Efficient catalyst-free one-pot three-component synthesis of novel spirooxindole derivatives, and their cytotoxic activities

Article abstract of DOI:10.1055/s-0033-1341028

A simple and efficient one-pot approach for assembling novel spiro[indolepyranopyrrole] derivatives was developed and used to prepare a series of biologically important compounds. The reaction was easily performed with high efficiency under very simple and mild conditions without any catalysts and it gave good yields, avoiding time-consuming costly synthesis and laborious workup and purification of products. The cytotoxic activities of these new spiro[indolepyranopyrrole] derivatives were evaluated in vitro. Most of the tested compounds exhibited significant cytotoxicities to Raji cell lines. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341028

PAPER
▌1389
paper
Efficient Catalyst-Free One-Pot Three-Component Synthesis of Novel
Spirooxindole Derivatives, and Their Cytotoxic Activities
Spirooxindole Derivatives
Chao Han,a Tao Zhang,a,b Anqi Zhang,a Dandan Wang,a Weimin Shi,a Jingchao Tao*a
a
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450052, Henan, P. R. of China
b
School of Pharmacy, Xinxiang Medical University, Xinxiang 453003, Henan, P. R. of China
Fax +86(371)67767200; E-mail: jctao@zzu.edu.cn
Received: 13.12.2013; Accepted after revision: 26.02.2014
algesic, myorelaxant,13 antitumor,14 and anti-HIV activi-
ties.15 There have been many reports16 on syntheses of
spiroindoline derivatives containing 4H-pyran moieties
by means of multicomponent reactions. Several synthetic
Abstract: A simple and efficient one-pot approach for assembling
novel spiro[indolepyranopyrrole] derivatives was developed and
used to prepare a series of biologically important compounds. The
reaction was easily performed with high efficiency under very sim-
ple and mild conditions without any catalysts and it gave good spiro heterocyclic compounds containing both indole and
yields, avoiding time-consuming costly synthesis and laborious
workup and purification of products. The cytotoxic activities of
these new spiro[indolepyranopyrrole] derivatives were evaluated in
tance of such compounds, we became interested in
vitro. Most of the tested compounds exhibited significant cytotox-
icities to Raji cell lines.
pyran moieties possess anticonvulsant, analgesic, herbi-
cidal, and antimicrobial activities.17 Because of the impor-
developing an efficient method for the synthesis of spiro-
indoline derivatives containing a 4H-pyran-fused pyrro-
Key words: polycyclic compounds, heterocyclic compounds, spiro
lidinone substructure by means of a three-component
compounds, multicomponent reactions, cytotoxins
condensation reaction, to provide novel structurally and
biologically interesting compounds for drug-discovery re-
search.
The development of highly efficient chemical reaction se-
Efficient, practical, and environmentally friendly synthe-
quences is a major challenge in modern drug discovery.
sis methods can reduce amounts of toxic wastes and by-
Recently developed multicomponent reactions offer a
products arising from chemical processes. Catalyst-free
wide range of possibilities for the efficient construction of
highly complex molecules by single procedural steps.1,2
Furthermore, convenient methods for constructing mole-
cules containing two or more separate biologically inter-
esting scaffolds fused in various sequences are of great
value to both organic and medical chemists.3
reactions have received particular attention in recent
years.18,19 However, there are few reports20 on syntheses
of spirooxindole derivatives under catalyst-free condi-
tions. In connection with our studies on the development
of multicomponent reactions, we report an efficient ap-
proach to a novel spiro[indolepyranopyrrole] derivatives
of chemical and, potentially, biological importance. The
compounds were prepared by the reaction of a tetramic
acid, an isatin, and malononitrile as starting materials in
ethanol. The main difference between our method and
other previously reported methods is the absence in our
method of any organic or metallic catalyst, as generally
used in previous syntheses of analogues of the spiroin-
doline compounds.
Spirocyclic moieties are present in many natural prod-
ucts.4 Because of their highly constrained nature, spiro
compounds have attracted considerable interest from me-
dicinal chemists.5 Spirooxindole heterocycles, in which a
simple heterocycle is linked to an indole ring through a
spiro atom in the 3-position, have been reported to show
an increased spectrum of biological activities,6–8 and these
compounds might be capable of being synthesized by
multicomponent methods.9 The spirooxindole system is a
core structure in many pharmacological agents and natu-
ral alkaloids, for example, spirotryprostatin B, pteropo-
dine, and isopteropodine.10 Therefore, heterocyclic
spiroindoles are attractive targets in terms of both organic
synthesis and the construction of drug candidates.11 More-
over, it is well known that derivatives of tetramic acid
(2,4-pyrrolidinedione) are important in medicinal chemis-
try, as they display antineoplastic, antiviral, HIV-1 prote-
ase-inhibiting, insecticidal, and antibacterial properties.12
Conventional methods for the three-component condensa-
tion of isatin with an active methylene component and a
1,3-dicarbonyl compound involve the use of a catalyst in
an organic or aqueous medium, microwave heating, the
use of an electro-generated base, or water-mediated sur-
factant catalysis. However, despite their merits, most of
the reported methods have drawbacks such as the use of
poisonous organic additives or the need for expensive cat-
alysts. Therefore, in developing practical methods for
one-pot three-component condensations, environmental
and economic impacts of the reactions must be among the
foremost considerations.
Compounds containing the pyran structural motif exhibit
a wide range of biological activities, such as diuretic, an-
Because some the three-component condensation of isat-
ins with other active components can be carried out in
aqueous media, we initially attempted a one-pot reaction
SYNTHESIS 2014, 46, 1389–1398
Advanced online publication: 26.03.2014
DOI: 10.1055/s-0033-1341028; Art ID: SS-2013-H0806-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

1390
C. Han et al.
PAPER
of N-benzyltetramic acid (1a), isatin (2a), and malononi- greatly simplifying the reaction procedure and the workup
trile (3) in water under catalyst-free conditions as a model in both large- and small-scale syntheses. Therefore, the
system. Unfortunately, the three-component reaction in optimal conditions that we identified for the catalyst-free
the absence of a catalyst did not occur favorably in water, three-component reaction have practical advantages and
even at the reflux, and product 4a was obtained in less are environmentally friendly.
than 30% yield after six hours. We then focused our atten-
By using the optimized reaction conditions, we prepared
tion on the use of some common organic solvents. The re-
a series of spirooxindole derivatives in good yields
actions were carried out in various solvents at various
through the one-pot, catalyst-free approach (Table 2). In
temperatures in the absence of any catalyst or additive.
particular, we assessed the method as a means of con-
structing a product library by using various substituted
The results obtained are listed in Table 1.
isatins, including isatins substituted with electron-with-
drawing or electron-donating groups, together with vari-
ous tetramic acid derivatives and malononitrile as starting
materials. The results obtained indicated that the method
Table 1 Optimization of Conditions for the Model Reaction
BnN
OH
O
O
O
CN
CN
solvent
NH2
reflux, 3 h
O
O
N
N
CN
O
Bn
H
Table 2 Synthesis of Spirooxindole Derivatives 4
N
H
OH
R3
O
1a
2a
3
4a
R1
O
Entrya
Solvent
Temp (°C) Time (h) Yieldb (%)
CN
N
EtOH
O
O
O
N
R2
N
R1
reflux, 3 h
R3
CN
NH2
1
2
H2O
100
66
84
82
110
61
65
79
78
78
78
60
30
80
6
3
3
3
3
3
3
3
3
3
6
3
3
3
<30
56
50
60
60
55
76
75
80
94
94
85
75
30
1
2
3
CN
O
THF
N
R2
4
3
DCE
4
MeCN
toluene
CHCl3
MeOH
Entrya
R1
R2
R3
Product Yield (%)
5
1
2
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Ph
Ph
Bn
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
94
93
92
90
90
91
92
92
90
91
91
93
92
90
90
91
91
91
90
6
Me
Et
Bu
Bn
H
7
3
8
80% EtOH–H2O
95% EtOH–H2O
EtOH
4
9
5
10
11
12
13
14
6
4-Cl
4-Br
5-Me
5-F
EtOH
7
H
4g
4h
4i
EtOH
8
H
EtOH
9
H
neat
10
11
12
13
14
15
16
17
18
19b
H
5-Cl
5-Br
5-NO2
6- Cl
6- Br
5,7-Br2
7-F3C
H
4j
a Reaction conditions: isatin (1a; 1 mmol), malononitrile (3a; 1
mmol), N-benzyltetramic acid (2a; 1 mmol), reflux.
b Isolated yield.
H
4k
4l
H
H
4m
4n
4o
4p
4q
4r
4a
Reactions in organic solvents all gave better yields than
that obtained in water (Table 1, entries 1–10). The yields
of the reactions in protonated organic solvents (entries 7–
10) were markedly higher than those in nonprotonated
solvents (entries 2–6). Ethanol was the best solvent for the
reaction, and the presence of water in ethanol was disad-
vantageous to the reaction (entries 8–10). Prolonging the
reaction time from three to six hours did not improve the
yield (entry 11). The results for reactions in ethanol at var-
ious temperatures indicated that higher temperatures sig-
nificantly favored the reaction. More importantly, all the
starting materials were soluble in ethanol, whereas the
spirooxindole products were all insoluble in this solvent,
H
H
H
H
H
5-O2N
H
H
a The general reaction was carried out on a 1.0-mmol scale for all the
three reactants.
b Carried out on a 10-mmol scale for all the three reactants.
Synthesis 2014, 46, 1389–1398
© Georg Thieme Verlag Stuttgart · New York

PAPER
Spirooxindole Derivatives
1391
Table 3 Synthesis of Chiral Spirooxindole Derivatives
Ph
Ph
S
S
N
N
R3
O
O
OH
R3
R3
O
O
O
NH2
NH2
S
R
CN
EtOH
O
CN
O
CN
O
reflux
N
O
CN
N
R2
2
N
R2
(S,S)-4
N
R2
(S,R)-4
Ph
1b
3
20
Product
R2
H
R3
H
Yield (%)
91
Config.
dra
[α]D
4s
4t
S,S
S,R
1:1
1:1
1:1
+171.8
+122.3
Me
H
H
90
90
S,S
S,R
+176.4
+206.7
4u
Me
S,S
S,R
+148.6
+90.2
a By 1H NMR spectroscopy of the crude product.
should be applicable to syntheses of libraries of com- To verify the absolute configuration of the spirooxindole
pounds with a high degree of diversity. The structures of derivatives, one of the two isomers of product 4u was ob-
all the products 4 were unambiguously characterized by tained as a single crystal and selected as a representative
means of IR, 1H NMR, and 13C NMR spectroscopy and by compound for X-ray crystallographic characterization;
electrospray-ionization high-resolution mass spectrome- this confirmed that the compound was the S,S-diastereo-
try.
isomer (Figure 1). With this isomer as a reference com-
pound, two pairs of other spirooxindole derivatives, 4s
and 4t, were also separated and characterized. The diaste-
reoisomeric ratio (dr) was determined by H NMR spec-
troscopy of the crude samples of 4s, 4t, and 4u.
To check the applicability of our method on a larger scale,
we examined the reaction on a 10-mmol scale, and we ob-
served a similar behavior (Table 2, entry 19). This method
should, therefore, find extensive use in the fields of com-
binatorial chemistry and drug discovery.
1
Generally, the spirooxindole derivatives formed by the
three-component one-pot reaction always possess a ste-
reogenic quaternary carbon center. There have been some
reports on asymmetric syntheses of spirooxindole deriva-
tives.21 Our successful development of the three-compo-
nent reaction for the synthesis of spirooxindole
derivatives enabled us to develop a strategy for preparing
the two diastereoisomers of the spirooxindole derivatives.
Because (1R)- and (1S)-(1-phenylethyl)amine are widely
used in separating diastereoisomers,22 we prepared 1-
[(1S)-1-phenylethyl]pyrrolidine-2,4-dione to permit di-
rect chromatographic separation of the two diastereoiso-
meric spirooxindole derivatives. As expected, the two
diastereoisomers (R,S and S,S) of the spirooxindole deriv-
atives were efficiently separated (Table 3).
Figure 1 The molecular structure of spirooxindole (S,S)-4u
As expected, the catalyst-free one-pot three-component
reaction method was also shown to be applicable to other
O
O
H
O
N
O
O
O
HN
NH
NH2
NH2
CN
O
HN
O
O
CN
O
O
O
O
CN
O
O
O
CN
EtOH, reflux
91%
N
EtOH, reflux
90%
N
N
H
H
H
10
2a
3
9
Scheme 1 Extended application of the catalyst-free reaction conditions
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1389–1398

1392
C. Han et al.
PAPER
OH
O
O
CN
CN
N
BnN
O
Bn
CN
1a
CN
CN
O
O
N
O
CN
3
H
O
N
H
2a
N
H
5
6
BnN
OH
O
O
BnN
O
BnN
O
NH
CN
NH2
CN
C
N
O
CN
O
O
O
N
H
N
H
N
H
4a
8
7
Scheme 2 Plausible mechanism for the reaction of isatin, malononitrile, and N-benzyltetramic acid
1,3-dicarbonyl compounds. When the tetramic acid 1 was To survey the bioactivities of this class of novel com-
replaced with tetronic acid or barbituric acid, the desired pounds, all the spirooxindole derivatives 4, 9, and 10 were
spirooxindole products 9 and 10, respectively, were ob- subjected in vitro cytotoxicity tests with the Raji cell line,
tained in good yields under the same reaction condition with cisplatin as a positive control. The IC50 values for
(Scheme 1).
growth inhibition of the Raji cell line in the presence of
4a–u, 9, and 10 are listed in Table 4. Several interesting
structure–activity relationships were identified by analy-
ses of the IC50 values of these compounds.
A proposed mechanism for the formation of the spiroox-
indole derivatives 4 is summarized in Scheme 2. The cat-
alyst-free three-component reaction represents a typical
cascade reaction in which isatin (2a) first condenses with In general, most of the tested compounds exhibited obvi-
malononitrile (3) to afford the derivative 5 by a Knoeve- ous cytotoxicity to Raji cell lines. Among the compounds
nagel condensation. Nucleophilic attack by the active tet- tested, 4n (R1 = Bn; R2 = H; R3 = 6-Br) showed the most
ramic acid 1a on the electron-deficient C=C double bond potent cytotoxicity, with an IC50 value of 17.56 μM,
then occurs to give intermediate 6 in equilibrium with its which was almost equal to that of cisplatin under the same
enol form 7. This leads to intramolecular nucleophilic at- conditions. Replacement of the N-hydrogen atom by var-
tack by the enol oxygen atom on the cyano group to give ious alkyl group did not affect the cytotoxicity markedly,
the spirooxindole imine 8, which then tautomerizes to the indicating that this is an unimportant subunit (4a vs 4b–e).
expected product 4a.
Note that when R1 was changed from benzyl group to an
α-phenylethyl group, the cytotoxicity of the spirooxindole
derivatives to the Raji cell line decreased markedly (4a vs
Table 4 Cytotoxic Activities of Compounds 4a–u, 9, and 10 to the Raji Cell Line In Vitro
Compound
IC50a (μM)
Compound
IC50a (μM)
Compound
IC50a (μM)
4a
4b
4c
4d
4e
4f
23.87
24.68
25.88
28.18
25.68
74.81
39.22
32.83
30.74
4j
33.34
28.25
84.97
25.43
17.56
61.89
25.01
32.21
87.67
(S,S)-4s
(S,R)-4s
(S,S)-4t
(S,R)-4t
(S,S)-4u
(S,R)-4u
9
62.21
62.30
70.66
70.87
65.45
65.69
35.29
42.68
17.32
4k
4l
4m
4n
4o
4p
4q
4r
4g
4h
4i
10
cisplatin
a Assayed by exposure for 48 h.
Synthesis 2014, 46, 1389–1398
© Georg Thieme Verlag Stuttgart · New York

PAPER
Spirooxindole Derivatives
1393
IR (KBr): 3423, 3246, 3138, 2198, 1710, 1680, 1656, 1599, 1367,
704 cm–1.
4s; 4b vs 4t). The electronic characters of various substit-
uents as well as their position on the benzene ring had a
marked effect on the cytotoxicity of the corresponding
products to the Raji cell line. Although strongly electron-
withdrawing groups, such as nitro, produced a marked de-
crease in the bioactivity (4r, R3 = 5-NO2; R1 = Ph;
IC50 = 87.67 μM; 4l, 5-NO2; R1 = Bn; IC50 = 84.97 μM),
the 7-trifluoromethyl-substituted spirooxindole derivative
showed a contrary result (4p, IC50 = 25.01 μM). The cyto-
toxicities of halo-substituted compounds were markedly
dependent on the position of the halo group on the ben-
zene ring. Generally, the trends in cytotoxicity followed
the sequence 6-X > 5-X > 4-X (X = Br, Cl; i.e. 4n > 4k >
4g; 4m > 4j > 4f). In addition, the bromo derivatives all
showed much higher cytotoxicities than the correspond-
ing chloro derivatives. Furthermore, compounds 9 and 10,
which have different heterocycles fused to the spiro pyran
ring, did not show noteworthy cytotoxicities, suggesting
that the tetramic acid subunit might also be beneficial to
cytotoxicity. Spirooxindole derivatives 4 with moderate
to strong cytotoxicities might become promising antitu-
mor drug candidates after further structural modifications
and biological investigations.
1H NMR (400 MHz, DMSO-d6): δ = 4.20 (s, 2 H, CH2), 4.38 (d,
J = 15.6 Hz, 1 H, CH2), 4.44 (d, J = 15.6 Hz, 1 H, CH2), 6.85 (d,
J = 7.6 Hz, 1 H, ArH), 6.97 (t, J = 7.2 Hz, 1 H, ArH), 7.13 (m, 3 H,
ArH), 7.24 (m, 2 H, ArH), 7.32 (t, J = 7.2 Hz, 2 H, ArH), 7.44 (s, 2
H, NH2), 10.58 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 176.72, 165.98, 161.28,
160.77, 142.00, 137.38, 132.16, 128.90, 128.59, 127.41, 127.25,
124.33, 122.07, 117.68, 109.56, 106.57, 56.61, 47.39, 46.62, 44.54.
MS (ESI): m/z [M + H]+ calcd for C22H17N4O3: 385.1; found: 385.0.
HRMS (ESI): m/z [M + H]+ calcd for C22H17N4O3: 385.1295; found:
385.1294.
2′-Amino-6′-benzyl-1-methyl-2,5′-dioxo-1,2,6′,7′-tetrahydro-
5′H-spiro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carbonitrile
(4b)
White powder; yield: 0.370 g (93%); mp 241–242 °C.
IR (KBr): 3433, 3268, 3121, 2196, 1711, 1683, 1633, 1594, 1362,
705 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 3.17 (s, 3 H, CH3), 4.22 (s, 2
H, CH2), 4.37 (d, J = 15.2 Hz, 1 H, CH2), 4.43 (d, J = 15.2 Hz, 1 H,
CH2), 7.07 (m, 2 H, ArH), 7.15 (m, 2 H, ArH), 7.21 (m, 1 H, ArH),
7.26 (m, 1 H, ArH), 7.33 (m, 3 H, ArH), 7.49 (s, 2 H, NH2).
13C NMR (100 MHz, DMSO-d6): δ = 175.13, 165.85, 161.38,
160.91, 143.39, 137.33, 131.34, 129.12, 128.59, 127.41, 127.27,
124.03, 122.85, 117.54, 108.55, 106.43, 56.19, 47.46, 46.27, 44.52,
26.45.
In summary, we have developed an efficient, catalyst-
free, and convenient method for the preparation of spiro-
oxindoles derivatives in ethanol as a solvent. To the best
of our knowledge, this is the first example of a multicom-
ponent reaction for the synthesis of spiroindoline deriva-
tives containing a 4H-pyran-fused pyrrolidinone subunit.
The present green synthesis shows attractive characteris-
tics, such as one-pot conditions, short reaction times, easy
workup and purification, and reduced waste production,
MS (ESI): m/z [M + H]+ calcd for C23H19N4O3: 399.1; found: 398.9.
HRMS (ESI): m/z [M + H]+ calcd for C23H19N4O3: 399.1452; found:
399.1452.
2′-Amino-6′-benzyl-1-ethyl-2,5′-dioxo-1,2,6′,7′-tetrahydro-
5′H-spiro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carbonitrile (4c)
White powder; yield: 0.379 g (92%); mp 248–250 °C.
without needing any catalyst or additive. The in vitro cy- IR (KBr): 3433, 3268, 3121, 2196, 1711, 1683, 1633, 1594, 1362,
705 cm–1.
totoxicities of these new spirooxindoles derivatives were
1H NMR (400 MHz, DMSO-d6): δ = 1.16 (t, J = 7.2 Hz, 3 H,
CH2CH3), 3.75 (m, 2 H, CH2CH3), 4.21 (s, 2 H, CH2), 4.40 (s, 2 H,
CH2), 7.04 (m, 1 H, ArH), 7.12 (m, 3 H, ArH), 7.20 (m, 1 H, ArH),
7.26 (m, 1 H, ArH), 7.32 (m, 3 H, ArH), 7.47 (s, 2 H, NH2).
13C NMR (100 MHz, DMSO-d6): δ = 174.70, 165.88, 161.39,
160.81, 142.36, 137.37, 131.67, 129.07, 128.58, 127.39, 127.24,
124.23, 122.60, 117.41, 108.64, 106.46, 56.40, 47.47, 46.13, 44.53,
34.49, 12.31.
investigated. Most of the tested compounds exhibited
moderate to strong cytotoxicities to Raji cell lines. Further
research and drug development on derivatives for cyto-
toxicity testing are ongoing in our laboratory, and the re-
sults will be reported in due course.
All reagents were obtained from commercial suppliers and used
without further purification. Commercial-grade solvents were dried
and purified by standard procedures. All the reactions were moni-
tored by TLC. 1H NMR and 13C NMR spectra were recorded on a
Bruker DPX 400 NMR spectrometer with TMS as an internal refer-
ence. Melting points were determined on a Beijing Keyi XT5 appa-
ratus and are uncorrected. IR spectra were recorded as KBr pellets
on a Thermo Nicolet (IR 200) spectrometer. High-resolution mass
spectra were recorded on a Waters Micromass Q-Tof Micro instru-
ment operated in the ESI mode. The optical rotations were mea-
sured by using a PerkinElmer model 343 polarimeter at 20 °C.
MS (ESI): m/z [M + H]+ calcd for C24H21N4O3: 413.2; found: 412.9.
HRMS (ESI): m/z [M + H]+ calcd for C24H21N4O3: 413.1608; found:
413.1593.
2′-Amino-6′-benzyl-1-butyl-2,5′-dioxo-1,2,6′,7′-tetrahydro-
5′H-spiro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carbonitrile
(4d)
White powder; yield: 0.396 g (90%); mp 225–22 °C.
IR (KBr): 3436, 3271, 3123, 2197, 1710, 1685, 1635, 1594, 1363,
757 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 0.89 (t, J = 7.6 Hz, 3 H,
CH2CH2CH2CH3), 1.38 (m, 2 H, CH2CH2CH2CH3), 1.61 (m, 2 H,
CH2CH2CH2CH3), 3.70 (m, 2 H, CH2CH2CH2CH3), 4.20 (s, 2 H,
CH2), 4.40 (s, 2 H, CH2), 7.04 (t, J = 7.2 Hz, 1 H, ArH), 7.08 (d,
J = 7.6 Hz, 1 H, ArH), 7.13 (d, J = 7.2 Hz, 2 H, ArH) 7.19 (d,
J = 7.2 Hz, 1 H, ArH), 7.25 (m, 1 H, ArH), 7.32 (m, 3 H, ArH), 7.47
(s, 2 H, NH2).
Spirooxindole Derivatives 4a–r; General Procedure
A mixture of tetramic acid 1a (1 mmol), isatin 2 (1 mmol), and
malononitrile (3; 1 mmol) in EtOH (2 mL) was stirred at reflux for
3 h. When the reaction was complete (TLC), the mixture was cooled
to r.t. The precipitated product was collected by filtration and
washed successively with H2O and cold EtOH.
2′-Amino-6′-benzyl-2,5′-dioxo-1,2,6′,7′-tetrahydro-5′H-spi-
ro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carbonitrile (4a)
White powder; yield: 0.361 g (94%); mp 224–226 °C.
13C NMR (100 MHz, DMSO-d6): δ = 175.05, 165.86, 161.40,
160.85, 142.86, 137.37, 131.53, 129.05, 128.58, 127.40, 127.25,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1389–1398

1394
C. Han et al.
PAPER
124.18, 122.56, 117.50, 108.71, 106.48, 56.48, 47.43, 46.20, 44.54,
39.39, 29.00, 19.25, 13.67.
MS (ESI): m/z [M + H]+ calcd for C26H25N4O3: 441.2; found: 441.0.
HRMS (ESI): m/z [M + H]+ calcd for C26H25N4O3: 441.1921; found:
441.1925.
2′-Amino-6′-benzyl-5-methyl-2,5′-dioxo-1,2,6′,7′-tetrahydro-
5′H-spiro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carbonitrile
(4h)
White powder; yield: 0.367 g (92%); mp 232–234 °C.
IR (KBr): 3347, 3290, 3151, 2194, 1710, 1683, 1650, 1594, 1364,
703 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.24 (s, 3 H, CH3), 4.17 (d,
J = 18.8 Hz, 1 H, CH2), 4.23 (d, J = 18.8 Hz, 1 H, CH2), 4.46 (d,
J = 15.6 Hz, 1 H, CH2), 4.36 (d, J = 15.6 Hz, 1 H, CH2), 6.73 (d,
J = 8.0 Hz, 1 H, ArH), 6.94 (s, 1 H, ArH), 7.02 (d, J = 8.0 Hz, 1 H,
ArH), 7.15 (d, J = 7.2 Hz, 2 H, ArH), 7.26 (t, J = 7.2 Hz, 1 H, ArH),
7.33 (t, J = 7.2 Hz, 2 H, ArH), 7.40 (s, 2 H, NH2), 10.46 (s, 1 H,
NH).
13C NMR (100 MHz, DMSO-d6): δ = 176.66, 166.03, 161.21,
160.72, 139.55, 137.38, 132.27, 130.92, 129.18, 128.58, 127.47,
127.27, 124.81, 117.72, 109.30, 106.69, 56.81, 47.39, 46.65, 44.58,
20.59.
2′-Amino-1,6′-dibenzyl-2,5′-dioxo-1,2,6′,7′-tetrahydro-5′H-spi-
ro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carbonitrile (4e)
White powder; yield: 0.427 g (90%); mp 203–206 °C.
IR (KBr): 3299, 3236, 3195, 2197, 1712, 1640, 1611, 1588, 1360,
750 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 4.25 (s, 2 H, CH2), 4.44 (s, 2
H, CH2), 4.94 (d, J = 16.0 Hz, 1 H, CH2), 4.99 (d, J = 16.0 Hz, 1 H,
CH2), 6.78 (d, J = 7.6 Hz, 1 H, ArH), 7.04 (t, J = 7.6 Hz, 1 H, ArH),
7.16 (d, J = 7.2 Hz, 2 H, ArH), 7.28 (m, 8 H, ArH), 7.44 (d, J = 7.2
Hz, 2 H, ArH), 7.54 (s, 2 H, NH2).
13C NMR (100 MHz, DMSO-d6): δ = 175.46, 165.95, 161.60,
160.94, 142.43, 137.35, 135.67, 131.44, 128.98, 128.60, 128.39,
127.40, 127.27, 127.18, 126.90, 124.27, 122.90, 117.70, 109.24,
106.37, 56.37, 47.50, 46.37, 44.58, 43.16.
MS (ESI): m/z [M + H]+ calcd for C23H19N4O3: 399.1; found: 398.9.
HRMS (ESI): m/z [M + H]+ calcd for C23H19N4O3: 399.1452; found:
399.1455.
MS (ESI): m/z [M + H]+ calcd for C29H23N4O3: 475.2; found: 475.9.
HRMS (ESI): m/z [M + H]+ calcd for C29H23N4O3: 475.1765; found:
2′-Amino-6′-benzyl-5-fluoro-2,5′-dioxo-1,2,6′,7′-tetrahydro-
5′H-spiro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carbonitrile (4i)
White powder; yield: 0.377 g (94%); mp 267–270 °C.
475.1767.
IR (KBr): 3346, 3294, 3148, 2193, 1727, 1681, 1651, 1593, 1369,
692 cm–1.
2′-Amino-6′-benzyl-4-chloro-2,5′-dioxo-1,2,6′,7′-tetrahydro-
5′H-spiro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carbonitrile (4f)
White powder; yield: 0.381 g (91%); mp 286–288 °C.
1H NMR (400 MHz, DMSO-d6): δ = 4.16 (d, J = 18.8 Hz, 1 H,
CH2), 4.23 (d, J = 18.8 Hz, 1 H, CH2), 4.39 (d, J = 15.6 Hz, 1 H,
CH2), 4.43 (d, J = 15.6 Hz, 1 H, CH2), 6.84 (m, 1 H, ArH), 7.06 (m,
1 H, ArH), 7.15 (m, 3 H, ArH), 7.26 (m, 1 H, ArH), 7.33 (m, 2 H,
ArH), 7.52 (s, 2 H, NH2), 10.62 (s, 1 H, NH).
IR (KBr): 3348, 3300, 3154, 2192, 1713, 1682, 1650, 1595, 1368,
706 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 4.20 (d, J = 19.2 Hz, 1 H,
CH2), 4.26 (d, J = 19.2 Hz, 1 H, CH2), 4.42 (d, J = 15.6 Hz, 1 H,
CH2), 4.46 (d, J = 15.6 Hz, 1 H, CH2), 6.86 (d, J = 7.6 Hz, 1 H,
ArH), 6.99 (d, J = 8.4 Hz, 1 H, ArH), 7.12 (d, J = 7.2 Hz, 2 H,
ArH), 7.26 (m, 2 H, ArH), 7.33 (m, 2 H, ArH), 7.54 (s, 2 H, NH2),
10.85 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 175.83, 165.93, 162.12,
161.57, 143.88, 137.33, 130.83, 130.08, 128.60, 127.26, 127.19,
126.86, 122.55, 117.38, 108.79, 104.73, 54.08, 47.33, 47.00, 44.47.
13C NMR (100 MHz, DMSO-d6): δ = 176.78, 165.95, 161.56,
1
4
160.86, 158.36 (d, JFC = 235.9 Hz), 138.19 (d, JFC = 1.5 Hz),
137.35, 133.84 (d, 3JFC = 7.6 Hz), 128.59, 127.42, 127.26, 117.58,
115.28 (d, JFC = 23.1 Hz), 112.23 (d, JFC = 24.5 Hz), 110.32 (d,
3JFC = 7.8 Hz), 106.04, 56.13, 47.47, 47.10, 44.55.
2
2
MS (ESI): m/z [M + H]+ calcd for C22H16FN4O3: 403.1; found:
402.9.
HRMS (ESI): m/z [M + H]+ calcd for C22H16FN4O3: 403.1201;
found: 403.1206.
MS (ESI): m/z [M + H]+ calcd for C22H16ClN4O3: 419.1; found:
418.9.
HRMS (ESI): m/z [M + H]+ calcd for C22H16ClN4O3: 419.0905;
found: 419.0919.
2′-Amino-6′-benzyl-5-chloro-2,5′-dioxo-1,2,6′,7′-tetrahydro-
5′H-spiro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carbonitrile (4j)
White powder; yield: 0.388 g (93%); mp 278–280 °C.
2′-Amino-6′-benzyl-4-bromo-2,5′-dioxo-1,2,6′,7′-tetrahydro-
5′H-spiro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carbonitrile (4g)
White powder; yield: 0.424 g (92%); mp 294–296 °C.
IR (KBr): 3353, 3298, 3142, 2192, 1711, 1680, 1650, 1590, 1365,
707 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 4.17 (d, J = 19.2 Hz, 1 H,
CH2), 4.22 (d, J = 19.2 Hz, 1 H, CH2), 4.38 (d, J = 15.6 Hz, 1 H,
CH2), 4.46 (d, J = 15.6 Hz, 1 H, CH2), 6.87 (d, J = 8.4 Hz, 1 H,
ArH), 7.16 (d, J = 7.2 Hz, 2 H, ArH), 7.28 (m, 3 H, ArH), 7.33 (t,
J = 7.2 Hz, 2 H, ArH) 7.52 (s, 2 H, NH2), 10.72 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 176.52, 165.97, 161.67,
160.90, 140.93, 137.34, 134.17, 128.88, 128.58, 127.46, 127.27,
126.08, 124.62, 117.58, 111.01, 105.87, 55.95, 47.54, 46.85, 44.59.
MS (ESI): m/z [M + H]+ calcd for C22H16ClN4O3: 419.1; found:
418.8.
HRMS (ESI): m/z [M + H]+ calcd for C22H16ClN4O3: 419.0905;
IR (KBr): 3350, 3298, 3154, 2191, 1712, 1680, 1649, 1590, 1367,
705 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 4.16 (d, J = 18.8 Hz, 1 H,
CH2), 4.26 (d, J = 18.8 Hz, 1 H, CH2), 4.41 (d, J = 15.6 Hz, 1 H,
CH2), 4.48 (d, J = 15.6 Hz, 1 H, CH2), 6.89 (d, J = 7.6 Hz, 1 H,
ArH), 7.13 (m, 3 H, ArH), 7.20 (t, J = 8.0 Hz, 1 H, ArH), 7.26 (t,
J = 7.2 Hz, 1 H, ArH), 7.33 (m, 2 H, ArH), 7.55 (s, 2 H, NH2), 10.85
(s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 175.84, 165.90, 162.29,
161.66, 144.12, 137.32, 131.04, 128.60, 128.29, 127.25, 127.15,
125.60, 118.98, 117.39, 109.24, 104.60, 54.08, 48.19, 47.30, 44.42.
MS (ESI): m/z [M + H]+ calcd for C22H16BrN4O3: 463.0; found:
found: 419.0912.
463.6.
2′-Amino-6′-benzyl-5-bromo-2,5′-dioxo-1,2,6′,7′-tetrahydro-
5′H-spiro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carbonitrile
(4k)
HRMS (ESI): m/z [M + H]+ calcd for C22H16BrN4O3: 463.0400;
found: 463.0401
White powder; yield: 0.424 g (92%); mp 274–276 °C.
Synthesis 2014, 46, 1389–1398
© Georg Thieme Verlag Stuttgart · New York

PAPER
Spirooxindole Derivatives
1395
IR (KBr): 3357, 3299, 3149, 2193, 1711, 1680, 1649, 1590, 1363,
699 cm–1.
13C NMR (100 MHz, DMSO-d6): δ = 177.36, 165.93, 162.15,
161.15, 148.45, 142.74, 137.26, 133.15, 128.58, 127.44, 127.28,
126.43, 120.36, 117.47, 109.91, 105.25, 55.12, 47.71, 46.72, 44.59.
MS (ESI): m/z [M + H]+ calcd for C22H16BrN4O3: 463.0; found:
463.3.
HRMS (ESI): m/z [M + H]+ calcd for C22H16BrN4O3: 463.0400;
found: 463.0405.
1H NMR (400 MHz, DMSO-d6): δ = 4.17 (d, J = 19.2 Hz, 1 H,
CH2), 4.22 (d, J = 19.2 Hz, 1 H, CH2), 4.38 (d, J = 15.6 Hz, 1 H,
CH2), 4.47 (d, J = 15.6 Hz, 1 H, CH2), 6.82 (d, J = 8.0 Hz, 1 H,
ArH), 7.16 (d, J = 6.8 Hz, 2 H, ArH), 7.26 (t, J = 7.2 Hz, 1 H, ArH),
7.33 (t, J = 7.2 Hz, 2 H, ArH), 7.41 (m, 2 H, ArH), 7.52 (s, 2 H,
NH2), 10.72 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 176.39, 165.99, 161.69,
160.90, 141.35, 137.34, 134.55, 131.72, 128.58, 127.47, 127.30,
127.27, 117.59, 113.77, 111.54, 105.86, 55.95, 47.55, 46.79, 44.60.
MS (ESI): m/z [M + H]+ calcd for C22H16BrN4O3: 463.0; found:
463.7.
HRMS (ESI): m/z [M + H]+ calcd for C22H16BrN4O3: 463.0400;
found: 463.0402.
2′-Amino-6′-benzyl-5,7-dibromo-2,5′-dioxo-1,2,6′,7′-tetra-
hydro-5′H-spiro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carboni-
trile (4o)
White powder; yield: 0.491 g (91%); mp 296–297 °C.
IR (KBr): 3373, 3292, 3156, 2195, 1735, 1712, 1680, 1640, 1589,
1367, 703 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 4.20 (s, 2 H, CH2), 4.38 (d,
J = 15.2 Hz, 1 H, CH2), 4.48 (d, J = 15.2 Hz, 1 H, CH2), 7.17 (d,
J = 7.2 Hz, 2 H, ArH), 7.28 (t, J = 7.2 Hz, 1 H, ArH), 7.34 (m, 2 H,
ArH), 7.48 (m, 1 H, ArH), 7.70 (m, 1 H, ArH), 7.49 (s, 2 H, NH2),
11.17 (s, 1 H, NH).
2′-Amino-6′-benzyl-5-nitro-2,5′-dioxo-1,2,6′,7′-tetrahydro-
5′H-spiro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carbonitrile (4l)
Yellow powder; yield: 0.386 g (90%); mp 254–256 °C.
13C NMR (100 MHz, DMSO-d6): δ = 176.50, 165.90, 161.85,
160.90, 141.00, 137.16, 135.47, 133.75, 128.62, 127.48, 127.36,
126.69, 117.49, 114.40, 105.47, 102.78, 55.48, 47.88, 47.63, 44.60.
MS (ESI): m/z [M + H]+ calcd for C22H15Br2N4O3: 541.0; found:
540.6.
HRMS (ESI): m/z [M + H]+ calcd for C22H15Br2N4O3: 540.9505;
found: 540.9512.
IR (KBr): 3364, 3307, 3183, 2191, 1735, 1715, 1675, 1650, 1588,
1370, 690 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 4.21 (d, J = 19.2 Hz, 1 H,
CH2), 4.26 (d, J = 19.2 Hz, 1 H, CH2), 4.38 (d, J = 15.2 Hz, 1 H,
CH2), 4.44 (d, J = 15.2 Hz, 1 H, CH2), 7.09 (d, J = 8.4 Hz, 1 H,
ArH), 7.15 (d, J = 6.8 Hz, 2 H, ArH), 7.25 (t, J = 6.8 Hz, 1 H, ArH),
7.32 (t, J = 7.2 Hz, 2 H, ArH), 8.17 (s, 1 H, ArH), 8.22 (d, J = 8.4
Hz, 1 H, ArH), 7.64 (s, 2 H, NH2), 11.34 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 177.36, 165.93, 162.15,
161.15, 148.44, 142.74, 137.26, 133.15, 128.58, 127.44, 127.28,
126.43, 120.35, 117.47, 109.91, 105.25, 55.11, 47.71, 46.72, 44.59.
MS (ESI): m/z [M + H]+ calcd for C22H16N5O5: 430.1; found: 429.8.
HRMS (ESI): m/z [M + H]+ calcd for C22H16N5O5: 430.1146; found:
2′-Amino-6′-benzyl-2,5′-dioxo-7-(trifluoromethyl)-1,2,6′,7′-tet-
rahydro-5′H-spiro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carbo-
nitrile (4p)
White powder; yield: 0.416 g (92%); mp 242–244 °C.
IR (KBr): 3438, 3294, 3184, 2198, 1731, 1714, 1681, 1630, 1369,
704 cm–1.
430.1147.
1H NMR (400 MHz, DMSO-d6): δ = 4.21 (d, J = 19.2 Hz, 1 H,
CH2), 4.26 (d, J = 19.2 Hz, 1 H, CH2), 4.38 (d, J = 15.2 Hz, 1 H,
CH2), 4.44 (d, J = 15.2 Hz, 1 H, CH2), 7.14 (d, J = 7.2 Hz, 2 H,
ArH), 7.18 (d, J = 7.6 Hz, 1 H, ArH), 7.26 (m, 1 H, ArH), 7.33 (m,
2 H, ArH), 7.48 (d, J = 7.2 Hz, 1 H, ArH), 7.53 (d, J = 8.0 Hz, 1 H,
ArH), 7.58 (s, 2 H, NH2), 11.09 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 177.30, 165.80, 161.75,
161.02, 139.42, 137.30, 133.90, 128.59, 128.54, 127.44, 127.28,
125.58, 122.32, 117.40, 110.77, 110.44, 105.87, 55.72, 47.54,
45.87, 44.57.
2′-Amino-6′-benzyl-6-chloro-2,5′-dioxo-1,2,6′,7′-tetrahydro-
5′H-spiro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carbonitrile
(4m)
White powder; yield: 0.385 g (92%); mp 289–291 °C.
IR (KBr): 3353, 3298, 3170, 2195, 1712, 1680, 1650, 1590, 1362,
704 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 4.19 (d, J = 18.8 Hz, 1 H,
CH2), 4.25 (d, J = 18.8 Hz, 1 H, CH2), 4.40 (d, J = 16.0 Hz, 1 H,
CH2), 4.48 (d, J = 16.0 Hz, 1 H, CH2), 6.89 (d, J = 8.4 Hz, 1 H,
ArH), 7.18 (t, J = 7.2 Hz, 2 H, ArH), 7.30 (m, 3 H, ArH), 7.36 (t,
J = 7.2 Hz, 2 H, ArH) 7.54 (s, 2 H, NH2), 10.74 (s, 1 H, NH).
MS (ESI): m/z [M + H]+ calcd for C23H16F3N4O3: 453.1; found:
452.9.
HRMS (ESI): m/z [M + H]+ calcd for C23H16F3N4O3: 453.1169;
found: 453.1175.
13C NMR (100 MHz, DMSO-d6): δ = 176.53, 165.98, 161.68,
160.90, 140.94, 137.34, 134.18, 128.89, 128.59, 127.47, 127.28,
126.09 124.63, 117.79, 111.02, 105.88, 55.96, 47.55, 46.86, 44.60.
MS (ESI): m/z [M + H]+ calcd for C22H16ClN4O3: 419.1; found:
418.9.
2′-Amino-2,5′-dioxo-6′-phenyl-1,2,6′,7′-tetrahydro-5′H-spi-
ro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carbonitrile (4q)
White powder; yield: 0.337 g (92%); mp 202–205 °C.
HRMS (ESI): m/z [M + H]+ calcd for C22H16ClN4O3: 419.0905;
found: 419.0907.
IR (KBr): 3429, 3290, 3203, 2197, 1737, 1710, 1632, 1594, 1362,
753 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 4.81 (d, J = 18.0 Hz, 1 H,
CH2), 4.89 (d, J = 18.0 Hz, 1 H, CH2), 6.87 (d, J = 7.6 Hz, 1 H,
ArH), 6.98 (t, J = 7.6 Hz, 1 H, ArH), 7.07 (t, J = 7.2 Hz, 1 H, ArH),
7.17 (d, J = 7.2 Hz, 1 H, ArH), 7.23 (t, J = 7.6 Hz, 1 H, ArH), 7.32
(m, 2 H, ArH), 7.59 (s, 1 H, ArH), 7.61 (s, 1 H, ArH), 7.57 (s, 2 H,
NH2), 10.65 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 176.60, 164.95, 161.55,
160.64, 141.99, 138.62, 131.87, 129.02, 128.85, 124.39, 123.41,
122.12, 118.21, 117.51, 109.62, 107.21, 56.68, 47.75, 46.48.
2′-Amino-6′-benzyl-6-bromo-2,5′-dioxo-1,2,6′,7′-tetrahydro-
5′H-spiro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carbonitrile
(4n)
White powder; yield: 0.416 g (90%); mp 290–291 °C.
IR (KBr): 3435, 3186, 3141, 2195, 1710, 1672, 1635, 1598, 1368,
704 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 4.21 (s, 2 H, CH2), 4.41 (s, 2
H, CH2), 7.01 (s, 1 H, ArH), 7.14 (m, 4 H, ArH), 7.28 (m, 3 H, ArH),
7.52 (s, 2 H, NH2), 10.75 (s, 1 H, NH).
MS (ESI): m/z [M + H]+ calcd for C21H15N4O3: 371.1; found: 371.0.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1389–1398

1396
C. Han et al.
PAPER
HRMS (ESI): m/z [M + H]+ calcd for C21H15N4O3: 371.1139; found:
371.1142.
13C NMR (100 MHz, DMSO-d6): δ = 176.73, 165.58, 161.44,
160.76, 141.96, 141.56, 132.24, 128.85, 128.49, 127.14, 126.41,
124.25, 122.09, 117.70, 109.52, 106.67, 56.65, 48.82, 46.58, 44.31,
18.48.
MS (ESI): m/z [M + H]+ calcd for C23H19N4O3: 399.1; found: 398.9.
HRMS (ESI): m/z [M + H]+ calcd for C23H19N4O3: 399.1452; found:
2′-Amino-5-nitro-2,5′-dioxo-6′-phenyl-1,2,6′,7′-tetrahydro-
5′H-spiro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carbonitrile (4r)
White powder; yield: 0.382 g (92%); mp 222–225 °C.
IR (KBr): 3360, 3303, 3198, 2193, 1735, 1711, 1675, 1640, 1589,
1370, 703 cm–1.
399.1452.
1H NMR (400 MHz, DMSO-d6): δ = 4.78 (d, J = 18.4 Hz, 1 H,
CH2), 4.92 (d, J = 18.4 Hz, 1 H, CH2), 7.12 (m, 2 H, ArH), 7.32 (m,
2 H, ArH), 7.61 (d, J = 8.4 Hz, 2 H, ArH), 8.21 (m, 2 H, ArH), 7.77
(s, 2 H, NH2), 11.42 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 177.20, 164.94, 162.35,
161.01, 148.45, 142.74, 138.56, 132.87, 128.87, 126.49, 123.53,
120.45, 118.16, 117.33, 109.94, 105.97, 55.26, 48.10, 46.57.
(3S)-2′-Amino-1-methyl-2,5′-dioxo-6′-[(1S)-1-phenylethyl]-
1,2,6′,7′-tetrahydro-5′H-spiro[indole-3,4′-pyrano[2,3-c]pyr-
role]-3′-carbonitrile (S,S-4t)
White powder; yield: 0.189 g (46%); mp 239–241 °C; Rf = 0.80
(CHCl3–MeOH, 15:1); [α]D20 +176.4 (c 0.100, MeOH).
IR (KBr): 3430, 3246, 3141, 2196, 1710, 1676, 1650, 1599, 1363,
705 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 1.47 (d, J = 7.2 Hz, 3 H, CH3),
3.16 (s, 3 H, CH3), 4.04 (d, J = 18.8 Hz, 1 H, CH2), 4.39 (d, J = 18.8
Hz, 1 H, CH2), 5.09 (q, J = 7.2 Hz, 1 H, CH), 7.07 (m, 2 H, ArH),
7.20 (m, 3 H, ArH), 7.27 (m, 1 H, ArH), 7.34 (m, 3 H, ArH), 7.51
(s, 2 H, NH2).
13C NMR (100 MHz, DMSO-d6): δ = 175.12, 165.38, 161.45,
160.92, 143.39, 141.66, 131.34, 129.10, 128.53, 127.19, 126.39,
124.02, 122.82, 117.56, 108.53, 106.58, 56.23, 48.78, 46.24, 44.32,
26.47, 18.37.
MS (ESI): m/z [M + H]+ calcd for C21H14N5O5: 416.1; found: 415.9.
HRMS (ESI): m/z [M + H]+ calcd for C21H14N5O5: 416.0989; found:
416.0990.
(S,S)- and (S,R)-Spirooxindole Diastereomers 4s–u; General
Procedure
A mixture of N-[(1S)-1-phenylethyl]tetramic acid 1b (1 mmol),
isatin 2 (1 mmol), and malononitrile (3; 1 mmol), in EtOH (2 mL)
was stirred at the reflux for 3 h. When the reaction was complete
(TLC), the mixture was cooled to r.t. The precipitate was collected
by filtration and washed successively with H2O and cold EtOH to
afford a mixture of the two diastereomers, which was then separated
by column chromatography [silica gel, CHCl3–MeOH (15:1)] to
give the pure (S,S)-4 and (S,R)-4.
MS (ESI): m/z [M + H]+ calcd for C24H21N4O3: 413.2; found: 413.1.
HRMS (ESI): m/z [M + H]+ calcd for C24H21N4O3: 413.1608; found:
413.1611.
(3R)-2′-Amino-1-methyl-2,5′-dioxo-6′-[(1S)-1-phenylethyl]-
1,2,6′,7′-tetrahydro-5′H-spiro[indole-3,4′-pyrano[2,3-c]pyr-
role]-3′-carbonitrile (S,R-4t)
(3S)-2′-Amino-2,5′-dioxo-6′-[(1S)-1-phenylethyl]-1,2,6′,7′-tet-
rahydro-5′H-spiro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carbo-
nitrile (S,S-4s)
White powder; yield: 0.182 g (44%); mp 238–239 °C; Rf = 0.70
(CHCl3–MeOH, 15:1); [α]D20 +206.7 (c 0.100, MeOH).
White powder; yield: 0.187 g (47%); mp 228–229 °C; Rf = 0.65
(CHCl3–MeOH, 15:1); [α]D20 +171.8 (c 0.100, MeOH).
IR (KBr): 3432, 3244, 3139, 2197, 1710, 1680, 1650, 1596, 1365,
703 cm–1.
IR (KBr): 3422, 3245, 3141, 2199, 1712, 1676, 1651, 1599, 1366,
748 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 1.47 (d, J = 7.2 Hz, 3 H, CH3),
3.16 (s, 3 H, CH3), 4.00 (d, J = 18.8 Hz, 1 H, CH2), 4.40 (d, J = 18.8
Hz, 1 H, CH2), 5.10 (q, J = 7.2 Hz, 1 H, CH), 7.05 (m, 2 H, ArH),
7.19 (m, 3 H, ArH), 7.24 (m, 1 H, ArH), 7.31 (m, 3 H, ArH), 7.50
(s, 2 H, NH2).
13C NMR (100 MHz, DMSO-d6): δ = 175.14, 165.44, 161.52,
160.94, 143.40, 141.52, 131.41, 129.07, 128.49, 127.15, 126.42,
123.95, 122.85, 117.59, 108.50, 106.57, 56.22, 48.83, 46.26, 44.34,
26.42, 18.44.
1H NMR (400 MHz, DMSO-d6): δ = 1.47 (d, J = 7.2 Hz, 3 H, CH3),
4.01 (d, J = 18.8 Hz, 1 H, CH2), 4.36 (d, J = 18.8 Hz, 1 H, CH2),
5.09 (q, J = 7.2 Hz, 1 H, CH), 6.84 (d, J = 7.6 Hz, 1 H, ArH), 6.97
(t, J = 7.6 Hz, 1 H, ArH), 7.11 (d, J = 7.2 Hz, 1 H, ArH), 7.21 (m,
3 H, ArH), 7.26 (m, 1 H, ArH), 7.33 (t, J = 7.2 Hz, 2 H, ArH), 7.45
(s, 2 H, NH2), 10.54 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 176.68, 165.51, 161.32,
160.78, 141.99, 141.61, 132.09, 128.87, 128.49, 127.18, 126.41,
124.32, 122.03, 117.68, 109.55, 106.70, 56.53, 48.70, 46.57, 44.18,
18.23.
MS (ESI): m/z [M + H]+ calcd for C24H21N4O3: 413.2; found: 413.0.
HRMS (ESI): m/z [M + H]+ calcd for C24H21N4O3: 413.1608; found:
MS (ESI): m/z [M + H]+ calcd for C23H19N4O3: 399.1; found: 398.9.
HRMS (ESI): m/z [M + H]+ calcd for C23H19N4O3: 399.1452; found:
413.1614.
(3S)-2′-Amino-5-methyl-2,5′-dioxo-6′-[(1S)-1-phenylethyl]-
1,2,6′,7′-tetrahydro-5′H-spiro[indole-3,4′-pyrano[2,3-c]pyr-
role]-3′-carbonitrile (S,S-4u)
399.1453.
(3R)-2′-Amino-2,5′-dioxo-6′-[(1S)-1-phenylethyl]-1,2,6′,7′-tet-
rahydro-5′H-spiro[indole-3,4′-pyrano[2,3-c]pyrrole]-3′-carbo-
nitrile (S,R-4s)
White powder; yield: 0.194 g (47%); mp 235–237 °C; Rf = 0.60
(CHCl3–MeOH, 15:1); [α]D20 +148.6 (c 0.100, MeOH).
White powder; yield: 0.175 g (44%); mp 227–228 °C; Rf = 0.55
IR (KBr): 3347, 3288, 3141, 2195, 1710, 1680, 1643, 1594, 1364,
704 cm–1.
(CHCl3–MeOH, 15:1); [α]D20 +122.3 (c 0.100, MeOH).
1H NMR (400 MHz, DMSO-d6): δ = 1.48 (d, J = 7.2 Hz, 3 H, CH3),
2.25 (s, 3 H, CH3), 4.00 (d, J = 18.8 Hz, 1 H, CH2), 4.36 (d, J = 18.8
Hz, 1 H, CH2), 5.11 (q, J = 6.8 Hz, 1 H, CH), 6.72 (d, J = 7.6 Hz, 1
H, ArH), 6.92 (s, 1 H, ArH), 7.02 (d, J = 7.6 Hz, 1 H, ArH), 7.20 (d,
J = 7.6 Hz, 2 H, ArH), 7.26 (d, J = 6.8 Hz, 1 H, ArH), 7.33 (t,
J = 7.2 Hz, 2 H, ArH), 7.42 (s, 2 H, NH2), 10.42 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 176.62, 165.55, 161.25,
160.73, 141.65, 139.56, 132.20, 130.86, 129.16, 128.49, 127.18,
126.40, 124.79, 117.73, 109.31, 106.81, 56.74, 48.68, 46.61, 44.16,
20.60, 18.25.
IR (KBr): 3423, 3240, 3143, 2197, 1711, 1673, 1649, 1595, 1366,
705 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 1.48 (d, J = 7.2 Hz, 3 H, CH3),
3.98 (d, J = 18.8 Hz, 1 H, CH2), 4.39 (d, J = 18.8 Hz, 1 H, CH2),
5.11 (q, J = 7.2 Hz, 1 H, CH), 6.83 (d, J = 7.6 Hz, 1 H, ArH), 6.94
(t, J = 7.6 Hz, 1 H, ArH), 7.10 (d, J = 7.2 Hz, 1 H, ArH), 7.19 (m,
3 H, ArH), 7.23 (m, 1 H, ArH), 7.31 (t, J = 7.2 Hz, 2 H, ArH), 7.45
(s, 2 H, NH2), 10.59 (s, 1 H, NH).
Synthesis 2014, 46, 1389–1398
© Georg Thieme Verlag Stuttgart · New York

PAPER
Spirooxindole Derivatives
1397
MS (ESI): m/z [M + H]+ calcd for C24H21N4O3: 413.2; found: 412.9.
HRMS (ESI): m/z [M + H]+ calcd for C24H21N4O3: 413.1608; found:
mmol/mL) for 48 h at 37 °C under 5% CO2. Following this treat-
ment, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bro-
mide (MTT; 0.5 mg/mL) was added. After an additional 4 h of
incubation, the assay was terminated by removal of the supernatant.
DMSO (200 μL) was then added to each well to dissolve the forma-
zan product, and the optical density of each well was measured at
570 nm with a PowerWaveX microplate scanning spectrophotome-
ter (BioTek Instruments). The percentage inhibition of cell growth
by each compound at various concentrations was then calculated.
413.1610.
(3R)-2′-Amino-5-methyl-2,5′-dioxo-6′-[(1S)-1-phenylethyl]-
1,2,6′,7′-tetrahydro-5′H-spiro[indole-3,4′-pyrano[2,3-c]pyr-
role]-3′-carbonitrile (S,R-4u)
White powder; yield: 0.177 g (43%); mp 230–231 °C; Rf = 0.50
(CHCl3–MeOH, 15:1); [α]D20 +90.2 (c 0.100, MeOH).
IR (KBr): 3345, 3288, 3140, 2195, 1711, 1681, 1646, 1594, 1365,
705 cm–1.
Acknowledgment
1H NMR (400 MHz, DMSO-d6): δ = 1.48 (d, J = 7.2 Hz, 3 H, CH3),
2.22 (s, 3 H, CH3), 3.98 (d, J = 18.8 Hz, 1 H, CH2), 4.39 (d, J = 18.8
Hz, 1 H, CH2), 5.12 (q, J = 6.8 Hz, 1 H, CH), 6.71 (d, J = 8.0 Hz, 1
H, ArH), 6.91 (s, 1 H, ArH), 6.99 (d, J = 7.6 Hz, 1 H, ArH), 7.19 (d,
J = 7.2 Hz, 2 H, ArH), 7.25 (d, J = 7.2 Hz, 1 H, ArH), 7.31 (t,
J = 7.6 Hz, 2 H, ArH), 7.40 (s, 2 H, NH2), 10.45 (s, 1 H, NH).
We are grateful for the financial support of the National Natural Sci-
ence Foundation of China (NSFC 20772113, 51243004) and the
Doctoral Foundation of Xinxiang Medical University (No.
505019).
13C NMR (100 MHz, DMSO-d6): δ = 176.65, 165.65, 161.39,
160.70, 141.55, 139.51, 132.36, 130.90, 129.15, 128.48, 127.17,
126.50, 124.75, 117.74, 109.24, 106.79, 56.83, 48.93, 46.61, 44.33,
20.57, 18.51.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
MS (ESI): m/z [M + H]+ calcd for C24H21N4O3: 413.2; found: 412.9.
HRMS (ESI): m/z [M + H]+ calcd for C24H21N4O3: 413.1608; found:
References
(1) (a) Tietze, L. F.; Modi, A. Med. Res. Rev. 2000, 20, 304.
(b) Zhu, J. Eur. J. Org. Chem. 2003, 1133. (c) Karmakar, B.;
Nayak, A.; Banerji, J. Tetrahedron Lett. 2012, 53, 5004.
(d) Kidwai, M.; Jain, A.; Bhardwaj, S. Mol. Diversity 2012,
16, 121. (e) Orru, R. V. A.; de Greef, M. Synthesis 2003,
1471.
(2) (a) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth,
A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36,
899. (b) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J.
Org. Chem. 2004, 4957. (c) Ramon, D. J.; Yus, M. Angew.
Chem. Int. Ed. 2005, 44, 1602. (d) Wu, Q.; Feng, H.; Guo,
D.-D.; Yi, M.-S.; Wang, X.-H.; Jiang, B.; Tu, S.-Q.
J. Heterocycl. Chem. 2013, 50, 599.
(3) (a) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51.
(b) Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Org.
Lett. 2007, 9, 4223. (c) Liéby-Muller, F.; Constantieux, T.;
Rodriguez, J. J. Am. Chem. Soc. 2005, 127, 17176.
(d) Knyazeva, I. V.; Groth, U.; Glasnov, T. N.; Kappe, C. O.
J. Org. Chem. 2008, 73, 5110. (e) Zhang, X.-N.; Li, Y.-X.;
Zhan, Z.-H. Tetrahedron 2011, 67, 7426.
(4) (a) Nakajima, T.; Yamashita, D.; Suzuki, K.; Nakazaki, A.;
Suzuki, T.; Kobayashi, S. Org. Lett. 2011, 13, 2980.
(b) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005,
105, 4406. (c) Kotha, S.; Dipak, M. K.; Mobin, S. M.
Tetrahedron 2011, 67, 4616. (d) Li, J.; Li, L.; Si, Y.; Jiang,
X.; Guo, L.; Che, Y. Org. Lett. 2011, 13, 2670.
(5) (a) Chande, M. S.; Verma, R. S.; Barve, P. A.; Khanwelkar,
R. R.; Vaidya, R. B.; Ajaikumar, K. B. Eur. J. Med. Chem.
2005, 40, 1143. (b) Palmer, L. I.; Read de Alaniz, J. Angew.
Chem. Int. Ed. 2011, 50, 7167. (c) Bandichhor, R.; Lowell,
A. N.; Kozlowski, M. C. J. Org. Chem. 2011, 76, 6475.
(d) Wang, G.-D.; Zhang, X.-N.; Zhang, Z.-H. J. Heterocycl.
Chem. 2013, 50, 61.
(6) (a) Kornet, M. J.; Thio, A. P. J. Med. Chem. 1976, 19, 892.
(b) Galliford, C. V.; Scheidt, K. A. Angew. Chem. Int. Ed.
2007, 46, 8748. (c) Marti, C.; Carreira, E. M. Eur. J. Org.
Chem. 2003, 2209.
413.1612.
2-Amino-2′,5-dioxo-1′,2′,5,7-tetrahydrospiro[furo[3,4-b]py-
ran-4,3′-indole]-3-carbonitrile (9)
White powder; yield: 0.269 g (92%); mp 234–236 °C.
IR (KBr): 3339, 3246, 3170, 2198, 1747, 1700, 1597, 1378, 1030,
918 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 5.09 (d, J = 20.8 Hz, 1 H,
CH2), 5.21 (d, J = 20.8 Hz, 1 H, CH2), 6.87 (s, 1 H, ArH), 7.00 (m,
1 H, ArH), 7.22 (m, 2 H, ArH), 7.66 (s, 2 H, NH2), 10.67 (s, 1 H,
NH).
13C NMR (100 MHz, DMSO-d6): δ = 176.04, 169.28, 167.99,
160.45, 141.87, 130.98, 129.37, 124.60, 122.30, 117.24, 109.78,
101.46, 65.97, 56.41, 46.09.
MS (ESI): m/z [M + H]+ calcd for C15H10N3O4: 296.1; found: 296.3.
HRMS (ESI): m/z [M + H]+ calcd for C15H10N3O4: 296.0666; found:
296.0674.
7′-Amino-2,2′,4′-trioxo-1,1′,2,2′,3′,4′-hexahydrospiro[indole-
3,5′-pyrano[2,3-d]pyrimidine]-6′-carbonitrile (10)
White powder; yield: 0.298 g (92%); mp 268–269 °C.
IR (KBr): 3354, 3305, 3143, 2830, 2204, 1723, 1674, 1535, 1340,
755 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 6.78 (d, J = 8.0 Hz, 1 H, ArH),
6.91 (t, J = 8.0 Hz, 1 H, ArH), 7.12–7.18 (m, 2 H), 7.36 (s, 2 H,
NH2), 10.47 (s, 1 H, NH), 11.11 (s, 1 H, NH), 12.28 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 177.60, 161.37, 158.21,
153.29, 149.19, 142.07, 133.46, 128.37, 123.71, 121.72, 116.88,
109.22, 86.77, 57.79, 46.60.
MS (ESI): m/z [M + H]+ calcd for C15H10N5O4: 324.1; found: 324.5.
HRMS (ESI): m/z [M + H]+ calcd for C15H10N5O4: 324.0727; found:
324.0725.
In Vitro Cytotoxicity Assay
Human B lymphoma Raji cell line was obtained from the China
Center for Type Culture Collection, Wuhan, China. The cells were
cultured in RPMI-1640 medium with 10% fetal bovine serum,
100 U/mL of penicillin, and 100 mg/mL of streptomycin under a
5% CO2 humidified atmosphere at 37 °C. Cell cytotoxicity was as-
sayed by the MTT method. Briefly, cells were seeded in 96-well
tissue-culture plates and incubated with the test compound (0–50
(7) (a) Yin, X.-G.; Liu, X.-Y.; Hu, Z.-P.; Yan, M. Org. Biomol.
Chem. 2012, 10, 1506. (b) MacDonald, J. P.; Badillo, J. J.;
Arevalo, G. E.; Silva-García, A.; Franz, A. K. ACS Comb.
Sci. 2012, 14, 285.
(8) (a) Kidwai, M.; Jain, A.; Nemaysh, V.; Kumar, R.; Luthra,
P. M. Med. Chem. Res. 2013, 22, 2717. (b) Ball-Jones, N. R.;
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1389–1398

1398
C. Han et al.
PAPER
Badillo, J. J.; Franz, A. K. Org. Biomol. Chem. 2012, 10,
5165.
(16) (a) Pore, D. M.; Patil, P. B.; Gaikwad, D. S.; Hegade, P. G.;
Patil, J. D.; Undale, K. A. Tetrahedron Lett. 2013, 54, 5876.
(b) Deng, J.; Mo, L.-P.; Zhao, F.-Y.; Zhang, Z.-H.; Liu, S.-
X. ACS Comb. Sci. 2012, 14, 335. (c) Jadidi, K.;
Ghahremanzadeh, R.; Bazgir, A. J. Comb. Chem. 2009, 11,
341. (d) Litvinov, Y. M.; Mortikov, V. Y.; Shestopalov, A.
M. J. Comb. Chem. 2008, 10, 741. (e) Wu, C.-L.; Shen, R.-
P.; Chen, J.-H.; Hu, C.-Q. Bull. Korean Chem. Soc. 2013, 34,
2431.
(17) (a) Tisseh, Z. N.; Ahmadi, F.; Dabiri, M.; Khavasi, H. R.;
Bazgir, A. Tetrahedron Lett. 2012, 53, 3603. (b) Joshi, K.
C.; Jain, R.; Arora, S. J. Indian Chem. Soc. 1988, 65, 277.
(c) Nandakumar, A.; Thirumurugan, P.; Perumal, P. T.;
Vembu, P.; Ponnuswamy, M. N.; Ramesh, P. Bioorg. Med.
Chem. Lett. 2010, 20, 4252.
(9) (a) Yu, F.-C.; Huang, R.; Ni, H.-C.; Fan, J.; Yan, S.-J.; Lin,
J. Green Chem. 2013, 15, 453. (b) Rahmati, A.; Khalesi, Z.
Tetrahedron 2012, 68, 8472. (c) Zhou, Y.-J.; Chen, D.-S.;
Li, Y.-L.; Liu, Y.; Wang, X.-S. ACS Comb. Sci. 2013, 15,
498. (d) Khalafi-Nezhad, A.; Mohammadi, S. ACS Comb.
Sci. 2013, 15, 512.
(10) (a) Kang, T. H.; Matsumoto, K.; Murakami, Y.; Takayama,
H.; Kitajima, M.; Aimi, N.; Watanabe, H. Eur. J.
Pharmacol. 2002, 444, 39. (b) Kidwai, M.; Jahan, A.;
Mishra, N. K. Appl. Catal., A 2012, 425, 35.
(11) (a) Dandia, A.; Singh, R.; Khaturia, S.; Merienne, C.;
Morgant, G.; Loupy, A. Bioorg. Med. Chem. 2006, 14, 2409.
(b) Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000,
122, 5666. (c) Edmondson, S.; Danishefsky, S. J.; Sepp-
Lorenzinol, L.; Rosen, N. J. Am. Chem. Soc. 1999, 121,
2147.
(18) (a) Watahiki, T.; Matsuzaki, M.; Oriyama, T. Green Chem.
2003, 5, 82. (b) Watahiki, T.; Ohba, S.; Oriyama, T. Org.
Lett. 2003, 5, 2679.
(12) (a) Royles, B. J. L. Chem. Rev. 1995, 95, 1981. (b) Schobert,
R.; Schlenk, A. Bioorg. Med. Chem. 2008, 16, 4203.
(c) Singh, S. B.; Zink, D. L.; Heimbach, B.; Genilloud, O.;
Teran, A.; Silverman, K. C.; Lingham, R. B.; Felock, P.;
Hazuda, D. J. Org. Lett. 2002, 4, 1123.
(19) (a) Iwanami, K.; Hinakubo, Y.; Oriyama, T. Tetrahedron
Lett. 2005, 46, 5881. (b) Khatik, G. L.; Kumar, R.;
Chakraborti, A. K. Org. Lett. 2006, 8, 2433. (c) Oriyama, T.;
Aoyagi, M.; Iwanami, K. Chem. Lett. 2007, 36, 612.
(20) (a) Li, Y.-L.; Chen, H.; Shi, C.-L.; Shi, D.-Q.; Ji, S.-J.
J. Comb. Chem. 2010, 12, 231. (b) Zhang, L.-J.; Wu, Q.;
Sun, J.; Yan, C.-G. Beilstein J. Org. Chem. 2013, 9, 846.
(c) Guo, R.-Y.; Wang, P.; Wang, G.-D.; Mo, L.-P.; Zhang,
Z.-H. Tetrahedron 2013, 69, 2056.
(13) Bonsignore, L.; Loy, G.; Secci, D.; Calignano, A. Eur. J.
Med. Chem. 1993, 28, 517.
(14) (a) Baraldi, P. G.; Manfredini, S.; Simoni, D.; Tabrizi, M.
A.; Balzarini, J.; De Clercq, E. J. Med. Chem. 1992, 35,
1877. (b) Perrella, F. W.; Chen, S.-F.; Behrens, D. L.;
Kaltenbach, R. F. III.; Seitz, S. P. J. Med. Chem. 1994, 37,
2232.
(21) (a) Trost, B. M.; Brennan, M. K. Synthesis 2009, 3003.
(b) Xie, X.; Peng, C.; He, G.; Leng, H.-J.; Wang, B.; Huang,
W.; Han, B. Chem. Commun. 2012, 48, 10487.
(15) (a) Kashman, Y.; Gustafson, K. R.; Fuller, R. W.;
Cardellina, J. H. II.; McMahon, J. B.; Currens, M. J.;
Buckheit, R. W. Jr.; Hughes, S. H.; Cragg, G. M.; Boyd, M.
R. J. Med. Chem. 1992, 35, 2735. (b) Patil, A. D.; Freyer, A.
J.; Eggleston, D. S.; Haltiwanger, R. C.; Bean, M. F.; Taylor,
P. B.; Caranfa, M. J.; Breen, A. L.; Bartus, H. R.; Johnson,
R. K.; Hertzberg, R. P.; Westley, J. W. J. Med. Chem. 1993,
36, 4131.
(c) Ramachary, D. B.; Venkaiah, C.; Madhavachary, R. Org.
Lett. 2013, 15, 3042.
(22) (a) Speelman, J. C.; Talma, A. G.; Kellogg, R. M.; De Boer,
J. L.; Beurskens, P. T.; Bosman, W. P. J. Org. Chem. 1989,
54, 1055. (b) Kimura, Y.; Atarashi, S.; Kawakami, K.; Sato,
K.; Hayakawa, I. J. Med. Chem. 1994, 37, 3344. (c) Park, T.
H.; Paik, S.; Lee, S. H. Bull. Korean Chem. Soc. 2003, 24,
1227.
Synthesis 2014, 46, 1389–1398
© Georg Thieme Verlag Stuttgart · New York