A novel method for the synthesis of spiro[indoline-pyrazolo[4',3':5,6] pyrido[2,3-d]pyrimidine]triones by alum as a reusable catalyst

Article abstract of DOI:10.1002/jhet.898

Synthesis of spiro[indoline-pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine] trione derivatives by a cyclo-condensation reaction of indolin-2-ones, barbituric acids, and 1,3-diphenyl-1H-pyrazol-5-amines with the ionic liquid as an effective green reaction media and in the presence of Alum as a reusable catalyst was reported. Excellent yields of products, green media, use of a reusable catalyst, and short reaction time are the main advantages of this new method.

Full text of DOI:10.1002/jhet.898

July 2012
A Novel Method for the Synthesis of
Spiro[indoline‐Pyrazolo[4′,3′:5,6]pyrido[2,3‐d]pyrimidine]triones
by Alum as a Reusable Catalyst
951
a
b
*
Sadif A. Shirvan, Ramin Ghahremanzadeh,
Mojtaba Mirhosseini Moghaddam,b Ayoob Bazgir,c
Amir Hassan Zarnani,b,d and Mohammad Mehdi Akhondie
aDepartment of Chemistry, Islamic Azad University, Omidieh Branch, Omidieh, Iran
bNanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
cDepartment of Chemistry, Shahid Beheshti University, G.C., Tehran, Iran
dImmunology Research Center, Iran University of Medical Sciences, Tehran, Iran
eReproductive Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
*
E-mail: sadif_shirvan@yahoo.com
Received January 1, 2011
DOI 10.1002/jhet.898
View this article online at wileyonlinelibrary.com.
Synthesis of spiro[indoline‐pyrazolo[4′,3′:5,6]pyrido[2,3‐d]pyrimidine]trione derivatives by a cyclo‐
condensation reaction of indolin‐2‐ones, barbituric acids, and 1,3‐diphenyl‐1H‐pyrazol‐5‐amines with
the ionic liquid as an effective green reaction media and in the presence of Alum as a reusable catalyst
was reported. Excellent yields of products, green media, use of a reusable catalyst, and short reaction time
are the main advantages of this new method.
J. Heterocyclic Chem., 49, 951 (2012).
INTRODUCTION
68% of them are heterocycles. Therefore, it is not surpris-
ing that research in the field of synthesis of polyfunctiona-
lized heterocyclic compounds has received special
attention [1].
With the emphasis on the search for atom‐efficient
transformations of easily available starting materials into
complex organic molecules, reactions that provide maxi-
mum diversity are especially desirable. Here, expeditious
domino and multicomponent reactions (MCRs) have
emerged as powerful strategies. These methodologies have
great utility, particularly when they lead to the formation of
privileged medicinal heterocyclic compounds. MCRs are
economically and environmentally very advantageous, be-
cause multistep syntheses produce considerable amounts of
waste mainly due to complex isolation procedures often
involving expensive, toxic, and hazardous solvents after
each step [1–3].
Spirocyclic systems containing one carbon atom com-
mon to two rings are structurally interesting [5]. The
asymmetric characteristic of the molecule due to the chiral
spiro carbon is one of the important criteria of the biolog-
ical activities. The presence of the sterically constrained
spiro structure in various natural products also adds to
the interest in the investigations of spiro compounds [6].
Spiro compounds represent an important class of naturally
occurring substances characteristic by their highly pro-
nounced biological properties [7,8].
The heterocyclic spirooxindole ring system is a
widely distributed structural framework present in a
number of pharmaceuticals and natural products [9], in-
cluding such cytostatic alkaloids as spirotryprostatins A,
B, and strychnophylline (Fig. 1) [10–12]. The unique
structural array and the highly pronounced pharmaco-
logical activity displayed by the class of spirooxindole
compounds have made them attractive synthetic targets
[13].
In recent years, the synthesis of combinatorial small‐
molecule heterocyclic libraries has emerged as a valuable
tool in the search for novel lead structures. Thus, the
success of combinatorial chemistry in drug discovery is
considerably dependent on further advances in heterocyclic
MCR methodology [4].
Polyfunctionalized heterocyclic compounds play impor-
tant roles in the drug discovery process, and analysis of
drugs in late development or on the market shows that
© 2012 HeteroCorporation

952
S. A. Shirvan, R. Ghahremanzadeh, M. M. Moghaddam,
A. Bazgir, A. H. Zarnani, and M. M. Akhondi
Vol 49
Scheme 1
Figure 1. Representatives of important indenone‐fused heterocycles.
decrease in the product yield. Apparently, recycling of cat-
alyst is possible for three successive times without signifi-
cant loss of activity (Table 2, entry 4c).
Further, the chemistry of spiro‐indoles in which an
indole ring is joined to sulfur‐ and nitrogen‐containing
heterocycles at the C‐3 position through a spiro carbon
atom is of great interest due to their physiological and
biological activities [14,15].
In addition, the synthesis of pyridopyrimidine and
their derivatives is of high interest in organic chemistry
due to their potential biological and pharmacological
activities such as antiviral, anti‐inflammatory, insecticidal,
antifolate, tyrosine kinase inhibitor, antimicrobial, calcium
channel antagonists, antileishmanial, diuretic, and potas-
sium‐sparing [16–24].
In continuation of our previous works for the synthe-
sis of heterocyclic compounds [25–30], recently, we
reported novel one‐pot, three‐component synthesis of
spiro[indoline‐pyrazolo[4′,3′:5,6]pyrido[2,3‐d]pyrimidine]
trione in refluxing condition at 24 h [31]. Herein, we re-
port a simple and efficient method for the synthesis of
these spirooxindoles with fused pyrazole, pyridine, and
pyrimidine rings, through the three‐component one‐pot
reaction in ionic liquid media, using Alum as a catalyst
at very short reaction times.
After optimizing the conditions, to delineate this ap-
proach, particularly in regard to library construction, this
methodology was evaluated by using different barbituric
acids, 1,3‐diphenyl‐1H‐pyrazol‐5‐amine, and isatins. Five
substituted isatins 1(a–e), three commercially available
barbituric acids 2(a–c) and two 1,3‐diphenyl‐1H‐pyrazol‐
5‐amine 3(a,b), were chosen for the library validation
(Scheme 2).
Corresponding spiro[indoline‐pyrazolo[4′,3′:5,6]pyrido
[2,3‐d]pyrimidine]triones 4(a–t) were synthesized by the
one‐pot, three‐component condensation reaction in excel-
lent yields at 100°C in the presence of catalytic amount
of Alum for 30 min. The reaction can be represented as
in Table 2.
EXPERIMENTAL
Melting points were measured on an Elecrtothermal 9100
apparatus. 1H‐NMR spectra were recorded on a BRUKER
DRX‐300 AVANCE spectrometer at 300.13 MHz. The starting
materials and TLC papers were obtained from Merck and
Aldrich.
RESULTS AND DISCUSSION
All the products 4(a–t) are known compounds and were char-
acterized by comparison of their 1H‐NMR spectrum with authen-
tic samples synthesized by reported procedures [31].
In this research, to reach the efficiency of three‐component
reaction of isatin 1a, barbirutic acid 2a, and 1,3‐diphenyl‐
1H‐pyrazol‐5‐amine 3a, various conditions were considered.
At first, we examined this simple model reaction in the
presence of diverse types of lewis and bronsted acids such
as Alum, SSA, SnCl4, p‐TSA, and CAN as catalysts. We
also tested the reaction in different ionic liquids media such
as [Bmim]Br, [Bmim]Cl, [Bmim]CF3COO, [Bmim]BF4,
and [Bmim]PF6. We have found that use of Alum has a
unique capability and best promoter to enhance the reac-
tion rate in [Bmim]PF6 medium (Scheme 1). The results
are summarized in Table 1.
As follow, we evaluated the amount of catalyst required
for this transformation. It was found that using 10 mol %
Alum in ionic liquid is sufficient to push the reaction for-
ward. We also checked the reusability of the catalyst by re-
covering the Alum and using it for new runs and found that
the catalyst could be reused several times without any
Table 1
Model reaction, conditions, and yields.a
Time
(min)
Temp.
(°C)
Yield
(%)
Conditions
[Bmim]Br
[Bmim]Br
[Bmim]Br
[Bmim]Br
[Bmim]Br
[Bmim]CF3CO2
[Bmim]Cl
[Bmim]BF4
[Bmim]PF6
Catalyst
CAN
p‐TSA
SnCl4
SSA
Alum
Alum
Alum
Alum
Alum
30
30
30
30
30
30
30
30
30
100
100
100
100
100
100
100
100
100
<50
60
57
62
70
82
63
76
95
aIsatin (1 mmol), barbituric acid (1 mmol), 1,3‐diphenyl‐1H‐pyrazol‐5‐
amine (1 mmol), catalyst (10 mol %), and ionic liquid (0.2 g).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
A Novel Method for the Synthesis of Spiro[indoline‐pyrazolo[4′,3′:5,6]pyrido
[2,3‐d]pyrimidine]triones by Alum as a Reusable Catalyst
953
Table 2
1‐Ethyl‐1′,3′‐diphenyl‐spiro[indoline‐3,4′‐pyrazolo[4′,3′:5,6]
pyrido[2,3‐d]pyrimidine]‐2,5′, 7′(6′H,8′H,9′H)‐trione (4f). White
powder (86%); m.p > 300°C. 1H‐NMR (300 MHz, DMSO‐d6): δH
(ppm) 0.77 (t, J = 6.93 Hz, 3H, CH3), 3.10–3.35 (m, 2H, CH2),
6.56–7.70 (m, 14H, H‐Ar), 9.44 (s, 1H, NH), 10.23 (s, 1H, NH),
10.70 (s, 1H, NH).
Model reaction and yield.
Producta
R1
R2
X
Y
Z
Yieldb (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
H
H
Me
H
Et
Me
Me
Et
H
H
Me
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
Me
Me
Me
H
H
H
H
H
H
H
H
Br
NO2
H
Me
H
NO2
Br
Br
Br
NO2
H
H
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
H
H
H
H
H
H
H
H
H
H
H
H
NO2
NO2
NO2
NO2
H
95
96
1‐Methyl‐5‐nitro‐1′,3′‐diphenyl‐spiro[indoline‐3,4′‐pyrazolo
[4′,3′:5,6]pyrido[2,3‐d]pyrimidine]‐2,5′,7′(6′H,8′H,9′H)‐trione
98 (98,96,96)c
92
88
86
87
84
83
89
91
85
89
88
90
84
85
89
91
83
1
(4g). White powder (87%); m.p > 300°C. H‐NMR (300 MHz,
DMSO‐d6): δH (ppm) 2.78 (s, 3H, CH3), 6.66–8.12 (m, 13H,
H‐Ar), 9.58 (s, 1H, NH), 10.29 (s, 1H, NH), 10.82 (s, 1H, NH).
1‐Methyl‐5‐bromo‐1′,3′‐diphenyl‐spiro[indoline‐3,4′‐pyrazolo
[4′,3′:5,6]pyrido[2,3‐d]pyrimidine]‐2,5′,7′(6′H,8′H,9′H)‐trione
1
4j
4k
4l
(4h). White powder (84%); m.p > 300°C. H‐NMR (300 MHz,
DMSO‐d6): δH (ppm) 2.67 (s, 3H, CH3), 6.59–7.71 (m, 13H,
H‐Ar), 9.48 (s, 1H, NH), 10.22 (s, 1H, NH), 10.78 (s, 1H, NH).
1‐Ethyl‐5‐bromo‐1′,3′‐diphenyl‐spiro[indoline‐3,4′‐pyrazolo
[4′,3′:5,6]pyrido[2,3‐d]pyrimidine]‐2,5′,7′(6′H,8′H,9′H)‐trione
4m
4n
4o
4p
4q
4r
4s
4t
Br
NO2
Me
H
1
(4i). White powder (83%); m.p > 300°C. H‐NMR (300 MHz,
DMSO‐d6): δH (ppm) 0.78 (t, J = 6.90 Hz, 3H, CH3), 3.08–3.39
(m, 2H, CH2), 6.63–7.71 (m, 13H, H‐Ar), 9.47 (s, 1H, NH),
10.21 (s, 1H, NH), 10.77 (s, 1H, NH).
Br
NO2
H
S
S
S
H
H
H
H
5‐Bromo‐6′,8′‐dimethyl‐1′,3′‐diphenyl‐spiro[indoline‐3,4′‐
pyrazolo[4′,3′:5,6]pyrido[2,3‐d]pyrimidine]2,5′,7′(6′H,8′H,9′H)‐
aAll the products are known compounds [31].
bIsolated yields.
1
trione (4j). White powder (89%); m.p > 300°C. H‐NMR (300
cIsolated yield after recycling of catalyst.
MHz, DMSO‐d6): δH (ppm) 3.03 (s, 3H, CH3), 3.54 (s, 3H, CH3),
6.41–7.80 (m, 13H, H‐Ar), 9.73 (s, 1H, NH), 10.14 (s, 1H, NH).
5‐Nitro‐6′,8′‐dimethyl‐1′,3′‐diphenyl‐spiro[indoline‐3,4′‐
pyrazolo[4′,3′:5,6]pyrido[2,3‐d]pyrimidine] 2,5′,7′(6′H,8′H,9′H)‐
trione (4k). White powder (91%); m.p >300°C. 1H‐NMR (300
MHz, DMSO‐d6): δH (ppm) 3.01 (s, 3H, CH3), 3.56 (s, 3H, CH3),
6.61–8.06 (m, 13H, H‐Ar), 9.86 (s, 1H, NH), 10.75 (s, 1H, NH).
1,6′,8′‐Triimethyl‐1′,3′‐diphenyl‐spiro[indoline‐3,4′‐pyrazolo
[4′,3′:5,6]pyrido[2,3‐d]pyrimidine] 2,5′,7′(6′H,8′H,9′H)‐trione
Typical procedure for the preparation of spiro[indoline‐
pyrazolo[4′,3′:5,6]pyrido[2,3‐d]pyrimidine]triones (4a). A mixture
of barbituric acid (1 mmol), 1,3‐diphenyl‐1H‐pyrazol‐5‐amine
(1 mmol), isatin (1 mmol), [Bmim]PF6 (0.2 g), and Alum
(0.02 g) was stirred for 30 min at 100°C (the progress of
the reaction was monitored by TLC). After completion, the
reaction mixture dissolved in water and filtered then the
precipitate washed with water (10 mL) and recrystallized by
EtOH to afford the pure product 4 as Cream powder (95%).
m.p > 300°C.
1
(4l). White powder (85%); m.p >300 °C. H‐NMR (300 MHz,
DMSO‐d6): δH (ppm) 2.68 (s, 3H, CH3), 3.01 (s, 3H, CH3),
3.57 (s, 3H, CH3), 6.60–7.81 (m, 14H, H‐Ar), 9.77 (s, 1H, NH).
1′‐Phenyl‐3′‐(4‐nitrophenyl)‐spiro[indoline‐3,4′‐pyrazolo
[4′,3′:5,6]pyrido[2,3‐d]pyrimidine]2,5′,7′(6′H,8′H,9′H)‐trione
(4m). White powder (89%); m.p > 300°C. 1H‐NMR (300 MHz,
DMSO‐d6): δH (ppm) 6.49–7.96 (m, 9H, H‐Ar), 7.97 (d, J = 9.0
Hz, 2H, H‐Ar), 8.45 (d, J = 9.0 Hz, 2H, H‐Ar), 9.64 (s, 1H, NH),
9.99 (s, 1H, NH), 10.52 (s, 1H, NH), 10.77 (s, 1H, NH).
5‐Bromo‐1′‐phenyl‐3′‐(4‐nitrophenyl)‐spiro[indoline‐3,4′‐
pyrazolo[4′,3′:5,6]pyrido[2,3‐d]pyrimidine]2,5′,7′(6′H,8′H,9′H)‐
1H‐NMR (300 MHz, DMSO‐d6): δH (ppm) 6.50–7.69 (m, 14H,
H‐Ar), 9.36 (s, 1H, NH), 9.93 (s, 1H, NH), 10.18 (s, 1H, NH),
10.67 (s, 1H, NH).
5‐Bromo‐1′,3′‐diphenyl‐spiro[indoline‐3,4′‐pyrazolo[4′,3′:5,6]
pyrido[2,3‐d]pyrimidine]‐2,5′, 7′(6′H,8′H,9′H)‐trione (4b).White
1
powder (96%); m.p > 300°C. H‐NMR (300 MHz, DMSO‐d6):
1
δH (ppm) 6.43–7.70 (m, 13H, H‐Ar), 9.43 (s, 1H, NH), 10.12 (s,
1H, NH), 10.19 (s, 1H, NH), 10.77 (s, 1H, NH).
trione (4n). White powder (88%); m.p > 300°C. H‐NMR (300
MHz, DMSO‐d6): δH (ppm) 6.63–7.99 (m, 8H, H‐Ar), 7.98 (d,
J = 8.8 Hz, 2H, H‐Ar), 8.46 (d, J = 8.7 Hz, 2H, H‐Ar), 9.68 (s,
1H, NH), 10.14 (s, 1H, NH), 10.48 (s, 1H, NH), 10.83 (s, 1H, NH).
5‐Nitro‐1′,3′‐diphenyl‐spiro[indoline‐3,4′‐pyrazolo[4′,3′:5,6]
pyrido[2,3‐d]pyrimidine]‐2,5′, 7′(6′H,8′H,9′H)‐trione (4c).White
1
powder (98%); m.p > 300°C. H‐NMR (300 MHz, DMSO‐d6):
δH (ppm) 6.63–8.06 (m, 13H, H‐Ar), 9.54 (s, 1H, NH), 10.28 (s,
1H, NH), 10.73 (s, 1H, NH), 10.82 (s, 1H, NH).
1‐Methyl‐1′,3′‐diphenyl‐spiro[indoline‐3,4′‐pyrazolo[4′,3′:5,6]
pyrido[2,3‐d]pyrimidine]‐ 2,5′, 7′(6′H,8′H,9′H)‐trione (4d). White
powder (92%); m.p > 300°C. 1H‐NMR (300 MHz, DMSO‐d6): δH
(ppm) 2.67 (s, 3H, CH3), 6.60–7.70 (m, 14H, H‐Ar), 9.45 (s, 1H,
NH), 10.24 (s, 1H, NH), 10.71 (s, 1H, NH).
Scheme 2
5‐Methyl‐1′,3′‐diphenyl‐spiro[indoline‐3,4′‐pyrazolo[4′,3′:5,6]
pyrido[2,3‐d]pyrimidine]‐2,5′, 7′(6′H,8′H,9′H)‐trione (4e). White
1
powder (88%); m.p > 300°C. H‐NMR (300 MHz, DMSO‐d6):
δH (ppm) 2.21 (s, 3H, CH3), 6.42–7.70 (m, 13H, H‐Ar), 9.38 (s,
1H, NH), 9.86 (s, 1H, NH), 10.20 (s, 1H, NH), 10.70 (s, 1H, NH).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

954
S. A. Shirvan, R. Ghahremanzadeh, M. M. Moghaddam,
A. Bazgir, A. H. Zarnani, and M. M. Akhondi
Vol 49
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5‐Nitro‐1′‐phenyl‐3′‐(4‐nitrophenyl)‐spiro[indoline‐3,4′‐
pyrazolo[4′,3′:5,6]pyrido[2,3‐d]pyrimidine]2,5′,7′(6′H,8′H,9′H)‐
1
trione (4o). White powder (90%); m.p > 300°C. H‐NMR (300
MHz, DMSO‐d6): δH (ppm) 6.60–8.46 (m, 12H, H‐Ar), 9.77 (s,
1H, NH), 10.55 (s, 1H, NH), 10.74 (s, 1H, NH), 10.87 (s, 1H,
NH).
1‐Methyl‐1′‐phenyl‐3′‐(4‐nitrophenyl)‐spiro[indoline‐3,4′‐
pyrazolo[4′,3′:5,6]pyrido[2,3‐d]pyrimidine]2,5′,7′(6′H,8′H,9′H)‐
1
trione (4p). White powder (84%); m.p > 300°C. H‐NMR (300
MHz, DMSO‐d6): δH (ppm) 2.66 (s, 3H, CH3), 6.61–7.30 (m, 9H,
H‐Ar), 7.97 (d, J = 9.0 Hz, 2H, H‐Ar), 8.46 (d, J = 9.0 Hz, 2H,
H‐Ar), 9.70 (s, 1H, NH), 10.55 (s, 1H, NH), 10.78 (s, 1H, NH).
1′,3′‐Diphenyl‐7′‐thioxo‐spiro[indoline‐3,4′‐pyrazolo[4′,3′:5,6]
pyrido[2,3‐d]pyrimidine]‐2,5′ (6′H,8′H,9′H)‐dione (4q).White
1
powder (85%); m.p > 300°C. H‐NMR (300 MHz, DMSO‐d6):
δH (ppm) 6.52–7.71 (m, 14H, H‐Ar), 9.41 (s, 1H, NH), 10.04 (s,
1H, NH), 11.75 (s, 1H, NH), 12.17 (s, 1H, NH).
5‐Bromo‐1′,3′‐diphenyl‐7′‐thioxo‐spiro[indoline‐3,4′‐pyrazolo
[4′,3′:5,6]pyrido[2,3‐d]pyrimidine]‐2,5′(6′H,8′H,9′H)‐dione (4r).
White powder (89%); m.p >300°C. 1H‐NMR (300 MHz, DMSO‐
d6): δH (ppm) 6.45–7.68 (m, 13H, H‐Ar), 9.44 (s, 1H, NH), 10.21
(s, 1H, NH), 11.73 (s, 1H, NH), 12.24 (s, 1H, NH).
5‐Nitro‐1′,3′‐diphenyl‐7′‐thioxo‐spiro[indoline‐3,4′‐pyrazolo
[4′,3′:5,6]pyrido[2,3‐d]pyrimidine]‐2,5′(6′H,8′H,9′H)‐dione (4s).
White powder (91%); m.p > 300°C. 1H‐NMR (300 MHz, DMSO‐
d6): δH (ppm) 6.65–8.01 (m, 13H, H‐Ar), 9.54 (s, 1H, NH), 10.82
(s, 1H, NH), 11.79 (s, 1H, NH), 12.28 (s, 1H, NH).
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[4′,3′:5,6]pyrido[2,3‐d]pyrimidine]‐2,5′(6′H,8′H,9′H)‐dione (4t).
White powder (83%); m.p >300°C. 1H‐NMR (300 MHz, DMSO‐
d6): δH (ppm) 2.69 (s, 3H, CH3), 6.62–7.71 (m, 14H, H‐Ar), 9.46
(s, 1H, NH), 11.77 (s, 1H, NH), 12.19 (s, 1H, NH).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet