro[indoline-3,7′-isoquinoline]-
5′-carbonitrile 4f: yellow solid, 92%, 0.582 g, mp 192.5−194.1
°C; 1H NMR (600 MHz, DMSO-d6) δ 7.79 (d, J = 8.4 Hz, 2H,
ArH), 7.50 (d, J = 7.8 Hz, 1H, ArH), 7.46 (d, J = 7.8 Hz, 2H,
ArH), 7.35 (t, J = 7.2 Hz, 2H, ArH), 7.28 (d, J = 7.2 Hz, 1H,
ArH), 7.26−7.20 (m, 3H, ArH), 7.11 (d, J = 7.2 Hz, 2H, ArH),
7.04 (t, J = 7.8 Hz, 1H, ArH), 6.88 (d, J = 9.0 Hz, 2H, ArH),
6.81 (t, J = 7.8 Hz, 1H, ArH), 6.61 (d, J = 7.8 Hz, 1H, ArH),
5.67 (s, 2H, NH2), 5.52 (s, 1H, CH), 4.97 (d, J = 15.6 Hz, 1H,
CH), 4.78 (d, J = 16.2 Hz, 1H, CH), 4.52 (d, J = 12.0 Hz, 1H,
CH), 3.80 (s, 3H, OCH3), 3.72 (brs, 1H, CH), 3.38 (s, 2H,
CH2), 3.29 (d, J = 15.0 Hz, 1H, CH), 2.79 (d, J = 17.4 Hz, 1H,
CH), 2.36 (dd, J1 = 10.4 Hz, J2 = 4.6 Hz, 1H, CH), 1.83 (t, J =
10.6 Hz, 1H, CH); 13C NMR (150 MHz, DMSO-d6) δ: 197.6,
174.4, 163.4, 154.7, 143.8, 137.8, 136.2, 130.7, 130.3, 130.1,
129.4, 128.7, 128.4, 128.1, 127.3, 126.9, 126.5, 124.7, 122.3,
117.6, 113.8, 113.7, 109.4, 79.8, 61.6, 55.5, 53.5, 53.4, 52.4,
49.3, 43.6, 33.0; IR (KBr) υ 3458, 3333, 3238, 3197, 3028,
2937, 2867, 2801, 2756, 2205, 1703, 1661, 1629, 1599, 1576,
1511, 1493, 1468, 1398, 1360, 134, 1311, 1269, 1247, 1173,
1080, 1030, 984, 847, 804 cm−1; MS (m/z) HRMS (ESI) Calcd
for C39H35N4O3 ([M + H]+) 607.2704; Found 607.2706.
6′-Amino-8′-benzoyl-1,2′-dibenzyl-5-fluoro-2-oxo-
2′,3′,8′,8a′-tetrahydro-1′H-spiro[indoline-3,7′-isoquinoline]-
5′-carbonitrile 4g: yellow solid, 95%, 0.564 g, mp 196.8−198.3
°C; 1H NMR (600 MHz, DMSO-d6) δ 7.76 (d, J = 7.8 Hz, 2H,
ArH), 7.56 (t, J = 7.2 Hz, 1H, ArH), 7.50 (dd, J1 = 8.4 Hz, J2 =
2.5 Hz, 1H, ArH), 7.45 (d, J = 7.2 Hz, 2H, ArH), 7.40−7.35
(m, 4H, ArH), 7.30−7.27 (m, 1H, ArH), 7.25−7.20 (m, 3H,
ArH), 7.09 (d, J = 6.6 Hz, 2H, ArH), 6.86 (td, J1 = 9.0 Hz, J2 =
2.4 Hz, 1H, ArH), 6.61 (dd, J1 = 8.6 Hz, J2 = 4.2 Hz, 1H, ArH),
5.89 (s, 2H, NH2), 5.53−5.52 (m, 1H, CH), 4.95 (d, J = 15.6
Hz, 1H, CH), 4.77 (d, J = 16.2 Hz, 1H, CH), 4.58 (d, J = 12.0
Hz, 1H, CH), 3.71 (t, J = 10.8 Hz, 1H, CH), 3.42−3.37 (m,
2H, CH2), 3.32−3.30 (m, 1H, CH), 2.81−2.78 (m, 1H, CH),
2.38 (dd, J1 = 10.4 Hz, J2 = 4.7 Hz, 1H, CH), 1.79 (t, J = 10.2
Hz, 1H, CH); 13C NMR (150 MHz, DMSO-d6) δ: 199.7,
174.1, 159.0, 157.5, 154.1, 140.1, 137.7, 137.2, 136.0, 133.7,
130.0, 128.7, 128.6, 128.5, 128.1, 128.0, 127.3, 126.9, 117.6,
115.8 (d, J = 23.0 Hz), 114.0, 112.9 (d, J = 26.0 Hz), 110.4 (d, J
= 8.4 Hz), 79.8, 61.5, 53.8, 53.2, 52.3, 49.7, 43.7, 32.9; IR (KBr)
υ 3457, 3330, 3240, 3200, 3028, 2917, 2868, 2800, 2753, 2206,
1703, 1671, 1630, 1580, 1494, 1451, 1394, 1359, 1337, 1271,
1241, 1202, 1172, 1143, 1081, 1028, 987, 969, 899, 858, 801
cm−1; MS (m/z) HRMS (ESI) Calcd for C38H32FN4O2 ([M +
H]+) 595.2504; Found 595.2508.
6′-Amino-1-benzyl-5-fluoro-8′-(4-methoxybenzoyl)-2′-
methyl-2-oxo-2′,3′,8′,8a′-tetrahydro-1′H-spiro[indoline-3,7′-
isoquinoline]-5′-carbonitrile 4c: yellow solid, 92%, 0.504 g,
1
mp 200.8−202.2 °C; H NMR (600 MHz, DMSO-d6) δ 7.87
(d, J = 7.8 Hz, 2H, ArH), 7.50 (d, J = 7.8 Hz, 1H, ArH), 7.46−
7.45 (m, 2H, ArH), 7.35 (t, J = 6.6 Hz, 2H, ArH), 7.29−7.28
(m, 1H, ArH), 6.91−6.86 (m, 3H, ArH), 6.60 (brs, 1H, ArH),
5.86 (s, 2H, NH2), 5.52 (s, 1H, CH), 4.97 (d, J = 15.6 Hz, 1H,
CH), 4.76 (d, J = 15.6 Hz, 1H, CH), 4.52 (d, J = 12.0 Hz, 1H,
CH), 3.80 (s, 3H, OCH3), 3.73 (brs, 1H, CH), 3.37 (brs, 1H,
CH), 2.68 (d, J = 16.8 Hz, 1H, CH), 2.23 (d, J = 6.0 Hz, 1H,
CH), 2.09 (s, 3H, CH3), 1.73 (t, J = 10.2 Hz, 1H, CH); 13C
NMR (150 MHz, DMSO-d6) δ 197.3, 174.1, 163.6, 159.0,
157.4, 154.2, 140.1, 136.0, 130.8, 129.9 (d, J = 16.5 Hz), 128.4,
128.1 (d, J = 5.1 Hz), 127.3, 117.6, 115.8, 115.6, 113.8, 113.0,
112.8, 110.3 (d, J = 8.4 Hz), 79.9, 55.5, 55.3, 54.5, 53.9, 49.0,
45.3, 43.7, 32.9, 18.5; IR (KBr) υ 3398, 3313, 3084, 2940, 2845,
2790, 2204, 1716, 1643, 1599, 1575, 1496, 1455, 1422, 1399,
1382, 1344, 1258, 1241, 1205, 1177, 1081, 1024, 984, 964, 845,
818, 792 cm−1; MS (m/z) HRMS (ESI) Calcd. for
C33H30FN4O3 ([M + H]+) 549.2296; Found 549.2313.
6′-Amino-8′-benzoyl-1-benzyl-5-chloro-2′-methyl-2-oxo-
2′,3′,8′,8a′-tetrahydro-1′H-spiro[indoline-3,7′-isoquinoline]-
5′-carbonitrile 4d: yellow solid, 88%, 0.470 g, mp 180.6−182.4
°C; 1H NMR (600 MHz, DMSO-d6) δ 7.88 (d, J = 7.8 Hz, 2H,
ArH), 7.68 (t, J = 7.2 Hz, 1H, ArH), 7.52 (t, J = 7.8 Hz, 2H,
ArH), 7.35−7.34 (m, 2H, ArH), 7.09 (t, J = 7.2 Hz, 1H, ArH),
6.94 (t, J = 7.8 Hz, 2H, ArH), 6.76 (d, J = 9.0 Hz, 1H, ArH),
6.66 (d, J = 7.8 Hz, 2H, ArH), 6.41 (s, 2H, NH2), 5.58 (brs, 1H,
CH), 4.92 (d, J = 16.2 Hz, 1H, CH), 4.37 (t, J = 4.8 Hz, 1H,
CH), 4.26 (d, J = 3.6 Hz, 1H, CH), 4.24 (d, J = 7.8 Hz, 1H,
CH), 3.37 (brs, 1H, CH), 2.72 (d, J = 17.4 Hz, 1H, CH), 2.30
(dd, J1 = 10.2 Hz, J2 = 4.6 Hz, 1H, CH), 2.11 (s, 3H, CH3),
1.81 (t, J = 10.2 Hz, 1H, CH); 13C NMR (150 MHz, DMSO-
d6) δ 196.9, 173.7, 153.6, 142.1, 136.3, 135.0, 134.3, 131.1,
128.9, 128.7, 128.6, 128.3, 128.2, 127., 126.9, 126.6, 124.4,
117.4, 114.7, 111.2, 78.7, 56.0, 55.0, 54.6, 54.3, 47.6, 45.1, 44.2,
34.9, 18.5; IR (KBr) υ: 3468, 3316, 3195, 2967, 2863, 2788,
2206, 1712, 1671, 1639, 1590, 1481, 1448, 1428, 1395, 1335,
1281, 1256, 1239, 1202, 1170, 1124, 1081, 1047, 983, 932, 886,
851, 819, 756 cm−1; MS (m/z) HRMS (ESI) Calcd. for
C32H28ClN4O2 ([M + H]+) 535.1895; Found 535.1903.
6′-Amino-1-benzyl-5-chloro-2′-methyl-8′-(4-methylben-
zoyl)-2-oxo-2′,3′,8′,8a′-tetrahydro-1′H-spiro[indoline-3,7′-
isoquinoline]-5′-carbonitrile 4e: yellow solid, 89%, 0.488 g,
1
mp 188.1−190.0 °C; H NMR (600 MHz, DMSO-d6) δ 7.78
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Research Article
6′-Amino-1,2′-dibenzyl-5-fluoro-8′-(4-methoxybenzoyl)-2-
oxo-2′,3′,8′,8a′-tetrahydro-1′H-spiro[indoline-3,7′-isoquino-
line]-5′-carbonitrile 4h: yellow solid, 94%, 0.587 g, mp 186.6−
phenacylideneoxindole (1.0 mmol) and piperidine (0.1 mmol)
in ethanol (10.0 mL) was stirred at room temperature for about
one hour. The resulting precipitate was collected by filtration
and washed with cold alcohol to give the pure product for
analysis.
1
188.3 °C; H NMR (600 MHz, DMSO-d6) δ 7.81 (s, 2H,
ArH), 7.51−7.45 (m, 3H, ArH), 7.35 (s, 2H, ArH), 7.28−7.24
(m, 4H, ArH), 7.12 (s, 2H, ArH), 6.90 (s, 3H, ArH), 6.59 (s,
1H, ArH), 5.86 (s, 2H, NH2), 5.52 (s, 1H, CH), 4.96 (d, J =
14.4 Hz, 1H, CH), 4.77 (d, J = 16.2 Hz, 1H, CH), 4.52 (d, J =
9.6 Hz, 1H, CH), 3.81 (s, 3H, OCH3), 3.71 (s, 1H, CH), 3.39
(s, 2H, CH2), 3.30 (d, J = 16.2 Hz, 1H, CH), 2.79 (d, J = 15.0
Hz, 1H, CH), 2.38 (s, 1H, CH), 1.81 (s, 1H, CH); 13C NMR
(150 MHz, DMSO-d6) δ 197.5, 174.2, 163.6, 159.0, 157.4,
154.3, 140.1, 137.8, 136.0, 130.7, 130.1(25.5), 128.6(33.1),
128.1, 127.3, 126.9, 117.6, 115.8(20.0), 113.8, 112.8(26.2),
110.3, 79.9, 61.6, 55.5, 53.9, 53.4, 52.4, 49.3, 43.7, 33.0; IR
(KBr) υ 3458, 3339, 3240, 3026, 2915, 2867, 2803, 2754, 2206,
1704, 1660, 1629, 1595, 1493, 1453, 1396, 1358, 1336, 1316,
1267,1245, 1203, 1169, 1079, 1023, 989, 898, 838, 791 cm−1;
MS (m/z) HRMS (ESI) Calcd. for C39H34FN4O3 ([M + H]+)
625.2609; Found 625.2611.
2-(2-(1-(1-Butyl-5-chloro-2-oxoindolin-3-yl)-2-(4-methoxy-
phenyl)-2-oxoethyl)cyclohexylidene)malononitrile (5a):
1
white solid, 81%, 0.458 g, mp 164.8−168.2 °C; H NMR
(600 MHz, DMSO-d6) δ 8.14 (d, J = 9.0 Hz, 2H, ArH), 7.57
(brs, 1H, ArH), 7.29 (d, J = 7.8 Hz, 1H, ArH), 7.11 (d, J = 9.0
Hz, 2H, ArH), 7.02 (d, J = 8.4 Hz, 1H, ArH), 4.96 (dd, J1 =
11.2 Hz, J2 = 1.7 Hz, 1H, CH), 3.87 (s, 3H, OCH3), 3.79 (brs,
1H, CH), 3.67−3.56 (m, 3H, CH2, CH), 2.94−2.90 (m, 1H,
CH), 2.65 (d, J = 12.6 Hz, 1H, CH), 2.12 (d, J = 12.0 Hz, 1H,
CH), 1.76−1.71 (m, 1H, CH), 1.59−1.57 (m, 1H, CH), 1.54−
1.46 (m, 3H, CH), 1.45−1.42 (m, 1H, CH), 1.40−1.36 (m, 1H,
CH), 1.35−1.31 (m, 2H, CH2), 0.92 (t, J = 7.2 Hz, 3H, CH3);
13C NMR (150 MHz, DMSO-d6) δ 197.7, 173.7, 164.0, 142.6,
131.3, 131.0, 128.3, 125.4, 114.5, 114.3, 109.8, 82.8, 55.7, 44.8,
42.0, 34.2, 32.1, 32.0, 30.2, 29.2, 27.3, 24.2, 19.6, 19.5, 13.6; IR
(KBr) υ 2960, 2934, 2866, 2228, 1713, 1667, 1599, 1510, 1480,
1425, 1353, 1312, 1266, 1210, 1175, 1114, 1026, 996, 958, 845,
815 cm−1; MS (m/z) HRMS (ESI) Calcd for C30H31ClN3O3
([M + H]+) 516.2054; Found 516.2048.
6′-Amino-1,2′-dibenzyl-5-chloro-8′-(4-methoxybenzoyl)-
2-oxo-2′,3′,8′,8a′-tetrahydro-1′H-spiro[indoline-3,7′-isoqui-
noline]-5′-carbonitrile 4i: yellow solid, 93%, 0.595g, mp
1
194.4−196.4 °C; H NMR (600 MHz, DMSO-d6) δ 7.80 (d,
J = 8.4 Hz, 2H, ArH), 7.66 (s, 1H, ArH), 7.44−7.43 (m, 2H,
ArH), 7.36−7.34 (m, 2H, ArH), 7.28 (t, J = 7.2 Hz, 1H, ArH),
7.24−7.21 (m, 3H, ArH), 7.11 (d, J = 6.6 Hz, 2H, ArH), 7.08
(d, J = 7.2 Hz, 1H, ArH), 6.90 (d, J = 7.8 Hz, 2H, ArH), 6.59
(d, J = 8.4 Hz, 1H, ArH), 5.90 (s, 2H, NH2), 5.51(s, 1H, CH),
4.97 (d, J = 16.2 Hz, 1H, CH), 4.75 (d, J = 15.6 Hz, 1H, CH),
4.54 (d, J = 11.4 Hz, 1H, CH), 3.81 (s, 3H, OCH3), 3.68 (s,
1H, CH), 3.39 (s, 2H, CH2), 3.29 (d, J = 16.8 Hz, 1H, CH),
2.78 (d, J = 16.2 Hz, 1H, CH), 2.37−2.36 (m, 1H, CH), 1.80
(t, J = 16.2 Hz, 1H, CH); 13C NMR (150 MHz, DMSO-d6) δ
197.5, 174.1, 163.6, 154.1, 142.7, 137.7, 135.8, 130.7, 130.1,
130.0, 129.2, 128.7, 128.4, 128.1, 127.3, 127.2, 126.9, 126.4,
125.2, 117.6, 113.8, 110.8, 79.8, 61.6, 55.6, 53.7, 53.3, 52.4,
49.3, 43.7, 32.9; IR (KBr) υ 3455, 3325, 3240, 3198, 3027,
2939, 2800, 2753, 2207, 1706, 1661, 1630, 1598, 1576, 1510,
1489, 1456, 1428, 1397, 1335, 1267, 1246, 1172, 1081, 1031,
985, 884, 844, 805 cm−1; MS (m/z) HRMS (ESI) Calcd for
C39H34ClN4O3 ([M + H]+) 641.2314; Found 641.2313.
2-(2-(1-(1-Benzyl-2-oxoindolin-3-yl)-2-(4-methoxyphenyl)-
2-oxoethyl)-4-tert-butylcyclohexylidene)malononitrile (5b):
1
white solid, 85%, 0.485 g, mp 193.1−193.7 °C; H NMR
(600 MHz, CDCl3) δ 8.24 (d, J = 8.4 Hz, 2H, ArH), 7.54 (d, J
= 7.2 Hz, 1H, ArH), 7.33−7.27 (m, 5H, ArH), 7.26 (brs, 1H,
ArH), 7.20 (t, J = 7.8 Hz, 1H, ArH), 7.05(d, J = 9.0 Hz, 2H,
ArH), 6.80 (d, J = 7.8 Hz, 1H, ArH), 5.30 (d, J = 15.6 Hz, 1H,
CH), 4.98 (d, J = 10.8 Hz, 1H, CH), 4.51 (d, J = 15.0 Hz, 1H,
CH), 3.92 (s, 3H, OCH3), 3.75 (d, J = 10.2 Hz, 1H, CH), 3.71
(s, 1H, CH), 2.91−2.82 (m, 2H, CH2), 2.15 (d, J = 12.0 Hz,
1H, CH), 1.94 (d, J = 12.6 Hz, 1H, CH), 1.56−1.51 (m, 1H,
CH), 1.24−1.11 (m, 2H, CH2), 0.65 (s, 9H, CH3); 13C NMR
(150 MHz, CDCl3) δ 197.3, 184.3 175.1, 164.5, 143.6, 135.2,
131.1, 129.4, 128.9, 128.6, 127.9, 127.4, 126.5, 124.5, 123.0,
114.5, 111.6, 109.6, 109.5, 83.2, 55.6, 46.2, 44.2, 43.4, 41.8,
41.6, 33.8, 32.4, 32.1, 31.4, 27.2; IR (KBr) υ 3064, 3024, 2963,
2870, 2230, 1701, 1679, 1600, 1575, 1511, 1483, 1463, 1440,
1421, 1371, 1351, 1295, 1262, 1212, 1180, 1111, 1079, 1029,
991, 898, 858, 840, 762 cm−1; MS (m/z) HRMS (ESI) Calcd
for C37H37N3NaO3 ([M + Na]+) 594.2727; Found 594.2725.
2-(2-(1-(1-Benzyl-5-fluoro-2-oxoindolin-3-yl)-2-oxo-2-p-
tolylethyl)-4-tert-butylcyclohexylidene)malononitrile (5c):
6′-Amino-1,2′-dibenzyl-5-chloro-8′-(4-methylbenzoyl)-2-
oxo-2′,3′,8′,8a′-tetrahydro-1′H-spiro[indoline-3,7′-isoquino-
line]-5′-carbonitrile 4j: yellow solid, 90%, 0.562 g, mp 188.6−
1
190.4 °C; H NMR (600 MHz, DMSO-d6) δ 7.69−7.66 (m,
1
3H, ArH), 7.43 (s, 2H, ArH), 7.35 (s, 2H, ArH), 7.28−7.20 (m,
6H, ArH), 7.11 (brs, 3H, ArH), 6.60 (d, J = 6.0 Hz, 1H, ArH),
5.90 (s, 2H, NH2), 5.52 (s, 1H, CH), 4.97 (d, J = 15.0 Hz, 1H,
CH), 4.76 (d, J = 15.6 Hz, 1H, CH), 4.55 (d, J = 11.4 Hz, 1H,
CH), 3.68 (s, 1H, CH), 3.38 (s, 2H, CH2), 3.30 (d, J = 16.2 Hz,
1H, CH), 2.78 (d, J = 16.2 Hz, 1H, CH), 2.35−2.32 (m, 4H,
CH, CH3), 1.80 (brs, 1H, CH); 13C NMR (150 MHz, DMSO-
d6) δ 199.0, 174.0, 154.0, 144.3, 142.7, 137.7, 135.8, 134.6,
130.1, 129.2, 128.7, 128.4, 128.3, 128.1, 127.3, 126.9, 126.5,
125.2, 117.6, 13.9, 110.8, 79.8, 61.6, 53.6, 53.2, 52.3, 49.6, 43.7,
32.9, 21.1; IR (KBr) υ 3454, 3324, 3239, 3198, 3028, 2917,
2867, 2799, 2752, 2207, 1705, 1666, 1631, 1607, 1576, 1489,
1455, 1430, 1399, 1335, 1273, 1246, 1176, 1081, 1032, 985,
884, 804, 784 cm−1; MS (m/z) HRMS (ESI) Calcd. for
C39H34ClN4O2 ([M + H]+) 625.2365; Found: 625.2359.
General Procedure for the Synthesis of Compound
5a−5l. A mixture of vinyl malononitrile (1.0 mmol) and 3-
white solid, 88%, 0.504 g, mp 189.5−190.5 °C; H NMR
(600 MHz, DMSO-d6) δ 8.05 (d, J = 7.8 Hz, 2H, ArH), 7.59
(d, J = 7.2 Hz, 1H, ArH), 7.38−7.35 (m, 4H, ArH), 7.33−7.31
(m, 2H, ArH), 7.26−7.24 (m, 1H, ArH), 6.94 (t, J = 7.8 Hz,
1H, ArH), 6.71 (brs, 1H, ArH), 5.08 (d, J = 10.8 Hz, 1H, CH),
4.92−4.89 (m, 1H, CH), 4.83−4.80 (m, 1H, CH), 3.88 (s, 2H,
CH2), 3.11−3.07 (m, 1H, CH), 2.77 (d, J = 12.6 Hz, 1H, CH),
2.38 (s, 3H, CH3), 2.18 (d, J = 10.8 Hz, 1H, CH), 1.78 (t, J =
12.6 Hz, 1H, CH), 1.58 (d, J = 13.2 Hz, 1H, CH), 1.33−1.23
(m, 2H, CH2), 0.53 (s, 9H, CH3); 13C NMR (150 MHz,
DMSO-d6) δ 199.6, 185.6, 174.2, 144.9, 139.5, 134.5, 129.5,
129.4, 128.8, 128.7, 128.5, 128.3, 127.3, 127.2, 126.8, 114.5,
113.1, 112.3, 112.1, 111.1, 109.5, 83.0, 44.8, 42.8, 42.4, 34.1,
32.7, 31.8, 31.7, 31.2, 28.1, 27.2, 26.9, 26.8, 21.1; IR (KBr) υ
3036, 2968, 2871, 2229, 1707, 1682, 1606, 1488, 1452, 1411,
1366, 1345, 1287, 1259, 1223, 1185, 1138, 1023, 995, 969, 941,
898, 877, 854, 829, 813, 783, 768 cm−1; MS (m/z) HRMS
277
dx.doi.org/10.1021/co500006c | ACS Comb. Sci. 2014, 16, 271−280

ACS Combinatorial Science
Research Article
(ESI) Calcd for C37H36FN3NaO2 ([M + Na]+) 596.2684;
Found 596.2684.
2-(2-(1-(1-Benzyl-5-chloro-2-oxoindolin-3-yl)-2-oxo-2-p-
phenacylideneoxindole (1.0 mmol) and p-dimethylaminopyr-
idine (1.0 mmol) in ethanol (10.0 mL) was stirred at room
temperature for about 30 min. The resulting precipitate was
collected by filtration and washed with cold alcohol to give the
pure product for analysis.
tolylethyl)-4-tert-butylcyclohexylidene)malononitrile (5d):
1
white solid, 87%, 0.512 g, mp 172.9−173.1 °C; H NMR
(600 MHz, DMSO-d6) δ 8.00 (d, J = 8.4 Hz, 2H, ArH), 7.83 (s,
1H, ArH), 7.37−7.31 (m, 6H, ArH), 7.27−7.24 (m, 1H, ArH),
7.13 (d, J = 8.4 Hz, 1H, ArH), 6.69 (d, J = 8.4 Hz, 1H, ArH),
5.11 (dd, J1 = 11.7 Hz, J2 = 2.4 Hz, 1H, CH), 4.86 (s, 2H,
CH2), 3.92 (m, J = 9.0 Hz, 1H, CH), 3.85 (s, 1H, CH), 3.16−
3.11 (m, 1H, CH), 2.78 (d, J = 12.6 Hz, 1H, CH), 2.37 (s, 3H,
CH3), 2.19−2.17 (m, 1H, CH), 1.83−1.79 (d, J = 12.6 Hz, 1H,
CH), 1.56 (d, J = 13.8 Hz, 1H, CH), 1.34−1.25 (m, 2H, CH2),
0.52 (s, 9H, CH3); 13C NMR (150 MHz, DMSO-d6) δ 199.6,
187.1, 174.0, 166.7, 144.9, 143.6, 142.0, 135.8, 135.7, 134.4,
132.0, 129.7, 129.4, 128.9, 128.8, 128.7, 128.5, 128.3, 127.3,
127.2, 126.8, 126.1, 125.4, 120.9, 112.1, 111.2, 110.0, 83.1, 80.5,
45.5, 43.0, 42.7, 42.5, 43.0, 42.7, 42.5, 34.0, 32.7, 32.1, 31.8,
31.7, 31.3, 28.1, 27.2, 26.9, 26.7, 21.3, 21.1; IR (KBr) υ 3072,
3024, 2968, 2253, 1708, 1681, 1606, 1582, 1484, 1454, 1431,
1344, 1283, 1175, 1101, 1079, 994, 910, 812, 784 cm−1; MS
(m/z) HRMS (ESI) Calcd for C37H36ClN3NaO2 ([M + Na]+)
612.2388; Found 612.2390.
2-(3-(1-Benzyl-5-chloro-2-oxoindolin-3-yl)-4-oxo-1,4-di(p-
tolyl)butylidene)malononitrile (5g): white solid, 92%, 0.523 g,
1
mp 152.3−154.6 °C; H NMR (600 MHz, DMSO-d6) δ 7.54
(d, J = 8.4 Hz, 2H, ArH), 7.38−7.37 (m, 2H, ArH), 7.35−7.32
(m, 6H, ArH), 7.29−7.26 (m, 3H, ArH), 7.20−7.18 (m, 2H,
ArH), 6.79 (d, J = 8.4 Hz, 1H, ArH), 4.96−4.87 (m, 2H, CH2),
4.32−4.30 (m, 1H, CH), 3.96 (d, J = 3.0 Hz, 1H, CH), 3.58
(dd, J1 = 14.8 Hz, J2 = 8.4 Hz, 1H, CH), 3.39 (dd, J1 = 14.8 Hz,
J2 = 5.8 Hz, 1H, CH), 2.38 (s, 3H, CH3), 2.36 (s, 3H, CH3);
13C NMR (150 MHz, DMSO-d6) δ 198.6, 177.5, 174.6, 144.5,
142.6, 142.2, 135.9, 132.7, 130.7, 129.5, 129.3, 128.6, 128.3,
128.0, 127.6, 127.4, 127.2, 126.1, 124.2, 113.2, 112.5, 110.4,
84.6, 45.4, 44.7, 43.0, 35.2, 21.1, 21.0 ; IR (KBr) υ: 3062, 2028,
2922, 2230, 1725, 1679, 1609, 1584, 1484, 1436, 1375, 1343,
1289, 1245, 1215, 1166, 1120, 1080, 1014, 973, 939, 917, 890,
826, 809, 779 cm−1; MS (m/z) HRMS (ESI) Calcd for
C36H29ClN3O2 ([M + H]+) 570.1948; Found 570.1946.
2-(3-(1-Benzyl-5-fluoro-2-oxoindolin-3-yl)-4-oxo-1,4-di(p-
tolyl)butylidene)malononitrile (5h): white solid, 90%, 0.498 g,
mp 135.8−138.6 °C; 1H NMR (600 MHz, CDCl3) δ 7.71 (d, J
= 8.4 Hz, 2H, ArH), 7.35−7.29 (m, 5H, ArH), 7.24−7.20 (m,
6H, ArH), 6.92−6.89 (m, 1H, ArH), 6.85 (d, J = 7.8 Hz, 1H,
ArH), 6.69 (dd, J1 = 8.5 Hz, J2 = 4.6 Hz, 1H, ArH), 5.11 (d, J =
15.6 Hz, 1H, CH), 4.79 (d, J = 15.6 Hz, 1H, CH), 4.31−4.29
(m, 1H, CH), 3.80 (brs, 1H, CH), 3.45 (dd, J1 = 15.0 Hz, J2 =
8.3 Hz, 1H, CH), 2.69 (dd, J1 = 15.0 Hz, J2 = 4.7 Hz, 1H, CH),
2.40 (s, 3H, CH3), 2.38 (s, 3H, CH3); 13C NMR (150 MHz,
CDCl3) δ: 198.2, 175.7 (d, J = 313.5 Hz), 172.7 (d, J = 240.4
Hz), 145.2, 143.2, 139.6, 135.4, 132.2, 130.7, 129.9 (d, J = 12.6
Hz), 128.6, 128.0, 127.9, 127.4, 125.5 (d, J = 8.4 Hz), 115.5 (d,
J = 23.5 Hz), 113.2 (d, J = 25.2 Hz), 112.9, 112.3, 110.2 (d, J =
7.8 Hz), 85.6, 47.1, 45.2, 44.4, 33.5, 21.6 (d, J = 20.1 Hz); IR
(KBr) υ: 3044, 2911, 1130, 1718, 1682, 1608, 1578, 1492,
1451, 1348, 1268, 1228, 1181, 1136, 1019, 966, 929, 882, 820
cm−1; MS (m/z) HRMS (ESI) Calcd for C36H29FN3O2 ([M +
H]+) 554.2244; Found 554.2236.
2-(2-(1-(1-Benzyl-2-oxoindolin-3-yl)-2-(4-methoxyphenyl)-
2-oxoethyl)cycloheptylidene)malononitrile (5e): white solid,
1
78%, 0.412 g, mp 192.6−193.4 °C; H NMR (600 MHz,
DMSO-d6) δ 7.84 (d, J = 7.8 Hz, 2H, ArH), 7.50−7.46 (m, 3H,
ArH), 7.35−7.33 (m, 2H, ArH), 7.28−7.26 (m, 1H, ArH),
7.06−7.03 (m, 1H, ArH), 7.01 (d, J = 7.8 Hz, 2H, ArH), 6.85−
6.82 (m, 1H, ArH), 6.71 (d, J = 7.8 Hz, 1H, ArH), 4.98−4.91
(m, 2H, CH2), 4.83 (d, J = 7.8 Hz, 1H, CH), 4.09 (brs, 1H,
CH), 4.04 (s, 1H, CH), 3.82 (s, 3H, OCH3), 2.90−2.86 (m,
1H, CH), 2.26 (brs, 1H, CH), 1.80−1.71 (m, 3H, CH2, CH),
1.35−1.32 (m, 1H, CH), 1.23−1.21 (m, 1H, CH), 0.95−0.93
(m, 1H, CH); 13C NMR (150 MHz, DMSO-d6) δ 197.6, 175.4,
163.5, 143.3, 136.5, 130.3, 128.4, 127.8, 127.4, 127.2, 123.4,
121.5, 114.1, 111.5, 111.3, 108.7, 86.7, 55.6, 49.5, 45.6, 42.7,
32.1, 30.0, 29.0, 28.8, 24.2; IR (KBr) υ 3466, 3033, 2926, 2855,
2227, 1699, 1674, 1598, 1513, 1488, 1467, 1351, 1310, 1264,
1232, 1212, 1172, 1105, 1020, 997, 952, 922, 892, 847, 782, 753
cm−1; MS (m/z) HRMS (ESI) Calcd for C34H31N3NaO3 ([M
+ Na]+) 552.2258; Found 552.2258.
2-(3-(1-Benzyl-2-oxoindolin-3-yl)-4-(4-chlorophenyl)-4-
2-(2-(1-(1-Butyl-2-oxoindolin-3-yl)-2-oxo-2-p-tolylethyl)-
oxo-1-p-tolylbutylidene)malononitrile(5i): white solid, 89%,
0.494 g, mp 136−138 °C; H NMR (600 MHz, DMSO-d6) δ
1
cycloheptylidene)malononitrile (6f): white solid, 90%, 0.431 g,
1
mp 223.7−224.5 °C; H NMR (600 MHz, DMSO-d6) δ 7.71
7.62 (d, J = 8.4 Hz, 2H, ArH), 7.52 (d, J = 7.8 Hz, 2H, ArH),
7.38−7.31 (m, 2H, ArH), 7.35−7.32 (m, 4H, ArH), 7.31−7.26
(m, 3H, ArH), 7.15 (t, J = 7.8 Hz, 1H, ArH), 7.07 (d, J = 7.8
Hz, 1H, ArH), 6.91 (t, J = 7.8 Hz, 1H, ArH), 6.82 (t, J = 7.8 Hz,
1H, ArH), 4.96 (d, J = 15.6 Hz, 1H, CH), 4.87 (d, J = 15.6 Hz,
1H, CH), 4.26−4.23 (m, 1H, CH), 3.98 (d, J = 3.0 Hz, 1H,
CH), 3.54 (dd, J1 = 14.9 Hz, J2 = 8.8 Hz, 1H, CH), 3.30 (dd, J1
= 14.9 Hz, J2 = 5.2 Hz, 1H, CH), 2.37 (s, 3H, CH3); 13C NMR
(150 MHz, CDCl3) δ 197.6, 176.5, 174.8, 143.5, 143.2, 140.5,
135.6, 133.1, 130.7, 130.1, 130.0, 129.8, 129.7, 129.5, 129.2,
129.0, 128.9, 128.0, 127.9, 127.8, 127.5, 127.4, 124.9, 123.6,
123.2, 122.8, 112.9, 112.3, 109.7, 109.6, 85.8, 46.8, 46.6, 46.4,
45.5, 44.3, 43.9, 36.6, 33.4, 21.6 ; IR (KBr) υ 3060, 3026, 2230,
1715, 1690, 1591, 1490, 1446, 1358, 1263, 1204, 1169, 1093,
1012, 966, 937, 821, 747 cm−1; MS (m/z) HRMS (ESI) Calcd
for C35H27ClN3O2 ([M + H]+) 556.1792; Found 556.1792.
2-(3-(1-Butyl-5-chloro-2-oxoindolin-3-yl)-4-oxo-1,4-di(p-
tolyl)butylidene)malononitrile (5j): white solid, 86%, 0.460 g,
(d, J = 4.2 Hz, 2H, ArH), 7.48 (brs, 1H, ArH), 7.29 (d, J = 4.8
Hz, 2H, ArH), 7.13 (brs, 1H, ArH), 6.92 (d, J = 4.8 Hz, 1H,
ArH), 6.84 (brs, 1H, ArH), 4.79 (d, J = 6.0 Hz, 1H, CH), 4.04
(s, 1H, CH), 3.88 (s, 1H, CH), 3.70 (d, J = 17.4 Hz, 2H, CH2),
2.84 (brs, 1H, CH), 2.50 (brs, 1H, CH), 2.34 (s, 3H, CH3),
2.19 (brs, 1H, CH), 2.06 (brs, 1H, CH), 1.79 (brs, 2H, CH2),
1.71−1.70 (m, 1H, CH), 1.62−1.61 (m, 2H, CH2), 1.40−1.39
(m, 2H, CH2), 1.32−1.31 (m, 1H, CH), 1.21−1.19 (m, 1H,
CH), 0.94 (brs, 4H, CH, CH3); 13C NMR (150 MHz, DMSO-
d6) δ 198.8, 188.4, 175.1, 144.2, 143.8, 134.9, 129.4, 127.9,
127.0, 123.4, 121.2, 111.4, 111.3, 108.1, 86.8, 49.7, 45.5, 41.9,
32.1, 29.9, 29.0, 28.8, 24.2, 21.1, 19.5, 13.7; IR (KBr) υ: 2931,
2826, 2228, 1701, 1678, 1608, 1486, 1466, 1352, 1273, 1231,
1205, 1185, 1135, 1096, 1024, 956, 921, 831, 793, 772 cm−1;
MS (m/z): HRMS (ESI) Calcd for C31H33N3NaO2 ([M +
Na]+) 502.2465. Found 502.2467.
General Procedure for the Synthesis of Compounds
5g−5l. A mixture of vinyl malononitrile (1.0 mmol) and 3-
1
mp 139.9−141.1 °C; H NMR (600 MHz, DMSO-d6) δ 7.53
278
dx.doi.org/10.1021/co500006c | ACS Comb. Sci. 2014, 16, 271−280

ACS Combinatorial Science
Research Article
(d, J = 8.4 Hz, 2H, ArH), 7.34−7.30 (m, 4H, ArH), 7.28 (dd, J1
= 8.4 Hz, J2 = 1.8 Hz, 1H, ArH), 7.26 (d, J = 8.4 Hz, 2H, ArH),
7.13 (brs, 1H, ArH), 7.02 (d, J = 8.4 Hz, 1H, ArH), 4.24−4.21
(m, 1H, CH), 3.80 (d, J = 3.0 Hz, 1H, CH), 3.66 (t, J = 7.8 Hz,
2H, CH), 3.49 (dd, J1 = 14.8 Hz, J2 = 8.2 Hz, 1H, CH), 3.26
(dd, J1 = 14.8 Hz, J2 = 5.8 Hz, 1H, CH), 2.38 (s, 3H, CH3),
2.35 (s, 3H, CH3), 1.59−1.54 (m, 2H, CH2), 1.36−1.32 (m,
2H, CH2), 0.92 (t, J = 7.8 Hz, 3H, CH3); 13C NMR (150 MHz,
CDCl3) δ 198.2, 176.8, 174.2, 145.1, 143.1, 142.5, 132.1, 130.7,
129.9, 129.8, 129.0, 128.5, 128.2, 127.8, 125.8, 125.4, 112.9,
112.2, 109.8, 85.5, 46.8, 45.1, 40.4, 33.5, 29.4, 21.7, 21.6, 20.2,
13.7; IR (KBr) υ 2961, 2928, 2871, 2223, 1709, 1673, 1607,
1557, 1484, 1432, 1353, 1311, 1268, 1180, 1114, 930, 824, 781
cm−1; MS (m/z) HRMS (ESI) Calcd for C33H31ClN3O2 ([M +
H]+) 536.2105; Found 536.2103.
have been deposited at the Cambridge Crystallographic
Database Centre.
AUTHOR INFORMATION
Corresponding Author
*E-mail: cgyan@yzu.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (Grant No. 21172189) and the
Priority Academic Program Development of Jiangsu Higher
Education Institutions.
2-(3-(1-benzyl-5-chloro-2-oxoindolin-3-yl)-4-(4-methyl-
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white solid, 85%, 0.501g, mp 154.2−156.6 °C; H NMR (600
MHz, DMSO) δ: 7.62 (d, J = 8.4 Hz, 2H, ArH), 7.59 (d, J = 7.8
Hz, 2H, ArH), 7.50 (d, J = 8.4 Hz, 2H, ArH), 7.39 (d, J = 7.2
Hz, 2H, ArH), 7.34 (t, J = 7.2 Hz, 2H, ArH), 7.28 (d, J = 7.8
Hz, 3H, ArH), 7.25 (s, 1H, ArH), 7.19 (d, J = 7.8 Hz, 1H,
ArH), 6.78 (d, J = 8.4 Hz, 1H, ArH), 4.96−4.89 (m, 2H, CH),
4.36−4.33 (m, 1H, CH), 3.97 (d, J = 2.4 Hz, 1H, CH), 3.62
(dd, J1 = 14.8 Hz, J2 = 8.1 Hz, 1H, CH), 3.47 (dd, J1 = 14.8 Hz,
J2 = 6.1 Hz, 1H, CH), 2.37 (s, 3H, CH3); 13C NMR (150 MHz,
CDCl3) δ: 197.8, 175.5, 174.5, 145.5, 142.1, 138.6, 135.1, 131.9,
130.0, 129.7, 129.6, 129.4, 129.2, 129.0, 128.6, 128.4, 128.1,
127.4, 127.3, 125.4, 112.3, 111.8, 110.6, 86.9, 47.0, 46.3, 46.0,
45.0, 44.4, 33.6, 21.8; IR (KBr) υ: 3063, 3030, 2925, 2231,
2015, 1723, 1679, 1609, 1587, 1486, 1436, 1405, 1344, 1269,
1244, 1218, 1168, 1120, 1091, 1012, 938, 918, 891, 838, 814,
799 cm−1; MS (m/z): HRMS (ESI) Calcd. for C35H26Cl2N3O2
([M+H]+): 590.1402. Found: 590.1393.
2-(3-(1-Benzyl-2-oxoindolin-3-yl)-4-oxo-1,4-di(p-
methoxyphenyl)butylidene)malononitrile 5l: white solid,
1
88%, 0.499 g, mp 140.8−142.6 °C; H NMR (600 MHz,
CDCl3) δ 7.67 (d, J = 8.4 Hz, 2H, ArH), 7.43 (d, J = 7.8 Hz,
2H, ArH), 7.39 (d, J = 7.8 Hz, 2H, ArH), 7.34 (t, J = 7.2 Hz,
2H, ArH), 7.27 (t, J = 7.2 Hz, 1H, ArH), 7.14 (t, J = 7.2 Hz,
1H, ArH), 7.08−7.06 (m, 3H, ArH), 6.99 (d, J = 7.8 Hz, 2H,
ArH), 6.91 (t, J = 7.2 Hz, 1H, ArH), 6.82 (d, J = 7.8 Hz, 1H,
ArH), 4.98 (d, J = 15.6 Hz, 1H, CH), 4.88 (d, J = 15.6 Hz, 1H,
CH), 4.26−4.25 (m, 1H, CH), 3.94 (s, 1H, CH), 3.84 (s, 3H,
OCH3), 3.82 (s, 3H, OCH3), 3.51 (dd, J1 = 14.7 Hz, J2 = 9.0
Hz, 1H, CH), 3.26 (dd, J1 = 14.7 Hz, J2 = 4.8 Hz, 1H, CH); 13C
NMR (150 MHz, CDCl3) δ 197.0, 176.1, 175.1, 164.1, 162.8,
143.5, 135.7, 130.8, 130.0, 129.0, 128.9, 127.9, 127.7, 127.5,
125.6, 125.1, 123.9, 123.1, 114.6, 114.3, 113.5, 112.7, 109.5,
84.1, 55.6, 55.5, 47.2, 45.2, 44.3, 33.2; IR (KBr) υ 3016, 2935,
2841, 2225, 1699, 1672, 1604, 1574, 1542, 1510, 1488, 1466,
1434, 1365, 1341, 1301, 1267, 1231, 1196, 1176, 1120, 1074,
1025, 949, 861, 830, 762 cm−1; MS (m/z) HRMS (ESI) Calcd
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for all compounds. This
material is available free of charge via the Internet at http://
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(CCDC 971476), 3h (CCDC 971477), 4e (CCDC 971478),
5a (CCDC 971472), 5e (CCDC 971473), 5i (CCDC 971474)
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