Efficient one-pot synthesis of spirooxindole derivatives by ethylenediamine diacetate catalyzed reactions in water

Article abstract of DOI:10.1055/s-0029-1217116

A simple and efficient one-pot synthetic approach was used for the preparation of biologically interesting spirooxindole derivatives by means of three-component reactions of isatins, malononitrile, and 1,3-dicarbonyl compounds catalyzed by ethylenediamine diacetate (EDDA) in an aqueous medium. This method is of great value because of its environmentally benign character, high yield, and easy handling. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1217116

PAPER
453
Efficient One-Pot Synthesis of Spirooxindole Derivatives by Ethylenediamine
Diacetate Catalyzed Reactions in Water
O
ne-Pot Synthesis
a
of Spiroox
l
indole
l
D
erivat
a
ive
s
Sri Hari, Yong Rok Lee*
School of Chemical Engineering and Technology, Yeungnam University, Gyeongsan 712-749, South Korea
Fax +82(53)8104631; E-mail: yrlee@yu.ac.kr
Received 2 September 2009; revised 16 October 2009
Me
N
H
Abstract: A simple and efficient one-pot synthetic approach was
used for the preparation of biologically interesting spirooxindole
N
H
O
derivatives by means of three-component reactions of isatins, mal-
ononitrile, and 1,3-dicarbonyl compounds catalyzed by ethylenedi-
amine diacetate (EDDA) in an aqueous medium. This method is of
great value because of its environmentally benign character, high
yield, and easy handling.
R
H
N
O
O
H
MeO2C
NH
N
pteropodine
H
R = OMe, horsfiline
R = H, coerulescine
O
O
Key words: spiro compounds, indoles, catalysis, Brønsted acids,
Brønsted bases, water
N
HO
H
H
H
elacomine
NH
H
O
N
H
O
H
O
Spirocyclic compounds represent an important class of
naturally occurring substances with highly pronounced
biological properties.1 Molecules bearing the spirooxin-
dole moiety are widely found in nature (Figure 1)2 and
have been shown to possess a variety of important biolog-
ical activities.2d,3 The unique structural array and highly
prominent pharmacological activities have stimulated in-
terest in the synthesis of spirooxindole derivatives. Thus,
the development of new and simple synthetic methods for
the preparation of spirooxindole derivatives has become
O
H
N
N
Me
alstonisine
N
O
H
O
O
N
MeO
N
H
spirotryprostatin A
O
N
H
spirotryprostatin B
an interesting challenge. Consequently, many synthetic Figure 1 Selected spirooxindole natural products
methodologies have been developed for constructing
these spirooxindole derivatives, most of which are based
clization or Knoevenagel/6p-electrocyclization.11 Very
recently, a new and efficient synthetic approach for bio-
logically interesting tetrahydroquinoline and benzopyra-
nobenzopyran analogues from 1,3-dicarbonyls or
resorcinols through domino Knoevenagel/hetero-Diels–
Alder reactions or aldol-type/hetero-Diels–Alder reac-
tions was also developed in this laboratory.12 As a part of
an ongoing study into the synthetic efficacy of EDDA as
a catalyst for organic reactions, this study examines dom-
ino, three-component reactions of isatins, malononitrile,
and 1,3-dicarbonyls to afford a variety of spirooxindole
derivatives. We report a simple and efficient one-pot syn-
thesis of a variety of spirooxindole derivatives in accor-
dance with this approach.
on cycloaddition or condensation reactions.4 In particular,
domino multicomponent reactions have emerged as an ef-
ficient and powerful tool in the synthesis of complex mol-
ecules as a one-pot procedure.5 Several reactions for the
synthesis of spirooxindoles through multicomponent re-
actions have been developed, by using tetrabutylammoni-
um fluoride6 and triethylbenzylammonium chloride
(TEBA)7 as phase-transfer catalysts, indium(III) chloride8
as a Lewis acid catalyst, and electrocatalysis.9 Although
several methods for the synthesis of spirooxindole deriv-
atives have been reported, there is still a demand for sim-
ple and facile methods.
Recently, the potential of Brønsted acids and bases as ac-
tive catalysts for a variety of synthetically useful reactions
in organic chemistry has been demonstrated.10 Herein, we
have developed a new and useful methodology for prepar-
ing a variety of benzopyrans by using ethylenediamine di-
acetate (EDDA) as an effective Brønsted acid and base
catalyst.11 These reactions involve a formal [3+3] cy-
cloaddition through a domino aldol-type/6p-electrocy-
The development of environmentally friendly techniques
is one of the priorities of chemical research at present,
with water emerging as a versatile solvent for organic
chemistry in recent years.13 Water as a solvent is not only
inexpensive and environmentally benign, but also gives
completely new reactivity.14 Therefore, we first investi-
gated an EDDA-catalyzed, three-component reaction of
isatin (1), malononitrile (2), and 5,5-dimethylcyclohex-
ane-1,3-dione (3) to afford a spirooxindole derivative in
an aqueous medium. The reaction of isatin (1), malononi-
trile (2), and 5,5-dimethylcyclohexane-1,3-dione (3) in
SYNTHESIS 2010, No. 3, pp 0453–0464
x
x
.
x
x
.2
0
0
9
Advanced online publication: 13.11.2009
DOI: 10.1055/s-0029-1217116; Art ID: F18109SS
© Georg Thieme Verlag Stuttgart · New York

454
G. S. Hari, Y. R. Lee
PAPER
EDDA
(10 mol%)
O
O
O
NC
O
+
+
NH2
H2O
90%
NC
O
O
N
H
CN
N
O
2
1
3
H
4
Scheme 1
the presence of 10 mol% EDDA at 60 °C for one hour in a far superior catalyst for this cyclization than p-toluene-
water provided compound 4 in 90% yield (Scheme 1). sulfonic acid (56%), sodium dodecylsulfate (78%), tet-
The identity of 4 was easily confirmed by comparison of rabutylammonium bromide (85%), and cetyl-
1
its characteristic H NMR chemical shifts with reported trimethylammonium chloride (87%) in aqueous medium.7
data in the literature.8 The 1H NMR spectrum of 4 showed We observed that while malononitrile (2) was added to
an amide proton as a singlet at d = 10.35 and two amine isatin (1) in the presence of EDDA at 60 °C in water, the
protons as a broad singlet at d = 7.43. In the IR spectrum, reaction mixture changed to a reddish-brown color due to
the absorption bands at 1723 and 1656 cm–1 correspond- the formation of the Knoevenagel product. Upon addition
ing to two carbonyls of the amide and enone confirmed of dimedone (3) to this mixture and stirring for 30 min-
the presence of this structure.
utes, the reaction mixture became colorless. After opti-
mizing the conditions, the generality of this reaction with
regard to various isatins and 1,3-dicarbonyls was next ex-
plored. The results are summarized in Table 1.
In related work, it was reported that this reaction in the ab-
sence of any catalyst in water afforded compound 4 in
very low yield (23%).7 We found that EDDA in water was
Table 1 EDDA-Catalyzed Reactions of Isatins, Malononitrile, and 1,3-Dicarbonyls
Entry
1
Isatin
1,3-Dicarbonyl
Producta
Time (h)
Yield (%)b
O
O
O
O
1
95
NH2
N
O
H
O
CN
N
H
O
1
8
15
O
O
2
1
90
O
NH2
O
CN
N
H
9
O
16
Ph
O
O
3
1
83
O
NH2
Ph
O
CN
N
H
10
O
17
Synthesis 2010, No. 3, 453–464 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of Spirooxindole Derivatives
455
Table 1 EDDA-Catalyzed Reactions of Isatins, Malononitrile, and 1,3-Dicarbonyls (continued)
Entry
Isatin
1,3-Dicarbonyl
Producta
Time (h)
Yield (%)b
OH
O
4
2
90
O
O
NH2
CN
N
H
O
11
18
O
O
O
NH2
5
6
1
1
92
85
O
CN
N
H
12
O
19
EtO
O
O
O
O
NH2
EtO
CN
13
N
H
O
20
EtO
O
Ph
O
O
O
7
8
NH2
2
1
78
85
EtO
Ph
CN
14
N
H
O
21
O
O
O
O
NH2
N
O
CN
O
Me
N
O
8
5
Me
22
O
O
O
9
1
84
NH2
O
CN
N
O
3
Me
23
O
O
10
2
81
O
NH2
O
CN
N
O
9
Me
24
Synthesis 2010, No. 3, 453–464 © Thieme Stuttgart · New York

456
G. S. Hari, Y. R. Lee
PAPER
Table 1 EDDA-Catalyzed Reactions of Isatins, Malononitrile, and 1,3-Dicarbonyls (continued)
Entry
Isatin
1,3-Dicarbonyl
Producta
Time (h)
Yield (%)b
OH
O
11
2
75
O
NH2
O
CN
N
O
11
Me
25
26
27
O
O
O
NH2
12
13
1
1
88
87
O
CN
N
O
12
Me
O
O
O
O
NH2
N
O
H
O
O
CN
N
H
O
6
8
O
14
2
72
O
NH2
O
CN
N
H
O
9
28
29
O
O
O
15
1
90
NH2
O
CN
N
H
O
3
O
O
O
NH2
16
17
1
1
88
87
O
CN
N
H
12
O
30
O
O
Br
O
O
Br
NH2
N
O
H
O
CN
N
O
7
H
8
31
Synthesis 2010, No. 3, 453–464 © Thieme Stuttgart · New York

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One-Pot Synthesis of Spirooxindole Derivatives
457
Table 1 EDDA-Catalyzed Reactions of Isatins, Malononitrile, and 1,3-Dicarbonyls (continued)
Entry
18
Isatin
1,3-Dicarbonyl
Producta
Time (h)
Yield (%)b
O
O
2
73
O
Br
NH2
O
CN
N
H
O
9
32
O
O
O
19
1
89
Br
NH2
O
CN
N
H
O
3
33
OH
O
20
1
85
O
Br
O
NH2
CN
N
H
O
11
34
O
O
O
Br
NH2
21
1
89
O
CN
N
H
O
12
35
a All products were characterized by IR, 1H and 13C NMR, and mass spectroscopy.
b Yields of isolated products obtained by filtration of the reaction mixture.
The reactions of isatins and malononitrile with a number stituted with an electron-donating group with malono-
of cyclic and acyclic 1,3-carbonyls were investigated. nitrile (2) and several 1,3-dicarbonyls afforded
Treatment of 1 and 2 with cyclohexane-1,3-dione (8), 5- cycloadducts 27–30 in 72–90% yield (entries 13–16),
isopropylcyclohexane-1,3-dione (9), and 5-phenylcyclo- while the reactions of 5-bromoisatin (7) containing an
hexane-1,3-dione (10) in the presence of 10 mol% EDDA electron-withdrawing group afforded products 31–35 in
at 60 °C for one hour in water afforded products 15–17 in 73–89% yield (entries 17–21). These reactions provide a
95, 90, and 83% yield, respectively (Table 1, entries 1–3). rapid synthetic route to biologically interesting spirooxin-
Interestingly, with 3-hydroxy-1H-phenalen-1-one (11) dole derivatives. All products were characterized by IR
1
and cyclopentane-1,3-dione (12), the cycloaddition reac- and H and 13C NMR spectra, as well as FAB-HRMS
tions were also successful. The reaction of 1 and 2 with 3- analysis. In cases of compounds 16, 17, 24, 28, and 32, the
hydroxy-1H-phenalen-1-one (11) afforded product 18 in cycloadducts were produced as 1:1 mixtures of diastereo-
90% yield, whereas with cyclopentane-1,3-dione (12), ad- mers. In addition, the structure of 23 was confirmed by
duct 19 formed in 92% yield (entries 4 and 5). In particu- X-ray crystallographic analysis, and is shown in Figure 2.
lar, with acyclic b-keto esters 13 and 14, cycloadducts 20
The formation of spirooxindole 4 can be explained by a
domino Knoevenagel condensation and Michael addition
followed by cyclization, as shown in Scheme 2. Isatin (1)
was first protonated by EDDA to give protonated isatin
and 21 were produced in 85 and 78% yields, respectively
(entries 6 and 7). Similarly, reactions of 1-methylisatin (5)
and malononitrile (2) with several 1,3-dicarbonyls provid-
ed products 22–26 in 75–88% yield (entries 8–12). Impor-
36, which was then attacked by the anion produced by the
tantly, reactions of isatins carrying electron-donating and
malononitrile in the presence of EDDA to yield interme-
electron-withdrawing substituents on the benzene ring
diate 37. The dehydration of 37 in the presence of EDDA
gave isatylidene malononitrile 38 as a Knoevenagel con-
were also successful. Reactions of 5-methylisatin (6) sub-
Synthesis 2010, No. 3, 453–464 © Thieme Stuttgart · New York

458
G. S. Hari, Y. R. Lee
PAPER
Nucleophilic addition of the hydroxyl group of intermedi-
ate 40 to the cyano moiety afforded imine intermediate 41,
which finally underwent further reaction to give desired
product 4.
To further extend the usefulness of this methodology, the
one-pot reaction of isatins and malononitrile with several
4-hydroxycoumarin derivatives was investigated. As
shown in Scheme 3, reaction of isatin (1) and malononi-
trile (2) with 4-hydroxycoumarin (42), in the presence of
10 mol% EDDA as a catalyst at 60 °C for one hour in wa-
ter, provided adduct 45 (92%) without any formation of
the possible regioisomers. The structural assignment of 45
is derived from the IR carbonyl absorptions at 1718 and
1674 cm–1 for the amide and ester groups. Further, clear
confirmation of the structure was obtained from the 13C
NMR spectrum that showed the expected carbonyl peaks
due to the ester and amide groups at d = 177.4 and 158.7.
Additional reactions of several isatins, malononitrile, and
4-hydroxycoumarins bearing substituents on the benzene
ring were carried out under standard conditions. The re-
sults are collected in Table 2. Reaction of isatin (1) and
malononitrile (2) with 6-methyl-4-hydroxycoumarin (43)
and 6,7-dimethyl-4-hydroxycoumarin (44) gave products
46 (91%) and 47 (92%), whereas treatment of 1-methyl-
isatin (5) and malononitrile (2) with 6-methyl-4-hydroxy-
coumarin (43) afforded adduct 48 in 85% yield (entries 1–
3). In the cases of isatins bearing substituents on the ben-
zene ring, the reactions were also successful. Treatment of
isatin 6 with 43 for one hour in water provided adduct 49
Figure 2 X-ray crystal structure of compound 23
densation product. Such a process for producing interme-
diate 38 generated by an EDDA-catalyzed reaction of 1,3-
diketones to carbonyls was suggested by Tietze.15 Then,
intermediate 38 was attacked by the enol of dimedone 3 of
the Michael reaction in the presence of EDDA to give in-
termediate 39, which then underwent a keto–enol tau-
tomerization to furnish the enol intermediate 40.
OH
H3N+
–OAc
+NH3
–OAc
H3N+
–OAc
+NH3
–OAc
CN
CN
NC
CN
–
HO
+OH
O
H
CN
O
O
– H2O
CN
CN
CN
H
+
N
N
H
N
H
N
O
O
O
H
H
1
36
37
38
O
OH
C
O
O
CN
CN
O
N
O
O
O
NH
NH2
CN
N
O
CN
CN
N
H
O
H
N
H
N
39
O
O
40
4
41
H
Scheme 2 Plausible mechanism for the synthesis of spirooxindole 4
O
OH
O
EDDA
(10 mol%)
O
NC
O
NH2
+
+
H2O
92%
NC
O
O
N
O
CN
N
H
H
O
1
2
42
45
Scheme 3
Synthesis 2010, No. 3, 453–464 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of Spirooxindole Derivatives
459
(88%), whereas that of 7 with 43 gave 50 in 88% yield ous medium. The key strategy for the formation of a vari-
(entries 4 and 5).
ety of spirooxindoles was a domino Knoevenagel
condensation/Michael addition, followed by cyclization.
This methodology offers several advantages, including
high product yield, an easy experimental procedure, being
environmentally benign, and being amenable to large-
scale operation.
In summary, an efficient and facile one-pot synthesis of
spirooxindole derivatives was achieved through a multi-
component reaction involving various isatins, malononi-
trile, and a number of cyclic and acyclic 1,3-dicarbonyls
in the presence of a catalytic amount of EDDA in an aque-
Table 2 EDDA-Catalyzed Reactions of Isatins, Malononitrile, and 4-Hydroxycoumarins
Entry
Isatin
4-Hydroxycoumarin
Producta
Time (h) Yield (%)b
OH
O
O
O
O
O
1
1
91
N
H
NH2
O
O
1
43
CN
N
H
O
46
OH
O
O
O
O
O
2
1
92
O
N
H
O
NH2
1
44
CN
N
H
O
47
O
O
OH
O
O
O
O
3
1
85
N
NH2
O
Me
CN
43
5
N
O
Me
48
OH
O
O
O
O
O
O
4
1
88
N
NH2
H
O
6
43
CN
N
O
H
49
OH
O
O
Br
O
O
5
1
88
O
N
Br
O
NH2
H
O
7
43
CN
N
O
H
50
a All products were characterized by IR, 1H and 13C NMR, and mass spectroscopy.
b Yields of isolated products obtained by filtration of the reaction mixture.
Synthesis 2010, No. 3, 453–464 © Thieme Stuttgart · New York

460
G. S. Hari, Y. R. Lee
PAPER
All experiments were carried out in an aqueous medium. Isatin, ma-
lononitrile, 1,3-dicarbonyl compounds, coumarins, and ethyl ace-
toacetate were obtained from Aldrich Chemicals. Merck precoated
silica gel plates (Art. 5554) with a fluorescent indicator were used
Compound 17
The reaction of 1 (147 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 10
(188 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 17.
Yield: 317 mg (83%); 1:1 diastereomeric mixture; mp 295–297 °C.
IR (KBr): 3310, 2194, 1722, 1671, 1619, 1341, 1215 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 9.85 (s, 1 H, NH), 6.83–6.20
(m, 11 H), 2.31–1.76 (m, 5 H).
13C NMR (75 MHz, DMSO-d6): d (one isomer) = 194.6, 178.4,
165.8, 165.2, 159.2, 142.8, 142.6, 134.9, 134.7, 128.9, 127.4, 123.8,
122.0, 117.8, 112.3, 109.6, 58.2, 47.3, 43.8, 38.0, 34.5.
13C NMR (75 MHz, DMSO-d6): d (other isomer) = 194.6, 178.4,
165.8, 165.1, 159.1, 142.8, 142.5, 134.6, 134.6, 128.6, 127.3, 123.6,
122.0, 117.7, 112.2, 109.6, 58.0, 47.3, 43.7, 37.9, 34.3.
1
for analytical TLC. H and 13C NMR spectra were recorded on a
Bruker ARX (300 and 75 MHz, respectively) spectrometer; DMSO-
d6 was used as the solvent. IR spectra were recorded on a Jasco
FTIR 5300 spectrophotometer. HRMS spectra (FAB) were ob-
tained at the Korea Basic Science Institute on a Jeol JMS 700 spec-
trometer.
Spiro Compounds 4, 15–35, and 45–50; General Procedure
To a soln of the appropriate isatin (1.0 mmol), malononitrile (2; 1.0
mmol), and the appropriate 1,3-dicarbonyl (1.0 mmol) in H2O (5.0
mL) was added EDDA (18.0 mg, 0.1 mmol) at r.t. The reaction mix-
ture was stirred at 60 °C for 1–2 h and then cooled to r.t. The solid
was collected by filtration, washed with H2O (2 × 10.0 mL) and
cold EtOH (5.0 mL), and dried in a vacuum oven; this gave the cor-
responding product as a white powder.
HRMS–FAB: m/z [M + H]+ calcd for C23H18N3O3: 384.1348;
found: 384.1345.
Compound 18
The reaction of 1 (147 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 11
(196 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 2 h afforded 18.
Compound 48
The reaction of 1 (147 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 3
(140 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 4.
Yield: 351 mg (90%); solid; mp >300 °C.
IR (KBr): 3404, 2199, 1725, 1666, 1624, 1333, 1218 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 10.60 (s, 1 H, NH), 8.43–6.87
(m, 12 H).
13C NMR (75 MHz, DMSO-d6): d = 183.3, 177.8, 161.8, 158.5,
157.8, 142.1, 135.3, 133.3, 132.6, 131.1, 129.6, 128.9, 128.0, 127.1,
126.9, 126.2, 123.1, 121.4, 120.7, 120.3, 117.0, 109.0, 57.0, 47.6.
HRMS–FAB: m/z [M]+ calcd for C24H13N3O3: 391.0957; found:
391.0960.
Yield: 302 mg (90%); solid; mp >300 °C.
IR (KBr): 3361, 2198, 1720, 1658, 1468, 1217 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 10.35 (s, 1 H, NH), 7.18 (s, 2
H, NH2), 7.12–6.70 (m, 4 H), 2.55–2.43 (m, 2 H), 2.14–1.99 (m, 2
H), 0.96 (s, 3 H), 0.93 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 194.7, 177.8, 164.0, 158.6,
141.9, 134.2, 128.0, 122.8, 121.5, 117.1, 110.6, 109.1, 57.4, 49.9,
46.7, 31.8, 27.4, 26.9.
Compound 158
Compound 19
The reaction of 1 (147 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 12
(98 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 19.
The reaction of 1 (147 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 8
(112 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 15.
Yield: 269 mg (92%); solid; mp >300 °C.
IR (KBr): 3347, 2195, 1718, 1665, 1346, 1232 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 10.55 (s, 1 H, NH), 7.48 (s, 2
Yield: 291 mg (95%); solid; mp >300 °C.
IR (KBr): 3341, 3295, 3176, 2198, 1711, 1679, 1656, 1617, 1468,
1350, 1216, 1012, 755 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 10.37 (s, 1 H, NH), 7.19 (s, 2
H, NH2), 7.16–6.75 (m, 4 H), 2.70–2.62 (m, 2 H), 2.27–2.18 (m, 2
H), 1.97–1.88 (m, 2 H).
13C NMR (75 MHz, DMSO-d6): d = 195.4, 1787.5, 166.4, 159.0,
142.4, 134.9, 128.5, 123.6, 122.0, 117.7, 112.3, 109.5, 58.1, 47.3,
36.8, 27.2, 20.2.
H, NH2), 7.22–6.80 (m, 4 H), 2.82–2.80 (m, 2 H), 2.37–2.35 (m, 2
H).
13C NMR (75 MHz, DMSO-d6): d = 199.7, 177.5, 176.6, 160.5,
142.0, 132.0, 128.8, 124.1, 121.9, 117.5, 114.8, 109.4, 56.4, 46.5,
33.1, 24.8.
HRMS–FAB: m/z [M + H]+ calcd for C16H12N3O3: 294.0879;
found: 294.0882.
Compound 16
The reaction of 1 (147 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 9
(154 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 16.
Compound 20
The reaction of 1 (147 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 13
(130 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 20.
Yield: 314 mg (90%); 1:1 diastereomeric mixture; mp 283–285 °C.
IR (KBr): 3305, 2195, 1703, 1667, 1340, 1213, 1049 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 10.35 (s, 1 H, NH), 7.16 (s, 2
H, NH2), 7.12–6.73 (m, 4 H), 2.64–2.42 (m, 2 H), 2.23–1.99 (m, 2
H), 1.88–1.790 (m, 1 H), 1.58–1.51 (m, 1 H), 0.85 (d, J = 6.9 Hz, 3
H), 0.82 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d (one isomer) = 195.1, 178.0,
165.9, 158.7, 142.0, 134.5, 128.2, 123.3, 121.5, 117.3, 111.6, 109.1,
57.4, 46.8, 38.2, 30.9, 30.5, 30.3, 19.3.
13C NMR (75 MHz, DMSO-d6): d (other isomer) = 195.0, 178.0,
165.4, 158.7, 141.9, 134.3, 128.1, 123.2, 121.5, 111.4, 117.3, 109.1,
57.4, 46.8, 38.2, 30.8, 30.5, 30.3, 19.2.
Yield: 276 mg (85%); solid; mp 255–256 °C.
IR (KBr): 3473, 2193, 1719, 1676, 1620, 1471, 1377, 1288 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 10.35 (s, 1 H, NH), 7.19–7.13
(m, 1 H), 7.09 (s, 2 H, NH2), 7.04–7.02 (m, 1 H), 6.92 (d, J = 7.8 Hz,
1 H), 6.77 (d, J = 7.5 Hz, 1 H), 3.76 (q, J = 6.3 Hz, 2 H), 2.29 (s, 3
H), 0.77 (t, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 178.9, 164.9, 159.4, 158.8,
142.6, 134.9, 128.9, 123.8, 122.2, 117.8, 109.7, 105.1, 60.6, 57.1,
49.4, 18.9, 13.4.
HRMS–FAB: m/z [M + H]+ calcd for C17H16N3O4: 326.1141;
found: 326.1141.
HRMS–FAB: m/z [M]+ calcd for C20H19N3O3: 349.1426; found:
349.1425.
Synthesis 2010, No. 3, 453–464 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of Spirooxindole Derivatives
Compound 25
461
Compound 21
The reaction of 1 (147 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 14
(192 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 2 h afforded 21.
The reaction of 5 (161 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 11
(196 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 2 h afforded 25.
Yield: 301 mg (78%); solid; mp 261–263 °C.
Yield: 303 mg (75%); solid; mp >300 °C.
IR (KBr): 3470, 2195, 1720, 1670, 1380, 1220 cm–1.
IR (KBr): 3358, 1722, 1574, 1515, 1473, 1227 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 9.62 (s, 1 H, NH), 7.39–7.28
(m, 8 H), 7.13–7.08 (m, 1 H), 6.94–6.87 (m, 1 H), 6.79 (d, J = 7.5
Hz, 1 H), 3.62–3.55 (q, J = 6.9 Hz, 2 H), 0.57 (t, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 178.4, 164.9, 160.4, 155.7,
142.7, 133.5, 132.9, 130.7, 129.3, 128.7, 124.4, 122.4, 117.8, 109.9,
107.1, 60.7, 56.7, 50.2, 13.2.
1H NMR (300 MHz, DMSO-d6): d = 8.30–8.27 (m, 6 H), 7.91–7.73
(m, 4 H), 7.20–7.12 (m, 2 H), 3.14 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 181.0, 177.1, 159.4, 155.4,
144.3, 136.0, 133.6, 132.0, 131.8, 130.4, 129.0, 127.7, 127.1, 126.9,
125.3, 123.6, 122.9, 120.9, 117.7, 113.3, 108.7, 105.9, 57.5, 47.9,
27.0.
HRMS–FAB: m/z [M + H]+ calcd for C22H18N3O4: 388.1297;
HRMS–FAB: m/z [M + H]+ calcd for C25H16N3O3: 406.1192;
found: 388.1299.
found: 406.1195.
Compound 226
Compound 26
The reaction of 5 (161 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 8
(112 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 22.
The reaction of 5 (161 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 12
(98 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 26.
Yield: 272 mg (85%); solid; mp 271–273 °C.
Yield: 270 mg (88%); solid; mp 278–280 °C.
IR (KBr): 3465, 2194, 1703, 1671, 1606, 1467, 1352, 1217 cm–1.
IR (KBr): 3558, 2194, 1702, 1611, 1490, 1348, 1236 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.27–7.22 (m, J = 7.2 Hz, 1 H),
7.18 (s, 2 H, NH2) 7.03–7.04 (m, 1 H), 6.99–6.94 (m, 2 H), 3.36 (s,
3 H), 2.68–2.64 (m, 2 H), 2.23–2.18 (m, 2 H), 1.94–1.90 (m, 2 H).
1H NMR (300 MHz, DMSO-d6): d = 7.51 (s, 2 H, NH2), 7.33–7.28
(m, 1 H), 7.12 (d, J = 7.2 Hz, 1 H), 7.05–7.02 (m, 2 H), 3.15 (s, 3
H), 2.84–2.81 (m, 2 H), 2.37–2.34 (m, 2 H).
13C NMR (75 MHz, DMSO-d6): d = 194.7, 176.4, 165.9, 161.7,
158.6, 143.4, 133.4, 128.2, 122.7, 122.2, 117.0 107.9, 57.2, 46.4,
36.2, 26.6, 26.2, 19.6.
13C NMR (75 MHz, DMSO-d6): d = 200.5, 178.5, 176.0, 161.6,
144.3, 132.1, 129.9, 124.7, 123.6, 118.2, 115.6, 109.3, 57.0, 47.1,
34.0, 27.3, 25.7.
HRMS–FAB: m/z [M + H]+ calcd for C17H14N3O3: 308.1035;
found: 308.1038.
Compound 237
The reaction of 5 (161 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 3
(140 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 23.
Compound 27
Yield: 293 mg (84%); solid; mp 264–266 °C.
IR (KBr) 3441, 2194, 1686, 1608, 1468, 1352, 1219 cm–1.
The reaction of 6 (161 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 8
(112 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 27.
Yield: 279 mg (87%); solid; mp 292–293 °C.
IR (KBr): 3360, 2196, 1705, 1661, 1349, 1212 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 10.22 (s, 1 H, NH), 7.10 (s, 2
H, NH2), 6.93 (d, J = 7.8 Hz, 1 H), 6.81 (s, 1 H), 6.67 (d, J = 7.8 Hz,
1 H), 2.65 (t, J = 5.5 Hz, 2 H), 2.27–2.22 (m, 2 H), 2.21 (s, 3 H),
1.93 (t, J = 6.0 Hz, 2 H).
1H NMR (300 MHz, DMSO-d6): d = 7.27–7.22 (m, 1 H), 7.20 (s, 2
H, NH2), 7.05–6.95 (m, 3 H), 3.27 (s, 3 H), 2.50 (s, 2 H), 2.18–2.05
(m, 2 H), 1.03 (s, 3 H), 1.00 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 194.6, 176.4, 164.0, 158.7,
144.3, 143.5, 133.4, 128.2, 122.6, 122.2, 110.6, 108.0, 57.1, 49.9,
46.4, 31.8, 27.4, 27.0, 26.2, 22.8.
13C NMR (75 MHz, DMSO-d6): d = 194.7, 177.9, 165.7, 161.7,
158.4, 139.5, 134.5, 130.2, 128.2, 123.6, 111.9, 108.7, 57.8, 46.8,
36.3, 26.6, 20.5, 19.6.
HRMS–FAB: m/z [M + H]+ calcd for C18H16N3O3: 322.1192;
found: 322.1194.
Compound 24
The reaction of 5 (161 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 9
(154 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 2 h afforded 24.
Yield: 294 mg (81%); 1:1 diastereomeric mixture; mp 256–258 °C.
IR (KBr): 3394, 2196, 1675, 1609, 1488, 1342, 1212 cm–1.
Compound 28
1H NMR (300 MHz, DMSO-d6): d = 7.27–7.22 (m, 1 H), 7.17 (s, 2
H), 7.08–6.96 (m, 3 H), 3.14 (s, 3 H), 2.68–2.55 (m, 2 H), 2.23–2.02
(m, 2 H), 1.90–1.88 (m, 1 H), 1.62–1.55 (m, 1 H), 0.89 (d, 3 H), (d,
J = 7.2 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 194.9, 176.3, 165.9, 165.4,
158.7, 143.5, 133.5, 128.2, 122.7, 122.1, 111.3, 107.9, 57.1, 46.4,
38.1, 30.7, 30.4, 30.2, 26.2, 19.1.
13C NMR (75 MHz, DMSO-d6): d (one isomer) = 194.9, 176.3,
165.9, 165.4, 158.7, 143.5, 133.5, 128.2, 122.8, 122.1, 111.5, 107.9,
57.1, 46.4, 38.1, 30.7, 30.4, 30.2, 26.2, 19.2.
The reaction of 6 (161 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 9
(154 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 2 h afforded 28.
Yield: 261 mg (72%); 1:1 diastereomeric mixture; mp 275–276 °C.
IR (KBr): 3442, 2197, 1710, 1672, 1342, 1213 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 10.24 (s, 1 H, NH), 7.14 (s, 2
H, NH), 6.93 (d, J = 7.0 Hz, 1 H), 6.82 (s, 0.5 H), 6.79 (s, 0.5 H),
6.66 (d, J = 7.0 Hz, 1 H), 2.68–2.50 (m, 2 H), 2.20 (s, 3 H), 2.17–
2.08 (m, 2 H), 1.92–1.84 (m, 1 H), 1.62–1.52 (m, 1 H), 0.89 (d,
J = 6.9 Hz, 3 H), 0.87 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d (other isomer) = 194.9, 176.3,
165.9, 165.4, 158.7, 143.4, 133.3, 128.2, 122.7, 122.1, 111.3, 107.9,
57.1, 46.4, 38.1, 30.6, 30.4, 30.2, 26.2, 19.1.
13C NMR (75 MHz, DMSO-d6): d (one isomer) = 195.6, 178.5,
166.3, 159.1, 140.0, 135.0, 130.8, 128.9, 124.3, 117.8, 112.1, 109.3,
58.2, 47.4, 38.6, 31.4, 31.3, 30.8, 21.1, 19.6.
HRMS–FAB: m/z [M + H]+ calcd for C21H22N3O3: 364.1661;
found: 364.1664.
13C NMR (75 MHz, DMSO-d6): d (other isomer) = 195.4, 178.4,
165.9, 159.1, 139.9, 134.8, 130.8, 128.8, 124.1, 117.8, 111.9, 109.3,
58.2, 47.4, 38.6, 31.4, 31.3, 30.8, 21.1, 19.6.
Synthesis 2010, No. 3, 453–464 © Thieme Stuttgart · New York

462
G. S. Hari, Y. R. Lee
PAPER
HRMS–FAB: m/z [M + H]+ calcd for C21H22N3O3: 364.1661;
Compound 339
found: 364.1664.
The reaction of 7 (226 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 3
(140 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 33.
Compound 29
Yield: 368 mg (89%); solid; mp >300 °C.
IR (KBr): 3293, 2194, 1726, 1658, 1473, 1351, 1220 cm–1.
The reaction of 6 (161 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 3
(140 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 29.
1H NMR (300 MHz, DMSO-d6): d = 10.54 (s, 1 H, NH), 7.36–7.32
(m, 1 H), 7.31 (s, 2 H), 7.22 (s, 1 H), 6.78 (d, J = 8.2 Hz, 1 H), 2.65–
2.55 (m, 2 H), 2.21–2.16 (m, 2 H), 1.05 (s, 6 H).
13C NMR (75 MHz, DMSO-d6): d = 195.5, 178.1, 165.0, 159.3,
141.9, 137.2, 131.4, 126.4, 117.6, 113.8, 111.6, 110.6, 57.3, 50.4,
47.5, 32.4, 28.0, 27.6.
Yield: 314 mg (90%); solid; mp 298–299 °C.
IR (KBr): 3367, 2190, 1710, 1660, 1352, 1221 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 10.22 (s, 1 H, NH), 7.11 (s, 2
H, NH2), 6.90 (d, J = 7.6 Hz, 1 H), 6.78 (s, 1 H), 6.68 (d, J = 7.6 Hz,
1 H), 2,28 (s, 3 H), 2.20 (s, 2 H), 2.08 (s, 2 H), 1.04 (s, 3 H), 1.02 (s,
3 H).
13C NMR (75 MHz, DMSO-d6): d = 194.6, 177.8, 163.8, 161.7,
158.6, 139.5, 134.4, 130.3, 128.3, 123.4, 110.8, 108.8, 57.8, 50.0,
46.8, 31.8, 27.3, 27.1, 24.3, 20.5.
Compound 34
The reaction of 7 (226 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 11
(196 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 34.
Yield: 398 mg (85%); solid; mp >300 °C.
IR (KBr): 3409, 2200, 1726, 1664, 1473, 1338, 1224 cm–1.
Compound 30
The reaction of 6 (161 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 12
(98 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 30.
1H NMR (300 MHz, DMSO-d6): d = 10.72 (s, 1 H, NH), 8.50–8.40
(m, 3 H), 8.30–8.28 (d, J = 7.2 Hz, 1 H), 7.94–7.83 (m, 2 H), 7.57
(s, 2 H), 7.38–7.34 (m, 2 H), 6.86–6.83 (d, J = 7.5 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 181.5, 178.6, 159.7, 156.1,
142.5, 137.8, 136.4, 134.4, 132.2, 131.9, 130.8, 130.7, 128.1, 127.6,
127.2, 125.8, 121.4, 118.0, 114.3, 113.1, 112.1, 57.5, 48.9.
Yield: 270 mg (88%); solid; mp >300 °C.
IR (KBr): 3357, 2195, 1725, 1660, 1492, 1347, 1235 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 10.47 (s, 1 H, NH), 7.48 (s, 2
H, NH2), 7.04 (d, J = 7.8 Hz, 1 H), 6.91 (s, 1 H), 6.76 (d, J = 8.1 Hz,
1 H), 2.86–2.84 (m, 2 H), 2.42–2.40 (m, 2 H), 2.26 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 200.2, 177.9, 177.1, 160.9,
140.0, 132.6, 131.3, 129.5, 125.1, 118.0, 115.4, 109.7, 57.2, 47.1,
33.6, 25.3, 21.0.
HRMS–FAB: m/z [M + H]+ calcd for C24H13BrN3O3: 470.0140;
found: 470.0142.
Compound 35
HRMS–FAB: m/z [M + H]+ calcd for C17H14N3O3: 308.1035;
The reaction of 7 (226 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 12
found: 308.1036.
(98 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 35.
Yield: 331 mg (89%); solid; mp >300 °C.
IR (KBr): 3363, 2193, 1710, 1676, 1474, 1345, 1234 cm–1.
Compound 319
The reaction of 7 (226 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 8
1H NMR (300 MHz, DMSO-d6): d = 10.68 (s, 1 H, NH), 7.54 (s, 2
H, NH2), 7.39–7.30 (m, 2 H), 6.80 (d, J = 8.1 Hz, 1 H), 2.81–2.80
(m, 2 H), 2.39–2.37 (m, 2 H).
13C NMR (75 MHz, DMSO-d6): d = 200.3, 178.4, 176.8, 161.1,
141.8, 134.8, 132.1, 127.6, 117.8, 114.8, 114.2, 111.9, 56.3, 47.2,
33.6, 25.4.
(112 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 31.
Yield: 334 mg (87%); solid; mp 298–300 °C.
IR (KBr): 3360, 2190, 1715, 1673, 1474, 1349, 1216 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 10.51 (s, 1 H, NH), 7.32–7.16
(m, 4 H), 6.74 (d, J = 8.2 Hz, 1 H), 2.75–2.61 (m, 2 H), 2.35–2.18
(m, 2 H), 2.05–1.90 (m, 2 H).
13C NMR (75 MHz, DMSO-d6): d = 195.6, 178.2, 167.0, 159.2,
141.8, 137.4, 131.3, 126.5, 117.6, 113.8, 111.7, 111.5, 57.4, 47.6,
36.7, 27.2, 20.1.
HRMS–FAB: m/z [M + H]+ calcd for C16H11BrN3O3: 371.9984;
found: 371.9980.
Compound 458
The reaction of 1 (147 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 42
in H2O (10 mL) at 60 °C for 1 h afforded 45.
Compound 32
The reaction of 7 (226 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 9
(154 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 2 h afforded 32.
Yield: 328 mg (92%); solid; mp >300 °C.
IR (KBr): 3306, 2203, 1717, 1673, 1609, 1472, 1358, 1108 cm–1.
Yield: 312 mg (73%); 1:1 diastereomeric mixture; mp 283–285 °C.
IR (KBr): 3310, 2197, 1733, 1668, 1613, 1472, 1216 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 10.50 (s, 1 H, NH), 7.30–7.18
(m, 4 H), 6.73 (d, J = 8.4 Hz, 1 H), 2.66–2.41 (m, 2 H), 2.24–2.06
(m, 2 H), 1.92–1.85 (m, 1 H), 1.58–1.50 (m, 1 H), 0.87 (d, J = 6.9
Hz, 3 H), 0.85 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d (one isomer) = 195.0, 177.3,
166.1, 166.0, 158.4, 141.0, 136.5, 130.5, 125.8, 116.7, 112.9, 110.7,
56.5, 46.7, 37.7, 30.6, 30.4, 29.9, 18.9, 18.7.
13C NMR (75 MHz, DMSO-d6): d (other isomer) = 194.8, 177.2,
166.1, 166.0, 158.4, 141.0, 136.3, 130.5, 125.7, 116.7, 112.9, 110.7,
56.5, 46.7, 37.7, 30.6, 30.4, 29.9, 18.9, 18.7.
1H NMR (300 MHz, DMSO-d6): d = 10.64 (s, 1 H, NH), 7.94 (d,
J = 8.1 Hz, 1 H), 7.78–7.73 (m, 1 H), 7.62 (s, 2 H, NH2), 7.55–7.46
(m, 2 H), 7.19 (d, J = 7.5 Hz, 2 H), 6.95–6.90 (m, 1 H), 6.85 (d,
J = 7.2 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 177.4, 158.7, 158.5, 155.3,
152.2, 142.4, 133.8, 133.3, 129.1, 125.2, 124.3, 122.9, 122.3, 117.2,
116.8, 112.7, 109.7, 101.7, 57.4, 47.9.
Compound 46
The reaction of 1 (147 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 43
(176 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 46.
Yield: 337 mg (91%); solid; mp >300 °C.
IR (KBr): 3280, 2195, 1705, 1665, 1625, 1360, 1220 cm–1.
HRMS–FAB: m/z [M + H]+ calcd for C20H19BrN3O3: 428.0610;
found: 428.0613.
Synthesis 2010, No. 3, 453–464 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of Spirooxindole Derivatives
463
1H NMR (300 MHz, DMSO-d6): d = 10.64 (s, 1 H, NH), 7.75 (s, 1
H), 7.60–7.57 (m, 3 H), 7.39 (d, J = 8.4 Hz, 1 H), 7.23–7.16 (m, 2
H), 6.95–6.90 (m, 1 H), 6.85 (d, J = 7.5 Hz, 1 H), 2.44 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 177.9, 159.6, 156.4, 151.3,
142.5, 136.4, 135.4, 132.6, 128.1, 123.2, 117.9, 117.4, 114.8, 113.3,
112.3, 101.7, 57.6, 49.8, 21.5.
13C NMR (75 MHz, DMSO-d6): d = 177.6, 166.0, 162.5, 158.9,
155.4, 152.1, 150.6, 142.6, 134.8, 133.8, 129.3, 124.4, 123.1, 122.6,
116.4, 112.5, 109.9, 101.8, 57.6, 48.1, 20.7.
HRMS–FAB: m/z [M + H]+ calcd for C21H13BrN3O4: 450.0089;
found: 450.0086.
HRMS–FAB: m/z [M + H]+ calcd for C21H14N3O4: 372.0984;
found: 372.0986.
Acknowledgment
This work was supported by grant no. RTI04-01-04 from the Regio-
nal Technology Innovation Program of the Ministry of Knowledge
Economy (MKE).
Compound 47
The reaction of 1 (147 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 44
(190 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 47.
Yield: 354 mg (92%); solid; mp >300 °C.
IR (KBr): 3202, 2199, 1706, 1668, 1624, 1468, 1361, 1064 cm–1.
References
(1) (a) James, D. M.; Kunze, H. B.; Faulkner, D. J. J. Nat. Prod.
1991, 54, 1137. (b) Kobayashi, J.; Tsuda, M.; Agemi, K.;
Shigemiri, H.; Ishibashi, M.; Sasaki, T.; Mikami, Y.
Tetrahedron 1991, 47, 6617. (c) Sannigrahi, M.
1H NMR (300 MHz, DMSO-d6): d = 10.62 (s, 1 H, NH), 7.68 (s, 1
H), 7.57 (s, 1 H), 7.30 (s, 1 H), 7.23–7.14 (m, 3 H), 6.95–6.83 (m, 2
H), 2.35 (s, 3 H), 2.33 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 177.7, 166.2, 162.6, 158.9,
155.5, 150.9, 144.1, 142.6, 134.0, 133.6, 129.3, 124.3, 123.3, 122.6,
117.4, 110.3, 109.9, 100.8, 57.6, 48.0, 20.2, 19.4.
Tetrahedron 1999, 55, 9007. (d) Heathcock, C. H.; Graham,
S. L.; Pirrung, M. C.; Plavac, F.; White, C. T. Spirocyclic
Systems, In The Total Synthesis of Natural Products, Vol. 5;
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127. (b) Galliford, C. V.; Scheidt, K. A. Angew. Chem. Int.
Ed. 2007, 46, 8748. (c) Cui, C. B.; Kakeya, H.; Osada, H.
J. Antibiot. 1996, 49, 832. (d) Cui, C. B.; Kakeya, H.;
Osada, H. Tetrahedron 1996, 52, 12651. (e) Cui, C. B.;
Kakeya, H.; Osada, H. Tetrahedron 1997, 53, 59. (f) Cui,
C. B.; Kakeya, H.; Okada, G.; Ubukata, M.; Takahashi, I.;
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HRMS–FAB: m/z [M + H]+ calcd for C22H16N3O4: 386.1141;
found: 386.1145.
Compound 48
The reaction of 5 (161 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 43
(176 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 48.
Yield: 327 mg (85%); solid; mp 299–300 °C.
IR (KBr): 3328, 2203, 1715, 1674, 1606, 1492, 1358 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.76 (s, 1 H), 7.65–7.57 (m, 3
H), 7.40–7.23 (m, 3 H), 7.08–7.01 (m, 2 H), 3.17 (s, 3 H), 2.44 (s, 3
H).
13C NMR (75 MHz, DMSO-d6): d = 176.1, 166.0, 162.4, 158.8,
155.5, 150.7, 144.1, 134.8, 133.9, 132.7, 129.5, 124.2, 123.2, 122.6,
116.8, 112.5, 108.9, 101.6, 57.2, 47.7, 26.9, 20.9.
HRMS–FAB: m/z [M + H]+ calcd for C22H16N3O4: 386.1141;
found: 386.1143.
(j) Rahman, A.; Silva, W. S. J.; Alvi, K. A.; De Silva, K. T.
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Compound 49
The reaction of 6 (161 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 43
(176 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 49.
Yield: 338 mg (88%); solid; mp >300 °C.
IR (KBr): 3359, 2199, 1708, 1672, 1498, 1358, 1212 cm–1.
(d) Matsuura, T.; Overmann, L. E.; Poon, D. J. J. Am. Chem.
Soc. 1998, 120, 6500.
1H NMR (300 MHz, DMSO-d6): d = 10.52 (s, 1 H, NH), 7.75 (s, 1
H), 7.62–7.58 (m, 4 H), 7.04–6.96 (m, 2 H), 6.74–6.72 (m, 1 H),
2.44 (s, 3 H), 2.19 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 177.6, 166.0, 158.8, 155.4,
152.0, 150.6, 140.1, 134.8, 133.9, 131.4, 129.6, 125.0, 123.1, 122.6,
116.8, 112.6, 109.7, 101.9, 57.7, 48.1, 21.0, 20.9.
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Pyne, S. G.; Ung, A. T.; Skelton, B. W.; White, A. H.;
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Vidulova, D. B.; Karatjas, A. G. J. Org. Chem. 2005, 70,
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G. D.; Wilson, H.; Kauffman, R. F.; Hayes, J. S. J. Med.
Chem. 1987, 30, 824. (k) Sebahar, P. R.; Osada, H.; Usui,
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HRMS–FAB: m/z [M + H]+ calcd for C22H16N3O4: 386.1141;
found: 386.1143.
Compound 50
The reaction of 7 (226 mg, 1.0 mmol), 2 (66 mg, 1.0 mmol), and 43
(176 mg, 1.0 mmol) in H2O (10 mL) at 60 °C for 1 h afforded 50.
Yield: 395 mg (88%); solid; mp >300 °C.
IR (KBr): 3359, 2199, 1708, 1672, 1498, 1358, 1212 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 10.77 (s, 1 H, NH), 7.75 (s, 1
H), 7.67 (s, 2 H), 7.60–7.58 (m, 1 H), 7.51 (s, 1 H), 7.40–7.38 (m, 2
H), 6.83–6.80 (d, J = 8.4 Hz, 1 H), 2.45 (s, 3 H).
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