Synthesis of unsymmetrical imidazolium salts by direct quaternization of N-substituted imidazoles using arylboronic acids

Article abstract of DOI:10.1039/c4cc00474d

Imidazolium salts were conveniently prepared by direct aryl quaternization using arylboronic acids. This process features the tolerance of a broad range of functional groups and excellent chemoselectivity, and is especially effective for the synthesis of unsymmetrical imidazolium salts.

Full text of DOI:10.1039/c4cc00474d

ChemComm
View Article Online
View Journal
COMMUNICATION
Synthesis of unsymmetrical imidazolium salts by
direct quaternization of N-substituted imidazoles
using arylboronic acids†
Cite this:DOI: 10.1039/c4cc00474d
Received 20th January 2014,
Accepted 21st February 2014
Shiqing Li, Fan Yang, Taiyong Lv, Jingbo Lan, Ge Gao* and Jingsong You*
DOI: 10.1039/c4cc00474d
www.rsc.org/chemcomm
Imidazolium salts were conveniently prepared by direct aryl quater- groups are suitable substrates.9 In 2002, Yoshida and Kunai et al.
nization using arylboronic acids. This process features the tolerance reported the use of arynes as the aryl source, but N-arylimidazoles
of a broad range of functional groups and excellent chemo- could not be arylated to afford 1,3-diarylimidazolium salts.10
selectivity, and is especially effective for the synthesis of unsymme- Because of our continuous interest in imidazolium compounds,11
trical imidazolium salts.
we are keen to find a general, convenient and effective method to
access imidazolium salts by direct quaternization. We previously
Imidazolium salts are important precursors of N-heterocyclic reported the use of diaryliodomium salts to quaternize N-substituted
carbenes1 (NHCs) and useful motifs of functional materials such imidazoles through copper(III) catalysis.12 Herein, we present a more
as anion receptors,2 fluorophores3 and ionic liquids.4 These convenient method by using arylboronic acids.
organic salts are generally synthesized via Arduengo’s classic
The key to the success of the direct quaternization of imid-
multicomponent cyclization5 and many variations.6 However, azoles using diaryliodonium salts relied on the ‘‘hyperleaving
these methods are not practically applicable for the synthesis group ability’’ of diaryliodonium salts and the super electro-
of unsymmetrical salts, which are very desirable1b and promising philicity of copper(III), which was oxidized by diaryliodonium
ligands/catalysts for asymmetric catalyses.7 Recently, an upgrade salts.12 However, diaryliodonium salts are not easily prepared
´
of this method by Basle and Mauduit et al. allowed the assembly and aryl-economical (an aryliodide is formed as waste after
of unsymmetrical imidazolium salts, but only arylcycloalkyl- each arylation). Arylboronic acids, which are one of the most
imidazolium salts were synthesized.8
abundant commercially available aryl sources, are known to
arylate N–H of imidazoles.13 However, the quaternization of
N-substituted imidazoles has not been disclosed yet. A previous
study also demonstrated that the highly reactive copper(III)
species could be generated in situ from copper(II) by an exotic
oxidant in the reaction flask.14 We therefore envisaged that aryl-
boronic acids could be used to directly quaternize N-substituted
imidazoles with the help of a copper salt in combination with a
suitable oxidant.
We initialized the study with the quaternization of N-phenyl-
imidazole 1a by phenylboronic acid 2a in DMF at 100 1C using
10 mol% Cu(OAc)2ꢀH2O as the catalyst. The reaction was run in
an open flask equipped with a condenser in expectation of the
formation of reactive copper(III) species by the air oxidation.
NaBF4 (2.5 equiv.) was chosen as the counterion source, con-
sidering the weak coordination ability of the tetrafluoroboron
anion. To our delight, the desired 1,3-diphenylimidazolium salt
3aa was obtained in 15% yield after chromatography on silica
gel (Table 1, entry 1). The GC–MS analysis showed a consider-
able amount of the phenol byproduct in the crude mixture,
which was formed by the oxidation of phenylboronic acid.15
The direct quaternization of N-substituted imidazoles is
apparently a straightforward strategy. However, only primary
alkyl halides and aryl halides with strong electron withdrawing
Key Laboratory of Green Chemistry and Technology of Ministry of Education,
College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064,
PR China. E-mail: gg2b@scu.edu.cn, jsyou@scu.edu.cn; Fax: +86 28-85412203
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4cc00474d This bypass could be suppressed by using HBF4 instead of
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun.

View Article Online
Communication
ChemComm
Table 1 Optimization of the reaction conditionsa
Table 2 Scope of the N-substituted imidazolesa,b
Entry
Additive (equiv.)
Oxidant
Yieldb (%)
1
2
3
4
5
6
7
8
NaBF4 (2.5)
HBF4 (2.5)
HBF4 (2.5)
HBF4 (2.5)
HBF4 (2.5)
HBF4 (2.5)
HBF4 (2.5)
HBF4 (2.5)
HBF4/NaBF4 (1.0/1.0)
HBF4/NaBF4 (1.0/1.5)
HBF4/NaBF4 (2.5/1.0)
HBF4/NaBF4 (1.0/2.5)
HBF4/NaBF4 (1.0/2.5)
HBF4/NaBF4 (1.0/2.5)
HBF4/NH4BF4 (1.0/2.5)
Air
Air
MnO2
15
45
39
61
65
83
0
c
c
K2S2O8
Fe(NO3)3ꢀ9H2O
FeCl3
FeCl3 (no air)
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
65d
62
78
85
90
78e
75 f
92
9
10
11
12
13
14
15
a
General conditions: 1a (0.25 mmol), 2a (0.375 mmol), Cu(OAc)2ꢀH2O
(10 mol%), FeCl3 (10 mol%), HBF4 (1.0 equiv.) and NH4BF4 (2.5 equiv.)
b
were stirred in DMF (1 mL) at 100 1C for 10 h under air. Isolated
yields. c 1.0 equivalent. d At 80 1C. e Cu(OAc)2ꢀH2O (5 mol%). f FeCl3 (5 mol%).
a
Reaction conditions: 1 (0.25 mmol), 2a (0.375 mmol), Cu(OAc)2ꢀH2O
(10 mol%), FeCl3 (10 mol%), HBF4 (1.0 equiv.) and NH4BF4 (2.5 equiv.)
NaBF4 and the yield was improved to 45% (Table 1, entry 2).
After screening a range of oxidants, K2S2O8 and iron(III) showed
better activities, and FeCl3 gave the highest yield of 83%
(Table 1, entries 3–6). Air was still necessary and the reaction
b
were stirred in DMF (1 mL) at 100 1C for 10 h. Isolated yields.
c
2.0 equiv. of phenylboronic acid was used.
under the nitrogen atmosphere gave only a trace amount of the N-tert-Butylphenylimidazolium salt 3ma, which could not
product (Table 1, entry 7). The reaction run at a lowered be obtained by the quaternization of N-phenylimidazole by
temperature of 80 1C resulted in a significantly decreased yield tert-butyl halides,10,17 was synthesized by the quaternization
of 65% (Table 1, entry 8).
of N-tert-butylimidazole using 2a in a high yield of 91%.
Further exploration showed that this procedure had very Diphenylimidazolium salt 3na was obtained in 46% yield
poor substrate generality, which was probably due to the strong probably due to the steric hindrance at the 4 and 5 positions.
acidic conditions. We then varied the buffer solution with Starting from (R)-1-(1-phenylethyl)-1H-imidazole, chiral imid-
different ratios of HBF4 and NaBF4. The yield was promoted azolium salt 3oa was assembled in a high yield of 90%,
to 90% at the HBF4/NaBF4 ratio of 1/2.5 (Table 1, entries 9–12). demonstrating a promising access to chiral NHC precursors.
Attempts to cut the usage of either Cu(OAc)2ꢀH2O or FeCl3 led to
To further examine the substrate scope of this method,
a large diminution of the yields (Table 1, entries 13 and 14). other boronic acids were tested and the results are summarized
16
Finally, we obtained the optimal conditions by using NH4BF4
instead of NaBF4 to afford the diphenylimidazolium BF4 salt significant impact on this reaction. While o-methylphenylboronic
3aa in 92% yield (Table 1, entry 15). acid only quaternized 1a to give 3ab in 31% yield, m- and
in Table 3. The steric effect on the boronic acid side showed a
With the optimized conditions in hand, a variety of p-methoxyphenylboronic acids delivered 3ac and 3ad in 65%
N-substituted imidazoles 1 were tested by using phenylboronic and 70% yields, respectively. Biphenylboronic acid directly
acid 2a, and the results are summarized in Table 2. N-Aryl imid- quaternized 1a to form the corresponding 3ae in 65% yield.
azoles with common substituents such as methyl, methoxy, Arylboronic acids with electron-withdrawing groups were also
halide, alkynyl, ester and dimethylamino groups at the ortho, suitable arylating reagents. (3-Nitrophenyl)boronic acid quater-
meta and para positions of the phenyl ring were all successfully nized 1a to afford 3af in 72% yield, and (4-acetylphenyl)boronic
quaternized to afford the corresponding unsymmetrical imid- acid quaternized 1a to give 3ag in a relatively low yield of 57%.
azolium salts in moderate to high yields (Table 2, 3aa–3la). This Monohalide-substituted diphenylimidazolium salts were suc-
reaction was not very sensitive to both the steric and electronic cessfully obtained in good yields, as exemplified here by the
factors on the imidazole substrate side. Bulky mesityl and products with fluoride 3ah and bromide 3ai in 73% and
2,6-diisopropylphenyl substituted imidazoles were smoothly 80% yields, respectively. Difunctional imidazolium salts could
quaternized by 2.0 equiv. of 2a to afford 3ja and 3ka in 66% also be synthesized, but the yields were lowered: symmetrical
and 49% yields, respectively. Heteroaryl substitution was 1,3-bis(4-bromophenyl)imidazolium salt 3fi was obtained in
also tolerated in this reaction. N-(2-Pyridyl)-imidazole could 43% yield and unsymmetrical imidazolium salt 3fj equipped
be selectively quaternized on the nitrogen of imidazole with bromo and ester groups was gained in 44% yield. These
instead of pyridine to form imidazolium salt 3la in 75% yield. substituents provided opportunities for the further derivation
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2014

View Article Online
ChemComm
Communication
Table 3 Scope of the arylboronic acidsa,b
around the copper center might impede the oxidation of
copper(II) to copper(III), resulting in the inferior activity of this
reaction toward sterically hindered boronic acids.
In summary, we have successfully developed a novel approach
for the direct quaternization of N-substituted imidazoles using
commercially available arylboronic acids. This method tolerated
a broad range of functional groups such as methoxy, halide,
ester, acetyl, nitro and N,N-dimethylamino groups, etc. on both
the imidazole side and the boronic acid side. The reaction could
be run under an air atmosphere, which makes it very convenient
and practical. The easy access to functional and unsymmetrical
imidazolium salts is especially attractive for novel ligand and
material synthesis.
We thank the NSFC (Nos 21172159, 21025205 and 21321061)
and the NCET-13-0384 for the financial support.
a
Reaction conditions: 1 (0.25 mmol), 2 (0.375 mmol), Cu(OAc)2ꢀH2O
Notes and references
1 (a) W. A. Herrmann, Angew. Chem., Int. Ed., 2002, 41, 1290;
(10 mol%), FeCl3 (10 mol%), HBF4 (1.0 equiv.) and NH4BF4 (2.5 equiv.)
were stirred in DMF (1 mL) at 100 1C for 10 h. Isolated yields.
b
´
´
(b) S. Bellemin-Laponnaz, E. Despagnet-Ayoub, S. Dıez-Gonzalez,
L. H. Gade, F. Glorius, J. Louie, S. P. Nolan, E. Peris, T. Ritter,
M. M. Rogers, S. S. Stahl and T. N. Tekavec, in N-Heterocyclic
Carbenes in Transition Metal Catalysis, Topics in Organometallic
Chemistry, ed. F. Glorius, Springer, Berlin, Germany, 2007, vol. 21.
2 For reviews, see: (a) J. Yoon, S. K. Kim, N. J. Singh and K. S. Kim,
Chem. Soc. Rev., 2006, 35, 355; (b) Z. Xu, S. K. Kim and J. Yoon,
Chem. Soc. Rev., 2010, 39, 1457.
of novel NHC precursors. It needs to be pointed out that all the
imidazolium salts associated with the BF4 anion could be easily
metathesized to the corresponding Cl salts by using anion
exchange resins.18 For instance, 3aa (in the BF4 form) was
converted into 3aa0 (in the Cl form) in 94% yield (ESI†).
3 A. J. Boydston, P. D. Vu, O. L. Dykhno, V. Chang, A. R. Wyatt II,
A. S. Stockett, E. T. Ritschdorff, J. B. Shear and C. W. Bielawski,
J. Am. Chem. Soc., 2008, 130, 3143.
4 For reviews, see: (a) T. Welton, Chem. Rev., 1999, 99, 2071;
(b) R. Giernoth, Angew. Chem., Int. Ed., 2010, 49, 5608.
5 (a) A. J. Arduengo III, US Pat., 5,077,414, 1991; (b) A. J. Arduengo III,
R. L. Harlow and M. Kline, J. Am. Chem. Soc., 1991, 113, 361.
6 For a review, see: L. Benhamou, E. Chardon, G. Lavigne, S. Bellemin-
Based on our previous study, a possible mechanism was
proposed (Scheme 1).12,14 Firstly, the transmetalation of an aryl-
boronic acid with copper acetate formed aryl copper species,
which further coordinated with a N-substituted imidazole to
form copper(II) intermediate I. In the presence of the counter
anion tetrafluoroboron, I was consequently oxidized by iron(III)
to form the highly reactive copper(III) intermediate II. The
subsequent fast reductive elimination released the product
imidazolium salt and generated copper(I) species. The oxygen
in air oxidized copper(I) and iron(II) to regenerate copper(II) and
iron(III) for the next catalytic cycle. The proton was involved in
these two oxidative processes, interpreting the beneficial effect
of the acidic environment as well as the inhibition of the
oxidation of boronic acids. In addition, the relative congestion
´
Laponnaz and V. Cesar, Chem. Rev., 2011, 111, 2705.
7 For recent reviews, see: (a) J. Tornatzky, A. Kannenberg and
S. Blechert, Dalton Trans., 2012, 41, 8215; (b) F. Wang, L. Liu,
W. Wang, S. Li and M. Shi, Coord. Chem. Rev., 2012, 256, 804.
8 P. Queval, C. Jahier, M. Rouen, I. Artur, J.-C. Legeay, L. Falivene,
´
´
L. Toupet, C. Crevisy, L. Cavallo, O. Basle and M. Mauduit, Angew.
Chem., Int. Ed., 2013, 52, 14103.
9 Z.-Q. Zhu, S. Xiang, Q.-Y. Chen, C. Chen, Z. Zeng, Y.-P. Cui and
J.-C. Xiao, Chem. Commun., 2008, 5016.
10 H. Yoshida, S. Sugiura and A. Kunai, Org. Lett., 2002, 4, 2767.
11 (a) C. Gao, H. Zhou, S. Wei, Y. Zhao, J. You and G. Gao, Chem.
Commun., 2013, 49, 1127; (b) H. Zhou, Z. Wang, C. Gao, J. You and
G. Gao, Chem. Commun., 2013, 49, 1832; (c) H. Zhou, Y. Zhao, G. Gao,
S. Li, J. Lan and J. You, J. Am. Chem. Soc., 2013, 135, 14908; (d) Z. Wang,
H. Zhou, J. Hu, J. You and G. Gao, Acta Chim. Sin., 2013, 71, 1257.
12 (a) T. Lv, Z. Wang, J. You, J. Lan and G. Gao, J. Org. Chem., 2013,
78, 5723; (b) T. Lv, L. Yang, Y. Zhao, F. Song, J. Lan, J. You and
G. Gao, Chin. Chem. Lett., 2013, 24, 773.
13 (a) P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters,
D. M. T. Chan and A. Combs, Tetrahedron Lett., 1998, 39, 2941;
(b) J.-B. Lan, L. Chen, X.-Q. Yu, J.-S. You and R.-G. Xie, Chem.
Commun., 2004, 188.
14 H. Wang, Y. Wang, C. Peng, J. Zhang and Q. Zhu, J. Am. Chem. Soc.,
2010, 132, 13217.
15 (a) J. Xu, X. Wang, C. Shao, D. Su, G. Chen and Y. Hu, Org. Lett.,
2010, 12, 1964; (b) H. Yang, Y. Li, M. Jiang, J. Wang and H. Fu,
Chem.–Eur. J., 2011, 17, 5652.
16 Using NH4BF4 gave constantly better yields than using NaBF4 when
varying different boronic acids.
´
17 A. Fu¨rstner, M. Alcarazo, V. Cesar and C. W. Lehmann, Chem.
Commun., 2006, 2176.
18 E. M. Higgins, J. A. Sherwood, A. G. Lindsay, J. Armstrong, R. S.
Massey, R. W. Alder and A. C. O’Donoghue, Chem. Commun., 2011,
47, 1559.
Scheme 1 Proposed mechanism for the quaternization of N-substituted
imidazoles with arylboronic acids.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun.