Unexpected microwave reaction of 1,3-disubstituted imidazolium salts: A novel synthesis of 1,3-disubstituted imidazole-2-thiones

Article abstract of DOI:10.1080/00397910601038947

Microwave-promoted reaction of 1,3-disubstituted imidazolium salts with potassium thioacetate or potassium thiocyanate under solvent-free conditions provided a rapid and efficient synthesis of 1,3-disubstituted imidazole-2-thiones. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601038947

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Unexpected Microwave Reaction of
1,3‐Disubstituted Imidazolium Salts: A
Novel Synthesis of 1,3‐Disubstituted
Imidazole‐2‐thiones
Xiao‐Le Tao a , Ming Lei a & Yan‐Guang Wang a
a Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang, China
Published online: 06 Feb 2007.
To cite this article: XiaoLe Tao , Ming Lei & YanGuang Wang (2007) Unexpected Microwave Reaction of
1,3‐Disubstituted Imidazolium Salts: A Novel Synthesis of 1,3‐Disubstituted Imidazole‐2‐thiones, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:3,
399-408, DOI: 10.1080/00397910601038947
To link to this article: http://dx.doi.org/10.1080/00397910601038947
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Synthetic Communicationsw, 37: 399–408, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601038947
Unexpected Microwave Reaction of 1,3-
Disubstituted Imidazolium Salts: A Novel
Synthesis of 1,3-Disubstituted Imidazole-2-
thiones
Xiao-Le Tao, Ming Lei, and Yan-Guang Wang
Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang,
China
Abstract: Microwave-promoted reaction of 1,3-disubstituted imidazolium salts with
potassium thioacetate or potassium thiocyanate under solvent-free conditions
provided a rapid and efficient synthesis of 1,3-disubstituted imidazole-2-thiones.
Keywords: microwave, imidazole-2-thiones, potassium thioacetate, potassium
thiocyanate
Imidazole-2-thiones are important organic compounds that have attracted
considerable attention because of their pharmacological activities. Some
imidazole-2-thione derivatives, such as 1-methylimidazole-2-thione (Methima-
zolew), have been clinically used for the treatment of several diseases.[1–3]
Imidazole-2-thione C-nucleosides are synthetic precursors of azidonucleosides
and fluronucleosides, which possess anti-AIDS activity.[4] Imidazole-2-
thiones have been used as rubber antioxidants[5] and as accelerators of
rubber vulcanization in industry.[6] 1,3-Disubstituted imidazole-2-thiones
are a class of versatile catalysts.[7,8] Furthermore, imidazole-2-thiones are
light-sensitive photographic[9] and high-speed photothermographic
materials.[10] Additionally, 1-propenyl-3-methylimidazole-2-thione is very
useful in the manufacture of printed circuit board.[11] Traditionally,
imidazole-2-thiones are prepared by reaction of an imidazolium ion with
Received April 17, 2006
Address correspondence to Ming Lei, Department of Chemistry, Zhejiang Univer-
sity, Hangzhou, Zhejiang 310027, China. E-mail: minglei701@yahoo.com.cn
399

400
X.-L. Tao et al.
Scheme 1.
sulfur in the presence of methanolic potassium carbonate (Scheme 1),[12] or
with sulfur dioxide, sulfines, or N-sulfinylamines.[13] In the reaction of imida-
zolium ion with sulfur, imidazol-2-ylidenes (carbenes) formed by deprotona-
tion of the imidazolium cations were presumed to be intermediates. The
synthesis is remarkably insensitive to varied conditions that allow different
substituents to be accommodated on the imidazole ring. The reaction can
even be run under dry air, but moisture is not well tolerated.[14] As part of
our interest in microwave-promoted organic transformations,[15] herein we
report a new procedure for the synthesis of 1,3-disubstituted imidazole-2-
thiones under microwave irradiation and solvent-free conditions.
In our initial experiments, we found unexpected that when a mixture of
1,3-disubstituted imidazolium salt and potassium thioacetate was heated
under microwave irradiation (50–200 W) for 5–15 min, 1,3-disubstituted
imidazole-2-thiones 1 could be obtained in moderate yields (Scheme 2
method A). A variety of 1,3-disubstituted imidazolium salts were examined,
and the results are summarized in Table 1 Interestingly, when we replaced
potassium thioacetate with potassium thiocyanate (Scheme 2) the same
products were obtained in improved yields under similar conditions
(Table 1 method B). It is noteworthy that the reaction did not work when con-
ventional heating was used.
As shown in Table 1, when irradiated at 50 W for 5 min, 1-n-butyl-3-
.
methylimidazolium tetrafluoroborate (bmim BF4) was transformed into 1a
in a comparatively low yield (method A: 45%, method B: 52%) (Table 1
entry 1). Both increasing the irradiation power (up to 100 W) and prolonging
the reaction time (up to 10 min) could improve the yields (Table 1, entries 2
and 3). However, further increasing the irradiation power (up to 200 W) led to
lower yields (Table 1, method A: entries 3 and 4; method B: entry 4).
Scheme 2.

Table 1. Microwave-assisted synthesis of 1,3-disubstituted imidazole-2-thionesa
Isolated yield
(%)
Time (min)
Power (w)
Entry
R1
Me
R2
X
A
B
A
B
Products
A
B
1
2
Bu
Bu
Bu
Bu
Bu
Bu
Me
Et
BF4
BF4
BF4
BF4
Br
Cl
5
5
50
100
150
200
100
100
100
100
100
100
100
150
100
100
150
100
50
100
150
200
150
150
150
150
150
150
150
200
150
150
200
150
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
45
60
48
35
60
58
52
55
63
65
70
65
65
58
70
68
52
62
70
60
68
66
65
68
69
70
70
68
65
62
75
75
Me
Me
Me
Me
Me
Me
Me
Et
10
10
15
10
10
8
10
10
15
10
10
10
10
10
10
10
10
10
8
3
4
5
6
7
I
8
Br
Cl
10
10
10
10
10
10
8
9
Bu
10
11
12
13
14
15
16
Et
CH2CH(CH3)2
CH3(CH2)11
PhCH2
Cl
Me
Me
Me
Me
PhCH2
Et
Br
Br
Br
Br
Br
Br
1g
1h
1i
CH2CO2Et
CH2CH55CH2
PhCH2
10
10
10
10
1j
1k
PhCH2
aMethod A: methylimidazolium (5 mmol), potassium thioacetate (1.2 equiv), 50–200 W power, 5–15 min.
Method B: methylimidazolium (5 mmol), potassium thiocyanate (1.2 equiv), 50–200 W power, 5–15 min.

402
X.-L. Tao et al.
We investigated the by-products for the synthesis of 1-n-butyl-3-methy-
limidazole-2-thione (1a). S-Methyl ethanethioic acid ester (2) and S-butyl
ethanethioic acid ester (3) were detected by gas chromatography-mass
spectra (GC-MS). These products presumably resulted from the nucleophi-
lic attack of potassium thioacetate on the methyl and butyl groups of the
imidazolium cation (Scheme 3). For this reason, it can be presumed that
the bulky group substituted imidazolium salts (Table 1, entries 11 and
16) should give comparatively higher yields than the small group substi-
tuted imidazolium salts (Table 1, entries 7 and 8). These observations
were also accordance with Gleen’s report that 1,3-dialkylimidazolium
cation decomposes in the presence of nucleophiles (thiophenol, sodium
thiophenolate, etc.) under microwave-heating conditions.[16]
In the reaction of 1-hydroylethyl-3-methyl imidazolium chloride (4) with
potassium thioacetate (1.2 equiv), besides the expected product 5[8,9] (24%
yield), acetyl substituted imidazole-2-thione (6) was also isolated in 32%
yield. When 2.5 equiv of potassium thioacetate was used, compound 6 was
obtained in 63% yield as a single product (Scheme 4).
The method was also applied for synthesis of the bridged imidazole-2-
thione 8, a ligand that could form complexes with mercury, palladium, and
copper salts[17] from the corresponding imidazolium salt 7 as show in
Scheme 5.
In a comparative experiment, the present procedure gave compound 1 h
in 65% yield, whereas the traditional method[13] resulted in a imidazole-2-
thione 9 with ester exchange in poor yield (Scheme 6). It is noteworthy that
the reaction could be carried out in the presence of a small amount of a
water using our procedure.
In summary, we have developed a practical synthesis of 1,3-disubstituted
imidazole-2-thiones via a microwave-promoted reaction of imidazolium salts
with potassium thioacetate or potassium thiocyanate under solvent-free con-
ditions. Compared with the traditional methods, the present protocol is
rapid, facile, and efficient. The reaction could be carried out in the presence
of a small amount of water. The mechanisms of these transformations are
under investigation and will be reported due course.
Scheme 3.

1,3-Disubstituted Imidazole-2-thiones
403
Scheme 4.
EXPERIMENTAL
All chemicals were reagent grade and used as purchased. 1H NMR spectra were
recorded in deuterated solvent on Bruker Avance-500 spectrometer operating
at 500 MHz or on Bruker Avance-300 spectrometer operating at 300 MHz. 13
C
NMR spectra were recorded at 125 MHz. Infrared spectra were recorded on a
Nicolet 470 Nexus FT-IR spectrometer and measured as thin film or in KBr.
ESI-MS spectra were recorded on a Bruker Daltonics Esquire 3000 plus instru-
ment. Melting points were measured on WRS-1B digital melting-point
apparatus. Capillary gas chromatography was performed on a Hewlett-
Packard HP 6890 gas chromatograph/mass spectra instrument (GC/MS).
General Procedure for Synthesis of 1,3-Disubstituted Imidazole-2-
thiones
1-n-Butyl-3-methyl-imidazolium tetrafluoroborate (5 mmol) and potassium
thioacetate or potassium thiocyanate (1.2 equiv) were mixed thoroughly and
then irradiated at 100 W for 10 min. (In the case of the reaction using
potassium thiocyanate, direct contact with the possible cyanide by-products,
such as hydrogen cyanide (HCN) and cyanopotassium (KCN), should be
avoided, although they have not been confirmed.) The mixture was cooled
to room temperature, diluted with ethyl ether (25 ml), washed with water,
Scheme 5.

404
X.-L. Tao et al.
Scheme 6.
and dried over anhydrous sodium sulfate. Removal of the solvent under
reduced pressure gave a crude product, which was purified by column chrom-
atography on silica gel using EtOAc/hexane (1:4) to give pure 1-n-butyl-3-
methylimidazole-2-thione (1a).
Data
1
1-n-Butyl-3-methylimidazole-2-thione (1a): Brown oil; H NMR (500 MHz,
CDCl3): d ¼ 6.71 (d, 1H, J ¼ 2.3 Hz), 6.70 (d, 1H, J ¼ 2.3 Hz), 4.03 (t,
2H, J ¼ 7.4 Hz), 3.61 (s, 3H), 1.74–1.77 (m, 2H), 1.35–1.40 (m, 2H), 0.96
(t, 3H, J ¼ 7.4 Hz) ppm; 13C NMR (125 MHz, CDCl3): d ¼ 162.4, 117.7,
116.6, 47.8, 35.1, 31.0, 19.8, 13.7 ppm; FT-IR (neat): 3108, 3094, 2976,
2936, 1568, 1462, 1415, 1330, 1263, 1223, 1168 cm21; MS (ESI): m/z 171
([MþH]þ).
1,3-Dimethylimidazole-2-thione (1b): White solid; mp 182–183.88C; 1H
NMR (500 MHz, CDCl3): d ¼ 6.71 (s, 2H), 3.57 (s, 6H) ppm; 13C NMR
(125 MHz, CDCl3): d ¼ 162.1, 117.7, 40.7 ppm; FT-IR (KBr): 3105, 3098,
2980, 2933, 1569, 1458, 1420, 1330, 1271, 1219, 1158 cm21; MS (ESI):
m/z 129 ([M þ H]þ).
1
1-Ethyl-3-methylimidazole-2-thione (1c): Brown oil; H NMR (500 MHz,
CDCl3): d ¼ 6.70 (d, 1H, J ¼ 2.2 Hz), 6.69 (d, 1H, J ¼ 2.2 Hz), 4.08 (q 2H,
J ¼ 7.1 Hz), 3.61 (s, 3H), 1.37 (t, 2H, J ¼ 7.2 Hz) ppm; 13C NMR
(125 MHz, CDCl3): d ¼ 162.1, 117.9, 116.0, 43.1, 35.2, 14.4 ppm; FT-IR
(neat): 3098, 3078, 2976, 2936, 1568, 1465, 1425, 1327, 1268, 1223,
1161 cm21; MS (ESI): m/z 143 ([MþH]þ).
1
1-n-Butyl-3-ethylimidazole-2-thione (1d): Brown oil; H NMR (500 MHz,
CDCl3): d ¼ 6.71 (d, 1H, J ¼ 2.3 Hz), 6.70 (d, 1H, J ¼ 2.3 Hz), 4.10 (q,
2H, J ¼ 7.2 Hz), 4.01 (t, 2H, J ¼ 7.4 Hz), 1.74–1.77 (m, 2H), 1.38–1.42
(m, 2H), 1.38 (t, 3H, J ¼ 7.2 Hz), 0.95 (t, 3H, J ¼ 7.3 Hz) ppm; 13C NMR

1,3-Disubstituted Imidazole-2-thiones
405
(125 MHz, CDCl3): d ¼ 162.3, 117.9, 116.6, 46.8, 35.1, 31.1, 19.8, 14.4,
13.7 ppm; FT-IR (neat): 3106, 3082, 2976, 2944, 1570, 1467, 1415, 1335,
1263, 1224, 1173 cm21; MS (ESI): m/z 185 ([MþH]þ); anal. calcd. for
C9H16N2S: C, 58.65; H, 8.75; N, 15.20. Found: C, 58.75; H, 8.79; N, 15.08.
1
1-iso-Butyl-3-ethylimidazole-2-thione (1e): Brown oil; H NMR (500 MHz,
CDCl3): d ¼ 6.71 (d, 1H, J ¼ 2.1 Hz), 6.67 (d, 1H, J ¼ 2.1 Hz), 4.11 (q, 2
H, J ¼ 5.4 Hz), 3.86 (d, 2H, J ¼ 7.4 Hz), 2.20–2.26 (m, 1H), 1.37 (t, 3H,
J ¼ 7.4 Hz), 0.95 (d, 6H, J ¼ 6.7 Hz) ppm; 13C NMR (125 MHz, CDCl3):
d ¼ 161.8, 117.8, 115.8, 55.3, 42.9, 29.9, 28.2, 20.1, 14.4 ppm; FT-IR
(neat): 3103, 3094, 2966, 2940, 1568, 1463, 1414, 1337, 1263, 1223,
1170 cm21; MS (ESI): m/z 185 ([MþH]þ); anal. calcd. for C9H16N2S:
C, 58.65; H, 8.75; N, 15.20. Found: C, 58.73; H, 8.80; N, 15.10.
1-n-Dodecyl-3-methylimidazole-2-thione (1f): Brown oil; 1H NMR (500 MHz,
CDCl3): d ¼ 6.72 (d, 1H, J ¼ 2.3 Hz), 6.70 (d, 1H, J ¼ 2.3 Hz), 4.03 (t, 2H,
J ¼ 7.4 Hz), 3.61 (s, 3H), 1.73–1.75 (m, 2H), 1.28–1.30 (m, 18H), 0.96 (t, 3
H, J ¼ 7.4 Hz) ppm; 13C NMR (125 MHz, CDCl3): d ¼ 162.5, 117.8, 116.6,
47.7, 35.4, 31.0, 28.5, 27.6, 27.2, 26.8, 26.5, 26.2, 25.8, 25.5, 19.8, 13.7 ppm;
FT-IR (neat): 3105, 3088, 2965, 2935, 1572, 1470, 1425, 1338, 1255, 1223,
1172 cm21; MS (ESI): m/z 283 ([MþH]þ); anal. calcd. for C16H30N2S: C,
68.03; H, 10.70; N, 9.92. Found: C, 68.25; H, 10.75; N, 9.87.
1
1-Benzyl-3-methylimidazole-2-thione (1g): Brown oil; H NMR (500 MHz,
CDCl3): d ¼ 7.29–7.33 (m, 5H), 6.66 (d, 1H, J ¼ 2.2 Hz), 6.56 (d, 1H,
J ¼ 2.2 Hz), 5.24 (s, 2H), 3.63 (s, 3H) ppm; 13C NMR (125 MHz,
CDCl3): d ¼ 162.4, 129.0, 128.4, 128.2, 118.1, 116.4, 51.5, 35.4 ppm; FT-
IR (neat): 3110, 3094, 2978, 2932, 1578, 1455, 1412, 1330, 1263, 1223,
1155 cm21; MS (ESI): m/z 205 ([MþH]þ).
1-Ethoxyacetyl-3-methylimidazole-2-thione (1h): Brown oil; 1H NMR
(500 MHz, CDCl3): d ¼ 6.78 (d, 1H, J ¼ 2.2 Hz), 6.74 (d, 1H, J ¼ 2.2 Hz),
4.86 (s, 2H), 4.25 (q, 2H, J ¼ 7.1 Hz), 3.61 (s, 3H) 1.30 (t, 3H, J ¼ 7.1 Hz)
ppm; 13C NMR (125 MHz, CDCl3): d ¼ 167.6, 163.8, 118.0, 117.4, 62.0,
48.8, 35.4, 14.2 ppm; FT-IR (neat): 3126, 2987, 2936, 1732, 1570, 1466,
1425, 1403, 1389, 1250, 1224, 1147, 1029 cm21; MS (ESI): m/z 201
([MþH]þ); anal. calcd. for C8H12N2O2S: C, 47.98; H, 6.04; N, 13.99.
Found: C, 47.95; H, 6.08; N, 13.86.
1-Propenyl-3-methylimidazole-2-thione (1i): Brown oil; 1H NMR (500 MHz,
CDCl3): d ¼ 6.71 (d, 1H, J ¼ 2.3 Hz), 6.70 (d, 1H, J ¼ 2.3 Hz), 5.90–5.95
(m, 1H), 5.27 (d, 2H, J ¼ 1.0 Hz), 4.68 (d, 2H, J ¼ 6.0 Hz), 3.63 (s, 3H)
ppm; 13C NMR (125 MHz, CDCl3): d ¼ 162.6, 132.1, 119.2, 117.9, 116.4,
50.4, 35.3 ppm; FT-IR (neat): 3159, 3110, 3091, 2979, 2925, 1644, 1568,
1459, 1398, 1344, 1242, 1210, 1157 cm21; MS (ESI): m/z 155 ([MþH]þ).

406
X.-L. Tao et al.
1,3-Dibenzylimidazole-2-thione (1j): Brown oil; 1H NMR (500 MHz,
CDCl3): d ¼ 7.30–7.35 (m, 10H), 6.53 (s, 2H), 5.29 (s, 4H) ppm; 13C NMR
(125 MHz, CDCl3): d ¼ 163.4, 136.0, 129.1, 128.6, 128.4, 116.9, 51.6 ppm;
FT-IR (neat): 3159, 3119, 3084, 3030, 2920, 1568, 1495, 1449, 1243,
1230 cm21; MS (ESI): m/z 281 ([MþH]þ); anal. calcd. for C17H16N2S: C,
72.82; H, 5.75; N, 9.99. Found: C, 72.95; H, 5.82; N, 9.93.
1
1-Benzyl-3-ethylimidazole-2-thione (1k): Brown oil; H NMR (500 MHz,
CDCl3): d ¼ 7.29–7.33 (m, 5H), 6.68 (d, 1H, J ¼ 2.3 Hz), 6.57 (d, 1H,
J ¼ 2.3 Hz), 5.20 (s, 2H), 4.13 (q, 2H, J ¼ 7.4 Hz), 1.38 (t, 3H, J ¼ 7.4 Hz)
ppm; 13C NMR (125 MHz, CDCl3): d ¼ 162.5, 136.0, 128.9, 128.5, 128.1,
117.9, 116.2, 47.8, 35.1, 16.7 ppm; FT-IR (neat): 3110, 3083, 2971, 2925,
1568, 1465, 1419, 1322, 1262, 1217, 1162 cm21; MS (ESI): m/z 219
([MþH]þ); anal. calcd. for C12H14N2S: C, 66.02; H, 6.46; N, 12.83. Found:
C, 66.11; H, 6.52; N, 12.75.
1-Hydroxyethyl-3-methylimidazole-2-thione (5): Brown oil; 1H NMR
(500 MHz, CDCl3): d ¼ 6.81 (d, 1H, J ¼ 2.2 Hz), 6.70 (d, 1H, J ¼ 2.2 Hz),
4.24 (t, 2H, J ¼ 5.1 Hz), 3.95 (q, 2H, J ¼ 5.1 Hz), 3.61 (s, 3H), 2.76 (t, 1
H, J ¼ 5.1 Hz, D2O exchange) ppm; 13C NMR (125 MHz, CDCl3):
d ¼ 162.6, 118.2, 117.9, 61.9, 50.6, 35.4 ppm; FT-IR (neat): 3380, 3159,
3120, 2960, 1570, 1460, 1422, 1235, 1161 cm21; MS (ESI): m/z 159
([MþH]þ); anal. calcd. for C6H10N2OS: C, 45.55; H, 6.37; N, 17.71.
Found: C, 45.67; H, 6.45; N, 17.63.
1-Acetyloxyethyl-3-methylimidazole-2-thione (6): Brown oil; 1H NMR
(500 MHz, CDCl3): d ¼ 6.73 (d, 1H, J ¼ 1.9 Hz), 6.69 (d, 1H, J ¼ 1.9 Hz),
4.40 (t, 2H, J ¼ 5.1 Hz), 4.31 (t, 2H, J ¼ 5.1 Hz), 3.61 (s, 3H), 2.06 (s, 3H)
ppm; 13C NMR (125 MHz, CDCl3): d ¼ 170.7, 162.6, 117.9, 117.5, 62.2,
47.0, 35.4, 21.0 ppm; FT-IR (neat): 3164, 3131, 2945, 1738, 1570, 1461,
1403, 1231, 1154 cm21; MS (ESI): m/z 201 ([MþH]þ); anal. calcd. for
C8H12N2O2S: C, 47.98; H, 6.04; N, 13.99. Found: C, 48.05; H, 6.12; N, 13.87.
1,10-(1,2-Ethanediyl)bis(2,3-dihydro-3-methyl-1H-imidazole-2-thione) (8):
White solid; mp 193.5–195.28C; 1H NMR (500 MHz, CDCl3): d ¼ 6.57
(d, 2H, J ¼ 2.1 Hz), 6.54 (d, 2H, J ¼ 2.1 Hz), 4.44 (s, 4H), 3.56 (s, 6H)
ppm; 13C NMR (125 MHz, CDCl3): d ¼ 162.5, 117.9, 45.6, 35.2 ppm; FT-
IR (KBr): 3154, 3113, 2937, 1568, 1468, 1421, 1235, 1193, 675 cm21; MS
(ESI): m/z 255 ([MþH]þ).
1-Methoxyacetyl-3-methylimidazole-2-thione (9): Brown oil; 1H NMR
(500 MHz, CDCl3): d ¼ 6.82 (d, 1H, J ¼ 2.2 Hz), 6.80 (d, 1H, J ¼ 2.2 Hz),
4.86 (s, 2H), 3.65 (s, 3H), 3.80 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3):
d ¼ 168.9, 163.5, 117.5, 117.2, 75.8, 55.6, 54.5 ppm; FT-IR (neat): 3120,
2987, 1735, 1572, 1464, 1427, 1405, 1388, 1250, 1224 cm21; MS (ESI):

1,3-Disubstituted Imidazole-2-thiones
407
m/z 187 ([MþH]þ); anal. calcd. for C7H10N2O2S: C, 45.15; H, 5.41; N, 15.04.
Found: C, 45.23; H, 5.52; N, 14.98.
ACKNOWLEDGMENT
This work was financially supported by the Teaching and Research Award
Program for Outstanding Young Teachers in Higher Education Institutions
of MOE, P.R.C.
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