Efficient one-pot synthesis of spirooxindole derivatives bearing hexahydroquinolines using multicomponent reactions catalyzed by ethylenediamine diacetate

Article abstract of DOI:10.1055/s-0033-1338506

A simple and efficient one-pot synthesis of biologically interesting spirooxindole derivatives bearing hexahydroquinoline skeleton was accomplished by EDDA-catalyzed, three-component reactions between isatins, malononitrile, and enaminones in good yields. The value of this methodology lies in its inexpensive and nontoxic organocatalyst, mild reaction conditions, and ease of handling.

Full text of DOI:10.1055/s-0033-1338506

PAPER
▌2593
paper
Efficient One-Pot Synthesis of Spirooxindole Derivatives Bearing Hexahydro-
quinolines Using Multicomponent Reactions Catalyzed by Ethylenediamine
Diacetate
One-Pot Synthesis of Spirooxindole Derivatives
So Rang Kang, Yong Rok Lee*
School of Chemical Engineering, Yeungnam University, Gyeongsan 712-749, Republic of Korea
Fax +82(53)8104631; E-mail: yrlee@yu.ac.kr
Received: 18.05.2013; Accepted after revision: 24.06.2013
nitrate,15 metal triflates,16 polymers,17 baker’s yeast,18 and
Abstract: A simple and efficient one-pot synthesis of biologically
p-TSA19 have been used in these reactions as catalytic and
interesting spirooxindole derivatives bearing hexahydroquinoline
stoichiometric reagents. Nevertheless, these known meth-
ods still suffer from several limitations, such as high reac-
skeleton was accomplished by EDDA-catalyzed, three-component
reactions between isatins, malononitrile, and enaminones in good
yields. The value of this methodology lies in its inexpensive and tion temperatures, long reaction times, the need for
nontoxic organocatalyst, mild reaction conditions, and ease of han-
dling.
expensive catalysts, and unsatisfactory yields. Therefore,
the search is still on for a better method of synthesizing
Key words: multicomponent reaction, spirooxindoles, enaminone,
hexahydroquinolines, ethylenediamine diacetate
hexahydroquinolines with a 1,4-dihydropyridine nucleus.
R
O
O
O
CN
Quinolines and their derivatives have received consider-
able attention as leading pharmaceutical compounds be-
cause of their pivotal roles in various biological activities
such as anti-inflammatory, antiasthmatic, antituberculo-
sis, antibacterial, antihypertensive, antitumor, and antima-
larial properties.1 Of these, hexahydroquinolines with a
1,4-dihydropyridine nucleus are particularly important
and have been shown to possess potent antibacterial, anti-
cancer, cytotoxic, myorelaxant, and neuroprotective, and
calcium channel modulatory activities.2 1,4-Dihydropyri-
dine moieties are well-known, significant compounds that
selectively block L-type calcium channels, and are one of
the most important classes of drugs for the treatment of
cardiovascular diseases including hypertension.3 Further-
more, they have been shown to possess a variety of bio-
logical activities, such as vasodilatory, bronchodilatory,
anti-atherosclerotic, antitumor, geroprotective, hepato-
protective, antidiabetic, antioxidant, antiviral, anticancer
activities.4 They also exhibit several medicinal properties,
which include neuroprotectant and platelet anti-aggrega-
tory activities, chemosensitization activities in tumor ther-
apy, and anti-ischemic activities during the treatment of
Alzheimer’s disease.5
H
CN
NH4OAc
+
CN
+
+
R
O
N
NH2
H
Scheme 1 Formation of 1,4-dihydropyridne products via the three-
component reaction
Molecules bearing the spirooxindole moiety are found
widely in nature20 and have been shown to possess a vari-
ety of important biological activities.21 Their unique struc-
tural array and prominent pharmacological activities have
stimulated interest in the synthesis of spirooxindole deriv-
atives. Thus, the development of new simpler synthetic
methods for the preparation of spirooxindole derivatives
has become an interesting challenge. Many synthetic
methodologies have been developed for constructing spi-
rooxindole derivatives, and the majority of these methods
were based on cycloaddition or condensation reactions.22
In particular, multicomponent reactions have emerged as
an efficient and powerful means of synthesizing complex
molecules using one-pot procedures.23 Several means of
synthesizing spirooxindoles based on multicomponent re-
actions have been developed using TBAF24 or triethylben-
zylammonium chloride (TEBA)25 as phase-transfer
catalysts, InCl326 as a Lewis acid catalyst, or electrocatal-
ysis.27
In view of the biological importance of hexahydroquino-
lines bearing a 1,4-dihydropyridine nucleus, several syn-
thetic methods have been reported based on four-
component reactions between dimedone, aromatic alde-
hydes, malononitrile, and ammonium acetate (Scheme
1).6–19 Microwaves,6 ionic liquids,7 ZnO nanoparticles,8
Bu4NHSO4,9 L-proline,10 HY-zeolite,11 silica-supported
acids,12 boronic acids,7a,13 TMSCl/NaI,14 ceric ammonium
In related work on the synthesis of spirooxindole deriva-
tives bearing a hexahydroquinoline moiety, one micro-
wave-assisted synthesis has been reported.28 However,
there is still demand for more concise and efficient syn-
thetic routes to biologically interesting spirooxindole de-
rivatives bearing a hexahydroquinoline moiety.
Recently, the potential of organocatalysts to serve as ac-
tive catalysts for a variety of synthetically useful reactions
was demonstrated.29 In particular, we developed a new
SYNTHESIS 2013, 45, 2593–2599
Advanced online publication: 19.07.2013
DOI: 10.1055/s-0033-1338506; Art ID: SS-2013-F0362-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

2594
S. R. Kang, Y. R. Lee
PAPER
and useful method for synthesizing a variety of benzopy-
Table 1 Effects of Catalyst and Solvents for the Synthesis of Spiro-
rans using ethylenediamine diacetate (EDDA) as an or- oxindole 4a Bearing Hexahydroquinoline Moiety
ganocatalyst.30 Pursuant to this, we reported a method for
synthesizing a variety of spirooxindole derivatives with a
2-aminotetrahydrochromene nucleus using EDDA-cata-
O
O
N
CN
catalyst
O
lyzed three-component reactions between isatins, malo-
+
O
+
NH2
solvent
r.t.
CN
N
N
nonitrile, and cyclohexane-1,3-diones (Scheme 2).31
H
H
CN
N
O
H
1a
2
3a
4a
.
R3
Catalyst
Solvent
Time
Yield (%)
R3
O
O
EDDA
O
Yb(OTf)3 (20 mol%)
InCl3 (20 mol%)
THF
THF
THF
THF
THF
THF
THF
H2O
24 h
24 h
12 h
10 h
12 h
12 h
12 h
24 h
24 h
24 h
7 h
0
0
CN
CN
(10 mol%)
O
R2
R3
R3
NH2
+
+
R2
N
R1
O
O
CN
N
R1
O
AcOH (10 mol%)
10
58
34
52
35
21
36
30
72
41
Scheme 2 Formation of spirooxoindoles via EDDA-catalyzed three-
NH2CH2CH2NH2 (10 mol%)
Ca(OH)2 (20 mol%)
component reaction
As part of our ongoing studies on the syntheses of novel K2CO3 (10 mol%)
types of spirooxindoles, we examined three-component
reactions between substituted isatins, malononitrile, and
enaminones in the presence of different catalysts and EDDA (10 mol%)
reagents. Here, we report the one-pot synthesis of biologi-
cally interesting spirooxindoles bearing hexahydroquino-
line nucleus using EDDA-catalyzed three-component EDDA (10 mol%)
Cs2CO3 (10 mol%)
EDDA (10 mol%)
DMF
MeOH
THF
CH2Cl2
reactions.
EDDA (10 mol%)
To produce spirooxindole derivatives bearing the hexahy-
droquinoline moiety, we first examined the reaction be-
EDDA (10 mol%)
24 h
tween isatin (1a), malononitrile (2), and 3-anilino-5,5-
dimethylcyclohex-2-en-1-one (3a) under several catalysts
and solvents. The results are summarized in Table 1. With
20 mol% of Yb(OTf)3 and InCl3 as a Lewis acid catalyst
in THF at room temperature for 24 hours, no desired prod-
ucts were produced. The use of AcOH (10 mol%) as a
Brønsted acid gave product 4a in low yield (10%), where-
as the use of ethylenediamine (10 mol%) as a Brønsted
base afforded 4a in 58% yield. Using Ca(OH)2 (20
mol%), K2CO3 (10 mol%), or Cs2CO3 (10 mol%), the de-
sired product 4a was produced in 34, 52, and 35% yields,
respectively. With 10 mol% of ethylenediamine diacetate,
the best yield (72%) was obtained in THF at room temper-
ature for 7 hours. This result is probably due to the driving
force of precipitation of product 4a, which is hardly
soluble in THF. When other solvents such as water, meth-
anol, dimethylformamide, or dichloromethane were used,
yields decreased. The structure of compound 4a was de-
termined by 1H NMR analysis and by comparison with re-
ported data.28 1H NMR spectrum of 4a showed an amide
proton at δ = 10.23 as a singlet and two amine protons at
δ = 5.38 as a broad singlet. In its 13C NMR spectrum, two
carbonyl peaks at δ = 193.8 and 179.4 were attributed to
an enone and an amide, and one characteristic quaternary
carbon peak on the spirooxindole ring was shown at δ =
49.3.
derivatives bearing the hexahydroquinoline moiety. Re-
sults are summarized in Table 2. Reactions between isatin
(1a), malononitrile, and cyclic enaminones 3b–e with
electron-donating or -withdrawing groups on the benzene
ring in the presence of 10 mol% of EDDA in THF at room
temperature for seven to eight hours afforded products
4b–e in 66–72% yields (Table 2, entries 1–4). Using 3-
anilinocyclohex-2-ene-1-one (3f), which does not have a
substituent on the cyclohexenone ring, the desired product
4f was produced in 69% yield (entry 5). Reactions using
isatins with electron-donating and -withdrawing groups
on the benzene ring were also successful. For example, re-
actions using 5-methylisatin (1b) with an electron-donat-
ing group on the benzene ring provided products 4g and
4h in 70 and 68% yield, respectively (entries 6, 7). Simi-
larly, reactions using 5-bromoisatin, 5-chloroisatin, and 5-
nitroisatin, which all possess an electron-withdrawing
group on the benzene ring, gave products 4i–n in 60–84%
yields (entries 8–13). When 1-methylisatin (1f) or 1-phe-
nylisatin (1g) was used, the desired products 4o–r were
produced in 65–76% yields (entries 14–17). Accordingly,
these reactions provided rapid routes to the synthesis of a
variety spirooxindole derivatives bearing the hexahydro-
quinoline moiety.
The formation of spirooxindole 4a could be explained by
domino Knoevenagel condensation and Michael addition
followed by cyclization, as shown in Scheme 3. We sup-
pose that isatin (1a) is first protonated by EDDA to give
the intermediate 5, which is then attacked by the carban-
To explore the generality and scope of this methodology,
additional reactions between isatins 1a–g, malononitrile,
and several cyclic enaminones 3a–f under the optimized
conditions were conducted to synthesize spirooxindole
Synthesis 2013, 45, 2593–2599
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of Spirooxindole Derivatives
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Table 2 Additional Reactions for the Synthesis of a Variety of Spirooxindole Derivatives Bearing Hexahydroquinoline Moieties
R3
R3
O
Ar
O
O
N
CN
CN
EDDA
(10 mol%)
R2
O
R3
R3
+
+
N
R1
O
NH2
ArHN
R2
1
2
3
CN
N
R1
O
4
Entry
Isatin
R1
R2
Enaminone R3
Ar
Time (h)
Product
Yield (%)
1
2
1a
1a
1a
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1f
H
H
3b
3c
3d
3e
3f
Me
4-MeC6H4
8
8
4b
4c
4d
4e
4f
72
70
66
70
69
70
68
68
70
84
76
62
60
65
67
76
74
H
H
Me
Me
Me
H
4-MeOC6H4
3
H
H
4-BrC6H4
7
4
H
H
4-ClC6H4
Ph
8
5
H
H
8
6
H
Me
Me
Br
Br
Cl
Cl
NO2
NO2
H
3a
3f
Me
H
Ph
9
4g
4h
4i
7
H
Ph
8
8
H
3a
3f
Me
H
Ph
9
9
H
Ph
9
4j
10
11
12
13
14
15
16
17
H
3a
3f
Me
H
Ph
9
4k
4l
H
Ph
9
H
3a
3f
Me
H
Ph
12
12
9
4m
4n
4o
4p
4q
4r
H
Ph
Me
Me
Ph
Ph
3a
3f
Me
H
Ph
1f
H
Ph
9
1g
1g
H
3a
3f
Me
H
Ph
12
12
H
Ph
ion produced by malononitrile in the presence of EDDA undergoes isomerization to furnish 9. Intramolecular at-
to yield the intermediate 6. Dehydration of 6 in the pres- tack of a nitrogen of 9 toward its cyano moiety affords the
ence of EDDA then gives isatylidene malononitrile 7 as a imine 10, which finally undergoes further reaction to give
Knoevenagel condensation product, and the intermediate the desired product 4a.
7 is attacked by the enaminone 3a to give 8, which then
H3N
+
NH2
–OAc
H3N
+
NH3
–OAc
+
+
–OAc
–OAc
CN
CN
NC
CN
O
–
HO
+
H
CN
CN
OH
O
CN
CN
H
– H2O
+
N
O
N
H
N
O
N
H
O
H
O
H
1a
2
5
6
7
N
H
3a
H
N
N
N
N
O
O
C
N
O
O
NH2
CN
NH
CN
CN
O
CN
O
CN
N
H
N
H
O
O
N
N
H
H
4a
10
8
9
Scheme 3 Plausible mechanism for the synthesis of spirooxindole 4a
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2593–2599

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S. R. Kang, Y. R. Lee
PAPER
2′-Amino-1′-(4-methoxyphenyl)-7′,7′-dimethyl-2,5′-dioxo-
In conclusion, we have described an efficient, one-pot,
EDDA-catalyzed syntheses of a variety of spirooxindole
derivatives bearing hexahydroquinolines starting from
readily available isatins, malononitrile, and enaminones.
These reactions provide a rapid synthetic route for the
preparation of biologically interesting spirooxindole de-
rivatives bearing hexahydroquinoline skeleton.
5′,6′,7′,8′-tetrahydro-1′H-spiro[indoline-3,4′-quinoline]-3′-car-
bonitrile (4c)
Reaction of 1a (147 mg, 1.0 mmol) with 2 (66 mg, 1.0 mmol) and
3c (245 mg, 1.0 mmol) in THF (4 mL) for 8 h afforded 4c; yield:
308 mg (70%); white solid; mp >300 °C.
IR (KBr): 3453, 3327, 3207, 2178, 1712, 1615, 1533, 1366, 1243
cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.14 (s, 1 H), 7.48–7.32 (m,
2 H) 7.16–7.09 (m, 3 H), 6.90 (t, J = 7.5 Hz, 2 H), 6.77 (d, J = 7.8
Hz, 1 H), 5.27 (s, 2 H), 3.86 (s, 3 H), 2.16–2.06 (m, 2 H), 1.98–1.84
(m, 2 H), 0.89 (s, 3 H), 0.83 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 195.0, 178.3, 151.9, 150.9,
141.4, 136.2, 134.1, 131.9, 131.0, 127.8, 125.0, 122.0, 121.0, 118.8,
110.7, 108.9, 60.2, 58.9, 55.1, 50.6, 42.1, 31.9, 27.8, 26.1.
All experiments were carried out under open air without using any
inert gases protection. Merck precoated silica gel plates (Art. 5554)
with a fluorescent indicator were used for analytical TLC. Flash col-
umn chromatography was performed using silica gel 9385 (Merck).
Melting points were determined with micro-cover glasses on a
Fisher-Johns apparatus and are uncorrected. 1H NMR spectra were
recorded on a Bruker-DPX (300 MHz) and Varian-VNS (600 MHz)
spectrometer in DMSO-d6 using 2.50 ppm as the solvent chemical
shift. 13C NMR spectra were recorded on a Bruker-DPX (75 MHz)
and Varian-VNS (150 MHz) spectrometer in DMSO-d6 using 39.51
ppm as the solvent chemical shift. IR spectra were recorded on a FT
IR (BIO-RAD) spectrophotometer. HRMS was carried out at Kore-
an Basic Science Institute (Daegu) on a JEOL JMS 700 spectrome-
ter.
HRMS (EI): m/z [M+] calcd for C26H24N4O3: 440.1848; found:
440.1845.
2′-Amino-1′-(4-bromophenyl)-7′,7′-dimethyl-2,5′-dioxo-
5′,6′,7′,8′-tetrahydro-1′H-spiro[indoline-3,4′-quinoline]-3′-car-
bonitrile (4d)
Reaction of 1a (147 mg, 1.0 mmol) with 2 (66 mg, 1.0 mmol) and
3d (293 mg, 1.0 mmol) in THF (4 mL) for 7 h afforded 4d; yield:
322 mg (66%); light yellow solid; mp >300 °C.
Compounds 4a–r; General Procedure
IR (KBr): 3464, 3339, 3213, 2193, 1734, 1643, 1362 cm–1.
To a solution of isatin 1 (1.0 mmol) and malononitrile (2; 66 mg, 1.0
mmol) and enaminone 3 (1.0 mmol) in THF (4 mL) was added
EDDA (18 mg, 10 mol%). The reaction mixture was stirred for 7 to
12 h until the completion of the reaction as indicated by TLC (elu-
ent: n-hexane–EtOAc, 1:1). The solvent was evaporated under re-
duced pressure to give a residue, which was purified by flash
column chromatography on silica gel with n-hexane–EtOAc (2:1)
(Table 2).
1H NMR (300 MHz, DMSO-d6): δ = 10.15 (s, 1 H), 7.71–7.60 (m,
3 H), 7.53 (t, J = 7.4 Hz, 1 H), 7.19–7.09 (m, 2 H), 6.90 (t, J = 7.2
Hz, 1 H), 6.76 (d, J = 7.2 Hz, 1 H), 5.42 (s, 2 H), 2.04–1.76 (m, 4
H), 0.92 (s, 3 H), 0.85 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 193.7, 179.0, 151.1, 150.3,
141.5, 136.7, 134.8, 132.1, 132.0, 129.7, 127.5, 123.1, 121.2, 118.8,
110.5, 108.6, 60.6, 49.4, 48.5, 41.9, 32.0, 27.6, 27.3.
HRMS (EI): m/z [M+] calcd for C25H21BrN4O2: 488.0848; found:
488.0850.
2′-Amino-7′,7′-dimethyl-2,5′-dioxo-1′-phenyl-5′,6′,7′,8′-tetra-
hydro-1′H-spiro[indoline-3,4′-quinoline]-3′-carbonitrile (4a)
Reaction of 1a (147 mg, 1.0 mmol) with 2 (66 mg, 1.0 mmol) and
3a (215 mg, 1.0 mmol) in THF (4 mL) for 7 h afforded 4a; yield:
295 mg (72%); white solid; mp >300 °C.
2′-Amino-1′-(4-chlorophenyl)-7′,7′-dimethyl-2,5′-dioxo-
5′,6′,7′,8′-tetrahydro-1′H-spiro[indoline-3,4′-quinoline]-3′-car-
bonitrile (4e)
Reaction of 1a (147 mg, 1.0 mmol) with 2 (66 mg, 1.0 mmol) and
3e (249 mg, 1.0 mmol) in THF (4 mL) for 8 h afforded 4e; yield:
311 mg (70%); light yellow solid; mp >300 °C.
IR (KBr): 3462, 3338, 2182, 1722, 1641, 1498, 1365, 1223, 1086,
1016, 756 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.23 (s, 1 H), 7.60–7.48 (m,
5 H), 7.18–7.10 (m, 2 H), 6.91 (t, J = 7.0 Hz, 1 H), 6.76 (d, J = 7.8
Hz, 1 H), 5.38 (s, 2 H), 2.15–1.99 (m, 2 H), 1.98–1.77 (m, 2 H), 0.87
(s, 3 H), 0.80 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 193.8, 179.4, 151.8, 151.1,
141.4, 136.6, 136.0, 130.2, 129.9, 127.6, 123.1, 121.3, 118.8, 110.4,
108.8, 61.0, 49.3, 48.5, 41.3, 32.0, 28.2, 26.6.
IR (KBr): 3438, 3323, 3253, 2188, 1743, 1645, 1365 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.15 (s, 1 H), 7.65 (d, J = 8.1
Hz, 2 H), 7.52 (d, J = 7.8 Hz, 2 H), 7.17–7.08 (m, 2 H), 6.90 (t,
J = 7.34 Hz, 1 H), 6.76 (d, J = 7.8 Hz, 1 H), 5.46 (s, 2 H), 2.16–2.07
(m, 2 H), 1.98–1.81 (m, 2 H), 0.90 (s, 3 H), 0.83 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 193.7, 179.3, 151.5, 151.0,
141.4, 136.5, 134.9, 134.5, 131.9, 130.2, 127.6, 123.1, 121.3, 118.7,
110.5, 108.7, 61.0, 49.3, 48.4, 41.3, 32.0, 28.1, 26.6.
HRMS (EI): m/z [M+] calcd for C25H22N4O2: 410.1745; found:
410.1743.
HRMS (EI): m/z [M+] calcd for C25H21N4O2: 444.1353; found:
444.1350.
2′-Amino-7′,7′-dimethyl-2,5′-dioxo-1′-(p-tolyl)-5′,6′,7′,8′-tetra-
hydro-1′H-spiro[indoline-3,4′-quinoline]-3′-carbonitrile (4b)
Reaction of 1a (147 mg, 1.0 mmol) with 2 (66 mg, 1.0 mmol) and
3b (229 mg, 1.0 mmol) in THF (4 mL) for 8 h afforded 4b; yield:
305 mg (72%); white solid; mp >300 °C.
2′-Amino-2,5′-dioxo-1′-phenyl-5′,6′,7′,8′-tetrahydro-1′H-spi-
ro[indoline-3,4′-quinoline]-3′-carbonitrile (4f)
Reaction of 1a (147 mg, 1.0 mmol) with 2 (66 mg, 1.0 mmol) and
3f (187 mg, 1.0 mmol) in THF (4 mL) for 8 h afforded 4f; yield: 264
mg (69%); white solid; mp >300 °C.
IR (KBr): 3321, 3244, 2185, 1715, 1615, 1366 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.12 (s, 1 H), 7.31 (d, J = 7.2
Hz, 2 H), 7.19–7.08 (m, 3 H), 6.90 (t, J = 7.2 Hz, 2 H), 6.78 (d,
J = 7.2 Hz, 1 H), 5.48 (s, 2 H), 2.34 (s, 3 H), 2.14–2.03 (m, 2 H),
1.94–1.73 (m, 2 H), 0.90 (s, 3 H), 0.84 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 193.9, 179.8, 151.0, 150.0,
141.8, 136.9, 134.8, 130.9, 129.8, 127.9, 123.2, 121.3, 119.1, 117.2,
110.1, 108.9, 60.72, 50.28, 48.18, 42.02, 32.12, 28.22, 27.99, 21.11.
IR (KBr): 3469, 3390, 3313, 3208, 2190, 1734, 1643, 1358 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.19 (s, 1 H), 7.63–7.59 (m,
3 H) 7.50–7.48 (m, 2 H), 7.19–7.09 (m, 2 H), 6.91 (t, J = 7.5 Hz, 1
H), 6.76 (d, J = 7.5 Hz, 1 H), 5.31 (s, 2 H), 2.20–2.07 (m, 3 H),
2.02–1.99 (m, 1 H), 1.79–1.66 (m, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 193.9, 179.5, 153.9, 150.8,
141.4, 136.8, 135.9, 130.1, 129.8, 127.6, 123.2, 121.3, 118.8, 111.6,
108.7, 61.0, 48.6, 36.0, 28.1, 20.8.
HRMS (EI): m/z [M+] calcd for C26H24N4O2: 424.1899; found:
424.1902.
Synthesis 2013, 45, 2593–2599
© Georg Thieme Verlag Stuttgart · New York

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One-Pot Synthesis of Spirooxindole Derivatives
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HRMS (EI): m/z [M+] calcd for C23H18N4O2: 382.1430; found:
382.1427.
HRMS (EI): m/z [M+] calcd for C23H17BrN4O2: 460.0535; found:
460.0537.
2′-Amino-5,7′,7′-trimethyl-2,5′-dioxo-1′-phenyl-5′,6′,7′,8′-tet-
rahydro-1′H-spiro[indoline-3,4′-quinoline]-3′-carbonitrile (4g)
Reaction of 1b (161 mg, 1.0 mmol) with 2 (66 mg, 1.0 mmol) and
3a (187 mg, 1.0 mmol) in THF (4 mL) for 9 h afforded 4g; yield:
296 mg (70%); white solid; mp >300 °C.
2′-Amino-5-chloro-7′,7′-dimethyl-2,5′-dioxo-1′-phenyl-
5′,6′,7′,8′-tetrahydro-1′H-spiro[indoline-3,4′-quinoline]-3′-car-
bonitrile (4k)
Reaction of 1d (181 mg, 1.0 mmol) with 2 (66 mg, 1.0 mmol) and
3a (215 mg, 1.0 mmol) in THF (4 mL) for 9 h afforded 4k; yield:
373 mg (84%); light yellow solid; mp >300 °C.
IR (KBr): 3457, 3339, 2191, 1707, 1642, 1362 cm–1.
IR (KBr): 3456, 3338, 2190, 1711, 1641, 1477, 1363 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.08 (s, 1 H), 7.65–7.60 (m,
3 H), 7.48–7.46 (m, 2 H), 6.94 (m, 2 H), 6.65 (d, J = 7.8 Hz, 1 H),
5.29 (s, 2 H), 2.25 (s, 3 H), 2.11–1.98 (m, 2 H), 1.92–1.82 (m, 2 H),
0.88 (s, 3 H), 0.83 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 193.9, 179.4, 151.8, 151.0,
139.1, 136.8, 136.0, 130.3, 130.1, 129.9, 127.9, 123.7, 118.9, 110.4,
108.6, 61.2, 49.3, 48.6, 41.4, 32.1, 28.0, 26.9, 20.7.
1H NMR (300 MHz, DMSO-d6): δ = 10.32 (s, 1 H), 7.62–7.52 (m,
5 H), 7.24 (d, J = 2.1 Hz, 1 H), 7.16 (dd, J = 8.1, 2.1 Hz, 1 H), 6.78
(d, J = 8.1 Hz, 1 H), 5.38 (s, 2 H), 2.10–2.01 (m, 3 H), 1.92–1.86
(m, 1 H), 0.88 (s, 3 H), 0.84 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 193.9, 179.1, 152.3, 151.1,
140.5, 138.6, 135.7, 130.2, 130.0, 127.4, 125.3, 123.2, 118.6, 115.0,
110.1, 109.6, 60.2, 49.2, 49.0, 41.3, 32.0, 27.7, 27.1.
HRMS (EI): m/z [M+] calcd for C26H24N4O2: 424.1899; found:
424.1903.
HRMS (EI): m/z [M+] calcd for C25H21ClN4O2: 444.1353; found:
444.1355.
2′-Amino-5-methyl-2,5′-dioxo-1′-phenyl-5′,6′,7′,8′-tetrahydro-
1′H-spiro[indoline-3,4′-quinoline]-3′-carbonitrile (4h)
Reaction of 1b (161 mg, 1.0 mmol) with 2 (66 mg, 1.0 mmol) and
3f (187 mg, 1.0 mmol) in THF (4 mL) for 8 h afforded 4h; yield:
269 mg (68%); white solid; mp >300 °C.
2′-Amino-5-chloro-2,5′-dioxo-1′-phenyl-5′,6′,7′,8′-tetrahydro-
1′H-spiro[indoline-3,4′-quinoline]-3′-carbonitrile (4l)
Reaction of 1d (226 mg, 1.0 mmol) with 2 (66 mg, 1.0 mmol) and
3f (187 mg, 1.0 mmol) in THF (4 mL) for 9 h afforded 4l; yield: 316
mg (76%); light yellow solid; mp >300 °C.
IR (KBr): 3437, 3329, 3194, 2185, 1720, 1644, 1357 cm–1.
IR (KBr): 3499, 3348, 3206, 2184, 1724, 1643, 1358 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.06 (s, 1 H), 7.62–7.59 (m,
3 H), 7.50–7.48 (m, 2 H), 6.97–6.90 (m, 2 H), 6.65 (d, J = 7.5 Hz, 1
H), 5.25 (s, 2 H), 2.14 (s, 3 H), 2.11–2.09 (m, 3 H), 2.03–1.96 (m, 1
H), 1.77–1.74 (m, 2 H).
1H NMR (300 MHz, DMSO-d6): δ = 10.36 (s, 1 H), 7.59–7.37 (m,
5 H), 7.29 (s, 1 H), 7.16 (d, J = 8.1 Hz, 1 H), 6.7 (d, J = 8.1 Hz, 1
H), 5.45 (s, 2 H), 2.11–2.01 (m, 4 H), 1.99–1.74 (m, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 194.1, 179.2, 154.5, 150.9,
140.4, 138.8, 135.7, 130.1, 130.0, 129.89, 127.4, 125.4, 123.4,
118.7, 110.8, 110.1, 60.2, 49.1, 35.9, 28.1, 20.7.
13C NMR (75 MHz, DMSO-d6): δ = 193.7, 179.2, 153.5, 150.6,
138.9, 136.7, 135.9, 129.9, 129.6, 129.6, 127.7, 123.4, 118.4, 111.7,
108.4, 61.9, 48.7, 35.9, 27.9, 20.5, 20.4.
HRMS (EI): m/z [M+] calcd for C23H17ClN4O2: 416.1040; found:
416.1037.
HRMS (EI): m/z [M+] calcd for C24H20N4O2: 396.1586; found:
396.1586.
2′-Amino-7′,7′-dimethyl-5-nitro-2,5′-dioxo-1′-phenyl-
5′,6′,7′,8′-tetrahydro-1′H-spiro[indoline-3,4′-quinoline]-3′-car-
bonitrile (4m)
Reaction of 1e (192 mg, 1.0 mmol) with 2 (66 mg, 1.0 mmol) and
3a (215 mg, 1.0 mmol) in THF (4 mL) for 12 h afforded 4m; yield:
282 mg (62%); light yellow solid; mp >300 °C.
2′-Amino-5-bromo-7′,7′-dimethyl-2,5′-dioxo-1′-phenyl-
5′,6′,7′,8′-tetrahydro-1′H-spiro[indoline-3,4′-quinoline]-3′-car-
bonitrile (4i)
Reaction of 1c (226 mg, 1.0 mmol) with 2 (66 mg, 1.0 mmol) and
3a (215 mg, 1.0 mmol) in THF (4 mL) for 9 h afforded 4i; yield: 332
mg (68%); light yellow solid; mp >300 °C.
IR (KBr): 3238, 2189, 1749, 1571, 1366, 1336, 1266, 707 cm–1.
IR (KBr): 3456, 3341, 2190, 1714, 1643, 1365 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.95 (s, 1 H), 8.14 (d, J = 8.7
Hz, 1 H), 8.02 (s, 1 H), 7.63–7.52 (m, 5 H), 7.00 (d, J = 8.4 Hz, 1
H), 5.48 (s, 2 H), 2.04–2.00 (m, 4 H), 0.89 (s, 3 H), 0.85 (s, 3 H).
1H NMR (300 MHz, DMSO-d6): δ = 10.35 (s, 1 H), 7.62–7.56 (m,
5 H), 7.35–7.28 (m, 2 H), 6.73 (d, J = 8.1 Hz, 1 H), 5.40 (s, 2 H),
2.09–1.96 (m, 2 H), 1.91–1.86 (m, 2 H), 0.88 (s, 3 H), 0.84 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 195.2, 180.9, 153.9, 152.4,
149.2, 143.2, 138.5, 136.4, 131.2, 131.0, 130.8, 126.2, 119.4, 119.4,
110.1, 109.9, 60.2, 50.0, 49.8, 42.3, 33.0, 28.4, 28.2.
13C NMR (75 MHz, DMSO-d6): δ = 194.1, 179.1, 152.4, 151.2,
141.0, 139.1, 135.7, 130.1, 130.0, 125.9, 118.7, 115.0, 113.1, 110.8,
109.6, 60.1, 49.2, 49.1, 41.4, 32.1, 27.7, 27.1.
HRMS (EI): m/z [M+] calcd for C25H21N5O4: 455.1594; found:
455.1596.
HRMS (EI): m/z [M+] calcd for C25H21BrN4O2: 488.0848; found:
488.0851.
2′-Amino-5-nitro-2,5′-dioxo-1′-phenyl-5′,6′,7′,8′-tetrahydro-
1′H-spiro[indoline-3,4′-quinoline]-3′-carbonitrile (4n)
Reaction of 1e (192 mg, 1.0 mmol) with 2 (66 mg, 1.0 mmol) and
3f (187 mg, 1.0 mmol) in THF (4 mL) for 12 h afforded 4n; yield:
256 mg (60%); light yellow solid; mp >300 °C.
2′-Amino-5-bromo-2,5′-dioxo-1′-phenyl-5′,6′,7′,8′-tetrahydro-
1′H-spiro[indoline-3,4′-quinoline]-3′-carbonitrile (4j)
Reaction of 1c (226 mg, 1.0 mmol) with 2 (66 mg, 1.0 mmol) and
3f (187 mg, 1.0 mmol) in THF (4 mL) for 9 h afforded 4j; yield: 322
mg (70%); light yellow solid; mp >300 °C.
IR (KBr): 3453, 3331, 3250, 2185, 1744, 1634, 1525, 1336 cm–1.
IR (KBr): 3350, 3262, 2183, 1722, 1642, 1570, 1359, 1248, 1186,
699 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.3 (s, 1 H), 7.61–7.59 (m, 3
H), 7.39–7.31 (m, 2 H), 7.18–7.13 (m, 2 H), 6.72 (d, J = 8.4 Hz, 1
H), 5.30 (s, 2 H), 2.17–2.08 (m, 4 H), 1.92–1.86 (m, 2 H).
1H NMR (300 MHz, DMSO-d6): δ = 10.99 (s, 1 H), 8.15–8.04 (m,
2 H), 7.70–7.51 (m, 3 H), 7.38 (t, J = 7.8 Hz, 1 H), 7.15 (t, J = 7.9
Hz, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 5.57 (s, 2 H), 2.17–2.06 (m, 4
H), 1.90–1.86 (m, 1 H), 1.79–1.70 (m, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 194.4, 180.0, 161.8, 155.2,
151.2, 148.2, 142.4, 137.7, 135.5, 130.1, 130.0 125.2, 118.8, 118.4,
110.3, 108.8, 59.3, 49.0, 35.7, 28.1, 20.7.
13C NMR (75 MHz, DMSO-d6): δ = 195.3, 178.8, 161.8, 150.7,
140.8, 139.0, 135.6, 130.0, 129.8, 129.5, 125.6, 124.0, 122.8, 112.8,
110.4, 98.2, 60.2, 48.9, 36.1, 28.2, 21.2.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2593–2599

2598
S. R. Kang, Y. R. Lee
PAPER
HRMS (EI): m/z [M+] calcd for C23H17N5O4: 427.1281; found:
427.1279.
128.5, 128.1, 124.1, 124.0, 119.4, 112.5, 109.9, 61.0, 50.2, 36.6,
29.1, 21.5.
HRMS (EI): m/z [M+] calcd for C29H22N4O2: 458.1743; found:
458.1740.
2′-Amino-1,7′,7′-trimethyl-2,5′-dioxo-1′-phenyl-5′,6′,7′,8′-tet-
rahydro-1′H-spiro[indoline-3,4′-quinoline]-3′-carbonitrile (4o)
Reaction of 1f (161 mg, 1.0 mmol) with 2 (66 mg, 1.0 mmol) and
3a (215 mg, 1.0 mmol) in THF (4 mL) for 9 h afforded 4o; yield:
275 mg (65%); white solid; mp >300 °C.
Acknowledgment
IR (KBr): 3457, 3373, 3317, 2186, 1716, 1650, 1363 cm–1.
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology
(2012R1A1A4A01009620).
1H NMR (300 MHz, DMSO-d6): δ = 7.64–7.61 (m, 3 H), 7.52–7.50
(m, 2 H), 7.25 (t, J = 7.5 Hz, 2 H), 7.04–6.96 (m, 2 H), 5.40 (s, 2 H),
3.16 (s, 3 H), 2.19–2.07 (m, 2 H), 2.00–1.81 (m, 2 H), 0.89 (s, 3 H),
0.82 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 193.8, 177.9, 151.9, 151.2,
142.9, 135.9, 135.7, 130.3, 129.9, 127.9, 122.9, 122.1, 118.7, 110.3,
107.6, 60.5, 49.2, 48.2, 41.3, 32.1, 28.1, 26.6, 26.2.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
HRMS (EI): m/z [M+] calcd for C26H24N4O2: 424.1899; found:
424.1902.
References
(1) (a) Robert, A.; Dechy-Cabaret, O.; Cazelles, J.; Meunier, B.
Acc. Chem. Res. 2002, 35, 167. (b) Ridley, R. G. Nature
2002, 415, 686. (c) Carosati, E.; Mannhold, R.; Wahl, P.;
Hansen, J. B.; Fremming, T.; Zamora, I.; Cianchetta, G.;
Baroni, M. J. Med. Chem. 2007, 50, 2117. (d) Matsuyama,
N.; Kato, T.; Kimura, K.; Mizutani, T.; Saeki, K. J. Health
Sci. 2006, 52, 821. (e) Nayyar, A.; Malde, A.; Jain, R.;
Coutinho, E. Bioorg. Med. Chem. 2006, 14, 847. (f) Kym, P.
R.; Kort, M. E.; Coghlan, M. J.; Moore, J. L.; Tang, R.;
Ratajczyk, J. D.; Larson, D. P.; Elmore, S. W.; Pratt, J. K.;
Stashko, M. A.; Falls, H. D.; Lin, C. W.; Nakane, M.; Miller,
L.; Tyree, C. M.; Miner, J. N.; Jacobson, P. B.; Wilcox, D.
M.; Nguyen, P.; Lane, B. C. J. Med. Chem. 2003, 46, 1016.
(g) Heitsch, H. Curr. Med. Chem. 2002, 9, 913.
2′-Amino-1-methyl-2,5′-dioxo-1′-phenyl-5′,6′,7′,8′-tetrahydro-
1′H-spiro[indoline-3,4′-quinoline]-3′-carbonitrile (4p)
Reaction of 1f (161 mg, 1.0 mmol) with 2 (66 mg, 1.0 mmol) and 3f
(187 mg, 1.0 mmol) in THF (4 mL) for 9 h afforded 4p; yield: 265
mg (67%); white solid; mp >300 °C.
IR (KBr): 3466, 3329, 2180, 1721, 1629, 1356 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 7.59–7.51 (m, 5 H), 7.27–7.19
(m, 2 H), 7.02–6.93 (m, 2 H), 5.38 (s, 2 H), 3.14 (s, 3 H), 2.17–1.89
(m, 4 H), 1.76–1.67 (m, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 193.8, 177.9, 154.0, 150.9,
142.8, 135.9, 130.1, 129.9, 129.1, 127.8, 122.9, 122.0, 118.7, 111.4,
107.5, 60.5, 48.3, 35.9, 28.0, 26.2, 20.7.
HRMS (EI): m/z [M+] calcd for C24H20N4O2: 396.1586; found:
396.1588.
(h) Narender, P.; Srinivas, U.; Ravinder, M.; Rao, B. A.;
Ramesh, C.; Harakishore, K.; Gangadasu, B.; Murthy, U. S.
N.; Rao, V. J. Bioorg. Med. Chem. 2006, 14, 4600.
(i) Muruganantham, N.; Sivakumar, R.; Anbalagan, N.;
Gunasekaran, V.; Leonard, J. T. Biol. Pharm. Bull. 2004, 27,
1683. (j) Tsotinis, A.; Vlachou, M.; Zouroudis, S.; Jeney, A.;
Timar, F.; Thurston, D. E.; Roussakis, C. Lett. Drug Des.
Discov. 2005, 2, 189. (k) Joshi, A. A.; Viswanathan, C. L.
Bioorg. Med. Chem. Lett. 2006, 16, 2613.
2′-Amino-7′,7′-dimethyl-2,5′-dioxo-1,1′-diphenyl-5′,6′,7′,8′-tet-
rahydro-1′H-spiro[indoline-3,4′-quinoline]-3′-carbonitrile (4q)
Reaction of 1g (223 mg, 1.0 mmol) with 2 (66 mg, 1.0 mmol) and
3a (215 mg, 1.0 mmol) in THF (4 mL) for 12 h afforded 4q; yield:
370 mg (76%); white solid; mp >300 °C.
IR (KBr): 3418, 3296, 2951, 2188, 1713, 1654, 1366 cm–1.
1H NMR (600 MHz, DMSO-d6): δ = 7.65–7.59 (m, 5 H), 7.58–7.51
(m, 2 H), 7.47 (t, J = 3.8 Hz, 1 H), 7.43 (d, J = 3.9 Hz, 2 H), 7.35 (d,
J = 3.6 Hz, 1 H), 7.18 (t, J = 3.8 Hz, 1 H), 7.06 (t, J = 3.8 Hz, 1 H),
6.64 (d, J = 3.9 Hz, 1 H), 5.50 (s, 2 H), 2.09–2.14 (m, 2 H), 2.00–
1.85 (m, 2 H), 0.90 (s, 3 H), 0.84 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 194.5, 177.7, 152.5, 151.4,
142.8, 136.1, 135.7, 135.5, 130.6, 130.3, 129.9, 129.8, 128.2, 128.1,
126.8, 123.8, 123.1, 119.0, 110.6, 108.4, 60.8, 49.4, 48.6, 41.6,
32.5, 28.5, 26.9.
(2) (a) El-Sabbagh, O. I.; Shabaan, M. A.; Kadry, H. H.; Al-Din,
E. S. Arch. Pharm. (Weinheim, Ger.) 2010, 9, 519. (b) Al-
Said, M. S.; Ghorab, M. M.; Al-Dosari, M. S.; Hamed, M.
M. Eur. J. Med. Chem. 2011, 46, 201. (c) Alqasoumi, S. I.;
Al-taweel, A. M.; Alafeefy, A. M.; Hamed, M. M.; Noaman,
E.; Ghorab, M. M. Bioorg. Med. Chem. Lett. 2009, 19, 6939.
(d) Gündüz, M. G.; Öztürk, G. S.; Vural, İ. M.; Şimşek, R.;
Sarioğlu, Y.; Şafak, C. Eur. J. Med. Chem. 2008, 43, 562.
(e) León, R.; de los Ríos, C.; Marco-Contelles, J.; Huertas,
O.; Barril, X.; Luque, F. J.; López, M. G.; García, A. G.;
Villarroya, M. Bioorg. Med. Chem. 2008, 16, 7759. (f) Miri,
R.; Javidnia, K.; Mirkhani, H.; Hemmateenejad, B.;
Sepeher, Z.; Zalpour, M.; Behzad, T.; Khoshneviszadeh, M.;
Edraki, N.; Mehdipour, A. R. Chem. Biol. Drug Des. 2007,
70, 329.
(3) (a) Godfraid, T.; Miller, R.; Wibo, M. Pharmacol. Rev.
1986, 38, 321. (b) Mager, P. P.; Coburn, R. A.; Solo, A. J.;
Triggle, D. J.; Rothe, H. Drug. Des. Discov. 1992, 8, 273.
(c) Mannhold, R.; Jablonka, B.; Voigt, W.; Schöenafinger,
K.; Schraven, E. Eur. J. Med. Chem. 1992, 27, 229.
(d) Triggle, D. J.; Langs, D. A.; Janis, R. A. Med. Res. Rev.
1989, 9, 123. (e) Shan, R.; Velazquez, C.; Knaus, E. E.
J. Med. Chem. 2004, 47, 254. (f) Sawada, Y.; Kayakiri, H.;
Abe, Y.; Mizutani, T.; Inamura, N.; Asano, M.; Hatori, C.;
HRMS (EI): m/z [M+] calcd for C31H26N4O2: 486.2056; found:
486.2058.
2′-Amino-2,5′-dioxo-1,1′-diphenyl-5′,6′,7′,8′-tetrahydro-1′H-
spiro[indoline-3,4′-quinoline]-3′-carbonitrile (4r)
Reaction of 1g (223 mg, 1.0 mmol) with 2 (66 mg, 1.0 mmol) and
3f (187 mg, 1.0 mmol) in THF (4 mL) for 12 h afforded 4r; yield:
339 mg (74%); white solid; mp >300 °C.
IR (KBr): 3466, 3334, 2184, 1727, 1640, 1497, 1364, 1296 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 7.62–7.55 (m, 6 H), 7.49–7.42
(m, 4 H), 7.36 (d, J = 6.9 Hz, 1 H), 7.18 (t, J = 7.5 Hz, 1 H), 7.06 (t,
J = 7.2 Hz, 1 H), 6.63 (d, J = 7.5 Hz, 1 H), 5.46 (s, 2 H), 2.26–2.09
(m, 3 H), 2.03–1.97 (m, 1 H), 1.81–1.70 (m, 2 H).
13C NMR (150 MHz, C6D6 + CD3OD): δ = 196.7, 180.5, 156.0,
152.1, 144.2, 136.4, 136.0, 131.0, 130.9, 130.2, 129.0, 128.9, 128.7,
Synthesis 2013, 45, 2593–2599
© Georg Thieme Verlag Stuttgart · New York

PAPER
Aramori, I.; Oku, T.; Tanaka, H. J. Med. Chem. 2004, 47,
One-Pot Synthesis of Spirooxindole Derivatives
2599
38, 3186. (c) Ashimori, A.; Bachand, B.; Overman, L. E.;
Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6477.
2853.
(4) (a) Aruoma, O.; Smith, C.; Cecchini, R.; Evans, P.;
Halliwell, B. Biochem. Pharmacol. 1991, 42, 735.
(b) Hilgeroth, A. Mini-Rev. Med. Chem. 2002, 2, 235.
(c) Kawase, M.; Shah, A.; Gaveriya, H.; Motohashi, N.;
Sakagami, H.; Varga, A.; Molnár, J. Bioorg. Med. Chem.
2002, 10, 1051.
(5) (a) Klusa, V. Drugs Future 1995, 20, 135. (b) Boer, R.;
Gekeler, V. Drugs Future 1995, 20, 499. (c) Sausins, A.;
Duburs, G. Heterocycles 1988, 27, 279. (d) Bretzel, R. G.;
Bollen, C. C.; Maester, E.; Federlin, K. F. Am. J. Kidney Dis.
1993, 21, 54.
(6) (a) Agarwal, A.; Chauhan, P. M. S. Tetrahedron Lett. 2005,
46, 1345. (b) Öhberg, L.; Westman, J. Synlett 2001, 1296.
(7) (a) Sridhar, R.; Perumal, P. T. Tetrahedron 2005, 61, 2465.
(b) Ji, S. J.; Jiang, Z. Q.; Lu, J.; Loh, T. P. Synthesis 2004,
831.
(8) Kassaee, M. Z.; Masrouri, H.; Movahedi, F. Monatsh. Chem.
2010, 141, 317.
(9) Tewari, N.; Dwivedi, N.; Tripathi, R. P. Tetrahedron Lett.
2004, 45, 9011.
(10) Karade, N. N.; Budhewar, V. H.; Shinde, S. V.; Jadhav, W.
N. Lett. Org. Chem. 2007, 4, 16.
(11) Das, B.; Ravikanth, B.; Ramu, R.; Rao, B. V. Chem. Pharm.
Bull. 2006, 54, 1044.
(d) Matsuura, T.; Overman, L. E.; Poon, D. J. J. Am. Chem.
Soc. 1998, 120, 6500. (e) Cui, C. B.; Kakeya, H.; Osada, H.
Tetrahedron 1996, 52, 12651.
(22) (a) Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677.
(b) Yong, S. R.; Ung, A. T.; Pyne, S. G.; Skelton, B. W.;
White, A. H. Tetrahedron 2007, 63, 1191. (c) Jiang, T.;
Kuhen, K. L.; Wolff, K.; Yin, H.; Bieza, K.; Caldwell, J.;
Bursulaya, B.; Wu, T. Y.-H.; He, Y. Bioorg. Med. Chem.
Lett. 2006, 16, 2105. (d) Yong, S. R.; Williams, M. C.; Pyne,
S. G.; Ung, A. T.; Skelton, B. W.; White, A. H.; Turner, P.
Tetrahedron 2005, 61, 8120. (e) Feldman, K. S.; Vidulova,
D. B.; Karatjas, A. G. J. Org. Chem. 2005, 70, 6429.
(f) Osman, F. H.; Samahy, F. A. Tetrahedron 2000, 56,
1863. (g) Mao, Z.; Baldwin, S. W. Org. Lett. 2004, 6, 2425.
(h) Feldman, K. S.; Karatjas, A. G. Org. Lett. 2006, 8, 4137.
(i) Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127,
11505. (j) Robertson, D. W.; Krushinski, J. H.; Pollock, G.
D.; Wilson, H.; Kauffman, R. F.; Hayes, J. S. J. Med. Chem.
1987, 30, 824. (k) Sebahar, P. R.; Osada, H.; Usui, T.;
Williams, R. M. Tetrahedron 2002, 58, 6311. (l) Lo, M. M.-
C.; Neumann, C. S.; Nagayama, S.; Perlstein, E. O.;
Schreiber, S. L. J. Am. Chem. Soc. 2004, 126, 16077.
(23) (a) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (b) Dömling, A. Chem. Rev. 2006, 106, 17. (c) Zhu, J.
Eur. J. Org. Chem. 2003, 1133.
(12) Maheswara, M.; Siddaiah, V.; Rao, Y. K.; Tzeng, Y.;
Sridhar, C. J. Mol. Catal. A: Chem. 2006, 260, 179.
(13) Debache, A.; Tafer, R.; Boulcina, R.; Belfaitah, A.; Rhouati,
S.; Carboni, B. Synthesis 2008, 2112.
(14) Sabitha, G.; Reddy, G. S. K. K.; Reddy, C. S.; Yadav, J. S.
Tetrahedron Lett. 2003, 44, 4129.
(24) Gao, S.; Tsai, C. H.; Tseng, C.; Yao, C. F. Tetrahedron
2008, 64, 9143.
(25) Zhu, S.-L.; Ji, S. J.; Zhang, Y. Tetrahedron 2007, 63, 9365.
(26) Shanthi, G.; Subbulakshmi, G.; Perumal, P. T. Tetrahedron
2007, 63, 2057.
(15) Ko, S.; Yao, C. F. Tetrahedron 2006, 62, 7293.
(16) (a) Wang, L. M.; Sheng, Z.; Zhang, L.; Han, J. W.; Fan, Z.;
Tian, H.; Qian, C. T. Tetrahedron 2005, 61, 1539.
(b) Donelson, J. L.; Gibbs, R. A.; De , S. K. J. Mol. Catal. A:
Chem. 2006, 256, 309.
(27) Elinson, M. N.; Ilovaisky, A. I.; Dorofeev, A. S.; Merkulova,
V. M.; Stepanov, N. O.; Miloserdov, F. M.; Ogibin, Y. N.;
Nikishin, G. I. Tetrahedron 2007, 63, 10543.
(28) Zhu, S.-L.; Zhao, K.; Su, X.-M.; Ji, S.-J. Synth. Commun.
2009, 39, 1355.
(17) (a) Legeay, J. C.; Goujon, J. Y.; Eynde, J. J. V.; Toupet, L.;
Bazureau, J. P. J. Comb. Chem. 2006, 8, 829. (b) Dondoni,
A.; Massi, A.; Minghini, E.; Bertolasi, V. Tetrahedron 2004,
60, 2311.
(18) (a) Lee, J. H. Tetrahedron Lett. 2005, 46, 7329. (b) Kumar,
A.; Maurya, R. A. Tetrahedron Lett. 2007, 48, 3887.
(19) Cherkupally, S. R.; Mekala, R. Chem. Pharm. Bull. 2008,
56, 1002.
(20) (a) Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36,
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.; Onose, R.; Ubukata, M.; Takahashi, I.; Isono,
K.; Osada, H. J. Antibiot. 1995, 48, 1382. (g) Cui, C. B.;
Kakeya, H.; Okada, G.; Onose, R.; Osada, H. J. Antibiot.
1996, 49, 527. (h) Cui, C. B.; Kakeya, H.; Osada, H.
J. Antibiot. 1996, 49, 534. (i) Kang, T. H.; Matsumoto, K.;
Tohda, M.; Murakami, Y.; Takayama, H.; Kitajima, M.;
Aimi, N.; Watanabe, H. Eur. J. Pharmacol. 2002, 444, 39.
(j) Rahman, A.; Silva, W. S. J.; Alvi, K. A.; De Silva, K. T.
D. Phytochemistry 1987, 26, 865. (k) Rahman, A.; Qureshi,
M. M.; Muzaffar, A.; De Silva, K. T. D. Heterocycles 1988,
27, 725. (l) Harada, M.; Ozaki, Y. Chem. Pharm. Bull. 1978,
26, 48.
(29) (a) Bolm, C.; Rantanen, T.; Schiffers, I.; Zani, L. Angew.
Chem. Int. Ed. 2005, 44, 1758. (b) Berrisford, D. J.; Bolm,
C.; Sharpless, K. B. Angew. Chem. Int. Ed. 1995, 34, 1059.
(c) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001,
1245. (d) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37,
570.
(30) (a) Lee, Y. R.; Choi, J. H.; Yoon, S. H. Tetrahedron Lett.
2005, 46, 7539. (b) Lee, Y. R.; Lee, W. K.; Noh, S. K.; Lyoo,
W. S. Synthesis 2006, 853. (c) Lee, Y. R.; Kim, D. H.
Synthesis 2006, 603. (d) Lee, Y. R.; Kim, J. H. Synlett 2007,
2232. (e) Wang, X.; Lee, Y. R. Tetrahedron Lett. 2007, 48,
6275. (f) Wang, X.; Lee, Y. R. Synthesis 2007, 3044.
(g) Lee, Y. R.; Xia, L. Synthesis 2007, 3240. (h) Lee, Y. R.;
Kim, Y. M. Helv. Chim. Acta 2007, 90, 2401. (i) Lee, Y. R.;
Li, X.; Kim, J. H. J. Org. Chem. 2008, 73, 4313. (j) Xia, L.;
Lee, Y. R. Synlett 2008, 1643. (k) Lee, Y. R.; Hung, T. V.
Tetrahedron 2008, 64, 7338. (l) Lee, Y. R.; Xia, L.
Tetrahedron Lett. 2008, 49, 3283. (m) Wang, X.; Lee, Y. R.
Tetrahedron 2009, 65, 10125. (n) Lee, Y. R.; Kim, Y. M.;
Kim, S. H. Tetrahedron 2009, 65, 101. (o) Jung, D. H.; Lee,
Y. R.; Kim, S. H. Helv. Chim. Acta 2010, 93, 635. (p) Kolla,
S. R.; Lee, Y. R. Tetrahedron 2010, 66, 8938. (q) Park, B.
H.; Lee, H. J.; Lee, Y. R. J. Nat. Prod. 2011, 74, 644.
(r) Wang, X.; Lee, Y. R. Tetrahedron 2011, 67, 9179.
(s) Narasimhulu, M.; Lee, Y. R. Tetrahedron 2011, 67,
9627. (t) Kolla, S. R.; Lee, Y. R. Tetrahedron 2012, 68, 226.
(u) Pandit, R. P.; Lee, Y. R. Synthesis 2012, 44, 2910.
(31) Hari, G. S.; Lee, Y. R. Synthesis 2010, 453.
(21) (a) Fischer, C.; Meyers, C.; Carreira, E. M. Helv. Chim. Acta
2000, 83, 1175. (b) Alper, P. B.; Meyers, C.; Lerchner, A.;
Siegel, D. R.; Carreira, E. M. Angew. Chem. Int. Ed. 1999,
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Synthesis 2013, 45, 2593–2599