Novel ionic liquid N,N-diethyl-N-sulfoethanaminium hydrogen sulfate: Design, characterization, and application as a highly efficient catalyst for the production of triazolo[1,2-a]indazole-triones and 2H-indazolo[2,1-b]phthalazine-triones

Article abstract of DOI:10.1080/10426507.2016.1149853

A novel Br?nsted acidic ionic liquid namely N,N-diethyl-N-sulfoethanamminium hydrogen sulfate ([Et₃N-SO₃H]HSO₄) was synthesized, and characterized using FT-IR,¹H NMR,¹³C NMR, and mass data. Then, its

Full text of DOI:10.1080/10426507.2016.1149853

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Novel ionic liquid N,N-diethyl-N-
sulfoethanaminium hydrogen sulfate: Design,
characterization and application as a highly
efficient catalyst for the production of triazolo[1,2-
a]indazole-triones and 2H-indazolo[2,1-
b]phthalazine-triones
Abdolkarim Zare & Fatemeh Masihpour
To cite this article: Abdolkarim Zare & Fatemeh Masihpour (2016): Novel ionic liquid N,N-
diethyl-N-sulfoethanaminium hydrogen sulfate: Design, characterization and application
as a highly efficient catalyst for the production of triazolo[1,2-a]indazole-triones and 2H-
indazolo[2,1-b]phthalazine-triones, Phosphorus, Sulfur, and Silicon and the Related Elements,
DOI: 10.1080/10426507.2016.1149853
To link to this article: http://dx.doi.org/10.1080/10426507.2016.1149853
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Date: 03 March 2016, At: 00:54

ACCEPTED MANUSCRIPT
Novel ionic liquid N,N-diethyl-N-sulfoethanaminium hydrogen sulfate: Design,
characterization and application as a highly efficient catalyst for the production of
triazolo[1,2-a]indazole-triones and 2H-indazolo[2,1-b]phthalazine-triones
Abdolkarim Zare and Fatemeh Masihpour
Department of Chemistry, Payame Noor University, PO BOX 19395-3697, Tehran, Iran
We thank Research Council of Payame Noor University for the partial support of this work.
Address correspondence to Abdolkarim Zare, Department of Chemistry, Payame Noor
University, PO BOX 19395-3697, Tehran, Iran. E-mail: abdolkarimzare@pnu.ac.ir or
abdolkarimzare@yahoo.com
Abstract
A novel Brønsted acidic ionic liquid namely N,N-diethyl-N-sulfoethanamminium hydrogen
1
sulfate ([Et3N-SO3H]HSO4) was synthesized, and characterized using FT-IR, H NMR, 13C
NMR and mass data. Then, its catalytic activity was examined for the preparation of triazolo[1,2-
a]-indazole-triones and 2H-indazolo[2,1-b]phthalazine-triones by the one-pot multi-component
condensation of arylaldehydes with dimedone and 4-phenylurazole/2,3-dihydrophthalazine-1,4-
dione under solvent-free conditions. [Et3N-SO3H]HSO4 efficiently promoted the reaction to
afford the products in high yields and in short reaction times.
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CH2Cl2
H2SO4
Neat
N
N
N
+
HSO4
HCl
+
ClSO3H
Cl
SO3H
SO3H
[Et3N-SO3H]HSO4
O
Ar
N
O
O
HN
HN
N
N Ph
N
Ph
O
O
O
[Et3N-SO3H]HSO4 (10 or 15 mol%)
90 °C, Solvent-free
or
Ar-CHO
or
+
+
O
O
O
Ar
O
HN
HN
N
N
O
O
Keywords
N,N-Diethyl-N-sulfoethanamminium hydrogen sulfate ([Et3N-SO3H]HSO4); Brønsted acidic
ionic liquid; triazolo[1,2-a]-indazole-trione; 2H-indazolo[2,1-b]phthalazine-trione; solvent-free
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INTRODUCTION
Ionic liquids have received considerable interest as eco-friendly solvents, catalysts and
reagents in green synthesis, because of their unique properties such as low volatility, non-
flammability, high thermal and chemical stability, negligible vapor pressure, ability to dissolve a
wide range of materials, and capability to catalyze different organic transformations.1-14 Among
the ionic liquids, Brønsted acidic ones have been extensively used as catalysts in organic
synthesis.4-14 It is noteworthy that this class of catalysts has the benefits of both liquid and solid
acid catalysts. As a result, synthesis of new Brønsted acidic ionic liquids, and application of them
as catalyst for organic transformations would be very significant and attractive.
Multi-component reactions are defined as reactions in which three or more starting
materials react in a single step to afford a product that contains the essential parts of all the
starting materials. These reactions are of importance in combinatorial chemistry, because they
prepare target molecules with greater efficacy and atom economy, and reduce the number of
synthetic steps, waste production as well as energy consumption.15-18
Heterocyclic compounds especially nitrogen-containing ones are widely found in nature,
and are essential for life. They are moiety of many fine chemicals, biologically active
compounds and pharmaceuticals.19 Urazole derivatives, as a class of nitrogen-containing
heterocycles, possess various biological and pharmaceutical activities, e.g. anti-cancer and
hypolipidemic properties.20 Moreover, these compounds are applied in the synthesis of
herbicides,21 and pesticides.22 The one-pot multi-component condensation of arylaldehydes with
dimedone and urazoles has been used as a practical method for preparation of triazolo[1,2-a]-
indazole-triones (as urazole-containing heterocycles).23-29 Several catalysts have been applied to
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promote this transformation, including (±)-camphor-10-sulfonic acid,23 p-toluene sulfonic acid,24
ZrOCl2.8H2O,25 sulfonated polyethylene glycol,26 quinuclidine stabilized on FeNi3
nanoparticles,27 1-ethyl-3-methylimidazolium acetate28 and sulfamic acid.29
2H-indazolo[2,1-b]phthalazine-trione derivatives, as another significant class of N-
heterocycles, have different biological and pharmacological activities, such as anti-
inflammatory,30 cardiotonic,31 anticonvulsant,32 antimicrobial,33 antifungal,34 and anticancer35
properties. Dodecylphosphonic acid,36 succinimidinium N-sulfonic acid hydrogen sulfate,37
sulfonated polyethylene glycol,38 montmorillonite K-10/microwave,39 nano-alumina sulforic
acid,40 Ca2CuO3/CaCu2O3/CaO nanocomposite41 and Fe3O4@silica sulfuric acid nanoparticles42
have been utilized as catalysts for this reaction.
Nevertheless, the reported methods suffer from one or more of the following drawbacks:
the use of large amount of catalyst, moderate product yield, long reaction time, the use of
expensive, corrosive and toxic catalysts, and poor compliance with the green chemistry
protocols.
In this work, we have introduced a novel Brønsted acidic ionic liquid (BAIL) namely N,N-
diethyl-N-sulfoethanamminium hydrogen sulfate ([Et3N-SO3H]HSO4), and characterized it by
1
FT-IR, H NMR, 13C NMR and mass data. Afterward, we have used the new BAIL as a
homogeneous catalyst for the efficient synthesis of triazolo[1,2-a]-indazole-triones and 2H-
indazolo[2,1-b]phthalazine-triones from
aromatic aldehydes,
dimedone, and 4-
phenylurazole/2,3-dihydrophthalazine-1,4-dione in the absence of solvent.
RESULTS AND DISCUSSION
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Recently, we have introduced a novel class of BAILs in which a SO3H group has bonded
with a positive nitrogen, and applied them as efficient catalysts and regents in organic
synthesis.9-14 In this research, we have prepared a novel member of this kind of BAIL, namely
N,N-diethyl-N-sulfoethanamminium hydrogen sulfate ([Et3N-SO3H]HSO4), by the simple
reaction between [Et3N-SO3H]Cl and sulfuric acid (Schemes 1 and 2). According to the high
efficacy of our previous BAILs to catalyze organic reactions,9-14 we predict that the novel BAIL,
[Et3N-SO3H]HSO4, can also promote different organic transformations.
[Et3N-SO3H]HSO4 was characterized by studying its FT-IR, 1H NMR, 13C NMR and mass
data. The explanations on the spectral data are given below.
The FT-IR spectrum (Figure S 1) confirmed presence of the expected functional groups in
[Et3N-SO3H]HSO4. The IR data are summarized in Table S 1 (Supplemental Materials).
1
The structure of [Et3N-SO3H]HSO4 was identified by H and 13C NMR data; the
corresponding spectra are shown in Figures S 2 and S 3.
1
In the H NMR spectrum (Figure S 2), four peaks were observed. The nine hydrogens of
the three CH3 groups in the catalyst showed a triplet peak at 1.42 ppm. The six hydrogens of the
three CH2 groups showed a quartet peak at 3.30 ppm. The two peaks observed at 8.43 and 11.59
−
ppm are related to the acidic hydrogens (HSO4 and SO3H).
1
In another study, the H NMR spectra of the reactants for the preparation of [Et3N-
SO3H]HSO4 (i.e. [Et3N-SO3H]Cl and H2SO4) were run in DMSO-d6, in order to show the acidic
1
peaks observed in the H NMR spectrum of the BAIL are actually related to the acidic
hydrogens, not the unreacted starting materials. In the resulting spectra, the acidic hydrogens
peaks were observed at 8.43 as well as 11.59 (for [Et3N-SO3H]HSO4), 11.24 (for [Et3N-
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SO3H]Cl) and 12.54 (for H2SO4). The difference between the acidic hydrogens of [Et3N-
SO3H]HSO4 and its reactants confirmed that the reaction of [Et3N-SO3H]Cl with H2SO4 has been
completely progressed to give [Et3N-SO3H]HSO4.
13
In the C NMR spectrum (Figure S 3), the peaks related to the carbons of CH3 and CH2
were observed at 8.3 and 45.7 ppm.
The mass spectrum of the ionic liquid (Figure S 4) showed the molecular mass (M+) and
(M++1) at m/z = 279 and 280. The other peaks which assist to characterize [Et3N-SO3H]HSO4
−
−
include 262 (M+-OH), 182 (M+-HSO4 ), and 101 (M+- SO3H,HSO4 ).
In another study, to verify complete conversion of [Et3N-SO3H]Cl to [Et3N-SO3H]HSO4, a
solution of AgNO3 in distilled water was added to a solution of the ionic liquid in distilled water.
The absence of AgCl precipitate indicated that [Et3N-SO3H]Cl has been completely converted to
[Et3N-SO3H]HSO4.
After characterization of the ionic liquid, its catalytic activity was tested for the synthesis of
triazolo[1,2-a]-indazole-triones and 2H-indazolo[2,1-b]phthalazine-triones.
The condensation of 3-nitrobenzaldehyde (1 mmol) with dimedone (1 mmol) and 4-
phenylurazole (1 mmol), to provide the corresponding triazolo[1,2-a]-indazole-trione, was
chosen as a model reaction (Scheme 3). This reaction was examined in catalyst-free and solvent-
free conditions at 90°C wherein the product was obtained in trace yield after 60 min. Afterward,
the solvent-free reaction was checked in the presence of various amounts of [Et3N-SO3H]HSO4
at a range of 80-100°C, in order to optimize the reaction conditions. The best results were
observed when 10 mol% of the catalyst was utilized at 90°C (time = 20 min, yield = 98%).
Moreover, the model reaction was examined in the presence of 10 mol% of [Et3N-SO3H]Cl and
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H2SO4 (as the reactants for the synthesis of [Et3N-SO3H]HSO4) at 90°C under solvent-free
conditions. [Et3N-SO3H]Cl afforded the desired triazolo[1,2-a]-indazole-trione in 76% yield
after 20 min; and H2SO4 gave the product in 71% after 20 min.
The reaction between 3-nitrobenzaldehyde (1 mmol), dimedone (1 mmol) and 4-
phenylurazole (1 mmol) using 10 mol% of [Et3N-SO3H]HSO4, was also tested in solvents (2
mL), such as DMSO, DMF, toluene and H2O at 90°C, and in EtOH and EtOAc under reflux
conditions. The solution conditions gave the corresponding product in lower yields and longer
reaction times in comparison with solvent-free conditions.
To obtain the optimized reaction conditions for the synthesis of 2H-indazolo[2,1-
b]phthalazine-trione derivatives, effect of reaction temperature and the catalyst amount was
investigated on the reaction of 3-nitrobenzaldehyde with dimedone and 2,3-dihydrophthalazine-
1,4-dione (Scheme 4). For this purpose, the reaction was examined using different molar ratios
of [Et3N-SO3H]HSO4 at range of 80-100°C in the absence of solvent. The reasonable results
were obtained when the reaction was achieved using 15 mol% of the ionic liquid at 90°C (time =
10 min, yield = 98%).
After the reactions were optimized, different types of aromatic aldehydes (including
aromatic aldehydes possessing electron-withdrawing substituents, halogens and electron-
releasing substituents on their aromatic rings) were reacted with dimedone and 4-phenylurazole
or 2,3-dihydrophthalazine-1,4-dione, to show the generality and the efficacy of [Et3N-
SO3H]HSO4. The results are displayed in Table 1. All reactions proceeded efficiently, and the
desired triazolo[1,2-a]indazole-trione and 2H-indazolo[2,1-b]phthalazine-trione derivatives were
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obtained in high yields (85-98%) after short reaction times (5-25 min). Thus, [Et3N-SO3H]HSO4
was general and highly efficient for these reactions.
In a proposed mechanism which is supported by the literature (Scheme 5),24,26,28 at first,
dimedone converts to its enol form in the presence of [Et3N-SO3H]HSO4, and reacts with the
activated aldehyde by the catalyst to give I. Intermediate II is produced by removing a molecule
of H2O from I, using [Et3N-SO3H]HSO4. Afterward, aza-Michael addition of 4-phenylurazole to
activated II by the catalyst affords intermediate III. Nucleophilic addition of the nitrogen of III
to the activated carbonyl by [Et3N-SO3H]HSO4 gives IV. Finally, a molecule of H2O is removed
from intermediate IV by the catalyst to produce the product. It should be mentioned that our
catalyst has two acidic hydrogens, and can catalyze the reaction by both acidic hydrogens.
To compare the efficacy of [Et3N-SO3H]HSO4 with the reported catalysts for the synthesis
of triazolo[1,2-a]-indazole-triones and 2H-indazolo[2,1-b]phthalazine-triones, the results of the
reaction between 3-nitrobenzaldehyde, dimedone and 4-phenylurazole (or 2,3-
dihydrophthalazine-1,4-dione) (to afford compounds 1c or 2c) using these catalysts, are tabulated
in Table 2. As this Table indicates, our catalyst was more efficient in terms of the reaction
temperature, catalyst amount, time and/or yield. Moreover, in most of the previous methods, only
4-phenylurazole or 2,3-dihydrophthalazine-1,4-dione has been applied in the reaction; however,
in our method, the two nitrogen-containing heterocycles have been used.
CONCLUSION
In conclusion, we have prepared a novel acidic ionic liquid namely N,N-diethyl-N-
sulfoethanaminium hydrogen sulfate, and used it as a highly efficient, general and homogeneous
catalyst for the preparation of triazolo[1,2-a]-indazole-triones and 2H-indazolo[2,1-
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b]phthalazine-triones
from
arylaldehydes,
dimedone
and
4-phenylurazole/2,3-
dihydrophthalazine-1,4-dione under solvent-free conditions.
EXPERIMENTAL
All chemicals were purchased from Merck or Fluka Chemical Companies. All known
compounds were identified by comparison of their melting points and spectral data with those
reported in the literature. Progress of the reactions was monitored by TLC using silica gel SIL
G/UV 254 plates. The 1H NMR (250 or 500 MHz) and 13C NMR (62.5 or 125 MHz) were run on
a Bruker Avance DPX, FT-NMR spectrometer. Mass spectra were obtained with Shimadzu GC-
MS-QP 1100 EX model. Melting points were recorded on a Büchi B-545 apparatus in open
capillary tubes. The Supplemental Materials contain sample characterization spectra for the
novel IL (Figures S 1 -- S 3)
Procedure for the synthesis of [Et3N-SO3H]HSO4
A solution of triethylamine (0.50 g, 5 mmol) in CH2Cl2 (40 mL) was added dropwise to a
stirring solution of chlorosulfonic acid (0.58 g, 5 mmol) in dry CH2Cl2 (40 mL) over a period of
10 min at 10°C. Afterward, the reaction mixture was allowed to heat to room temperature
(accompanied with stirring), and stirred for another 4 h. The solvent was evaporated, and the
liquid residue was triturated with t-butylmethyl ether (3×10 mL) and dried under powerful
vacuum at 90°C to give [Et3N-SO3H]Cl as a viscous pale yellow oil in 93% yield.11 Then,
sulfuric acid (99.99%) (0.49 g, 5 mmol) was added dropwise to [Et3N-SO3H]Cl (1.089 g, 5
mmol) over a period of 5 min at room temperature under pressure of nitrogen gas (to remove
HCl produced during the reaction). The resulting mixture was stirred for 10 h at 60°C under a
continuous flow of nitrogen gas to give [Et3N-SO3H]HSO4 as a viscous pale yellow liquid in
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99% yield. IR (nujol): 583, 880, 1059, 1167, 1207, 2950, 2500-3500 cm−1; 1H NMR (250 MHz,
DMSO-d6): δ 1.42 (t, J = 7.5 Hz, 9H), 3.30 (q, J = 7.5 Hz, 6H), 8.43 (br., 1H), 11.59 (br., 1H);
13C NMR (62.5 MHz, DMSO-d6): δ 8.3, 45.7; MS: m/z 280 (M++1), 279 (M+), 262 (M+-OH),
−
−
182 (M+-HSO4 ), 101 (M+- [SO3H,HSO4 ]).
General procedure for the synthesis of triazolo[1,2-a]indazole-trione (1a-g) and 2H-
indazolo[2,1-b]phthalazine-triones (2a-g)
To a well-ground mixture of arylaldehyde (1 mmol), dimedone (0.140 g, 1 mmol) and 4-
phenylurazole (0.177 g, 1 mmol) or 2,3-dihydrophthalazine-1,4-dione (0.162 g, 1 mmol), was
added [Et3N-SO3H]HSO4 [(0.028 g, 0.1 mmol) for the preparation of 1a-g or (0.042 g, 0.15
mmol] for the synthesis of 2a-g}. The obtained mixture was firstly stirred magnetically at 90°C,
and after solidification of the reaction mixture, it was stirred with a small rod at same
temperature. After the reaction was completed (as observed by TLC), the reaction mixture was
cooled to room temperature, water (2 mL) was added, stirred for 3 min, and filtered. The solid
residue was recrystallized from EtOH/H2O (4/1) to give the pure product.
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Table 1 [Et3N-SO3H]HSO4-catalyzed the production of triazolo[1,2-a]-indazole-triones (1a-g)
and 2H-indazolo[2,1-b]phthalazine-triones (2a-g)
O
Ar
O
O
N
N
HN
HN
N
N Ph
Ph
O
O
1a-g
O
[Et3N-SO3H]HSO4 (10 or 15 mol%)
90 °C, Solvent-free
or
Ar-CHO
or
+
+
O
O
O
Ar
N
O
HN
HN
N
O
O
2a-g
Product
1a
Ar
Time (min)
Yielda (%)
M.p. °C (Lit.)
C6H5
25
25
20
20
15
15
15
5
98
86
98
90
85
90
85
98
96
98
98
90
98
98
187-189 (188-190)24
176-178 (178)28
128-130 (126-128)24
103-105 (105-108)26
168-170 (166)28
170-172 (173-175)24
107-109 (106-107)26
201-203 (204-206)32
225-227 (223-225)32
270-272 (271-273)40
264-266 (264-266)40
214-216 (216-218)38
262-264 (262-264)38
222-224 (224-226)42
4-O2NC6H4
3-O2NC6H4
4-FC6H4
1b
1c
1d
1e
4-ClC6H4
2-ClC6H4
1f
3-CH3OC6H4
C6H5
1g
2a
4-O2NC6H4
3-O2NC6H4
4-ClC6H4
4-FC6H4
5
2b
2c
10
10
7
2d
2e
4-BrC6H4
4-CH3C6H4
7
2f
5
2g
aIsolated yield.
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Table 2 The results of the synthesis of compounds 1c and 2c using [Et3N-SO3H]HSO4 compared
with the reported catalysts
Compound 1c
Compound 2c
Catalyst (mol%)
Conditions
Time (min)/Yield
Time (min)/Yield
(%)
20/98
(%)
10/98
[Et3N-SO3H]HSO4
(10 or 15 mol%)
Solvent-free, 90°C
H2O/EtOH, Reflux
Solvent-free, 80°C
(±)-Camphor-10-
25/80
15/83
-
-
sulfonic acid23 (20)
p-Toluene sulfonic
acid24 (30)
ZrOCl2.8H2O25 (30) Solvent-free, 80°C
60/88
30/91
60/82
-
PEG-SO3H26 (10)
Solvent-free, 80°C
1-Ethyl-3-
methylimidazolium
acetate28 (15)
Solvent-free, r.t.
24/81
-
Sulfamic acid29 (20)
H2O, 50°C
60/88
-
-
Dodecylphosphonic
acid36 (10)
Solvent-free, 80°C
5/92
Succinimidinium N-
sulfonic acid
Solvent-free,
100°C
-
20/94
hydrogen sulfate37
PEG-OSO3H38 (8)
Solvent-free, 80°C
-
-
10/92
15/83
Nano-alumina
sulforic acid40
Solvent-free,
110°C
Nano
Ca2CuO3/CaCu2O3/
CaO41
Nano Fe3O4@silica
sulfuric acid42
Solvent-free,
125°C
-
-
10/83
30/94
Solvent-free,
100°C
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CH2Cl2
N
+
ClSO3H
N
Cl
SO3H
[Et3N-SO3H]Cl
Scheme 1 The preparation of [Et3N-SO3H]Cl.
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H2SO4
HCl
+
N
N
Cl
HSO4
SO3H
SO3H
Neat
[Et3N-SO3H]HSO4
Scheme 2 The production of the novel BAIL.
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O2N
O
O
O
N Ph
CHO
HN
[Et3N-SO3H]HSO4 (10 mol%)
90 °C, Solvent-free
O
N
+
+
HN
N
O
N
O
Ph
NO2
O
Scheme 3 The synthesis of triazolo[1,2-a]indazole-triones.
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O2N
O
O
O
O
CHO
O
[Et3N-SO3H]HSO4 (15 mol%)
90 °C, Solvent-free
HN
HN
+
+
N
N
O
NO2
O
Scheme 4 The production of 2H-indazolo[2,1-b]phthalazine-triones.
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O
O
O S NEt3 O S OH
H
O
O
OH
O
O
O
Ar
O
[Et3N-SO3H]HSO4
Ar
H
[Et3N-SO3H]HSO4
-H2O
OH
O
O
O
(I)
O
O S NEt3 O S OH
O
H
O
O
HN
HN
N Ph
O
Ar
O
O
Ar
O
Ar
O
[Et3N-SO3H]HSO4
[Et3N-SO3H]HSO4
O
N
N Ph
HN
O
O
O
(II)
O
(III)
O
O
Ar
Ar
Ar
N
O
[Et3N-SO3H]HSO4
-H2O
N
O
O
N
N Ph
HN
N
N
O
N
N
O
O
Ph
Ph
O
O
H
H
O
O
(IV)
O S NEt3 O S OH
The product
O
O
Scheme 5 The proposed mechanism for the production of triazolo[1,2-a]indazole-triones.
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