One-pot, pseudo four-component synthesis of a spiro[diindeno[ 1,2-b:2', 1'-e]pyridine-11,3'-indoline] -trione library

Article abstract of DOI:10.1021/cc900130a

A one-pot, pseudo four-component method for the efficient and simple synthesis of spiro[diindeno[1,2-b: 2',l'-e]pyridine-11,3'-indoline]-2',10,12- trione derivatives in refluxing acetonitrile is reported. The features of this procedure are mild reaction conditions, high yields of products, and operational simplicity.

Full text of DOI:10.1021/cc900130a

J. Comb. Chem. 2010, 12, 191–194
191
One-Pot, Pseudo Four-Component Synthesis of a
Spiro[diindeno[1,2-b:2′,1′-e]pyridine-11,3′-indoline]-trione Library
Ramin Ghahremanzadeh, Ghazaleh Imani Shakibaei, Somayeh Ahadi, and
Ayoob Bazgir*
Department of Chemistry, Shahid Beheshti UniVersity, G.C., P.O. Box 19396-4716, Tehran, Iran
ReceiVed August 22, 2009
A one-pot, pseudo four-component method for the efficient and simple synthesis of spiro[diindeno[1,2-b:
2′,1′-e]pyridine-11,3′-indoline]-2′,10,12-trione derivatives in refluxing acetonitrile is reported. The features
of this procedure are mild reaction conditions, high yields of products, and operational simplicity.
1. Introduction
enhance biological activity.9 The spirooxindole system is the
core structure of many pharmacological agents and natural
alkaloids.10 For example, spirotryprostatin A and B, two
natural alkaloids isolated from the fermentation broth of
Aspergillus fumigatus, have been identified as novel inhibi-
tors of microtubule assembly,10d and pteropodine and
isopteropodine have been shown to modulate the function
of muscarinic serotonin receptors (Figure 1).10a
Considering the above reports, and as part of our program
aimed at developing new methodologies for the preparation
of heterocyclic compounds,11 very recently, we have reported
some procedures for the synthesis of spirooxindole fused
heterocycles.12 We are currently investigating the synthesis
of various spiro[diindeno[1,2-b:2′,1′-e]pyridine-11,3′-indo-
line]-2′,10,12-triones via a facile, atom-economical, and one-
pot pseudo four-component condensation reaction.
Multicomponent reactions (MCRs), in which multiple
reactions are combined into the synthetic operation, have
been used extensively to form carbon-carbon bonds in
synthetic chemistry.1 Such reactions offer a wide range of
possibilities for the efficient construction of highly complex
molecules in a single procedural step, thus avoiding the
complicated purification operations and allowing savings of
both solvents and reagents. In the past decade, there has been
tremendous development in three- and four-component
reactions, and great efforts continue to be made to develop
new MCRs.2 In this context, heterocycles containing an
indenone moiety show interesting features that make them
attractive for use in MCRs.
Indenone-fused heterocycles represent important biological
and medicinal scaffolds. Thus, the indenopyridine skeleton
is present in the 4-azafluorenone group of alkaloids, repre-
sented by its simplest member onychnine (Figure 1).3
Indenopyrazoles (A) and indenopyridazines (B) have been
investigated as cyclin-dependent kinase4 and selective
monoamine oxidase B (MAO-B)5 inhibitors, respectively.
Further, indenopyridines (C) exhibit cytotoxic,6a phosphodi-
esterase inhibitory,6b adenosine A2a receptor antagonistic,6c
antiinflammatory/antiallergic,6d coronary dilating,6e and calcium
modulating activities.6f These compounds have also been
investigated for the treatment of hyperlipoproteinemia and
arteriosclerosis,6g as well as neurodegenerative diseases.6h
Lastly, indenopyridone NSC 314622 is serving as a lead
compound for the development of anticancer agents targeting
topoisomerase I. Its polycyclic planar structure allows for DNA
intercalation and inhibition of DNA religation by topoisomerase
I in a manner similar to the polycyclic natural product
camptothecin and its clinically useful derivative topotecan.7
The indole moiety is probably the most well-known
heterocycle, a common and important feature of a variety
of natural products and medicinal agents.8 Furthermore, it
has been reported that sharing of the indole 3-carbon atom
in the formation of spiroindoline derivatives can highly
2. Results and Discussion
The choice of an appropriate reaction media is of crucial
importance for successful synthesis. Initially, the pseudo four-
component reaction of 1,3-indandione 1, aniline 2a, and isatin
Table 1. Model Reaction, Conditions, and Yieldsa
entry
conditions
catalyst (mol %)
time (h)
yield (%)
1
2
3
4
5
6
7
8
CHCl3 (reflux)
water (reflux)
p-TSA (30)
p-TSA (30)
p-TSA (20)
p-TSA (30)
p-TSA (40)
4
4
1
1
<30
<30
74
81
82
<30
<40
60
CH3CN (reflux)
CH3CN (reflux)
CH3CN (reflux)
CH3CN (reflux)
CH3CN/ r.t.
EtOH (reflux)
MeOH (reflux)
CH3CN (reflux)
CH3CN (reflux)
CH3CN (reflux)
1
10
10
1
1
1
p-TSA (30)
p-TSA (30)
p-TSA (30)
LiCl (30)
ZnCl2 (30)
AlCl3 (30)
9
53
10
11
12
<30
<30
66
1
1
* To whom correspondence should be addressed. E-mail: a_bazgir@
sbu.ac.ir.
a 1,3-Indandione(2 mmol), aniline (1 mmol), isatin (1 mmol).
10.1021/cc900130a CCC: $40.75  2010 American Chemical Society
Published on Web 10/28/2009

192 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Ghahremanzadeh et al.
Figure 1. Representatives of important indenone-fused heterocycles and spirooxindoles.
Scheme 1. Synthesis of Spiro[diindenopyridine-indoline]-triones 4
Scheme 2. Two-Step Synthesis of Spirooxindole 4a
3a as a simple model substrate was investigated to establish
the feasibility of the strategy and optimize the reaction
conditions. Different solvents in the presence of p-toluene-
sulfonic acid (p-TSA) as an inexpensive and available
catalyst and various Lewis acids were screened in the model
reaction. As can be seen from Table 1, in the presence of
p-TSA, acetonirile is the solvent of choice for the reaction,
and the desired product is obtained in excellent yields and
high purity (Entry 3), while without p-TSA and over long
period of time (10 h) the yield of product was very low (Entry
4).
The reaction proceeds very cleanly under mild conditions
and is compatible with a wide range of functional groups.
In addition, the advantage of such methodology is that
products sedimented from the reaction medium after cooling
it to room temperature and spirooxindoles 4 were obtained
with high purity.
When this reaction was carried out with aliphatic amines
1
such as n-propylamine or ethylamine, TLC and H NMR
spectra of the reaction mixture showed a combination of
starting materials and numerous products; the yield of the
expected product was very poor.
Given the large number of commercially available isatins
and aromatic amines, the present method should be applicable
to synthesis of libraries with high diversity. We expect this
method to find extensive application in the field of combi-
natorial chemistry, diversity-oriented synthesis, and drug
discovery.
Encouraged by this success, we extended this reaction of
1,3-indandione 1 with a range of other aromatic amines 2a-e
and isatins 3a-d with both electron withdrawing and electron
releasing substituents under similar conditions (MeCN,
p-TSA), and corresponding spiro[diindeno[1,2-b:2′,1′-e]py-
ridine-11,3′-indoline]-2′,10,12-triones 4a-t were synthesized
in high yields (Scheme 1). We have shown that the use of a
wide diversity of substituents in aromatic amines 2 and
isatins3 in this pseudo four-component reaction makes
possible the synthesis of libraries under similar circumstances
(Table 2).
For the investigation of the reaction mechanism, it is
notable that when 1,3-indandione 1 and isatin 3a were reacted
for 1 h, the intermediate 5 was isolated and characterized
by spectroscopic methods. When intermediate 5 and aniline
2a were reacted in the presence of p-TSA under the same

Spiro[diindenopyridine-indoline]-triones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 193
Scheme 3. Synthesis of Spiro[acenaphthylene-1,11′-diindenopyridine]-triones 7
Table 2. Spiro[diindenopyridine-indoline]-triones 4
cooled to room temperature. Then, the precipitated product
was filtered and washed with water (10 mL) and ethanol (5
mL) to afford the pure product 4a as a red powder (0.39 g,
82%); mp >300 °C. IR (KBr) (νmax /cm-1): 3437, 3132, 1703,
1624. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 5.46 (2H,
d,3JHH ) 6.0 Hz, H-Ar), 6.45-8.14 (15H, m, H-Ar), 10.65
(1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 46.1,
109.5, 111.9, 121.8, 121.9, 122.7, 124.9, 125.9, 128.5, 129.0,
130.7, 132.1, 132.8, 134.8, 136.5, 138.2, 142.6, 156.2, 178.0,
190.0. Anal. Calcd for C32H18N2O3: C, 80.32; H, 3.79; N,
5.85. Found: C, 80.41; H, 3.71; N, 5.76.
compound 4
X
R′
R
yield (%)a
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
H
Br
NO2
Me
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
82
85
80
90
92
78
78
75
84
87
80
80
76
85
88
84
82
77
88
91
H
Me
Me
Me
Me
Me
H
H
H
H
H
Br
NO2
Me
OMe
H
H
H
Br
Br
Br
Br
Br
NO2
NO2
NO2
NO2
NO2
Br
NO2
Me
OMe
H
Acknowledgment. We gratefully acknowledge financial
support from the Research Council of Shahid Beheshti
University.
H
H
H
H
Br
NO2
Me
OMe
Supporting Information Available. Experimental pro-
cedures, and IR, 1H NMR, and 13C NMR spectra for
compounds 4 and 7. This material is available free of charge
via the Internet at http://pubs.acs.org.
t
H
a Isolated yields.
reaction conditions, the product 4a was obtained in 73% yield
(Scheme 2). According to the results, a reasonable possibility
for the formation of spiro[diindenopyridine-indoline]-triones
4 is shown in the Supporting Information.
As expected, when the isatin 3 was replaced by acenaph-
thylene-1,2-dione 6, 5′-aryl-2H,5′H-spiro[acenaphthylene-
1,11′-diindeno[1,2-b:2′,1′-e]pyridine]-2,10′,12′-triones 7a-f
was obtained in good yield under the same reaction condi-
tions (Scheme 3).
References and Notes
(1) (a) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P.
Chem.sEur. J. 2000, 6, 3321. (b) Tietze, L. F.; Modi, A. Med.
Res. ReV. 2000, 20, 304. (c) Do¨mling, A.; Ugi, I. Angew.
Chem., Int. Ed. 2000, 39, 3168. (d) Zhu, J. Eur. J. Org. Chem.
2003, 1133. (e) Orru, R. V. A.; de Greef, M. Synthesis 2003,
1471. (f) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.;
Sreekanth, A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem.
Res. 2003, 36, 899.
(2) (a) Nair, V.; Vinod, A. U.; Rajesh, C. J. Org. Chem. 2001,
66, 4427. (b) List, B.; Castello, C. Synlett 2001, 1687. (c)
Shestopalov, A. M.; Emeliyanova, Y. M.; Shestiopolov, A. A.;
Rodinovskaya, L. A.; Niazimbetova, Z. I.; Evans, D. H. Org.
Lett. 2002, 4, 423. (d) Bertozzi, F.; Gustafsson, M.; Olsson,
R. Org. Lett. 2002, 4, 3147. (e) Yuan, Y.; Li, X.; Ding, K.
Org. Lett. 2002, 4, 3309. (f) Cheng, J. F.; Chen, M.; Arthenius,
T.; Nadzen, A. Tetrahedron Lett. 2002, 43, 6293.
(3) Zhang, J.; El-Shabrawy, A.-R. O.; El-Shanawany, M. A.;
Schiff, P. L.; Slatkin, D. J. J. Nat. Prod. 1987, 50, 800.
(4) Nugiel, D. A.; Etzkorn, A.-M.; Vidwans, A.; Benfield, P. A.;
Boisclair, M.; Burton, C. R.; Cox, S.; Czerniak, P. M.;
Doleniak, D.; Seitz, S. P. J. Med. Chem. 2001, 44, 1334.
(5) Fa`ede´rick, R.; Dumont, W.; Ooms, F.; Aschenbach, L.; Van
der Schyf, C. J.; Castagnoli, N.; Wouters, J.; Krief, A. J. Med.
Chem. 2006, 49, 3743.
(6) (a) Miri, R.; Javidnia, K.; Hemmateenejad, B.; Azarpira, A.;
Amirghofran, Z. Bioorg. Med. Chem. 2004, 12, 2529. (b)
Heintzelman, G. R.; AverillK. M.; Dodd, J. H. PCT Int. Appl.
WO 2002085894 A1 20021031, 2002; (c) Heintzelman, G. R.;
Compounds 4 and 7 are stable solids whose structures were
1
established by IR, H NMR, 13C NMR spectroscopy, and
elemental analysis.
In conclusion, an efficient, atom-economical, and simple
method for the preparation of spiro[diindenopyridine-indo-
line]-triones and spiro[acenaphthylene-diindenopyridine]-
triones using readily available starting materials is reported.
Prominent among the advantages of this new method are
operational simplicity, good yields in short reaction times,
and easy workup procedures employed.
Typical Procedure for Preparation of 5-Phenyl-5H-
spiro[diindeno[1,2-b:2′,1′-e]pyridine-11,3′-indoline]-2′,10,12-
trione (4a). A mixture of 1,3-indandione (0.30 g, 2 mmol),
aniline (0.09 g, 1 mmol), isatin (0.15 g, 1 mmol), and p-TSA
(30 mol %) in refluxing acetonitrile (5 mL) was stirred for
30 min. After completion of the reaction confirmed by TLC
(eluent: EtOAc/n-hexane, 1:3), the reaction mixture was

194 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Ghahremanzadeh et al.
Averill, K. M.; Dodd, J. H.; Demarest, K. T.; TangY.; Jackson,
P. F. Pat. Appl. Publ. U.S. 2004082578 A1 20040429,
2004; (d) Cooper, K.; Fray, M. J.; CrossP. E.; Richardson,
K. Eur. Pat. Appl. EP 299727 A1 19890118, 1989; (e)
Vigante, B.; Ozols, J.; Sileniece, G.; KimenisA.; Duburs, G. U.
S. S. R. SU, 794006 19810107, 1989; (f) Safak, C.; Simsek,
R.; Altas, Y.; Boydag, S.; Erol, K. Boll. Chim. Farm. 1997,
136, 665. (g) Brandes, A.; Loegers, M.; Schmidt, G.; Anger-
bauer, R.; Schmeck, C.; Bremm, K.-D.; Bischoff, H.;
SchmidtD.; Schuhmacher, J. Ger. Offen. DE 19627430 A1
19980115, 1998; (h) Heintzelman, G. R.; Averill, K. M.;
Dodd, J. H.; Demarest, K. T.; TangY.; Jackson, P. F. PCT
Int. Appl. WO 2003088963 A1 20031030, 2003.
Osada, H. Biochem. J. 1998, 333, 543. (d) Khafagy, M. M.;
El-Wahas, A. H. F. A.; Eid, F. A.; El-Agrody, A. M. Farmaco
2002, 57, 715.
(11) (a) Bazgir, A.; Seyyedhamzeh, M.; Yasaei, Z.; Mirzaei, P.
TetrahedronLett.2007,48,8790.(b)Sayyafi,M.;Seyyedhamzeh,
M.; Khavasi, H. R.; Bazgir, A. Tetrahedron 2008, 64, 2375.
(c) Dabiri, M.; Arvin-Nezhad, H.; Khavasi, H. R.; Bazgir, A.
J. Heterocycl. Chem. 2007, 44, 1009. (d) Dabiri, M.; Azimi,
S. C.; Arvin-Nezhad, H.; Bazgir, A. Heterocycles 2008, 75,
87. (e) Dabiri, M.; Delbari, A. S.; Bazgir, A. Synlett 2007,
821. (f) Dabiri, M.; Arvin-Nezhad, H.; Khavasi, H. R.; Bazgir,
A. Tetrahedron 2007, 63, 1770. (g) Dabiri, M.; Delbari, A. S.;
Bazgir, A. Heterocycles 2007, 71, 543. (h) Ghahremanzadeh,
R.; Imani Shakibaei, G.; Bazgir, A. Synlett 2008, 1129. (i)
Imani Shakibaei, G.; Khavasi, H. R.; Mirzaei, P.; Bazgir, A.
J. Heterocycl. Chem. 2008, 45, 1481.
(7) Nagarajan, M.; Morrell, A.; Fort, B. C.; Meckely, M. R.;
Antony, S.; Kohlhagen, G.; Pommier, Y.; Cushman, M.
J. Med. Chem. 2004, 47, 5651.
(8) Sundberg, R. J. The Chemistry of Indoles; Academic: New
York, 1996.
(12) (a) Bazgir, A.; Noroozi Tisseh, Z.; Mirzaei, P. Tetrahedron
Lett. 2008, 49, 5165. (b) Jadidi, K.; Ghahremanzadeh, R.;
Bazgir, A. Tetrahedron 2009, 65, 2005. (c) Dabiri, M.; Azimi,
S. C.; Khavasi, h. R.; Bazgir, A. Tetrahedron 2008, 64, 7307.
(d) Ahadi, S.; Khavasi, H. R.; Bazgir, A. Chem. Pharm. Bull.
2008, 56, 1328. (e) Ghahremanzadeh, R.; Sayyafi, M.; Ahadi,
S.; Bazgir, A. J. Comb. Chem. 2009, 11, 393. (f) Jadidi, K.;
Ghahremanzadeh, R.; Bazgir, A. J. Comb. Chem. 2009, 11,
341.
(9) (a) Joshi, K. C.; Chand, P. Pharmazie 1982, 37, 1. (b) Da-
Silva, J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz. Chem.
Soc. 2001, 12, 273. (c) Abdel-Rahman, A. H.; Keshk, E. M.;
Hanna, M. A.; El-Bady, Sh. M. Bioorg. Med. Chem. 2004,
12, 2483. (d) Zhu, S.-L.; Ji, S.-J.; Yong, Z. Tetrahedron 2007,
63, 9365.
(10) (a) Kang, T.-H.; Matsumoto, K.; Murakami, Y.; Takayama,
H.; Kitajima, M.; Aimi, N.; Watanabe, H. Eur. J. Pharmacol.
2002, 444, 39. (b) Ma, J.; Hecht, S. M. Chem. Commun. 2004,
1190. (c) Usui, T.; Kondoh, M.; Cui, C.-B.; Mayumi, T.;
CC900130A