Preparation of imidazolinium salts by the Pd-catalyzed reduction of thioureas with triethylsilane and trialkylsilyl triflate

Article abstract of DOI:10.1016/j.tetlet.2014.01.022

A Pd-catalyzed method for the preparation of imidazolinium salts from the corresponding thioureas that could then be used for the synthesis of imidazolium and amidinium salts is described. This method has great potential because all the required reagents are readily available and thioureas are safely converted to their corresponding precursors of NHCs under mild conditions.

Full text of DOI:10.1016/j.tetlet.2014.01.022

Tetrahedron Letters 55 (2014) 1412–1415
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Tetrahedron Letters
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Preparation of imidazolinium salts by the Pd-catalyzed reduction
of thioureas with triethylsilane and trialkylsilyl triflate
⇑
Takehiko Matsumura, Masahisa Nakada
Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A Pd-catalyzed method for the preparation of imidazolinium salts from the corresponding thioureas that
could then be used for the synthesis of imidazolium and amidinium salts is described. This method has
great potential because all the required reagents are readily available and thioureas are safely converted
to their corresponding precursors of NHCs under mild conditions.
Received 20 November 2013
Revised 31 December 2013
Accepted 7 January 2014
Available online 13 January 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Imidazolinium salt
Palladium
Carbon–sulfur bond cleavage
Thiourea
NHC
Since the first isolation of a stable N-heterocyclic carbene (NHC)
by Arduengo at al. in 1991,1 the use of NHCs as ligands2 and cata-
lysts3 has been increasing steadily. The synthesis of NHCs mainly
depends on the conversion of the corresponding imidazolium
and imidazolinium salts; therefore, the preparation of imidazolium
and imidazolinium salts is important.
Many imidazolium and imidazolinium salts have been reported,
and the most widely used methods for their preparation, as
summarized in Scheme 1,2n are as follows: (i) N-alkylation of an
imidazole or imidazoline (method A),4 (ii) reaction of the
corresponding diamine with an orthoformate and a source of HX
(method B),5 and (iii) reaction of a formamidine with an ethyl
dication equivalent (method C).6
Although several methods are available for the synthesis of imi-
dazolium and imidazolinium salts, including those in Scheme 1,
the methods suffer from a limited substrate scope. Therefore, a
new preparation method for imidazolium and imidazolinium salts
is required to expand the substrate scope.
Recently, we have developed the Pd-catalyzed reductive cleav-
age of alkyl aryl sulfides using triethylsilane (TESH) that increased
both the reaction rate and the functional group selectivity in the
presence of trimethylsilyl chloride (TMSCl) (Scheme 2).7,8 This li-
gand-free approach has many advantages such as mild conditions,
ease of operation, use of readily available reagents, and high func-
tional group selectivity. In this study, we found that thioureas can
be converted to the corresponding imidazolium, imidazolinium,
and amidinium salts using TESH and trialkylsilyl triflate in the
presence of a catalytic amount of Pd catalyst.
NHCs have also been directly generated by the corresponding
thioureas with potassium (Scheme 1). This method has advantage
in that a variety of thioureas are available but also has drawbacks
arising from the nature of potassium. That is, the strong reducing
ability of potassium limits the scope of substrates and a risk of
accidental fire accompanies during operation owing to the pyro-
phoric nature of potassium.
Because the reaction of thioureas with electrophiles usually
takes place at the S atom owing to the electron-donating nature
of the N atoms, the reaction of thioureas with silylation reagents
was expected to afford the corresponding imidazolium and imidaz-
olinium salts. The resulting trialkylsilylthio group at the sp2-
hybridized carbon atom of these heterocycles was intended to be
removed by the Pd-catalyzed reaction with trialkylsilanes.
Thus, the reaction of thiourea 1a was attempted using a cata-
lytic amount of PdCl2 (5 mol %), TESH (3.0 equiv), and TMSCl
(1.2 equiv) in THF (Scheme 3), which are the optimized conditions
for the reductive cleavage of alkyl aryl sulfides developed by us.7
The reaction did not proceed; however, the same reaction using
trimethylsilyl trifluoromethanesulfonate (TMSOTf) in toluene at
80 °C afforded imidazolinium salt 2a in 35% yield. The reaction in
the absence of PdCl2 did not afford any products.
Table 1 (entries 1–12) shows the results of further optimization
of reaction conditions using thiourea 1a as the substrate. The use of
Pd(OAc)2 (5 mol %), as the catalyst, improved the yield to 96%
(entry 1). When 10 mol % of Pd(OAc)2 was used, the reaction was
completed within 2 h to afford 2a in 99% yield (entry 2) while
⇑
Corresponding author. Tel./fax: +81 3 5286 3240.
E-mail address: mnakada@waseda.jp (M. Nakada).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2014.01.022

T. Matsumura, M. Nakada / Tetrahedron Letters 55 (2014) 1412–1415
1413
used (entry 5). When less amount (0.6 equiv) of TMSOTf was used,
the yield decreased to 56% and the unreacted starting material
remained (entry 6), indicating that TMSOTf can be used to activate
thiourea 1a. Thus, the use of TMSOTf is important in the Pd-cata-
lyzed reaction because the reaction in the presence of TMSCl (enrty
7) or in the absence of TMSOTf (enrty 8) did not afford the desired
products.
R1
N
N
N
R1X
+
This Work
S
A
B
R2
N
R1
R2
NR1H
+
N
K
X
HC(OR)3
(metal)
NR2H
N
When (TfOSiMe2CH2)29 (0.6 equiv) was used instead of TMSOTf
(1.2 equiv), the reaction also proceeded, though the yield was 79%
(entry 9). The reaction with (TfOSiMe2CH2)2 (0.6 equiv) and TESH
(5.0 equiv) afforded 2a in 92% yield (entry 10). The use of
10 mol % of Pd(OAc)2 afforded 2a in 97% yield (entry 11), while
the use of 3 mol % of Pd(OAc)2 afforded 2a in 77% yield (entry 12).
Although the reactions employing Pd/C and Pd2(dba)3 as the
catalyst afforded the product, the starting material remained,
resulting in a low yield of the desired product in both the cases.
The reactions with triphenylphosphine-ligated Pd catalysts re-
sulted in a complex mixture of products, while the desired product
was not formed. Other organosilanes except TESH, for example,
Ph3SiH or (EtO)3SiH did not improve the yield. The reaction in
THF and 1,4-dioxane resulted in S-alkylation of 1a with the sol-
vents owing to their activation by TMSOTf, and the reaction in
1,2-dichloroethane was slow.
R2
R1
N
R1
N
C
base
+
N
N
R2
R2
Scheme 1. Preparation methods of imidazolinium salt and imidazolium salt.
Et3SiH (2.1 equiv)
R1
R2
SR3
R1
R2
H
PdCl2 (3 mol%)
TMSCl (1.0 equiv)
R3 = alkyl
THF, rt, 79-98%
Scheme 2. Pd-Catalyzed reductive cleavage of alkyl aryl sulfides with triethylsilane
reported by us.7
With the optimized reaction conditions in hand, the scope of
this reaction was studied using thioureas 1b–k under the opti-
mized reaction conditions A and B (Table 2). The reaction of 1-ada-
mantyl derivative 1b was completed within 3 h to afford 2b in 98%
(entry 1, reaction conditions A) and 97% yields (reaction conditions
B). The reaction of 2-methylphenyl derivative 1c was fast and
afforded 2c in 92% yield (entry 2, reaction conditions A). The reac-
tion of 1c under the reaction conditions B resulted in over-reduc-
tion to afford the cyclic aminal that was converted to the acyclic
formamide after workup. The reactions of 2,6-dimethylphenyl
derivative 1d and 2,6-diethylphenyl derivative 1e successfully
afforded the corresponding products 2d and 2e in 99% yield (entry
3, reaction conditions B) and 96% yield (entry 4, reaction conditions
A), respectively.
H
2
S
Et3SiH (3.0 equiv)
PdCl2 (5 mol%)
R
R
R
R
N
N
N
N
X
conditions
R = 2,4,6-trimethylphenyl
1a
TMSCl (1.2 equiv) in THF, rt, 0%
TMSOTf (1.2 equiv) in toluene, 80 °C, 35%
Scheme 3. Preliminary experimental results of Pd-catalyzed transformations of 1a
(R = 2,4,6-trimethylphenyl) to 2.
the reaction using 3 mol % Pd(OAc)2 did not proceed to completion
even after 24 h, and the final yield was 69% (entry 3). The yield of
the reaction was improved to 98% when an excess amount
(5.0 equiv) of TESH was used (entry 4), too; however, the yield
decreased to 80% when a lesser amount (2.2 equiv) of TESH was
The reaction of 2,6-diisopropylphenyl derivative 1f was slug-
gish owing to the steric hindrance and 2f was obtained in 58% yield
(entry 5, reaction conditions B). The reactions of 2,4,6-trimethyl-
phenyl derivative 1g, a six-membered thiourea, and 4-methoxy-
2,6-dimethylphenyl derivative 1h afforded the corresponding
Table 1
Preparation of imidazolinium salt 2a
S
H
Et3SiH, Pd (OAc)2 (cat), R23SiX
solvent, 80 °C
N
N
N
N
X
1a
2a
R23SiX (equiv)
Entry
Pd(OAc)2 (mol %)
Et3SiH (equiv)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
5
10
3
5
5
5
5
5
10
5
3.0
3.0
3.0
5.0
2.2
5.0
3.0
3.0
3.0
5.0
5.0
5.0
TMSOTf (1.2)
TMSOTf (1.2)
TMSOTf (1.2)
TMSOTf (1.2)
TMSOTf (1.2)
TMSOTf (0.6)
TMSCl (1.2)
—
(TfOSiMe2CH2)2 (0.6)
(TfOSiMe2CH2)2 (0.6)
(TfOSiMe2CH2)2 (0.6)
(TfOSiMe2CH2)2 (0.6)
24
2
96
99
24
24
24
24
24
24
3.5
2
69b
98
80
56b
NRc
NRc
79b
92
9
10
11
12
10
3
1.5
18
97
77b
a
b
c
Isolated yields.
Starting material remained.
NR: no reaction.

1414
T. Matsumura, M. Nakada / Tetrahedron Letters 55 (2014) 1412–1415
Table 2
Preparation of imidazolinium salts 2b-j from thiourea 1b-j
H
2
S
Et3SiH, Pd(OAc)2, R3SiOTf
toluene, 80 °C
R
R
N
N
R
R
N
N
TfO
n
n
1
Entry
Thiourea (R)
Reaction conditions Aa
Reaction conditions Bb
Time (h)
Time (h)
Yieldc (%)
Yieldc (%)
1
2
3
4
5
6
7
8
9
10
1-Adamantyl-(n = 1) (1b)
2-Methylphenyl-(n = 1) (1c)
3
1
98
92
85
96
44
92
96
28
2
1
3
2
24
3
3
10
2
1
97
0d
2,6-Dimethylphenyl-(n = 1) (1d)
2,6-Diethylphenyl-(n = 1) (1e)
2,6-Diisopropylphenyl-(n = 1) (1f)
2,4,6-Trimethylphenyl-(n = 2) (1g)
4-Methoxy-2,6-dimethylphenyl-(n = 1) (1h)
4-Methoxycarbonyl-2,6-dimethylphenyl-(n = 1) (1i)
4-Carboxy-2,6-dimethylphenyl-(n = 1) (1j)
4-Fluoro-2,6-dimethylphenyl-(n = 1) (1k)
37
24
35
24
22
24
24
12
99
94
58
94
93
32
19
98
38 (73)e
91
a
b
c
Reaction conditions A: Et3SiH (3.0 equiv), TMSOTf (1.2 equiv), Pd(OAc)2 (5 mol %).
Reaction conditions B: Et3SiH (5.0 equiv), (TfOSiMe2CH2)2 (0.6 equiv), Pd(OAc)2 (10 mol %).
Isolated yields.
No desired products were obtained owing to overreduction.
Et3SiH (10.0 equiv), Pd(OAc)2 (10 mol %), and TMSOTf (4.0 equiv) were used.
d
e
imidazolinium salts 2g and 2h in 94% yield (entry 6, reaction con-
ditions B) and 96% yield (entry 7, reaction conditions A), respec-
The 1H NMR spectrum of a CDCl3 solution of thiourea 1a and
TMSOTf indicated the formation of imidazolinium salt 3a (Fig. 1),
which was confirmed to be converted to 2a under the reaction con-
ditions A. Therefore, the Pd-catalyzed reaction of 1a is proposed to
proceed via 3a, that is, the reaction of 3a with TESH is proposed to
afford 2a. Another possible product of the reaction would be vola-
tile TES-S-TMS. Hence, in this preparation method, imidazolinium,
imidazolium, and amidinium salts could be easily obtained by
filtration of the Pd catalyst by removal of volatile materials after
the completion of the reaction.
Interestingly, the Pd-catalyzed reaction of 4a (Fig. 1) afforded
thiourea 1a, which was assumed to be formed by the cleavage of
the S-Me bond by attack of the iodide on the methyl group during
the reaction. The Pd-catalyzed reaction of 5a (Scheme 5), which
was prepared by the corresponding thiourea with methyl triflate
in 75% yield, expectedly afforded 2a in 83% yield; however, the
use of TMSOTf is advantageous because the yield is higher and in
addition, methyl triflate causes alkylation of heteroatoms in sub-
strates owing to its high reactivity, limiting the substrate scope.
In summary, we have developed a Pd-catalyzed method for the
preparation of imidazolinium salts from the corresponding
tively.
However,
4-methoxycarbonyl-2,6-dimethylphenyl
derivative 1i underwent hydrolysis of the methyl ester under all
the reaction conditions probably owing to the formation of conju-
gated system with the formed electron-withdrawing imidazolini-
um salt, affording 2i in low yields (entry 8). The reaction of
4-carboxy-2,6-dimethylphenyl derivative 1j required an excess
amount of TESH and TMSOTf because TESH and TMSOTf were con-
sumed in the reaction with the carboxy group of 1j. Thus, the yield
of 2j was 38% yield (entry 9); however, the yield was improved to
73% when Et3SiH (10.0 equiv), Pd(OAc)2 (10 mol %), and TMSOTf
(4.0 equiv) were used. The reaction of 4-fluoro-2,6-dimethylphenyl
derivative 1k afforded 2k in 98% yield (entry 10, reaction condi-
tions B). As summarized in Table 2, although TMSOTf has advan-
tage in commercial availability, the reactions using (TfOSiMe2
CH2)2 are generally faster than those using TMSOTf and the yields
are higher in some cases.
Imidazolium salts were successfully prepared by the developed
method, too. for example, the imidazolinium salt 2l was formed
from 1l in 85% yield (Scheme 4). Moreover, amidinium salts were
successfully synthesized by the reaction of acyclic thioureas, for
example, the amidinium salt 2m was obtained from 1m in 99%
yield.
TMS
S
SMe
N
N
N
N
I
Et3SiH (3.0 equiv)
Pd(OAc)2 (10 mol%)
OTf
H
S
3a
4a
R
R
R
R
N
X
N
N
N
Figure 1. Structures of 3a and 4a.
TMSOTf (1.2 equiv)
toluene, 80 °C, 24 h
85%
R = 2,4,6-trimethyphenyl
2l
(X = OTf)
1l
Et3SiH (3.0 equiv)
Pd(OAc)2 (10 mol%)
S
H
H
S
Me
Reaction conditions A
60 °C, 2 h, 99%
R
R
R
N
R
N
N
N
N
N
N
N
toluene, 80 °C, 24 h
83%
X
X
X
R = 2,4,6-trimethyphenyl
2a
(X = OTf)
1m
2m
5a
(X = OTf)
(X = OTf)
Scheme 4. Preparation of 2l and 2m.
Scheme 5. Preparation of 2a from 5a.

T. Matsumura, M. Nakada / Tetrahedron Letters 55 (2014) 1412–1415
1415
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Acknowledgments
This work was financially supported in part by Waseda
University Grant for Special Research Projects, The Grant-in-Aid
for Scientific Research on Innovative Areas ‘Organic Synthesis
based on Reaction Integration, Development of New Methods and
Creation of New Substances’ (No. 2105), and Grants for Excellent
Graduate Schools (Practical Chemical Wisdom), MEXT, Japan.
Supplementary data
Supplementary data (full characterization of new compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.01.022.
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