Synthesis of thiophenes in a deep eutectic solvent: heterocyclodehydration and iodocyclization of 1-mercapto-3-yn-2-ols in a choline chloride/glycerol medium

Article abstract of DOI:10.1016/j.tet.2016.05.062

The heterocyclodehydration and iodocyclization of readily available 1-mercapto-3-yn-2-ols has been performed in a deep eutectic solvent (DES), that is, ChCl/Gly (1:2 molar ratio; ChCl=choline chloride, Gly=glycerol), as a non-conventional green solvent. T

Full text of DOI:10.1016/j.tet.2016.05.062

Tetrahedron 72 (2016) 4239e4244
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Tetrahedron
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Synthesis of thiophenes in a deep eutectic solvent:
heterocyclodehydration and iodocyclization of 1-mercapto-3-yn-2-
ols in a choline chloride/glycerol medium
,
a
b
b
b
Raffaella Mancuso a , Asif Maner , Luciana Cicco , Filippo M. Perna , Vito Capriati ,
*
,
Bartolo Gabriele a
*
a Laboratory of Industrial and Synthetic Organic Chemistry (LISOC), Department of Chemistry and Chemical Technologies, University of Calabria, Via
Pietro Bucci, 12/C, 87036 Arcavacata di Rende (CS), Italy
b
ꢀ
Dipartimento di Farmacia-Scienze del Farmaco, Universita di Bari ‘Aldo Moro’, Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, 70125 Bari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The heterocyclodehydration and iodocyclization of readily available 1-mercapto-3-yn-2-ols has been
performed in a deep eutectic solvent (DES), that is, ChCl/Gly (1:2 molar ratio; ChCl¼choline chloride,
Gly¼glycerol), as a non-conventional green solvent. The processes, carried out at 50 ꢀC for 8 h in the
presence of the PdI2/KI catalytic system or at room temperature for 5 h with 1.2 equiv of I2, led to the
formation of the corresponding thiophenes and 3-iodothiophenes in good to high yields. The DES/cat-
alytic system could be easily recycled several times without appreciable loss of activity, after extraction of
the thiophene product with hexane or Et2O. The alkynylation reaction of a-mercapto ketones, necessary
for the preparation of the alkynylthiol substrates, was also successfully accomplished in the above protic
eutectic mixture competitively with protonolysis.
Received 29 March 2016
Received in revised form 10 May 2016
Accepted 23 May 2016
Available online 26 May 2016
Keywords:
Deep eutectic solvents
Heterocyclization
Iodocyclization
Alkynyl thiols
Thiophenes
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
give thiophene derivatives9 in DESs as safer and greener un-
conventional solvents, thereby expanding the field of metal-
Deep eutectic solvents (DESs) are an emerging new class of
unconventional solvents, characterized by low toxicity and high
eco-friendliness.1 They are increasingly being used in synthetic
organic chemistry as well as in process technology, particularly
for their unusual solvent properties. Emerging applications are in
the field of biotransformations, organocatalysis, organometallic
chemistry, and metal-catalyzed reactions.2e4 The use of DESs as
possible alternative ‘green’ solvents for organic transformations,
while of particular importance and attractiveness, has apparently
to face the issue related with the chemical inertness of DESs,
which are generally less chemically inert with respect to classical
organic solvents and ionic liquids,5 so the success in using DESs
in a particular chemical transformation cannot be taken for
granted.
catalyzed reactions and introducing the use of DES in
iodocyclizations.
2. Results and discussion
The first heterocyclization experiments were carried out using
4-mercapto-3-methyl-1phenylpent-1-yn-3-ol 1a as the substrate,
which was allowed to react in the presence of PdI2 (2 mol %) and KI
(20 mol %) in 1:2 ChCl/urea as the solvent (ChCl¼choline chloride)
at 50 ꢀC for 8 h. After cooling, the reaction mixture was extracted
with hexane and analyzed by GLC and TLC, which showed the
presence of the substrate almost unreacted (7% conversion). We
next changed the nature of one of the component of the eutectic
mixture, and conducted the same experiment in a 1:2 ChCl/Gly
mixture (Gly¼glycerol). We were pleased to find that, using this
DES, the formation of the desired thiophene 2a now occurred in
80% yield after 8 h at 50 ꢀC (Table 1, entry 1, run 1). This result
testifies that DESs are not interchangeable with each other and that
their nature can have a profound and unpredictable influence on
the outcome of a particular reaction. The process leading to 2a may
be interpreted as occurring through 5-endo-dig intramolecular
In this work, we have studied both the Pd-catalyzed hetero-
cyclodehydration6 and the iodocyclization7,8 of 1-mercapto-3-yn-
2-ols 1 (readily available by alkynylation of a-mercapto ketones) to
* Corresponding authors. Tel.: þ39 0984 492816; fax: þ39 0984 492044 (R.M.);
tel.: þ39 0984 492815; fax: þ39 0984 492044 (B.G.); e-mail addresses: raffaella.
mancuso@unical.it (R. Mancuso), bartolo.gabriele@unical.it (B. Gabriele).
http://dx.doi.org/10.1016/j.tet.2016.05.062
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

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R. Mancuso et al. / Tetrahedron 72 (2016) 4239e4244
Table 1
Synthesis of substituted thiophenes 2 by PdI2/KI-catalyzed heterocyclization of 1-mercapto-3-alkyn-2-ols 1 in ChCl/Gly (1:2) as the solvent and recycling experimentsa
Entry
1
2
Yield of 2b,c (%)
Run 1
Run 2
Run 3
79
Run 4
80
Run 5
79
Run 6
78
1
80
80
79
68
2
3
80
69
79
68
78
67
78
69
79
67
4
5
78
83
77
82
76
82
76
83
75
82
77
82
6
7
73
65
73
63
72
64
73
64
73
63
72
64
a
All reactions were carried out at 50 ꢀC for 8 h in 1:2 ChCl/Gly mixture (ChCl¼choline chloride; Gly¼glycerol) as the solvent (0.20 mmol of starting 1 per mL of DES) in the
presence of PdI2 (2 mol %) in conjunction with KI (20 mol %). Conversion of 1 was quantitative in all cases.
b
Isolated yield based on starting 1.
Run 1 corresponds to the first experiment, the next runs to recycles. See text for details.
c
attack of the mercapto group to the triple bond coordinated to the
metal center, followed by protonolysis and dehydrative aromati-
zation or vice versa (Scheme 1, path a; anionic iodide ligands are
omitted for clarity).
We next verified the possibility of recycling the catalyst/solvent
system, by adding fresh substrate to the residue obtained after
extraction of the thiophene product with hexane and repeating the
catalytic procedure. After 8 h, 2a was formed again with the same
path a
PdI2
PdI2
OH
SH
I+
R2 PdI
R1 R3
+ HI
OH
OH
S
path b
PdI
R3
R2
R1
R2
R1
R2
R1
R3
R3
HO
R2
I2
R3
HI
H2O
H2O
HI
SH
S
1
R1 SH
+ HI
PdI2
PdI2
H+
R2
R1
R2
I
OH
OH
S
R2
R1
I
R2
R1
R3
R1
R3
S
R3
R3
S
3
H2O
S
2
Scheme 1. Formation of substituted thiophenes 2 and 3-iodothiophenes 3 from 1-mercapto-3-yn-2-ols by PdI2-catalyzed heterocyclodehydration (path a) or iodocyclization (path
b), respectively.

R. Mancuso et al. / Tetrahedron 72 (2016) 4239e4244
4241
yield as that of the first experiment (Table 1, entry 1, run 2). The
recycling procedure was repeated for additional four runs, with 2a
being consistently obtained in 78e80% yields (Table 1, entry 1, runs
3e6). The generality of the process was then assessed, by varying
the nature of the substituent on the triple bond. As can be seen
from the results reported in Table 1 (entries 2e7), satisfactory
yields were obtained with all the substrates tested, bearing a p-tolyl
(entry 2), a cyclohexen-1-yl (entry 3), or an alkyl substituent (en-
tries 4e7) on the triple bond (including a sterically demanding tert-
butyl group, entry 7). In all cases, the recyclability of the DES/cat-
alyst system could be successfully achieved.
I2 and in the absence of base, the iodocyclization of 1 proceeded
smoothly under mild conditions (room temperature) to afford
the corresponding 3-iodothiophenes in good yields (up to 80%)
and with an excellent recyclability of the solvent (up to 5 addi-
tional runs, Table 2). The iodocyclization process may occur
through the formation of an iodonium cation intermediate fol-
lowed by cyclization and dehydration (Scheme 1, path b). As far
as we know, this reaction represents the first example in the
literature of an iodocyclization reaction carried out in a DES as
the reaction medium.
In order to increase the green merit of the overall trans-
Table 2
Base-free synthesis of 3-iodothiophenes 3 by iodocyclization of 1-mercapto-3-alkyn-2-ols 1 in ChCl/Gly (1:2) as the solvent and recycling experimentsa
Entry
1
2
Yield of 3b,c (%)
Run 1
Run 2
Run 3
80
Run 4
79
Run 5
79
Run 6
79
1
1a
79
80
77
2
1b
78
75
75
74
76
3
4
5
6
1c
69
72
76
76
68
72
74
73
68
71
75
74
67
73
74
74
69
71
76
76
67
72
75
75
1d
1e
1f
7
8
1g
65
62
63
62
64
60
63
61
62
60
63
61
a
All reactions were carried out with I2 (1.2 equiv) at 25 ꢀC for 5 h in a 1:2 Chl/Gly (ChCl¼choline chloride; Gly¼glycerol) mixture as the solvent (0.20 mmol of starting 1 per
mL of DES). Conversion of 1 was quantitative in all cases.
b
Isolated yield based on starting 1.
Run 1 corresponds to the first experiment, the next runs to recycles. See text for details.
c
Considering the good results obtained in the Pd-catalyzed
heterocyclization of 1-mercapto-3-yn-2-ols 1, we next studied
the reactivity of the same substrates under iodocyclization con-
ditions in 1:2 ChCl/Gly as the reaction medium. With 1.2 equiv of
formation from commercially available a-mercapto ketones to the
final thiophenes, and in consideration of the fact that nucleophilic
additions to carbonyl compounds promoted by Grignard and
organolithium reagents have been proved to be effective in

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R. Mancuso et al. / Tetrahedron 72 (2016) 4239e4244
DESs,3b,4def we have also investigated the possibility of carrying out
the alkynylation reactions for the preparation of 1-mercapto-3-yn-
2-ols 1 in such unconventional solvents. Thus, we first subjected
a cyclopentyl methyl ether (CPME) solution of phenylacetylene 4a
(1.2 mmol) to lithiation with n-BuLi (1.5 mmol). The resulting so-
lution of the putative lithiated intermediate 4a-Li was then added
to a solution of 3-mercaptobutan-2-one 5 (0.6 mmol) in a 1:2
ChCleGly eutectic mixture (1 g) in the presence of 0.6 mmol of LiBr
at room temperature and under air. Pleasingly, the corresponding
alkynylation product 1a was recovered with a yield of 50% after
10 min reaction time (Table 3, entry 1). When performed in other
different eutectic mixtures, the reaction proved to be less effective,
and afforded lower yields of 1a (up to 28%, Table 3, entries 2e4).
The nucleophilic addition of other lithium acetylides, bearing a p-
tolyl (4b) or a butyl (4d) group, run in the above ChCl/Gly (1:2)
eutectic mixture, furnished the expected 1-mercapto-3-yn-2-ols 1b
and 1d in 61% and 41% yield, respectively (Table 3, entries 5 and 6).
Although these yields are overall lower than those obtained in THF
at low temperature,7a these results testify that alkynylation re-
conjunction with 10 equiv of KI, which could be conveniently
recycled together with the DES several times without loss of ac-
tivity. The DES solvent could also be easily recycled in the iodo-
cyclization process leading to 3-iodothiophenes 3.
4. Experimental section
4.1. General experimental methods
Melting points are uncorrected. 1H NMR and 13C NMR spectra
were recorded at 25 ꢀC in CDCl3 solutions with a Bruker DPX Avance
300 spectrometer operating at 300 MHz and 75 MHz, respectively,
with Me4Si as internal standard. Chemical shifts (d) and coupling
constants (J) are given in ppm and in Hz, respectively. IR spectra
were taken with a JASCO FTIR 4200 spectrometer. Mass spectra
were obtained using a Shimadzu QP-2010 GCeMS apparatus at
70 eV ionization voltage. Microanalyses were carried out with
a Thermo-Fischer Elemental Analyzer Flash 2000. All reactions
were analyzed by TLC on silica gel 60 F254 (Merck) or on neutral
alumina (Merck) and by GLC using a Shimadzu GC-2010 gas chro-
matograph and capillary columns with polymethylsilicone þ5%
polyphenylsilicone as the stationary phase (HP-5). Column chro-
actions of a-mercaptoketones can also be alternatively run in DESs
as unconventional solvents, at RT under air, and competitively with
protonolysis.
Table 3
Addition reaction of various lithium acetylides 4-Li to 3-mercaptobutan-2-one 5 in DES mixturesa
Entry
1
4
DES
1
Yield of 1 (%)
ChCl/Gly (1:2)
ChCl/urea (1:2)
ChCl/
ChCl/
50b
2
3
4
4a
4a
4a
1a
1a
1a
8c
28c
23c
D
-sorbitol (1:1)
-fructose (1:1)
D
5
6
ChCl/Gly (1:2)
ChCl/Gly (1:2)
61b
41b
a
1 g of DES per 1.2 mmol of 4.
b
c
Isolated yield based on 5.
Determined by 1H NMR analysis of the crude reaction mixture.
3. Conclusions
matography was performed on silica gel 60 (Merck, 70e230 mesh).
Evaporation refers to the removal of solvent under reduced
pressure.
In conclusion, we have reported the S-heterocyclization and
iodocyclization of 1-mercapto-3-yn-2-ols in choline chloride/glyc-
erol both run in the deep eutectic solvent ChCl/Gly (1:2) as a non-
conventional, safe, inexpensive and ‘green’ reaction medium.
Substituted thiophenes 2 and 3-iodothiophenes 3 were efficiently
obtained starting from readily available 1-mercapto-3-alkyne-2-ols
1, which, in turn, could also be synthesized by carrying out the
alkynylation of commercially available a-mercaptoketone 5 in the
above DES. The heterocyclodehydration of 1 to thiophenes 2 was
carried out using a simple catalytic system, consisting of PdI2 in
4.2. Preparation of substrates
Starting 1-mercapto-3-alkyne-2-ols 1aeh were prepared as we
already reported.7a Substrates 1a, 1b, and 1d were also prepared by
alkynylation of commercially available 3-mercaptobutan-2-one 5
in the ChCl/Gly (1:2) eutectic mixture (Table 3), as described below.
All other materials were commercially available and were used
without further purification.

R. Mancuso et al. / Tetrahedron 72 (2016) 4239e4244
4243
4.3. Preparation of DESs
4.7. Characterization of thiophenes 2
Eutectic mixtures of solvents [ChCleGly (1:2 mol/mol); ChCl/
fructose (1:1 mol/mol); ChCleurea (1:2 mol/mol); ChCl/ -sorbitol
(1:1 mol/mol)] were prepared by heating with stirring up to 90 ꢀ
for 10e30 min the corresponding individual components until
a clear solution was obtained.
D
-
Thiophenes 2a, 2b, and 2d were characterized by spectroscopic
comparison with the corresponding products obtained in our pre-
vious report.6 All other thiophene derivatives were fully charac-
terized by MS spectrometry, IR, 1H NMR and 13C NMR
spectroscopies, and elemental analysis, as reported below.
D
C
4.4. Preparation of 1-mercapto-3-alkyne-2-ols 1a, 1b, and 1d
in DES
4.7.1. 5-Cyclohex-1-enyl-2,3-dimethylthiophene (2c). Yellow oil. IR
(film):
(m), 1167 (w), 1111 (w), 1007 (w), 742 (w) cmꢂ1; 1H NMR (300 MHz,
CDCl3):
n
¼2957 (m), 2924 (m), 2863 (m), 1562 (w), 1456 (s), 1375
A solution of the desired lithium acetylide was initially prepared
by adding, at 0 ꢀC and under nitrogen, 0.6 mL of a 2.5 M solution of
n-BuLi in hexanes (1.5 mmol) to a stirred solution of the 1-alkyne 4
[1.2 mmol; phenylacetylene (4a) 124 mg; p-tolylacetylene (4b),
140 mg; 1-hexyne (4d), 100 mg] dissolved in cyclopentyl methyl
ether (1 mL). To a stirred solution of commercially available 3-
mercapto-2-butanone 5 (63 mg, 0.60 mmol) and LiBr (52 mg,
0.6 mmol) in ChCleGly (1:2) (1.0 g) was added, at RT and under air,
a solution of the above alkynyllithium reagent (1.2 mmol). After
stirring for 10 min, the reaction was quenched by adding a satu-
rated aqueous solution of NH4Cl and 1 N HCl (2 mL). The mixture
was then extracted with Et2O (3ꢁ10 mL), and the collected organic
phases were washed with brine and dried over anhydrous Na2SO4.
After filtration and evaporation of the solvent, the residue was
purified by column chromatography on silica gel (95:5 hexane/
AcOEt as the eluent), to give the pure product as a ca. 1:1 mixture of
diastereoisomers: 4-mercapto-3-methyl-1-phenylpent-1-yn-3-ol
1a was a yellow oil (62 mg, 50%); 4-mercapto-3-methyl-1-p-tol-
ylpent-1-yn-3-ol 1b was a yellow oil (82 mg, 61%); 2-mercapto-3-
methylnon-4-yn-3-ol 1d was a yellow oil (46 mg, 41%). The spec-
troscopic properties agreed with those previously reported.7a
d
¼6.60 (s, 1 H,¼CH), 6.02 (s, 1 H,¼CH), 2.41e2.28 (m, 1H,
cyclohexenyl ring), 2.28 (s, 3H, Me), 2.18e2.08 (m, 1H, cyclohexenyl
ring), 2.06 (s, 3H, Me), 1.81e1.54 (m, 4H, cyclohexenyl ring); 13C
NMR (75 MHz, CDCl3):
d
¼142.0,132.9,131.2,130.1,124.2,122.6, 27.2,
25.6, 22.8, 22.3, 13.6, 13.1; GCeMS: m/z¼192 (100) [Mþ], 191 (19),
178 (10), 177 (71), 164 (34), 163 (20), 149 (42), 135 (10), 125 (9), 115
(7), 91 (7), 77 (7); Anal. Calcd for C12H16S (192.32): C, 74.94; H, 8.39;
S, 16.67; found C, 74.91; H, 8.38; S, 16.69.
4.7.2. 2,3-Dimethyl-5-phenethylthiophene (2e). Yellow solid, mp
28e30 ꢀC. IR (KBr):
n
¼2939 (m), 2916 (m), 2855 (m), 1492 (m), 1450
(m), 1151 (w), 1069 (w), 848 (m), 824 (m), 749 (s), 702 (s) cmꢂ1; 1H
NMR (300 MHz, CDCl3):
d
¼7.31e7.23 (m, 2H, aromatic), 7.22e7.13
(m, 3 H, aromatic), 6.45 (s, 1H,¼CH), 3.05e2.85 (m, 4H, CH2CH2Ph),
2.27 (s, 3H, Me), 2.05 (s, 3H, Me); 13C NMR (75 MHz, CDCl3):
d
¼141.3, 139.6, 132.4, 130.1, 128.4, 128.3, 127.2, 126.0, 38.1, 31.9, 13.5,
12.9; GCeMS: m/z¼216 (28) [Mþ], 127 (7), 126 (11), 125 (100), 110
(2), 97 (3), 91 (16), 79 (2); Anal. Calcd for C14H16S (216.34): C, 77.72;
H, 7.45; S, 14.82; found C, 77.69; H, 7.48; S, 14.81.
4.7.3. 5-Benzyl-2,3-dimethylthiophene (2f). Yellow solid, mp
38e39 ꢀC. IR (KBr):
n
¼2914 (w), 2854 (w), 1498 (m), 1462 (m), 1442
4.5. General procedure for the synthesis of substituted thio-
phenes 2 by PdI2/KI-catalyzed heterocyclization of 1-
mercapto-3-alkyn-2-ols 1 in ChCl/Gly (1:2) as the solvent
(Table 1)
(w), 1203 (w), 1072 (w), 1029 (w), 831 (m), 754 (s), 687 (s) cmꢂ1; 1H
NMR (300 MHz, CDCl3):
d
¼7.40e7.30 (m, 5H, aromatic), 6.45 (s,
1H,¼CH), 4.01 (s, 2H, CH2Ph), 2.25 (s, 3H, Me), 2.04 (s, 3H, Me); 13
C
NMR (75 MHz, CDCl3):
d
¼140.6, 139.0, 132.6, 131.1, 128.6, 128.5,
128.0, 126.3, 36.1, 13.5, 12.9; GCeMS: m/z¼202 (95) [Mþ], 201 (39),
188 (16), 187 (100), 172 (8), 171 (6), 153 (8), 152 (6), 141 (4), 125 (32),
115 (7), 111 (4), 91 (10), 77 (4); Anal. Calcd for C13H14S (202.32): C,
77.18; H, 6.97; S, 15.85; found C, 77.23; H, 6.99; S, 15.88.
To a solution of 1 (0.42 mmol) (1a, 87 mg; 1b, 93 mg; 1c, 88 mg;
1d, 78 mg; 1e, 99 mg; 1f, 93 mg; 1g, 78 mg) in ChCl/Gly (1:2; 2 mL)
were added PdI2 (3.0 mg, 8.3ꢁ10ꢂ3 mmol) and KI (13.8 mg,
8.3ꢁ10ꢂ2 mmol) in this order under nitrogen in a Schlenk flask. The
mixture was allowed to stir at 50 ꢀC for 8 h. After cooling, the
product was extracted with hexane (6ꢁ5 mL), and the residue (still
containing the catalyst dissolved in the DES) was used as such for
the next recycle (see below). The hexane phases were collected and,
after evaporation of the solvent, products 2aeg were purified by
column chromatography on silica gel using 99: 1 hexaneeAcOEt as
the eluent: 2,3-dimethyl-5-phenylthiophene 2a was a yellowish
solid, mp 49e50 ꢀC (yield: 63 mg, 80%); 2,3-dimethyl-5-p-tolylth-
iophene 2b was a yellow solid, mp 47e49 ꢀC (68 mg, 80%); 5-
cyclohexenyl-2,3-dimethylthiophene 2c was a yellow oil (56 mg,
69%); 5-butyl-2,3-dimethylthiophene 2d was a yellow oil (55 mg,
78%); 2,3-dimethyl-5-phenethylthiophene 2e was a yellow solid,
mp¼28e30 ꢀC (75 mg, 83%); 5-benzyl-2,3-dimethylthiophene 2f
was a yellow solid, mp 38e39 ꢀC (62 mg, 73%); 5-tert-butyl-2,3-
dimethylthiophene 2g was a yellow oil (46 mg, 65%). Rf values
were as follows (pure hexane): 2a, 0.54; 2b, 0.51; 2c, 0.75; 2d, 0.75;
2e, 0.43; 2f, 0.52; 2g, 0.72.
4.7.4. 5-tert-Butyl-2,3-dimethylthiophene (2g). Yellow oil. IR (film):
n
¼2923 (s), 2851 (m),1642 (m),1464 (m),1215 (w), 760 (s) cmꢂ1; 1H
NMR (300 MHz, CDCl3):
d
¼6.48 (s, 1 H,¼CH), 2.27 (s, 3 H, Me), 2.06
(s, 3 H, Me), 1.33 (s, 9 H, t-Bu); 13C NMR (75 MHz, CDCl3):
d¼152.4,
132.0, 129.4, 124.2, 34.1, 32.4, 13.6, 12.9; GCeMS: m/z¼168 (31)
[Mþ], 154 (13), 153 (10), 137 (6), 125 (8), 113 (8), 105 (2), 97 (2), 91
(4), 77 (3); Anal. Calcd for C10H16S (168.30): C, 71.36; H, 9.58; S,
19.05; found C, 71.33; H, 9.55; S, 19.10.
4.8. General procedure for the synthesis of 3-iodothiophenes
3 by iodocyclization of 1-mercapto-3-alkyn-2-ols 1 in ChCl/Gly
(1:2) as the solvent (Table 2)
To a solution of 1 (0.50 mmol) (1a, 103 mg; 1b, 110 mg; 1c,
105 mg; 1d, 93 mg; 1e, 117 mg; 1f, 110 mg; 1g, 93 mg; 1h, 143 mg)
in ChCl/Gly (1:2) (2.5 mL) was added I2 (152 mg, 0.60 mmol) under
nitrogen. The mixture was allowed to stir at 25 ꢀC for 5 h and then
extracted with Et2O (6ꢁ5 mL). After evaporation of the solvent, the
products 3aeh were purified by column chromatography on silica
gel using 99: 1 hexaneeAcOEt as the eluent: 3-iodo-4,5-dimethyl-
2-phenylthiophene 3a was a yellow oil (124 mg, 79%); 3-iodo-4,5-
dimethyl-2-p-tolylthiophene 3b was a yellow solid, mp 54e55 ꢀC
(128 mg, 78%); 2-cyclohex-1-enyl-3-iodo-4,5-dimethylthiophene
3c was a yellowish solid, mp 25e26 ꢀC (110 mg, 69%); 2-butyl-3-
4.6. Recycling procedure
To the DES residue obtained as described above was added
a solution of 1 (0.42 mmol) in Et2O (3 mL). The Et2O was removed
under vacuum and then the same procedure described above was
followed.

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R. Mancuso et al. / Tetrahedron 72 (2016) 4239e4244
iodo-4,5-dimethylthiophene 3d was a yellow solid, mp 115e117 ꢀC
(106 mg, 72%); 3-iodo-4,5-dimethyl-2-phenethylthiophene 3e was
a yellow oil (130 mg, 76%); 2-benzyl-3-iodo-4,5-dimethylthiophene
2. For very recent reviews on applications of DESs, see: (a) Abo-Hamad, A.; Hay-
yam, M.; AlSaadi, M. A.; Hashim, M. A. Chem. Eng. J. 2015, 273, 551e567; (b) Tang,
B.; Zhang, H.; Row, K. H. J. Sep. Sci. 2015, 38, 1053e1064; (c) Farran, A.; Cai, C.;
Sandoval, M.; Xu, Y.; Liu, J.; Hernaiz, M. J.; Linhardt, R. J. Chem. Rev. 2015, 115,
6811e6853; (d) Zhao, H. J. Chem. Technol. Biotechnol. 2015, 90, 19e25.
3f was
a yellow oil (125 mg, 76%); 2-tert-butyl-3-iodo-4,5-
3. For recent reviews on the use of DESs as reaction media in organic synthesis,
dimethylthiophene 3g was a yellow solid, mp 114e115 ꢀC (96 mg,
65%); 2-(4-bromophenyl)-3-iodo-4,5-dimethylthiophene 3h was
a colorless solid, mp 104e105 ꢀC (122 mg, 62%). Rf values were as
follows (pure hexane): 3a, 0.76; 3b, 0.69; 3c, 0.81; 3d, 0.83; 3e,
0.63; 3f, 0.63; 3g, 0.82; 3h, 0.72.
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see: (a) García-Alvarez, J. Eur. J. Inorg. Chem. 2015, 5147e5157; (b) García-Alvarez,
J.; Hevia, E.; Capriati, V. Eur. J. Org. Chem. 2015, 6779e6799; (c) Liu, P.; Hao, J.-W.;
Mo, L.-P.; Zhang, Z.-H. RSC Adv. 2015, 5, 48685e48704; (d) Wang, A.; Zheng, X.;
Zhao, Z.; Li, C.; Zheng, X. Prog. Chem. 2014, 26, 784e795; (e) del Monte, F.;
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Carriazo, D.; Serrano, M. C.; Gutierrez, M. C.; Ferrer, M. L. ChemSusChem 2014, 7,
999e1009.
4. For selected very recent examples on the use of DESs as reaction media in or-
ganic synthesis, see: (a) Masolo, E.; Palmieri, S.; Benaglia, M.; Capriati, V.; Perna,
F. M. Green Chem. 2016, 18, 792e797; (b) Martínez, R.; Berbegal, L.; Guillena, G.;
Ramon, D. J. Green Chem. 2016, 18, 1724e1730; (c) Muller, C. R.; Meiners, I.;
Domínguez de María, P. RSC Adv. 2014, 4, 46097e46101; (d) Mallardo, V.; Rizzi,
R.; Sassone, F. C.; Mansueto, R.; Perna, F. M.; Salomone, A.; Capriati, V. Chem.
4.9. Recycling procedure
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€
To the DES residue obtained as described above was added
a solution of 1 (0.50 mmol) and I2 (0.60 mmol) in Et2O (3 mL). The
Et2O was removed under vacuum and then the same procedure
described above was followed.
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Commun. 2014, 8655e8658; (e) Vidal, C.; García-Alvarez, J.; Hernan-Gomez, A.;
Kennedy, A. R.; Hevia, E. Angew. Chem., Int. Ed. 2014, 53, 5969e5973; (f) Sassone,
F. C.; Perna, F. M.; Salomone, A.; Florio, S.; Capriati, V. Chem. Commun. 2015,
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9459e9462; (g) Rodríguez-Alvarez, M. J.; Vidal, C.; Díez, J.; García-Alvarez, J.
Chem. Commun. 2014, 12927e12929; (h) Vidal, C.; Merz, L.; García-Alvarez, J.
4.10. Characterization of thiophenes 3
Green Chem. 2015, 17, 3870e3878; (i) Lu, J.; Li, X.-T.; Ma, E.-Q.; Mo, L.-P.; Zhang,
€
Z.-H. ChemCatChem 2014, 6, 2854e2859; (j) Imperato, G.; Hoger, S.; Lenoir, D.;
€
€
Konig, B. Green Chem. 2006, 8, 1051e1055; (k) Imperato, G.; Vasold, R.; Konig, B.
Adv. Synth. Catal. 2006, 348, 2243e2247.
All thiophenes 3aeh were characterized by spectroscopic
comparison with the corresponding products obtained in our pre-
vious report.7a
5. For very recent reviews on ionic liquids, see: (a) Marr, P. C.; Marr, A. C. Green
́
Chem. 2016, 18, 105e128; (b) Dai, Z.; Noble, R. D.; Gin, D. L.; Zhang, X.; Deng, L. J.
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Membr. Sci. 2016, 497, 1e20; (c) Amde, M.; Liu, J.-F.; Pang, L. Environ. Sci. Technol.
2015, 49, 12611e12627; (d) Greaves, T. L.; Calum, C. J. Chem. Rev. 2015, 115,
11379e11448; (e) Potdar, M. K.; Kelso, G. F.; Schwarz, L.; Zhang, C.; Hearn, M. T.
W. Molecules 2015, 20, 16788e16816; (f) Hayes, R.; Warr, G. G.; Atkin, R. Chem.
Rev. 2015, 115, 6357e6426; (g) Hajipour, A. R.; Rafiee, F. Org. Prep. Proced. Int.
2015, 47, 1e60; (h) Hunt, P. A.; Ashworth, C. R.; Matthews, R. P. Chem. Soc. Rev.
2015, 44, 1257e1288; (i) Xie, Z.-L.; Su, D. S. Eur. J. Inorg. Chem. 2015, 1137e1147;
(j) Jordan, A.; Gathergood, N. Chem. Soc. Rev. 2015, 44, 8200e8237; (k) Zhang, S.;
Dokko, K.; Watanabe, M. Chem. Sci. 2015, 6, 3684e3691; (l) García-Verdugo, E.;
Altava, B.; Burguete, M. I.; Lozano, P.; Luis, S. V. Green Chem. 2015, 17, 2693e2713.
6. We recently described the PdI2/KI-catalyzed heterocyclodehydration of 1-
mercapto-3-yn-2-ols carried out either in a conventional organic solvent, such
as MeOH, or in an IL, such as 1-butyl-3-methylimidazolium tetrafluoroborate
(BmimBF4): Gabriele, B.; Mancuso, R.; Veltri, L.; Maltese, V.; Salerno, G. J. Org.
Chem. 2012, 77, 9905e9909.
Acknowledgements
This research work was partially supported by MIUR PON R&C
2007e2013 Project ‘DIRECT FOOD’ cod. PON01_00878 and by the
Interuniversities Consortium C.I.N.M.P.I.S. (Bari).
Supplementary data
Supplementary data (1H and 13C NMR spectra for all products)
associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2016.05.062.
7. We recently reported the iodocyclization of 1-mercapto-3-yn-2-ols in MeCN or
1-ethyl-3-methylimidazolium ethyl sulfate (EmimEtSO4): (a) Gabriele, B.; Man-
cuso, R.; Salerno, G.; Larock, R. C. J. Org. Chem. 2012, 77, 7640e7645; (b) Mancuso,
R.; Pomelli, C. S.; Chiappe, C.; Larock, R. C.; Gabriele, B. Org. Biomol. Chem. 2014,
12, 651e659.
References and notes
8. For a recent review on the synthesis of iodoheterocycles, including iodothio-
phenes, via iodocyclization of functionalized alkynes, see: Gabriele, B.; Mancuso,
R.; Larock, R. C. Curr. Org. Chem. 2014, 18, 341e358.
9. For a recent review on the synthesis of thiophene derivatives by cyclization of
functionalyzed alkynes, see: Mancuso, R.; Gabriele, B. Molecules 2014, 19,
15687e15719.
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1. For very recent reviews on DESs, see: (a) Bubalo, M. C.; Vidovic, S.; Redovnikovic,
ꢁ
I. R.; Jokic, S. J. Chem. Technol. Biotechnol. 2015, 90, 1631e1639; (b) Kud1ak, B.;
Owczarek, K.; Namiesnik, J. Environ. Sci. Pollut. Res. 2015, 22, 11975e11992; (c)
Smith, E. L.; Abbott, A. P.; Ryder, K. S. Chem. Rev. 2014, 114, 11060e11082; (d)
Paiva, A.; Craveiro, R.; Aroso, I.; Martins, M.; Reis, R. L.; Duarte, A. R. C. ACS
Sustainable Chem. Eng. 2014, 2, 1063e1071.
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