Enantioselective synthesis of spiro[4H-pyran-3,3′-oxindole] derivatives catalyzed by cinchona alkaloid thioureas: Significant water effects on the enantioselectivity

Article abstract of DOI:10.1080/00397911.2019.1651866

An efficient stereoselective three-component reaction for the synthesis of functionalized spiro[4H-pyran-3,3′-oxindole] derivatives was realized through an organocatalyzed domino Knoevenagel/Michael/cyclization reaction using a cinchonidine-derived thiourea as the catalyst. Using water as the additive was found to improve the product ee values significantly. Under the optimized conditions, the reactions between isatins, malononitrile, and 1,3-dicarbonyl compounds yield the desired spirooxindole products in good yields (71–92%) and moderate to high ee values (up to 87% ee).

Full text of DOI:10.1080/00397911.2019.1651866

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Enantioselective synthesis of spiro[4H-pyran-3,3′-
oxindole] derivatives catalyzed by cinchona
alkaloid thioureas: Significant water effects on the
enantioselectivity
Swapna Konda, Satish Jakkampudi, Hadi D. Arman & John C.-G. Zhao
To cite this article: Swapna Konda, Satish Jakkampudi, Hadi D. Arman & John C.-G. Zhao (2019):
Enantioselective synthesis of spiro[4H-pyran-3,3′-oxindole] derivatives catalyzed by cinchona
alkaloid thioureas: Significant water effects on the enantioselectivity, Synthetic Communications,
DOI: 10.1080/00397911.2019.1651866
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https://doi.org/10.1080/00397911.2019.1651866
Enantioselective synthesis of spiro[4H-pyran-3,30-oxindole]
derivatives catalyzed by cinchona alkaloid thioureas:
Significant water effects on the enantioselectivity
Swapna Konda, Satish Jakkampudi, Hadi D. Arman, and John C.-G. Zhao
Department of Chemistry, University of Texas at San Antonio, San Antonio, TX, USA
ABSTRACT
ARTICLE HISTORY
Received 10 June 2019
An efficient stereoselective three-component reaction for the synthe-
sis of functionalized spiro[4H-pyran-3,30-oxindole] derivatives was
realized through an organocatalyzed domino Knoevenagel/Michael/
cyclization reaction using a cinchonidine-derived thiourea as the
catalyst. Using water as the additive was found to improve the prod-
uct ee values significantly. Under the optimized conditions, the reac-
tions between isatins, malononitrile, and 1,3-dicarbonyl compounds
yield the desired spirooxindole products in good yields (71–92%)
and moderate to high ee values (up to 87% ee).
KEYWORDS
Asymmetric organocatalysis;
cinchona alkaloid;
enantioselective; spirooxin-
dole; water effect
GRAPHICAL ABSTRACT
Introduction
Multicomponent reactions (MCRs), in which three or more starting materials react to
form a product in a one-pot fashion, are convergent and environmentally friendly in
nature and easy to operate.[1–7] As a result, there have been tremendous developments
CONTACT John C.-G. Zhao
cong.zhao@utsa.edu
Department of Chemistry, University of Texas at San Antonio,
One UTSA Circle, San Antonio, TX 78249-0698, USA.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article is available online at on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
S. KONDA ET AL.
Figure 1. Structure of spiro[4H-pyran-3,30-oxindole].
in the MCRs in the past decades and these reactions have been extensively used in
organic synthesis.[1–10] Spirooxindole, which constitutes the core structure of many nat-
ural alkaloids and drug candidates, represents one of the most important heterocyclic
frameworks and has become a privileged skeleton in drug discovery.[11–14] Because of
their biological relevance and the unique structural feature (containing a spiro tetrasub-
stituted stereogenic center), the stereoselective construction of such a spiro framework
has attracted a lot of attention in recent years and numerous successes have been
recorded for the stereoselective synthesis of a plethora of spirooxindole structures over
past years.[15–18] Among the reported methods, the domino reaction[19–22] is one of the
most important strategy for the asymmetric synthesis of spirooxindole derivatives.[15–18]
Despite these advances, the stereoselective synthesis of one unique spirooxindole,
spiro[4H-pyran-3,30-oxindole], that incorporates a 2-amino-4H-pyran-3-carbonitrile ring
at the C3 position of the oxindole, is still very limited (Fig. 1).[23–36] Most of the
reported methods focus on the synthesis of the racemic products of these spiro[4H-
pyran-3,30-oxindole] derivatives.[23–28] In 2010 Yuan and coworkers reported the first
catalytic asymmetric synthesis of these spiro[4H-pyran-3,30-oxindole] derivatives via
two- or three-component reactions of N-protected isatins using cupreine (60-hydroxycin-
chonidine) as the catalyst.[29] Soon after, Macaev briefly studied a similar three-component
reaction using (S)-brevicolline [(S)-1-methyl-4-(1-methyl-2-pyrrolidinyl)-9H-pyrido[3,4-
b]indole] as the catalyst.[30] In addition, these authors also realized a diastereoselective syn-
thesis of this type of compounds in 2014.[31] Nevertheless, there is no systematic study for
synthesizing these spiro[4H-pyran-3,30-oxindole] derivatives directly from N-unsubsti-
tuted isatins in optically enriched forms.[31]
Our group is interested in developing novel asymmetric methods for the synthesis of
chiral 2-amino-4H-pyran-3-carbonitrile[37–41] and isatin derivatives.[42–49] During the
course of our research, we became interested in the synthesis of spiro[4H-pyran-3,30-
oxindole] derivatives using the three-component reaction of isatin, malononitrile, and
ethyl acetoacetate, and in this study we found that water had a significant impact[50–56]
on the asymmetric induction of the cinchona alkaloid thiourea catalysts when they were
applied in the three-component reaction. It has been known that water can play a very
important role in catalysis,[50–56] and many organocatalyzed reactions have been suc-
cessfully conducted either in water, on water, or in the presence of water.[50–59] Herein
we wish to report that water can significantly improve the enantioselectivity of the
three-component reaction of isatins, malononitrile, and 1,3-dicarbonyl compounds (ace-
toacetate and 1,3-diketone) catalyzed by cinchona alkaloid thioureas and an efficient
enantioselective synthesis of functionalized spiro[4H-pyran-3,30-oxindole] derivatives
can be achieved by employing a cinchonidine-derived thiourea as the catalyst and water
as the additive.

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3
Figure 2. Catalysts screened in this study [Ar ¼ 3,5–(CF3)2C6H3–].
Results and discussion
Some readily available cinchona alkaloid derivatives (1–5, Fig. 2)[60–64] were adopted as
the catalysts and isatin (6a), malononitrile (7), and ethyl acetoacetate (8a) as the model
substrates. The results of the catalyst screening and reaction condition optimizations are
summarized in Table 1. As shown in Table 1, when quinidine thiourea (1a) was used as
the catalyst in toluene at rt for 15 h, the desired product 9a was obtained in a good
yield of 76%, but a low ee value of 40% (entry 1). This result actually surpassed our
expectations since this catalyst had been briefly evaluated by Yuan and coworkers for
N-MOM protected isatin and an almost racemic product was obtained.[29] In contrast,
when cupreine (2) was used, the ee value of 9a dropped to 32% (entry 2). This was
very surprising since cupreine was reported to be a highly selective catalyst for N-pro-
tected isatins.[29] On the other hand, slightly better yields and ee values were obtained
when cinchonine thiourea (1b), quinine thiourea (3a), cinchonidine thiourea (3b) were
used as the catalysts (entries 3–5), with cinchonidine thiourea (3b) giving the best
results (82% yield, 56% ee, entry 5). Nonetheless, the more sterically demanding N,N’-
bisquinidine thiourea (4) and N,N0-bisquinidine squaramide (5) both failed to improve
the product yield or ee value (entries 6 and 7). It should be pointed out that opposite
enantiomers were obtained as the major products from the quinidine-derived catalysts
(i.e., 1a, 1b, 4, and 5) and the quinine-derived ones (i.e., 3a and 3b), except for
cupreine (2), which yields the same major enantiomer as that of the quinidine-derived
catalysts. Since water is formed as a side product in this reaction, in order to rule out
the effect of water on the stereoselectivity of this reaction, molecular sieves were added
as an additive to the reaction mixture with 3b as the catalyst (entry 8). Surprisingly, we
found that a much lower ee value of 9a (40% ee) was obtained (For a similar observa-
tion in thiourea catalysis, see reference 58 in the references list). Since it appeared that
water might actually have some beneficial effects on the product ee value, it was inten-
tionally added to the reaction as an additive (entry 9), and, to our pleasure, the ee value
of 9a increased to 62% when 0.025 mL of water was added. The ee value of 9a could be
further increased to 66% without affecting the product yield by increasing the volume
of water to 0.050 mL (entry 10) or 0.100 mL (entry 11). However, further increase of the

4
S. KONDA ET AL.
Table 1. Optimization of the reaction conditions of the three-component reactiona.
+
+
Entry
6
8
Additive
Catalyst
9
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
6c
6a
6a
6a
6a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8b
8c
8d
8e
None
None
None
None
None
None
None
MS 4Åe
H2Of
1a
2
1b
3a
3b
4
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9b
9c
9d
9e
9f
76
73
82
78
82
80
78
78
83
84
84
78
52
32
70
72
84
82
78
74
80
78
80
82
76
40d
32d
50d
50
56
40d
40d
40
5
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
9
62
66
66
62
18
12
19
6
10
11
12i
13j
14k
15l
16m
17n
18o
19p
20n
21n
22n
23n
24n
25n
H2Og
H2Oh
H2Og
H2Og
H2Og
H2Og
H2Og
H2Og
H2Og
H2Og
H2Og
H2Og
H2Og
H2Og
H2Og
H2Og
72
70
46
28d,q
71d,r
64
53
87
82
9g
aUnless otherwise specified, all reactions were carried out with
6 (0.10 mmol), 7 (0.10 mmol), 8 (0.10 mmol), and the catalyst (0.010 mmol, 10 mol%) in
toluene (1.0 mL) at room temperature. bYield of the isolated product after flash column chromatography. cDetermined by HPLC analysis on a ChiralPak
IB, IC, or AD-H column. The absolute configuration of the reaction products was determined by the X-ray crystallographic analysis of compound 9m
(vide infra). dThe opposite enantiomer was obtained as the major product. eMolecular sieves (30.0 mg) were used. f0.025 mL of water was used.
g0.050 mL of water was used. h0.100 mL of water was used. iThe solvent was xylene. jThe solvent was MeOH. kThe solvent was DMSO. lThe solvent
was CH Cl . mThe solvent was THF. nReaction was carried out at 0 ꢀC. oReaction was carried out at ꢁ5 ꢀC. pReaction was carried out at 40 ꢀC. qThe
2
2
stereochemistry of this compound was assigned based on analogy with compound 9c. rThe absolute configuration of product 9c was determined by
comparing the measured optical rotation with that reported in the literature.[29]
water amount resulted in a lower product ee value (data not shown). Using 3b as the
catalyst and 0.050 mL of water as the additive, we then screened some common organic
solvents. Except for xylene (entry 12), in which slightly lower yield and ee value were
obtained, poor product yields and ee values were obtained in methanol (entry 13),
DMSO (entry 14), CH2Cl2 (entry 15), and THF (entry 16). When the reaction was car-
ried out in toluene at 0 ꢀC with water (0.050 mL), the ee value of 9a was further

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5
Table 2. Substrate scope of the three-component reactiona.
Entry
X
R
Time (h)
9/Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
5-H
5-H
5-F
OEt
Oi-Pr
OEt
Oi-Pr
OEt
Oi-Pr
OEt
Oi-Pr
OEt
15
15
15
15
24
24
15
15
15
24
15
15
15
20
15
22
9a/84
9f/82
9h/86
9i/81
9j/82
9k/78
9l/80
9m/83
9n/92
9o/78
9p/80
9q/78
9r/80
9s/80
9t/78
9u/71
72
87
60
71
59
74
59
58
65
44
62
83
67
71
60
38
5-F
5-Cl
5-Cl
5-Br
5-Br
5-I
4-Cl
6-Cl
7-Cl
5-NO2
5-CH3
5-OMe
H
9
10
11
12
13
14
15
16
OEt
Oi-Pr
Oi-Pr
Oi-Pr
OEt
OEt
Me
aUnless otherwise specified, all reactions were carried out with
6 (0.10 mmol), 7 (0.10 mmol), 8 (0.10 mmol), and 3b (0.010 mmol, 10 mol%) in toluene
(1.0 mL) and water (0.050 mL) at 0 ꢀC. bYield of the isolated product after flash column chromatography. cDetermined by HPLC analysis on a ChiralPak
IB, IC, or AD-H column.
increased to 72% (entry 17). Further dropping (to ꢁ5 ꢀC) or increasing (to 40 ꢀC) the
temperature resulted in worse product ee values (entries 18–19). Next, the effects of the
N-substituent on isatin (6) was evaluated under the optimized conditions (entries
20–21), and, it was found that the best results were obtained with N-unsubstituted isatin
(6a, entry 17), whereas the N-methyl substituted 6b (entry 20) and N-benzyl substituted
6c (entry 21) gave much and slightly worse results, respectively. Moreover, the opposite
enantiomers (i.e., the R-enantiomers) were obtained as the major products in these
cases. The ester alkyl group of the acetoacetate was also found to have significant effects
on the product ee value. While the methyl (8b) and benzyl (8c) esters both yielded
worse ee values of the products (entries 22–23) than that of the ethyl ester (entry 17),
the more sterically demanding isopropyl (8d) and tert-butyl (8e) esters led to higher
product ee values (entries 24–25), with the highest ee value (87%) obtained with the iso-
propyl acetoacetate (8d, entry 24).
Once the reaction conditions were optimized, the substrate scope of this three-
component domino Knoevenagel/Michael/cyclization reaction was then established.
The results in Table 2 are a collection of the best results of the reaction under the
optimized conditions. It was found that, with different isatin derivatives, the isopro-
pyl acetoacetate would produce the corresponding the spiro[4H-pyran-3,30-oxindole]
derivatives in slightly higher ee values than or practically identical ee values as the
ethyl acetoacetate. As the results in Table 2 show, while the electronic nature and
the position of the substituent on the isatin ring have minimal effects on the prod-
uct yield, they do have some influence on the enantioselectivity of this reaction. For
5-substituted isatins (entries 3–9, and 13–15), electron-withdrawing groups usually

6
S. KONDA ET AL.
Figure 3. ORTEP drawing of compound 9m.
Scheme 1. Proposal for the favored transition state for the formation of 9a.
give slightly lower ee values of the desired products than the electron-donating
groups, except for 5-nitroisatin (entry 13). Also 4-chloroisatin (entry 10) leads to a
much lower ee value than 5-chloro- (entry 5), 6-chloro- (entry 11), or 7-chloroisatin
(entry 12). Finally, when the acetoacetate is replaced with a 1,3-ketone (2,4-petane-
dione), the desired product 9u was obtained in a similar yield of 71%, but the prod-
uct ee value was only 38% (entry 16).

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7
The absolute configuration of the stereogenic center in the reaction product was
assigned as S according to the X-ray crystallographic analysis of compound 9m (Fig. 3).
A pure enantiomer of 9m was obtained through repeated recrystallization of the initial
reaction product. CCDC 1883860 contains the supplementary crystallographic data for
compound 9m. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data-
request/cif, or by emailing data_request@ccdc.cam.ac.uk.
On the basis of the absolute stereochemistry of 9a, a plausible transition state model
is proposed (Scheme 1). As shown in Scheme 1, isatin (6a) first reacts with malononi-
trile (7) to yield the isatylidenemalononitrile intermediate, which hydrogen-bonded to
the thiourea moiety of the catalyst. Meanwhile, the enolate form of ethyl acetoacetate
(8a) is hydrogen-bonded to the ammonium moiety of the catalyst. In the favored transi-
tion state, the enolate is attacking the Re face of isatylidenemalononitrile from the back,
which yields intermediate 10. Further intramolecular cyclization of 10 gives 11, which
tautomerizes to give the expected product 9a. Water probably helps improve the enan-
tioselectivity of this reaction through the formation of additional hydrogen bonds
between isatylidenemalononitrile and the catalyst (Scheme 1), which results in a more
compact transition state and better control of the isatylidenemalononitrile orientation in
the transition state. However, such an orientation of isatylidenemalononitrile will not be
favorable if the N-atom of the isatylidenemalononitrile is substituted with a large group,
such as a benzyl group, due to the steric interactions between that substituent and the
thiourea moiety of the catalyst, and that might be the reason why the opposite enan-
tiomers were obtained with the N-substituted isatins.
Conclusion
In summary, we have developed an enantioselective method for the synthesis of
spiro[4H-pyran-3,30-oxindole] derivatives from the three-component reaction of isatins,
malononitrile, and 1,3-dicarbonyl compounds (acetoacetates and one 1,3-diketone).
Using a cinchonidine-derived thiourea catalyst (3b, 10 mol% loading) and water as the
additive in toluene at 0 ꢀC, the corresponding spirooxindole derivatives of N-unsubsti-
tuted isatins may be obtained in good yields (71–92%) and moderate to high ee values
(38–87% ee). A significant improvement of the product ee values was observed in the
presence of the water additive.
Experimental
General information
1
Unless otherwise mentioned, all reactions were carried out in a closed vial. H NMR
spectra were recorded on a 500 MHz spectrometer (126 MHz for 13C). The following
abbreviations were used to designate chemical shift mutiplicities: s ¼ singlet, d ¼ doublet,
t ¼ triplet, q ¼ quartet, h ¼ heptet, and m ¼ multiplet. All first-order splitting patterns
were assigned on the basis of the appearance of the multiplet. Splitting patterns that
could not be easily interpreted are designated as multiplets (m). TLC was performed
with silica gel GF254 precoated on aluminum plates and spots were visualized with UV.
Flash column chromatography was performed using silica gel. HPLC analysis was

8
S. KONDA ET AL.
performed on an HPLC instrument equipped with a UV-Vis detector. Solvents were
freshly distilled under a nitrogen atmosphere before use, using the standard protocols.
All the reagents were purchased from commercial sources and used as received.
General procedure for the domino Knoevenagel/Michael/cyclization reaction
To a vial, the catalyst cinchonidine thiourea (3b, 5.6 mg, 0.010 mmol, 10 mol%), isatin
(6a, 14.7 mg, 0.10 mmol), malononitrile (7, 6.6 mg, 0.10 mmol), toluene (1.0 mL) and
water (0.050 mL) were added sequentially. The mixture was stirred at 0 ꢀC for 10 min
before the addition of isopropyl acetoacetate (8d, 14.4 mg, 0.10 mmol). The reaction
mixture was further stirred at 0 ꢀC for 15 h. Upon the completion (monitored by TLC),
the reaction mixture was dried over anhydrous sodium sulfate, filtered, and the solvent
was evaporated. The crude reaction mixture was purified by flash column chromatog-
raphy with a 40:60 hexane/EtOAc mixture as the eluent to yield to product 9f (27.8 mg,
82%) as a white solid. The enantiomeric ratio was determined by HPLC analysis on a
chiral ChiralPak IB column.
Acknowledgments
The authors thank Dr. Wendell P. Griffith for help with the HRMS analysis of the samples.
Funding
The generous financial support for this research from the Welch Foundation [AX-1593] and the
National Science Foundation [CHE-1664278] is gratefully acknowledged. Some of the NMR data
reported in this paper were collected on an NMR spectrometer acquired with the funding from
the National Science Foundation [CHE-1625963]. The HRMS used in this research was supported
by a grant from the National Institute on Minority Health and Health Disparities [G12
MD007591] from the National Institutes of Health.
ORCID
John C.-G. Zhao
http://orcid.org/0000-0001-7174-5956
References
ꢀ
[1] Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Maximizing Synthetic Efficiency: Multi-
Component Transformations Lead the Way. Chem. Eur. J. 2000, 6, 3321–3329. DOI: 10.
1002/1521-3765(20000915)6:18<3321::AID-CHEM3321>3.0.CO;2-A.
[2] Tietze, L. F.; Modi, A. Multicomponent Domino Reactions for the Synthesis of
Biologically Active Natural Products and Drugs. Med. Res. Rev. 2000, 20, 304–322. DOI:
10.1002/1098-1128(200007)20:4<304::AID-MED3>3.0.CO;2-8.
€
[3] Domling, A.; Ugi, I. Multicomponent Reactions with Isocyanides. Angew. Chem. Int. Ed.
Engl. 2000, 39, 3168–3210. DOI: 10.1002/1521-3773(20000915)39:18<3168::AID-
ANIE3168>3.0.CO;2-U.
[4] Zhu, J. Recent Developments in the Isonitrile-Based Multicomponent Synthesis of
Heterocycles. Eur. J. Org. Chem. 2003, 2003, 1133–1144. DOI: 10.1002/ejoc.200390167.

R
SYNTHETIC COMMUNICATIONSV
9
[5] Simon, C.; Constantieux, T.; Rodriguez, J. Utilisation of 1,3-Dicarbonyl Derivatives in
Multicomponent Reactions. Eur. J. Org. Chem. 2004, 2004, 4957–4980. DOI: 10.1002/ejoc.
200400511.
ꢀ
[6] Ramon, D. J.; Yus, M. Asymmetric Multicomponent Reactions (AMCRs): The New
Frontier. Angew. Chem. Int. Ed. 2005, 44, 1602–1634. DOI: 10.1002/anie.200460548.
[7] Ahmadi, T.; Mohammadi Ziarani, G.; Gholamzadeh, P.; Mollabagher, H. Recent Advances
in Asymmetric Multicomponent Reactions (AMCRs). Tetrahedron 2017, 28, 708–724.
DOI: 10.1016/j.tetasy.2017.04.002.
[8] Terrett, N. K. Combinational Chemistry; Oxford University Press: New York, NY, 1998.
[9] Hulme, C.; Dietrich, J. Emerging Molecular Diversity from the Intra-Molecular Ugi
Reaction: iterative Efficiency in Medicinal Chemistry. Mol. Divers. 2009, 13, 195–207.
DOI: 10.1007/s11030-009-9111-6.
[10] Sepehri, S.; Sanchez, H. P.; Fassihi, A. Hantzsch-Type Dihydropyridines and Biginelli-
Type Tetra-Hydropyrimidines: A Review of Their Chemotherapeutic Activities. J. Pharm.
Pharm. Sci. 2015, 18, 1–52. DOI: 10.18433/J3Q01V.
[11] Singh, G. S.; Desta, Z. Y. Isatins as Privileged Molecules in Design and Synthesis of Spiro-
Fused Cyclic Frameworks. Chem. Rev. 2012, 112, 6104–6155. DOI: 10.1021/cr300135y.
[12] Williams, R. M.; Cox, R. J. Paraherquamides, Brevianamides, and Asperparalines:
Laboratory Synthesis and Biosynthesis. An Interim Report. Acc. Chem. Res. 2003, 36,
127–139. DOI: 10.1021/ar020229e.
[13] Yang, Y.-T.; Zhu, J.-F.; Liao, G.; Xu, H.-J.; Yu, B. The Development of Biologically
Important Spirooxindoles as New Antimicrobial Agents. Curr. Med. Chem. 2018, 25,
2233–2244. DOI: 10.2174/0929867325666171129131311.
[14] Panda, S. S.; Jones, R. A.; Bachawala, P.; Mohapatra, P. P. Spirooxindoles as Potential
Pharmacophores. Mini. Rev. Med. Chem. 2017, 17, 1515–1536. DOI: 10.2174/
1389557516666160624125108.
[15] Mohammadi Ziarani, G.; Moradi, R.; Lashgari, N. Asymmetric Synthesis of Chiral
Oxindoles Using Isatin as Starting Material. Tetrahedron 2018, 74, 1323–1353. DOI: 10.
1016/j.tet.2018.01.025.
[16] Mei, G.-J.; Shi, F. Catalytic Asymmetric Synthesis of Spirooxindoles: Recent
Developments. Chem. Commun. 2018, 54, 6607–6621. DOI: 10.1039/C8CC02364F.
[17] Santos, M. M. M. Recent Advances in the Synthesis of Biologically Active Spirooxindoles.
Tetrahedron 2014, 70, 9735–9757. DOI: 10.1016/j.tet.2014.08.005.
[18] Cheng, D.; Ishihara, Y.; Tan, B.; Barbas, C. F. Organocatalytic Asymmetric Assembly
Reactions: Synthesis of Spirooxindoles via Organocascade Strategies. ACS Catal. 2014, 4,
743–762. DOI: 10.1021/cs401172r.
[19] Pellissier, H. Recent Developments in Asymmetric Organocatalytic Domino Reactions.
Recent Developments in Asymmetric Organocatalytic Domino Reactions. Adv. Synth.
Catal. 2012, 354, 237–294. DOI: 10.1002/adsc.201100714.
[20] Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. Bifunctional Amine-
Squaramides: Powerful Hydrogen-Bonding Organocatalysts for Asymmetric Domino/
Cascade Reactions. Adv. Synth. Catal. 2015, 357, 253–281. DOI: 10.1002/adsc.201401003.
[21] Ardkhean, R.; Caputo, D. F. J.; Morrow, S. M.; Shi, H.; Xiong, Y.; Anderson, E. A.
Cascade Polycyclizations in Natural Product Synthesis. Chem. Soc. Rev. 2016, 45,
1557–1569. DOI: 10.1039/C5CS00105F.
[22] Chanda, T.; Zhao, J. C.-G. Recent Progress in Organocatalytic Asymmetric Domino
Transformations. Adv. Synth. Catal. 2018, 360, 2–79. DOI: 10.1002/adsc.201701059.
[23] Chen, H.; Shi, D. Efficient One-Pot Synthesis of Novel Spirooxindole Derivatives via
Three-Component Reaction in Aqueous Medium. J. Comb. Chem. 2010, 12, 571–576.
DOI: 10.1021/cc100056p.
[24] Hao, W.-J.; Wang, S.-Y.; Ji, S.-J. Iodine-Catalyzed Cascade Formal [3 þ 3] Cycloaddition
Reaction of Indolyl Alcohol Derivatives with Enaminones: Constructions of
Functionalized Spirodihydrocarbolines. ACS Catal. 2013, 3, 2501–2504. DOI: 10.1021/
cs400703u.

10
S. KONDA ET AL.
[25] Khalafi-Nezhad, A.; Mohammadi, S. Magnetic, Acidic, Ionic Liquid-Catalyzed One-Pot
Synthesis of Spirooxindoles. ACS Comb. Sci. 2013, 15, 512–518. DOI: 10.1021/co400080z.
[26] Mondal, A.; Mukhopadhyay, C. FeCl3-Catalyzed Combinatorial Synthesis of
Functionalized Spiro[Indolo-3,100-indeno [1,2-b]quinolin]-trione Derivatives. ACS Comb.
Sci. 2015, 17, 404–408. DOI: 10.1021/acscombsci.5b00038.
[27] Litvinov, Y. M.; Mortikov, V. Y.; Shestopalov, A. M. Versatile Three-Component
Procedure for Combinatorial Synthesis of 2-Aminospiro[(30H)-Indol-30,4-(4H)-Pyrans]. J.
Comb. Chem. 2008, 10, 741–745. DOI: 10.1021/cc800093q.
[28] Li, Y.; Chen, H.; Shi, C.; Shi, D.; Ji, S. Efficient One-Pot Synthesis of Spirooxindole
Derivatives Catalyzed by l-Proline in Aqueous Medium. J. Comb. Chem. 2010, 12,
231–237. DOI: 10.1021/cc9001185.
[29] Chen, W.-B.; Wu, Z.-J.; Pei, Q.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Highly
Enantioselective Construction Of Spiro, [4H-Pyran-3.30-Oxindoles] Through a Domino
Knoevenagel/Michael/Cyclization Sequence Catalyzed by Cupreine. Org. Lett. 2010, 12,
3132–3135. DOI: 10.1021/ol1009224.
[30] Macaev, F.; Sucman, N.; Shepeli, F.; Zveaghintseva, M.; Pogrebnoi, V. Facile and
Convenient One-Pot Process for the Synthesis of Spirooxindole Derivatives in High
Optical Purity Using (ꢁ)-(S)-Brevicolline as an Organocatalyst. Symmetry 2011, 3,
165–170. DOI: 10.3390/sym3020165.
[31] Macaev, F. Z.; Sucman, N. S.; Pogrebnoi, S. I.; Logina, L. P.; Barba, A. N. Initial Synthesis
of Diastereomeric Pyran Spirooxoindolinones Based on (–)-Carvone and (þ)-3-Carene.
Chem. Nat. Compd. 2014, 50, 103–108. DOI: 10.1007/s10600-014-0877-0.
[32] Jiang, X.; Sun, Y.; Yao, J.; Cao, Y.; Kai, M.; He, N.; Zhang, X.; Wang, Y.; Wang, R. Core
Scaffold-Inspired Concise Synthesis of Chiral Spirooxindole-Pyranopyrimidines with
Broad-Spectrum Anticancer Potency. Adv. Synth. Catal. 2012, 354, 917–925. DOI: 10.
1002/adsc.201100792.
[33] Zhu, Q.-N.; Zhang, Y.-C.; Xu, M.-M.; Sun, X.-X.; Yang, X.; Shi, F. Enantioselective
Construction of Tetrahydroquinolin-5-one-Based Spirooxindole Scaffold via an
Organocatalytic Asymmetric Multicomponent [3 þ 3] Cyclization. J. Org. Chem. 2016, 81,
7898–7907. DOI: 10.1021/acs.joc.6b01598.
[34] Kumari, P.; Nandi, S.; Kumar, G.; Khan, N. H. R.; Kureshy, I.; Abdi, S. H. R.; Suresh, E.;
Bajaj, H. C. Construction of Highly Enantioselective Spiro-Oxindole Derivatives with
Fused Chromene via Organocascade Catalysis. RSC Adv. 2016, 6, 52384–52390. DOI: 10.
1039/C6RA06812J.
[35] Chennapuram, M.; Owolabi, I. A.; Seki, C.; Okuyama, Y.; Kwon, E.; Uwai, K.; Tokiwa, M.;
Takeshita, M.; Nakano, H. New Hybrid-Type Squaramide-Fused Amino Alcohol
Organocatalyst for Enantioselective Domino Michael Addition/Cyclization Reaction of
Oxoindolines with Cyclic 1,3-Diketones. ACS Omega 2018, 3, 11718–11726. DOI: 10.1021/
acsomega.8b01271.
[36] Hu, J.-L.; Sha, F.; Li, Q.; Wu, X.-Y. Highly Enantioselective Michael/Cyclization Tandem
Reaction between Dimedone and Isatylidene Malononitriles. Tetrahedron 2018, 74,
7148–7155. DOI: 10.1016/j.tet.2018.10.029.
[37] Gogoi, S.; Zhao, C.-G. Organocatalyzed Enantioselective Synthesis of 6-Amino-5-
Cyanodihydropyrano[2,3-c]Pyrazoles. Tetrahedron Lett. 2009, 50, 2252–2255. DOI: 10.
1016/j.tetlet.2009.02.210.
[38] Muramulla, S.; Zhao, C.-G. A New Catalytic Mode of the Modularly Designed
Organocatalysts (MDOs): Enantioselective Synthesis of Dihydropyrano[2,3-c]Pyrazoles.
Tetrahedron Lett. 2011, 52, 3905–3908. DOI: 10.1016/j.tetlet.2011.05.092.
[39] Ding, D.; Zhao, C.-G. Organocatalyzed Synthesis of 2-Amino-8-Oxo-5,6,7,8-Tetrahydro-
4H-Chromene-3-Carbonitriles. Tetrahedron Lett. 2010, 51, 1322–1325. DOI: 10.1016/j.tet-
let.2009.12.139.
[40] Ramireddy, N.; Abbaraju, S.; Zhao, C.-G. Organocatalyzed Enantioselective Synthesis of 2-
Amino-5-Oxo-5,6,7,8-Tetrahydro-4H-Chromene-3-Carboxylates. Tetrahedron Lett. 2011,
52, 6792–6795. DOI: 10.1016/j.tetlet.2011.10.040.

R
SYNTHETIC COMMUNICATIONSV
11
[41] Ramireddy, N.; Abbaraju, S.; Ding, D.; Arman, H.; Zhao, J. C.-G. Organocatalyzed
Enantioselective Synthesis of 2-Amino-4H-Chromene Derivatives. J. Heterocyclic Chem.
2017, 54, 677–691. DOI: 10.1002/jhet.2641.
[42] Guo, Q.; Bhanushali, M.; Zhao, C.-G. Quinidine Thiourea-Catalyzed Aldol Reaction of
Unactivated Ketones: Highly Enantioselective Synthesis of 3-Alkyl-3-Hydroxyindolin -2-
Ones. Angew. Chem. Int. 2010, 49, 9460–9464. DOI: 10.1002/ange.201004161.
[43] Guang, J.; Guo, Q.; Zhao, J. C.-G. Acetylphosphonate as a Surrogate of Acetate or
Acetamide in Organocatalyzed Enantioselective Aldol Reactions. Org. Lett. 2012, 14,
3174–3177. DOI: 10.1021/ol301270w.
[44] Guo, Q.; Zhao, J. C.-G. Primary Amine Catalyzed Aldol Reaction of Isatins and
Acetaldehyde. Tetrahedron Lett. 2012, 53, 1768–1771. DOI: 10.1016/j.tetlet.2012.01.108.
[45] Guang, J.; Zhao, C.-G. Organocatalytic Enantioselective Tandem Aldol-Cyclization
Reaction of a-Isothiocyanato Imides and Activated Carbonyl Compounds. Tetrahedron
2011, 22, 1205–1211. DOI: 10.1016/j.tetasy.2011.06.028.
[46] Ramireddy, N.; Zhao, J. C.-G. Base-Catalyzed Reaction between Isatins and N-Boc-3-
Pyrrolin-2-One. Tetrahedron. Lett. 2014, 55, 706–709. DOI: 10.1016/j.tetlet.2013.11.118.
[47] Abbaraju, S.; Zhao, J. C.-G. Asymmetric Aldol Reaction of 3-Acetyl-2H-Chromen-2-Ones
and Isatins Catalyzed by a Bifunctional Quinidine Urea Catalyst. Adv. Synth. Catal. 2014,
356, 237–241. DOI: 10.1002/adsc.201300623.
[48] Abbaraju, S.; Ramireddy, N.; Rana, N. K.; Arman, H.; Zhao, J. C.-G. Organocatalytic
Enantioselective Synthesis of Polysubstituted Spirooxindoles Using
a
Tandem
Michael–Michael Reaction. Adv. Synth. Catal. 2015, 357, 2633–2638. DOI: 10.1002/adsc.
201500298.
[49] Huang, H.; Bihani, M.; Zhao, J. C.-G. Stereoselective Synthesis of Spirooxindole
Derivatives Using an Organocatalyzed Tandem Michael–Michael Reaction. Org. Biomol.
Chem. 2016, 14, 1755–1763. DOI: 10.1039/C5OB02348C.
[50] Chanda, A.; Fokin, V. V. Organic Synthesis “On water”. Chem. Rev. 2009, 109, 725–748.
DOI: 10.1021/cr800448q.
[51] Butler, R. N.; Coyne, A. G. Water: Nature’s Reaction Enforcer—Comparative Effects for
Organic Synthesis “in-Water” and “on-Water. Chem. Rev. 2010, 110, 6302–6337. DOI: 10.
1021/cr100162c.
[52] Brogan, A. P.; Dickerson, T. J.; Janda, K. D. Enamine-based aldol organocatalysis in water:
are they really “All wet”? Angew. Chem. Int. Ed. Engl. 2006, 45, 8100–8102. DOI: 10.1002/
anie.200601392.
[53] Hayashi, Y. In Water or in the Presence of Water? Angew. Chem. Int. Ed. Engl. 2006, 45,
8103–8104. DOI: 10.1002/anie.200603378.
[54] Paradowska, J.; Stodulski, M.; Mlynarski, J. Catalysts Based on Amino Acids for
Asymmetric Reactions in Water. Angew. Chem. Int. Ed. Engl. 2009, 48, 4288–4297. DOI:
10.1002/anie.200802038.
[55] Lipshutz, B. H.; Ghorai, S.; Cortes-Clerget, M. The Hydrophobic Effect Applied to
Organic Synthesis: Recent Synthetic Chemistry “in Water. Chem. Eur. J. 2018, 24,
6672–6695. DOI: 10.1002/chem.201705499.
[56] Kitanosono, T.; Masuda, K.; Xu, P.; Kobayashi, S. Catalytic Organic Reactions in Water
toward Sustainable Society. Chem. Rev. 2018, 118, 679–746. DOI: 10.1021/acs.chemrev.
7b00417.
[57] Cruz-Acosta, F.; de Armas, P.; Garcia-Tellado, F. Water-Compatible Hydrogen-Bond
Activation: A Scalable and Organocatalytic Model for the Stereoselective Multicomponent
Aza-Henry Reaction. Eur. J. Chem. 2013, 19, 16550–16554. DOI: 10.1002/chin.201422022.
[58] Lykke, L.; Monge, D.; Nielsen, M.; Jørgensen, K. A. Asymmetric Organocatalytic Formal
Aza-Michael Addition of Ammonia to Nitroalkenes. Chem. Eur. J. 2010, 16, 13330–13334.
DOI: 10.1002/chem.201002415.
[59] Ma, Z.-W.; Liu, Y.-X.; Zhang, W.-J.; Tao, Y.; Zhu, Y.; Tao, J.-C.; Tang, M.-S. Highly
Enantioselective Michael Additions of Isobutyraldehyde to Nitroalkenes Promoted by

12
S. KONDA ET AL.
Amphiphilic Bifunctional Primary Amine-Thioureas in Organic or Aqueous Medium. Eur.
J. Org. Chem. 2011, 2011, 6747–6754. DOI: 10.1002/ejoc.201101086.
ꢀ
ꢀ
[60] Hamza, A.; Schubert, G.; Soos, T.; Papai, I. Theoretical Studies on the Bifunctionality of
Chiral Thiourea-Based Organocatalysts: Competing Routes to C ꢁ C Bond Formation.
J. Am. Chem. Soc. 2006, 128, 13151–13160. DOI: 10.1021/ja063201x.
ꢀ
ꢀ
[61] Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Highly Enantioselective Conjugate Addition
of Nitromethane to Chalcones Using Bifunctional Cinchona Organocatalysts. Org. Lett.
2005, 7, 1967–1969. DOI: 10.1021/ol050431s.
ꢀ
[62] Vakulya, B.; Varga, S.; Soos, T. Epi-Cinchona Based Thiourea Organocatalyst Family as an
Efficient Asymmetric Michael Addition Promoter: Enantioselective Conjugate Addition of
Nitroalkanes to Chalcones and a,b-Unsaturated N-Acylpyrroles. J. Org. Chem. 2008, 73,
3475–3480. DOI: 10.1021/jo702692a.
[63] Ma, A.; Ma, D. Enantioselective Synthesis of Polysubstituted Cyclopentanones by
Organocatalytic Double Michael Addition Reactions. Org. Lett. 2010, 12, 3634–3637. DOI:
10.1021/ol101414b.
ꢀ
ꢀ
ꢀ
[64] Kotai, B.; Kardos, G.; Hamza, A.; Farkas, V.; Papai, I.; Soos, T. On the Mechanism of
Bifunctional Squaramide-Catalyzed Organocatalytic Michael Addition: A Protonated
Catalyst as an Oxyanion Hole. Chem. Eur. J. 2014, 20, 5631–5639. DOI: 10.1002/chem.
201304553.