An efficient combined electrochemical and ultrasound assisted synthesis of imidazole-2-thiones

Article abstract of DOI:10.1002/adsc.200900359

The electrochemical reduction of 1,3-dialkylimidazolium ionic liquids gave the corresponding N-heterocyclic carbenes that, after reaction with elemental sulfur and ultrasound irradiation, yielded l,3-dialkylimidazole-2-thiones in very high yields. The rea

Full text of DOI:10.1002/adsc.200900359

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DOI: 10.1002/adsc.200900359
An Efficient Combined Electrochemical and Ultrasound Assisted
Synthesis of Imidazole-2-Thiones
Marta Feroci,a,* Monica Orsini,b and Achille Inesia,*
a
Department of Ingegneria Chimica Materiali Ambiente, University “La Sapienza”, via Castro Laurenziano, 7, 00161
Roma, Italy
Fax : (+39)-06-497-66749; phone: (+39)-06-497-66563; e-mail: marta.feroci@uniroma1.it or achille.inesi@uniroma1.it
Department of Elettronica Applicata, University Roma Tre, via Vasca Navale, 84, 00146 Roma, Italy
b
Received: May 22, 2009; Revised: June 24, 2009; Published online: September 8, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900359.
Abstract: The electrochemical reduction of 1,3-di-
ACHTUNGTRENNUNGalkylimidazolium ionic liquids gave the correspond-
also used as complexing agents in electroless plating
solutions.[4]
ing N-heterocyclic carbenes that, after reaction with
elemental sulfur and ultrasound irradiation, yielded
1,3-dialkylimidazole-2-thiones in very high yields.
The reaction is very clean, produces no side-prod-
ucts and avoids the use of any other added reagent.
More recently, these heterocycles have been em-
ployed as precursors of ionic liquids in entirely
halide-free forms, by oxidative desulfurization with
benzoyl peroxide.[5] In fact, one of the major problems
in the use of ionic liquids is their purity, due mainly
to halide impurities that derive from the non-exhaus-
tive anion exchange in their synthesis.
Keywords: electrochemistry; imidazole-2-thiones;
imidazole2-ylidenes; ionic liquids; sulfur
Since the first synthesis of 1-substituted imidazole-
2-thiones was established by Marckwald in 1889,[6] by
the reaction of a isothiocyanate with an amino acetal,
many synthetic routes to this important class of com-
pounds have been described.
Imidazole-2-thiones are important molecules used in
There are two main strategies of synthesis: a cycli-
the pharmaceutical and chemical industry. They are, zation of linear thioureas and the sulfurization of N-
in fact, important drugs. In particular, methimazole heterocyclic carbenes. Matsuda and co-workers[7] car-
(I) and carbimazole (II) (Figure 1) are the most com- ried out the synthesis of 1-substituted imidazole-2-thi-
monly used drugs for treatment of hyperthyroidism,[1] ones by cyclization of a substituted thiourea in a one-
as they block thyroid hormone biosynthesis by inhibit- pot reaction between an isothiocyanate and amino
ing the thyroid peroxidase (TPO)-catalyzed iodina- acetal in toluene, with concentrated HCl, at 1108C for
tion of tyrosine residues in thyroglobulin. Methima- 1–3 h; Schreiner and co-workers,[5] instead, synthe-
zole derivatives can be utilized as inhibitors of cell ad- sized these compounds by thioureidation of N-butyl-
hesion in cell adhesion-mediated pathologies.[2]
glycinate and subsequent reduction with sodium boro-
Moreover, they have been used as efficient catalysts hydride (55% yield from ethyl N-butylglycinate). N-
in cross-linking reactions between polymers with Substituted imidazole-2-thiones have been also syn-
pendent anhydrides and polymers with hydroxy or thesized by the electrochemically induced cyclization
epoxy functionality.[3] Imidazole-2-thiones have been of phenacyl azide thiosemicarbazones, on a mercury
cathode.[8]
The alternative way for the synthesis of these com-
pounds is the one patented by Arduengo,[9] that is, the
reaction of sulfur with an N-heterocyclic carbene, ob-
tained by reaction of a strong base with an imidazoli-
um salt, either in methanol over a period of 24 h, or
in solventless conditions in 20 h, obtaining imidazole-
2-thiones in high yields. The same reaction has been
carried out by O. Yang and co-workers,[10] with BuLi
in THF at À788C or with EtMgBr, in THF at room
Figure 1. Structures of drugs methimazole and carbimazole. temperature; in this case the yields in thiones are 40–
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Marta Feroci et al.
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84%. Also Lei and co-workers[11] used an imidazolium electrolysis, elemental sulfur was added to the catho-
salt for the synthesis of thiones, by reaction with po- lyte and the mixture left under stirring at room tem-
tassium thioacetate or thiocyanate, under solventless perature. After two hours, the corresponding thione
conditions and under microwave irradiation, obtain- 2a was isolated in 35% yield (after extraction with di-
ing 1,3-disubstituted imidazole-2-thiones in 35–70% ethyl ether) (Table 1, run 1).
yields.
As the literature reports that this reaction requires
Herein we report the first example of the reaction long times,[9] in order to accelerate it we tried to fur-
of an electrogenerated N-heterocyclic carbene with nish heat. As reported in Table 1, run 2, this “expedi-
elemental sulfur accelerated by ultrasound irradiation, ent” gave no result (34% yield in 2a).
yielding imidazole-2-thiones in very high yields and
short times.
An increase in the number of Faradays per mol of
S increased the yield (45% at 2.0 F/mol, run 4), but
The electrochemical reduction of a 1,3-substituted not to a satisfactory value, while diminishing the con-
imidazolium ion is a monoelectronic process that centation of sulfur from 2 mmol in 1.5 mL to 1 mmol
leads to the formation of the corresponding carbene in the same volume (run 5) gave the same result, leav-
and dihydrogen (Scheme 1).[12]
ing the ionic liquid cleaner (and so more easily reusa-
ble). To try to increase the yield, we combined vari-
ous factors, following the reaction Scheme reported in
Scheme 3.
Scheme 1. Electrochemical reduction of imidazolium salts.
This methodology for the generation of carbenes
permits one to avoid the use of strong bases and the
formation of by-products[13] (the imidazolium salt, an
ionic liquid, acts as solvent, as supporting electrolyte
and as reagent, needing no other compound in the
Scheme 3. General Scheme of reaction.
D is the heat furnished to the system at the end of
electrolytic cell). This singlet carbene[14] can behave as the electrolysis and after the addition of sulfur, while
a base or a nucleophile.[15] When reacting with ele- US stands for ultrasound irradiation; we tried with
mental sulfur, it acts as nucleophile, opening the heat (runs 7 and 8) with good results (73 and 88%
eight-membered ring of sulfur and probably giving a yields), and with ultrasound irradiation, that gave the
linear intermediate (Scheme 2) (an analogous mecha- best results (runs 9–12).[18]
nism has been reported in the case of the reaction be-
Having established that 10 min of ultrasound irradi-
ation were sufficient to obtain a complete conversion
tween elemental sulfur and phosphonium ylides).[16]
As at the end of the reaction all eight atoms of (run 11), we tried to establish if a lower amount of
sulfur have been used, S7 can re-enter the reaction electricity was sufficient, but with negative results
and go on till all sulfur atoms are used.
(runs 16 and 17); we also checked the influence of the
Our first attempt to synthesize thiones used BMIM counter ion of BMIM in this reaction. The anion has
BF4 (1-butyl-3-methylimidazolium tetrafluoroborate) an appreciable effect on this synthesis, but the yields
(1a) as starting ionic liquid, 1.0 Faraday per mol of S remain always high (78–99%, runs 11 and 13–15), the
and the experimental conditions used in our previous fluorinated ones being the best.
papers regarding the electrochemical generation of
Last, this reaction was extended to imidazolium
carbene,[17] that is, a divided cell, N2 atmosphere, ionic liquids containing different substituents on the
room temperature, platinum electrodes and galvano- nitrogen atoms, and in all cases the yields of isolated
static conditions (I=30 mAcmÀ2). At the end of the thiones were very high (runs 18–22 and 24), with the
Scheme 2. Hypothesis for mechanism.
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An Efficient Combined Electrochemical and Ultrasound Assisted Synthesis
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Table 1. Electrochemical reduction of ionic liquids (ILs) 1a–
k,[a] followed by the addition of elemental sulfur.[b] Energy
was supplied to the catholyte (heat, or ultrasound irradia-
tion US[c]) for a time t (see Scheme 3).
mixture, due to a de-allylation reaction that probably
occurred during the electrolysis.
As one of the characteristics that renders ionic liq-
uids interesting solvents is their recyclability, the cath-
olyte relative to run 11 of Table 1 was kept under re-
duced pressure at room temperature for 30 min (to
eliminate the residues of diethyl ether) after having
extracted 1-butyl-3-methylimidazole-2-thione, and
then reused for an electrolysis. This procedure was
carried out for four times, and in all cases very high
yields of 2a were obtained (as reported in Table 2),
confirming the important role of this kind of solvent
in modern chemistry.
Run 1,
R[d]
1,
anion
F/mol D or Irrad.
2
of S
US
time
[%][e]
À
1[f] 1a, C4
2[f] 1a, C4
3[f] 1a, C4
4[f] 1a, C4
BF4À
1.0
1.0
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
–
2 h
2a, 35[10]
2a, 34
2a, 41
2a, 45
2a, 46
2a, 35
2a, 73
2a, 88
BF4À
BF4À
BF4À
BF4À
BF4À
BF4À
BF4À
BF4À
BF4À
BF4À
BF4
608C 2 h
–
–
–
–
2 h
2 h
2 h
20 h
5
6
7
8
1a, C4
1a, C4
1a, C4
1a, C4
1a, C4
1a, C4
1a, C4
1a, C4
1b, C4
608C 20 h
1008C 20 h
9
US
US
US
US
US
US
US
US
US
US
US
US
US
US
US
US
30 min 2a, 99
20 min 2a, 99
Table 2. Recycle of BMIM BF4 in the synthesis of 1-butyl-3-
methyl-1H-imidazole-2(3H)-thione 2a.[a]
10
11
12
13
10 min 2a, 99
5 min 2a, 78
10 min 2a, 81
10 min 2a, 99
10 min 2a, 92
10 min 2a, 51
10 min 2a, 72
10 min 2e, 99[10]
10 min 2f, 99
10 min 2g, 99[9b]
10 min 2h, 99
10 min 2i,[j] 7510
10 min 2j,[k] 57[10]
10 min 2k, 86[10]
Cycle
1[b]
99
2
3
4
5
À
MeSO4 2.0
À
14[g] 1c, C4
PF6
2.0
2.0
1.0
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
% 2a
99
99
99
95
15
16
17
18
19
1d, C4
1a, C4
1a, C4
1e, C2
1f, C6
IÀ
[a]
À
Electrolysis conditions as in Table 1, run 11.
Same electrolysis of Table 1, run 11, reported for a useful
comparison.
BF4À
BF4À
BF4À
BF4À
BF4À
BF4À
[b]
20[h] 1g, C8
21[h] 1h, C10
In conclusion, we have carried out a combined elec-
22[i] 1i, PhCH2 BF4
trochemical and ultrasound assisted synthesis of 1,3-
disubstituted imidazole-2-thiones by cathodic reduc-
tion of an imidazolium ionic liquid (that behaves as
solvent, supporting electrolyte and reagent), yielding
23[i] 1j, Allyl
24
ClÀ
À
1k, HOEt BF4
[a]
Divided cell, Pt electrodes (apparent area: ca. 1 cm2),
room temperature, N2 atmosphere, galvanostatic condi- the corresponding carbene. The reaction of this elec-
tions (30 mA/cm2), catholyte: 1.5 mL IL 1a–k, anolyte:
0.5 mL IL 1a–k.
1 mmol (if not otherwise stated) of S8 was added at the
end of the electrolysis to the catholyte.
trogenerated carbene with elemental sulfur, induced
by ultrasound irradiation, gave 1,3-disubstituted imi-
dazole-2-thiones in very high yields. The use of a sol-
vent with very low vapour pressure, along with the
possibility of its recycle without any loss of reactivity,
renders this synthesis environmental friendly.
[b]
[c]
[d]
22.5 kHertz.
C4: n-butyl; HO-Et: 2-hydroxyethyl; C2: ethyl; C6: n-
hexyl; C8: n-octyl; C10: n-decyl.
[e]
[f]
Yields are based on starting sulfur.
2 mmol of S8 were used.
During this electrolysis it was necessary to add BMIM
[g]
BF4 into the anodic compartment as the anodic process
(oxidation of PF6 to PF5 and F) led to the formation of
Experimental Section
À
a foam that lowered very much the conductivity of the
anolyte.
This electrolysis was carried out at 508C, due to the high
viscosity of this ionic liquid.
This electrolysis was carried out at 808C, due to the melt-
ing point of this ionic liquid.
The work-up of this electrolysis led to a less efficient ex-
traction of 2i from the catholyte due to the fact that IL
Constant current electrolyses were carried out using a glass
two-compartment home-made cell. Anolyte (ca. 0.5 mL)
and catholite (ca. 1.5 mL) were separated through a glass
[h]
[i]
disk (porosity 4). The electrode apparent surface areas were
1.0 cm2 for the cathodic Pt spiral (99.9%) and 0.8 cm2 for
the anodic Pt spiral (99.9%). The current density was
[j]
30 mA/cm2.
Preparative electrolyses were carried out at room temper-
ature, under nitrogen atmosphere, using IL 1 as anolyte and
catholyte. After the consumption of the number of Faradays
per mol of sulfur reported in Table 1, the current was
switched off and elemental sulfur was added to the catholyte
(see Table 1, note b). The mixture was kept at room temper-
ature, or at 608C, or at 1008C for the required time
(Table 1). Otherwise, it was submitted to ultrasound irradia-
1i is solid at room temperature.
1-Methylimidazole was obtained in this case, due to a de-
allylation reaction.
[k]
exception
of
1-allyl-3-methylimidazole-2-thione
(run 23) that was isolated in 57% yield. In this case,
1-methylimidazole was also isolated from the cathodic tion (22.5 kHz, 100 W).
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Marta Feroci et al.
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The catholyte was extracted with diethyl ether (10 mL) References
for three times, the solvent was removed under reduced
1
pressure and the residue was analyzed by H NMR. Yields
were based on starting sulfur. When the purity of the corre-
sponding thione 2 was not acceptable, the residue was puri-
fied by flash chromatography (n-hexane/ethyl acetate=7/3),
affording the corresponding pure 2. All known compounds
gave spectral data in accordance with the ones reported in
the literature.
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Recycle of IL 1a
After the extraction of product 2a from the solution, the
catholyte was kept under vacuum at room temperature for
30 min to eliminate diethyl ether residues, then it was used
as catholyte for the following electrolysis, adding 1 mmol of
new IL in replacement of the one converted in thione.
1-Hexyl-3-methyl-1H-imidazole-2(3H)-thione (2f): Brown
oil; 1H NMR (200 MHz, CDCl3): d=6.64 (s, 2H), 3.96 (t,
2H, J=7.4 Hz), 3.56 (s, 3H), 1.74–1.67 (m, 2H), 1.32–1.20
(m, 6H), 0.83 (app. t, 3H, J=6.3 Hz); 13C NMR (50 MHz,
CDCl3): d=162.0, 117.5, 116.4, 48.0, 35.0, 31.3, 28.8, 26.1,
22.4, 13.9; EI-MS, m/z=200 (6%, M+ +2), 198 (57%, M+.),
169 (5%), 165 (100%), 141 (10%), 114 (27%); anal. calcd.
for C10H18N2S: C 60.56, H 9.15, N 14.12; found: C 60.58, H
9.18, N 14.09.
1-Decyl-3-methyl-1H-imidazole-2(3H)-thione (2h): Brown
oil; 1H NMR (200 MHz, CDCl3): d=6.63 (s, 2H), 3.95 (t,
2H, J=7.3 Hz), 3.55 (s, 3H), 1.74–1.66 (m, 2H), 1.26–1.19
(m, 14H), 0.81 (app. t, 3H, J=6.3 Hz); 13C NMR (50 MHz,
CDCl3): d=162.0, 117.4, 116.4, 48.0, 34.9, 31.8, 29.4, 29.4,
29.2, 29.1, 28.8, 26.5, 22.6, 14.0. EI-MS: m/z=254 (29%,
M+.), 221 (100%), 128 (9%), 141 (10%), 114 (24%); anal.
calcd. for C14H26N2S: C 66.09, H 10.30, N 11.01; found: C
66.12, H 10.33, N 10.99.
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Acknowledgements
This study was supported by MIUR (PRIN 2006) and CNR
(Rome).
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2070
asc.wiley-vch.de
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2067 – 2070