Iron(III)-catalyzed highly efficient, one-pot synthesis of triazolo[1,2-a]indazoletriones and spirotriazolo[1,2-a]indazoletetraones

Article abstract of DOI:10.1246/cl.130164

Three-component coupling (3CC) of aldehyde, 1,3-dione and 4-phenylurazole has been achieved in the presence of 10 mol% anhydrous FeCl₃ in acetonitrile under reflux conditions to afford the corresponding triazolo[1,2-a]indazoletriones in excelle

Full text of DOI:10.1246/cl.130164

doi:10.1246/cl.130164
Published on the web May 30, 2013
927
Iron(III)-catalyzed Highly Efficient, One-pot Synthesis of Triazolo[1,2-a]indazoletriones
and Spirotriazolo[1,2-a]indazoletetraones
B. V. Subba Reddy,* N. Umadevi, G. Narasimhulu, and J. S. Yadav
Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
(Received March 1, 2013; CL-130164; E-mail: basireddy@iict.res.in)
Three-component coupling (3CC) of aldehyde, 1,3-dione,
and 4-phenylurazole has been achieved in the presence of
10 mol % anhydrous FeCl3 in acetonitrile under reflux conditions
to afford the corresponding triazolo[1,2-a]indazoletriones in
excellent yields while the coupling of isatins with 4-phenyl-
urazole and 1,3-diones gave the spirotriazolo[1,2-a]indazole-
tetraones under similar conditions.
O
O
MeO
N
N
N
Ph
N
O
N
HN
H
O
O
O
HO
O
Inhibitor of HSP induction (I)
Spirotryprostatin (II)
O
N
H
Multicomponent reactions (MCRs) are highly important
because of their wide range of applications in pharmaceutical
chemistry for the rapid generation of structural diversity in
combinatorial libraries for drug discovery.1 MCRs are extremely
convergent, producing a remarkably high increase in molecular
complexity in a single-step process.2,3 In particular, triazolo[1,2-
a]indazoletrione, spirotriazolo[1,2-a]indazoletetraone, and their
derivatives are important structural motifs in medicinal and
pharmaceutical chemistry. They are known to exhibit promising
physiological and biological properties such as anticancer
and hypolipidemic,4 anticonvulsant,5 fungicidal activity,6 and a
catalytic role in radical polymerization.7 These compounds are
also used for the preparation of herbicides, pesticides, insecti-
cides, and polymeric materials with unique properties such as
heat-resistant coatings, and high grip ability for rubber tires and
melamine resins. Triazolo[1,2-a]indazoletriones are present in
many pharmacological agents and natural alkaloids like HSP-72
induction inhibitors (I and III) and novel microtubule assembly
inhibitors, spirotryprostatin (II), as shown in Figure 1.4b,8
As a result, numerous approaches have been reported for the
synthesis of triazolo[1,2-a]indazoletrione and spirotriazolo[1,2-
a]indazoletetraone derivatives.9 However, many of these meth-
ods often involve long reaction times, harsh reaction conditions,
and expensive catalysts. Thus, there is a need to develop a
simple and cost-effective method for the synthesis of triazolo-
[1,2-a]indazoletriones and spirotriazolo[1,2-a]indazoletetraones.
The Lewis acid catalyzed carbon-carbon and carbon-
heteroatom bond-forming reactions are of great importance in
organic synthesis because of their high reactivity, selectivity,
and mild reaction conditions.10,11 In particular, iron(III) chloride
has emerged as a powerful Lewis acid to facilitate various
organic transformations under mild reaction conditions.12 More-
over, iron salts are inexpensive, easy to handle, and environ-
mentally friendly. To the best of our knowledge, this is the first
report on the synthesis of triazolo[1,2-a]indazoletrione and
spirotriazolo[1,2-a]indazoletetraone derivatives using FeCl3 as
the catalyst via a three-component reaction.
O
O
N
O
N
N
O
H
HO
O
Cl
Inhibitor of HSP 72 induction (III)
Figure 1. Biologically active urazole and spirooxindole de-
rivatives.
Table 1. Screening of various acid catalysts and solvents in the
formation of product 4b
Mol % of
the catalysta
Time Yield
/h /%b
Entry Acid catalyst
Solvent
a
b
c
d
e
f
g
h
i
CAN
10
10
10
10
10
10
5
10
10
10
CH3CN 8.5 75
CH3CN 8.2 80
CH3CN 3.5 70
THF
DCE
EtOH
CH3CN 5.0 78
CH3CN 2.0 90
CH3CN 8.5 75
CH3CN 8.0 60
Phosphomolybdic acid
Cellulose-SO3H
FeCl3
12.0 60
12.0 75
6.5 85
FeCl3
FeCl3
FeCl3
FeCl3
I2
j
k
ln(ClO4)3
CeCl3¢7H2O/LiI
20/1.0 equiv CH3CN 12.0 55
aThe reaction was performed at 1 mmol scale at 80 °C.
bIsolated yield.
we attempted a three-component coupling of 4-phenylurazole
(1), 4-bromobenzaldehyde (2), and dimedone (3) in the presence
of various amounts of FeCl3 in acetonitrile. Initially, 5 mol %
FeCl3 was used to perform the reaction. However, the product 4b
was obtained in a low yield either in acetonitrile or in ethanol
at room temperature even after a long reaction time (10 h).
Therefore, the catalyst loading was gradually increased from 5 to
50 mol %. After several experiments, it was found that 10 mol %
of FeCl3 is optimal to achieve a high conversion at 80 °C
(Table 1). The use of excess catalyst also did not alter either
reaction time or yield. Therefore, the treatment of 4-phenyl-
urazole (1) with 4-bromobenzaldehyde (2) and dimedone (3) in
the presence of 10 mol % FeCl3 at 80 °C in acetonitrile afforded
In continuation of our interest in exploring the synthetic
utility of FeCl313 and MCRs,14 we herein report a highly efficient
three-component approach for the synthesis of triazolo[1,2-
a]indazoletrione derivatives from 4-phenylurazole, aldehydes,
and 1,3-diones using an iron(III) catalyst. In a model reaction,
Chem. Lett. 2013, 42, 927-929
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

928
Br
HN
O
O
O
N
O
O
O
CHO
10 mol% FeCl3
CH3CN, reflux
NH
NH
O
O
+
+
N
N
O
Ph
NH
NH
10 mol% FeCl3
CH3CN, reflux
N
N
O
O
O
Ph
H
+
+
N
Ph
O
N
O
O
6a
N
Ph
1
3
5
N
O
Br
O
1
2
3
4b
Scheme 2. 3CC reaction between 4-phenylurazole, dimedone,
and isatin.
Scheme 1. Three-component coupling (3CC) of 4-phenyl-
urazole, 4-bromobenzaldehyde, and dimedone.
Table 3. FeCl3-catalyzed 3CC reaction for the synthesis of
spirotriazolo[1,2-a]indazoletetraones
Table 2. FeCl3-catalyzed 3CC reaction for the synthesis of
triazolo[1,2-a]indazoletriones
Entry
Ketone (5)
Diketone (3)
Product (6)a
Time/min
Yield/%b
O
O
Ar
HN
O
O
O
O
10 mol% FeCl3
R
CH3CN, reflux
NH
NH
O O
O
+
Ar-CHO
N
N
+
N
Ph
a
90
85
N
O
O
O
N
Ph
N
N
H
N
O
R
Ph
O
R
O
1
O
R
O
2
3
4a-m
Producta Time/min Yield/%b
Me
Entry Ar
R
N
O
O
a
b
c
d
e
f
g
h
i
Ph
4-BrC6H4
4-NO2C6H4
4-CH3C6H4
3-CH3OC6H4 CH3
3-PhOC6H4
3-ClC6H4
2-Naphthyl
4-ClC6H4
3-PhOC6H4
4-FC6H4
4-NO2C6H4
4-CH3OC6H4
CH3
CH3
CH3
CH3
4a
4b
4c
4d
4e
4f
4g
4h
4i
30
27
29
30
35
35
32
38
28
34
40
35
40
87
90
92
86
84
82
90
86
93
83
92
90
82
O O
N
O
b
c
80
75
91
87
N
N
N
Ph
O
Me
O
Bn
O O
N
O
O
O
CH3
CH3
CH3
H
H
H
N
N
N
N
Ph
O
Bn
O
j
k
l
4j
4k
4l
O
O
O
O
O O
N
d
90
82
N
H
H
O
N
Ph
m
4m
O
aAll products were characterized by NMR and IR spectroscopy
and mass spectroscopy. bYield refers to pure products after
chromatography.
aAll products were characterized by NMR and IR spectroscopy
and mass spectroscopy. bYield refers to pure products after
chromatography.
the corresponding 9-(4-bromophenyl)-6,6-dimethyl-2-phenyl-
6,7-dihydro-[1,2,4]triazolo[1,2-a]indazole-1,3,8(2H,5H,9H)-tri-
one (4b) in 90% yield (Table 1 and Scheme 1).
in 86% yield (Entry h, Table 2). Both dimedone and 1,3-
cyclohexanedione furnished the corresponding products in
excellent yields. The scope and generality of this process is
illustrated in Table 2.15 However, most of the reported Brønsted
acids such as p-TSA, nanosilica-SO3H sulfamic acid, and
AlKIT-5 are successful only with aldehydes not with ketones.
Although PEG-SO3H has successfully been utilized to catalyze
the reaction with isatin derivatives, the catalyst is not readily
available. Notably, FeCl3 works with both aldehydes and
ketones in short reaction times. Therefore, the present method
is advantageous over Brønsted acids.
Encouraged by the results obtained with aldehydes, we
turned our attention toward ketones. Accordingly, the coupling
of 4-phenylurazole (1) and dimedone (3) with isatin (5) afforded
the spirotriazolo[1,2-a]indazoletetraone in 85% yield under
similar conditions (Scheme 2).
In order to realize the catalytic efficiency, we performed
the above reaction with various acid catalysts such as FeCl3,
CeCl3¢7H2O/LiI, In(ClO4)3, iodine, ceric ammonium nitrate
(CAN), heteropolyacid, and cellulose-sulfonic acid. Among
these catalysts, anhydrous FeCl3 was found to be more effective
than others in terms of reaction time and yield (Entry h,
Table 1). Next, we examined the effect of various solvents such
as 1,2-dichloroethane, tetrahydrofuran, ethanol, and acetonitrile.
Of these, acetonitrile appeared to give the best results (Table 1).
Inspired by the above results, we extended this method to
other substrates. Interestingly, a variety of aldehydes including
ortho-, meta-, and para-substituted benzaldehydes participated
effectively in this reaction (Table 2).
As summarized in Table 2, the substituent on the aromatic
ring had shown some effect on conversion. For instance, halo-
substituted aromatic aldehydes gave the products in compara-
tively higher yields than electron-rich aldehydes such as
methoxy, phenoxy, and methyl derivatives did. Remarkably, a
sterically hindered 2-naphthaldehyde also afforded the product
Other isatin derivatives such as N-methyl and N-benzyl
derivatives also participated well in this reaction (Entries b and
c, Table 3). Interestingly, acenaphthoquinone also gave the
desired product in 85% yield (Entry d, Table 3). The results
obtained with ketones are presented in Table 3.15
Chem. Lett. 2013, 42, 927-929
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

929
O
Ar
O
5
6
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O
O
..
H
Ar
R
HN
N
Ph
+
R
NH
O
O
R
R
O
Fe
(III)
7
8
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Ar
O
Ar
O
O
O
N
N
N
Ph
N
Ph
R
R
HN
N
-H2O
R
R
OH
O
O
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Scheme 3. A plausible reaction pathway.
The reaction was proposed to proceed via the formation of
the enone from aldehyde and 1,3-diketone. This is followed by
the attack of 4-phenylurazole on the enone, and a subsequent
cyclodehydration would result in the formation of the desired
product, as depicted in Scheme 3.
In summary, we have developed a highly efficient method
for the synthesis of triazolo[1,2-a]indazoletrione and spirotria-
zolo[1,2-a]indazoletetraone derivatives through the coupling of
aldehyde or ketone with 1,3-dione and 4-phenylurazole using a
catalytic amount of FeCl3. The use of FeCl3 makes this method
quite simple, more convenient, and cost-effective, and thus, it
provides an easy access to triazolo[1,2-a]indazole derivatives in
a single-step process.
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15 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
NU thanks UGC, and GNL thanks CSIR, New Delhi, for
awarding the fellowships.
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Chem. Lett. 2013, 42, 927-929
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/