A modular synthesis of highly substituted imidazolium salts

Article abstract of DOI:10.1021/ol8029609

A versatile and modular one-pot method for the preparation of differently substituted symmetrical and unsymmetrical imidazolium salts is reported, and 19 examples are given. In the key step, readily available formamidines and α-halo ketones are coupled to give imidazolinium salts 3, followed by imidazolium salt formation by acylation-induced elimination. For many substitution patterns of the imidazolium salt products, this efficient strategy compares favorably with well-known processes in terms of yield, ease of synthesis, and robustness.

Full text of DOI:10.1021/ol8029609

ORGANIC
LETTERS
2009
Vol. 11, No. 4
1019-1022
A Modular Synthesis of Highly
Substituted Imidazolium Salts
Keiichi Hirano,§ Slawomir Urban,§ Congyang Wang, and Frank Glorius*
Organisch-Chemisches Institut der Westfa¨lischen Wilhelms-UniVersita¨t Mu¨nster,
Corrensstrasse 40, 48149 Mu¨nster, Germany
glorius@uni-muenster.de
Received December 23, 2008
ABSTRACT
A versatile and modular one-pot method for the preparation of differently substituted symmetrical and unsymmetrical imidazolium salts is
reported, and 19 examples are given. In the key step, readily available formamidines and r-halo ketones are coupled to give imidazolinium
salts 3, followed by imidazolium salt formation by acylation-induced elimination. For many substitution patterns of the imidazolium salt products,
this efficient strategy compares favorably with well-known processes in terms of yield, ease of synthesis, and robustness.
N-Heterocyclic carbenes (NHCs) have found widespread
applications as ligands in organometallic chemistry and
transition metal catalysis1 and as organocatalysts themselves.2
Of the different kinds of NHCs, imidazolylidenes are
especially popular,3 and the most common way of preparation
is the deprotonation of the corresponding imidazolium salts.
Therefore, efficient methods for the formation of 2-unsub-
stituted imidazolium salts with different substitution patterns
are highly desirable. Until recently, the two standard routes
for the formation of imidazolium salts were the alkylation
of imidazoles (Scheme 1, A) and the alkylation/cyclization
Scheme 1. Most Important Routes to Imidazolium Salts
§ These two authors have contributed equally to this work.
(1) (a) Arduengo, A. J., III. Acc. Chem. Res. 1999, 32, 913. (b)
Bourissou, D.; Guerret, O.; Gabbai, F. P.; Bertrand, G. Chem. ReV. 2000,
100, 39. (c) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290. (d)
Peris, E.; Crabtree, R. H. Coord. Chem. ReV. 2004, 248, 2239. (e) Crudden,
C. M.; Allen, D. P. Coord. Chem. ReV. 2004, 248, 2247. (f) Diez-Gonzalez,
S.; Nolan, S. P. Coord. Chem. ReV. 2007, 251, 874. (g) Nolan, S. P., Ed.
N-Heterocyclic Carbenes in Synthesis; Wiley-VCH: Weinheim, Germany,
2006. (h) Glorius, F., Ed. N-Heterocyclic Carbenes in Transition Metal
Catalysis; Springer: Berlin, 2007. (i) Kantchev, E. A. B.; O’Brien, C. J.;
Organ, M. J. Angew. Chem. Int. Ed. 2007, 46, 2768.
(2) For excellent reviews, see: (a) Marion, N.; Diez-Gonzalez, S.; Nolan,
S. P. Angew. Chem., Int. Ed. 2007, 46, 2988. (b) Enders, D.; Niemeier, O.;
Henseler, A. Chem. ReV. 2007, 107, 5606.
(3) Imidazolylidenes are the only class of NHCs that plays a significant
role in transition-metal catalysis and in organocatalysis. A Web of Science
search on 23.12.2008 for the topics “imidazolium”, “imidazolinium”,
“triazolium”, and “thiazolium” resulted in 3846, 168, 398, and 634 hits,
respectively. Moreover, searching for these azolium salts in addition to the
two topics “carbene” and “catalysis” resulted in 211, 24, 17, and 25 hits,
respectively.
of 1,2-bisimines (Scheme 1, B).4 However, these approaches
are limited and generally do not allow the facile formation
10.1021/ol8029609 CCC: $40.75
Published on Web 01/26/2009
2009 American Chemical Society

of differently 1,3-diaryl-substituted or 4,5-disubstituted imi-
dazolium salts.5 The situation changed with a procedure
recently developed by Fu¨rstner et al. (Scheme 1, C).6 This
latter method provides a variety of imidazolium salts with
different substitution patterns, for example, differently 1,3-
diaryl-substituted ones. However, the step count is quite high,
and the linear nature of this sequence/route decelerates the
rapid synthesis of a series of related imidazolium salts.
Table 1. Synthesis of Various IMes Derivativesa
Recently, Bertrand et al. reported a new retrosynthetic
disconnection of imidazolidinium salts and prepared them
by an alkylation of lithiated formamidines.7 Subsequently,
Grubbs et al. developed a powerful method for the synthesis
of saturated imidazolinium salts by coupling of formamidines
with 1,2-dichloroethane.8,9 In addition, Bielawski et al.
formed a quinone-annulated imidazolium salt from 2,3-
dichloro-1,4-naphthoquinone and N,N′-dimesitylformami-
dine.10 On the basis of our continuous interest in the
synthesis, structure, and catalytic activity of metal-NHC
complexes11 and of NHCs as organocatalysts,12 these reports
inspired us to evaluate a new approach to imidazolium salts:
the formation of highly and differently substituted unsaturated
imidazolium salts by coupling of formamidines with readily
available R-halo ketones, followed by an acylation-induced
elimination. Because of a lack of synthetic methods, almost
all imidazolylidenes applied in catalysis are 4,5-unsubstituted
ones. Therefore, we were especially intrigued by the pos-
sibility to rapidly form 4,5-dialkyl-substituted NHC precur-
sors, enabling the investigation of their electronic and
catalytic properties. Here we report the realization of this
efficient and versatile approach toward imidazolium salts.
As coupling partners of the formamidines, R-halogenated
ketones were chosen since they are commercially available
or easily prepared, for example, by R-bromination of the
corresponding ketones. In addition, the carbonyl group
increases the reactivity of the halide for substitution reactions,
(4) (a) Arduengo, A. J., III. Preparation of 1,3-Disubstituted Imidazolium
Salts. U.S. Patent No. 5077414, 1991. (b) Arduengo, A. J., III; Krafczyk,
R.; Schmutzler, R. Tetrahedron 1999, 55, 14523. For a mild but powerful
alternative, see: (c) Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C.
Chem. Commun. 2002, 2704.
(5) For a notable exception, see: Kison, C.; Opatz, T. Synthesis 2006,
3727.
(6) (a) Fu¨rstner, A.; Alcarazo, M.; Ce´sar, V.; Lehmann, C. W. Chem.
Commun. 2006, 2176. (b) Fu¨rstner, A.; Alcarazo, M.; Ce´sar, V.; Krause,
H. Org. Synth. 2008, 85, 34.
(7) (a) Jazzar, R.; Liang, H.; Donnadieu, B.; Bertrand, G. J. Organomet.
Chem. 2006, 691, 3201. (b) Jazzar, R.; Bourg, J.-B.; Dewhurst, R. D.;
Donnadieu, B.; Bertrand, G. J. Org. Chem. 2007, 72, 3492.
(8) Kuhn, K. M.; Grubbs, R. H. Org. Lett. 2008, 10, 2075
(9) See also: Iglesias, M.; Beetstra, D. J.; Knight, J. C.; Ooi, L.-L.;
Stasch, A.; Coles, S.; Male, L.; Hursthouse, M. B.; Cavell, K. J.; Dervisi,
.
a Reaction conditions. Step 1: 1a (3 mmol), 2 (6 mmol), NEt(iPr)2 (3.6
mmol), MeCN (6 mL). Step 2: Ac2O (9 mmol), HCl or HBr (4.5 mmol),
toluene (7.6 mL). b Isolated yield of the desired IMes derivative. c Due to
the slow reaction in the first step, another portion of R-bromoketone (5.41
mmol) was added after 125 h.
A.; Fallis, I. A. Organometallics 2008, 27, 3279
(10) Sanderson, M. D.; Kamplain, J. W.; Bielawski, C. W. J. Am. Chem.
Soc. 2006, 128, 16514.
.
(11) (a) Wu¨rtz, S.; Glorius, F. Acc. Chem. Res. 2008, 41, 1523. (b)
Altenhoff, G.; Wu¨rtz, S.; Glorius, F. Tetrahedron Lett. 2006, 47, 2925. (c)
Burstein, C.; Lehmann, C. W.; Glorius, F. Tetrahedron 2005, 61, 6207. (d)
Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F. J. Am. Chem.
Soc. 2004, 126, 15195. (e) Altenhoff, G.; Goddard, R.; Lehmann, C. W.;
Glorius, F. Angew. Chem., Int. Ed. 2003, 42, 3690. See also ref. 4b.
(12) (a) Hirano, K.; Piel, I.; Glorius, F. AdV. Synth. Catal. 2008, 350,
984. (b) Glorius, F.; Hirano, K. Ernst Schering Found. Symp. Proc. 2008,
2, 159. (c) Tewes, F.; Schlecker, A.; Harms, K.; Glorius, F. J. Organomet.
Chem. 2007, 692, 4593. (d) Burstein, C.; Tschan, S.; Xie, X.; Glorius, F.
Synthesis 2006, 2418. (e) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed.
2004, 43, 6205.
which should be beneficial for the desired coupling with
formamidines. Our study commenced with the reaction of
N,N′-dimesitylformamidine and commercially available 3-chlo-
robutan-2-one (Table 1, entry 1). By means of an extensive
screening of solvents, temperature, and additives, the suitable
reaction conditions were identified. For the initial coupling
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Org. Lett., Vol. 11, No. 4, 2009

reaction, polar aprotic solvents like acetonitrile (MeCN) and
dimethylformamide (DMF) proved to be better suited than
unpolar or polar protic solvents like toluene, dioxane, or
ethanol, though product formation was observed in each case.
An increase of the reaction temperature resulted in a shorter
reaction time with the best results obtained at 110 °C. Nitrile
solvents with higher boiling points like propionitrile and
isobutyronitrile led to longer reaction times at 110 °C
compared to MeCN and caused an increased formation of
side products at temperatures above 110 °C.
Table 2. Synthesis of Various 1,3-Disubstituted Imidazolium Saltsa
Several bases have been screened as additives to increase
reaction rate and yield. Notably, and in agreement with
the results obtained by Grubbs et al.,8 diisopropylethylamine
(NEt(iPr)2) was found to be optimal. Inorganic bases like K2CO3
and NaOAc did not affect the reaction time much, perhaps due
to their low solubility in MeCN. In addition, stronger bases like
NaH caused formation of many side products.
MeCN did not prove to be a suitable solvent for the
elimination step. Therefore, after completion of the first step,
MeCN was evaporated in vacuo and toluene was added. The
sequence was completed by acylation using acetic anhydride
and elimination of acetic acid in the presence of hydrochloric
acid in toluene at 90 °C.6
Following this method, the reaction of N,N′-dimesitylfor-
mamidine and commercially available 3-chlorobutan-2-one
proceeded smoothly to produce the hydroxyimidazolidinium
chloride by substitution of the chloride and intramolecular
cyclization. Subsequent dehydration using Ac2O gave the
desired imidazolium salt in 89% overall yield (Table 1, entry
1). In addition, using these optimized conditions, differently
substituted R-halogenated ketones were employed while
keeping the same mesitylamine derived formamidine (Table
1). Our new method proved to be compatible with many
different R-halogenated ketones and led to various literature
known as well as novel IMes-derivatives with varying 4-
and 5-substituents in good to excellent overall yields. Acyclic
(entries 1-3), cyclic (entries 4-8), as well as aromatic
ketones of different chain length and ring size were suc-
cessfully converted into the imidazolium salts. Especially
noteworthy is the formation of (-)-menthone-derived imi-
dazolium salt 4h, which could prove useful for applications
in asymmetric catalysis.
Finally, the generality of this method was further examined
using various symmetrical and unsymmetrical formamidines
with 2-bromocyclohexanone or 3-chloro-2-butanone (Table
2). Notably, most formamidines performed very well and
led to new symmetrical and unsymmetrical imidazolium salts
in good yields. The synthesis of larger gram quantities
proceeds smoothly (Table 2, entry 2). In a few cases (entries
7, 9, and 10), lower yields were obtained; however, the ease
of synthesis still renders these results useful. Only the
sterically very demanding N,N-bis(2-tert-butylphenyl)for-
mamidine did not provide significant amounts of the desired
product (not shown).
a Reaction conditions. Step 1: 1 (3 mmol), 2a (6 mmol), NEt(iPr)2 (3.6
mmol), MeCN (6 mL). Step 2: Ac2O (9 mmol), HCl or HBr (4.5 mmol),
toluene (7.6 mL); b Isolated yield of the desired IMes derivative. c Reaction
run on larger scale (10 mmol scale of 1). d 3-Chlorobutanone used instead
of 2-bromocyclohexanone (2a).
To the best of our knowledge, all imidazolium salts formed
in the course of this study are new compounds.13 Therefore,
with these highly substituted NHC precursors in hand, most of
them 4,5-disubstituted, we were eager to determine the influence
Org. Lett., Vol. 11, No. 4, 2009
1021

4,5-dialkyl substitution has on the electronic properties. Many
different methods for the determination of the electronic
properties of NHC ligands in transition-metal complexes have
been applied.14 The most widely accepted methodology,
however, is the IR-spectroscopic analysis of the CO stretching
frequencies of (L)Ni(CO)3, (L)Rh(CO)2Cl, (L)Ir(CO)2Cl, or
related complexes.15,16 A lot of reference data exist for
(NHC)Ir(CO)2Cl complexes,15d and thus, the corresponding
iridium complex of carbene precursor 4a was prepared in
high yield following standard methods (Scheme 2).
In summary, we have developed an efficient and versatile
method for the one-pot synthesis of various highly substituted
imidazolium salts. Compared to existing methods, the method
described allows the realization of new substitution patterns
and/or significantly increases the simplicity and robustness
of the synthetic access. In addition, the rather strong influence
of 4,5-dialkyl substitution on the NHC’s electronic properties
renders them more electron rich than the corresponding 4,5-
unsubstituted NHCs. Consequently, this convenient method
should prove useful for the synthesis of differently substituted
NHCs for applications in transition-metal catalysis and in
organocatalysis. The preparation, investigation, and applica-
tion of otherwise difficult to make imidazolium salts are
underway. The synthesis of chiral NHC precursors like 4h
by use of chiral R-halogenated ketones and chiral amines is
attractive, and this will be reported in due course.
Scheme 2. Formation of Iridium Complex 5
Acknowledgment. We are grateful to Mrs. Karin Gottschalk
(WWU) for skillful technical assistance. Generous financial
support by the Deutsche Forschungsgemeinschaft, the Fonds
der Chemischen Industrie, the Deutsche Akademische Aus-
tauschdienst (fellowship for K.H.), and the Alexander von
Humboldt Foundation (fellowship for C.W.) is gratefully
acknowledged. The research of F.G. was supported by the
Alfried Krupp Prize for Young University Teachers of the
Alfried Krupp von Bohlen and Halbach Foundation.
It has to be noted that for reasons of comparability the IR
spectra have to be measured in CH2Cl2 solution (Scheme
2). Comparison of the IR νCO data obtained for 5 with the
one reported for the corresponding iridium complex of
IMes15d suggests that the NHC derived from 4a is signifi-
cantly more electron rich than the 4,5-unsubstituted IMes.
Moreover, this system even surpasses IAd15d in its electron
richness. It seems that the 4,5-dialkyl substitution has a
distinct influence on the carbene’s electronic properties.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL8029609
(15) (a) Tolman, C. A. Chem. ReV. 1977, 77, 313. (b) Chianese, A. R.;
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2006, 691, 4652. (b) Grotevendt, A.; Bartolome, M.; Nielsen, D. J.;
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J. Am. Chem. Soc. 2004, 126, 8717. (b) Huang, J.; Schwarz, H.-J.; Stevens,
E. D.; Nolan, S. P. Organometallics 1999, 18, 2370. (c) Luo, L.; Nolan,
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(16) An excellent discussion of NHC donor abilities can be found in
the Supporting Information of this publication: Fu¨rstner, A.; Alcazaro, M.;
Krause, H.; Lehmann, C. W. J. Am. Chem. Soc. 2007, 129, 12676.
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