Experimental and DFT mechanistic insights into one-pot synthesis of 1: H -pyrazolo[1,2- b] phthalazine-5,10-diones under catalysis of DBU-based ionic liquids

Article abstract of DOI:10.1039/d0nj03478a

Benzylation of DBU followed by anion exchange of the resulting salt with trifluoroacetate gave nearly quantitatively the ionic liquid [Bn-DBU][TFA]. It is shown here to be an efficient catalyst for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones via the three-component reaction of phthalhydrazide, aromatic aldehydes, and active α-methylene nitriles. DFT calculations at the B3LYP/SVP level and the experimental results are in agreement with a three-step mechanism for this reaction. Based on the DFT calculations, the catalytic effect largely arises from the intrinsic ionic properties of the ionic liquid rather than its action as a simple base. These calculations also predict the existence of two close-in-energy activated complexes whose rate determining roles and energies depend on their interaction with the anionic component of the ionic liquid, as [Bn-DBU][TFA] has shown a higher catalytic activity than [Bn-DBU][OAc]. This mechanistic approach opens up new and promising insights into the rational design of ionic liquid catalysts for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones. The synthetic method presented here has several prominent advantages.

Full text of DOI:10.1039/d0nj03478a

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Experimental and DFT mechanistic insights
into one-pot synthesis of 1H-pyrazolo[1,2-b]-
phthalazine-5,10-diones under catalysis
of DBU-based ionic liquids†
Cite this:DOI: 10.1039/d0nj03478a
Sara Fallah-Ghasemi Gildeh, Morteza Mehrdad,* Hossein Roohi,
Khatereh Ghauri, Sahar Fallah-Ghasemi Gildeh and Kurosh Rad-Moghadam
*
Benzylation of DBU followed by anion exchange of the resulting salt with trifluoroacetate gave nearly
quantitatively the ionic liquid [Bn-DBU][TFA]. It is shown here to be an efficient catalyst for the synthesis
of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones via the three-component reaction of phthalhydrazide,
aromatic aldehydes, and active a-methylene nitriles. DFT calculations at the B3LYP/SVP level and the
experimental results are in agreement with a three-step mechanism for this reaction. Based on the DFT
calculations, the catalytic effect largely arises from the intrinsic ionic properties of the ionic liquid rather
than its action as a simple base. These calculations also predict the existence of two close-in-energy
activated complexes whose rate determining roles and energies depend on their interaction with
the anionic component of the ionic liquid, as [Bn-DBU][TFA] has shown a higher catalytic activity than
Received 11th July 2020,
Accepted 2nd September 2020
[Bn-DBU][OAc]. This mechanistic approach opens up new and promising insights into the rational design
DOI: 10.1039/d0nj03478a
of ionic liquid catalysts for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones. The synthetic
rsc.li/njc
method presented here has several prominent advantages.
antihyperglycemic, antibacterial, antiviral, anti-inflammatory,
Introduction
1
4,15
analgesic, antihypoxic, and antipyretic activities.
Conse-
Multicomponent reactions (MCRs) are typically chemical trans- quently, many methods have been developed for the synthesis
1
6–18
formations which yield products in one pot from the structural of pyrazolo[1,2-b]phthalazines.
These involve largely the
moieties of three or more reacting components. These types of synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones via the
reactions enable us to synthesize a vast array of structurally three-component reaction of an aldehyde, phthalhydrazide,
diverse compounds in one-step procedures and to introduce and active methylene C–H acid using diverse catalysts such as
16
19
cost effective and environmentally friendly synthetic protocols. sulfonated titania–carbon composite C@TiO
2 3 2
–SO H, Cu(OTf) ,
Hence, MCRs have captivated much attention especially toward N,N,2,2,6,6-hexamethyl-N-(3-(trimethoxysilyl)propyl)piperidin-4-
1
–3
20
the production of heterocyclic compounds.
2 4
Methodologies onium iodide grafted onto titania-coated NiFe O nanoparticles,
1
8
21
based on MCRs are very useful particularly when they result in triethylamine under ultrasonication, L-proline, zirconium
the formation of the medicinally privileged heterocyclic scaf- tetrachloride, Fe O nanoparticles grafted by triethoxy(3-amino-
folds. Of these heterocyclic compounds, those embedding N–N propyl)silane, 2-hydroxyethylammonium acetate, N,N,N ,N -
bonds in their ring systems hold a unique place among a large tetrabromobenzene-1,3-disulfonamide and poly(N-bromo-N-
variety of compounds, and have attracted immense attention ethylbenzene-1,3-disulfonamide), b-cyclodextrin,
because of their valuable pharmacological properties and clinical supported on amino-functionalized magnetite nanoparticles,
Pyrazoles and pyrazole-fused ring systems are [Bu
recurrent members of this N-heterocyclic family, being found ([bmim]OH),
2
2
3
4
2
3
24
0
0
2
5
26
4
H W
12SiO40
2
7
4
–9
28
applications.
3
NH][HSO
4
],
1-butyl-3-methylimidazolium hydroxide
2
9
30
31
CAN in PEG-400,
and InCl
3
.
However,
1
0–13
as cores of numerous biologically active compounds.
although many of the recently reported protocols have remark-
For example, pyrazolo[1,2-b]phthalazines are known for their able merits, some suffer from one or more disadvantages such
as harsh reaction conditions, tedious workup procedures,
long reaction times, use of metal catalysts, and emission of
hazardous materials into the environment. Therefore, there
Chemistry Department, University of Guilan, P. O. Box 41335-1914, Rasht, Iran.
E-mail: radmm@guilan.ac.ir, m-mehrdad@guilan.ac.ir; Fax: +98 1333367066
remains room to develop greener, milder, and simpler protocols
based on application of retrievable catalysts or solvents such as
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0nj03478a
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ionic liquids (ILs) to avoid the emission of hazardous substances
into the environment and run the synthesis of phthalazine
containing ring systems efficiently. ILs are salts consisting of
organic cations and suitable anions, which melt below 100 1C.
These low-temperature molten salts have shown interesting
properties such as high thermal stability, wide liquid state range,
Scheme 1 Synthesis of the Bn-DBU-based ionic liquids (see S1 of the ESI†
for their optimized structures).
32
and high solvating capability for a wide range of solutes. ILs,
irrespective of widespread applications as powerful solvents of
both organic and inorganic materials, have found fascinating uses 2h, and malononitrile was chosen as the model to be examined in
33
34–37
in the last two decades as mild reagents, catalysts
and different media including the ionic liquid, 8-benzyl-DBU trifluoro-
supports of catalysts. The evolution of ILs as modern homo- acetate ([Bn-DBU][TFA]), and in different temperatures.
38
geneous catalysts largely arises from the efforts that have been
paid to functionalization of their ions with acidic and basic
As Table 1 shows, the trial reaction gives negligible yields in
the absence of any catalyst at 80 1C (entry 1) or in the presence
39
40
groups, along with scarce studies directed toward employing the of [Bn-DBU][TFA] but at room temperature (entry 2). Increasing
41
intrinsic catalytic activities of their parent ions. ILs, due to their the amount of [Bn-DBU][TFA] and the reaction temperature
ionic and organic nature, are capable of establishing a wide range lead to significant improvements in the yield of the model
of interactions with the reacting solutes including the reaction product. The best result in terms of the reaction time and the
intermediates and transition states. Thus, depending on the yield was obtained by performing the trial reaction under
nature of the considered reactions, they may result in significant solvent-free conditions at 100 1C using 28 mol% of the IL
rate enhancements. The dominant type of interaction between an (entry 5). Gentle refluxing of the reaction mixture with the IL
IL and the reacting species significantly depends on the ions (28 mol%) in some solvents gave no desirable yields (entries 9–14).
42
constituting the IL. Strongly bound ions in ILs may be unable It is worth noting that [Bn-DBU][OAc] has not appeared as
4
3
to approach the substrates due to electrostatic inhibitions.
efficient as [Bn-DBU][TFA] in catalysis of the model reaction
ꢀ
Hence, careful selection of ions is crucial to achieve low-melting (entry 8). Considering that AcO is a stronger Brønsted base
and catalytically active ionic liquids. Herein is explained the than TFA (pK
ꢀ
b
= 9.24 vs. 13.77), the greater catalytic activity of
ionic characteristics led to such a selection we made between [Bn-DBU][TFA] in comparison with [Bn-DBU][OAc] should arise
two DBU-based IL-catalysts used for green and efficient synthesis from a significant interaction it establishes with the reacting
of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones via the three- species and not from cooperation of TFA and Bn-DBU as two
component reaction of phthalhydrazide, aromatic aldehydes, base catalysts. Encouraged by these results, we set out to
and active a-methylene nitriles. However, although a common explore the substrate scope and versatility of the method by
undetailed mechanism has usually been proposed for this employing different arylaldehydes in the reaction with phthal-
reaction even under various catalytic conditions, no experimental hydrazide 1 and malononitrile or ethyl cyanoacetate 3. Aromatic
evidence in support of this mechanism was reported. This is due aldehydes substituted with electron-donating or electron-
to the fact that no intermediate other than the Knoevenagel withdrawing groups react nearly equally well with malononitrile
condensate of aldehyde and the nitrile can be resolved from the
reaction mixtures. In this background, we aimed at studying
a
Table 1 Optimization of the reaction conditions for the synthesis of 4h
the details of the mechanism especially under catalysis of two
DBU-based ILs by density-functional theory (DFT). As a result,
we show that the second intermediate of the reaction has a higher
energy and exists between two rate determining activated
complexes. This finding indicates why it has not been separated
b
up to now from any reaction mixture. The relative energies of the
two activated complexes significantly alters on interaction with
the ionic liquids and this encourages the catalyst-designers to
consider the ionic properties of ILs beside functionalization of
them with acidic and basic groups.
Ent. Catalyst (mol%)
Solvent Temp. (1C) Time (min) Yield (%)
1
2
3
4
5
6
7
8
9
1
—
—
80
r.t.
80
100
60
60
8
Trace
Trace
65
[Bn-DBU][TFA] (22) —
[Bn-DBU][TFA] (22) —
[Bn-DBU][TFA] (22) —
[Bn-DBU][TFA] (28) —
[Bn-DBU][TFA] (28) —
[Bn-DBU][TFA] (39) —
[Bn-DBU][OAc] (28) —
8
71
90
100
8
120
100
8
8
89
90
100
100
80
8
76
Results and discussion
[Bn-DBU][TFA] (28) H O
[Bn-DBU][TFA] (28) EtOH
120
120
120
120
120
120
NC
NC
NC
NC
NC
NC
2
0
The DBU-based ILs were prepared via benzylation of DBU fol- 11 [Bn-DBU][TFA] (28) CH
3
OH 60
CN 80
80
1
1
1
2
3
4
[Bn-DBU][TFA] (28) CH
[Bn-DBU][TFA] (28) THF
[Bn-DBU][TFA] (28) DMF
3
lowed by anion exchange of the resulting product with appro-
priate salts (Scheme 1). Next, in order to explore the optimal
conditions for the synthesis of 3-amino-5,10-dioxo-1-phenyl-5,10-
dihydro-1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile 4h (Table 1),
100
a
Reaction conditions: 1 mmol of each reactant in 4 mL of solvent
if used). Isolated yields. The parameters of the bold entries (5 and 8)
b
(
the domino reaction of phthalhydrazide 1, 4-chlorobenzaldehyde were identified as optimal for the applied ILs. NC (not completed).
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Table 2 Synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones 4a–4z under the optimal conditions and [Bn-DBU][TFA] catalysis
a
b
ꢀ1
Product
Ar
X
Time (min)
Yield (%)
TOF (h
)
Mp (1C)
Mp (1C) (lit.)
16
40
18
41
18
43
43
40
18
16
44
42
40
45
40
44
17
41
43
17
44
44
18
18
18
44
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
4-(NO
3-(NO
2-(NO
2
2
2
)–C
)–C
)–C
6
6
6
H
H
H
4
4
4
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CO
CO
CO
CO
CO
CO
8
8
8
15
8
8
8
8
8
12
12
15
12
15
12
12
15
12
15
10
18
18
20
20
18
25
92
93
92
76
89
90
91
90
91
89
90
82
86
87
82
87
88
82
77
91
92
90
89
88
84
87
24.6
24.9
24.6
10.8
23.8
24.1
24.4
24.1
24.4
15.9
16.1
11.2
15.3
12.4
14.6
15.5
12.8
14.6
11.0
19.5
10.9
10.7
9.5
225–227
267–269
265–267
269–271
270–271
260–261
269–271
270–272
267–269
259–260
243–245
243–245
235–237
232–232
240–243
265–267
155–157
268–270
213–215
276–278
240–242
235–236
233–235
200–202
210–212
202–204
(226–227)
(269–271)
(265–266)
(266–268)
(263–265)
(262–264)
(270–272)
(273–276)
(266–267)
(258–289)
(242–244)
(247–249)
(236–238)
(230–232)
(240–242)
(264–266)
(154–156)
(270–272)
(212–214)
(274–276)
(239–241)
(236–238)
(235–237)
(205–206)
(211–213)
(201–203)
2-Cl–3-F–C
6
H
3
4-F–C
6
H
4
3-Br–C
4-Br–C
4-Cl–C
3-Cl–C
2-Cl–C
2,4-(Cl) –C H
2 6 3
2-Me–C
4-Me–C
6
H
4
4
4
4
4
6
H
6
H
H
H
6
6
6
H
H
4
6
4
3 2 6 4
4-N(CH ) –C H
4-MeO–C
3-MeO–C
2-MeO–C
4-HO–C
2-HO–C
6
6
6
H
H
H
4
4
4
6
H
H
4
s
t
u
v
w
x
6
4
6 5
C H
4-(NO
3-(NO
2-(NO
2
2
2
)–C
)–C
)–C
6
6
6
H
H
H
4
2
2
2
2
2
2
Et
Et
Et
Et
Et
Et
4
4
4-Br–C
3-Cl–C
6 4
4-Me–C H
6
H
4
9.4
10.0
7.5
y
z
6
H
4
a
b
Yields of the isolated products. Turnover frequency.Reaction conditions: 1 mmol of each reacting component and 28 mol% of [Bn-DBU][TFA]
under solvent-free conditions at 100 1C.
and phthalhydrazide to give 1H-pyrazolo[1,2-b]phthalazine-5,10-
dione derivatives (Table 2) in fairly high yields. Similar yields
are obtained, however within slightly longer reaction times and
with relatively lower turnover frequencies (TOFs), by using ethyl
cyanoacetate (X = COOEt) in place of malononitrile (X = CN).
These results listed in Table 2 clearly indicate that the reaction
can be applied to a wide range of arylaldehydes with different
substituents and that the electronic nature of the substituents has
no remarkable effect on the yield and rate of the reactions carried
out under the optimized conditions. Nevertheless, the arylaldehydes
having electron-donating groups on their aromatic rings and those
that have steric hindrance due to their ortho-substituents react
slightly slower than others and give slightly lower yields.
Scheme 2 A mechanistic proposal for the synthesis of 4. The optimized
structures of the reacting species at the B3LYP/SVP level of DFT in the gas
phase are given in Fig. S7 of the ESI.†
In the next phase of this investigation, we performed DFT
46,47
(density functional theory) calculations using the B3LYP/SVP
However, although there are almost general agreements on
level of theory to suggest a reasonable explanation for the efficient the intermediacy of the adduct 6, it has not yet been isolated
2
8,48
catalysis of the reaction by the two ionic liquids and the supremacy from any similar reaction mixture.
Moreover, direct appli-
of [Bn-DBU][TFA]. These calculations were performed for the first cation of 5 in place of aldehyde and malononitrile has no effect
time on the mechanism generally proposed for the reaction in on the rate of the synthetic reaction. In this background, one
which the three-component synthesis initiates by Knoevenagel may admit that 6 and 4 are the kinetic and the thermodynamic
condensation of benzaldehyde 2 and malononitrile 3 to give the products of the reaction, respectively.
alkene 5. Michael addition of this alkene onto phthalhydrazide 1
Based on the gas phase DFT calculations, the transition
proceeds via the transition state TS6 and results in formation states TS6 and TS4 which lead, respectively, to formation of the
of the intermediate adduct 6 which subsequently undergoes intermediate 6 and the product 4 are close in Gibbs free energy
a Thorpe–Ziegler type cyclization to deliver the product 4t (Fig. 1). Under these conditions, the intermediate 6 needs about
ꢀ
1
(Scheme 2).
1.74 kcal mol less Gibbs free energy to dissociate into the
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An important reaction of TS4a and TS4b is the transfer of H
3
to
N
5
in 6, which seems to be mediated by delocalization of the p
ꢀ
ꢀ
electrons from CQO groups of [OAc] and [TFA] anions into
the s* orbital of the N –H bond. As a result, this transfer has
1
3
ꢀ
ꢀ
low activation energies in the two ILs. The [OAc] and [TFA]
anions are held in proximity to the dissociating N –H bond by
a weak H-bond between their O atoms and H . The anions not
only weaken the original N –H bond but also mediate proton
transfer from N to N , accompanied by formation of the
pyrazole ring which includes the N –C bond. The DFT calcula-
tions also reveal a similar energy profile for the case of using
Bn-DBU][TFA], except that the TS of the first step, namely TS6b,
1
3
6
1
3
1
5
1
5
[
has a higher energy than that of the second step, namely TS4b,
and is the rate determinant of the reaction. In other words,
the energy required for production of the intermediate 6 is
sufficient to convert it into the product 4. In practice, the model
reaction in [Bn-DBU][TFA] is slightly faster than in [Bn-DBU]-
[OAc] and this fact lends credit to the DFT calculations. The
different efficiencies of the two ILs can be referred to the DFT
+
calculations that estimate the ionic bond of [Bn-DBU] with
ꢀ
ꢀ1
ꢀ
[
OAc] about 10.53 kcal mol more stronger than with [TFA] .
ꢀ
Moreover, based on these calculations, [OAc] takes an orienta-
+
tion orthogonal to the averaged plane of [Bn-DBU] , while
ꢀ
ꢀ
[
TFA] lies side by side on this plane. In [TFA] , the electro-
negative fluorine atoms cause the negative charge to be dis-
ꢀ
tributed over all the hetero atoms, so it behaves, unlike [OAc] ,
as a soft anion with no preferred orientation to approach
+
ꢀ
ꢀ
+
[
Bn-DBU] . Consequently, [TFA] is loosely bound to [Bn-DBU]
and is more available than [OAc] to form a complex, namely 1b,
with phthalhydrazide by H-bonding. Thus, 5 can push away
+
[
Bn-DBU] more easily from 1b than from 1a (the complex of 1
and [Bn-DBU][OAc]) to approach the phthalhydrazide during the
Michael addition reaction (Scheme 3).
A comparison between the catalytic efficiency of [Bn-DBU][TFA]
Fig. 1 The energy profile calculated at the B3LYP/SVP level of DFT for the
three-component synthesis of 4 in the gaseous phase and absence of IL and some previously reported catalysts for the synthesis of 4h is
(
black); with the aid of [Bn-DBU][AcO] (trace a, red); and with catalysis of seen in Table 3. As this table shows, most of the reported catalysts
[
Bn-DBU][TFA] (trace b, blue). The optimized structures of the above
need longer times (entries 1, 4, 5, 7, 8, 11 and 12) to give
species at the B3LYP/SVP level of theory in the gas phase are given in
comparable yields of 4h. Some catalysts are expensive and cannot
be prepared conveniently (entries 1, 3, 6 and 9) and some others
are made of heavy metals (entries 5, 12, 13) or cannot be separated
Fig. S8 of the ESI.†
substrates (1 and 5) than to reach the energy level of TS4 and to easily from the reaction mixtures (entries 2, 4 and 8). Notably,
form the thermodynamic product 4. These findings delineate [Bn-DBU][TFA] is mildly basic and reasonably amenable to
pre-equilibrium kinetics for the three-component reaction in
which the adduct 6 is formed reversibly by the initial reaction
and next undergoes a rate determining reaction to give the
product 4. Interestingly, the energy profile significantly alters
by addition of the ionic liquids to the reaction mixture in the
gaseous phase. Notably, the product 4 gains a considerably
higher energy on interaction with either of the two ionic liquids
while the energies of the intermediate 6 and the transition
states TS6 and TS4 decrease. In the case of binding with
[Bn-DBU][OAc], the transition state of the first reaction step,
namely TS6a, is more stabilized than that of the second step,
namely TS4a, so the reaction acquires the energy profile of true
pre-equilibrium kinetics in which the rate determining
Scheme 3 The approach of 5 to phthalhydrazide in its complexes with
Bn-DBU][AcO] (1a) and [Bn-DBU][TFA] (1b). The optimized structures at
the B3LYP/SVP level of theory in the gas phase are given in Fig. S9 of the
[
TS4a has a lower energy than under the IL-free conditions. ESI.†
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Table 3 Comparative catalytic efficiency of [Bn-DBU][TFA] and some previously reported catalysts in the model synthesis of 4h
Ref.
a
Ent.
Catalyst
Amount of catalyst
Conditions
O, 100 1C
EtOH, ultrasonication
PEG-400, 80 1C
Time (min)
Yield (%)
1
6
1
2
3
4
5
6
7
8
9
0
1
2
3
4
C@TiO
2
–SO
3
H
2.7 mol%
20 mol%
20 mg
10 mol%
20 mol%
10 mol%
10 mol%
20 mol%
10 mg
20 mol%
10 mol%
5 mol%
20 mol%
28 mol%
H
2
900
60
10
600–720
300
15
720
150
27
9
60
50
25
92
96
97
89
86
93
94
93
96.6
94
97
90
94
90
18
Et
3
N
2
0
Nano-NiFe
L-Proline
2
O
4
@TiO
2
–ILPip
2
1
H
2
O : EtOH (1 : 1), 80 1C
22
ZrCl
APTES-MNPs
4
Solvent-free, 80 1C
Solvent-free, 100 1C
EtOH, r.t.
H O : EtOH (4 : 1), 80–100 1C
2
MeOH, 60 1C
Solvent-free, 80 1C
EtOH, 60 1C
PEG-400, 45 1C
Solvent-free, 80 1C
Solvent-free, 100 1C
2
3
+
ꢀ 24
[H
b-Cyclodextrin
STA-amine-Si-magnetite
3
N CH
2
CH
2
OH] [CH
3
COO ]
26
27
2
8
1
1
1
1
1
[Bu
3
NH][HSO
4
]
2
9
[bmim]OH
3
0
CAN
3
1
InCl
[Bn-DBU][TFA]
3
8
a
Per 1 mmol of each reactant.
tolerate a wider range of substrates in comparison with Brønsted
acidic or basic ILs (entries 10 and 11). Therefore, these merits
tend to introduce [Bn-DBU][TFA] as an alternative to already
existing catalysts for the synthesis of 4.
An important feature of this protocol is that the catalyst can
be easily separated from the reaction mixture. At the end of the
model reaction, performed under the optimized conditions,
water was added to the reaction mixture and the IL was
separated from the solid product by decantation of the super-
natant aqueous solution. The aqueous extract was then evapo-
rated under vacuum and the remaining IL was collected for
reuse in the next cycle of the trial reaction using appropriate
amounts of the reactants. It is interesting to note that the IL can
be recycled at least four times without appreciable loss of its
activity (Fig. 2).
The IR spectrum of [Bn-DBU][TFA] after the 4th recycling is
Fig. 3 The IR spectra of fresh [Bn-DBU][TFA] and after the 4th recycling in
almost identical to that of the fresh IL and this means that it the synthesis of 4h.
remains intact during use in the synthesis of 4h (Fig. 3).
Nearly identical spectra were also obtained by energy-
dispersive X-ray (EDX) analysis of these two samples (Fig. 4).
The slight differences that are seen between the intensities of
the peaks in the resulting EDX spectra can be attributed to the
Fig. 2 Reusability tests for [Bn-DBU][TFA] in terms of yield and reaction
time of the model reaction.
Fig. 4 The EDX spectra of fresh [Bn-DBU][TFA] and after the 4th recycling
in the synthesis of 4h.
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error of EDX analysis and to the minute contamination of the authentic samples prepared independently by the previously
recycled sample (see S4 of the ESI†).
reported methods. Melting points were determined using a
Kofler hot stage apparatus and are uncorrected. Monitoring of
the reactions was performed by TLC on silica gel (polygram
SILG/UV 254) plates. The Fourier transform infrared (FT-IR)
spectra were obtained by using KBr discs on a PerkinElmer
Conclusions
The two ionic liquids denoted here as [Bn-DBU][AcO] and
ꢀ1
Spectrum One apparatus in the range of 400–4000 cm . The
[Bn-DBU][TFA] were prepared by benzylation of DBU and anion
1
H NMR (400 MHz) spectra were recorded on a Bruker-AVANCE
ꢀ
exchange of the resulting salt with AcO and trifluoroacetate
spectrometer and the chemical shifts were measured with
respect to the deuterated solvent. Water contents of the ILs
were measured by using Karl Fischer titration (Metrohm 890
Titrando).
ꢀ
(
TFA ), respectively. These ionic liquids show significant catalytic
efficiencies in the synthesis of 3-amino-5,10-dioxo-1-aryl-5,10-
dihydro-1H-pyrazolo[1,2-b]phthalazin-2-carbonitriles from the
domino reaction of phthalhydrazide, arylaldehyde, and malono-
nitrile/ethyl cyanoacetate. DFT calculations at the B3LYP/SVP level
of theory based on the mechanism generally proposed for this
Synthesis of [Bn-DBU][OAc] and [Bn-DBU][TFA] ILs
reaction are in agreement with the catalytic efficiency of these The ionic liquids were prepared via anion exchange from the
49
two ionic liquids and the supremacy of [Bn-DBU][TFA]. These pre-synthesized [Bn-DBU]Cl salt. To synthesize the [Bn-DBU]Cl
unprecedented calculations show that two transition states can salt, DBU (50 mmol, 7.6 g) and benzyl chloride (80 mmol, 10.1 g)
be postulated for this reaction whose energies are considerably were added to a flask (100 mL) containing ethyl acetate (50 mL)
decreased by the ionic liquids. Moreover, the transition states are and a magnetic stirring bar. The reaction mixture was stirred at
not affected similarly and symmetrically by the two ionic liquids room temperature for 48 h, during which the solution turns into
and this results in different energy profiles for the reaction in two separate liquid phases. The supernatant ethyl acetate phase
the two ionic liquids. However, although the energy profiles was separated off and the remaining pasty solid was washed with
correspond to pre-equilibrium kinetics for the reaction in diethyl ether (3 ꢁ 4 mL) to remove the unreacted starting
[
Bn-DBU][OAc], they introduce the first reaction step as the rate materials. The residual solvent was evaporated under vacuum
limiting step for the reaction in [Bn-DBU][TFA]. In addition, the and the remaining salt [Bn-DBU]Cl was collected. To derive the
energy profiles display a slightly lower activation energy for the desirable ILs, [Bn-DBU]Cl (30 mmol, 8.3 g) and a slight excess
ꢀ
reaction in [Bn-DBU][TFA], which accounts for its slightly higher amount (35 mmol) of NaY (Y
1
= OAc 4.8 g and Y
2
= TFA (CF CO
3 2
)
rate in comparison with the reaction in [Bn-DBU][AcO]. These 2.9 g) was added to acetonitrile (60 mL) in a canonical flask
agreements between the DFT calculations and the experimental (100 mL) containing a magnetic stirring bar. The mixture was
data lend substantial credits to the proposed mechanism. This stirred at room temperature for about 48 h. The solid (excess NaY
reaction is very similar to the synthesis of many other hetero- and NaCl) was removed by centrifugation and the liquid
cycles. Thus, the results can help us to understand the mecha- phase was heated at 80 1C in vacuo to evaporate acetonitrile and
nism and therefore the limits of the relevant syntheses. The volatile impurities. Accordingly, the ILs, [Bn-DBU][OAc] and
present study also shows that the slight difference between the [Bn-DBU][TFA], were prepared in 92% and 94% yields, respectively
catalytic activities of the two ionic liquids comes from their (Scheme 1). The optimized structures of [Bn-DBU][OAc] and
differences in ionic bond strength and orientation of their anions. [Bn-DBU][TFA] ILs at the B3LYP/SVP level of theory in the gas
Due to these differences, the ionic liquids affected the kinetics of phase are given in Fig. S1 of the ESI.† The water contents of
the reaction differently. [Bn-DBU][TFA], as the better ionic catalyst, [Bn-DBU][TFA] and [Bn-DBU][OAc] were measured by Karl Fischer
can be easily separated from the reaction mixtures and can be titration to be 11.13% and 1.10%, respectively.
reused several times without significant decrease in its catalytic
activity. Overall, a catalyst ion (like TFA) should have a weak ionic
bond with its counter ion in an IL to assemble a low-energy TS
with the substrates. TFA in addition to possessing this character is
a carboxylate ion with the ability to mediate a proton transfer by
the aid of its p-system in a rate determining TS of the reaction.
We anticipate that these facts will help chemists to organize the
design of ILs and redirect the current efforts on unsystematic
functionalization and use of ILs as simple bases or acids.
Spectroscopic characterization of the ILs
1
For the FT-IR and H NMR spectra of the synthesized ILs see
Fig. S2 and S3 in the ESI.†
1
Selected data for [Bn-DBU][OAc]. Pale yellow oil; H NMR
(
D
2
O, 400.13 MHz) d
t, J 7.2 Hz, Ar–H), 7.17 (2H, d, J 7.2 Hz, Ar–H), 4.50 (2H, br s,
CH ), 3.55 (2H, br s, CH ), 3.47–3.39 (4H, m, 2 CH ), 2.71–2.69
2H, m, CH ), 2.01–1.99 (2H, m, CH ), 1.87 (3H, br s, CH ), 1.60
4H, br s, 2 CH ), 1.44 (2H, br s, CH
861, 1645, 1620, 1527, 1496, 1325.
H
7.35 (2H, t, J 7.2 Hz, Ar–H), 7.29 (1H,
2
2
2
(
(
2
2
2
3
ꢀ
1
2
2
); FT-IR (KBr, cm ): 2935,
Experimental
Materials and methods
1
Selected data for [Bn-DBU][TFA]. Pale yellow oil; H NMR
(
D O, 500 MHz) d 7.45 (2H, t, J 7.3 Hz, Ar–H), 7.39 (1H, t,
2 H
All the chemicals were purchased from Merck or Aldrich J 7.1 Hz, Ar–H), 7.27 (2H, d, J 7.3 Hz, Ar–H), 4.45 (2H, br s, CH
2
),
);
chemical companies. The products were identified by compar- 3.57–3.48 (6H, m, 3 CH
2
), 2.82–2.80 (2H, m, CH
2
), 2.11–2.08
ison of their melting points and spectral data with those of the (2H, m, CH ), 1.70 (4H, br s, 2 CH
2
2
), 1.53 (2H, br s, CH
2
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ꢀ
1
0
FT-IR (KBr, cm ): 3126, 3058, 2936, 1710, 1647, 1598, 1447, 14 F. Al -Assar, K. N. Zelenin, E. E. Lesiovskaya, I. P. Bezhan
1
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General procedure for the synthesis of 1H-pyrazolo[1,2-b]-
phthalazine-5,10-diones
To a mixture of an aromatic aldehyde (1 mmol), malononitrile
(1 mmol, 0.066 g) or ethyl cyanoacetate (1 mmol, 0.113 g), and
phthalhydrazide (1 mmol, 0.162 g) was added the Bn-DBU-
based ionic liquid (0.28 mmol, 0.085 g of [Bn-DBU][OAc] or
0
.10 g of [Bn-DBU][TFA]). The mixture was stirred at 100 1C and
progress of the reaction was monitored by TLC using n-hexane
and ethyl acetate (in the ratio of 2 : 1) as an eluent. After
completion of the reaction, according to the times specified
in Table 1, the mixture was cooled at room temperature and to
this, while stirring, was added distilled water (6 mL). The solid
crude product, which precipitated at this end, was separated
by decantation of the supernatant aqueous solution and then
recrystallized from hot ethanol (95%). The aqueous solutions of
several experiments were combined and evaporated at 60 1C
under vacuum. The dried IL was collected and stored until
reuse in the next cycle of the same synthesis.
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Conflicts of interest
There are no conflicts of interest to declare.
Acknowledgements
The authors are grateful to the Research Council of University
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