Highly efficient synthesis of triazolo[1,2-a]indazole-triones and novel spiro triazolo[1,2-a]indazole-tetraones under solvent-free conditions

Article abstract of DOI:10.1016/j.tet.2010.11.029

A new, convenient, and high yielding procedure for the synthesis of triazolo[1,2-a]indazole-triones by the condensation reaction between dimedone, aryl aldehydes, and ueazoles in the presence of a catalytic amount of sulfonated polyethylene glycol (PEG-SO

Full text of DOI:10.1016/j.tet.2010.11.029

Tetrahedron 67 (2011) 390e400
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly efficient synthesis of triazolo[1,2-a]indazole-triones and novel spiro
triazolo[1,2-a]indazole-tetraones under solvent-free conditions
,
b
,
a
Alireza Hasaninejad a , Abdolkarim Zare , Mohsen Shekouhy
*
*
a Department of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran
b Department of Chemistry, Payame Noor University (PNU), Bushehr 1698, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 June 2010
Received in revised form 21 October 2010
Accepted 8 November 2010
Available online 12 November 2010
A new, convenient, and high yielding procedure for the synthesis of triazolo[1,2-a]indazole-triones by
the condensation reaction between dimedone, aryl aldehydes, and ueazoles in the presence of a catalytic
amount of sulfonated polyethylene glycol (PEG-SO3H) as a highly stable and reusable eco-friendly de-
gradable polymeric catalyst is described under solvent-free conditions. This procedure has also been
applied successfully for the synthesis of novel spiro triazolo[1,2-a]indazole-tetraones.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Combinatorial chemistry
Multi-component reaction
PEG-SO3H
Urazole
Triazolo[1,2-a]indazole-triones
Spiro triazolo[1,2-a]indazole-tetraone
1. Introduction
H
N
N
O
O
Heterocyclic compounds occur very widely in nature and are
essential to life. Nitrogen-containing heterocyclic molecules con-
stitute the largest portion of chemical entities, which are part of
many natural products, fine chemicals, and biologically active
pharmaceuticals vital for enhancing the quality of life.1 Amongst
them, urazole derivatives are very interesting compounds, found to
have some biological as well as pharmaceutical activity, such as
anti-cancer and hypolipidemic.2 These compounds are also used in
the preparation of herbicides,3 pesticides,4 insecticides,5 and
polymeric materials with unique properties, such as heat-resistant
coatings,6 tyre rubbers with high gripability,7 and melamine
resins.8 One of the most important biologically active compound
containing a urazole moiety in its structure is compound a, that has
been shown to have HSP inhibitory9 (Fig. 1). Beside this several
indolines, spiro-annulated with heterocycles at the 3-position, have
shown good biological activities.10,11 These compounds are the core
structure of many pharmacological agents and natural alka-
loids.12e14 For example, spirotryprostatins (b), natural alkaloids
isolated from the fermentation broth of Aspergillus fumigatus, have
been identified as novel inhibitors of microtubule assembly.14
Moreover, Compound (c) has shown antimicrobial activity10 (Fig.1).
N
O
O
O
N
O
N
H2N
N
N
N
Ph
O
O
H
O
N
H
N
H
O
OH
MeO
(c)
(a)
(b)
Fig. 1. Biological active compounds base on urazole and/or spirooxindole derivatives.
Multi-component reactions (MCRs), have many advantages over
conventional synthetic methodologies, such as higher productivity,
simpleprocedures, and facile execution, and playanimportantrolein
combinatorial chemistry.15 Despite the spectacular investment in,
and organic growth of, combinatorial chemistry as a platform tech-
nology within the pharmaceutical industry during two past decades,
few new MCRs were discovered or developed. Typical examples are
Biginelli,16 Passerini,17 Ugi,15b,18 and Mannich19 reactions that used
successfullyinmanyorganicsyntheses. Uponthesefacts, greatefforts
have been and still are being made to find and develop new MCRs.
The utility of polymer catalysts is now well-recognized because
of their ease of workup and of separation of products and catalysts,
from the economical point of view, and in application to industrial
processes, etc.20 In general, catalysts are immobilized on polymers
* Corresponding authors. Tel.: þ98 771 4222319; fax: þ98 771 4541494 (A.H.);
tel.: þ98 771 559486; fax: þ98 771 5559489 (A.Z.); e-mail addresses: ahassani-
nejad@yahoo.com (A. Hasaninejad), abdolkarimzare@yahoo.com (A. Zare).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.029

A. Hasaninejad et al. / Tetrahedron 67 (2011) 390e400
391
via coordinate or covalent bonds. High reactivity, lack of diffusion
phenomena, and analytical simplicity (advantageous features of
homogeneous solution chemistry) beside the ready isolation and
purification of products (advantageous features of solid phase
methods)21 introduce PEGs as an important group of polymeric
supports for the preparation of polymer supported catalysts.
Sulfonated polyethylene glycol (PEG-SO3H) is an interesting ex-
ample of PEG-supported catalysts that functionalized by acidic
groups, and has been used for the synthesis of 3,4-dihydropyr-
imidones22 and thiocyanohydrines.23
The resultant pharmacological interest in compounds, which
belong to the urazole, indoline, and spirooxindole family, has led us
to develop the synthesis of some novel spiro triazolo[1,2-a]inda-
zole-tetraones. In continuation of our interest in using the solid
acid catalysts in organic transformations,24 herein we report the
catalytic activity of sulfonated polyethylene glycol as an eco-
friendly degradable polymeric catalyst for the synthesis of triazolo
[1,2-a]indazole-triones and novel spiro triazolo[1,2-a]indazole-
tetraone derivatives via the one-pot three-component reaction of
dimedone, carbonyl compounds and 4-substituted urazoles under
solvent-free conditions (Schemes 1 and 3).
40 min. Increasing the amount of PEG-SO3H to more than 20 mol %
showed no substantial improvement in the yield, whereas the yield
decreased by decreasing the amount of the catalyst to 5 mol %.
Moreover, it was observed that the reaction did not proceed effi-
ciently in the absence of PEG-SO3H after a long time (3 h).
In the next step, the scope and efficiency of the catalyst were
explored under the optimized reaction conditions for the conden-
sation of different 4-substituted urazoles with a broad range of
structurally diverse aldehydes and dimedone to furnish the corre-
sponding products (Scheme 1). The results are displayed in Table 2.
As it can be seen the triazolo[1,2-a]indazole-trione derivatives were
obtained in high yields and short reaction times.
The influence of electron-withdrawing and electron-donating
substituents on the aromatic ring of aldehydes upon the reaction
yields was investigated. The results showed that both electron-
withdrawing and electron-donating substituents had no significant
effect on the reaction yields (Table 2, entries 2, and 8e13). More-
over, the presence of halogen on the aromatic ring of aldehydes had
negligible effect on the reaction results (Table 2, entries 3e7).
Interestingly, the catalyst was effectively used for the synthesis
of a complex structure, bis-triazolo[1,2-a]indazole-trione with the
R1
N
O
O
O
O
PEG-SO3H (10 mol%)
Solvent-free / 80 oC
O
HN
HN
+
+
R2
N
R1
H
N
O
N
R2
O
O
(4a-q)
(1)
(2)
(3)
Scheme 1. One-pot three-component synthesis of triazolo[1,2-a]indazole-triones in the presence of PEG-SO3H (10 mol %) at 80 ꢀC under solvent-free conditions.
2. Results and discussions
condensation reaction between dimedone, terphthaldehyde, and
4-phenylurazole for the first time (Table 3, entry 15). The reaction of
2 equiv of dimedone and 4-phenylurazole with terephthalaldehyde
proceeded rapidly to give compound 4o in 89% yield. Compound 4o
has two carbon chiral centers and could exist in two diastereomeric
forms. We proposed a mechanism for the formation of these di-
astereomeric compounds in Scheme 2. First, in the presence of
PEG-SO3H two molecules of dimedone are added to a molecule of
therphetalaldehyde by aldol condensation to form intermediate a.
Then, an urazole molecule is added to this intermediate by Michael
addition reaction and intra molecular cyclization to form in-
termediate b. After that, there are two path ways for the addition of
second urazole molecule to this intermediate (path 1 and 2) that
Our initial efforts focused on the search for a catalyst for the
condensation reaction between dimedone, aryl aldehydes, and
urazoles. For this purpose, the condensation reaction between
dimedone (1 mmol), benzaldehyde (1 mmol), and 4-phenylurazole
(1 mmol) for the synthesis of compound 4a was selected as a model
reaction in the presence of different catalytic systems and the re-
sults are summarized in Table 1.
After extensive screening, we found that the optimized best
yields and time profiles were obtained with 10 mol % of PEG-SO3H
under solvent-free conditions at 80 ꢀC, which furnished the cor-
responding triazolo[1,2-a]indazole-trione 4a in 91% yield within
Table 1
One-pot three-component synthesis of compound 4a from dimedone (1 mmol), benzaldehyde (1 mmol), and 4-phenylurazole (1 mmol) in the presence of various catalytic
systems (10 mol %)
Entry
Catalyst
Reaction conditions
Time (min)
Yielda (%)
1
2
3
4
5
6
7
8
SiO2-OSO3Hb (0.5 g)
P2O5/SiO2 (5% w/w)
NaHSO4$SiO2
InCl3$3H2O
(NH4)6Mo7O24$4H2O
[Bmim]HSO4
[Bmim]OH
ZnO
Ni(OAc)2
PEG-SO3H
PEG-SO3H
PEG-SO3H
Solvent-free, 80 ꢀC
Solvent-free, 80 ꢀC
Solvent-free, 80 ꢀC
Solvent-free, 80 ꢀC
Solvent-free, 80 ꢀC
Solvent-free, 80 ꢀC
Solvent-free, 80 ꢀC
Solvent-free, 80 ꢀC
Solvent-free, 80 ꢀC
Solvent-free, 80 ꢀC
H2O, 80 ꢀC
EtOH, reflux
CH3CN, reflux
CHCl3, reflux
EtOAc, reflux
Solvent-free, 80 ꢀC
240
240
360
180
180
240
360
480
240
40
240
240
240
240
240
240
81
57
46
50
26
50
34
Trace
20
91
Trace
65
76
52
9
10
11
12
13
14
15
16
PEG-SO3H
PEG-SO3H
PEG-SO3H
d
43
Trace
a
Isolated yields.
b
Silica sulfuric acid (for the preparation of this catalyst see Ref. 26).

392
A. Hasaninejad et al. / Tetrahedron 67 (2011) 390e400
Table 2
One-pot three-component synthesis of triazolo[1,2-a]indazole-triones in the presence of PEG-SO3H as a catalyst under solvent-free conditions at 80 ꢀC
Entry
R1
R2
Product
Time (min)
Yielda (%)
O
O
1
C6H5
C6H5
40
91
N
N
N
O
(4a)
CH3
O
2
p-CH3eC6H4
C6H5
45
89
O
N
N
N
O
(4b)
Br
O
O
3
m-BreC6H4
C6H5
35
83
N
N
N
O
(4c)
Br
O
4
p-BreC6H4
C6H5
35
91
O
N
N
N
(4d)
O
Cl
O
5
p-CleC6H4
C6H5
35
90
O
N
N
N
O
(4e)
O
Cl
O
6
o-CleC6H4
C6H5
65
84
N
N
N
F
(4f)
O
O
O
7
p-FeC6H4
C6H5
40
90
N
N
N
O
(4g)

A. Hasaninejad et al. / Tetrahedron 67 (2011) 390e400
393
Table 2 (continued)
Entry
R1
R2
Product
Time (min)
Yielda (%)
NO2
O
8
p-NO2eC6H4
C6H5
30
92
O
N
N
N
N
N
(4h)
O
NO2
O
O
9
m-NO2eC6H4
C6H5
30
91
N
(4i)
O
O
10
p-CH(CH3)2eC6H4
C6H5
55
89
O
N
N
N
N
N
4j)
(
O
CF3
O
11
p-CF3eC6H4
C6H5
35
90
O
N
N
(4k)
O
CN
O
12
p-CNeC6H4
C6H5
40
89
O
N
N
(4l)
O
OCH3
O
O
13
m-OCH3eC6H4
C6H5
65
88
N
N
N
(4m)
O
O
O
N
14
2-Naphthyl
C6H5
60
90
N
N
(4n)
O
(continued on next page)

394
A. Hasaninejad et al. / Tetrahedron 67 (2011) 390e400
Table 2 (continued)
Entry
R1
R2
Product
Time (min)
Yielda (%)
O
N
N
N
O
O
O
15b
4-OHCeC6H3
C6H5
180
89
O
N
N
N
O
(4o)
O
O
16
C6H5
C6H11
360
82
N
N
N
(4p)
O
O
O
O
N
17
m-OC6H4eC6H4
C6H11
300
88
N
N
O
(4q)
a
Isolated yields.
b
Reaction conditions: dimedone (2 equiv), 4-phenylurazole (2 equiv) and terephthaldehyde (1 equiv).
Table 3
One-pot three-component synthesis of spiro triazolo[1,2-a]indazole-tetraones in the presence of PEG-SO3H as a catalyst under solvent-free conditions at 80 ꢀC
Entry
Substrate
R3
Product
Time (h)
Yielda (%)
H
N
O
O
O
O
1
C6H5
6
89
N
N
O
N
N
H
(7a)
O
H
N
O
O
O
F
F
O
O
2
3
C6H5
8
5
90
92
N
N
O
N
N
N
H
(7b)
O
H
N
O
O
O
Br
Br
C6H5
N
O
N
N
H
(7c)
O
H
N
O
O
O
H3C
CH3
O
4
C6H5
5
86
N
O
N
N
N
H
(7d)
O

A. Hasaninejad et al. / Tetrahedron 67 (2011) 390e400
395
Table 3 (continued )
Entry
Substrate
R3
Product
Time (h)
Yielda (%)
O
O
N
N
O
O
5
C6H5
7
89
O
N
N
N
(7e)
O
O
O
O
O
6
7
8
C6H5
3
7
4
92
90
91
O
N
N
N
(7f)
O
H
N
O
O
O
O
N
p-CleC6H4
O
N
N
N
H
(7g)
O
Cl
O
O
O
O
O
p-CleC6H4
N
N
N
(7h)
O
Cl
H
N
O
O
O
O
9
C6H11
8
87
N
O
N
N
H
N
(7i)
O
O
O
O
O
10
C6H11
4
89
O
N
N
N
(7j)
O
a
Isolated yield.
lead to form of two diastereomeric intermediates c and c0. Finally,
the intra molecular cyclization and elimination reaction lead to
form of two diastereomeric form for compound 4o (d and d0).
NMR data show that we only obtained a single diastereomeric
form for compound 4o in this reaction condition. We tried to get its
crystallographic structure but unfortunately, we could not get single
crystal and X-ray structure for compound 4o. So, according to these
observations, we think that this diastereomeric selectivity referred
to this fact that the addition of second urazole molecule can be done
from the less hindered side of intermediate b and according to the
bulky structure of molecules and catalyst, intermediate c has the less
activation energy in comparison with intermediate c0 and com-
pound 4o has the stereo structure of d shown in Scheme 2.
After the successful synthesis of triazolo[1,2-a]indazole-triones,
this catalytic system was used for the synthesis of new spiro triazolo
[1,2-a]indazole-tetraone derivatives for the first time. For this purpose,
dimedone and 4-substituted urazoles were condensed with ace-
naphthenequinone (5) and or isatin derivatives (6) under optimized
reaction conditions to afford the corresponding products (7aej)
(Scheme 3). The results of the reactions are summarized in Table 3.

396
A. Hasaninejad et al. / Tetrahedron 67 (2011) 390e400
O
O
Ph
O
N
Ph
N
N
O
H
HN
HN
N
O
H
O
CHO
CHO
O
O
and its enantiomer
+ 2
O
O
O
O
H
HN
HN
H
N
Ph
O
O
O
(a)
(b)
O
Ph
O
O
N
N
Ph
N
N
N
H
O
N
O
O
H
-H2O
O
O
Path 1
H
O
O
H
N
N
N
N
N
Ph
HN
Ph
O
O
O
(d)
(c)
O
N
O
Ph
Ph
N
N
N
N
O
O
N
H
N
-H2O
H
Path 2
O
O
O
O
O
H
N
H
O
N
N
Ph
HN
N
O
O
(d')
Ph
(c')
O
Scheme 2. Two diastereomeric forms of compound 4o.
O
O
O
O
O
O
O
N
N
HN
HN
N R3
+
N
N
R3
O
O
O
(5)
R1
N
PEG-SO3H (10 mol%) / 80 oC
Solvent-free
O
O
O
4-8 h / 86-92%
R2
R2
O
N
O
N
N
R3
R1
O
(6)
(7a-j)
Scheme 3. One-pot three-component synthesis of triazolo[1,2-a]indazole-tetraones in the presence of PEG-SO3H as a catalyst under solvent-free conditions at 80 ꢀC.

A. Hasaninejad et al. / Tetrahedron 67 (2011) 390e400
397
Various structurally diverse of spiro triazolo[1,2-a]indazole-
tetraones were synthesized by the condensation reaction of
dimedone, 4-substituted urazoles, and acenaphthenequinone as
well as isatin derivatives in the presence of PEG-SO3H as an efficient
catalyst.
mp¼190e192 ꢀC (188e190 ꢀC),25 nmax (KBr) 3040, 2960, 1720, 1650,
1610, 1370 cmꢁ1 1H NMR (500 MHz, CDCl3):
. d (ppm) 1.23 (s, 3H,
CH3), 1.24 (s, 3H, CH3), 2.37 (Distorted AB system, 2H, CH2),
2.94e2.95 (Distorted AB System, 2H, CH2), 6.24 (s, 1H, CHePh),
7.42e7.52 (10H, m, Ph). 13C NMR (125 MHz, CDCl3):
d (ppm) 28.1,
The experimental procedure is remarkably simple because after
the completion of the reaction, water was added to the reaction
mixture and the insoluble crude products were isolated by simple
filtration and recrystallized to obtain pure products. In order to
resumption of catalyst, water was evaporated in reduced pressure
and recovered catalyst was washed by diethyl ether two times and
reused for another reaction. Any loose of rates or yields was ob-
served by use of recovered PEG-SO3H for five cycle of reactions.
28.6, 34.8, 35.4, 51.6, 64.7, 120.4, 125.6, 127.3, 128.7, 128.9, 129.1,
130.6, 131.5, 136.8, 149.0, 150.6, 151.1, 192.0. Anal. Calcd for
C23H21N3O3: C, 71.30; H, 5.46; N, 10.85%. Found: C, 71.28; H, 5.33; N,
10.91%.
4.4.2. 6,6-Dimethyl-2-phenyl-9-p-tolyl-6,7-dihydro-[1,2,4]triazolo
[1,2-a]indazole-1,3,8(2H,ꢀ5H,9H)-trione, 4b, (0.357 g, 89%). White
powder, mp¼163e164 C (160e162 ꢀC),25 nmax (KBr) 3030, 2940,
1720, 1670, 1620, 1380 cmꢁ1 1H NMR (500 MHz, CDCl3):
. d (ppm)
3. Conclusions
1.23 (s, 3H, CH3), 1.24 (s, 3H, CH3), 2.36e2.49 (m, 5H, Ph-CH3, and
CH2), 2.88 (AB System, 2J¼16.0 Hz, 1H, CH2), 2.96 (AB System,
2J¼16.0 Hz, 1H, CH2), 6.20 (s, 1H, CHeAr), 7.22 (d, J¼8.0 Hz, 2H, Ar),
7.34 (d, J¼8.0 Hz, 2H, Ar), 7.42e7.45 (m, 1H, Ar), 7.55 (d, J¼4.0 Hz,
In conclusion, an extremely efficient method has been de-
veloped for the synthesis of triazolo[1,2-a]indazole-triones and
novel spiro triazolo[1,2-a]indazole-tetraones via a one-pot three-
component condensation reaction using sulfonated polyethylene
glycol as an eco-friendly degradable polymeric catalyst. This
method is bestowed with several unique merits, such as high
conversions, simplicity in operation, cost efficiency, use of solvent-
free and mild conditions, simple workup, high yields and usage in
synthesis of complex molecules.
4H, Ar). 13C NMR (125 MHz, CDCl3):
d (ppm) 21.6, 28.7, 29.1, 35.1,
35.9, 51.7, 64.4, 120.6, 126.0, 127.4, 129.1, 129.7, 130.0, 131.2, 134.2,
139.1, 139.3, 150.8, 151.2, 192.3. Anal. Calcd for C24H23N3O3: C, 71.80;
H, 5.77; N, 10.47%. Found: C, 71.72; H, 5.86; N, 10.59%.
4.4.3. 9-(3-Bromophenyl)-6,6-dimethyl-2-phenyl-6,7-dihydro-[1,2,4]
triazolo[1,2-a]indazole-1,3,8(2H,5H,9H)-trione, 4c, (0.387 g, 83%). White
powder, mp¼172e174 ꢀC (174e176 ꢀC),25 nmax (KBr) 3060, 2960, 1720,
4. Experimental
4.1. General
1660, 1620,1380 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d (ppm) 1.22 (s, 3H,
CH3), 1.23 (s, 3H, CH3), 2.36e2.37 (Distorted AB System, 2H, CH2),
2.93e2.95 (Distorted AB System, 2H, CH2), 6.20 (s, 1H, CHeAr),
7.34e7.52 (m, 9H, Ar). 13C NMR (125 MHz, CDCl3):
d (ppm) 28.8, 29.0,
All chemicals were purchased from Merck or Fluka Chemical
Companies. The 1H NMR (500 MHz) and 13C NMR (125 MHz) were
run on a Bruker Avance DPX-250, FT-NMR spectrometer (d in ppm).
35.2, 35.9, 51.7, 63.8, 120.0, 125.9, 126.0, 127.5, 129.2, 129.4, 129.7, 130.5,
131.0, 135.2, 139.3, 149.5, 151.5, 151.7, 192.3. Anal. Calcd for
C23H20BrN3O3: C, 59.24; H, 4.32; N, 9.01%. Found: C, 59.33; H, 4.29; N,
8.89%.
Microanalysis was performed on a PerkineElmer 240-B micro-
€
analyzer. Melting points were recorded on a Buchi B-545 apparatus
in open capillary tubes.
4.4.4. 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)-trione, 4d, (0.424 g, 91%). White
25
ꢀ
4.2. Preparation of PEG-SO3H
powder, mp¼185e187 C (184e186 ꢀC), nmax (KBr) 3050, 2960,
1660,1610,140,1380 cmꢁ1.1H NMR (500 MHz, CDCl3):
d
(ppm) 1.21 (s,
At 0 ꢀC, chlorosulfonic acid (1.16 g, 10 mmol) was added to
a solution of PEG-6000 (6.0 g, 1 mmol) in CH2Cl2 (10 mL). Then the
resulting solution was stirred at room temperature overnight, and
the solution was concentrated under vacuum. Appropriate ether
(50 mL) was added, and the precipitate filtered and washed with
ether (30 mL) three times to afford the PEG-SO3H.23
6H, CH3), 2.34 (Distorted AB System, 2H, CH2), 2.84e2.96 (Distorted
AB System, 2H, CH2), 6.17 (s, 1H, CHeAr), 7.35e7.55 (m, 9H, Ar). 13
NMR (125 MHz, CDCl3): (ppm) 28.6, 29.1, 35.1, 35.9, 51.7, 63.9, 120.1,
123.3, 125.9, 129.2, 129.7, 131.1, 132.4, 136.4, 149.5, 149.9, 151.3, 151.6,
192.3. Anal. Calcd for C23H20BrN3O3: C, 59.24; H, 4.32; N, 9.01%. Found:
C, 59.25; H, 4.33; N, 8.99%.
C
d
4.3. Typical procedure for the synthesis of triazolo[1,2-a]
indazole-trione (4a)
4.4.5. 9-(4-Chlorophenyl)-6,6-dimethyl-2-phenyl-6,7-dihydro-[1,2,4]
triazolo[1,2-a]indazole-1,3,8(2H,5H,9H)-trione, 4e, (0.379 g, 90%). White
powder, mp¼173e175 ꢀC (166e168 ꢀC),25 nmax (KBr) 3050, 2950,
Dimedone (0.14 g, 1 mmol), benzaldehyde (0.1 g, 1 mmol), and
4-phenylurazole (0.177 g, 1 mmol) were mixed with PEG-SO3H
(0.6 g, 0.1 mmol) and the obtained mixture was stirred magneti-
cally at 80 ꢀC for 40 min. After the completion of the reaction warm
water (20 mL) was added and the mixture stirred for about 5 min.
The insoluble crude product was filtered and recrystallized from
EtOH/H2O 4:1 and the pure product was obtained (0.352 g, 91%). In
order to recover the catalyst, the filtrate was dried under reduced
pressure and recovered catalyst was washed with diethyl ether and
reused after drying under reduced pressure. The equivalent pro-
cedure was used for the synthesis of triazolo[1,2-a]indazole-
tetraones.
1660, 1610, 1200 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d (ppm) 1.22 (s, 6H,
CH3), 2.34 (AB System, 2J¼19.0 Hz, 1H, CH2), 2.39 (AB System,
2J¼19.0 Hz, 1H, CH2), 2.90 (AB System, 2J¼18.5 Hz, 1H, CH2), 2.96 (AB
System, 2J¼18.5 Hz, 1H, CH2), 6.21 (s, 1H, CHeAr), 7.38e7.51 (m, 9H,
Ar). 13C NMR (125 MHz, CDCl3):
d (ppm) 28.1, 28.8, 34.5, 35.3, 51.1,
63.6, 119.4, 125.5, 128.3, 128.7, 129.0, 129.3, 130.6, 134.3, 135.5, 149.2,
151.1, 151.4, 191.9. Anal. Calcd for C23H20ClN3O3: C, 65.48; H, 4.78; N,
9.96%. Found: C, 65.59; H, 4.88; N, 9.81%.
4.4.6. 9-(2-Chlorophenyl)-6,6-dimethyl-2-phenyl-6,7-dihydro-[1,2,4]
triazolo[1,2-a]indazole-1,3,8(2H,5H,9H)-trione, 4f, (0.354 g, 84%). White
powder, mp¼177e178 ꢀC (173e175 ꢀC),25 nmax (KBr) 3050, 2950, 1720,
1650, 1610, 1380 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d (ppm) 1.23 (s, 6H,
4.4. Selected spectral data
CH3), 2.31 (AB System, 2J¼16.5 Hz, 1H, CH2), 2.35 (AB System,
2J¼16.5 Hz, 1H, CH2), 2.90 (AB System, 2J¼17.0 Hz, 1H, CH2), 2.99 (AB
System, 2J¼17.0 Hz, 1H, CH2), 6.37 (s, 1H, CHeAr), 7.32e7.50 (m, 9H,
4.4.1. 6,6-Dimethyl-2,9-diphenyl-6,7-dihydro-[1,2,4]triazolo[1,2-a]
indazole-1,3,8(2H,5H,9H)-trione, 4a, (0.352 g, 91%). White powder,
Ar). 13C NMR (125 MHz, CDCl3):
d (ppm) 28.6, 29.3, 35.0, 35.8, 51.6,

398
A. Hasaninejad et al. / Tetrahedron 67 (2011) 390e400
63.9, 118.9, 126.1, 127.9, 129.1, 129.6, 130.9, 131.1, 131.2, 131.7, 132.4,
133.2, 148.7, 150.4, 151.1, 192.0. Anal. Calcd for C23H20ClN3O3: C, 65.48;
H, 4.78; N, 9.96%. Found: C, 65.38; H, 4.75; N, 9.88%.
HeAr), 7.63 (d, J¼8.2 Hz, 2H, HeAr), 7.69 (d, J¼8.2 Hz, 2H, HeAr). 13
C
NMR (125 MHz, CDCl3): d (ppm) 28.6, 29.1, 35.2, 35.9, 51.9, 63.9, 120.0,
1
124.2 (q, JCeF¼278.7 Hz), 126.0, 126.32, 126.35, 127.9, 129.3, 129.8,
131.0, 131.5, 141.2, 149.6, 151.6, 192.3. 19F NMR (470.5 MHz, CDCl3):
4.4.7. 9-(4-Fluorophenyl)-6,6-dimethyl-2-phenyl-6,7-dihydro-[1,2,4]tri-
azolo[1,2-a]indazole-1,3,8(2H,5H,9H)-trione, 4g, (0.364 g, 90%). White
powder, mp¼105e108 ꢀC (102e103 ꢀC),25 nmax (KBr) 3060, 2960,
d (ppm) -63.0 (s, 3F), Anal. Calcd for C24H20F3N3O3: C, 63.29; H, 4.43; N,
9.23%. Found: C, 63.32; H, 4.46; N, 9.28%.
1730,1680,1620,1500,1380 cmꢁ1.1H NMR (500 MHz, CDCl3):
d
(ppm)
4.4.12. 4-(6,6-Dimethyl-1,3,8-trioxo-2-phenyl-1,2,3,5,6,7,8,9-octahydro-
[1,2,4]triazolo[1,2-a]indazol-9-yl)benzonitrile, 4l, (0.367 g, 89%). White
powder, mp¼240e242 ꢀC, nmax (KBr) 3040, 2960, 2210, 1730, 1710,
1.25 (s, 6H, CH3), 2.36 (AB System, 2J¼16.5 Hz, 1H, CH2), 2.43 (AB
System, 2J¼16.5 Hz, 1H, CH2), 2.95e2.96 (m, 2H, CH2), 6.24 (s, 1H,
CHeAr), 7.11 (t, J¼8.2 Hz, 2H, Ar), 7.45e7.48 (m, 3H, Ar), 7.52e7.53 (m,
1670, 1610, 1370 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d (ppm) 1.20 (s, 3H,
4H, Ar). 13C NMR (125 MHz, CDCl3):
d
(ppm) 28.5, 29.1, 35.1, 35.9, 51.6,
CH3), 1.21 (s, 3H, CH3), 2.35 (AB System, 2J¼18.5 Hz, 1H, CH2), 2.41 (AB
System, 2J¼18.5 Hz, 1H, CH2), 2.87e2.98 (m, 2H, CH2), 6.25 (s, 1H,
CHeAr), 7.43e7.54 (m, 4H, HeAr), 7.62 (d, J¼8.0 Hz, 2H, HeAr), 7.69
63.9, 120.7, 126.9, 129.2, 129.7, 131.5, 132.9, 137.4, 149.5, 149.9, 151.6,
1
151.7, 161.3 (d, JCeF¼273.5 Hz), 193.4. 19F NMR (470.5 MHz, CDCl3):
d
(ppm) ꢁ113.2 (s, 1F). Anal. Calcd for C23H20FN3O3: C, 68.14; H, 4.97;
(d, J¼8.0 Hz, 2H, HeAr). 13C NMR (125 MHz, CDCl3):
d (ppm) 28.7, 29.0,
N, 10.36%. Found: C, 68.19; H, 5.02; N, 10.18%.
35.2, 35.9, 51.6, 63.9, 113.0, 118.8, 119.6, 125.9, 128.3, 129.3, 129.8, 130.9,
133.1, 142.4, 149.6, 151.9, 152.0, 192.3. Anal. Calcd for C24H20N4O3: C,
69.89; H, 4.89; N, 13.58%. Found: C, 69.92; H, 4.85; N, 13.62%.
4.4.8. 6,6-Dimethyl-9-(4-nitrophenyl)-2-phenyl-6,7-dihydro-[1,2,4]tri-
azolo[1,2-a]indazole-1,3,8(2H,5H,9H)-trione, 4h, (0.397 g, 92%). White
powder, mp¼179e181 ꢀC (175e177 ꢀC),25 nmax (KBr) 3040, 2960, 1730,
1660, 1610, 1520, 1410, 1390, 1350 cmꢁ1. 1H NMR (500 MHz, CDCl3):
4.4.13. 9-(3-Methoxyphenyl)-6,6-dimethyl-2-phenyl-6,7-dihydro-
[1,2,4]triazolo[1,2-a]indazole-1,3,8(2H,5H,9H)-trione, 4m, (0.367 g,
88%). White powder, mp¼106e107 ꢀC, nmax (KBr) 3050, 2960, 1720,
d
(ppm) 1.21 (s, 3H, CH3), 1.23 (s, 3H, CH3), 2.35 (AB System,
2J¼18.5 Hz, 1H, CH2), 2.42 (AB System, 2J¼18.5 Hz, 1H, CH2), 2.91 (AB
System, 2J¼18.5 Hz, 1H, CH2), 2.98 (AB System, 2J¼18.5 Hz, 1H, CH2),
2.89e3.00 (m, 2H, CH2), 6.32 (s, 1H, CHeAr), 7.47 (s, 1H, HeAr), 7.53 (s,
4H, HeAr), 7.75 (d, J¼7.6 Hz, 2H, HeAr), 8.27 (d, J¼7.6 Hz, 2H, HeAr).
1660, 1490, 1280 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d (ppm) 1.24 (s,
6H, CH3), 2.35 (AB System, 2J¼16.5 Hz, 1H, CH2), 2.39 (AB System,
2J¼16.5 Hz, 1H, CH2), 2.92 (AB System, 2J¼18.5 Hz, 1H, CH2), 2.96
(AB System, 2J¼18.5 Hz, 1H, CH2), 3.84 (s, 3H, AreOCH3), 6.20 (s, 1H,
CHeAr), 6.90e6.91 (m, 1H, HeAr), 7.02 (s, 1H, HeAr), 7.04 (d,
J¼7.5 Hz, 1H, HeAr), 7.33 (t, J¼7.75 Hz, 1H, HeAr), 7.2e7.46 (m, 1H,
HeAr), 7.51 (d, J¼4.0 Hz, 2H, Ar). 13C NMR (125 MHz, CDCl3):
13C NMR (125 MHz, CDCl3):
d (ppm) 28.6, 29.0, 35.2, 36.0, 51.6, 63.7,
119.6, 124.5, 125.9, 128.5, 129.4, 129.8, 130.9, 144.2, 148.5, 149.6, 152.0,
152.2, 192.3. Anal. Calcd for C23H20N4O5: C, 63.88; H, 4.66; N, 12.96%.
Found: C, 63.95; H, 4.56; N, 12.93%.
d
(ppm) 28.4, 29.2, 34.9, 35.8, 51.6, 53.4, 63.9, 111.8, 115.7, 116.8,
119.3,120.4, 123.6, 124.1, 130.7, 130.8, 147.5, 157.2, 157.3, 159.4, 163.5,
196.5. Anal. Calcd for C24H23N3O4: C, 69.05; H, 5.55; N, 10.07%.
Found: C, 69.09; H, 5.61; N, 10.11%.
4.4.9. 6,6-Dimethyl-9-(3-nitrophenyl)-2-phenyl-6,7-dihydro-[1,2,4]tri-
azolo[1,2-a]indazole-1,3,8(2H,5H,9H)-trione, 4i, (0.393 g, 91%). White
powder, mp¼131e133 ꢀC (126e128 ꢀC),25 nmax (KBr) 3060, 2960,1720,
1650,1620,1520,1400,1380 cmꢁ1.1H NMR (500 MHz, CDCl3):
d
(ppm)
4.4.14. 6,6-Dimethyl-9-(naphthalen-2-yl)-2-phenyl-6,7-dihydro-
[1,2,4]triazolo[1,2-a]indazole-1,3,8(2H,5H,9H)-trione, 4n, (0.393 g,
90%). White powder, mp¼139e142 ꢀC, nmax (KBr) 3050, 2950, 1700,
1.20 (s, 6H, CH3), 2.35 (AB System, 2J¼18.5 Hz, 1H, CH2), 2.41 (AB
System, 2J¼18.5 Hz, 1H, CH2), 2.92 (AB System, 2J¼18.5 Hz, 1H, CH2),
2.98 (AB System, 2J¼18.5 Hz, 1H, CH2), 6.34 (s, 1H, CHeAr), 7.46e7.52
(m, 5H, HeAr), 7.61 (t, J¼7.5 Hz, 1H, HeAr), 7.91 (d, J¼7.0 Hz, 1H,
HeAr), 8.22 (d, J¼7.0 Hz, 1H, HeAr), 8.32 (s, 1H, HeAr). 13C NMR
1615, 1600, 1390 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d (ppm) 1.24 (s,
3H, CH3), 1.25 (s, 3H, CH3), 2.37 (Distorted AB System, 2H, CH2), 2.97
(AB System, 2J¼15.0 Hz, 1H, CH2), 3.01 (AB System, 2J¼15.0 Hz, 1H,
CH2), 6.41 (s, 1H, CHeAr), 7.42e7.56 (m, 8H, HeAr), 7.85e7.86 (m,
1H, HeAr), 7.88e7.91 (m, 2H, HeAr), 7.96 (s, 1H, HeAr). 13C NMR
(125 MHz, CDCl3): d (ppm) 28.7, 28.9, 35.2, 33.9, 51.6, 63.6, 119.5,122.3,
124.1, 126.0, 129.3, 129.8, 130.3, 130.9, 134.2, 139.7, 148.9, 149.6, 11.3,
152.1, 192.4. Anal. Calcd for C23H20N4O5: C, 63.88; H, 4.66; N, 12.96%.
Found: C, 63.81; H, 4.69; N, 12.92%.
(125 MHz, CDCl3):
d (ppm) 28.7, 29.1, 35.2, 36.0, 51.7, 64.8, 120.6,
124.5,126.0,126.8,126.9,127.2,128.1,128.7,131.1,133.6,133.8,134.5,
149.5, 151.1, 151.5, 192.3. Anal. Calcd for C27H23N3O3: C, 74.12; H,
5.30; N, 9.60%. Found: C, 74.18; H, 5.36; N, 6.99%.
4.4.10. 9-(4-Isopropylphenyl)-6,6-dimethyl-2-phenyl-6,7-dihydro-
[1,2,4]triazolo[1,2-a]indazole-1,3,8(2H,5H,9H)-trione, 4j, (0.382 g,
89%). White powder, mp¼164e166 ꢀC, nmax (KBr) 3040, 2950, 1710,
4.4.15. 9,90-(1,4-Phenylene)bis(6,6-dimethyl-2-phenyl-6,7-dihydro-
[1,2,4]triazolo[1,2-a]indazole-1,3,8(2H,5H,9H)-trione), 4o, (0.620 g,
89%). White powder, mp¼225e228 ꢀC dec, nmax (KBr) 3080, 2950,
1640, 1600, 1390 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d (ppm) 1.23 (s,
3H, CH3), 1.26 (s, 6H, CH(CH3)2), 1.27 (s, 3H, CH3), 2.37e2.38 (m, 2H,
CH2), 2.90e2.95 (m, 3H, CH2, and CH(CH3)2), 6.23 (s, 1H, CHeAr),
7.28 (t, J¼8.0 Hz, 2H, HeAr), 7.38 (d, J¼8.5 Hz, 2H, HeAr), 7.42e7.45
(m, 1H, HeAr), 7.50e7.51 (m, 4H, HeAr). 13C NMR (125 MHz,
1710,1650,1390 cmꢁ1.1H NMR (500 MHz, CDCl3):
d (ppm) 1.22 (s, 6H,
CH3),1.24 (s, 6H, CH3), 2.34 (AB System, 2J¼18.0 Hz, 2H, CH2), 2.39 (AB
System, 2J¼18.0 Hz, 2H, CH2), 2.89 (AB System, 2J¼19.0 Hz, 2H, CH2),
2.96 (AB System, 2J¼19.0 Hz, 2H, CH2), 6.26 (s, 2H, CHeAr), 7.42e7.52
CDCl3):
d (ppm) 24.3, 28.8, 29.1, 34.2, 35.1, 35.9, 51.7, 64.3, 120.5,
126.0, 127.44, 127.48, 129.1, 129.7, 131.2, 134.5, 149.4, 149.9, 151.0,
151.3, 191.3. Anal. Calcd for C26H27N3O3: C, 72.71; H, 6.34; N, 9.78%.
Found: C, 72.75; H, 6.32; N, 9.83%.
(m, 14H, HeAr). 13C NMR (125 MHz, CDCl3):
d (ppm) 28.9, 29.07, 35.1,
35.9, 51.7, 63.9, 120.2, 126.0, 128.05, 128.08, 129.2, 129.7, 131.1, 137.9,
149.6,151.3,151.4,192.3. Anal. Calcd for C40H36N6O6: C, 68.95; H, 5.21;
N, 12.06%. Found: C, 68.98; H, 5.29; N, 12.13%.
4.4.11. 6,6-Dimethyl-2-phenyl-9-(4-(trifluoromethyl)phenyl)-6,7-dihy-
dro-[1,2,4]triazolo[1,2-a]indazole-1,3,8(2H,5H,9H)-trione, 4k, (0.409 g,
90%). White powder, mp¼184e185 ꢀC, nmax (KBr) 3020, 2970, 1850,
4.4.16. 2-Cyclohexyl-6,6-dimethyl-9-phenyl-6,7-dihydro-[1,2,4]triazolo
[1,2-a]indazole-1,3,8(2H,5H,9H)-trione, 4p, (0.322 g, 82%). Yellow pow-
der, mp¼112e114 ꢀC, nmax (KBr) 3050, 2950, 1705, 1670, 1620,
1720, 1670, 1610, 1405, 1380, 1305, 1250, 1110 cmꢁ1 1H NMR
.
(500 MHz, CDCl3):
d
(ppm) 1.23 (s, 6H, CH3), 2.34 (AB System,
1380 cmꢁ1 1H NMR (CDCl3, 500 MHz):
. d (ppm) 1.21 (s, 6H, CH3),
2J¼18.6 Hz, 1H, CH2), 2.40 (AB System, 2J¼18.6 Hz, 1H, CH2), 2.91 (AB
System, 2J¼18.5 Hz, 1H, CH2), 2.97 (AB System, 2J¼18.5 Hz, 1H, CH2),
6.28 (s, 1H, CHeAr), 7.43e7.45 (m, 1H, HeAr), 7.51e7.54 (m, 4H,
1.33e1.39 (m, 2H, CH2), 1.69e1.72 (m, 2H, CH2), 1.79e1.81 (m, 2H,
CH2),1.87e1.89 (m, 2H, CH2), 2.08e2.17 (m, 2H, CH2), 2.33 (s, 2H, CH2),
2.83e2.91 (m, 2H, CH2), 3.88e3.94 (m, 1H, NeCHC5H10), 6.11 (s, 1H,

A. Hasaninejad et al. / Tetrahedron 67 (2011) 390e400
399
CHeAr), 7.33e7.34 (m, 1H, HePh), 7.38e7.42 (m, 4H, HePh). 13C NMR
(CDCl3, 125 MHz): (ppm) 25.2, 26.0, 28.6, 29.1, 29.7, 29.7, 35.1, 35.9,
CH2), 2.85e2.95 (m, 2H, CH2), 6.76 (br, 1H, HeAr), 6.98e7.00 (br, 2H,
HeAr), 7.93 (br, 5H, HeAr), 9.94 (br, 1H, NH). 13C NMR (125 MHz,
d
51.6, 53.2, 64.2,120.2,127.4,129.1,120.2,137.6,150.7,151.4,152.9,192.4.
Anal. Calcd for C23H27N3O3: C, 70.21; H, 6.92; N, 10.68%. Found: C,
70.25; H, 6.98; N, 10.77%.
CDCl3): d (ppm) 21.4, 28.3, 29.0, 35.3, 35.9, 51.4, 71.1, 111.4, 119.5, 125.0,
125.5, 126.2, 129.1, 129.5, 131.0, 131.6, 132.7, 140.3, 148.4, 150.0, 152.0,
171.5, 191.2. Anal. Calcd for C25H22N4O4: C, 67.86; H, 5.01; N, 12.66%.
Found: C, 67.88; H, 5.11; N, 12.71%.
4.4.17. 2-Cyclohexyl-6,6-dimethyl-9-(3-phenoxyphenyl)-6,7-dihydro-
[1,2,4]triazolo[1,2-a]indazole-1,3,8(2H,5H,9H)-trione,
4q,
(0.427 g,
4.4.22. 6,6-Dimethyl-10-(naphthalen-1-ylmethyl)-2-phenyl-6,7-dihy-
dro-1H-spiro[[1,2,4]triazolo[1,2-a]indazole-9,30-indoline]-1,20,3,8
(2H,5H)-tetraone, 7e, (0.506 g, 89%). White powder, mp¼294e296 ꢀC
dec, nmax (KBr) 3040, 2950, 1780, 1710, 1700, 1650, 1600, 1390 cmꢁ1. 1H
88%). White powder, mp¼167e169 ꢀC, nmax (KBr) 3050, 2960, 1720,
1660, 1490 cmꢁ1. 1H NMR (500 MHz, DMSO-d6):
d (ppm) 1.21 (s, 6H,
CH3),1.25e1.36 (m, 2H, CH2),1.69e1.89 (m, 6H, CH2), 2.11e2.16 (m, 2H,
CH2), 2.33 (m, 2H, CH2), 2.86 (m, 2H, CH2), 3.89e3.92 (m, 1H,
NeCHC5H10), 6.09 (s, 1H, CHeAr), 6.75 (s, 1H), 6.80 (d, J¼8.0 Hz, 1H,
HeAr), 6.91 (d, J¼8.0 Hz, 1H, HeAr), 6.97e7.01 (m, 5H, HeAr), 7.13 (t,
J¼7.2 Hz, 1H, HeAr), 7.29 (t, J¼7.7 Hz, 1H, HeAr), 7.37 (t, J¼8.0 Hz, 2H,
NMR (500 MHz, CDCl3):
d (ppm) 1.11 (s, 3H, CH3), 1.26 (s, 3H, CH3),
2.37e2.41 (Distorted AB System, 2H, CH2), 2.98 (AB System,
2J¼18.5 Hz, 1H, CH2), 3.12 (AB System, 2J¼18.5 Hz, 1H, CH2), 5.49 (AB
System, 2J¼17.0 Hz, 1H, CH2eNaphtyl), 5.61 (AB System, 2J¼17.0 Hz,
1H, CH2-Naphtyl), 6.66 (d, J¼8.0 Hz, 1H, HeAr), 7.12 (t, J¼7.5 Hz, 1H,
HeAr), 7.24 (t, J¼7.7 Hz, 1H, HeAr), 7.37 (d, J¼7.0 Hz, 1H, HeAr),
7.44e7.64 (m, 8H, HeAr), 7.70 (d, J¼7.0 Hz, 1H, HeAr), 7.81 (d,
J¼8.0 Hz, 1H, HeAr), 7.94 (d, J¼7.5 Hz, 1H, HeAr), 8.08 (d, J¼8.5 Hz,
HeAr). 13C NMR (125 MHz, CDCl3):
d (ppm) 25.9, 26.0, 26.1, 28.6, 29.7,
33.1, 35.3, 51.6, 53.2, 64.2, 113.2, 117.4, 118.0, 119.4, 120.4, 123.0, 124.3,
130.8, 130.8, 147.8, 157.2, 157.5, 159.3, 163.5, 196.4. Anal. Calcd for
C29H31N3O4: C, 71.73; H, 6.43; N, 8.65%. Found: C, 71.71; H, 6.48; N,
8.74%.
1H, HeAr). 13C NMR (125 MHz, CDCl3):
d (ppm) 28.6, 28.9, 35.5, 36.1,
42.9, 51.5, 63.4, 111.12, 127.122.12, 122.84, 124.0, 124.2, 124.9, 126.2,
126.3, 126.8, 127.1, 127.8, 127.9, 128.3, 129.3, 129.6, 129.7, 131.3, 133.6,
133.8, 134.5, 144.9, 148.7, 152.5, 152.9, 171.7, 191.7. Anal. Calcd for
C36H30N4O4: C, 74.21; H, 5.19; N, 9.62%. Found: C, 74.28; H, 5.10; N,
9.64%.
4.4.18. 6,6-Dimethyl-2-phenyl-6,7-dihydro-1H-spiro[[1,2,4]triazolo
[1,2-a]indazole-9,30-indoline]-1,20,3,8(2H,5H)-tetraone, 7a, (0.381 g,
89%). White powder, mp¼298e300 ꢀC dec, nmax (KBr) 3310, 3050,
2950, 1790, 1740, 1650, 1600, 1360 cmꢁ1. 1H NMR (500 MHz, CDCl3):
d
(ppm) 1.22 (s, 3H, CH3), 1.24 (s, 3H, CH3), 2.20e2.40 (m, 2H, CH2),
2.93 (AB System, 2J¼16.0 Hz, 1H, CH2), 3.09 (AB System, 2J¼16.0 Hz,
1H, CH2), 6.96 (d, J¼7.0 Hz, 1H, HeAr), 7.26e7.51 (m, 8H, HeAr), 8.40
4.4.23. 6,6-Dimethyl-2-phenyl-6,7-dihydro-1H,20H-spiro[[1,2,4]tri-
azolo[1,2-a]indazole-9,10-acenaphthylene]-1,20,3,8(2H,5H)-tetraone,
7f, (0.426 g, 92%). Yellow powder, mp¼278e279 ꢀC, nmax (KBr)
3050, 2960, 1720, 1660, 1620, 1410, 1380 cmꢁ1. 1H NMR (500 MHz,
(s, 1H, NH). 13C NMR (125 MHz, CDCl3):
d (ppm) 28.3, 29.1, 35.3, 35.5,
51.3, 71.3,111.4,119.0,125.1,125.8,126.2,129.1,129.5,131.1,131.5,132.5,
140.3, 140.3, 148.0, 152.1, 171.1, 191.2. Anal. Calcd for C24H20N4O4: C,
67.28; H, 4.71; N, 13.08%. Found: C, 67.22; H, 473; N, 13.11%.
CDCl3): d (ppm) 1.24 (s, 3H, CH3), 1.26 (s, 3H, CH3), 2.22 (AB System,
2J¼16.0 Hz, 1H, CH2), 2.31 (AB System, 2J¼16.0 Hz, 1H, CH2), 2.99
(AB System, 2J¼18.5 Hz, 1H, CH2), 3.14 (AB System, 2J¼18.5 Hz, 1H,
CH2), 7.41 (t, J¼6.7 Hz, 1H, HeAr), 7.46e7.52 (m, 4H, HeAr), 7.62 (d,
J¼7.0 Hz, 1H, HeAr), 7.71 (t, J¼7.5 Hz, 1H, HeAr), 7.83 (d, J¼7.5 Hz,
1H, HeAr), 7.99 (d, J¼8.0 Hz, 1H, HeAr), 8.22 (d, J¼8.0 Hz, 1H,
4.4.19. 50-Fluoro-6,6-dimethyl-2-phenyl-6,7-dihydro-1H-spiro
[[1,2,4]triazolo[1,2-a]indazole-9,30-indoline]-1,20,3,8(2H,5H)-tet-
raone, 7b, (0.401 g, 90%). White powder, mp¼311e313 ꢀC dec, nmax
(KBr) 3390, 3060, 2950, 1730, 1710, 1690, 1630 cmꢁ1
.
1H NMR
HeAr). 13C NMR (125 MHz, CDCl3):
d (ppm) 28.3, 29.2, 35.5, 36.0,
(500 MHz, CDCl3):
d
(ppm) 1.05 (s, 3H, CH3), 1.09 (s, 3H, CH3),
51.4, 71.2, 120.5, 121.1, 123.5, 126.2, 127.2, 128.9, 129.0, 129.2, 130.9,
131.0, 131.1, 133.2, 134.7, 142.8, 148.6, 150.5, 152.1, 191.3, 197.4. Anal.
Calcd for C28H21N3O4: C, 72.56; H, 4.57; N, 9.07%. Found: C, 72.51; H,
4.63; N, 9.14%.
2.03e2.20 (m, 2H, CH2), 2.75e2.91 (m, 2H, CH2), 6.78e7.32 (m, 8H,
HeAr), 10.41 (s, 1H, NH). 13C NMR (125 MHz, CDCl3/DMSO-d6):
d
(ppm) 28.2, 29.00, 35.3, 35.8, 51.3, 71.3, 112.2, 117.6, 118.1, 118.9,
119.9, 126.2, 129.2, 129.5, 130.9, 139.0, 178.8, 150.0, 152.1, 159.8 (d,
1JCeF¼275.0 Hz), 171.9, 191.1. 19F NMR (470.5 MHz, DMSO-d6):
4.4.24. 2-(4-Chlorophenyl)-6,6-dimethyl-6,7-dihydro-1H-spiro
[[1,2,4]triazolo[1,2-a]indazole-9,30-indoline]-1,20,3,8(2H,5H)-tet-
raone, 7g, (0.416 g, 90%). White powder, mp¼303e304 ꢀC dec, nmax
d
(ppm) -121.3 (s,1F). Anal. Calcd for C24H19FN4O4: C, 64.57; H, 4.29;
N, 12.55%. Found: C, 64.49; H, 4.33; N, 12.59%.
(KBr) 3350, 3060, 2950, 1770, 1710, 1650, 1600 cmꢁ1 1H NMR
.
4.4.20. 50-Bromo-6,6-dimethyl-2-phenyl-6,7-dihydro-1H-spiro
[[1,2,4]triazolo[1,2-a]indazole-9,30-indoline]-1,20,3,8(2H,5H)-tet-
raone, 7c, (0.466 g, 92%). White powder, mp¼292e293 ꢀC, nmax
(KBr) 3350, 2950, 1790, 1705, 1680, 1610, 1490, 1380 cmꢁ1. 1H NMR
(500 MHz, CDCl3): d (ppm) 1.19 (s, 3H, CH3), 1.25 (s, 3H, CH3), 2.31
(AB System, 2J¼16.0 Hz, 1H, CH2), 2.35 (AB System, 2J¼16.0 Hz, 1H,
CH2), 2.93 (AB System, 2J¼18.5 Hz, 1H, CH2), 3.06 (AB System,
2J¼18.5 Hz, 1H, CH2), 6.90 (d, J¼8.0 Hz, 1H, HeAr), 7.10 (t, J¼7.5 Hz,
1H, HeAr), 7.26e7.34 (m, 2H, HeAr), 7.43e7.47 (m, 4H, HeAr), 7.88
(500 MHz, CDCl3):
d (ppm) 1.22 (s, 3H, CH3), 1.26 (s, 3H, CH3), 2.30
(AB System, 2J¼16.0 Hz, 1H, CH2), 2.38 (AB System, 2J¼16.0 Hz, 1H,
CH2), 2.93 (AB System, 2J¼18.5 Hz, 1H, CH2), 3.09 (AB System,
2J¼18.5 Hz, 1H, CH2), 6.64 (d, J¼8.5 Hz, 1H, HeAr), 7.34e7.36 (dd,
J¼2.0, 8.5 Hz, 1H, HeAr), 7.39 (d, J¼1.5 Hz, 1H, HeAr), 7.43e7.53 (m,
(s, 1H, NH). 13C NMR (125 MHz, CDCl3):
d (ppm) 28.4, 29.0, 35.5,
36.0, 51.4, 71.1, 111.6, 119.4, 121.1, 123.9, 124.6, 125.9, 126.5, 127.3,
129.9, 131.4, 135.1, 141.6, 152.3, 161.1, 171.1, 191.2. Anal. Calcd for
C24H19ClN4O4: C, 62.27; H, 4.14; N, 12.10%. Found: C, 62.34; H, 4.16;
N, 12.15%.
5H, HeAr), 8.40 (s 1H, NH). 13C NMR (125 MHz, CDCl3):
d (ppm)
28.2, 29.2, 35.6, 36.0, 51.4, 71.2, 113.2, 116.1, 118.9, 126.3, 127.3, 127.7,
129.5, 129.8, 130.7, 134.2, 141.0, 148.5, 150.7, 153.0, 170.6, 191.7. Anal.
Calcd for C24H19BrN4O4: C, 56.82; H, 3.77; N, 11.04%. Found: C,
56.88; H, 3.70; N, 11.12%.
4.4.25. 2-(4-Chlorophenyl)-6,6-dimethyl-6,7-dihydro-1H,20H-spiro
[[1,2,4]triazolo[1,2-a]indazole-9,10-acenaphthylene]-1,20,3,8(2H,5H)-
tetraone, 7h, (0.453 g, 91%). Yellow powder, mp¼269e271 ꢀC, nmax
(KBr) 3080, 2960, 1760, 1700, 1640, 1610, 1500, 1370 cmꢁ1. 1H NMR
4.4.21. 50,6,6-Trimethyl-2-phenyl-6,7-dihydro-1H-spiro[[1,2,4]triazolo
[1,2-a]indazole-9,30-indoline]-1,20,3,8(2H,5H)-tetraone, 7d, (0.380 g,
86%). White powder, mp¼308e310 ꢀC, nmax (KBr) 3410, 3045, 2950,
(500 MHz, CDCl3): d (ppm) 1.23 (s, 3H, CH3), 1.26 (s, 3H, CH3), 2.22
(AB System, 2J¼16.2 Hz, 1H, CH2), 2.30 (AB System, 2J¼16.2 Hz, 1H,
CH2), 2.98 (AB System, 2J¼18.5 Hz, 1H, CH2), 3.13 (AB System,
2J¼18.5 Hz, 1H, CH2), 7.44e7.49 (m, 4H, HeAr), 7.46e7.52 (m, 4H,
HeAr), 7.61 (d, J¼7.0 Hz, 1H, HeAr), 7.70 (d, J¼8.5 Hz, 1H, HeAr),
1790, 1750, 1730, 1650, 1605, 1500, 1370 cmꢁ1 1H NMR (500 MHz,
.
CDCl3):
d (ppm) 1.13 (s, 6H, CH3), 2.22 (s, 3H, AreCH3), 2.64 (m, 2H,

400
A. Hasaninejad et al. / Tetrahedron 67 (2011) 390e400
7.83 (t, J¼7.5 Hz, 1H, HeAr), 8.00 (d, J¼8.5 Hz, 1H, HeAr), 8.09 (d,
J¼7.0 Hz, 1H, HeAr), 8.23 (d, J¼8.0 Hz, 1H, Ar). 13C NMR (125 MHz,
References and notes
1. (a) Noga, E. J.; Barthalmus, G. T.; Mitchell, M. K. Cell Biol. Int. Rep. 1986, 10,
239e247; (b) Craig, P. N. In Comprehensive Medicinal Chemistry; Drayton, C. J.,
Ed.; Pergamon: New York, NY, 1991; Vol. 8; (c) Kodama, T.; Tamura, M.; Oda, T.;
Yamazaki, Y.; Nishikawa, M.; Takemura, S.; Doi, T.; Yoshinori, Y.; Ohkuchi, M. U.
S. Patent 983,928, 2003.
CDCl3):
d (ppm) 28.3, 29.2, 35.7, 36.0, 51.4, 71.0, 120.6, 121.1, 123.6,
127.2, 12.3, 128.9, 129.1, 129.6, 129.8, 130.8, 131.2, 133.3, 134.5,
135.0, 142.8, 148.2, 150.1, 151.9, 191.3, 197.3. Anal. Calcd for
C28H20ClN3O4: C, 67.54; H, 4.05; N, 8.44%. Found: C, 67.61; H, 4.08;
N, 8.51%.
2. Izydore, R.A.; Hall, I.H. U.S. Patent 4,866,058; file date, Sep. 12, 1989; Chem.
Abstr. 1990, 112, 151876X.
3. Wakabayashi, O.; Matsuya, K.; Ohta, H.; Jikihara, T.; Suzuki, S. Ger Offen.
2,526,358 Jpn.; Chem. Abstr. 1976, 84, 135700h.
4. Ovadia, D.; Peleg, N.; Bracha, P. U.S. Patent 4,087,534, Israeli; file date, May 2,
4.4.26. 2-Cyclohexyl-6,6-dimethyl-6,7-dihydro-1H-spiro[[1,2,4]tri-
azolo[1,2-a]indazole-9,30-indoline]-1,20,3,8(2H,5H)-tetraone,
7i,
1978; Chem. Abstr. 1978, 89, 109513h.
(0.378 g, 87%). Yellow powder, mp¼297e299 ꢀC, nmax (KBr) 3380,
5. (a) Von Bredow, B.; Brechbuehler, H. Ger Offen. 2,343,347; file date, March 14,
1974; Chem. Abstr. 1974, 80, 140210s; (b) Von Bredow, B.; Brechbuehler, H. Ger
Offen. 2,343,526; file date, March 14; Chem. Abstr. 1974, 80, 146185n; (c) Von
Bredow, B.; Brechbuehler, H. Ger Offen. 2,446,900; file date, April 10, 1975;
Chem. Abstr. 1975, 83, 58835f.
6. Giesecke, H.; Merten, R.; Rottmaier, L. Ger Offen. DE 3,027,612; file date, Feb. 18,
1985; Chem. Abstr. 1982, 96, 182879f.
7. Oikawa, M.; Ebina, C.; Inui, N.; Nagasaki, H.; Yago, S. JP 4,249,552 Jpn.; file date,
Sep. 4, 1992; Chem. Abstr. 1993, 118, 61373a.
2980, 1780, 1710, 1620, 1600, 1360 cmꢁ1 1H NMR (500 MHz,
.
CDCl3):
d (ppm) 1.19 (s, 3H, CH3), 1.20 (s, 3H, CH3), 1.33e2.37 (m,
12H, CH2), 2.90 (AB System, 2J¼14.2 Hz, 1H, CH2), 3.08 (AB Sys-
tem, 2J¼14.2 Hz, 1H, CH2), 3.63e3.87 (m, 1H, NeCHC5H10), 6.75
(m, 1H, HeAr), 6.98 (m, 1H, HeAr), 7.11e7.38 (m, 2H, HeAr) 8.56
(br, 1H, NH). 13C NMR (125 MHz, CDCl3):
d (ppm) 25.7, 26.0, 28.3,
8. Rottmaier, L.; Merten, R. Ger offen. 3,106,944; Chem. Abstr. 1982, 97, 198209u.
9. Kiriazis, A.; Ruffer, T.; Jantti, S.; Lang, H.; Yli-Kauhaluama, J. J. Comb. Chem. 2007,
9, 263e266.
10. Joshi, K. C.; Chand, P. Pharmazie 1982, 37, 864e865.
11. Abdel-Rahman, A. H.; Keshk, E. M.; Hanna, M. A.; El-Bady, S. M. Bioorg. Med.
29.0, 29.4, 29.7, 31.3, 35.5, 36.1, 51.9, 53.5, 71.1, 114.1, 115.1, 123.0,
127.0, 129.0, 129.1, 136.5, 143.7, 150.0, 152.0, 171.4, 197.8. Anal.
Calcd for C24H26N4O4: C, 66.34; H, 6.03; N, 12.89%. Found: C,
66.39; H, 6.08; N, 12.83%.
Chem. 2006, 12, 2483e2488.
12. Kang, T.-H.; Matsumoto, K.; Murakami, Y.; Takayama, H.; Kitajima, M.; Aimi, N.;
Watanabe, H. Eur. J. Pharmacol. 2002, 444, 39e45.
4.4.27. 2-Cyclohexyl-6,6-dimethyl-6,7-dihydro-1H,20H-spiro[[1,2,4]
triazolo[1,2-a]indazole-9,10-acenaphthylene]-1,20,3,8(2H,5H)-tet-
raone, 7j, (0.417 g, 89%). Yellow powder, mp¼246e248 ꢀC, nmax
13. Ma, J.; Hecht, S. M. Chem. Commun. 2004, 1190e1191.
14. Khafagy, M. M.; El-Wahas, A. H. F. A.; Eid, F. A.; El-Agrody, A. M. Farmaco 2002,
57, 715e722.
(KBr) 3050, 2950, 1790, 1710, 1670, 1610 cmꢁ1
.
1H NMR
ꢀ
15. (a) Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley-VCH: Weinheim,
(500 MHz, CDCl3):
d (ppm) 1.19 (s, 3H, CH3), 1.21 (s, 3H, CH3),
€
Germany, 2005;(b) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168e3210.
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man, L. E., Ed.; Wiely-VCH: Weinheim, 2004; 63, p 1; (b) Kappe, C. O. QSAR
Comb. Sci. 2003, 22, 630; (c) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879e888; (d)
Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043e1052; (e) Kappe, C. O. Tetrahedron
1993, 49, 6937e6963.
1.66 (m, 1H, CH2), 1.85e1.87 (m, 4H, CH2), 2.17e2.27 (m, 7H,
CH2), 2.91 (AB System, 2J¼18.5 Hz, 1H, CH2), 3.08 (AB System,
2J¼18.5 Hz, 1H, CH2), 3.84e3.91 (m, 1H, NeCHC5H10), 7.55 (d,
J¼6.5 Hz, 1H, HeAr), 7.68 (t, J¼7.5 Hz, 1H, HeAr), 7.81 (t,
J¼7.7 Hz, 1H, HeAr), 7.97 (d, J¼8.5 Hz, 1H, HeAr), 8.07 (d,
J¼7.0 Hz, 1H, HeAr), 8.21 (d, J¼8.5 Hz, 1H, HeAr). 13C NMR
17. (a) Banfi, L.; Riva, R. The Passerini Reaction In. Organic Reactions; Overman, L. E.,
Ed.; Wiley: Hoboken, New Jersey (USA), 2005; 65, p 1; (b) Banfi, L.; Basso, A.;
Guanti, G.; Riva, R. Asymmetric Isocyanide-Based MCRs In Multicomponent
ꢀ
Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim, 2005; p 1.
(125 MHz, CDCl3):
d (ppm) 25.2, 26.0, 28.4, 29.0, 29.6, 29.7, 31.3,
18. Ugi, I.; Werner, B.; Domling, A. Molecules 2003, 8, 53e66.
35.4, 36.0, 51.3, 53.5, 71.0, 120.1, 121.0, 123.3, 127.0, 128.9, 129.0,
130.9, 131.1, 133.0, 135.0, 142.7, 150.0, 152.0, 152.4, 191.4, 197.8.
Anal. Calcd for C28H27N3O4: C, 71.62; H, 5.80; N, 8.95%. Found: C,
71.66; H, 5.87; N, 8.96%.
19. (a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37,
1044e1070; (b) Overman, L. E.; Ricca, D. J. The Intramolecular Mannich and
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35, 695e705; (d) Trost, B. M. Angew. Chem., Int. Ed. 1995, 34, 259e281.
€
20. Macromolecule-Metal Complexes; Ciardelli, F., Tsuchida, E., Wohrle, D., Eds.;
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The authors thank the Research Committee of Persian Gulf
University for the financial support of this work. Also, the authors
thank from Dr. M.R. Mohammadizadeh for his helpful discussions.
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Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.11.029. These data include
MOL files and InChiKeys of the most important compounds de-
scribed in this article.