Rapid and efficient ultrasound-assisted method for the combinatorial synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives

Article abstract of DOI:10.1021/co200128k

An efficient one-pot synthesis of spiro[indoline-3,4′-pyrano[2,3-c] pyrazole] derivatives by four-component reaction of hydrazine, β-keto ester, isatin, and malononitrile or ethyl cyanoacetate catalyzed by piperidine under ultrasound irradiation is descri

Full text of DOI:10.1021/co200128k

Research Article
pubs.acs.org/acscombsci
Rapid and Efficient Ultrasound-Assisted Method for the
Combinatorial Synthesis of Spiro[indoline-3,4′-pyrano[2,3-
c]pyrazole] Derivatives
Yi Zou,†,‡ Yu Hu,† Hai Liu,† and Daqing Shi*,†
†Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, P.R. China
‡School of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou 221116, P.R. China
S
* Supporting Information
ABSTRACT: An efficient one-pot synthesis of spiro[indoline-3,4′-pyrano[2,3-
c]pyrazole] derivatives by four-component reaction of hydrazine, β-keto ester,
isatin, and malononitrile or ethyl cyanoacetate catalyzed by piperidine under
ultrasound irradiation is described. This synthesis was confirmed to follow the
group-assistant-purification chemistry (GAP) chemistry process, which can
avoid traditional chromatography and recrystallization purifications.
KEYWORDS: combinatorial synthesis, ultrasound irradiation, multicomponent reaction, heterocycle, spiroindoline
activity.7 The spirooxindole system is the core structure of
INTRODUCTION
Use of ultrasound as a means of accelerating reactions has
■
many pharmacological agents and natural alkaloids.8 As a
consequence, a number of methods have been reported for the
preparation of spirooxindole-fused heterocycles.9
long been known in both industry and academia. Nevertheless,
the “green” value of the nonhazardous acoustic radiation has
been recognized by synthetic and environmental chemists only
recently.1 The role of sonochemistry in the creation of “benign-
by-design” synthetic methods is clear from the definition: low
level of waste, inherently safe, material- and energy-saving, with
an optimized use of nonrenewable resources, and a preferential
exploitation of renewable ones. The application of ultrasound in
organic synthesis has been increasing because of its advantages
such as shorter reaction times, milder reaction condition, and
higher yields in comparison with the classical methods.2 The
chemical and physical effects of ultrasound arise from the
cavitational collapse which produces extreme conditions locally
and thus induce the formation of chemical species not easily
attained under conventional conditions.3
Traditional structure−activity relationship evaluations in
medicinal chemistry typically involve the preparation of an
advanced intermediate that can be analogued readily to introduce
the molecular diversity necessary to prepare a collection, or
library, of structurally related compounds. One strategy that
potentially meets the goals of total synthesis and library
production is multicomponent reactions (MCRs) chemistry, in
which three or more starting materials are brought together in a
highly convergent approach to rapidly build up molecular
structure and complexity.4 According to this method, the products
are formed in one-pot and the diversity can be achieved simply by
varying the reacting components.
Dihydropyrano[2,3-c]pyrazoles play an essential role in
biologically active compounds and therefore represent an
interesting template for medicinal chemistry. They have been
widely used as medicinal intermediates because of their useful
biological and pharmacological properties. Many of those
compounds are known as antimicrobial,10 and anti-inflamma-
tory.11 Furthermore, dihydropyrano[2,3-c]pyrazoles showed
molluscicidal activity12,13 and were identified as a screening
hit for Chk1 kinase inhibitor.14 Recently, Shestopalov et al.
reported the synthesis of spiro[indoline-3,4′-pyrano[2,3-c]-
pyrazol]-2-ones via one-pot, two-step reaction of isatin,
hydrazine, malononitrile, and β-keto ester catalyzed by Et3N.15
As a consequence of our interest in ultrasonic-assisted
organic synthesis (UAOS)16 and our continued work on the
synthesis of indole derivatives17 guided by the observation that
the presence of two or more different heterocyclic moieties in a
single molecule often enhances the biocidal profile remarkably,
we investigated the sonocatalytic synthesis of spiro[indoline-
3,4′-pyrano[2,3-c] pyrazole] derivatives in the presence of
piperidine at room temperature.
RESULTS AND DISCUSSION
■
Initial studies were carried out by reaction of hydrazine 1{1},
ethyl acetoacetate 2{1}, isatin 3{1}, and malononitrile 4{1}
under various reaction conditions (Scheme 1).
The indole nucleus is a well-known heterocyclic component
in a variety of natural products and medicinal agents.5
Compounds carrying the indole moiety exhibit antibacterial
and antifungal activities.6 Furthermore, it has been reported
that C-3 spiroindoline derivatives highly enhance biological
Received: August 9, 2011
Revised: November 27, 2011
Published: December 5, 2011
© 2011 American Chemical Society
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dx.doi.org/10.1021/co200128k | ACS Comb. Sci. 2012, 14, 38−43

ACS Combinatorial Science
Research Article
5{1,1,1,1} being isolated in 80% yield (Table 2, entry 6).
Subsequently, we further turned to testing the effect of catalyst
loading. Ten mol %, 20 mol %, 30 mol % of piperidine were
tested respectively. The results are summarized in Table 2
showing that 20 mol % loading of piperidine was optimal.
Higher amounts of piperidine did not lead to significant change
in the reaction yields (Table 2, entry 8).
To further improve the yield and decrease the reaction time,
we tried to increase the reaction temperature under ultrasound
irradiation. The results are summarized in Table 3. It can been
Scheme 1. Model Reaction
The ultrasonic-assisted reaction to obtain 5{1,1,1,1} was
examined using a variety of solvents (Table 1). Although the
Table 1. Solvent Optimization for the Synthesis of
a
5{1,1,1,1}
Table 3. Effect of Temperature on Model Reaction under
a
b
Ultrasound Irradiation
yield (%)
c
b
c
d
entry
catalyst (mol %)
temperature (°C)
time (h)
yield (%)
entry
solvent
time (h)
without US
with US
1
2
3
4
5
6
piperidine (20)
piperidine (20)
piperidine (20)
piperidine (20)
piperidine (20)
piperidine (20)
r.t.
1
1
1
1
1
1
92
90
88
88
90
89
1
2
3
4
5
6
7
acetonitrile
ethanol
1
1
1
1
1
1
1
12
56
48
15
9
34
92
88
37
27
33
25
40
50
methanol
THF
60
70
chloroform
1,4-dioxane
water
reflux
11
20
a
Reaction conditions: hydrazine (1.5 mmol), ethyl acetoacetate (1 mmol),
a
isatin (1 mmol), malononitrile (1 mmol), and ethanol (15 mL), under
Reaction conditions: hydrazine (1.5 mmol), ethyl acetoacetate (1 mmol),
isatin (1 mmol), malononitrile (1 mmol), solvent (15 mL), and piperidine
ultrasonic waves at room temperature and the ultrasonic power 250 W,
b
c
b
c
irradiation frequency 40 kHz. Yields of isolated products. r.t. = room
temperature.
(20 mol %). Yields of isolated products. Reaction under thermal
condition. Reaction under ultrasonic waves at room temperature and
d
the ultrasonic power 250 W, irradiation frequency 40 kHz.
seen from the Table 3 that there was no remarkable tem-
perature effect on this reaction.
The optimized reaction conditions were then tested for library
construction with four hydrazines 1{1−4}, three β-keto esters
2{1−3}, nine isatins 3{1−9}, and two acetonitrile derivatives
4{1−2} (Figure 1 and Scheme 2). The corresponding spiro-
reaction was successful both with and without ultrasound in all
solvents tested, the use of ultrasound afforded higher yielding
product quicker in every solvent. Ethanol proved to be the
solvent of choice and was adopted for all future studies.
Liquids irradiated with ultrasound can produce tiny bubbles
that can undergo a violent collapse known as cavitation, which
generates localized microscopic “hot spots” with transient high
temperatures and pressures to induce favorable conditions for
reactions.18 In some cases sonication can also provide more
efficient stirring of the reaction.19
Next, the effects of catalysts were evaluated for this model
reaction, and the results are summarized in Table 2. It was
Table 2. Effect of Catalyst on Model Reaction under
a
Ultrasound Irradiation
c
b
entry
catalyst (mol %)
temperature (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
8
no cat. (-)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
1
1
1
1
1
1
1
1
0
C2H5ONa (10)
NaOH (10)
57
45
67
72
80
92
90
Na2CO3 (10)
KOH (10)
piperidine (10)
piperidine (20)
piperidine (30)
a
Reaction conditions: hydrazine (1.5 mmol), ethyl acetoacetate (1 mmol),
isatin (1 mmol), malononitrile (1 mmol), and ethanol (15 mL), under
Figure 1. Diversity of Reagents.
ultrasonic waves at room temperature and the ultrasonic power 250 W,
b
c
irradiation frequency 40 kHz . Yields of isolated products. r.t. = room
temperature.
[indoline-3,4′-pyrano [2,3-c]pyrazole] derivatives 5 were ob-
tained in good yields at room temperature in ethanol under
ultrasonic irradiation. The results are summarized in Table 4.
The protocol was effective with isatins having either electron-
withdrawing (halides) or electron-donating groups (alkyl).
The yield of compound 5{1,1,1,1} (92%) prepared by our
method was higher than in a previously reported protocol
found that when the reaction was carried out without any
catalysts no product was detected (Table 2, entry 1). Common
bases, such as C2H5ONa, NaOH, Na2CO3, and KOH, can
catalyze this reaction with low yields (Table 2, entries 2−5).
However, piperidine was identified as the optimal catalyst with
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ACS Combinatorial Science
Research Article
Scheme 2. Synthesis of Spiro[indoline-3,4′-pyrano[2,3-
c]pyrazole] Derivatives 5
Table 4. Synthesis of Spiro[indoline-3,4′-pyrano[2,3-
a
c]pyrazole] Derivatives 5
b
c
entry
product
yield (%)
mp (°C)
m.p. (°C)
1
5{1,1,1,1}
5{1,1,2,1}
5{1,1,3,1}
5{1,1,4,1}
5{1,1,5,1}
5{1,1,6,1}
5{1,1,7,1}
5{2,1,1,1}
5{2,1,3,1}
5{2,1,8,1}
5{2,1,9,1}
5{1,2,1,1}
5{1,2,2,1}
5{1,2,5,1}
5{1,2,7,1}
5{1,2,3,1}
5{1,2,8,1}
5{1,2,9,1}
5{1,2,1,2}
5{1,2,2,2}
5{1,2,5,2}
5{1,2,3,2}
5{1,2,7,2}
5{1,2,4,2}
5{3,1,1,1}
5{3,1,2,1}
5{3,1,3,1}
5{1,3,1,1}
5{4,1,1,1}
92
93
90
89
86
80
81
86
76
69
72
87
80
87
79
78
70
68
79
81
73
76
73
75
83
85
89
80
87
285−286
282−283
279−281
297−298
274−275
>300
275
2
>300
3
269−271
306−307
4
5
6
7
270−272
227−229
222−224
>300
260
Figure 2. Crystal structure of compound 5{1,1,6,1}.
8
220
9
230−232
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
288−290
280−281
256−257
255−257
284−286
247−249
>300
279−280
258−259
>300
242−243
257−259
258−260
260−263
224−226
265−267
198−200
221−222
220−221
268−270
270−272
Figure 3. Crystal structure of compound 5{3,1,1,1}.
Scheme 3. Proposed Mechanism for the Synthesis of 5
a
Reaction of hydrazine, β-keto esters, isatins, and malononitrile or
ethyl cyanoacetate at room temperature in ethanol in the presences of
piperdine (20 mol %), and the ultrasonic power 250 W, irradiation
b
c
frequency 40 kHz. Yields of isolated products. Already reported in
literature20.
(85%).15 Moreover, this synthesis was confirmed to follow the
GAP chemistry (group-assistant-purification chemistry)21 proc-
ess, which can avoid traditional chromatography and recrystal-
lization purifications, that is, all the pure products can be simply
obtained by washing the solid crude products with ethanol.
The structures of all products 5 were characterized by IR, 1H
NMR, and HRMS analysis. Some new compounds were also
established by 13C NMR spectroscopy. The structures of
5{1,1,6,1} and 5{3,1,1,1} were further confirmed by X-ray
diffraction analysis. The molecular structures of 5{1,1,6,1} and
5{3,1,1,1} are shown in Figure 2 and Figure 3, respectively.
Although the detailed mechanism of this reaction remains to
be fully clarified, the formation of compounds 5 could be
explained by the reaction sequence in Scheme 3. First, a
condensation of hydrazine 1 with β-keto esters 2 is proposed to
give the intermediate 6. A Knoevenagel condensation of isatin 3
with malononitrile or ethyl cyanoacetate 4 is also proposed to
give the intermediate 8. Michael addition of intermediate 6 to 8
catalyzed by base should then occur to provide intermediate 9,
which undergoes intramolecular cyclization to give intermediate
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ACS Combinatorial Science
Research Article
11. In the last step, the intermediate 11 is tautomerized to
product 5.
Ethyl 6′-Amino-5-bromo-2-oxo-3′-phenyl-1′H-spiro-
[indoline-3,4′-pyrano[2,3-c]pyrazole]-5′-carboxylate
(5{1,2,2,2}). mp: 257−259 °C. IR (KBr) ν: 3421, 3260, 1718,
1
1677, 1618, 1543, 1491, 1475, 1380, 960 cm−1; H NMR
CONCLUSION
■
(400 MHz, DMSO-d6) δ: 0.70 (t, J = 6.0 Hz, 3H, CH3), 3.70
(q, J = 6.8 Hz, 2H, CH2O), 6.42 (d, J = 8.0 Hz, 1H, ArH), 6.67
(d, J = 6.4 Hz, 2H, ArH), 7.11 (s, 1H, ArH), 7.21 (d, J = 7.2 Hz,
3H, ArH), 7.32 (s, 1H, ArH), 8.12 (s, 2H, NH2), 10.11 (s, 1H,
NH), 12.68 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ:
13.25, 58.93, 74.27, 97.51, 110.94, 112.92, 125.66, 127.98,
128.63, 128.96, 130.15, 139.35, 140.52, 141.99, 154.54, 162.78,
165.94, 168.04, 179.46. HRMS calculated for C22H1779BrN4O4
[M]+: 480.0433, found: 480.0455.
The new GAP synthesis of spiro[indoline-3,4′-pyrano[2,3-
c]pyrazole] derivatives has been achieved by four-component
reaction of hydrazine, β-keto esters, isatin, and malononitrile or
ethyl cyanoacetate at room temperature under ultrasound
irradiation. Excellent chemical yields have been achieved
without the use of the traditional purifications, chromatography
and recrystallization.
EXPERIMENTAL PROCEDURES
6′-Amino-5-bromo-3′-methyl-2-oxo-1′-(m-tolyl)-1′H-
spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-5′-carbonitrile
(5{3,1,2,1}). mp: 221−222 °C. IR (KBr) ν: 3368, 3315, 3186,
3041, 2206, 1703, 1650, 1611, 1517, 1476, 1398, 1283, 1135,
■
General Information. Commercial solvents and reagents
were used as received. Melting points are uncorrected. IR
spectra were recorded on a Varian F-1000 spectrometer in KBr
1
1038, 808, 773 cm−1. H NMR (400 MHz, DMSO-d6) δ: 1.58
with absorptions in wavenumbers (cm−1). H NMR and 13C
1
(s, 3H, CH3), 2.39 (s, 3H, CH3), 6.90 (s, 1H, ArH), 7.16 (s,
1H, ArH), 7.39−7.66 (m, 7H, ArH and NH2), 10.90 (s, 1H,
NH). 13C NMR (75 MHz, DMSO-d6) δ: 11.79, 21.06, 48.03,
55.53, 95.64, 111.86, 114.43, 117.43, 118.03, 120.90, 127.30,
127.90, 129.24, 132.11, 134.75, 137.21, 139.11, 140.86, 143.66,
145.05, 161.13, 177.21. HRMS calculated for
C22H1679BrN5O2Na [M+Na]+: 484.0380, found: 484.0392.
NMR were determined on Varian Inova-300 MHz or Inova-
400 MHz spectrometer in DMSO-d6 solution. J values are in
hertz (Hz). Chemical shifts are expressed in parts per million
downfield from internal standard TMS. High-resolution mass
spectra (HRMS) were obtained using Bruker microTOF-Q
instrument. X-ray diffractions were recorded on a Rigaku
Mercury CCD/AFC diffractometer.
Ultrasonication was performed in a KQ-250E medical
ultrasound cleaner with a frequency of 40 kHz and an output
power of 250 W (Built-in heating, 30−110 °C thermostatically
adjustable). The reaction flask was located at the maximum
energy area in the cleaner, and the surface of the reactants was
placed slightly lower than the level of the water. Observation of
the surface of the reaction solution during vertical adjustment
of vessel depth will show the optimum position by the point at
which maximum surface disturbance occurs. The reaction
temperature was controlled by addition or removal of water
from ultrasonic bath.
General Procedure for the Synthesis of 5{1,1,1,1}
(Without US). A 100 mL flask was charged with hydrazine
1{1} (1 mmol), ethyl acetoacetate 2{1} (1 mmol), isatin 3{1}
(1 mmol), malononitrile 4{1} (1 mmol), and piperdine (20 mol %,
0.2 mmol) in ethanol (15 mL). The mixture was stirred at room
temperature. After the completion of the reaction (monitored by
TLC), the resulting precipitate was filtered and washed with
ethanol to afford the pure product as solid in good to excellent
yields.
Ultrasound-Promoted Synthesis of 5 (With US). Another
100 mL flask was charged with hydrazine 1{1} (1 mmol), ethyl
acetoacetate 2{1} (1 mmol), isatin 3{1} (1 mmol), malono-
nitrile 4{1} or ethyl cyanoacetate 4{2} (1 mmol) and piperdine
(20 mol %, 0.2 mmol) in ethanol (15 mL). The mixture was
sonicated in the water bath of an ultrasonic cleaner at 25−
30 °C. After the completion of the reaction (monitored by
TLC), the resulting precipitate was filtered and washed with
ethanol to afford the pure product as solid in good to excellent
yields.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, IR, 1H NMR, 13C NMR, and HRMS
spectra for compounds 5, and the X-ray crystallographic
information for compound 5{1,1,6,1} and 5{3,1,1,1}. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dqshi@suda.edu.cn.
Funding
We acknowledge the financial support from the Foundation of
the Natural Science Foundation of China (No. 21072144), the
Major Basic Research Project of the Natural Science
Foundation of the Jiangsu Higher Education Institutions (No.
10KJA150049), a project funded by the Priority Academic
Project Development of Jiangsu Higher Education Institutions
and Key Laboratory of Organic Synthesis of Jiangsu Province
(No. KJS0812).
REFERENCES
■
(1) Cintas, P.; Luche, J. L. Green chemistry. The sonochemical
approach. Green Chem. 1999, 1, 115−125.
(2) (a) Li, J. T.; Yin, Y.; Sun, M. X. An efficient one-pot synthesis of
2,3-epoxyl-1,3-diaryl-1-propanone directly from acetophenones and
aromatic aldehydes under ultrasound irradiation. Ultrason. Sonochem.
2010, 17, 363−366. (b) Li, J. T.; Wang, S. X.; Chen, G. F.; Li, T. S.
Some application of ultrasound irradiation in organic synthesis. Curr.
Org. Synth. 2005, 2, 415−436. (c) Mamaghani, M.; Dastmard, S. An
efficient ultrasound-promoted synthesis of the Baylis-Hillman adducts
catalyzed by imidazole and L-proline. Ultrason. Sonochem. 2009, 16,
445−447. (d) Saleh, T. S.; El-Rahman, N. M. A. Ultrasound promoted
synthesis of substituted pyrazoles and isoxazoles containing Sulphone
moiety. Ultrason. Sonochem. 2009, 16, 237−242.
6′-Amino-3′-methyl-2-oxo-1′H-spiro[indoline-3,4′-
pyrano[2,3-c]pyrazole]-5′-carbonitrile (5{1,1,1,1}). mp: 285−
286 °C. IR (KBr) ν: 3420, 3389, 3337, 3134, 2182, 1710, 1642,
1
1583, 1517, 1409, 1320, 1207, 1155, 1054, 931, 696 cm−1. H
NMR (400 MHz, DMSO-d6) δ: 1.54 (s, 3H, CH3), 6.91 (s, 1H,
ArH), 7.02 (s, 2H, ArH), 7.17 (s, 2H, NH2), 7.23 (s, 1H, ArH),
10.55 (s, 1H, NH), 12.25 (s, 1H, NH). HRMS calculated for
C15H11N5O2Na [M+Na]+: 316.0805, found: 316.0805.
(3) Cella, R.; Stefani, H. A. Ultrasound in heterocycles chemistry.
Tetrahedron 2009, 65, 2619−2641.
41
dx.doi.org/10.1021/co200128k | ACS Comb. Sci. 2012, 14, 38−43

ACS Combinatorial Science
Research Article
(4) (a) Domling, A.; Ugi, I. Multicomponent reactions with
(10) El-Tamany, E. H.; El-Shahed, F. A.; Mohamed, B. H. Synthesis
and biological activity of some pyrazole derivatives. J. Serb. Chem. Soc.
1999, 64, 9−18.
̈
isocyanides. Angew. Chem., Int. Ed. 2000, 39, 3168−3210.
(b) Domling, A. Recent developments in Isocyanide based
̈
(11) Zaki, M. E. A.; Soliman, H. A.; Hiekal, O. A.; Rashad, A. E.
Pyrazolopyranopyrimidines as a class of anti-inflammatory agents. Z.
Naturforsch. 2006, 61, 1−5.
multicomponent reactions in applied chemistry. Chem. Rev. 2006,
́
106, 17−89. (c) Zhu, J.; Bienayme, H. Multicomponent Reactions;
Wiley-VCH: Weinheim, Germany, 2005; (d) Dou, G. L.; Shi, C. L.;
Shi, D. Q. Highly regioselective synthesis of polysubstituted pyrroles
through three-component reaction induced by low-valent titanium
reagent. J. Comb. Chem. 2008, 10, 810−813. (e) Wu, H.; Lin, W.;
Wan, Y.; Xin, H. Q.; Shi, D. Q.; Shi, Y. H.; Yuan, R.; Bo, R. C.;
Yin, W. Silica gel-catalyzed one-pot synthesis in water and fluores-
cence properties studies of 5-amino-2-aryl-3H-chromeno[4,3,2-de]-
[1,6]naphthyridine-4-carbonitriles and 5-amino-2- aryl-3H-quinolino-
[4,3,2-de][1,6]naphthyridine-4-carbonitriles. J. Comb. Chem. 2010, 12,
31−34.
(12) Abdelrazek, F. M.; Metz, P.; Metwally, N. H.; El-Mahrouky, S. F.
Synthesis and molluscicidal activity of new cinnoline and pyrano[2,3-
c]pyrazole derivatives. Arch. Pharm. 2006, 339, 456−460.
(13) Abdelrazek, F. M.; Metz, P.; Kataeva, O.; Jaeger, A.; El-
Mahrouky, S. F. Synthesis and molluscicidal activity of new chromene
and pyrano[2,3-c]pyrazole derivatives. Arch. Pharm. 2007, 340, 543−
548.
(14) Foloppe, N.; Fisher, L. M.; Howes, R.; Potter, A.; Robertson, A.
G. S.; Surgenor, A. E. Identification of chemically diverse Chk1
inhibitors by receptor-based virtual screening. Bioorg. Med. Chem.
2006, 14, 4792−4802.
(5) Houlihan, W. J.; Remers, W. A.; Brown, R. K. Indoles: Part I;
Wiley: New York, 1992.
(15) Litvinov, Y. M.; Shestopalov, A. A.; Rodinovskaya, L. A.;
Shestopalov, A. M. New convenient four-component synthesis of 6-
amino-2,4-dihydropyrano[2,3-c]pyrazol-5- carbonitriles and one-pot
synthesis of 6′-aminospiro[(3H)-indol-3,4′-pyrano[2,3-c] pyrazol]-
(1H)-2-one-5′-carbonitriles. J. Comb. Chem. 2009, 11, 914−919.
(16) (a) Zou, Y.; Wu, H.; Hu, Y.; Liu, H.; Zhao, X.; Ji, H. L.; Shi,
D. Q. A novel and environment-frienfly method for preparing
dihydropyrano[2,3-c]pyrazoles in water under ultrasound irradiation.
Ultrason. Sonochem. 2011, 18, 708−712. (b) Wang, H. Y.; Zou, Y.;
Zhao, X.; Shi, D. Q. A novel and convenient synthesis of 4-hydroxy-6-
methyl-3-(1-(phenylimino)ethyl)-2H-pyran-2-one derivatives under
ultrasound irradiation. Ultrason. Sonochem. 2011, 18, 1048−1051.
(17) (a) Liu, H.; Dou, G. L.; Shi, D. Q. Regio- and stereo-selective
synthesis of novel dispiropyrrolidine bisoxindole derivatives via
multicomponent reactions. J. Comb. Chem. 2010, 12, 292−294.
(b) Liu, H.; Dou, G. L.; Shi, D. Q. Regioselective synthesis of novel
spiropyrrolidinesand spirothiapyrrolizidines through multicomponent
1,3-dipolar cycloaddition reaction of azomethine ylides. J. Comb. Chem.
2010, 12, 633−637. (c) Li, Y. L.; Chen, H.; Shi, C. L.; Shi, D. Q.; Ji, S.
J. Efficient one-pot synthesis of spirooxindole derivatives catalyzed by
L-proline in aqueous medium. J. Comb. Chem. 2010, 12, 231−237.
(d) Chen, H.; Shi., D. Q. Efficient one-pot synthesis of novel
spirooxindole derivatives via three-component reaction in aqueous
medium. J. Comb. Chem. 2010, 12, 571−576.
(18) Zolfigol, M. A. Silica sulfuric acid/NaNO2 as a novel
heterogeneous system for production of thionitrites and disulfides
under mild conditions. Tetrahedron 2001, 57, 9509−9511.
(19) (a) Mason, T. J.; Peters, D. Practical Sonochemistry, 2nd ed.; Ellis
Horwood: London, U.K., 2002. (b) Dahlem, O.; Reisse, J.; Halloin, V.
The radially vibrating horn: A scaling-up possibility for sonochemical
reactions. Chem. Eng. Sci. 1999, 54, 2829−2838. (c) Li, J. T.; Zhai, X.
L.; Chen, G. F. Ultrasound promoted one-pot synthesis of 3-aza-6,10-
diaryl-2-oxa-spiro[4.5]decane-1,4,8-trione. Ultrason. Sonochem. 2010,
17, 356−358.
(20) (a) Abd El-Latif, F. F.; Gohar, A. E. M. N.; Fahmy, A. M.; Badr,
M. Z. A. Novel synthesis of furo[2,3-b]indole derivatives. Bull. Chem.
Soc. Jpn. 1986, 59, 1235−1238. (b) Liu, Y.; Zhou, D.; Ren, Z. J.; Cao,
W. G.; Chen, J.; Deng, H. M.; Gu, Q. A green efficient synthesis of
spiro[indoline-3,4′(1H′)-pyrano[2,3-c]pyrazol]-2-one derivatives.
J. Chem. Res. 2009, 154−156. (c) Redkin, R. G.; Shemchuk, L. A.;
Chernykh, V. P.; Shishkin, O. V.; Shishkina, S. V. Synthesis and
molecular structure of spirocyclic 2-oxindole derivatives of 2-amino-
4H-pyran condensed with the pyrazolic nucleus. Tetrahedron 2007, 63,
11444−11450. (d) Elinson, M. N.; Dorofeev, A. S.; Miloserdov, F. M.;
Nikishin, G. I. Electrocatalytic multicomponent assembling of isatins,
3-methyl-2-pyrazolin-5-ones and malononitrile: facile and convenient
way to functionalized spirocyclic [indole-3,4′-pyrano[2,3-c]pyrazole]
system. Mol. Diversity 2009, 13, 47−52.
(6) Sundberg, R. J. The Chemistry of Indoles; Academic: New York,
1996.
(7) (a) Da-Silva, J. F. M.; Garden, S. J.; Pinto, A. C. The chemistry of
isatins: a review from 1975 to 1999. J. Braz. Chem. Soc. 2001, 12, 273−
324. (b) Joshi, K. C.; Chand, P. Biologically active indole derivatives.
Pharmazie 1982, 37, 1−12. (c) Joshi, K. C.; Jain, R.; Sharma, K.;
Bhattacharya, S. K.; Goel, R. K. Studies in spiro-heterocycles. Part-XII.
Synthesis of some fluorine containing spiro[3H-indole-3,4(4H)-
pyrano[2,3-d]pyrimidine]-2,5,7(1H)-triones as CNS agents. J. Indian
Chem. Soc. 1988, 115, 202−204. (d) Abdel-Rahman, A. H.; Keshk, E.
M.; Hanna, M. A.; El-Bady, S. M. Synthesis and evaluation of some
new spiro indoline-based heterocycles as potentially active
antimicrobial agents. Bioorg. Med. Chem. 2004, 12, 2483−2488.
(8) (a) Dandia, A.; Singh, R.; Khaturia, S.; Merienne, C.; Morgant,
G.; Loupy, A. Efficient microwave enhanced regioselective synthesis of
a series of benzimidazoly/triazolyl spiro [indole-thiazolidinones] as
potent antifungal agents and crystal structure of spiro[3H- indole-3,2′-
triazolidine]-3′(1,2,4-triazol-3-yl)-2,4′(1H)-dione. Bioorg. Med. Chem.
2006, 14, 2409−2417. (b) Khafagy, M. M.; El-Wahas, A. H. F. A.; Eid,
F. A.; El-Agrody, A. M. Synthesis of halogen derivatives of
benzo[h]chromene and benzo[a]anthracene with promising
antimicrobial activities. Farmaco 2002, 57, 715−722. (c) Sebahar, P.
R.; Williams, R. M. The asymmetric total synthesis of (+) and
(-)-spirotryprostatin B. J. Am. Chem. Soc. 2000, 122, 5666−5667.
(d) Ma, J.; Hecht, S. M. Javaniside, a novel DNA cleavage agent from
Alangium javanicum having an unusual oxindole skeleton. Chem.
Commun. 2004, 1190−1191. (e) Edmondson, S.; Danishefsky, S. J.;
Sepp-Lorenzinol, L.; Rosen, N. Total synthesis of Spirotryprostatin A,
leading to the discovery of some biologically promising analogues.
J. Am. Chem. Soc. 1999, 121, 2147−2155. (f) Kang, T. H.; Matsumoto,
K.; Tokda, M.; Murakami, Y.; Takayama, H.; Kitajima, M.; Aimi, N.;
Watanabe, H. Peteropodine and isopteropodine positively modulate
the function of rat muscarinic M1 and 5-HT2 receptors expressed in
xenopus oocyte. Eur. J. Pharmacol. 2002, 444, 39−45.
(9) (a) Bazgir, A.; Tisseh, Z. N.; Mirzaei, P. An efficient synthesis of
spiro[dibenzo[b,i] xanthene-1,3,3′-indoline]-pentaones and 5H-
dibenzo[b,i]xanthene-tetraones. Tetrahedron Lett. 2008, 49, 5165−
5168. (b) Jadidi, K.; Ghahremanzadeh, R.; Bazgir, A. Spirooxindoles:
reaction of 2,6-diaminopyrimidin-4(3H)-one and isatins. Tetrahedron
2009, 65, 2005−2009. (c) Dabiri, M.; Azimi, S. C.; Khavasi, H. R.;
Bazgir, A. A novel reaction of 6-amino-uracils and isatins. Tetrahedron
2008, 64, 7307−7311. (d) Jadidi, K.; Ghahremanzadeh, R.; Bazgir, A.
Efficient synthesis of spiro[chromeno[2,3-d]pyrimidine-5,3′-indoline]-
tetraones by a one-pot and three-component reaction. J. Comb. Chem.
2009, 11, 341−344. (e) Ghahremanzadeh, R.; Sayyafi, M.; Ahadi, S.;
Bazgir, A. Novel one-pot, three-component synthesis of spiro
[indoline-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidine]trione library.
J. Comb. Chem. 2009, 11, 393−396. (f) Wang, L. M.; Jiao, N.; Qiu,
J.; Yu, J. J.; Liu, J. Q.; Guo, F. L.; Liu, Y. Sodium stearate-catalyzed
multicomponent reactions for efficient synthesis of spirooxindoles in
aqueous micellar media. Tetrahedron 2010, 66, 339−343.
(21) (a) Kaur, P.; Pindi, S.; Wever, W.; Rajale, T.; Li, G. Asymmetric
catalytic Strecker reaction of N-phosphonyl imines with Et2AlCN
using amino alcohols and BINOLs as catalysts. Chem. Commun. 2010,
46, 4330−4332. (b) Kaur, P.; Pindi, S.; Wever, W.; Rajale, T.; Li, G.
42
dx.doi.org/10.1021/co200128k | ACS Comb. Sci. 2012, 14, 38−43

ACS Combinatorial Science
Research Article
Asymmetric catalytic N-phosphonyl imine chemistry: The use of
primary free amino acids and Et2AlCN for asymmetric catalytic
Strecker reaction. J. Org. Chem. 2010, 75, 5144−5150. (c) Kaur, P.;
Wever, W.; Pindi, S.; Milles, R.; Gu, P.; Shi, M.; Li, G. The GAP
chemistry for chiral N-phosphonyl imine-based Strecker reaction.
Green Chem. 2011, 13, 1288−1292.
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