A recyclable and base-free method for the synthesis of 3-iodothiophenes by the iodoheterocyclisation of 1-mercapto-3-alkyn-2-ols in ionic liquids

Article abstract of DOI:10.1039/c3ob41928b

The first example of an iodocyclisation reaction made recyclable by the use of an ionic liquid as the reaction medium is reported. Readily available 1-mercapto-3-alkyn-2-ols were smoothly converted into the corresponding 3-iodothiophenes (50-81% yields, 10 examples) when allowed to react with iodine (1-2 equiv.) in a proper ionic liquid, such as 1-ethyl-3-methylimidazolium ethyl sulfate (EmimEtSO₄), as the solvent under mild reaction conditions (25 °C) and in the absence of an external base. The reaction medium can be recycled several times without significantly affecting the reaction outcome. Theoretical calculations have also been performed to investigate the role of the ionic liquid anion in the reaction. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3ob41928b

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A recyclable and base-free method for the
synthesis of 3-iodothiophenes by the
iodoheterocyclisation of 1-mercapto-3-alkyn-
2-ols in ionic liquids†
Cite this: Org. Biomol. Chem., 2014,
12, 651
Raffaella Mancuso,*a Christian S. Pomelli,b Cinzia Chiappe,b Richard C. Larockc and
Bartolo Gabriele*a
The first example of an iodocyclisation reaction made recyclable by the use of an ionic liquid as the reac-
tion medium is reported. Readily available 1-mercapto-3-alkyn-2-ols were smoothly converted into the
corresponding 3-iodothiophenes (50–81% yields, 10 examples) when allowed to react with iodine
(1–2 equiv.) in a proper ionic liquid, such as 1-ethyl-3-methylimidazolium ethyl sulfate (EmimEtSO4), as
the solvent under mild reaction conditions (25 °C) and in the absence of an external base. The reaction
medium can be recycled several times without significantly affecting the reaction outcome. Theoretical
calculations have also been performed to investigate the role of the ionic liquid anion in the reaction.
Received 23rd September 2013,
Accepted 11th November 2013
DOI: 10.1039/c3ob41928b
www.rsc.org/obc
Recently, we reported a novel application of the iodocycli-
sation approach, which has permitted the direct synthesis of
Introduction
The iodocyclisation of functionalised alkynes, bearing
a
3-iodothiophene derivatives 2 starting from readily available
nucleophilic group in a suitable position, is a powerful 1-mercapto-3-alkyn-2-ols 1, according to eqn (1).2 Reactions
method for the one-step regioselective synthesis of iodine-con- were carried out at 25 °C in MeCN as the solvent, with I2 as the
taining carbo- and heterocyclic derivatives starting from iodine source and in the presence of NaHCO3 as the base
readily available substrates (Scheme 1).1 The reaction is usually (1 : I2 : NaHCO3 molar ratio = 1 : 2 : 2, 1 : 2 : 1, or 1 : 3 : 3,
carried out in an aprotic organic solvent, such as MeCN or depending on the nature of the starting material).
CH2Cl2, in the presence of an electrophilic iodine species (gene-
rally indicated by I+) under mild reaction conditions (room
temperature). The presence of the iodo substituent in the final
product allows for further functionalisation and diversification
ð1Þ
through metal-catalysed cross-coupling reactions, thus increas-
ing the attractiveness of the iodocyclisation process.
As shown in Scheme 1, the iodocyclisation process takes
place through the formation of an iodirenium intermediate
from the reaction between the carbon–carbon triple bond and
I+, followed by intramolecular exo- or endocyclic nucleophilic
attack. The reaction is usually carried out in the presence of a
base (B), necessary to trap the acid generated during the
process.
We have now found that the reaction can also be con-
veniently carried out in ionic liquids (ILs) as the solvent, still
under very mild reaction conditions (25 °C, eqn (2)). The use
of such unconventional media allows one to carry out the iodo-
heterocyclisation process in the absence of the external base
and with the possibility to recycle the reaction medium several
times without significantly affecting the reaction outcome. To
aDipartimento di Chimica e Tecnologie Chimiche, Università della Calabria,
Via P. Bucci, 12/C, 87036 Arcavacata di Rende (CS), Italy.
E-mail: raffaella.mancuso@unical.it, bartolo.gabriele@unical.it
bDipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy
cDepartment of Chemistry, Iowa State University, Ames, Iowa 50011, USA
†Electronic supplementary information (ESI) available: Copies of 1H NMR
spectra for products 2a–2j and tables of atom coordinates and absolute energies.
See DOI: 10.1039/c3ob41928b
Scheme 1 Iodocyclisation of acetylenes bearing
nucleophilic group leading to iodine-containing carbo- and
heterocycles.
a suitably placed
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the best of our knowledge, this is the first example of the use
of ionic liquids as solvents3 in an iodocyclisation reaction. The
screening, carried out using several ILs characterised by sig-
nificant hydrogen bond basicity, shows that substrate conver-
sion and product yields strongly depend on the structure of
the ILs. Additional information about the role played by the IL
anion in the iodocyclisation reaction has been obtained
through a theoretical investigation.
Table 1 Iodocyclodehydration of 4-mercapto-3-methyl-1-phenylpent-
1-yn-3-ol (1a) to 3-iodo-4,5-dimethyl-2-phenylthiophene (2a) in
different ionic liquidsa
Entry
1
Ionic liquid
Yield of 2ab (%)
43
ð2Þ
2
55
40
29
10
13
70
11
7
Results and discussion
Iodoheterocyclisation of 1-mercapto-3-alkyn-2-ols in ionic
liquids
3
4-Mercapto-3-methyl-1-phenylpent-1-yn-3-ol (1a) was chosen as
the model substrate for testing the reactivity of 1-mercapto-
3-alkyn-2-ols in ionic liquids. Initially, the reaction of 1a was
carried out in 3-butyl-1-methyl-imidazolium dicyanamide,
BmimN(CN)2, as the solvent (0.25 mmol of 1a per mL of
solvent) at 25 °C for 24 h, affording the desired 3-iodo-4,5-
dimethyl-2-phenylthiophene (2a) in a 43% isolated yield
(entry 1, Table 1). This result was very promising, since it
suggested the possibility of carrying out the iodoheterocycli-
sation process in an ionic liquid under base-free conditions.
We then tested several other ILs, all characterised by signifi-
cant hydrogen bond basicity (the Kamlet–Taft β values ranged
from 0.44 to 1),4 and the results are reported in Table 1,
entries 2–13. As can be seen from these data, not all of the ILs
tested were equally effective in promoting the process; the best
result in terms of product yield (70%) was observed with
1-ethyl-3-methylimidazolium ethyl sulfate (EmimEtSO4) (entry
7), which was accordingly chosen as the reference solvent to
verify IL recyclability and to generalize the process to other
differently substituted 1-mercapto-3-alkyn-2-ols.
4c
5d
6
7
Regarding the IL recycling experiments, the reaction crude
obtained from 1a in EmimEtSO4 (Table 2, entry 1, run 1) was
extracted with Et2O to separate the 3-iodothiophene 2a, and
then fresh substrates 1a and I2 (1 : 1 molar ratio) were added to
the IL residue and the mixture was allowed to stir at 25 °C for
24 h. Gratifyingly, 2a was formed again in a comparable yield
(68%) with respect to the parent reaction (Table 2, entry 1, run 2).
The recycling procedure was then repeated up to 6 times,
without significant variation of the reaction outcome (Table 2,
entry 1, runs 3–7). We also carried out the reaction with a
slight excess of I2 (1.5 equiv., Table 2, entry 2), but the result
was similar to that obtained using an equimolar amount with
respect to 1a (Table 2, entry 1, run 1).
8
9
10e
29
A variety of 1-mercapto-3-alkyn-2-ols 1 were then allowed to
react under the same reaction conditions successfully
employed for 4-mercapto-3-methyl-1-phenylpent-1-yn-3-ol (1a)
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in order to develop a general, base-free and recyclable syn-
thesis of 3-iodothiophenes 2. The results obtained by varying
the nature of the substituent α to the mercapto group, α to the
hydroxyl group, and on the triple bond are reported in Table 2.
As can be seen, good to excellent yields of the corresponding
3-iodothiophenes were obtained with all of the substrates
tested. In some cases, the reaction worked better with an
excess of I2 (1.5–2 equiv.) with respect to the substrate; this
was particularly evident in the case of a substrate bearing a
hindered triple bond, such as 2-mercapto-3,6,6-trimethylhept-
4-yn-3-ol (2g) (Table 2, entries 13–15). The method also worked
nicely with substrates bearing an additional alkynyl substitu-
ent at C-2, such as 3-(1-mercaptoethyl)-1,5-diphenylpenta-1,4-
diyn-3-ol (1i), which was smoothly converted into the corres-
Table 1 (Contd.)
Entry
11
Ionic liquid
Yield of 2ab (%)
21
12f
13
14
26
ponding
3-iodo-5-methyl-2-phenyl-4-(2-phenylethynyl)thio-
phene (2i) without affecting the additional triple bond
(Table 2, entries 18 and 19). The recycling procedure was
tested in several cases, still with satisfactory results (Table 2;
entries 3, 11, 14, 15 and 19).
a Unless otherwise noted, all iodocyclisation reactions were carried out
under nitrogen at 25 °C for 24 h with a substrate concentration of
0.25 mmol of 1a per mL of ionic liquid. Unless otherwise noted,
substrate conversion was quantitative. The formation of a complex
mixture of products accounted for the difference between substrate
conversion and the yield of 2a. b Isolated yield based on the starting
thiol 1a. c Substrate conversion was 85%. d Substrate conversion was
80%. e Substrate conversion was 55%. f Substrate conversion was 60%.
Theoretical calculations
Data reported in Table 1 show that substrate conversion and
product yields strongly depend on the IL structure. As expected
for a reaction involving a rate determining cyclisation with
proton abstraction, the nature of the IL anion significantly
affected both these parameters, although a simple correlation
a
Table 2 Recyclable and base-free synthesis of 3-iodothiophenes 2 by iodocyclisation of 1-mercapto-3-alkyn-2-ols 1 in EmimEtSO4
Yield of 2b (%)
Entry
1
1
2
Run 1c
70
Run 2c
68
Run 3c
70
Run 4c
71
Run 5c
72
Run 6c
70
Run 7c
72
2d
3
1a
1b
2a
2b
66
65
67
68
62
65
65
60
4d
5
81
54
6d
1c
2c
63
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Table 2 (Contd.)
Yield of 2b (%)
Entry
7
1
2
Run 1c
Run 2c
Run 3c
Run 4c
Run 5c
Run 6c
Run 7c
50
8d
9
1d
1e
1f
2d
2e
2f
62
61
10d
11
69
77
68
25
67
23
69
68
70
71
12d
13
95
20
14d
15e
1g
1g
2g
2g
64
77
60
73
59
70
60
65
65
61
66
60
63
60
16
50
17d
18
1h
2h
62
40
19d
20
1i
2i
81
50
73
76
75
72
73
74
a All reactions were carried out at 25 °C for 24 h in EmimEtSO4 as the solvent (0.25 mmol of starting 1 per mL of solvent). Conversion of 1 was
quantitative in all cases. b Isolated yield based on starting 1. c Run 1 corresponds to the 1st experiment, and the next runs to recycles. See text for
details. d The reaction was carried out with a substrate : I2 molar ratio of 1.5. e The reaction was carried out with a substrate : I2 molar ratio of 2.
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Scheme 2
hypothesize that the IL anion can easily replace the I3− species
as a counterion for I+. Furthermore, another IL anion is prob-
ably involved in the proton abstraction process from the SH
group determining the ring closure. The reaction model
employed is consequently represented in Scheme 2.
Fig. 1 Product yield (%) with respect to IL hydrogen bond acceptor
ability (β). The numbers refer to the entries in Table 1. β values for entries
3, 4, and 6 are not available.
Both the molecular clusters 1ec and 1r carry a total single
between hydrogen bond acceptor ability (β) and conversion/ negative charge and, with the exception of the hydroxyl group,
yield cannot be established (Fig. 1).
all of the functional groups are solvated by the IL anion.
The ILs characterised by a high β value (i.e. chloride 0.94) However, steric and electrostatic interactions exclude the possi-
give relatively low yields and/or conversions. Nevertheless, bility of placing another ion in the proximity of the hydroxyl
EmimNO3 and EmimEtSO4, two ILs characterised by similar group. It is noteworthy that in the calculated reaction paths
β values (0.66 and 0.71, respectively), provide the same product this group interacts alternatively with both of the anions. In
with significantly different yields. In the case of halide based the IL, the interactions between a single charged system of the
ILs, this behaviour can be attributed, at least partially, to the type reported here and the bulk can be considered to be
ability of these anions (Cl− and Br−) to interact with molecular aspecific and, in our approach, disregarded.6 The main weak-
iodine to give trihalide anions (I2Cl−, ICl2−, I3 or I2Br−, IBr2
)
ness of this model might be, however, the total absence of
−
−
that, despite being electrophilic species, are significantly less cations that hamper the evaluation of the role played by the
reactive than the free halogen.5 A similar explanation, however, concurrent interactions between anions–cations and anions–
cannot account for the reactivity of the other anions. There- substrate. However, in a relevant number of computational
fore, to better define the role of the ionic solvent anion in the investigations on chemical reactivity in ILs, one of the two
reaction profile for the iodocyclisation of 1-mercapto-3-alkyn- ions is often omitted. There are indeed computational studies
−
2-ols, a theoretical investigation on three anions (Br−, NO3
on anion related reactions and cation related reactions. In the
and EtSO4−) characterised by similar β values (0.74, 0.66 and first category can be included many metal catalysed reactions,
0.71, respectively), but giving significantly different yields, has in which the metal is coordinated by the IL anion.7 In the
been performed. For this investigation, since the effects of ILs second category are included reactions such as the Diels–Alder
on chemical reactions have not yet been sufficiently rational- cycloaddition,8 in which the specific IL effect is due to the
ised to allow the development of a computational model that hydrogen bonding between the IL cation and the polar group
takes into account their activity, and with a limited compu- on a reagent (the dienophile in the case of the Diels–Alder
tational effort, it was necessary to plan carefully the model cycloadditions). On the other hand, for reactions such as the
system in order to obtain useful data. In particular, consider- Menschutkin substitution,9 in which two neutral reagents give
ing that the iodocyclisation reaction is a multistep process, we a charged product (an ion pair), it is necessary to take into
decided to focus our efforts exclusively on the “critical” step(s). account both IL components. The presently investigated
The reaction implies the initial formation of an iodirenium- process can be classified, with good approximation, as an
(iodide)triiodide intermediate by electrophilic attack of I2 on anion related reaction, although a small cation effect can be
the triple bond, followed by the intramolecular nucleophilic evidenced comparing the yield values obtained in four dicya-
attack of the S atom on the iodirenium carbon to give a hetero- namide based ILs (Table 1, entries 1 and 11–13). The limited
cyclic system. The subsequent dehydration–aromatisation reac- number of data does not allow us to rationalize the cation
tion allows isolation of the aromatic compounds 2. Since the effect; small differences might be due to transport phenomena
formation of an iodirenium ion is generally a reversible related to the different viscosities; however it is possible that
process, we considered as the “key-step” for the development also this parameter might be used to fine tune the reaction
of the model system the cyclisation reaction. At this point, the outcome.
main questions were: (i) what is the IL component that plays a
Finally, to optimize the setup of the computational experi-
specific role during the attack of the SH group on the iodi- ment, it was necessary to select the reaction coordinate and
renium carbon; and (ii) how many IL ions are necessary to the level of the theory to adopt. The reaction coordinate was
define the model system? The iodirenium intermediate is a defined considering as the main target of this reaction the for-
positively charged species; therefore, it is reasonable to mation of the C–S bond, and the distance RSC between sulfur
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and carbon was taken into account. Reactions that involve
organic molecules, without the presence of critical issues like
radical intermediates, carbenes, transition metal catalysts, etc.,
are well described by standard density functional theory.
Therefore, we have chosen the widely used B3LYP functional
and, considering the computational resources available nowa-
days, the use of a triple-zeta basis set has been mandatory. All
of the calculations have been performed using the 6-311++G(d,p)
basis set for hydrogen, second and third row elements. For
heavier elements, like iodine and bromine, we used the triple
zeta LANL0810 basis set with pseudopotentials. LANL08 has
been conceived as a heavy element companion to the 6-311G
basis set family. All calculations have been performed using
the Gaussian package.11
As explained above, to evaluate the role of the IL anion
(size, hydrogen acceptor ability or basicity), we decided to
investigate the effect of EtSO4−, Br− and NO3−. Furthermore,
we have considered two different side chains on the substrate,
investigating the effect of an aliphatic flexible chain (n-butyl
moiety, R = Bu) and of a rigid aromatic ring (phenyl, R = Ph). A
total of six reaction paths have been investigated. The calcu-
lated reaction paths are represented in Fig. 2, whereas some
energetic and geometrical quantities related to the reaction
paths are reported in Table 3. It is noteworthy that all of the
six reaction profiles show minima corresponding to the 1r
structure, at a value of RSC of about 1.8 Å. Furthermore, the
stationary point at about 5 Å corresponded to the structure
1ec. Profiles corresponding to reactions performed in ILs
having the same anion, but on substrates bearing different
substituents, are very similar. It is notable that profiles related
to nitrate-based ILs are very irregular and contain several local
minima connected by transition states.
Table 3 Geometric and energetic quantities related to the reaction
profilesa
Molecular
system
RCS/Å RSH/Å RAH
ΔE
Barrier Structure
Chelate
Bu–Br
1ec 5.131 1.379 2.394 23.63
1h
1r
4.6
1.388 2.371 34.30 10.67
0.00
1.819 2.159 1.498
Ph–Br
1ec 5.067 1.356 3.046 23.69
1ts 4.595 1.380 2.397 28.37 4.68
Cyclic
1r
1.823 2.198 1.490
0.00
Bu–NO3
Ph–NO3
ec
1h
1r
5.300 1.349 4.421 33.35
Chelate
Chelate
Cyclic
4.2
1.879 1.084 55.37 22.02
1.816 2.171 1.006
0.00
1ec 5.026 1.370 1.896 39.54
1h
1r
4.6
1.863 1.091 53.87 14.33
0.00
1.819 2.184 1.004
Bu–EtSO4 1ec 5.001 1.348 3.380 37.55
1h
1r
3.2
1.365 1.929 49.73 12.18
0.00
1.812 2.170 1.004
Ph–EtSO4 1ec 4.937 1.354 2.221 37.28
Cyclic
1h
1r
4.2
1.82
1.356 2.094 43.77 6.49
2.177 1.003 0.00
a Distances in Å; energies in kcal mol−1. The H–A distance is referred
to the atom of the anion nearest to the hydrogen. A = Br for Br−, A = O
for NO3−, A = O for EtSO4−. The structures of 1ec and 1r are shown in
Scheme 2. 1ts = transition state. 1h = higher value of the energy profile
when the transition state is not available. Barrier refers to 1ec→1ts or
1ec→1h ones. 1r→1ts or 1r→1h values correspond to the 1ts or 1h
energies.
and ΔE = 0.14 kcal mol−1. Undoubtedly, the molecular systems
under investigation present several conformational degrees of
freedom (rotation of methyl and phenyl groups, conformation-
al motion of aliphatic substituents, and so on) and conse-
quently it can be too complex for the automated procedures
used to find stationary points, in particular the transition
states. However, useful information can be simply obtained by
the reaction profiles, also without an exact knowledge of the
transition states.
Some relevant structures are shown in Fig. 3. Structures 1ec
represent a situation of optimal solvation in the absence of
any reactive process. In particular, we have found two kinds of
structures:
Attempts to obtain the transition state structures (1ts) were
carried out exclusively for the higher energetic structure (1h) of
each profile, disregarding the other transition states and inter-
mediate minima. Only for the model system based bromide
and a phenyl substituted substrate was it possible to achieve
the goal; consequently, in all of the other cases, we used the
higher energy structure to estimate the activation barrier. It is
noteworthy that for the sole case for which both structures are
available, the difference in the reaction coordinate is 0.005 Å
• The chelated structure, in which one anion is chelated to
the OH and SH moieties. Both of these groups point outward
with respect to the reactive site (the iodirenium complex). A
structure of this type is represented in Fig. 3b.
• The cyclic structure, in which the SH group is coordinated
to the anion pointing toward the reactive site. Structures of
this type are represented in Fig. 3a, c and d.
The chelate structures correspond to higher activation bar-
riers than the cyclic ones. From the geometrical point of view,
the cyclic structures are more similar to the final products. In
particular, the position of the anion coordinating the SH
group is in the cyclic structure nearer to the final location,
thus playing a fundamental role in the reaction pathway.
Related to these structures, some considerations need to be
made for the anion and substrate dependent selectivity
Fig. 2 Reaction profiles (distances in Å and energies in kcal mol−1).
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Fig. 3 Some molecular structures discussed in the paper. (a) 1ec with R = phenyl and A = bromine. (b) 1ec with R = phenyl and A = NO3−. (c) 1ec
with R = phenyl and A = EtSO4−. (d) 1ec with R = butyl and A = EtSO4−. (e) 1r with R = phenyl and A = EtSO4−. (f) 1ts with R = phenyl and A =
bromine.
towards the cyclic or chelate (less reactive) molecular structure
1ec, arising from ab initio calculations. In the case of the
monoatomic bromide ion, the cyclic structure is probably
favoured by the interaction of Br− with the phenyl group on
the substrate. The nitrate anion appears too small to stabilize
the large ring of the cyclic structure and, in contrast, ethyls-
ulfate too sterically hindered to form a chelate system. Comple-
tely different is the situation for the 1r structures. As easily
deduced from the geometrical parameters reported in Table 3
and from Fig. 3, the 1r structures are very similar, regardless of
Fig. 4 Possible resonance structures for phenyl-substituted substrates,
showing the interaction between the hydrogen atom in the ortho posi-
tion of the phenyl ring and the IL anion.
the anion structure and the substituent; they can be con-
sidered to be equivalent from the point of view of bonding and
solvation. Consequently, they have been chosen as zero in the more that the anions always exert the same function, although
energy profiles.
the anion structure, and therefore the extent of the inter-
An accurate analysis of the reaction paths shows further-
It is remarkable that phenyl-substituted substrates are actions, affect significantly the reaction course. In particular,
always characterised by lower activation barriers with respect the anion associated with the iodirenium moiety plays a func-
to the analogous butyl-substituted structures. As shown in tion which is independent of the anion structure and becomes
Fig. 3a and 3c, the hydrogen atom in the ortho position of the totally marginal in 1r, where the charged iodirenium species is
phenyl ring is able to interact with the IL anion due to the transformed into a neutral iodine substituent. In contrast, the
partial positive charge on the related carbon, represented by other anion, initially coordinated to the thiol group and sub-
the resonance structures shown in Fig. 4.
sequently primarily involved in proton abstraction, exerts a
The iodirenium asymmetry, clearly visible in Fig. 3a and 3c function that is profoundly affected by the anion shape, size
(where R = phenyl), but not in 3b and 3d (where R = butyl), and nature. These features determine the structure of 1ec and
reinforces this interpretation. The difference between 1ec consequently the energetic differences between 1ec and 1r.
with A = Br– and R = phenyl (Fig. 3a) and the corresponding The reaction paths involving ethylsulfate and bromide are
1ts structure (Fig. 3f) is essentially
CH2CH(CH3)SH group around its first C–C bond.
a
torsion of the indeed very similar, but the energetic difference between 1ec
and 1r, larger for ethylsulfate, ensures in the latter case a
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minor reversibility of the cyclisation step. The lower yields (0.5, 0.75, or 1.0 mmol) in Et2O (3 mL). The Et2O was removed
characterizing the reactions performed in bromide-based ILs under vacuum and then the same procedure described above
can therefore be ascribed not only to the ability of bromide to was followed.
−
form with I2 less reactive trihalide species (I2Br−, IBr2 and
Characterisation of products. All products 2a–j were charac-
I3−), but also to a higher reversibility of the cyclisation process. terised by spectroscopic comparison with the corresponding
The reversibility of the cyclisation step, related to the stability products obtained in our previous report.2
of 1ec, might be the key factor that determines the IL anion
dependence of this reaction. Since the structure of 1ec is sig-
nificantly affected by anion shape and dimensions, features Conclusions
not affecting the β parameters, calculations help explain the
In conclusion, we have reported the first example of an iodocy-
clisation reaction in several ionic liquids, showing that 1-ethyl-
3-methylimidazolium ethyl sulfate (EmimEtSO4) is the best
poor (if any) correlation found between yields and β.
solvent for this reaction. This has allowed the smooth conver-
sion of a variety of 1-mercapto-3-alkyn-2-ols 1 into the corres-
Experimental
Materials and methods
ponding 3-iodothiophenes 2 under base-free conditions and
with the possibility to recycle the reaction medium several
times without affecting the reaction outcome. The compu-
tational results show that the IL anion strongly affects the cycli-
sation step favouring or disfavouring the right disposition of
the atoms (S–C) involved, depending on the shape and size.
General experimental methods. Melting points were taken
on a Reichert Thermovar apparatus and are uncorrected.
1H-NMR and 13C-NMR spectra were recorded at 25 °C in CDCl3
solutions using a Bruker DPX Avance 300 spectrometer operat-
ing at 300 MHz and 75 MHz, respectively, with Me4Si as an
internal standard. Chemical shifts (δ) and coupling constants
(J) are given in ppm and in Hz, respectively. IR spectra were
taken using a JASCO FT-IR 4200 spectrometer. Mass spectra were
obtained using a Shimadzu QP-2010 GC-MS apparatus at 70 eV
ionisation voltage. Microanalyses were carried out using a Carlo
Erba Elemental Analyzer Mod. 1106. All reactions were analysed
by TLC on silica gel 60 F254 (Merck) or on neutral alumina
(Merck) and by GLC using a Shimadzu GC-2010 gas chromato-
graph and capillary columns with polymethylsilicone + 5% poly-
phenylsilicone as the stationary phase (HP-5). Column
chromatography was performed on silica gel 60 (Merck,
70–230 mesh) or neutral alumina 90 (Merck, 70–230 mesh). Evap-
oration refers to the removal of solvent under reduced pressure.
Preparation of substrates. All starting 1-mercapto-3-alkyn-
2-ols 1a–j were prepared as we had already reported.2 All other
materials were commercially available and were used without
further purification.
Acknowledgements
Thanks are due to the European Commission, FSE (Fondo
Sociale Europeo) and Calabria Region for a fellowship grant to
R.M.
Notes and references
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Chem., 2012, 10, 8041; (d) A. V. Dubrovskiy, N. A. Markina
and R. C. Larock, Comb. Chem. High Throughput Screening,
2012, 15, 451; (e) B. Gabriele, R. Mancuso and R. C. Larock,
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DOI:
10.2174/
Synthetic procedures
13852728113179990034, in press.
General procedure for the iodocyclisation of 1-mercapto-
3-alkyn-2-ols 1a–j to 3-iodothiophenes 2a–j. To a solution of 1
(0.5 mmol) (1a, 103 mg; 1b, 110 mg; 1c, 142 mg; 1d, 106 mg;
1e, 105 mg; 1f, 93 mg; 1g, 93 mg; 1h, 118 mg, 1i, 146 mg; 1j,
178 mg) in EmimEtSO4 (2 mL) was added I2 (127, 190, or
253 mg; 0.5, 0.75, or 1.0 mmol; see Table 1) under nitrogen.
The mixture was allowed to stir at 25 °C for 24 h and then
extracted with Et2O (7 × 3 mL). After evaporation of the solvent,
the products 2a–j were purified by column chromatography on
silica gel using 99 : 1 hexane–AcOEt as the eluent. The IL
residue was reused in the recycling procedure as described
below. The water content as well as the amount of the residual
iodine in the IL residue was not determined, because they did
not affect the outcome of the recycling process.
2 B. Gabriele, R. Mancuso, G. Salerno and R. C. Larock,
J. Org. Chem., 2012, 77, 7640.
3 The use of ILs in organic synthesis has recently attracted a
great deal of attention, due to the very important character-
istics of these non-conventional solvents; they are stable,
non-flammable, non-volatile, recyclable, and in some cases
may even promote organic reactions. For recent books and
reviews, see: (a) T. L. Greaves and C. J. Drummond, Chem.
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Recycling procedure. To the IL residue obtained as
described above was added a solution of 1 (0.5 mmol) and I2
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