A Sulfone-Containing Imidazolium-Based Br?nsted Acid Ionic Liquid Catalyst Enables Replacing Dipolar Aprotic Solvents with Butyl Acetate

Article abstract of DOI:10.1002/adsc.201900246

Replacing dipolar and aprotic solvents with environmentally benign media has emerged as a new facet of green chemistry. In this paper, a sulfone-containing imidazolium-based Br?nsted acid ionic liquid was prepared and used as a recyclable acid catalyst. The ionic liquid catalyst enables the use of an industrially acceptable and environmentally benign solvent, butyl acetate, as the reaction medium. The ionic liquid/butyl acetate biphasic system was successfully utilized in many organic reactions, which generally relied heavily on dipolar and aprotic solvents. (Figure presented.).

Full text of DOI:10.1002/adsc.201900246

Title: A Sulfone-Containing Imidazolium-Based Brønsted Acid Ionic
Liquid Catalyst Enables Replacing Dipolar Aprotic Solvents with
Butyl Acetate
Authors: Ahmed El-Harairy, Yiliqi -, Bingbing Lai, Luigi Vaccaro,
Minghao Li, and Yanlong Gu
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900246
Link to VoR: http://dx.doi.org/10.1002/adsc.201900246

10.1002/adsc.201900246
Advanced Synthesis & Catalysis
Very Important Publication
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
A Sulfone-Containing Imidazolium-Based Brønsted Acid Ionic
Liquid Catalyst Enables Replacing Dipolar Aprotic Solvents
with Butyl Acetate
Ahmed El-Harairy,a Yiliqi,a Bingbing Lai,a Luigi Vaccaro,b Minghao Li,*a and Yanlong
Gu*a,c.
a
Key laboratory of Material Chemistry for Energy Conversion and Storage, Ministry of Education, Hubei Key
Laboratory of Material Chemistry and Service Failure, School of Chemistry and Chemical Engineering Huazhong
University of Science and Technology, 1037 Luoyu road, Hongshan District, Wuhan 430074, China.
E-mail: liminghaochem@hust.edu.cn, klgyl@hust.edu.cn
b
Laboratory of Green Synthetic Organic Chemistry – Dipartimento di Chimica, Biologia e Biotecnologie, Università di
Perugia Via Elce di Sotto, 8 - 06123 Perugia, Italy.
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Lanzhou,
c
730000, China.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: Replacing dipolar and aprotic solvents with environmentally benign media has emerged as a new facet of green
chemistry. In this paper, a sulfone-containing imidazolium-based Brønsted acid ionic liquid was prepared and used as a
recyclable acid catalyst. The ionic liquid catalyst enables the use of an industrially acceptable and environmentally benign
solvent, butyl acetate, as the reaction medium. The ionic liquid/butyl acetate biphasic system was successfully utilized in
many organic reactions, which generally relied heavily on dipolar and aprotic solvents.
Keywords: Brønsted acid; Ionic liquid; Biphasic reaction; Dipolar aprotic solvent; Green solvent
Introduction
ionic liquid as a solvent (or component) to replace
nitromethane, which is an explosive polar solvent.[5]
Some interesting options have been found in the
world of bio-based chemicals and in fact, cyrene ((–)-
dihydrolevoglucosenone),[6] N-butylpyrrolidinone,[7]
A crucial problem in modern organic chemistry is the
large use of toxic, hazardous, and flammable solvents
both as reaction media and for the isolation and
purification steps of the desired products.[1] Among
the plethora of chemicals used as solvents, dipolar
aprotic media such as dimethylformamide (DMF), N-
methyl pyrrolidone (NMP), and nitromethane, are
commonly used in several useful organic
transformations.[2] In fact, these solvents are able to
create a unique solvation environment that can
stabilize or destabilize reaction intermediates, thus
facilitating the control of both reaction rate and
selectivity. However, most of these solvents are toxic.
For example, DMF is teratogenic, and 1,4-dioxane is
carcinogenic. Some of them are very difficult to
recycle due to their high boiling points and
γ-valerolactone,[8]
2-methyltetrahydrofuran
(2-
MeTHF)[9] have been proposed obtaining relevant
results. Other possibilities have been envisaged in the
use of solvent-pair mixtures composed of hydrogen
bond donor/acceptor (HBD−HBA)[10] couples that
have been proposed again to replace polar aprotic
solvents. An alternative approach has been suggested
by Lipshutz who proposed the use of water as the
solvent in a combination of TPGS-750-M, bio-based
nonionic surfactant,[11] showing that with the
constructed micellar system, some organic reactions
no longer need the use of dipolar aprotic media.
Despite the achievements gained by the
aforementioned methods, it is still very challenging
the individuation of generally efficient media to
replace dipolar aprotic solvents. For instance, in
many acid-catalyzed reactions, classic dipolar aprotic
media can be hardly replaced in the efficient
hydrophilicity. For these reasons, in all the solvent
selection guides[3,
most of the dipolar aprotic
4]
solvents are classified as not-recommended-solvents,
and one of the main goals of current research in green
chemistry is to replace them with green,
environmentally friendly alternatives.[4]
stabilization
of
the
generated
carbocation
In recent years, several efforts have been made to
find chemical efficiency and safer alternatives to
classic dipolar aprotic solvents. In 2011, we proposed
the use of a NO2-functionalized imidazolium-based
intermediate, and chemical stability of bio-based
solvents toward acids is generally limited. To solve
this problem, Xiao and Sun have recently used a
mesoporous material that has a high density of polar
1
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10.1002/adsc.201900246
Advanced Synthesis & Catalysis
moieties as support to anchor sulfonic acid.[12] The
solvation environment in the inside pore of this
material to some extent may be similar to that of
DMSO, enabling the synthesis of 5-hydroxyfurfural
from glucose, which is a typical solvent-dependent
reaction, to be performed in tetrahydrofuran.
Results and Discussion
The ionic liquid 1a was synthesized using a three-
step procedure as shown in Scheme 1. It involved (i)
the heating equimolar amounts of 1-(3-
aminopropanyl)imidazole and divinylsulfone in
methanol at 60 °C for 24 h that after removal of
volatile methanol, allowed 2a to be obtained in nearly
quantitative yield; (ii) the synthesis of 3a via
quaternization of 2a with 1,3-propanesulfonateto give
3a as a white solid (see Scheme 1) after filtration and
washing with acetone; and (iii) acidification of 3a
with triflic acid to finally give 1a as a yellow-pale
viscous liquid. Using this three-step synthetic strategy,
ionic liquid 1a was synthesized in an overall 88%
yield.
It is noteworthy that ionic liquid 1a is immiscible
with many organic solvents, including butyl acetate,
1,2-dichloroethane, and toluene. Importantly, these
solvents are not able to extract triflic acid from 1a.
Therefore, this tailor-made ionic liquid should bring
all the features to be a recyclable catalyst when used
in an organic solvent.
This work demonstrated explicitly that by means of
catalyst design, it is possible to avoid the use of toxic
polar aprotic solvents. Inspired by this elegant
approach, and in order for the catalyst to significantly
affect the reaction in a concerted solvation
environment, we envisioned that a strongly polar
liquid should be an ideal choice for the catalyst
support. With proper liquid support, the catalyst can
be designed to be insoluble in the reaction system,
while being sufficiently able to stabilize the
carbocation intermediate, therefore, allowing to
perform
a
reaction in an industrially and
environmentally acceptable solvent as an ester
(Figure 1).
We previously reported that a sulfone-containing
Brønsted acid ionic liquid, can act as a unique
solvent-conserving catalyst, allowing acid-catalyzed
reactions to be performed under solvent-free
conditions (Figure 1).[13] The ionic liquid was poorly
soluble in the organic phase (Table S1 in supporting
information) while the presence of the highly polar
sulfone fragment was able to create a unique dipolar
aprotic microenvironment, allowing the reaction to
proceed smoothly and efficiently. However, a major
drawback is that this ionic liquid is highly viscous,
and could only be efficiently utilized in a few
reactions until now.[13] In addition, the triflic acid
component is not always steadily combined with the
zwitterionic salt. And in the presence of an organic
solvent able to dissolve triflic acid, the acidic
component can thus be extracted, hampering the
recyclability of the ionic liquid.
Scheme 1. Preparation of ionic liquid 1a.
The catalytic activity of ionic liquid 1a was
examined in a representative reaction of 4-
chloroaniline (4a) and ethyl pyruvate (5a) to
synthesize the corresponding 1,2-dihydroquinoline 6a.
This is a typical acid-catalyzed reaction, and previous
[14]
[15]
studies have indicated that iodine,
MgBr2,
AuCl3,[16] (p-BrC6H4)3N˙SbCl6,[17] Bi(OTf)3,[18] and
[19]
In(OTf)3
are effective catalysts for this process.
However, most of the reported catalytic systems
required the use of toxic solvents, such as acetonitrile
and 1,2-dichloroethane and could not be recycled
after the first reaction.
Our preliminary results are listed in Table 1. In
classic solvents, such as acetonitrile, 1,2-
dichloroethane, and 1,4-dioxane, common triflic acid
worked well, promoting the formation of 6a in 55%-
75% yields (entries 1–3). In an alternative to these
toxic solvents, butyl acetate was also considered as a
representative recommended greener solvent.[3]
Unfortunately, performing the reaction with triflic
acid in this medium, 6a was obtained in only 44%
yield (entry 4).
Most importantly, when ionic liquid 1a was used
as a catalyst, the reaction proceeded very well in
butyl acetate, and the yield of 6a reached the highest
value of 96% (entry 5). As the ionic liquid catalyst is
insoluble in butyl acetate, the reaction proceeded
Figure 1. Our previous ionic liquid and a biphasic system
and our new ionic liquid 1a.
To solve all these issues, we designed a new
imidazolium-based sulfone-containing Brønsted acid
ionic liquid, 1a (Figure 1). This compound can be
used as an acid catalyst in many organic reactions in
combination with butyl acetate as a reaction medium.
Intriguingly, without this ionic liquid, the reactions
generally require the use of toxic and hazardous
dipolar aprotic solvents to proceed efficiently.
2
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10.1002/adsc.201900246
Advanced Synthesis & Catalysis
under practically biphasic conditions (see the
photograph in Table 1). However, a similar biphasic
system composed of butyl acetate and Forbes’s ionic
liquid, 1b, was proven to be only moderately
effective for the synthesis of 6a (entry 6). It is worth
mentioning that the acid strength of 1a and 1b were
(entries 10 and 11). Moreover, increasing the amount
of catalyst generally led to improving the conversion
of 4a, but using more than 10 mol% of 1a had no
positive effect on the yield of 6a (entries 12 and 13).
It is worth noting that the reaction can also be
effectively scaled up with similar efficiency and in a
scrutinized by Hammett method.[20a,b] No significant representative 10-mmol-scale process, 6a could be
difference on their acid strength is observed obtained in 95% yield (3.1 g, entry 5).
(Scheme S1 and table S1), which rules out the
One of the main goals to achieve when using an
effect of acid strength on the catalytic activity.[20c] ionic liquid as a catalyst is to test and optimize its
Replacing ionic liquid 1b by 1c slightly increased the
reaction yield, and 6a could be only obtained in 76%
yield under identical conditions (entry 7).
recycling and reuse. The synthesis of 6a was
consecutively carried out for representative four runs
with only a slight decrease in the isolated yields
(Table 1, entry 14). On the contrary, ionic liquid 1c
could not be satisfactorily recovered due to the partial
leaching of triflic acid (entry 7). This result proved
that a tailored design of the ionic liquid is necessary
to perfectly combine all the features of the process
and access a process efficiently from chemical, safety,
and environmental point of views.
In the absence of butyl acetate, the reaction with
catalyst 1a hardly proceeded, and 6a could be
prepared in only 24% yield after 3 h under solvent-
free conditions (entry 8). 1,2-Dichloroethane was also
proven to be a suitable solvent with exploiting the
catalytic efficiency of 1a in the conversion of 4a and
5a to 6a (entry 9). For evident safety and
environmental reasons, further investigation on the
process and on the efficiency of 1a was continued
using butyl acetate. Temperature and time of the
reaction influenced the process significantly and the
optimal conditions were found to be 90 °C and 3 h
When an ionic liquid is used as a reaction medium
or catalyst, the use of a traditional (volatile) organic
solvent is generally necessary to extract the product
from the ionic liquid. In many cases, ethyl acetate is
utilized. However, owing to the high volatility, it is
not easy to fully recover the ethyl acetate solvent.
The insufficient recovery of ethyl acetate not only
increased the cost of synthesis but also generated
environmental problems, such as Volatile organic
Table 1. Reaction of 4a and 5a under different
conditions.[a]
compounds
(VOC)
emissions
and
water
contaminations. Considering the fact that the polarity
of butyl acetate is very close to that of ethyl acetate,
we tried to use butyl acetate as a dual reaction
medium/extracting solvent in the reaction of 4a and
5a. Thus, 4a (1.28 g, 10 mmol) and 5a (2.32 g, 20
mmol) was mixed with 1a (0.64 g, 1 mmol) in butyl
acetate (15 mL). The mixture was heated at 80 °C for
3 h. Then, it was cooled to room temperature. The
organic phase was decanted out. The ionic liquid
phase was extracted by butyl acetate (5 mL × 3). The
organic phase was combined together and dried over
anhydrous Na2SO4, and then subjected to
concentration in a rotary evaporator equipped with a
circulating water vacuum pump. The residue was
subjected to isolation with silica column
chromatography. Our attention was paid not only to
the synthesis efficiency of 6a but also the recovery of
the solvent. As shown in Table 2, after 3 h of
reaction at 80°C, the expected product 6a was
isolated in 93% yield. And the solvent, butyl acetate,
can be recovered in the rotary evaporator in 94% of
recovery ratio. We also used ethyl acetate as the
solvent for synthesizing 6a. However, the yield of 6a
reached only 83% under identical conditions,
partially due to the low boiling point of ethyl acetate
(77 °C). By increasing the reaction time to 5 h, the
yield of 6a can be increased to 89%. But, a part of
ethyl acetate solvent was lost during the reaction,
extraction, and concentration. The recovery ratio of
ethyl acetate solvent reached only about 70%.
Therefore, butyl acetate is an appropriate solvent to
cooperate with the ionic liquid 1a. In the 1a/butyl
Yield
(%)
75
55
57
44
96 (95[b])
46
Entry
Solvent
Catalyst
1
2
3
4
5
6
7
8
Acetonitrile
1,2-Dichloroethane
1,4-Dioxane
Butyl acetate
Butyl acetate
Butyl acetate
Butyl acetate
—
1,2-Dichloroethane
Butyl acetate
Butyl acetate
Butyl acetate
Butyl acetate
Butyl acetate
Triflic acid
Triflic acid
Triflic acid
Triflic acid
1a
1b
1c
1a
76 (41[c])
24
9
1a
1a
1a
94
10
11
12
13
71[d]
85[e]
72
1a (5 mol%)
1a (15 mol%)
1a
96
93[f]
14
[a]
Reaction conditions: 4a, 0.3 mmol; 5a, 0.6 mmol, catalyst,
0.03 mmol; solvent, 0.5 mL, 80 °C, 3 h.
[b] 10.0 mmol scale reaction.
[c] Result obtained with recovered 1c after the first run.
[d] Reaction performed at 60 °C.
[e] After 2 h of reaction time.
[f] Yield obtained with recovered 1a after the fifth run. The results
obtained with recovered 1a in the 2nd, 3rd, and 4th runs are
96%, 94%, and 94%, respectively.
3
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10.1002/adsc.201900246
Advanced Synthesis & Catalysis
Table 2. Comparison of butyl acetate and ethyl acetate for the synthesis of 6a.
Solvent
Temp. (°C)
80
Reflux
Reflux
Reaction time (h)
Yield (%)
Recovery of solvent
Butyl acetate
Ethyl acetate
Ethyl acetate
3
3
5
93
83
89
94%
71%
70%
trimethylaniline (4l) and 3,4,5-trimethoxyaniline
(4m), also readily reacted, generating the
corresponding products, 6l and 6m, in 86% and 83%
yields, respectively. 1-Aminonaphthalene (4p)
smoothly reacted with 5a, producing 6p in 93% yield.
Catalyst 1a in combination with butyl acetate
allowed also the reaction of indoline (4q) with ethyl
pyruvate (5a), and the resulting tricyclic compound
of 6v was obtained in 78% yield (Scheme 3).
Figure 2. Schematic illustration of recycling 1a and butyl
acetate (BA) in the synthesis of 6a.
acetate system, the catalyst and the solvent can all be
sufficiently recycled (Figure 2), strengthening thus
the greenness of the synthetic methodology.
Scheme 3. Reaction of 4q and 5a
.
Using the optimized conditions defined in Table 1
entry 5, we investigated the scope of the reaction
with respect to both the aniline and the pyruvate
components. As evidenced by the results in Scheme
2, anilines with different substituents smoothly
reacted with 5a, producing the corresponding
dihydroquinoline products 6a–p with generally good
yields. Both electron-rich (6c–e, 6n, and 6o) and
electron-poor (6i–k) anilines readily reacted. Ester,
ether, and cyano groups were all tolerated leading the
corresponding products with very satisfactory yields
and with no detectable formation of decomposition
products (6d–e and 6i–j). Anilines containing
sterically demanding substituents, such as 3,4,5-
The scope of the reaction with respect to alkyl
pyruvate was also investigated. The reaction of
methyl pyruvate (5b) confirmed those of ethyl
pyruvate allowing the preparation of products 6q–s in
excellent yields ranging from 92 to 94% (Scheme 4).
trans-3-Hexenyl pyruvate (5c) also smoothly reacted
with p-toluidine in butyl acetate using 1a as a catalyst,
and the trans-C–C double bond was successfully
retained in the isolated product 6t. While in the
literature the synthesis of 1,2-dihydroquinolines 6 is
readily accomplished with anilines and alkyl
pyruvates, the use of α-substituted pyruvates is very
rare and, and until now, only In(OTf)3 has proven to
be capable of catalyzing such a reaction.[19] We found
that our biphasic system is also applicable in the
reaction of p-toluidine (4c) and ethyl 2-oxohexanoate
Scheme 4. Scope of substrate with respect to
pyruvates.
Scheme 2. Scope of substrate with respect to aromatic
amines.
4
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10.1002/adsc.201900246
Advanced Synthesis & Catalysis
(5d). After 7 h of reaction, the expected product 6u
could be isolated in 91% yield. Obviously, the ionic
liquid 1a/butyl acetate system is applicable in the
reactions of structurally distinct anilines 4a–p and
pyruvates 5a–d with steric bulky and various
electronic properties, which provide an efficient and
a practical protocol for synthesizing richly decorated
1,2-dihydroquinolines 6a–u.
Table 3. Condensation of 7a and p-anisidine 4d [a]
.
Entry
Catalyst
Yield (%)
95 (94[e])
42
The 1a/butyl acetate system was also used in a
reaction of 2-acetylbenzoic acid 7a and p-
anisidine 4d, that can hopefully give a 3-
1
2
3
4
5
6
7
8
9
1a
Triflic acid
methyleneisoindolin-1-one derivative 8a
.
3-
PTSA
—
65
Methyleneisoindolin-1-one a subunit found in a
variety of natural and biologically active
14
magallanesine,[21]
1a
15[b]
molecules,
such
as
fumaridine,[22] and narceine imide.[23] Many
methods have been developed for their synthesis,
such as dehydration of 3-hydroxyisoindolin-1-
1b
55
1c
72
ones,[24]
substituted
cycloisomerization
of
2-alkynyl
Pd-catalysed
1a
33[c]
45[d]
benzamides,[25]
1a
carbonylation-hydroamination reaction of 1-halo-
2-alkynylbenzene with amines,[26] domino
Heck−Suzuki−Miyaura reactions of ynamides
[a] Reaction conditions: 7a, 0.3 mmol; 4d, 0.3 mmol, catalyst,
0.03 mmol, 100 °C, 8 h.
[b] Solvent-free conditions.
and
boronic
acids,[27]
Rh(III)-catalysed
[c] 1,4-Dioxane as solvent.
amidation/annulation of aryl ketone oximes with
isocyanates,[28] and Cu-promoted coupling of
benzamides with nitroalkanes.[29] A Pd-catalysed
C–H functionalization approach was also
developed by using carboxamides and carboxylic
acids or anhydrides as substrates.[30] From the
viewpoint of precursor availability and simplicity
of operation, direct condensation of 2-
acetylbenzoic acids with amines is probably one
of the most attractive ways to synthesize 3-
methyleneisoindolin-1-ones. However, until now,
only the reactions with aliphatic amine were
successful.[31] When aromatic amines were used,
the reactions had to be performed in toxic organic
solvents, such as o-dichlorobenzene, at high
temperature (180 °C).[32] Nevertheless, the
reactions generally gave low yield.[33]
[d] Toluene as solvent.
[e] Recovered 1a was used as catalyst.
can effectively catalyze the reaction, and 8a can
be isolated in 94% yield (entry 1).
Upon repeating the reaction with 7a in the 1a/butyl
acetate system, anilines with different functional
groups on the arene ring all work well under the
standard conditions, efficiently offering the
corresponding 3-methyleneisoindolin-1-ones 8b–q
with yields ranging from 70% to 97% (Scheme 5). A
variety of functional groups, such as methoxy (8a,
8l), phenoxyl (8e), cyano (8i), ethoxycarboxyl (8k),
fluoro (8f), chloro (8g), bromo (8h), and iodo (8j),
can tolerate the acidic conditions well. It should be
noted that the reaction efficiency was not
significantly affected when electron-deficient anilines
We found that 1a can effectively catalyze the
condensation of 7a and 4d in butyl acetate at
100 °C, giving 8a in 95% yield after 8 h of
reaction (Table 3, entry 1). Replacing 1a with
triflic acid or PTSA resulted in a dramatic yield
decrease, and 8a was obtained in 42–65% yield
(entries 2 and 3). In the absence of the catalyst,
the reaction proceeded sluggishly, and the yield
of 8a reached only 14% (entry 4). The solvent,
butyl acetate, is necessary, as the reaction under
solvent-free conditions is not successful (entry 5).
Ionic liquids 1b and 1c displayed mild catalytic
activities under identical conditions, and 8a can
be isolated in moderate yield (entries 6 and 7).
Other organic solvents, such as 1,4-dioxane and
toluene, were also used as the reaction media
instead of butyl acetate. However, the reaction
proceeded slowly in these solvents, and 8a was
obtained in 33–45% yield (entries 8 and 9). In
this reaction, 1a can also be recovered and reused.
And in the second run, the recovered ionic liquid
Scheme 5. Reactions of 7a with different aromatic amines.
5
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10.1002/adsc.201900246
Advanced Synthesis & Catalysis
at 100 °C for 24 h. The generated ionic liquid was washed
with ethyl acetate (5.0 ml × 3) and diethyl ether (5.0 ml ×
3); then, water and volatile solvents were removed under
reduced pressure; finally, 1a was obtained as a yellow-pale
viscous liquid. Through all these three-step reactions, the
ionic liquid 1a can be synthesized in 88% yield.
were used as substrates (8i, 8k). Heterocycle-anilines,
such
as
3,4-(methylenedioxy)aniline,
3-
dibenzofuranamine, and 4-morpholinoaniline can
also be smoothly converted without affecting the
stability of these moieties (8o−q). We thus developed
an
effective
way
for
synthesizing
3-
A
typical procedure for synthesis of 1,2-
methyleneisoindolin-1-one derivatives from 7a and
aromatic amines. This reaction demonstrated also that
combination of 1a and butyl acetate is indeed useful
for organic synthesis.
dihydroquinolines
All reactions were carried out in a 10 mL of V-type flask
equipped with triangle magnetic stirring. In a typical
reaction, 1a (19.1 mg, 0.03 mmol) was mixed with 4-
chloroaniline 4a (38.3 mg, 0.3 mmol) and ethyl pyruvate
5a (69.7 mg, 0.6 mmol) in 0.5 mL of butyl acetate. The
mixture was stirred for 3 h at 80 °C. After the completion
of the reaction, the mixture was cooled to room
temperature. The butyl acetate was decanted out. The ionic
liquid phase was extracted with butyl acetate (0.5 mL × 3).
The organic phase was combined and then subjected to
isolation with preparative TLC (eluting solution:
petroleum ether/ ethyl acetate = 10/1v/v). The desired
product 6a was obtained in 96 % of yield. Tests for
substrate scope were performed according to an analogous
procedure. The large scale synthesis of 6a was performed
in a round-bottom flask equipped with an egg-shaped
magnetic stirring bar. 1a (0.6 g, 1.0 mmol) was mixed with
4-chloroaniline 4a (1.3 g, 10.0 mmol) and ethyl pyruvate
5a (2.3 g, 20.0 mmol) in 30 mL of butyl acetate. The
mixture was stirred for 4 h at 80 °C. After the completion
of the reaction, the mixture was cooled to room
temperature. The butyl acetate was collected and the ionic
liquid phase was extracted with butyl acetate (20.0 mL ×
3). The organic phase was combined and evaporated. The
residual mixture was submitted to silica column
chromatography (eluting solution: petroleum ether/ ethyl
acetate = 20/1v/v). After purification, 3.1 gram (95% yiled)
of 6a was obtained. The recovered ionic liquid was treated
at 100 °C under vacuum (10 mmHg) for 30 minutes and
then used in the next run.
Conclusion
A
sulfone-containing
imidazolium-based
Brønsted acid ionic liquid 1a was prepared. By
using this ionic liquid as an acid catalyst, the use
of toxic and hazardous dipolar aprotic solvents
was avoided. The reactions can be performed in
an environmentally benign solvent, butyl acetate,
and the ionic liquid is also recyclable. The
combined use of 1a as a catalyst and butyl acetate
as a solvent offers a possible means for chemists
to minimize the utilization of toxic and hazardous
dipolar aprotic solvents in acid-catalyzed
reactions. Designing a catalyst that enables the
replacement of a less-green solvent with a green
one is a promising direction of catalysis research,
and this work can hopefully trigger the
enthusiasm of researchers to develop more
efficient catalytic systems.
A typical procedure for reaction of 2-acetylbenzoic acid
and p-anisidine
Experimental Section
All reactions were carried out in a 10 mL of V-type flask
equipped with triangle magnetic stirring. In a typical
reaction, 1a (19.1 mg, 0.03 mmol) was mixed with 2-
acetylbenzoic (49.2 mg, 0.3 mmol) and p-anisidine (36.9
mg, 0.3 mmol) in 0.5 mL of butyl acetate. The mixture was
stirred for 8 h at 100 °C. After the completion of the
reaction, the mixture was cooled to room temperature. The
butyl acetate was decanted out. The ionic liquid phase was
extracted with butyl acetate (0.5 mL × 3). The organic
phase was combined and then subjected to isolation with
preparative TLC (eluting solution: petroleum ether/ ethyl
acetate = 10/1v/v). The desired product 8a was obtained in
95 % of yield. Tests for substrate scope were performed
according to an analogous procedure.
All reactions were determined by microscopic melting
1
point meter (Yu Hua Instrument, X–4). H, 13C, and 19F
NMR spectra were recorded on a Bruker AV-400 (400
MHz 1H, 100 MHz 13C, 375 MHz 19F) at room
temperature. Fourier transform infrared (FT-IR) spectra
were recorded on a FT-IR Bruker (VERTEX 70) using
liquid film technology. High-resolution mass spectra
(HRMS) was recorded on a Bruker micrOTOF-Q II
instrument. Ionic liquid 1b and 1c were prepared according
to literature’s methods with slight modification.[13, 34]
Synthesis of ionic liquid 1a
Brønsted acid ionic liquid 1a was synthesized through the
following three steps: (i) synthesis of 2a: in 100 ml of
around bottomed flask equipped with mechanical stirring,
equal amount of divinyl sulfone 2a (5.0 g, 42.3 mmol) was
mixed with 1-(3-aminopropanyl)imidazole (5.2 g, 42.3
mmol) in 75 ml of methanol; the mixture was stirred at 60
°C for 24 h; then, volatile methanol was removed by a
rotary evaporator; a yellow-pale oil was obtained, which is
2a, in nearly quantitative yield. (ii) synthesis of 3a via
quaternization: 2a (10.0 g, 41.1 mmol), 1,3-
propanesulfonate (11.0 g, 90.4 mmol), and acetonitrile (75
ml) were mixed in a 250 ml of around bottomed flask
equipped with mechanical stirring; the mixture was stirred
at 80 °C for 24 h; a yellow solid was generated; then the
solvent was decanted out; the yellow solid was filtrated,
and washed with acetone (5.0 ml × 3); 3a can be obtained
as white solid; then, the white solid was dried at 60 °C
under vacuum (20 mmHg) for 4 h; and (iii) acidification:
3a (10.0 g, 20.5 mmol) was mixed with triflic acid (3.1 g,
20.5 mmol) in 25 mL of around bottomed flask; to
facilitate the reaction, a small amount of water (0.25 ml)
was also added in this step. Then, the mixture was stirred
Spectroscopic data of ionic liquid and selected products
4-(3-(1H-Imidazol-1-yl) propyl)thiomorpholine 1, 1-
1
dioxide (2a): 10.2 gram, 99% yield, a yellow-pale oil, H
NMR (400 MHz, D2O, 25 °C, TMS) δ = 7.56 (s, 1H), 7.05
(s, 1H), 6.91 (s, 1H), 3.96 – 3.75 (m, 2H), 3.41 – 3.23 (m,
2H), 3.10 (s, 3H), 2.91 (s, 3H), 2.38 (t, J = 8.0 Hz, 2H),
1.90 – 1.80 ppm (m, 2H); 13C NMR (100 MHz, D2O, 25
°C) δ = 140.5, 130.3, 122.6, 54.7, 52.4, 52.1, 47.6, 47.2,
32.4, 29.7 ppm. . IR (cm-1): 3111, 2934, 2827, 1663, 1509,
1451, 1297, 1231, 1190, 1124, 1080, 1042, 910, 855, 751,
667, 667, 525, 436. HRMS-ESI (m/z) calcd for
C10H18N3O2S, [M + H]+ 244.1120, found 244.1154.
3-(1,1-Dioxido-4-(3-(3-(3-sulfonatopropyl)-1H-
imidazol-3-ium-1-yl)propyl)
thiomorpholino-4-ium)
propane-1-sulfonate (3a): 18.0 gram, 90% yield, a white
1
solid; H NMR (400 MHz, D2O, 25 °C, TMS) δ = 8.86 –
8.80 (m, 1H), 7.56 – 7.49 (m, 2H), 4.32–4.06 (m, 6H), 3.82
– 3.53 (m, 4H), 3.28 – 3.19 (m, 5H), 2.96 – 2.70 (m, 5H),
2.41 – 2.09 ppm (m, 6H); 13C NMR (100 MHz, D2O, 25
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900246
Advanced Synthesis & Catalysis
°C) δ = 136.1, 135.7, 123.1, 122.9, 122.6, 122.4, 57.9,
52.0, 50.1, 49.2, 48.1, 47.9, 47.3, 47.1, 46.6, 45.8, 45.1,
25.9, 25.1, 22.4, 17.5 ppm. IR (cm-1): 3109, 2933, 1638,
1567, 1320, 1194, 1043, 950, 920, 848, 744, 609, 530, 439.
HRMS-ESI (m/z) calcd for C16H30N3O8S3, [M + H]+
488.1195, found 488.1180.
e) S. Doherty, J. G. Knight, T. Backhouse, E. Abood, H.
Alshaikh, A. R. Clemmet, J. R. Ellison, R. A. Bourne,
T. W. Chamberlain, R. Stones, N. J. Warren, I. J. S.
Fairlamb, K. R. J. Lovelockd, Adv. Synth. Catal. 2018,
360, 3716; f) A. Reina, I. Favier, C. Pradel, M.
Gomeza, Adv. Synth. Catal. 2018, 360, 3544; g) S. Mao,
X. Shi, J. -F. Soule, H. Douceta, Adv. Synth. Catal.
2018, 360, 3306; h) S. E. Hooshmand, B. Heidari, R.
Sedghi, R. S. Varma, Green Chem., 2019, 21, 381; i) M.
C. Bryan, P. J. Dunn, D. Entwistle, F. Gallou, S. G.
Koenig, J. D. Hayler, M. R. Hickey, S. Hughes, M. E.
Kopach, G. Moine, P. Richardson, F. Roschangar, A.
3-(1,1-Dioxido-4-(3-(3-(3-sulfopropyl)-1H-imidazol-3-
ium-1-yl)
propyl)thiomorpholino-4-ium)propane-1-
sulfonate trifluoromethanesulfonate (1a): 12.9 gram, 99%
1
yield, a yellow-pale viscous ionic liquid; H NMR (400
MHz, D2O, 25 °C, TMS) δ = 8.76 (d, J =10.4 Hz, 1H),
7.45 (t, J = 9.2 Hz, 2H), 4.23 – 3.99 (m, 6H), 3.78 –
3.46(m, 8H), 3.29 – 3.24(m, 2H), 3.04 – 2.76 (m, 2H), 2.33
– 1.81 ppm (m, 7H); 13C NMR (100 MHz, D2O, 25 °C) δ =
135.9, 122.9, 122.5, 57.9, 53.2, 51.0, 48.1, 47.7, 47.3, 46.6,
46.2, 45.8, 45.1, 25.0, 24.6, 22.4, 17.5 ppm. IR (cm-1):
3460, 3103, 2978, 2932, 1646, 1566, 1462, 1318, 1197,
1139, 1038, 950, 850, 729, 605, 529. HRMS-ESI (m/z)
calcd for C16H30N3O8S3, [M - CF3SO3] 488.1190, found
488.1180.
Steven, F. J. Weiberth, Green Chem., 2018, 20, 5082
.
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Diethyl
6-chloro-2-methyl-1,2-dihydroquinoline-2,4-
dicarboxylate (6a):[14] 93.2 mg, 96% yield, a yellow oil,
1H NMR (400 MHz, CDCl3, 25 °C, TMS) δ = 7.86 (d, J =
1.6 Hz, 1H), 6.94 (dd, J = 1.6, 8.4 Hz, 1H), 6.73 (s, 1H),
6.55 (d, J = 8.4 Hz, 1H), 4.56 (brs, 1H), 4.32 (q, J = 6.9
Hz, 2H), 4.25 – 4.12 (m, 2H), 1.54 (s, 3H), 1.37 (t, J = 7.2
Hz, 3H), 1.26 ppm (t, J = 7.2 Hz, 3H), 13C NMR (100
MHz, CDCl3, 25 °C) δ = 173.5, 165.2, 141.2, 133.9, 129.3,
127.4, 126.4, 123.3, 117.2, 115.2, 62.0, 61.2, 58.6, 27.3,
14.2, 14.1 ppm. HRMS-ESI (m/z) calcd for C16H19ClNO4,
[M + H] 324.1003, found 324.0091.
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Diethyl
4-methyl-1,2-dihydro-4H-pyrrolo[3,2,1-
ij]quinoline-4,6-dicarboxylate (6q):[35] 73.8 mg, 78%
1
yield, a yellow oil, H NMR (400 MHz, CDCl3, 25 °C,
TMS) δ = 7.58 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 7.2 Hz,
1H), 6.57 (t, J = 7.6 Hz, 1H), 6.41 (s, 1H), 4.31 (q, J = 7.2
Hz, 2H), 4.16 (q, J = 6.5 Hz, 2H), 3.64 – 3.52 (m, 2H),
3.14 – 2.99 (m, 2H), 1.63 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H),
1.22 ppm (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3,
25 °C) δ = 166.7, 160.8, 143.6, 128.6, 123.5, 121.6, 120.4,
118.8, 113.0, 108.0, 58.6, 56.7, 56.2, 42.8, 23.5, 17.9, 9.5,
9.4 ppm. HRMS-ESI (m/z) calcd for C18H22NO4, [M + H]
316.1549, found 316.1536.
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2-(4-Methoxyphenyl)-3-methyleneisoindolin-1-one (8a):
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L. Moity, C. R. McElroy, T. J. Farmer, T. Duncan,
W. Raverty, A, J, Hunt, J. H. Clark, Chem.
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1
71.6 mg, 95% yield, a gum-like yellow oil, H NMR (400
MHz, CDCl3, 25 °C, TMS) δ = 7.82 (d, J = 7.4 Hz, 1H),
7.66 (d, J = 7.6 Hz, 1H), 7.54 (t, J = 7.3 Hz, 1H), 7.46 (t, J
= 7.4 Hz, 1H), 7.20 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8
Hz, 2H), 5.12 (s, 1H), 4.66 (s, 1H), 3.76 ppm (s, 3H); 13C
NMR (100 MHz, CDCl3, 25 °C) δ = 166.9, 159.2, 143.6,
136.2, 132.2, 129.7, 129.3, 129.0, 127.1, 123.5, 120.1,
114.7, 90.3, 55.5 ppm. IR (cm-1): 3397, 3068, 3005, 2841,
1893, 1712, 1641, 1512, 1468, 1386, 1298, 1250, 1137,
1026. HRMS-ESI (m/z) calcd for C16H13NNaO2, [M +
Na]+ 274.0844, found 274.0841.
[7] J. Sherwood, H. L. Parker, K. Moonen, T. J.
Farmer, A. J. Hunt, Green Chem., 2016, 14, 3990.
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Vaccaro, Sci. Rep. 2018, 8, 10571; b) F. Ferlin, L.
Luciani, S. Santoro, A. Marrocchi, D. Lanari, A.
Bechtoldt, L. Ackermann, L. Vaccaro, Green Chem.,
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A. Marrocchi, D. Lanari, A. Bechtoldt, L.
Ackermann, L. Vaccaro, Green Chem., 2018, 20,
2888; d) F. Ferlin, S. Santoro, L. Ackermann, L.
Vaccaro, Green Chem., 2017, 19, 2510; e) S.
Santoro, F. Ferlin, L. Luciani, L. Ackermann, L.
Vaccaro, Green Chem., 2017, 19, 1601; f) G.
Strappaveccia, E. Ismalaj, C. Petrucci, D. Lanari, A.
Marrocchi, M. Drees, A. Facchetti, L. Vaccaro,
Green Chem., 2015, 17, 365; g) G. Strappaveccia, L.
Acknowledgements
The authors thank the National Natural Science Foundation of
China (2171101076 and 21872060) and the Fundamental
Research Funds for the Central Universities of China
(2016YXZD033) for the financial support. The Cooperative
Innovation Center of Hubei Province is also acknowledged.
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Advanced Synthesis & Catalysis
Green Chemistry
FULL PAPER
A Sulfone-Containing Imidazolium-Based
Brønsted Acid Ionic Liquid Catalyst Enables
Replacing Dipolar Aprotic Solvents with Butyl
Acetate
Adv. Synth. Catal. Year, Volume, Page – Page
Ahmed El-Harairy, Yiliqi, Bingbing Lai, Luigi
Vaccaro, Minghao Li,* and Yanlong Gu*
9
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