Efficient Thiophene Synthesis Mediated by 1,3-Bis(carboxymethyl)imidazolium Chloride: C-C and C-S Bond Formation

Article abstract of DOI:10.1002/ejoc.202000484

Thiophene derivatives have been prepared by means of a functionalized imidazolium salt [1,3-bis(carboxymethyl)imidazolium chloride] acting as a catalyst. The heterogeneous catalyst has allowed to carry out the reactions with no solvent or inert atmosphere

Full text of DOI:10.1002/ejoc.202000484

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Efficient thiophene synthesis mediated by 1,3-
bis(carboxymethyl)imidazolium chloride: C-C and C-S bond
formation
Authors: Patricia Gisbert and Isidro Manuel Pastor
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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to this Accepted Article as a result of editing. Readers should obtain
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000484
Link to VoR: https://doi.org/10.1002/ejoc.202000484
01/2020

10.1002/ejoc.202000484
European Journal of Organic Chemistry
FULL PAPER
Efficient thiophene synthesis mediated by 1,3-
bis(carboxymethyl)imidazolium chloride: C-C and C-S bond
formation
Patricia Gisbert,[a] and Isidro M. Pastor*[a]
[a]
Dr. P. Gisbert, Dr. I. M. Pastor
Organic Chemistry Department and Instituto de Síntesis Orgánica (ISO)
University of Alicante
Apdo. 99, 03080 Alicante, Spain
E-mail: ipastor@ua.es
https://orcid.org/0000-0002-8271-0641
Supporting information for this article is given via a link at the end of the document.
Abstract: Thiophene derivatives have been prepared by means of a
functionalized imidazolium salt [1,3-bis(carboxymethyl)imidazolium
chloride] acting as a catalyst. The heterogeneous catalyst has allowed
to carry out the reactions with no solvent or inert atmosphere. Different
aryl methyl ketones have reacted with elemental sulfur to selective
produce 2,4-substituted thiophenes. Furthermore, the reaction of
sulfur with cyclic ketones has enabled the preparation of polycyclic
compounds. This protocol is simple and effective for preparing
thiophene derivatives, even in a preparative scale. The thiophene
synthesis described presents remarkable sustainability with an E-
factor of 7.4, the solvent-free conditions being crucial for this feature.
The catalyst is straightforwardly prepared, and it is easily separated
from the reaction mixture, being possible its reuse.
thioglycolic acid derivatives with acetylenic esters),7 and the
Hinsberg synthesis (a reaction of a thiodiglycolate and a 1,2-
dicarbonyl compound under basic conditions).8
From
a green chemistry perspective, the construction of
functionalized molecules with complex structures from readily
available reagents is of great significance, drawing the attention
of organic chemists. It is desirable to find more sustainable
synthetic processes for pharmacologically active compounds,
improving the environmental impact during their industrial
production.9 New and efficient protocols for the construction of
substituted thiophenes are still desirable to achieve this aim. Thus,
microwave-assisted thiophene synthesis has been described for
different protocols, such as Paal-Knorr condensation10 and
Gewald reaction.11 An efficient and simple copper catalyzed route
for the synthesis of di-, tri- and tetrasubstituted thiophenes, with
excellent yields, has been reported starting from 1,4-diiodo-1,3-
dienes and potassium sulfide.12 Some methodologies use
different sulfur reagents (such as K2S,13 KSCN14 or KSAc)15 that
decrease the atomic economy of the process. Therefore, the use
of elemental sulfur (S8) is a more sustainable alternative for
preparing sulfur-containing compounds, being considered a
cheap and environmentally friendly reagent.16 Recently, it has
been described a base-promoted (t-BuONa) cyclization of 1,3-
diynes in the presence of sulfur to form 3,4-diarylsubstituted
thiophenes.17 A simple and effective method for the formation of
π-system fused-thiophene derivatives has been reported,
reacting arylethynyl substituted polycyclic arenes with elemental
sulfur via C-H activation.18 The preparation of 2,3,5-
trisubstitutedthiophenes have been achieved by the reaction
between arylacetaldehydes and 1,3-dicarbonyl compounds in the
presence of elemental sulfur,19 and 2,4-diarylthiophenes has
been obtained from a redox condensation between acetophenone
derivatives and sulfur.20 These protocols need the use of organic
Introduction
Sulfur-containing heterocycles are an important class, among
other heterocyclic compounds, in the field of pharmacology.1
Among them, thiophene derivatives have shown interesting
applications in the field of medicinal chemistry. Compounds
containing a thiophene unit have shown antimicrobial activity,
anticancer activity, antioxidant activity, anti-inflammatory activity,
anti-urease activity, anticonvulsant activity, and antithrombic
activity.2 In addition, thiophene-derived compounds have a
significant role in the development of organic semiconductors,
which are useful in the advance of organic electronics.3 Therefore,
the progress and improvement of methodologies that allow the
preparation of these heterocyclic derivatives are of interest, both
from an applied and fundamental point of view. The principal
synthetic methodologies can be divided into two different
categories, (a) functionalization of a formed thiophene ring,4 and
(b) ring formation from acyclic precursors. Among the most
conventional protocols are the Paal-Knorr synthesis (reaction of
1,4-dicarbonyl compounds with a sulfur reagent),5 the Gewald
synthesis (a multicomponent reaction between a carbonyl
compound, an activated nitrile and sulfur, in the presence of a
base, to form substituted 2-aminothiophenes),6 the Fiesselmann
synthesis (a condensation, in the presence of a base, of
solvents
(such
as
N,N-dimethylformamide
and
dimethylsulfoxide),17-19 and the use of inert atmosphere.20
Therefore, the use of more benign reaction media is an interesting
improvement to obtain more sustainable processes. Recently, the
use of alternative solvents such as deep eutectic solvents (DES)
has proved to be very useful21 albeit it is even better to carry out
organic transformations under solvent-free conditions.22 Aware of
1
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10.1002/ejoc.202000484
European Journal of Organic Chemistry
FULL PAPER
this, our research group has focused on the development of
synthetic catalytic processes in the absence of solvents. Thus,
metal-organic frameworks (MOF) have been used, as
heterogeneous catalysts under solvent-free conditions,23 to carry
out the preparation of amides,24 and the synthesis of quinoline
derivatives.25 Iron-based Lewis acidic imidazolium salts have
been employed as catalysts, under neat conditions, in preparing
thiomides,26 and the selective synthesis of 2-allylanilines, 4-
allylanilines or quinolines starting from the same starting
materials.27 More recently, we have explored the use of carboxy-
functionalized imidazolium halides, which are ionic organic solids
(IOS), as heterogeneous catalysts, being possible to perform
reaction without solvents. Thus, N-allylanilines,28 quinoline and
acridine derivatives29 have been prepared by the use of 1,3-
bis(carboxymethyl)imidazolium chloride (bcmim-Cl). The
imidazolium salt presents different moieties which are important
for the catalytic activity due to favorable interactions with the
reactants, which are crucial in the absence of a reaction solvent.
Based on that, we considered that this type of catalyst could favor
the formation of thiophenes via a more sustainable protocol
without any solvent and/or the need for inert atmosphere. Herein,
we described our findings in the evaluation of 1,3-
bis(carboxymethyl)imidazolium chloride (bcmim-Cl) as a metal-
free heterogeneous catalyst for the preparation of thiophene
derivatives.
footnote [c]). Extending the reaction time, up to 90 minutes, did
not result in a significant improvement (85% conversion), so
conventional heating was chosen to continue.
Table 1. Optimization of the reaction conditions[a]
catalyst
O
mol%)
S
(10
+
2
1/8
S8
Ph
Ph
Ph
aniline
mol%)
(50
T
t
(ºC), (h)
1
Entry
Catalyst (mol%)
Time (h)
Temp. (ºC)
Conversion (%)
1
2
3
4
5
6
7
8
9
10
bcmim-Cl (10)
bcmim-Cl (10)
bcmim-Cl (10)
bcmim-Cl (10)
bcmim-Cl (10)
bcmim-Cl (10)
No catalyst
16
16
16
8
80
13
100
120
120
120
120
120
120
120
120
68
>99
>99
97 (95)[b]
87
6
4
6
<1
bcmim-Cl (5)
bcmim (10)
6
42
6
15
Results and Discussion
bcmim-Cl (10)
1[c]
82 (76)[b]
Initial efforts were focused on the optimization of the reaction
conditions between acetophenone and elemental sulfur as model
reactants. The reaction was carried out, under solvent-free
conditions, using 1,3-bis(carboxymethyl)imidazolium chloride
(bcmim-Cl, 10 mol%) as the catalyst at 80 ºC, in the presence of
aniline. After 16 h, the expected 2,4-diphenylthiophene (1) was
observed with a 13% conversion (Table 1, entry 1). The reaction
failed when lower temperatures (60 ºC) were used providing the
expected thiophene in less than 5% conversion. As expected, the
reaction outcome was improved by increasing the temperature,
obtaining thiophene 1 with 68% conversion at 100 ºC, and with
full conversion at 120 ºC (Table 1, entries 2 and 3). At this
temperature (120 ºC), the reaction time could be reduced until 8
h without observing any decrease in the conversion (Table 1,
entry 4), and the conversion remains at high values even after 6
h (97%, Table 1, entry 5). It is worthy to mention that the product
was isolated in 95% yield (Table 1, entry 5, footnote [b]), proving
the effectiveness of the protocol described. Moreover, bcmim-Cl
proved to be crucial for the reaction to proceed, since the non-
catalyzed reaction gave no conversion after 6 h (Table 1, entry 7).
Reducing the amount of the catalyst to 5 mol% resulted in lower
conversion (42%) after 6 h (Table 1, entry 8). Moreover, it was
observed that the reaction catalyzed by the zwitterionic imidazole
derivate bcmim (10 mol%) gave only 15% conversion to the
thiophene 1 (Table 1, entry 9), proving that the presence of the
counterion chloride is significant during the catalytic process, as
previously observed for other transformations.29 In addition, the
reaction under microwave heating was also tested since it has
been described to be a sustainable alternative.30 Thus, the
reaction was performed under microwave irradiation at 120 ºC
(constant temperature using 80 W of initial potency) during 1 h,
giving the desired product in 82% conversion (Table 1, entry 10,
[a] Reaction conditions: acetophenone (0.5 mmol), sulfur (0.75 mmol) and
catalyst (10 mol%), aniline (50 mol%). Conversion determined by GC analysis.
[b] In parenthesis, yield of the isolated product after purification by column
chromatography. [c] Reaction performed using microwave irradiation as heating
source (constant temperature, using 80 W of initial potency).
To find the scope of the reaction using the bcmim-Cl as the
catalyst, several acetophenones were evaluated, the expected
2,4-diarylthiophenes 1-12 being exclusively formed (Scheme 1).
Acetophenones bearing electron-withdrawing groups, such as
halogens, provided the corresponding thiophenes, which were
isolated in good yields, regardless of the position of the
substituent. Thus, 4-halophenyl methyl ketones reacted with
sulfur to form thiophenes 2-4 with yields in the range of 60-87%
(Scheme 1). Likewise, 3-chlorophenyl methyl ketone produced
compound 5 with 84% yield (Scheme 1). In the case of 2-chloro-
and 2-bromoacetophenone, the products 6 and 7 were obtained
with 67% and 52% yield, respectively, being slightly lower
compared with thiophenes 3, 4, and 5 probably due to steric
hindered. In addition, it was observed that the presence of a
strong electron-withdrawing group, such as trifluoromethyl,
resulted in the formation of the corresponding product 8 with a
37% yield (Scheme 1). Interestingly, the presence of electron-
donating substituents, such as methyl and methoxy, led to the
formation of the thiophenes 9-12 with comparable yields as the
electron-withdrawing groups (Scheme 1). Similarly, the
substituent in ortho-position hampered the formation of the
thiophene resulting in lower yield (compare thiophene 10 with 9
and 11, Scheme 1). In general, these results demonstrate the
robustness of the protocol described with different aryl methyl
ketones.
2
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10.1002/ejoc.202000484
European Journal of Organic Chemistry
FULL PAPER
bcmim-Cl
O
mol%)
S
R2
R2
(10
+
2
1/8
S8
Ar
Ar
Ar
S
aniline
120
mol%)
6 h
bcmim-Cl
(50
ºC,
O
R1
R2
R2
mol%)
(10
1-12
+
2
1/8
S8
R1
R2
aniline
120
mol%)
16 h
(50
ºC,
R1
R2
S
13-17
S
X
X
Ph
Ph
S
S
S
S
=
=
=
1
2
3
4
87%)
Cl, 73%)
Br, 60%)
F,
(95%)
(X
(X
(X
Cl
Cl
X
X
15
13
14
(34%)
(70%)
(41%)
S
S
5
(84%)
S
=
=
6
7
Cl, 67%)
Br, 52%)
(X
(X
S
17
16
(20%)
(49%)
F
3C
CF3
S
8
(37%)
S
Scheme 2. Scope evaluation of cyclic ketones for the synthesis of polycyclic
thiophenes. Reaction conditions: ketone (1 mmol), S (1.5 mmol), bcmim-Cl (0.1
mmol), aniline (0.5 mmol), 120 ºC, 16 h. In parenthesis, yield of the isolated
product after column chromatography or preparative TLC.
9
(83%)
S
R
R
Furthermore, the imidazolium chloride bcmim-Cl was also
examined as a catalyst, under neat conditions, on the thiophene
preparation in preparative scale to prove the applicability of the
process (Figure 1). Thus, acetophenone (5.8 mL, 50 mmol) and
elemental sulfur (75 mmol) were reacted, at 120 °C for 6 hours,
to afford the corresponding 2,4-diphenylthiophene 1 (Figure 1).
After recrystallization, 4.5 g of pure product 1 (77% yield) was
isolated. To better identify the environmental impact of the
process, the E-factor was calculated considering the
recrystallization step. An E-factor of 7.4 was obtained for the
preparation of compound 1 (Figure 1), which is in the lower level
of the reported range for Fine Chemical production in the
industry.9 Next, the recyclability of the catalyst was considered
because the catalyst remains solid at the end of the reaction, the
catalyst not being completely soluble during the reaction. Thus,
the product was removed from the reaction media using ethyl
acetate, which is considered as a recommended (or preferred)
solvent in the selection guide of solvents for the pharmaceutical
industry.31 The remaining mixture was employed in the following
cycle. The reaction was set again by only adding the starting
materials. A slight decrease in the conversion was observed in
the second cycle (Figure 1). The catalyst is reducing its activity in
the successive cycles (Figure 1), probably due to the presence of
sulfur by-products. Interestingly, it has recently established that
acid treatment can easily perform the catalyst reactivation.32
Different control experiments were carried out to gain
understanding into the reaction mechanism, which seems to
proceed via an imine/enamine intermediate. Indeed, the reaction
in the absence of aniline resulted in the recovery of the starting
materials. Besides, the formation of the product got reduced to
61% by using less aniline (30 mol%). The use of other amines
10
(64%)
=
11
Me, 82%)
(R
=
12
OMe, 87%)
(R
Scheme 1. Scope evaluation of acetophenones for the synthesis of thiophenes
using bcmim-Cl. Reaction conditions: acetophenone (1 mmol), S (1.5 mmol),
bcmim-Cl (0.1 mmol), aniline (0.5 mmol), 120 ºC, 6 h. In parenthesis, yield of
the isolated product after column chromatography or preparative TLC.
The catalyzed protocol was next applied to different
cycloalkanones to promote the formation of polycyclic derivatives.
Thus, cyclopentanone led to the formation of the expected tricyclic
thiophene derivative 13, which was isolated in good yield (70%,
Scheme 2), although it was necessary to extend the reaction time
up to 16 h to complete the reaction. Furthermore, non-
symmetrically 2,2-dimethylcyclopentanone gave solely the
corresponding thiophene derivative 14 with moderate yield
(Scheme 2). Likewise, cyclohexanone derivatives reacted via a
sulfurative self-condensation leading exclusively to the formation
of the corresponding thiophenes. Cyclohexanone and 4-
methylcyclohexanone produced compounds 15 and 16 (Scheme
2). The reaction employing other cycloalkanones (i.e. 3-
ethylcyclopentanone, 2-methylcyclopentanonte or tetrahydro-4H-
thiopyran-4-one) afforded complex reaction mixtures. In these
cases, the corresponding tricyclic products were formed, being
unbearable to isolate. Nevertheless, the desired product 17 was
isolated in 20% yield when α-tetralone was reacted with sulfur
(Scheme 2).
3
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10.1002/ejoc.202000484
European Journal of Organic Chemistry
FULL PAPER
with different nucleophilicity33 (i.e. p-anisidine, hydroxylamine,
and benzylamine) was tested. The reaction failed when p-
anisidine or hydroxylamine was employed as an additive, being
less effective in the promotion of the reaction. In the presence of
with the amine and the ketone (Scheme 4). Likewise, this
enamine could react, using the catalyst, with another molecule of
ketone to form imine 19 (Scheme 4). The extended enamine 19’,
in equilibrium with imine 19, could act as nucleophile reacting with
benzylamine, the conversion to the product was incomplete (53%), sulfur, being favored by their positive interactions with catalyst
observing also the imine intermediate. Furthermore, N,1-
diphenylethanimine (18) could react with elemental sulfur in the
presence of catalyst bcmim-Cl forming, as expected, thiophene
1 (Scheme 3a). Moreover, the reaction of acetophenone in the
absence of sulfur, under standard conditions, produced N,1,3-
triphenylbut-2-en-1-imine (19), as a result of the condensation of
two acetophenone molecules. This imine 19 could be successfully
converted in the thiophene 1 by treatment with sulfur in the
presence of catalyst bcmim-Cl (Scheme 3b).
bcmim-Cl (Scheme 4). Then, the intramolecular cyclization
reaction could form the expected thiophene by the elimination of
aniline (Scheme 4). At this point, the reaction of acetophenone
under the standard conditions was catalyzed with an imidazolium
salt
lacking
the
carboxylic
acid
[such
as
1-
(methoxycarbonylmethyl)-3-methylimidazolium
chloride,
(mcm)mim-Cl] to prove the relevance of the H-bonding in the
mechanistic proposal. The reaction was performed under
microwave irradiation getting thiophene 1 in 10% conversion after
1 h. This result is significantly lower compared with the obtained
employing catalyst bcmim-Cl (Table 1, entry 10).
OH
O
O
bcmim-Cl
+
PhNH2
O
O
O
N
N
N
N
O
H
Ph
Cl
H
+
O
bcmim-Cl
H
2O
H
N
Ph
Ph
Ph
Ph
OH
O
O
N
HN
bcmim-Cl
PhCOMe
N
O
H
Ph
Ph
Cl
18
18'
H
N
+
bcmim-Cl
H
2O
Ph
Ph
Figure 1. Reaction in multigram scale, E-factor in the preparation of 1, and
recycling of the catalyst.
Ph
Ph
Ph
Ph
Ph
OH
O
bcmim-Cl
Ph
bcmim-Cl
N
O
H
PhCOMe
N
S
HN
Ph
N
mol%)
(10
(a)
+
Cl
1/8
S8
Ph
Ph
Ph
Ph
120
6 h
ºC,
Ph
Ph
H
S8
19'
19
18
1
N
(83%)
Ph
bcmim-Cl
mol%)
Ph
N
O
OH
O
S
(10
NHPh
Ph
(b.1)
(b.2)
O
Ph
Ph
Ph
Ph
N
N
O
aniline
120
mol%)
6 h
(50
ºC,
Ph
7S
bcmim-Cl
19
H
Cl
(70%)
S
PhNH2
Ph
Ph
Ph
H
S
S
bcmim-Cl
Ph
Ph
N
S6
N
mol%)
(10
S
Ph
Ph
Ph
1/8 S8
120
6 h
ºC,
Ph
19
1
(84%)
1
Scheme 3. Control experiments. In parentheses, conversion determined by GC
analysis.
Scheme 4. Proposed mechanism for the thiophene synthesis meditated by the
bcmim-Cl.
28, 29
Based on that and the literature,20,
a possible reaction
mechanism for the thiophene formation is depicted in Scheme 4.
The structure of the catalyst (bcmim-Cl) provides favorable
interactions during the catalytic process. As described,29 the
catalyst could help in the formation of the imine 18, which is in
equilibrium with the corresponding enamine 18’, by interacting
Next, the reaction of two different ketones with sulfur was
considered as a more challenging transformation. To address this
question,
a
reaction of sulfur, acetophenone, and 3-
methoxyacetophenone was performed under the optimal reaction
conditions, four thiophenes can be formed. Although the
4
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10.1002/ejoc.202000484
European Journal of Organic Chemistry
FULL PAPER
conversion was excellent, it was not observed any significant
difference in the selectivity process, being the four isomers
formed in similar amounts (Scheme 5). As well, other
combinations of ketones (such as acetophenone/4-
Experimental Section
Instruments and reagents. All commercially available reagents and
solvents were purchased (Acros, Aldrich, Fluka, Fluorochem, Merck) and
used without further purification. 1H NMR and 13C NMR spectra were
recorded at the technical service of the University of Alicante (SSTTI-UA),
employing a Bruker AC-300 or a Bruker Advance-400.§ Chemical shifts (δ)
are given in ppm and the coupling constants (J) in Hz. Melting points were
determined using a Gallenkamp capillary melting point apparatus (model
MPD 350 BM 2.5) and are uncorrected. Low-resolution mass spectra (EI)
were obtained at 70 eV with an Agilent 5973 Network spectrometer, with
fragment ions m/z reported with relative intensities (%) in parentheses.
Infrared spectra were recorded with an FT-IR/4100 LE (JASCO, Pike
Miracle ATR) spectrometer. Spectra were recorded from neat samples and
results are given in cm-1. Analytical TLC was performed on Merck
aluminium sheets with silica gel 60 F254, 0.2 mm thick. Silica gel 60 (0.04-
0.06 mm) was employed for column chromatography. P/UV254 silica gel
with CaSO4 supported on glass plates was employed for preparative TLC.
The conversion of the reactions and purity of the products were determined
by GC analysis using a Younglin 6100GC, equipped with a flame ionization
detector and a Phenomenex ZB-5MS column (5% PH-ME siloxane): 30 m
(length), 0.25 mm (inner diameter) and 0.25 µm (film).
hydroxyacetophenone,
acetophenone/4-methylacetophenone,
acetophenone/4-chloroacetophenone,
and 4-
chloroacetophenone/3-methoxyacetophenone) were reacted, in
the presence of sulfur, giving in all the cases the four possible
isomers in equimolecular amounts. The reaction between
acetophenone and 3,3-dimethylbutan-2-one, in the presence of
sulfur, gave the thiophene 1 (36% conversion) together with the
imine of 3,3-dimethylbutan-2-one (47% conversion), not being
observed any thiophene with two different substituents. Then, to
conduct the selectivity of the process, equimolecular amounts of
imine 18 and 3-methoxyacetophenone were combined with sulfur,
in the presence of bcmim-Cl (10 mol-%), obtaining again a
mixture of the different isomers. Probably, both reactants
equilibrate initially giving a mixture of both possible imines what
resulted in the formation of the different thiophenes, being not
possible to direct the selectivity under the studied conditions.
General procedure for thiophenes synthesis. A mixture of ketone (1
mmol), elemental sulfur (1.5 mmol, 48 mg), aniline (0.25 mmol, 22 µL) and
bcmim-Cl (10 mol%, 11 mg) were put in a reaction flask and heated at
120 ºC for 6 or 16 hours. After completion of the reaction, the crude mixture
was stirred vigorously with ethyl acetate (5 mL), then filtered. Other
portions of ethyl acetate (2×5 mL) were used to remove thoroughly all the
soluble compounds from the solid residue. The solvent was removed
under vacuum, and the residue was usually purified by flash silica gel
column chromatography (n-hexane/TBME) or preparative TLC, to give the
corresponding thiophene.
O
S
S
Ph
R
Ph
R
R
Ph
bcmim-Cl
Ph
R
mol%)
(10
+
1
20
(21%)
S
(26%)
S
aniline
1/8 S8
120
16 h
mol%)
(50
O
ºC,
Ph
21
R
12
(26%)
(26%)
=
[R 3-MeO-phenyl]
2,4-Diphenylthiophene (1).34 Yellow solid; purification by column
chromatography (n-hexane/TBME 9.8/0.2), 95% yield (112.1 mg); m.p.:
118-119 °C (CH2Cl2) (Lit:35 120-120.5 ºC); IR (ATR): ν = 3055, 1596, 1486,
1447, 1364, 1199, 1074, 1028, 965, 885, 834, 752, 735 cm-1; 1H NMR (300
MHz, CDCl3): δH = 7.67-7.59 (m, 5H, 5×CHAr), 7.44-7.37 (m, 5H, 5×CHAr),
7.33-7.24 (m, 2H, SCHAr and SCCHAr) ppm; 13C NMR (75 MHz, CDCl3): δC
= 145.2, 143.3, 136.0, 134.5, 129.1, 129.0, 127.8, 127.4, 126.5, 126.0,
122.5, 119.9 ppm; MS (EI): m/z 237 (M++1, 18%), 236 (M+, 100), 234 (13).
Scheme 5. Synthesis of thiophenes from two different ketones (acetophenone
and 3-methoxyacetophenone) meditated by the bcmim-Cl. In parentheses,
conversion determined by GC analysis.
Conclusion
In conclusion, a robust, simple, and effective process to
synthesize thiophenes, starting from two ketones and elemental
sulfur, has been developed by means of the use of 1,3-
2,4-Bis(4-fluorophenyl)thiophene (2).20 White solid; purification by
column chromatography (n-hexane/TBME 9.8/0.2), 87% yield (118.5 mg);
m.p.: 127-128 °C (EtOAc) (Lit:36 124-124.5 ºC); IR (ATR): ν = 1475, 1408,
1237, 1075, 1006, 963, 885, 847, 840, 813, 749, 730, 704 cm-1; 1H NMR
(300 MHz, CDCl3): δH = 7.62-7.54, 7.45-7.45, 7.31-7.30 (3m, 4H, 1H and
1H, 4×CHAr, SCHAr and SCCHAr), 7.13-7.06 (m, 4H, 4×CHAr) ppm; 13C
NMR (75 MHz, CDCl3): δC = 162.6 (d, J = 247.7 Hz), 162.4 (d, J = 246.7
Hz), 144.3, 142.3, 132.1 (d, J = 3.0 Hz), 130.6 (d, J = 3.2 Hz), 128.0 (d, J
= 7.9 Hz), 127.7 (d, J = 8.2 Hz), 122.4, 119.5, 116.1 (d, J = 21.5 Hz), 115.9
(d, J = 21.1 Hz) ppm; MS (EI): m/z 274 (M+, 6%), 273 (M+-1, 19), 272 (100),
227 (12).
bis(carboxymethyl)imidazolium chloride (bcmim-Cl) as
a
heterogeneous catalyst. Different aryl methyl ketones proved to
be effective reactants under the optimal conditions, giving the
corresponding
2,4-disubstituted
thiophene
derivatives.
Furthermore, the catalyst allows to use cycloalkanones as
precursors in the reaction, expanding the applicability of this
methodology to the preparation of polycyclic compounds.
Regarding the structural design, the moieties in this metal-free
catalyst provide favorable interactions with the reactants allowing
the reaction to be performed under solvent-less conditions and
without inert atmosphere. This fact is significant for the
sustainability of the synthetic protocol. Thus, the protocol
described allows the preparation of potentially interesting
bioactive compounds, in preparative scale, and with an E-factor
(7.4) in the low range of the Fine Chemical production. Moreover,
the heterogeneous catalyst (employed in 10 mol%) is easily
recovered and reused (with a slight decrease in activity) taking in
advantage the “solid” state of the catalyst throughout the process.
2,4-Bis(4-chlorophenyl)thiophene (3).20 White solid; purification by
column chromatography (n-hexane/TBME 9.8/0.2), 73% yield (111.4 mg);
m.p.: 147-148 °C (EtOAc) (Lit:36 140 ºC); IR (ATR): ν = 1480, 1414, 1238,
1202, 1092, 1011, 962, 886, 830, 815, 750, 706, 667 cm-1; 1H NMR (300
MHz, CDCl3): δH = 7.55-7.48, 7.38-7.34 (2m, 5H and 5H, 8×CHAr, SCHAr
and SCCHAr) ppm; 13C NMR (75 MHz, CDCl3): δC = 144.2, 142.1, 134.2,
133.7, 133.3, 132.8, 129.2, 129.1, 127.6, 127.1, 122.5, 120.4 ppm; MS
(EI): m/z 308 (M++3, 15%), 307 (M++2, 12), 306 (M++1, 72), 305 (M+, 20),
304 (100), 234 (18), 189 (11).
2,4-Bis(4-bromophenyl)thiophene (4).20 White solid; purification by
column chromatography (n-hexane/TBME 9.8/0.2), 60% yield (118.2 mg);
m.p.: 172-173 °C (EtOAc) (Lit:36 173.5-174.5 ºC); IR (ATR): ν = 1474, 1407,
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000484
European Journal of Organic Chemistry
FULL PAPER
1235, 1074, 1008, 965, 887, 840, 810, 750, 729, 705 cm-1; 1H NMR (300
MHz, CDCl3): δH = 7.55-7.45, 7.40-7.38 (2m, 9H and 1H, 8×CHAr, SCHAr
and SCCHAr) ppm; 13C NMR (75 MHz, CDCl3): δC = 144.3, 142.2, 134.7,
133.2, 132.2, 132.1, 128.0, 127.5, 122.5, 121.9, 121.5, 120.5 ppm; MS
(EI): m/z 237 (M++1, 52%), 236 (M+, 18), 393 (100), 392 (49), 189 (14),
117 (15).
1H, SCCHAr), 7.12 (d, J = 1.5 Hz, 1H, SCHAr), 2.47 (s, 3H, CH3), 2.40 (s,
3H, CH3) ppm; 13C NMR (75 MHz, CDCl3): δC = 142.7, 142.3, 136.8, 136.2,
135.8, 134.3, 131.0, 130.7, 130.5, 129.8, 128.5, 128.0, 127.5, 126.1, 126.0,
122.5, 21.4, 21.0 ppm; MS (EI): m/z 265 (M++1, 21%), 264 (M+, 100), 231
(9), 216 (26), 215 (25), 115 (14). HRMS (GC/MS-EI/Q-TOF) calcd. for
C
18H16S 264.0973, found 264.0974.
2,4-Bis(3-chlorophenyl)thiophene (5).20 White solid; purification by
column chromatography (n-hexane/TBME 9.8/0.2), 84% yield (128.2 mg);
m.p.: 85-86 °C (EtOAc); IR (ATR): ν = 1593, 1569, 1473, 1096, 1078, 902,
874, 837, 777, 742, 734, 681 cm-1; 1H NMR (300 MHz, CDCl3): δH = 7.62-
7.57 (m, 2H, 2×CHAr), 7.54 (d, J = 1.5 Hz, 1H, SCCHAr), 7.51-7.42 (m, 2H,
2×CHAr), 7.41 (d, J =1.5 Hz, 1H, SCHAr), 7.36-7.24 (m, 4H, 2×CHAr) ppm;
13C NMR (75 MHz, CDCl3): δC = 143.9, 141.9, 137.4, 135.9, 135.0, 134.9,
130.3, 130.2, 127.9, 127.5, 126.5, 125.9, 124.5, 124.1, 122.9, 121.2 ppm;
MS (EI): m/z 308 (M++3, 14%), 307 (M++2, 13), 306 (M++1, 71), 305 (M+,
18), 304 (M+-1, 100), 234 (16).
2,4-Bis(3-methylphenyl)thiophene (11). Orange oil; purification by
column chromatography (n-hexane/TBME 9.8/0.2), 82% yield (108.4 mg);
IR (ATR): ν = 2917, 1601, 1485, 1458, 1208, 1094, 899, 879, 836, 796,
781, 746, 688 cm-1; 1H NMR (300 MHz, CDCl3): δH = 7.57 (d, J = 1.5 Hz,
1H, SCCHAr), 7.50-7.40 (m, 4H, 4×CHAr), 7.35 (d, J = 1.5 Hz, 1H, SCHAr),
7.34-7.25 (m, 2H, 2×CHAr), 7.16-7.05 (m, 2H, 2×CHAr), 2.41 and 2.40 (2s,
6H, 2×CH3) ppm; 13C NMR (75 MHz, CDCl3): δC = 145.2, 143.3, 138.7,
138.5, 136.0, 134.4, 129.0, 128.9, 128.6, 128.1, 127.2, 126.7, 123.6, 123.1,
122.4, 119.6, 21.7, 21.6 ppm; MS (EI): m/z 265 (M++1, 21%), 264 (M+,
100), 248 (5). HRMS (GC/MS-EI/Q-TOF) calcd. for C18H16S 264.0973,
found 264.0978.
2,4-Bis(2-chlorophenyl)thiophene (6).20 Yellow oil; purification by
column chromatography (n-hexane/TBME 9.8/0.2), 67% yield (102.3 mg);
2,4-Bis(3-methoxyphenyl)thiophene (12).39 Yellow oil; purification by
column chromatography (n-hexane/TBME 9.5/0.5), 87% yield (128.9 mg);
IR (ATR): ν = 1599, 1579, 1483, 1465, 1435, 1287, 1264, 1202, 1166,
1042, 839, 778, 734 cm-1; 1H NMR (300 MHz, CDCl3): δH = 7.56 (d, J = 1.5
Hz, 1H, SCCHAr), 7.37 (d, J = 1.5 Hz, 1H, SCHAr), 7.35-7.27 (m, 2H,
2×CHAr), 7.25-7.22 (m, 2H, 2×CHAr), 7.21-7.13 (m, 2H, 2×CHAr), 6.91-6.83
(m, 2H, 2×CHAr), 3.85 (s, 6H, 2×OCH3) ppm; 13C NMR (75 MHz, CDCl3):
δC = 160.15, 160.1, 145.0, 143.1, 137.4, 135.8, 130.1, 130.0, 122.7, 120.2,
119.0, 118.6, 113.4, 112.8, 112.3, 111.7, 55.5, 55.4 ppm; MS (EI): m/z 296
(M++1, 21%), (M+, 100).
1
IR (ATR): ν = 903, 725 cm-1; H NMR (300 MHz, CDCl3): δH = 7.61-7.57
(m, 2H, CHAr and SCCHAr), 7.51-7.39 (m, 4H, SCHAr and 3×CHAr), 7.32-
7.24 (m, 4H, 4×CHAr) ppm; 13C NMR (75 MHz, CDCl3): mixture of two
rotamers displayed δC = 141.0, 139.7, 139.5, 135.5, 133.1, 132.6, 132.5,
131.5, 131.4, 131.2, 130.8, 130.7, 130.4, 129.6, 128.9, 128.85, 128.7,
127.9, 127.1, 127.05, 125.0 ppm; MS (EI): m/z 308 (M++3, 15%), 307
(M++2, 13), 306 (M++1, 70), 305 (M+, 18), 304 (M+-1, 100), 234 (25), 116
(19).
2,4-Bis(2-bromophenyl)thiophene (7). Yellow oil; purification by column
chromatography (n-hexane/TBME 9.8/0.2), 52% yield (102.5 mg); IR
1,2,3,5,6,7-Hexahydrodicyclopenta[b,d]thiophene (13).20 Greenish oil;
purification by preparative TLC (n-hexane/TBME 9.8/0.2), 70% yield (57.5
mg); IR (ATR): ν = 2925, 2854, 2360, 1684, 1571, 1457, 1376, 1240, 1209,
1094, 1012, 988, 700 cm-1; 1H NMR (300 MHz, CDCl3): δH = 2.88-2.77 (m,
4H, 2×SCCCH2), 2.64-2.59 (m, 4H, 2×2SCCH2), 2.44-2.36 (m, 4H,
2×CH2CH2CH2) ppm; 13C NMR (75 MHz, CDCl3): δC = 144.8, 140.4, 29.7,
29.3, 27.5 ppm; MS (EI): m/z 165 (M++1, 16%), 164 (M+, 100), 163 (M+-1,
86), 149 (27), 137 (30), 136 (35), 135 (28), 131 (20), 115 (11).
1
(ATR): ν = 2359, 2341, 1461, 1433, 1024, 906, 751, 732 cm-1; H NMR
(300 MHz, CDCl3): δH = 7.68 (td, J = 7.8 and 1.6 Hz, 2H, 2×CHAr), 7.57-
7.50 (m, 2H, 2×CHAr), 7.45 (dd, J = 7.4 and 1.6 Hz, 2H, SCCHAr and CHAr),
7.35 (td, J = 7.8 and 1.3 Hz, 2H, SCHAr and CHAr), 7.19 (tt, J = 7.4 and 1.6
Hz, 2H, 2×CHAr) ppm; 13C NMR (75 MHz, CDCl3): mixture of two rotamers
displayed δC = 142.5, 141.2, 141.1, 137.5, 135.2, 133.9, 133.6, 132.05,
132.0, 131.4, 129.8, 129.3, 129.2, 128.9, 127.8, 127.65, 127.6, 124.7,
122.9, 122.7 ppm; MS (EI): m/z 396 (M++2, 10%), 395 (M++1, 55), 394 (M+,
100), 392 (M+-1, 52), 234 (42), 232 (11), 202 (11), 189 (20). HRMS
(GC/MS-EI/Q-TOF) calcd. for C16H10Br2S 391.8870, found 391.8874.
1,1,5,5-Tetramethyl-1,2,3,5,6,7-
hexahydrodicyclopenta[b,d]thiophene (14). Yellow oil; purification by
preparative TLC (n-hexane/TBME 9.9/0.1), 41% yield (45.2 mg); IR (ATR):
ν = 2952, 2925, 2849, 2360, 2335, 1708, 1460, 1363, 1253, 1184, 739 cm-
1; 1H NMR (300 MHz, CDCl3): δH = 2.67 (s, 3H, CH2 and CHH), 2.63-2.57
(m, 1H, CHH), 2.43-2.41 (m, 3H, CH2 and CHH), 2.23-2.18 (m, 1H, CHH),
1.29 (s, 3H, CH3), 1.22 (s, 9H, 3×CH3) ppm; 13C NMR (75 MHz, CDCl3):
δC = 142.1, 139.2, 130.5, 121.8, 45.55, 45.5, 45.1, 45.0, 43.1, 43.0, 30.45,
30.4, 29.8, 26.4 ppm; MS (EI): m/z 220 (M+, 19%), 206 (14), 205 (100).
HRMS (GC/MS-EI/Q-TOF) calcd. for C14H20S 220.1286, found 220.1280.
2,4-Bis[4-(trifluoromethyl)phenyl]thiophene (8).37 Yellow solid;
purification by column chromatography (n-hexane/TBME 9.8/0.2), 37%
yield (68.9 mg); m.p.: 136-137 °C (EtOAc); IR (ATR): ν = 2926, 1600, 1546,
1491, 1234, 1160, 1101, 1012, 888, 821, 799, 749, 710 cm-1; 1H NMR (300
MHz, CDCl3): δH = 7.67-7.51 (m, 4H, 4×CHAr), 7.45 (d, 1H, SCCHAr), 7.30
(d, 1H, SCCHAr), 7.13-7.06 (m, 4H, 4×CHAr) ppm; 13C NMR (75 MHz,
CDCl3): δC = 143.9, 142.0, 138.8, 137.3, 129.8 (q, J = 32.6 Hz), 129.5 (q,
J = 32.6 Hz), 126.5, 126.0 (q, J = 3.8 Hz), 125.9, 125.85 (q, J = 3.9 Hz),
124.0 (q, J = 255 Hz), 123.9 (q, J = 255 Hz), 123.3, 122.4 ppm; MS (EI):
m/z 274 (M+, 6%), 273 (M+-1, 19), 272 (100), 227 (12).
1,2,3,4,6,7,8,9-Octahydrodibenzo[b,d]thiophene (15).20 Yellow oil;
purification by preparative TLC (n-hexane/TBME 9.9/0.1), 34% yield (32.7
mg); IR (ATR): ν = 2924, 2854, 2839, 1665, 1444, 1335, 1293, 1262, 1115,
1067, 1027, 816, 737 cm-1; 1H NMR (300 MHz, CDCl3): δH = 2.71-2.68 (m,
4H, 2×CH2), 2.42-2.38 (m, 4H, 2×CH2), 1.76-1.48 (m, 8H, 4×CH2) ppm;
13C NMR (75 MHz, CDCl3): δC = 134.0, 132.0, 25.0, 24.0, 23.8, 22.7 ppm;
MS (EI): m/z 192 (M+, 64%), 191 (M+-1, 31), 165 (14), 164 (100), 163 (27),
136 (17).
2,4-Bis(4-methylphenyl)thiophene (9).20 White solid; purification by
column chromatography (n-hexane/TBME 9.8/0.2), 83% yield (109.7 mg);
m.p.: 147-148 °C (EtOAc) (Lit:38 145 ºC); IR (ATR): ν = 3022, 2913, 2857,
1547, 1498, 1375, 1124, 1017, 887, 848, 808, 784, 748 cm-1; 1H NMR (300
MHz, CDCl3): δH = 7.55-7.50, 7.24-7.22 (2m, 5H and 1H, 4×CHAr, SCHAr
and SCCHAr), 7.21-7.18 (m, 4H, 4×CHAr) 2.37 (s, 6H, 2×CH3) ppm; 13
C
NMR (75 MHz, CDCl3): δC = 145.2, 143.2, 137.7, 137.1, 133.3, 131.8,
129.7, 129.6, 126.3, 125.9, 122.0, 118.7, 21.35, 21.3 ppm; MS (EI): m/z
265 (M++1, 21%), 264 (M+, 100), 263 (M+-1, 21).
2,7-Dimethyl-1,2,3,4,6,7,8,9-octahydrodibenzo[b,d]thiophene
(16).
Colorless oil (mixture of two diastereoisomers); purification by preparative
TLC (n-hexane/TBME 9.8/0.2), 49% yield (54.0 mg); IR (ATR): ν = 2948,
2920, 2840, 1455, 1439, 1375, 1266, 1132, 1117, 1073, 984, 831 cm-1; 1H
NMR (300 MHz, CDCl3): mixture of two diastereoisomers, δH = 2.83-2.68
(m, 6H, 6×CHH), 2.58-2.21 (m, 8H, 8×CHH), 2.06-1.77 (m, 10H, 6×CHH
and 4×CH), 1.57-1.32 (m, 4H, 4×CHH), 1.06 (d, 12H, J = 6.3 Hz, 4×CH3)
2,4-Bis(2-methylphenyl)thiophene (10). Colorless oil; purification by
column chromatography (n-hexane/TBME 9.8/0.2), 64% yield (84.6 mg);
IR (ATR): ν = 2952, 2359, 2342, 1481, 1457, 1379, 1191, 1116, 1035, 907,
757, 732 cm-1; 1H NMR (300 MHz, CDCl3): δH = 7.51-7.43 (m, 1H, CHAr),
7.40-7.35 (m, 1H, CHAr), 7.29-7.22 (m, 6H, 6×CHAr), 7.19 (d, J = 1.5 Hz,
ppm; 13C NMR (75 MHz, CDCl3): mixture of two diastereoisomers, δC
134.1, 133.7, 132.2, 131.9, 33.4, 32.8, 32.7, 32.15, 32.1, 31.2, 31.1, 30.2,
=
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000484
European Journal of Organic Chemistry
FULL PAPER
30.15, 29.15, 29.1, 25.0, 24.0, 23.9, 22.0, 21.8 ppm; MS (EI): m/z 221
(M++1, 15%), 220 (M+, 87), 219 (M+-1, 14), 205 (15), 179 (21), 178(100),
163 (14), 136 (34). HRMS (GC/MS-EI/Q-TOF) calcd. for C14H20S 220.1286,
found 220.1283.
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5,6,12,13-Tetrahydrodinaphtho[2,1-b;2,1-d]thiophene (17). Yellow oil;
purification by preparative TLC (n-hexane/TBME 9.9/0.1), 20% yield (28.9
mg); IR (ATR): ν = 2929, 1598, 1580, 1550, 1477, 1448, 1421, 960, 862,
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1
808, 756, 737, 682 cm-1; H NMR (300 MHz, CDCl3): δH = 7.28-7.13 (m,
8H, 4×CHAr), 3.14-3.11 (m, 4H, 2×CH2), 3.01-2.94 (m, 4H, 2×CH2) ppm;
13C NMR (75 MHz, CDCl3): δC = 136.1, 135.8, 135.7, 133.8, 133.3, 127.9,
127.8, 127.7, 126.9, 126.8, 126.6, 126.3, 124.3, 124.1, 124.0, 123.8, 31.3,
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(M+-1, 25), 286 (19), 285 (17), 284 (19), 271 (11), 253 (11), 252 (11).
HRMS (GC/MS-EI/Q-TOF) calcd. for C20H16S 288.0973, found 288.0972.
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Recycling experiments. A mixture of acetophenone (1 mmol, 120 µL),
elemental sulfur (1.5 mmol, 48 mg) and aniline (0.25 mmol, 22 µL) was
stirred at 120 °C in the presence of bcmim-Cl (10 mol%, 11 mg). Then,
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using ethyl acetate (5 mL). The catalyst was rinsed with ethyl acetate (6×5
mL), dried under vacuum and reused for the next catalytic cycle.
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This work was financially supported by the University of Alicante
(VIGROB-173, VIGROB-285, VIGROB-316FI and UAUSTI19-21),
the Spanish Ministerio de Economía y Competitividad (CTQ2015-
66624-P, CTQ2017-88171-P), the Spanish Ministerio de Ciencia,
Innovación y Universidades (PGC2018-096616-B-I00) and the
Generalitat Valenciana (AICO/2017/007). P.G. thanks the ISO
(University of Alicante) for a grant.
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Keywords: imidazolium salt • metal-free • sulfur • sustainable
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10.1002/ejoc.202000484
European Journal of Organic Chemistry
FULL PAPER
Thiophene synthesis
An ionic organic solid, such as 1,3-bis(carboxymethyl)imidazolium chloride, mediates metal-free thiophene derivatives syntheses by
favoring the reaction under solvent-free conditions, representing an efficient and sustainable protocol.
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