One-pot, four-component synthesis of new 3,4,7,8-tetrahydro-3,3-dimethyl-11-aryl-2H-pyridazino[1,2-a]indazole-1,6,9(11H)-triones and 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-triones using an acidic ionic liquid N,N-diethyl-N-sulfoethanammonium chloride ([Et3N-SO3H]Cl) as a highly efficient and recyclable catalyst

Article abstract of DOI:10.1016/j.tetlet.2016.01.074

A rapid and efficient one-pot, four-component protocol for the synthesis of novel 2H-pyridazino[1,2-a]indazole-1,6,9(11H)-triones (6) and 2H-indazolo[2,1-b]phthalazine-1,6,11-triones (7) has been developed using a stable and reusable Br?nsted acidic ionic liquid N,N-diethyl-N-sulfoethanammonium chloride ([Et₃N-SO₃H]Cl). A range of diverse aldehydes were successfully applied and the corresponding products obtained in good to excellent yields without any by-products.

Full text of DOI:10.1016/j.tetlet.2016.01.074

Accepted Manuscript
One-pot, four-component synthesis of new 3,4,7,8-tetrahydro-3,3-dimethyl-11-
aryl-2H-pyridazino[1,2-a]indazole-1,6,9(11H)-triones and 2H-indazolo[2,1-
b]phthalazine-1,6,11(13H)-triones using an acidic ionic liquid N,N-diethyl-N-
sulfoethanammonium chloride ([Et3N–SO3H]Cl) as a highly efficient and
recyclable catalyst
Behjat Pouramiri, Esmat Tavakolinejad Kermani
PII:
S0040-4039(16)30073-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.01.074
TETL 47238
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 November 2015
2 January 2016
20 January 2016
Please cite this article as: Pouramiri, B., Kermani, E.T., One-pot, four-component synthesis of new 3,4,7,8-
tetrahydro-3,3-dimethyl-11-aryl-2H-pyridazino[1,2-a]indazole-1,6,9(11H)-triones and 2H-indazolo[2,1-
b]phthalazine-1,6,11(13H)-triones using an acidic ionic liquid N,N-diethyl-N-sulfoethanammonium chloride
([Et3N–SO3H]Cl) as a highly efficient and recyclable catalyst, Tetrahedron Letters (2016), doi: http://dx.doi.org/
10.1016/j.tetlet.2016.01.074
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Graphical Abstract
One-pot, four-component synthesis of new
3,4,7,8-tetrahydro-3,3-dimethyl-11-aryl-2H-
pyridazino[1,2-a]indazole-1,6,9(11H)-triones
and 2H-indazolo[2,1-b]phthalazine-
1,6,11(13H)-triones using an acidic ionic
liquid N,N-diethyl-N-sulfoethanammonium
chloride ([Et3N–SO3H]Cl) as a highly
efficient and recyclable catalyst
Behjat Pouramiria and Esmat Tavakolinejad Kermania*

1
Tetrahedron Letters
One-pot, four-component synthesis of new 3,4,7,8-tetrahydro-3,3-dimethyl-11-
aryl-2H-pyridazino[1,2-a]indazole-1,6,9(11H)-triones and 2H-indazolo[2,1-
b]phthalazine-1,6,11(13H)-triones using an acidic ionic liquid N,N-diethyl-N-
sulfoethanammonium chloride ([Et3N–SO3H]Cl) as a highly efficient and
recyclable catalyst
Behjat Pouramiria and Esmat Tavakolinejad Kermania, 
a
Department of Chemistry, Shahid Bahonar University,76177 Kerman, Iran
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A rapid and efficient one-pot, four-component protocol for the synthesis of novel 2H-
pyridazino[1,2-a]indazole-1,6,9(11H)-triones (6) and 2H-indazolo[2,1-b]phthalazine-1,6,11-
triones (7) has been developed using a stable and reusable Brønsted acidic ionic liquid N,N-
diethyl-N-sulfoethanammonium chloride ([Et3N–SO3H]Cl). A range of diverse aldehydes were
successfully applied and the corresponding products obtained in good to excellent yields without
any by-products.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Multi-component reaction (MCRs);
Solvent-free conditions;
Pyridazino[1,2-a]indazole-triones;
Indazolo[2,1-b]phthalazine-trione;
Ionic liquid
1. Introduction
chemistry.15 In fact, compounds containing the indazole moiety
are known to show a variety of biological activities, such as high
binding affinity for the estrogen receptor,16 inhibition of protein
kinase C-β,17 5-HT2 and 5-HT3 receptor antagonism,18 human
immunodeficiency virus (HIV) protease inhibition,19 and anti-
tumor activity.20 Different catalysts such as supported
polyphosphoric acid,21 dodecylphosphonic acid,22 Ce(SO4)2,23
Multi-component reactions (MCRs) play an important role in
organic and medicinal chemistry because of their ability to
synthesize target compounds with high efficiency and atom
economy by generating structural complexity in a single step
from three or more reactants. Moreover, MCRs offer the
advantage of simplicity and synthetic efficiency over
conventional chemical reactions.1 Therefore, the design of these
reactions for the synthesis of diverse groups of compounds,
especially those that are biologically active, have gained great
attention in organic synthesis.2-4
modified
PEG-6000,24
heteropolyacids,25
trimethylsilyl
chloride,26 Mg(HSO4)2,27 and cyanuric chloride28 have been
reported for the preparation of these compounds.
A recent protocol directed toward the design of structural
motifs containing the pyridazino[1,2-a]indazole ring fragment by
condensation of aldehydes and dimedone followed by the
reaction with 2,3-dihydro-1,4-1,2-dihydropyridazine-3,6-dione
has been reported.29
Recently, the use of ionic liquids (ILs) as green solvents has
found versatile applications in organic reactions due to their
promising features such as the ability to control product
distribution,5 enhanced rate6 and/or reactivity,7 ease of product
recovery,8 catalyst immobilization,9 and recycling.10 Ionic liquids
have also been effectively utilized for the synthesis of novel
bioactive compounds.11
In a continuation of our research on ionic liquids and their
application as catalysts in organic synthesis,30 we have
investigated the one-pot, four-component synthesis of new
derivatives
of
3,4,7,8-tetrahydro-3,3-dimethyl-11-aryl-2H-
and known
Among heterocyclic compounds, great focus has been directed
towards bridgehead nitrogen-containing heterocycles especially
those containing the hydrazine group such as pyridazine since
they possess pharmacological and biological activities such as
herbicides, insecticides and fungicides.12-14
pyridazino[1,2-a]indazole-1,6,9(11H)-trione
derivatives of 2H-indazolo[2,1-b]phthalazine-1,6,11-trione using
N,N-diethyl-N-sulfoethanammonium chloride ([Et3N–SO3H]Cl)
as a highly efficient and recyclable catalyst under solvent-free
conditions. The ionic liquid was prepared according to the
reported literature procedure.31
Indazole [2,1-b]phthalazine-trione are another category of
bridgehead hydrazine-containing heterocycles which are
bioisosteres of indoles and have been widely used in medicinal
———
 Corresponding author. Tel.: +0-913-341-4671; fax: +0-343-322-2033; e-mail: etavakoly@yahoo.com

2
Tetrahedron Letters
2. Results and Discussion
min
Solvent-Free (80 oC)
40
min
93
Firstly, the four-component reaction of benzaldehyde (2a) (1
18
[Et3N–SO3H]Cl (40)
mmol), dimedone (1) (1 mmol), hydrazine hydrate (3) (1.2
mmol) and succinic anhydride (4) (1 mmol) was chosen as the
model reaction and examined in the presence of various ionic
liquids and Brønsted acid heterogeneous catalysts under different
a Reaction conditions: 1 (1 mmol), 2a (1 mmol), 3 (1.1 mmol) and 4 (1mmol).
b Isolated yield.
conditions.
In the absence of catalyst, the reaction did not
After optimization of the reaction conditions, the generality of
this method was examined by the reaction of dimedone (1),
succinic/phthalic anhydride (4/5), hydrazine hydrate (3) and
different aromatic aldehydes (2a-2j) in the presence of [Et3N–
SO3H]Cl at 50 oC under solvent-free conditions (Table 2).
proceed even after a prolonged reaction time (Table1, entry 1). In
the presence of acidic catalysts, the reaction produced the desired
product in low yields and starting materials remained even after
24 h (Table 1, entries 2-10). The model reaction was conducted
in the presence of [Et3N–SO3H]Cl under solvent-free conditions
(Table 1, entries 11-14). The best result was obtained using 20
mol% of [Et3N–SO3H]Cl at 50 oC (Table 1, entry 13). Decreasing
It was observed that aromatic aldehydes having both electron-
withdrawing and electron-donating groups participated in the
reaction and there was no significant difference in the reaction
yield. However, electron-withdrawing substituents had shorter
reaction times (Table 2, entries 2c and 2d).
o
the temperature to 30 C (Table 1, entry 12) led to a lower yield
and longer reaction time. The reaction was also examined in the
presence of different quantities of [Et3N–SO3H]Cl (Table 1,
entries 13-17). Use of 20 mol% [Et3N–SO3H]Cl was found to be
optimal and afforded 6a in 40 min in 93% yield (Entry 16).
Table 1. Optimization of the reaction conditionsa
Entry
Catalyst (mol%)
Conditions
Time
(h)
Yield
(%)b
o
1
-
Solvent-Free (100 C)
20
24
24
4
trace
40
25
30
35
10
25
40
25
35
40
80
80
85
2
La(NO3) (25)
EtOH (Reflux)
3
La(NO3) (25)
THF (Reflux)
o
4
La(NO3) (30)
Solvent-Free (100 C)
5
LaCl3•7H2O (20)
LaCl3•7H2O (20)
LaCl3•7H2O (20)
ZnCl2 (30)
EtOH (Reflux)
3
6
CH2Cl2 (Reflux)
24
1
o
7
Solvent-Free (100 C)
o
8
Solvent-Free (100 C)
2
9
ZnCl2 (20)
THF (Reflux)
24
12
1
10
11
12
13
14
ZnCl2 (20)
EtOH (Reflux)
[Et3N–SO3H]Cl (10)
[Et3N–SO3H]Cl (20)
[Et3N–SO3H]Cl (5)
[Et3N–SO3H]Cl (10)
Solvent-Free (rt)
Solvent-Free (30 oC)
Solvent-Free (50 oC)
Solvent-Free (50 oC)
1
1
50
min
15
16
17
[Et3N–SO3H]Cl (15)
[Et3N–SO3H]Cl (20)
[Et3N–SO3H]Cl (25)
Solvent-Free (50 oC)
Solvent-Free (50 oC)
Solvent-Free (50 oC)
45
90
93
92
min
40
min
40

3
Table 2. Four-component synthesis of 3,4,7,8-tetrahydro-3,3-dimethyl-11-aryl-2H-pyridazino[1,2-a]indazole-1,6,9 (11H)-
trione and 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione derivativesa
Entry
Aldehyde
PhCHO
Anhydride
4
Product
Time (min)
40
Yield (%)a,b
1
93
2
4-ClC6H4CHO
4
4
30
25
93
3
4-O2NC6H4CHO
95
4
5
3-O2NC6H4CHO
4-CH3OC6H4CHO
4
4
20
55
87
95
6
7
4-CH3C6H4CHO
4
4
50
60
89
90
2,4-(Cl)2-C6H3CHO
8
9
4-(CH3)2NC6H4CHO
4
4
15
50
86
90
4-BrC6H4CHO

4
Tetrahedron Letters
10
4-HOC6H4CHO
4
35
87
11
12
PhCHO
5
5
15
17
8732
4-ClC6H4CHO
8933
13
4-O2NC6H4CHO
5
10
8032
3-O2NC6H4CHO
5
5
18
20
8832
14
15
4-CH3OC6H4CHO
8521
4- CH3C6H4CHO
4-HOC6H4CHO
5
5
25
20
8034
16
11
9035
aReaction conditions: 1 (1 mmol), 2 (1 mmol), 3 (1.1 mmol), 4 (1 mmol), [Et3N–SO3H]Cl (20 mol%), solvent-free, 50 oC.
bIsolated yield.
4 (1 mmol), solvent-free, 50 oC.
b Isolated yield.
Finally, we investigated the possibility of recycling [Et3N–
SO3H]Cl using the model reaction forming 6a. After reaction
completion, ice cold water was added to the reaction mixture and
the product was extracted with Et2O. The aqueous layer
consisting of the acidic IL, was recovered after removal of water
under reduced pressure and was reused for subsequent reactions.
It showed the same activity as that of the fresh catalyst without
any loss of activity in terms of yield and purity. The ionic liquid
could be recycled and reused in the same reaction at least four
times (Table 3).
In summary, we have synthesized 3,4,7,8-tetrahydro-
3,3-dimethyl-11-phenyl-2H-pyridazino[1,2-a]indazole-
1,6,9(11H)-trione (6) and 2H-indazolo[2,1-b]phthalazine-
1,6,11(13H)-trione (7) derivatives by a one-pot, four-component
condensation reaction of succinic/phthalic anhydride, dimedone,
hydrazine hydrate, and aromatic aldehydes under solvent-free
conditions using [Et3N–SO3H]Cl as a recoverable and highly
efficient catalyst. The attractive features of this protocol are the
simple procedure, clean reaction, a reusable catalyst, good yield,
simple purification, as well as the ease of catalyst preparation.
Table 3. Catalyst recycling yieldsa.
No of Cyclesa
Yieldb
Fresh
93
Run 1
93
Run 2
92
Run 3
91
Run 4
91
Acknowledgment
Time (min)
40
40
40
40
40
a Reaction conditions: 1 (1 mmol), 2 (benzaldehyde, 1 mmol), 3 (1.1 mmol),

5
29.
30.
31.
Sayyafi, M.; Abolhasani Soorki, A.; Bazgir, A. Chem. Pharm.
Bull. 2008, 56, 1289-1291.
Khabazzadeh, H.; Tavakolinejad Kermani,E.; Jazinizadeh, T.
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The authors express appreciation to the Shahid Bahonar
University of Kerman Faculty Research committee funds for its
support of this investigation.
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