Pseudo five-component synthesis of 5-phenyldihydrospiro[diindenopyridine- indenoquinoxaline]dione derivatives via a one-pot condensation reaction

Article abstract of DOI:10.1007/s00706-013-1118-0

Simple and efficient synthesis of novel 5-phenyl-5,5a-dihydro-4bH- spiro[diindeno[1,2-b:2′,1′-e]pyridine-11,11′-indeno[2,1-b] quinoxaline]-10,12(10aH,11aH)-diones via a one-pot pseudo five-component cyclocondensation reaction of 1H-indene-1,2,3-trione, benzene-1,2-diamine, 1H-indene-1,3(2H)-dione, and anilines in refluxing acetonitrile is reported. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-013-1118-0

Monatsh Chem
DOI 10.1007/s00706-013-1118-0
ORIGINAL PAPER
Pseudo five-component synthesis of 5-
phenyldihydrospiro[diindenopyridine-indenoquinoxaline]dione
derivatives via a one-pot condensation reaction
•
Tayebeh Amanpour Ayoob Bazgir
•
•
Ali M. Ardekani Ramin Ghahremanzadeh
Received: 10 June 2013 / Accepted: 31 October 2013
Ó Springer-Verlag Wien 2013
Abstract Simple and efficient synthesis of novel 5-phe-
nyl-5,5a-dihydro-4bH-spiro[diindeno[1,2-b:20,10-e]pyri-
dine-11,110-indeno[2,1-b]quinoxaline]-10,12(10aH,11aH)-
diones via a one-pot pseudo five-component cyclocon-
densation reaction of 1H-indene-1,2,3-trione, benzene-1,2-
diamine, 1H-indene-1,3(2H)-dione, and anilines in reflux-
ing acetonitrile is reported.
to create target compounds by the introduction of several
diversity elements in a single chemical operation [8–11].
Over the past decade, great efforts have been made to
develop novel MCRs, which have led to tremendous
advances in the context of generating libraries of molecules
for the discovery of biologically active leads and also for
the optimization of potent drug candidates [4, 12].
Heterocyclic compounds occur commonly in nature and
are essential to life. Nitrogen-containing heterocyclic
molecules constitute the largest portion of chemical enti-
ties, which are part of many natural products, fine
chemicals, and biologically active pharmaceuticals critical
for enhancing the quality of life [13, 14]. Improvement of
new efficient methods to synthesize N-heterocycles with
structural diversity is an important goal of modern syn-
thetic organic chemistry [15–17].
Keywords Multicomponent reaction ꢀ Quinoxaline ꢀ
Indenoquinoxaline ꢀ Spiro compound
Introduction
Multicomponent reactions (MCRs) have attracted much
attention because of their convergence, efficiency, ease of
execution, and generally high yields of products [1, 2]. This
methodology affords molecular diversity and complexity,
and leads to interesting heterocyclic scaffolds useful for
combinatorial chemistry [3–7] because of its valuable
features such as atom economy, environmental friendli-
ness, straightforward reaction design, and the opportunity
Quinoxalines are a main class of nitrogen-containing
benzoheterocycles which have received much attention in
recent years owing to both their biological properties and
pharmaceutical applications. These derivatives are partic-
ularly interesting because some of them show antimicrobial
[18–20], anticancer [21–26], antimalarial [27–34], anti-
inflammatory [35–38], antinociceptive [39, 40], antituber-
cular [41, 42], anthelmintic [43–45], antidiabetic [46, 47],
antiepileptic [48], antimetabolism and antiviral properties
[49]. Also, quinoxaline moieties are present in the structure
of various antibiotics such as echinomycin, levomycin, and
actinoleutin, which are known to inhibit the growth of
gram positive bacteria and they are active against various
transplantable tumors [50–52].
T. Amanpour ꢀ A. Bazgir
Department of Chemistry, Shahid Beheshti University, General
Campus, Tehran, Iran
A. M. Ardekani
Reproductive Biotechnology Research Center, Avicenna
Research Institute, ACECR, Tehran, Iran
Indenoquinoxaline derivatives are another important
class of nitrogen-containing heterocycles which are useful
intermediates in organic synthesis (e.g., of organic semi-
conductors) [53, 54] and they also have applications in
dyes.
R. Ghahremanzadeh (&)
Nanobiotechnology Research Center, Avicenna Research
Institute, ACECR, Tehran, Iran
e-mail: r.ghahremanzadeh@yahoo.com;
r.ghahremanzadeh@avicenna.ac.ir
123

T. Amanpour et al.
Scheme 1
Table 1 Screening of solvents for the synthesis of 5a
Table 2 Screening of ionic liquids for the synthesis of 5a
Yield/%a
Entry
Solvent
Time/h
Yield/%a
Ionic liquid
Time/h
1
2
3
4
5
6
7
8
MeOH
EtOH
24
24
24
16
24
30
20
24
51
56
[bmim]Br
24
24
24
24
51
58
53
61
[bmim]PF6
[bmim]BF4
[HNMP]HSO4
DMF
55
CH3CN
Water
THF
96
48
The reaction was carried out using 1H-indene-1,2,3-trione (1), ben-
zene-1,2-diamine (2), 1H-indene-1,3(2H)-dione (3), and aniline (4) in
the presence of p-TSA (10 mol%) and 1 cm3 ionic liquid
\50
45
HOAc
Toluene
a
Isolated yield of pure compound
–
The reaction was carried out using 1H-indene-1,2,3-trione (1), ben-
zene-1,2-diamine (2), 1H-indene-1,3(2H)-dione (3), and aniline (4) in
the presence of p-TSA (10 mol%) and 5 cm3 solvent
Table 3 Screening of catalyst for the synthesis of 5a
Catalyst
Yield/%a
a
Isolated yield of pure compound
Nano ZnO
\50
\50
52
In continuation of our previous works on the synthesis
of heterocyclic spiro compounds [55–61], herein, we report
a simple and efficient one-pot, pseudo five-component
method for the preparation of novel 5-phenyldihydrospi-
ro[diindenopyridine-indenoquinoxaline]dione derivatives
in refluxing conditions by using p-toluenesulfonic acid
(p-TSA) as an inexpensive and nontoxic catalyst.
Nano MgO
Nano Fe3O4
Nano CuFe2O4
Nano MnFe2O4
53
55
The reaction was carried out using 1H-indene-1,2,3-trione (1), ben-
zene-1,2-diamine (2), 1H-indene-1,3(2H)-dione (3), and aniline (4) in
the presence of p-TSA (10 mol%) and 5 cm3 acetonitrile
a
Isolated yield of pure compound
Results and discussion
various nano-catalysts in acetonitrile in refluxing condi-
tions, but the yields were only moderate. Therefore,
acetonitrile was chosen as the most appropriate solvent
(Table 1, entry 4), and p-TSA was chosen as the most
appropriate catalyst for this reaction. TLC showed that a
new compound, which turned out to be the desired product,
was formed and general workup afforded the product 5a in
excellent yield (96 %) and high purity. It contrast, without
p-TSA the yield of product was very low (\40 %) even
after 24 h.
We first tested the condensation reaction of 1H-indene-
1,2,3-trione (1), benzene-1,2-diamine (2), 1H-indene-
1,3(2H)-dione (3), and aniline (4) as a simple model sub-
strate in various polar and nonpolar solvents in the
presence of p-TSA as an inexpensive and available catalyst
(Scheme 1). The results are summarized in Table 1. Of the
various solvents screened, acetonitrile resulted in the best
yield and shortest reaction time. The model reaction was
also carried out in different ionic liquids at 80 °C and
different catalysis. The results are summarized in Tables 2
and 3.
In order to optimize the reaction conditions, we also
evaluated the amount of catalyst required for this trans-
formation. The model reaction was performed in the
presence of different amounts of catalyst. It was found that
using 30 mol% p-TSA in acetonitrile was sufficient to
drive the reaction to completion. Increasing the amount of
p-TSA to more than 30 mol% showed no substantial
As can be seen in Table 2, the model reaction was done
in various ionic liquids in the presence of p-TSA as catalyst
in 80 °C, but the yields were not very high. Also, as can be
seen in Table 3, the model reaction was carried out with
123

Pseudo five-component synthesis
improvement in the yield, whereas the yield was decreased
by using less than 30 mol% of the catalyst. Thus, 30 mol%
of catalyst was chosen as the optimal quantity.
reaction mixture showed a combination of starting mate-
rials and numerous products; and the yield of the expected
product was very poor.
A catalyst plays a crucial role in the success of a reaction
in terms of the reaction rate and yield. The recovery and
reuse of catalyst are highly preferable for synthesis. As
shown in Fig. 1, the possibility of recycling the p-TSA was
studied in model substrates. It is important to highlight that
the catalyst was recovered in excellent yield (94–96 %) after
each reaction. The recovered catalyst was simply washed
with acetone several times. The procedure was repeated and
the results indicated that in four consecutive runs, the iso-
lated yields remained similar with no detectable loss.
Encouraged by this success, we extended the scope of
this reaction to 1H-indene-1,2,3-trione (1), benzene-1,2-
diamines 2a, 2b, and 1H-indene-1,3(2H)-dione (3) with a
range of aromatic amines 4a–4e with both electron-with-
drawing and electron-releasing substituents under similar
conditions (MeCN, p-TSA), and corresponding 5-phenyl-
5,5a-dihydro-4bH-spiro[diindeno[1,2-b:20,10-e]pyridine-
11,110-indeno[2,1-b]quinoxaline]-10,12(10aH,11aH)-di-
ones 5a–5j were synthesized in high yields (Scheme 2).
We have shown that the use of a wide diversity of sub-
stituents in benzene-1,2-diamines 2 and aromatic amines 4
in this pseudo five-component reaction makes possible the
synthesis of libraries under similar circumstances
(Table 4). All indenoquinoxalines synthesized by this
pseudo five-component reaction were novel.
Although the detailed mechanism of the reaction has not
been clarified yet, we propose a pathway wherein the spiro
product 5 is formed via domino reactions. As shown in
Scheme 3, compound 5 could be synthesized via sequential
iminization–aromatization, condensation, addition, enam-
ination, and cyclization. The reaction may proceed in a
stepwise manner, in which the 1H-indene-1,2,3-trione (1)
first reacts with benzene-1,2-diamine (2) to afford 11H-
indeno[2,1-b]quinoxalin-11-one (6) in the presence of p-
TSA in acetonitrile. This step was regarded as a fast imi-
nization–aromatization reaction. Then, compound 6 is
condensed with 1H-indene-1,3(2H)-dione (3) to afford
2-(11H-indeno[2,1-b]quinoxalin-11-ylidene)-1H-indene-
1,3(2H)-dione (7). This step was regarded as a fast Knoe-
venagel condensation reaction. Then, compound 7 is
attacked by Michael-type addition with another 1H-indene-
1,3(2H)-dione (3) to produce the intermediate 8. Finally,
compound 8 reacted with aniline 4 to produce 2-[11-[1-oxo-
3-(phenylamino)-1H-inden-2-yl]-11H-indeno[2,1-b]quinox-
alin-11-yl]-1H-indene-1,3(2H)-dione (9), followed by
Table 4 Synthesis of novel 5-phenyldihydrospiro[diindenopyridine-
indenoquinoxaline]dione derivatives 5a–5j
Product
R
X
Yield/%a
When this reaction was carried out with aliphatic amines
1
such as n-propylamine, TLC and H NMR spectra of the
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
H
96
95
71
68
62
67
91
83
72
51
H
Me
OMe
Br
H
H
H
NO2
H
Me
Me
Me
Me
Me
Me
OMe
Br
5j
a
NO2
Isolated yields
Fig. 1 Recyclability study of catalyst in the synthesis of 5a
Scheme 2
123

T. Amanpour et al.
Scheme 3
intramolecular cyclization and tautomerization to afford the
product 5.
Bruker DRX-300 AVANCE spectrometer at 300.13 and
1
75.47 MHz, respectively. H and 13C NMR spectra were
In conclusion, we have described a successful strategy for
the efficient and convenient synthesis of novel 5-phenyldi-
hydrospiro[diindenopyridine-indenoquinoxaline]diones in
a one-pot, pseudo five-component cyclocondensation reac-
tion of 1H-indene-1,2,3-trione, benzene-1,2-diamine,
1H-indene-1,3(2H)-dione, and anilines using an inexpen-
sive, nontoxic, and easily available catalyst.
obtained on solutions in DMSO-d6 using TMS as internal
standard. IR spectra were recorded using an FTIR appa-
ratus. Elemental analyses were performed using a Heracus
CHN-O-Rapid analyzer. The chemicals used in this work
were obtained from Fluka and Merck and were used
without purification.
Typical procedure: 5-phenyl-5H-spiro[diindeno-
[1,2-b:20,10-e]pyridine-11,110-indeno[2,1-b]quinoxaline]-
10,12-dione (5a, C39H21N3O2)
Experimental
A mixture of 0.16 g 1H-indene-1,2,3-trione (1 mmol),
0.11 g benzene-1,2-diamines (1 mmol), and p-TSA
(30 mol%) in 5 cm3 refluxing acetonitrile was stirred for
Melting points were measured on an Electrothermal 9100
1
apparatus. H and 13C NMR spectra were recorded on a
123

Pseudo five-component synthesis
5 min then 0.30 g 1,3-indandione (2 mmol) and 0.09 g
aniline (1 mmol) were added to the mixture and stirred for
16 h. After completion of the reaction confirmed by TLC
(EtOAc/n-hexane, 1:3), the reaction mixture was cooled to
room temperature. Then, the precipitated product was
filtered and washed with 10 cm3 water and 5 cm3 hot
ethanol to afford the pure product 5a as a dark red powder.
(18H, m, ArH) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 48.5, 115.7, 123.8, 125.5, 127.6, 128.2, 130.2, 132.8,
133.3, 134.9, 135.6, 135.9, 136.3, 137.0, 138.7, 139.9,
143.5, 145.3, 153.4, 157.2, 158.6, 168.1, 192.4 ppm.
70,80-Dimethyl-5-phenyl-5H-spiro[diindeno[1,2-b:20,10-e]-
pyridine-11,110-indeno[2,1-b]quinoxaline]-10,12-dione
(5f, C41H25N3O2)
ꢀ
Yield 96 %; m.p.: [280 °C; IR (KBr): m = 1,697,
Dark-red powder; yield 67 %; m.p.: [280 °C; IR (KBr):
1,623 cm-1
;
1H NMR (300 MHz, DMSO-d6): d = 5.50
1
m = 1,700, 1,616 cm-1; H NMR (300 MHz, DMSO-d6):
ꢀ
(2H, bs, ArH), 7.09–8.21 (19H, m, ArH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 113.3, 121.9, 126.5, 129.4,
129.6, 130.8, 132.2, 132.5, 132.9, 136.6, 141.5, 142.3,
155.0, 156.9, 165.3, 190.1 ppm.
d = 2.42 (6H, s, CH3), 5.52 (2H, d, J = 8 Hz, ArH),
7.08–8.29 (17H, m, ArH) ppm; because of very low
solubility of the product 4f, we cannot report the 13C NMR
data for this product.
70,80-Dimethyl-5-(p-tolyl)-5H-spiro[diindeno[1,2-b:20,10-e]-
pyridine-11,110-indeno[2,1-b]quinoxaline]-10,12-dione
(5g, C42H27N3O2)
5-(p-Tolyl)-5H-spiro[diindeno[1,2-b:20,10-e]pyridine-
11,110-indeno[2,1-b]quinoxaline]-10,12-dione
(5b, C40H23N3O2)
Dark-red powder; yield 91 %; m.p.: 260–270 °C (dec); IR
(KBr): m = 1,697, 1,626 cm
Dark-red powder; yield 95 %; m.p.: 193–205 °C (dec); IR
-1
;
1H NMR (300 MHz,
(KBr): m = 1,693, 1,649 cm-1; 1H NMR (300 MHz, DMSO-
ꢀ
ꢀ
DMSO-d6): d = 2.27 (3H, s, CH3), 2.40 (3H, s, CH3),
2.56 (3H, s, CH3), 5.60 (2H, d, J = 8 Hz, ArH), 7.07–8.12
(16H, m, ArH) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 20.2, 20.3, 21.6, 46.2, 113.4, 121.6, 121.9, 125.9,
128.6, 129.4, 129.9, 130.3, 130.8, 132.2, 132.6, 133.0,
135.8, 136.7, 138.5, 139.5, 140.3, 141.1, 142.1, 145.5,
151.8, 154.0, 156.9, 164.4, 190.1 ppm.
d6): d = 2.08 (3H, s, CH3), 5.61 (2H, d, J = 8 Hz, ArH),
7.08–8.32 (18H, m, ArH) ppm; 13C NMR (75 MHz, DMSO-
d6): d = 21.3, 79.6, 113.3, 121.92, 125.9, 126.5, 128.7, 129.4,
130.3, 130.8, 131.2, 132.6, 133.0, 135.7, 136.7, 138.7, 141.5,
142.0, 142.4, 145.3, 152.0, 157.1, 165.4, 190.1 ppm.
5-(4-Methoxyphenyl)-5H-spiro[diindeno[1,2-b:20,10-e]-
pyridine-11,110-indeno[2,1-b]quinoxaline]-10,12-dione
(5c, C40H23N3O3)
5-(4-Methoxyphenyl)-70,80-dimethyl-5H-spiro[diindeno-
[1,2-b:20,10-e]pyridine-11,110-indeno[2,1-b]quinoxaline]-
10,12-dione (5h, C42H27N3O3)
Dark-red powder; yield 71 %; m.p.: 233–240 °C (dec); IR
-1
ꢀ
(KBr): m = 1,694, 1,621 cm
;
1H NMR (300 MHz,
Dark-red powder; yield 83 %; m.p.: 260–270 °C (dec); IR
(KBr): m = 1,696, 1,626 cm
DMSO-d6): d = 2.42 (6H, s, CH3), 3.98 (3H, s, OCH3),
5.67 (2H, d, J = 8 Hz, ArH), 7.08–8.17 (16H, m, ArH)
ppm; because of very low solubility of the product 4h, we
cannot report the 13C NMR data for this product.
DMSO-d6): d = 3.98 (3H, s, OCH3), 5.68 (2H, d,
J = 8 Hz, ArH), 7.08–8.25 (18H, m, ArH) ppm; 13C
NMR (75 MHz, DMSO-d6): d = 46.3, 56.3, 113.2, 115.6,
115.9, 121.9, 122.1, 126.5, 129.4, 129.5, 130.3, 130.7,
130.8, 131.4, 131.7, 132.6, 132.7, 133.1, 136.5, 136.8,
141.5, 142.4, 152.0, 155.0, 157.4, 161.5, 165.4, 190.2 ppm.
-1
;
1H NMR (300 MHz,
ꢀ
5-(4-Bromophenyl)-70,80-dimethyl-5H-spiro[diindeno[1,2-
b:20,10-e]pyridine-11,110-indeno[2,1-b]quinoxaline]-10,12-
dione (5i, C41H24BrN3O2)
5-(4-Bromophenyl)-5H-spiro[diindeno[1,2-b:20,10-e]-
pyridine-11,110-indeno[2,1-b]quinoxaline]-10,12-dione
(5d, C39H20BrN3O2)
Dark-red powder;yield 72 %; m.p.: 260–270 °C (dec); IR
(KBr): m = 1,698, 1,625 cm
Dark-red powder; yield 68 %; m.p.: 210–220 °C (dec); IR
(KBr): m = 1,697, 1,623 cm
-1
1H NMR (300 MHz,
;
1H NMR (300 MHz,
-1
ꢀ
ꢀ
;
DMSO-d6): d = 2.40 (3H, s, CH3), 2.47 (3H, s, CH3), 5.64
(2H, d, J = 8 Hz, ArH), 7.08–8.30 (16H, m, ArH) ppm; 13
DMSO-d6): d = 5.63 (2H, bs, ArH), 7.11–8.25 (18H, m,
ArH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 46.3,
113.4, 121.9, 122.1, 125.6, 126.6, 129.3, 129.5, 130.3,
130.9, 132.5, 132.7, 133.2, 134.0, 136.6, 17.6, 141.5,
142.4, 151.9, 155.0, 156.7, 165.3, 190.1 ppm.
C
NMR (75 MHz, DMSO-d6): d = 20.2, 20.3, 21.2, 46.2,
79.6, 113.6, 121.6, 121.8, 122.0, 125.5, 125.9, 128.5, 128.7,
130.8, 132.2, 132.5, 133.2, 136.6, 136.6, 137.7, 138.6, 139.6,
140.3, 141.1, 145.4, 151.7, 154.0, 156.6, 164.3, 190.1 ppm.
5-(4-Nitrophenyl)-5H-spiro[diindeno[1,2-b:20,10-e]-
pyridine-11,110-indeno[2,1-b]quinoxaline]-10,12-dione
(5e, C39H20N4O4)
70,80-Dimethyl-5-(4-nitrophenyl)-5H-spiro[diindeno[1,2-
b:20,10-e]pyridine-11,110-indeno[2,1-b]quinoxaline]-10,12-
dione (5j, C41H24N4O4)
Dark-red powder; yield 62 %; m.p.: 175–180 °C (dec); IR
(KBr): mꢀ = 1,695, 1,627 cm-1
;
1H NMR (300 MHz,
Dark-red powder; yield 51 %; m.p.: 260–270 °C (dec); IR
-1
ꢀ
(KBr): m = 1,698, 1,625 cm
;
1H NMR (300 MHz,
DMSO-d6): d = 5.63 (2H, d, J = 8 Hz, ArH), 6.58–8.65
123

T. Amanpour et al.
32. Carta A, Loriga M, Piras S, Paglietti G, La Colla P, Busonera B,
Collu G, Loddo R (2006) Med Chem 2:113
33. Liu CH, Wang B, Li WZ, Yun LH, Liu Y, Su RB, Li J, Liu H
(2004) Bioorg Med Chem 12:4701
34. Colotta V, Catarzi D, Varano F, Calabri FR, Lenzi O, Filacchioni
G, Martini C, Trincavelli L, Deflorian FM (2004) J Med Chem
47:3580
DMSO-d6): d = 2.42 (6H, s, CH3), 5.63 (2H, d, J = 8 Hz,
ArH), 7.09–8.65 (16H, m, ArH) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 20.3, 113.7, 122.1, 125.9, 126.1, 128.5,
129.5, 130.8, 132.4, 133.4, 136.4, 136.9, 140.3, 143.6,
149.7, 156.3, 190.0 ppm.
35. Zarranz B, Jaso A, Lima LM, Aldana I, Monge A, Maurel S,
Sauvain M (2006) Braz J Pharm Sci 42:357
Acknowledgments We gratefully acknowledge financial support
from the Avicenna Research Institute.
36. Zarranz B, Jaso A, Aldana I, Monge A, Maurel S, Deharo E,
Jullian V, Sauvain M (2005) Arzneim Forsch 55:754
37. Guillon J, Grellier P, Labaied M, Sonnet P, Leger JM, Deprez-
Poulain R, Forfar-Bares I, Dallemagne P, Lemaitre N, Pehourcq
F, Rochette J, Sergheraert C, Jarry C (2004) J Med Chem 47:1997
38. Zarranz B, Aldana I, Jaso A, Monge A (2003) Bioorg Med Chem
11:2149
References
1. Nair V, Rajesh C, Vinod AU, Bindu S, Sreekanth AR, Mathen JS,
Balagopal L (2003) Acc Chem Res 36:899
39. Lieu F, Ouellet C, Ruediger EH, Belema M, Qiu Y, Yang X,
Banville J, Burke JR, Gregor KR, MacMaster JF, Martel A,
McIntyre KW, Pattoli MA, Zusi FC, Vyas D (2007) Bioorg Med
Chem Lett 17:1233
40. Singh SK, Saibaba V, Ravikumar V, Rudrawar SV, Daga P, Rao
CS, Akhila V, Hegde P, Rao YK (2004) Bioorg Med Chem
12:1881
2. Armstrong RW, Combs AP, Tempest PA, Brown SD, Keating TA
(1996) Acc Chem Res 29:123
3. Tietze LF, Modi A (2000) Med Res Rev 20:304
4. Domling A, Ugi I (2000) Angew Chem Int Ed 39:3168
5. Weber L (2002) Curr Med Chem 9:2085
6. Jiang B, Rajale T, Wever W, Tu SJ, Li G (2010) Chem Asian J
5:2318
41. Vierfond JM, Legendre L, Martin C, Rinjard P, Miocque M
(1990) Eur J Med Chem 25:251
7. Ruijter E, Scheffelaar R, Orru RV (2011) Angew Chem Int Ed
50:6234
42. Carta A, Piras S, Loriga G, Paglietti G (2006) Mini Rev Med
Chem 6:1179
8. Pokhodylo NT, Matiychuk VS, Obushak MD (2009) J Comb
Chem 11:481
43. Ortega MA, Aldana I, Jaso A, Monge A, Montoya ME, Sainz Y,
Zarranz B (2002) Arzneim Forsch 52:113
9. Zhang L, Lushington GH, Neuenswander B, Hershberger JC,
Malinakova HC (2008) J Comb Chem 10:285
10. Tu SJ, Zhang XH, Han ZG, Cao XD, Wu SS, Yan S, Hao WJ,
Zhang G, Ma N (2009) J Comb Chem 11:428
11. Wang XS, Li Q, Wu JR, Tu SJ (2009) J Comb Chem 11:433
12. Zhu J, Bienayme H (2005) Multicomponent reactions. Wiley-
VCH, Weinheim
44. Aldana OA, Monge I, Zarranz A (2003) Eur J Med Chem 38:791
45. Zanetti LA, Sechi P, Molicotti S, Cannas A, Bua A, Deriu A,
Paglietti G (2005) Int J Antimicrob Agents 25:179
46. Sun G, Uretsky NJ, Wallace LJ, Shams G, Weinstein DM, Miller
DD (1996) J Med Chem 39:4430
47. Fisher MH, Lusi A, Egerton JR (1977) J Pharm Sci 66:1349
48. Bahekar RH, Jain MR, Gupta AA, Goel A, Jadav PA, Patel DN,
Prajapati VM, Patel PR (2007) Arch Pharm 340:359
49. Dell A, William DH, Morris HR, Smith GA, Feeney J, Roberts
GCK (1975) J Am Chem Soc 97:2497
13. Noga EJ, Barthalmus GT, Mitchell MK (1986) Cell Biol Int Rep
10:239
14. Craig PN (1991) In: Drayton CJ (ed) Comprehensive medicinal
chemistry, vol 8. Pergamon, New York
15. Franklin EC (1935) Chem Rev 16:305
50. Heravi MM, Bakhtiari K, Tehrani MH, Javadi NM, Oskooie HA
(2006) Arkivoc xvi:16
51. Raw SA, Wilfred CD, Taylor RJK (2003) Chem Commun
18:2286
52. Bigge CF, Malone TC, Boxer PA, Nelson CB, Ortwine DF,
Schelkun RM, Retz DM, Lescosky LJ, Borosky SA, Vartanian
MG (1995) J Med Chem 38:3720
16. Bergstrom FW (1944) Chem Rev 35:77
17. Lichtenthaler FW (2002) Acc Chem Res 35:728
18. Padwa A, Waterson AG (2000) Curr Org Chem 4:175
19. Orru RVA, De Greef M (2003) Synthesis 1471
20. Kirsch G, Hesse S, Comel A (2004) Curr Org Chem 1:47
21. Kotharkar SA, Shinde DB (2006) Bioorg Med Chem Lett
16:6181
53. Cheng Ch, Jiang B, Tu SJ, Li G (2011) Green Chem 13:2107
54. Sehlstedt U, Aich P, Bergman J, Vallberg EI, Norden B, Graslund
A (1998) J Mol Biol 278:31
55. Ghahremanzadeh R, Amanpour T, Bazgir A (2009) J Heterocycl
Chem 46:1266
22. El-Hawash SA, Habib NS, Kassem MA (2006) Arch Pharm
(Weinheim) 339:564
23. Khan SA, Saleem K, Khan Z (2007) Eur J Med Chem 42:103
24. Corona P, Vitale G, Loriga M, Paglietti G, La Colla P, Collu G,
Sanna G, Loddo R (2006) Eur J Med Chem 41:1102
25. Tandon VK, Yadav DB, Maurya HK, Chaturvedi AK, Shukla PK
(2006) Bioorg Med Chem 14:6120
56. Ghahremanzadeh R, Amanpour T, Bazgir A (2010) J Heterocycl
Chem 47:46
57. Ghahremanzadeh R, Ahadi S, Bazgir A (2009) Tetrahedron Lett
50:7379
58. Ghahremanzadeh R, Amanpour T, Sayyafi M, Bazgir A (2010) J
Heterocycl Chem 47:421
59. Ghahremanzadeh R, Imani Shakibaei G, Ahadi S, Bazgir A
(2010) J Comb Chem 12:191
60. Ghahremanzadeh R, Ahadi S, Imani Shakibaei G, Bazgir A
(2010) Tetrahedron Lett 51:499
26. Abid M, Azam A (2006) Bioorg Med Chem Lett 16:2812
27. Zarranz B, Aldana I, Jaso A, Monge A (2004) Bioorg Med Chem
12:3711
28. Yan L, Liu FW, Dai GF, Liu HM (2007) Bioorg Med Chem Lett
17:609
29. Grande F, Aiello F, Grazia OD, Brizzi A, Garofalo A, Neamati N
(2007) Bioorg Med Chem 15:288
30. Lenzi O, Colotta V, Catarzi D, Varano F, Filacchioni G, Martini
C, Trincavelli L, Ciampi O, Varani K, Marighetti F, Morizzo E,
Moro S (2006) J Med Chem 49:3916
61. Ghahremanzadeh R, Sayyafi M, Ahadi S, Bazgir A (2009) J
Comb Chem 11:393
31. Jung JK, Jung EK, Nam-Goong K, Cho JS, Kim HM, Park SG,
Yoo YA, Kwon JH, Lee HS (2006) Arch Pharm Res 9:276
123