Novel Non-toxic and Non-hazardous Solvent Systems for the Chemistry of Indoles: Use of a Sulfone-containing Br?nsted Acid Ionic Liquid Catalyst in Butyl Acetate

Article abstract of DOI:10.1002/cctc.201900784

Dipolar and aprotic solvents are often required in acid-catalyzed reactions, however, many of them are listed in solvent selection guides as not-recommended due to their toxicity or explosivity. A catalytically functionalized ionic liquid, namely a sulfone-containing imidazolium-based Br?nsted acid ionic liquid, was synthesized. It alleviates the detrimental effect of classical dipolar aprotic solvents because this ionic liquid integrates the function of a dipolar aprotic solvent able to stabilize carbocation intermediates and the activating effect of a strong Br?nsted acid on electrophiles. The use of this tailor-made ionic liquid was exemplified in some transformation reactions of indoles, which proceeded with high yield and selectivity using a green and an industrially acceptable solvent, butyl acetate. The recyclability of the ionic liquid catalyst was also demonstrated.

Full text of DOI:10.1002/cctc.201900784

Accepted Article
Title: Novel non-toxic and non-hazardous solvent systems for the
chemistry of indoles: use of a sulfone-containing Brønsted acid
ionic liquid catalyst in butyl acetate
Authors: Ahmed El-Harairy, Yiliqi -, Meie Yue, Weigang Fan, Florence
Popowycz, Yves Queneau, Minghao Li, and Yanlong Gu
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10.1002/cctc.201900784
ChemCatChem
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Novel non-toxic and non-hazardous solvent systems for the chemistry of
indoles: use of a sulfone-containing Brønsted acid ionic liquid catalyst in
butyl acetate
Ahmed El-Harairy,[a] Yiliqi,[a] Meie Yue,[b] Weigang Fan,[d] Florence Popowycz,[d] Yves Queneau,*,[d]
Minghao Li,[a] and Yanlong Gu*[a, c]
Abstract: Dipolar and aprotic solvents are often required in acid-
catalyzed reactions, however, many of them are listed in solvent
selection guides as not-recommended due to their toxicity or
conjunction with dipolar aprotic solvents which stabilize the
carbocation intermediate.[5] However, acid-compatible solvents,
such as dichloromethane, nitromethane, and 1,4-dioxane, are
generally not recommended in all the solvent selection guides
due to their toxicity and hazardous property.[6] Therefore,
increasing the greenness of the indole-transformation methods
in the future will include efforts for finding safer solvent
systems.[7]
explosivity.
A catalytically functionalized ionic liquid, namely a
sulfone-containing imidazolium-based Brønsted acid ionic liquid, was
synthesized. It alleviates the detrimental effect of classical dipolar
aprotic solvents because this ionic liquid integrates the function of a
dipolar aprotic solvent able to stabilize carbocation intermediates
and the activating effect of a strong Brønsted acid on electrophiles.
The use of this tailor-made ionic liquid was exemplified in some
transformation reactions of indoles, which proceeded with high yield
and selectivity using a green and an industrially acceptable solvent,
butyl acetate. The recyclability of the ionic liquid catalyst was also
demonstrated.
In fact, several safer alternatives to classic dipolar aprotic
solvents have been reported recently. We proposed the use of a
NO2-functionalized imidazolium-based ionic liquid as a solvent
(or a solvent system component) to replace nitromethane, which
is an explosive dipolar and aprotic solvent.[8] Some interesting
options have also been found in the field of bio-based chemicals,
such
as
cyrene
((–)-dihydrolevoglucosenone),[9]
γ-valerolactone[11]
or
N-
2-
butylpyrrolidinone,[10]
Introduction
methyltetrahydrofuran (2-MeTHF).[12] Another alternative is the
use of solvent-pair mixtures composed of hydrogen bond
donor/acceptor (HBD−HBA) couples.[13] Recently, Lipshutz
proposed the use of water as a solvent in combination with
TPGS-750-M, a bio-based nonionic surfactant,[14] leading to a
micellar medium in which organic reactions proceed like in
dipolar aprotic media. However, most of the reported alternative
solvents are not compatible with acidic conditions. For example,
cyrene, an endocyclic acetal, tends to form a complex mixture of
products under acidic conditions.[9-g] Hydrolysis of 2-MeTHF may
also occur in the presence of acid,[15] hampering its use in acid-
catalyzed reaction.
The indole ring system, one of the most ubiquitous heterocycles
in nature, has become an important building block for designing
biologically active molecules and pharmaceutical agents.[1]
Therefore, the chemistry of indoles, covering synthesis and
downstream transformations of indoles, is an important field in
organic chemistry.[2] Indole can be considered as a π‐excessive
heterocycle having a characteristic enamine embedded in its
framework, making its C3 position strongly nucleophilic. This
enables indoles to readily participate in some Friedel–Crafts
type electrophilic substitutions, such as halogenations, Mannich
and Michael reactions.[3] Many variations of these reactions,
including multicomponent and domino reactions, have also been
developed.[4] Most of the Friedel–Crafts type reactions of indoles
involve the generation of carbocation intermediates. To facilitate
the progress of such reactions, acid catalysts are often used in
An alternative strategy has been developed based on the
rational design of a tailor-made catalyst which integrates not
only the function of dipolar aprotic solvent to stabilize reaction
intermediates, but also the activating effect of the acid toward
the substrate. In 2014, we reported
a sulfone-containing
Brønsted acid ionic liquid which is able to act as a unique
solvent-conserving catalyst, allowing acid-catalyzed reactions to
proceed under solvent-free conditions (Table 1, 1d).[16] The ionic
liquid was insoluble in the organic phase, while the high density
of polar functional groups created a unique dipolar aprotic
microenvironment, allowing the reaction to proceed smoothly
and efficiently. Quite recently, Xiao and Sun have used a
mesoporous material with a high density of polar moieties as a
support to anchor sulfonic acid.[17] The solvation environment in
the inside pores of this material may be similar to that of DMSO
to some extent, enabling the synthesis of 5-hydroxyfurfural from
glucose, which is a typical solvent-dependent reaction, to be
performed in tetrahydrofuran. These studies demonstrated
explicitly that, by means of wise catalyst design, it is possible to
avoid the use of toxic solvents including polar aprotic ones.
However, designing generally efficient media to replace dipolar
aprotic solvents remains very challenging.
[a]
Prof. Dr. Y. Gu, Dr. M. Li, A. El-Harairy, Yiliqi, 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, 430074, Wuhan, China.
E-mail: klgyl@hust.edu.cn (Y. Gu)
[b]
[c]
Dr. M. Yue, College of Chemistry and Molecular Engineering, Qingdao
University of Science and Technology, 266042, Qingdao, China.
Prof. Dr. Y. Gu, State Key Laboratory for Oxo Synthesis and Selective
Oxidation, Lanzhou Institute of Chemical Physics, Lanzhou, 730000,
China.
[d]
Prof. Dr. Y. Queneau, Dr. F. Popowycz, W. Fan, Institut de Chimie et
Biochimie Moléculaires et Supramoléculaires, Univ Lyon, CNRS,
Université Lyon 1, INSA Lyon, CPE Lyon, ICBMS, UMR 5246 ; Université
Claude Bernard, Bâtiment Lederer,
1
Rue Victor Grignard, 69622
France
Villeurbanne Cedex,
E-mail: yves.queneau@insa-lyon.fr (Y. Queneau)
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
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Brønsted acid ionic liquids have been widely used in organic
reactions as catalysts. However, in the most of the reported
reactions, the ionic liquids simply played the role of acid
catalysts just like an acidic resin,[18] and only little attention was
given to the use of Brønsted acid ionic liquids as dual catalysts
and alternative media to organic solvents.[19] In order to minimize
the use of dipolar and aprotic solvents in acid-catalyzed
reactions, in this work, we developed a new sulfone-containing
imidazolium-based Brønsted acid ionic liquid. Intriguingly, this
ionic liquid is insoluble in weakly polar solvents, allowing us to
use butyl acetate, a largely available and industrially acceptable
organic solvent, as the reaction medium. The established
catalytic system was proved to be very effective for some acid-
catalyzed transformations of indoles which normally require the
use of toxic and hazardous dipolar aprotic solvents.
Figure 1. Mixing 1d or 1c with butyl acetate (picture a for 1d; picture b for 1c.
Photos were taken after 5 minutes of shaking at room temperature).
The catalytic activity of 1e was examined in the three-
component reaction of 2-methylindole (2a), phenylglyoxal
monohydrate (3a), and sesamol (4a), which provides a C3
(indol-3-yl)-substituted benzofuran derivative 5a. Such an
assembly of a glyoxal hydrate with an activated phenol and
carbon- or nitrogen-based nucleophile is a typical acid-catalyzed
reaction.[21] However, this reaction is generally performed in toxic
solvents such as dichloromethane and DMF.[22] We found that,
by using 1c as catalyst and butyl acetate as the solvent, the
three-component reaction, although visibly under biphasic
conditions, proceeded very well in these conditions, producing
the benzofuran 5a in 97% yield (Table 1, entry 1). Under
solvent-free conditions, likely due to the poor mass transfer
efficiency resulting from the high viscosity of the ionic liquid, the
yield of 5a reached only 31% (entry 2). Replacing 1c with triflic
Results and Discussion
The ionic liquid 1c was synthesized using
a three-step
procedure as shown in Scheme 1, involving (i) heating
equimolar amounts of 1-(3-aminopropanyl)imidazole and
divinylsulfone in methanol at 60 °C for 24 h leading, after
removal of the volatile solvent, to the cyclic tertiary amine 1a in
nearly quantitative yield; (ii) double quaternization of 1a with 1,3-
propanesulfonate giving the imidazolium 1b as a white solid
after filtration and washing with acetone; and (iii) acidification of
1b with triflic acid to provide targeted compound 1c as a pale-
yellow viscous liquid, in 88% yield over the full three-step
synthetic sequence.
acid led to
a homogeneous system, but the yield was
significantly lower (22%, entry 3). This is quite reasonable
because the weakly polar butyl acetate solvent was reported to
be less appropriate for the homogeneous acid-catalyzed
reaction.[23] Ionic liquids 1d and Forbes’s ionic liquid 1e, although
both also are strong acids and immiscible with butyl acetate,
were found much less effective for the model reaction than 1c,
leading to the expected product 5a in 69% and 48% yield
respectively (entries 4 and 5). We also measured the acid
strength of 1c and 1e by the Hammett method using 4-
nitroaniline as an indicator. It was found that the acidities of
them are quite similar (See ESI, Table S1). This implies that the
acidity of the ionic liquid shouldn’t be a reason to explain the
good catalytic performance of 1c. A unique microenvironment
created in the ionic liquid phase of 1c was thus expected to be
responsible for such a significant improvement on the catalytic
performance. Acid-stable solvents 1,2-dichloroethane (DCE),
1,4-dioxane, and acetonitrile are also unable to dissolve 1c. And
biphasic systems can also be formed by combining 1c with all
these solvents. However, the reactions in these biphasic system
lead to slightly inferior yields (entries 6–8). A biphasic system
composed of 1c and nitromethane gave 5a in 94% (entry 9). But,
nitromethane is not a relevant solvent in terms of greenness
being toxic and explosive. Ethyl acetate was also examined and
found to cooperate well with 1c, producing 5a in 84% yield. But,
ethyl acetate was less appropriate due to its higher volatility
compared to butyl acetate, and only a part of solvent being liquid
and playing the role of solvent (entry 10). Furthermore, the
1c/ethyl acetate system cannot be applied in the other reactions
that would need high temperatures (> 80 °C) due to lower
volatility. The system 1c /butyl acetate was then selected for the
Scheme 1. Preparation of ionic liquid 1c.
It is important to note that ionic liquid 1c is immiscible with
organic solvents such as butyl acetate, 1,2-dichloroethane, and
toluene. Intriguingly, these solvents were not able to extract triflic
acid (TfOH) from 1c (Figure 1, picture b). This behavior is
different from that of the ionic liquid 1d previously reported by us,
which misses the imidazolium moiety compared to 1c. The triflic
acid component in 1d did leach out when an organic solvent, for
example butyl acetate that is able to dissolve TfOH, was added.
This was visibly evidenced by the fact that the precursor of 1d, a
solid zwitterion salt, was generated and precipitated out, lying in
the vial bottom (Figure 1, picture a). Apparently, the core
imidazolium-based Brønsted acid ionic liquid structure of 1c,
similar to that of Forbes’s ionic liquid 1e played a key role in
keeping the TfOH component in the ionic phase.[20]
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next investigations in this study. When the loading of 1c was
decreased to 5 mol%, the yield of 5a decreased to 75% (entry
11). Further investigations revealed that the reaction was also
affected by temperature and reaction time, the optimal
conditions are 80 °C and 2 h (entries 12 and 13).
Table 1. Three-component reaction of 2a, 3a and 4a under
different conditionsa
Figure 2. Recycling of 1c in the model reaction.
It is also worth noting that, butyl acetate can be used as an
extracting solvent to isolate the product from the ionic liquid.
This allowed both the ionic liquid catalyst and butyl acetate to be
recyclable. Although a very small part of butyl acetate (less than
5%) was mechanically lost, the greenness of this reaction was
thus further strengthened by the satisfactory recyclability level of
both the ionic liquid and the solvent (Figure 3). Therefore, the
ionic liquid 1c enabled us to establish an efficient and a
recyclable acid catalytic system in combination with the use of a
green organic solvent.
Entry
Solvent
Catalyst
Yield (%)
1
Butyl acetate
—
1c
97
31
22
69
48
75
70
80
94
84
75
55
57
2
1c
3
Butyl acetate
Butyl acetate
Butyl acetate
1,2-Dichloroethane
1,4-Dioxane
Acetonitrile
Triflic acid
4
1d
1b
Reaction
5
1e
6
1c
7
1c
8
1c
Extraction and ionic
Solvent recycling
liquid recovery
9
Nitromethane
Ethyl acetate
Butyl acetate
Butyl acetate
Butyl acetate
1c
10
11
12b
13c
1c
Figure 3. A schematic illustration of recycling butyl acetate solvent in the
model reaction.
1c (5 mol%)
With the optimized conditions in hand, we investigated then
the structural scope of the reaction with respect to all the three
components, and the results are given in Scheme 2. Upon
repeating the reaction with 3a and 4a, all indoles 2a exhibiting
different functional groups on the arene ring worked well under
the standard conditions, efficiently offering the corresponding
functionalized C3-(indol-3-yl)-substituted benzofurans 5b–h with
yields ranging from 65% to 99%. A variety of functional groups
such as methyl (5d), ethyl (5b and 5e), phenyl (5c–e), bromo
(5g), and methoxy (5h), can tolerate the acid-promoted
conditions well. Resorcine 4b and phloroglucinol 4c participated
readily in the reactions with 2a and 3a, affording the desired
products, 5i and 5j, in 77% and 80% yields, respectively. Phenol
was also tried but the reaction failed. This implies that an
electron-donating activating group in the arene ring of the
phenols is a requisite to facilitate the three-component assembly.
Other alkylglyoxals were also used to react with 2a and 4a. In
the biphasic system of 1c/butyl acetate, 5k can be formed in
77% yield from (4-bromophenyl)glyoxal monohydrate. 2-
Benzofuranylglyoxal hydrate was proven to be a viable substrate
as well, the benzofuran fragment being delivered into the
product without any structural damage (5l). Aliphatic
1c
1c
a reaction conditions: 2a, 0.3 mmol; 3a, 0.3 mmol, 4a, 0.3 mmol, catalyst, 0.03
mmol; medium, 0.5 mL, 80 °C, 2 h. b 60 °C. c 1 h.
The reaction using the 1c/butyl acetate system can be
effectively scaled up with similar performance. For example, the
reaction at 10.0 mmol scale gave the corresponding product 5a
in 96% yield (3.5 g). In this case, the ionic liquid could be easily
recovered and reused. Indeed, in the model reaction, 1c could
be recycled at least five times without significant loss of activity
(Figure 2).
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alkylglyoxals are also amenable to 1c-catalyzed condensation
with 2a and 4a. Methylglyoxal is commercially available as an
aqueous solution (40 wt. %). Despite the presence of water, it
can be used uneventfully in our system. After 2 h of reaction at
80 °C, the expected product 5m was isolated in 70% yield.
Despite the cyclopropyl being an acid-labile group, the 1c/butyl
dicarbonyl compounds and their alkyne-, allene-, dihydrofuran-,
and donor-and-acceptor-cyclopropane-type variations, have
been reported.[26] However, most of these 1,4-biselectrophiles
are not
commercially available.
As
2,5-dihydro-2,5-
[27]
dimethoxyfuran contains two electrophilic centers,
we
conjectured that it might be a suitable 1,4-biselectrophic reagent
to react with indole for synthesizing carbazole.
acetate
system
allowed
the
reaction
of
cyclopropaneglyoxylaldehyde, 2a, and 4a which proceeded
smoothly, leading to the desired product 5n in 88% yield.
Overall, the ionic liquid 1c/butyl acetate system is applicable in
the reactions of structurally distinct indoles 2a–h, electron-rich
phenols 4a–c, and alkylglyoxals 3a–e with different electronic
properties. The reaction provided an efficient and practical
protocol for synthesizing richly decorated benzofurans 5a–n.
Compared with the previous catalytic system established in
nitromethane,[23] the use of butyl acetate as the solvent and 1c
as the recyclable catalyst strengthened significantly the
greenness of the methodology.
Preliminary experiments indicated that in the presence of a
catalytic amount of triflic acid, 2,5-dihydro-2,5-dimethoxyfuran
could indeed react with two molecules of N-methylindole 2i to
form carbazole derivative 6a (Scheme 3). However, the reaction
had to be performed in nitromethane, giving 6a 61 % yield after
2 h of reaction at 80 °C. 1,4-Dioxane can also be a solvent for
this reaction, but leading to a lower yield. To alleviate the
detrimental effect of these toxic solvents, the reaction with triflic
acid was performed in butyl acetate, but the yield reached only
50%. However, when 1c was used as catalyst instead of triflic
acid, the reaction in butyl acetate proceeded very efficiently with
6a being isolated in 91% yield. These results demonstrated that
the biphasic system constructed by 1c/butyl acetate is the best
one to ensure completion of the reaction.
Scheme 3. Synthesis of carbazoles 6a-k from indoles and 2,5-dihydro-2,5-
dimethoxyfuran.
For this reaction towards carbazole 6a, the ionic liquid 1d also
effectively promoted the condensation reaction in butyl acetate,
with a 70% yield under identical conditions (Scheme 3).
However, the real advantage of ionic liquid 1c is in the catalyst
recycling. While ionic liquid 1d gives only a moderate yield in the
second run due to the leaching of acid species, the efficiency of
1c was retained very well. By using the recovered 1c in the
second run, 6a can be obtained in 90% yield. The biphasic
system composed of Forbes’ ionic liquid 1e and butyl acetate
was found to be inefficient for the synthesis of 6a. This reaction
towards the formation of carbazole illustrates again that the use
of 1c as a catalyst and butyl acetate as a solvent is able to
promote the transformations of indoles while keeping out of the
use of toxic dipolar aprotic solvents.
Scheme 2. Scope of substrate of the model three-component reaction, 5(b-n).
Inspired by these promising results, we investigated the
applicability of the 1c/butyl acetate system in other organic
reactions. The carbazole nucleus is the core unit of many
therapeutic agents, organic photoelectronic materials and
chromophores.[24] Although a number of procedures have been
developed and reported in literature,[25] the indole-to-carbazole
[4+2] annulation remains probably one of the most efficient ways
of synthesizing carbazoles. To meet the reactivity of 2,3-
unsubstituted indoles, various 1,4-biselectrophiles, such as 1,4-
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A scope of indoles was then subjected to the reaction with
2,5-dihydro-2,5-dimethoxyfuran (Scheme 3). Both electron-rich
(6a−c, 6f−h, and 6k) and moderately electron-poor (6d−e and
6i−j) indoles readily reacted in this process. Somehow, N-
benzylindole was not as reactive. Due to their poor
nucleophilicity, indoles with a strong electron-withdrawing group
such as 5-nitroindole and 5-cyanoindole, were unreactive in
these conditions. Mechanistically, the synthesis of 6a is an acid–
acid-catalyzed tandem reaction involving (i) the electrophilic
ring-opening of 2,5-dihydro-2,5-dimethoxyfuran with two
molecules of 2i, generating an intermediate I (Scheme 3);[28] and
(ii) the intra-molecular Diels Alder/methanol elimination of I to
form 6a.[29] As indolyl-substituted carbazoles involve an
expended π-conjugated system, these compounds are expected
to be useful in the preparation of some photoelectronic materials.
A method for synthesizing 1-(indol-3-yl)carbazoles was reported
during the preparation of this manuscript by Nagarajan et al.[30]
The present protocol is able to produce a different class of
indolyl-substituted carbazoles, 4-(indol-3-yl)carbazoles, and
offers thus a complementary route to access these heterocycles.
Inspired by the above reaction, a protected thioacetal 7a was
used as a 1,4-biselectrophile to construct a carbazole scaffold.[31]
As shown in Scheme 4, triflic acid was able to catalyze the [4+2]
annulation of 7a and 2i. However, the reaction in nitromethane
produced two regioisomers in nearly 1:1 ratio. After 2 h of
reaction at 80 °C, the total yield of 8a and 8b was 67%. In
acetonitrile, the yield of 8a slightly increased up to 40%, while
the yield of 8b remained nearly unchanged.
be formed through two reaction pathways, which are: (i) the first-
step push model, where the C3 position of 2i reacts first with the
most reactive site of II, i.e. the aldehyde site, to form an
intermediate III, after which the C2 position attacks the ketone
carbonyl group, affording 8a (Scheme 5), and (ii) the second-
step pull model, where the less reactive site of 2i, the C2
position, reacts first with the aldehyde site of II, to form
intermediate IV, after that the highly nucleophilic C3 position of
the indole attacks the ketone carbonyl group, affording 8b. In
nitromethane, the two reaction models worked with the same
kinetics, and therefore, nearly the same amounts of 8a and 8b
were formed.
Scheme 5. Mechanism of the formation of 8a and 8b.
We conjectured that, under biphasic conditions, because most
of the organic substances are contained in the butyl acetate
organic phase, the reaction rate of deacetalization of 7a was
decreased. Therefore, the concentration of the intermediate
aldehyde II in the reaction mixture might be very low, giving the
opportunity for the aldehyde to distinguish the reactivity
difference between the C3 position and C2 position of the indole
ring. Because the C3 position is the most favored to react with
the aldehyde site, 8a was formed as the major product.
Scheme 4. Synthesis of carbazoles via a [4+2] annulation of 2i and 7a.
The last example illustrates that, besides the benefit in terms
of yield and safety, the combined use of ionic liquid 1c as a
catalyst and butyl acetate as a solvent is also able to influence
the reaction selectivity. It should be also noted that our reaction
shown in Scheme 4 offers an alternative route to synthesize 1-
When butyl acetate was used as the reaction solvent, the
reaction proceeded sluggishly, with a total yield dropped to 20%.
Comparatively, when 1c was used as the catalyst and butyl
acetate as the solvent, the [4+2] annulation proceeded very well,
with an 81% global yield. Remarkably, the regioselectivity was
also significantly changed in favor of 8a, with a 7/1 ratio for the
carbazoles 8a/8b (Scheme 4). In this reaction, the ionic liquid 1c
can also be recovered and reused with nearly the same
performance.
phenyl-9H-carbazoles
under
metal-free conditions, an
alternative strategy compared to reported ones based on a
Suzuki reaction which requires a Cl or Br substituent at the C-1
position of carbazole and a noble-metal catalyst.[32]
The formation of the two products can be discussed in terms
of the nucleophilicity of 2i. The C2 and C3 positions of 2i are
both reactive nucleophilic sites, with the C3 position exhibiting
generally higher reactivity than the C2 one. The electrophile, 7a,
has also two different reactive sites, the ketone carbonyl group
and, the acetal fragment. The latter undergoes deacetalization to
form the aldehyde intermediate II. The carbazole products can
Conclusions
With the aim of establishing novel catalyst and solvent systems
for some acid-catalyzed transformations of indoles that are able
to avoid the use of toxic and explosive dipolar aprotic solvents, a
sulfone-containing imidazolium-based Brønsted acid ionic liquid
was designed and synthesized. The use of this tailor-made ionic
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Tests for substrate scope were performed according to an analogous
procedure.
liquid as an acid catalyst allows several selected transformation
reactions of indoles to proceed very well in green and industrially
acceptable solvent, butyl acetate. Because the ionic liquid is
immiscible with butyl acetate, the reactions actually proceeded
under biphasic conditions. The ionic liquid can be recycled and
reused without significant loss of its catalytic activity. The
examples shown in this study illustrate that this catalytic system
is not only able to increase the reaction yields, but also capable
of altering the reaction selectivity. This work demonstrates that
designing such innovative catalysts contribute to the
replacement of less-green solvents by greener ones is a
promising direction in catalysis research, and we are actively
working in this direction.
Large scale synthesis of 5a was performed in a 25 mL single neck
flask. Ionic liquid 1c (0.64g, 1.0 mmol) was mixed with phenylglyoxal
monohydrate (1.52 g, 10.0 mmol), sesamol (1.38 mg, 10.0 mmol) and 2-
methylindole (1.31 g, 10.0) in butyl acetate (15 mL). The mixture was
stirred for 2 h at 80 °C. After the completion of the reaction, the mixture
was cooled to room temperature. Butyl acetate was decanted out, and
the ionic liquid phase was extracted at 60 °C with butyl acetate (5 mL ×
3). The organic phase was dried over anhydrous Na2SO4. Then, the
organic phase was subjected to distillation with a rotary evaporator to
recover butyl acetate solvent. The residue was subjected to isolate with
silica column chromatography (eluting solution: petroleum ether/ethyl
acetate = 10/1v/v). The recovered ionic liquid was treated under reduced
pressure for 30 minutes at 80 °C, and then used in the next run.
Experimental Section
A typical procedure for reaction of indoles and 2,5-dihydro-2,5-
dimethoxyfuran
Melting points of the products were determined by microscopic
melting point meter (Yu Hua Instrument, X–4). 1H, 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 1d and 1e were prepared according to literature’s methods
with slight modification.[16, 20]
In a typical reaction, 1c (19.1 mg, 0.03 mmol) was mixed with indole
(98.4 mg, 0.75 mmol) and 2,5-dihydro-2,5-dimethoxyfuran (39.0 mg, 0.3
mmol) in 1.0 ml of butyl acetate. The mixture was stirred for 2 h at 80 °C.
After the completion of the reaction, the mixture was cooled to room
temperature. The butyl acetate was decanted out, and 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 = 20/1v/v). The desired
product 6a was obtained in 91 % of yield (calculated with respect to 2,5-
dihydro-2,5-dimethoxyfuran). Tests for substrate scope were performed
according to an analogous procedure.
Synthesis of ionic liquid 1c
Brønsted acid IL 1c was synthesized through the following three steps: (i)
synthesis of 1a: in 100 mL round-bottomed flask equipped with
mechanical stirring, an equal amount of divinyl sulfone (5.0 g, 42.3 mmol)
and 1-(3-aminopropanyl)imidazole (5.2 g, 42.3 mmol) were mixed 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 1a, in nearly quantitative yield. (ii) synthesis of 1b via
quaternization: 1a (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 round-
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); 1b was obtained as a white solid which was then dried at
60 °C under vacuum (20 mmHg) for 4 h; and (iii) acidification: 1b (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 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, 1c was
obtained as a yellow-pale viscous liquid. Over this three-step sequence,
the ionic liquid 1c is obtained in 88% yield.
A
typical procedure for reaction of indole and 1-
((ethoxycarbonothioyl)thio)-4-oxo-4-phenylbutyl pivalate (7a):
The reaction was carried out in a 10 mL of V-type flask equipped with
triangle magnetic stirring. Ionic liquid 1c (19.1 mg, 0.03 mmol) was mixed
with indole (39.4 mg, 0.3 mmol) and 1-((ethoxycarbonothioyl)thio)-4-oxo-
4-phenylbutyl pivalate 7a (165.6 mg, 0.45 mmol) in 0.5 mL of butyl
acetate. The mixture was stirred for 2 h at 90 °C. After the completion of
the reaction, the mixture was cooled to room temperature. The upper
butyl acetate phase was decanted out, and the bottom ionic phase was
extracted with butyl acetate (0.5 mL × 3). The organic phase was
combined together and subjected to isolation with preparative TLC
(eluting solution: petroleum ether/ethyl acetate= 50/1 v/v). The desired
product 8a and 8b were obtained in 71 % and 10 % yields, respectively.
The recovered ionic liquid was treated at 100 °C under vacuum (10
mmHg) for 30 minutes and then used in the next run.
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 financial support. The Cooperative
Innovation Center of Hubei Province is also acknowledged.
Finally, support of HUST and the French Ministry of Europe and
Foreign Affairs to YQ visiting professorship is also gratefully
acknowledged.
A typical procedure for the reaction of phenylglyoxal
monohydrate, sesamol, and indoles
All reactions were carried out in a 10 mL V-type flask equipped with
triangle magnetic stirring bar. In a typical reaction, 1c (19.1 mg, 0.03
mmol) was mixed with phenylglyoxal monohydrate (45.6 mg, 0.3 mmol),
sesamol (41.4 mg, 0.3 mmol) and 2-methylindole (39.4 mg, 0.3 mmol) in
butyl acetate (0.5 mL). The mixture was stirred for 2 h at 80 °C. After the
completion of the reaction, the mixture was cooled to room temperature.
Butyl acetate was decanted out, and the ionic liquid phase was extracted
at 60 °C with butyl acetate (0.5 mL × 3). The product was obtained by
isolation with preparative TLC (eluting solution: petroleum ether/ethyl
acetate = 5/1v/v). The desired product 5a was obtained in 97 % of yield.
Keywords: ionic liquid
• dipolar aprotic solvent • indole
transformation • acid catalysis • green solvent
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10.1002/cctc.201900784
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Dipolar and aprotic solvents are
widely used in organic synthesis.
Ahmed El-Harairy, Yiliqi, Meie Yue,
Weigang Fan, Florence Popowycz, Yves
Queneau,* Minghao Li, and Yanlong Gu*
These
solvents
are
however
generally toxic and hazardous. We
Page No. – Page No.
created a new ionic liquid that allow
the
acid-catalyzed
reactions
Novel non-toxic and non-hazardous
solvent systems for the chemistry of
indoles: use of a sulfone-containing
Brønsted acid ionic liquid catalyst in
butyl acetate
performed very well in green and
an industrially acceptable solvent,
butyl
acetate.
Indole
model
transformations
are
reactions to show the proof-of-the-
concept.
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