Novel synthon for incorporating 1,3-dimethyl-imidazolium group into molecular architecture

Article abstract of DOI:10.1016/j.tetlet.2006.12.051

The synthesized 1,3-dimethylated imidazolium-carbaldehydes serves as synthons for incorporating a permanently cationic imidazolium group into molecular framework. The utility of new synthon was demonstrated in a variety of reactions: Knoevenagel, Wittig,

Full text of DOI:10.1016/j.tetlet.2006.12.051

Tetrahedron Letters 48 (2007) 1195–1199
Novel synthon for incorporating 1,3-dimethyl-imidazolium
group into molecular architecture
Mikhail Berezin and Samuel Achilefu*
Department of Radiology, Washington University School of Medicine, 4525 Scott Ave, St. Louis, MO 63110, USA
Received 14 November 2006; accepted 12 December 2006
Abstract—The synthesized 1,3-dimethylated imidazolium-carbaldehydes serves as synthons for incorporating a permanently
cationic imidazolium group into molecular framework. The utility of new synthon was demonstrated in a variety of reactions:
Knoevenagel, Wittig, Schiff base formation, based-mediated electrophilic substitution, and oxidation, including synthesis of the
natural product norzooanemonin.
Ó 2006 Elsevier Ltd. All rights reserved.
Imidazole is an important functionality in biological
systems and 5-imidazole-carbaldehydes, including their
mono-N-methylated analogs are often used as building
blocks in medicinal chemistry. Because methylation is
the major histamine catabolic pathway in mammalian
tissues, mono-N-methylated imidazole derivatives are
commonly found in imidazole metabolites. Beside natu-
ral occurrence, other compounds bearing this group
have been widely studied due to their anticancer,1 anti-
malarial,2 antibacterial,3 antifungal,4 and ocular anti-
hypertensive5 properties. In addition, several drugs
and drug candidates (pilocarpine, tipifarnib) that incor-
porate N-methyl imidazoles have been developed. These
findings have been facilitated by the commercial avail-
ability of suitable synthons such as 1-methyl-1H-imid-
azole-5-carbaldehyde for inclusion in SAR studies.
of imidazolium-containing compounds, the availability
of a suitable building block for its incorporation into
diverse molecules would add an important functionality
to a variety of compound libraries.
Unfortunately, 1,3-dimethyl-5-imidazolium-carbalde-
hyde suitable for facile incorporation of di-N-methyl-
ated imidazolium is unknown. With a few exceptions
that include their use as protective agents against chem-
ical weapons (soman),12 non-natural basic amino acid-
containing peptides,13 and antibacterial compounds,3
the literature is sparse on the use of dimethylated imid-
azolium-containing molecules in biological applica-
tions. There are number of synthetic14 and enzymatic15
methods available for the methylation of imidazoles.
The most common chemical method utilizes MeI as
the alkylating agent. Although the methylation of N-1
proceeds smoothly even at low temperature, alkylation
of the tertiary N-3 requires prolonged heating at high
temperature, for several days,16 apparently due to the
reduced nucleophilicity of the N-3 atom.17
Although rare, di-N-methylated imidazolium occurs in
natural compounds. Some examples include 1,3-dimeth-
ylhistidine, zooanemonin,6 norzooanemonin, methyl
ester of norzooanemonin, (+)-echinobetaine B,7 Chryso-
physarin A,8 and the insect peptide extracted from
Heliothis virescens9 (Fig. 1). These compounds have
some promising biological properties such as antiviral,9
nematocidal, and antifouling10 activities. Biologically,
1,3-dimethyl-imidazolium group is metabolically stable.
For example, the methyl groups in 1,3-dimethylhisti-
dine-1,3-(C14H3)2 were not eliminated in a variety of
animals studies.11 Considering the potential usefulness
In this Letter, we describe an effective method to prepare
imidazoliums by using trimethyloxonium salts, also
known as Meerwein salt,18 which has been used previ-
ously to quaternize a variety of heterocyclic amines.17,19
We also report solvent dependent tautomerism of the
synthesized compounds and their ability to participate
in different reactions.
Imidazole 3 is soluble in ethylacetate,20 while the
alkyloxonium salt has a low solubility. Because of this
limited solubility, the reaction mixture is heterogeneous
*
Corresponding author. Tel.: +1 314 362 8599; fax: +1 314 747
5191; e-mail: achilefus@mir.wustl.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.051

1196
M. Berezin, S. Achilefu / Tetrahedron Letters 48 (2007) 1195–1199
MeO
RO2C
R- H, Me
N
N
N
N
N
O2C
O2C
N
zooanemonin
norzooanemonin
(+)echinobetaine B
and its methyl ester
O
O
N
H
N
N
H
OH
Chrysophysarin A
SH
O
O
O
O
O
H
H
N
H
N
N
C13H27
N
H
N
H
N
H
O
O
O
N
N
Myristoyl-Cys-Ala-Val-Ala-Tyr-(1,3-dimethyl)His-OMe
Figure 1. Naturally occurring 1,3 dimethyl 5-imidazoliums.
BF4
N
4
+H
-H
6
5
HO
(CH3)3O BF4
3
O
O
N
N
2
N
1
N
N
EtOAc
(4 oC- r.t.)
1keto
3
1enol
BF4
+H
-H
(CH3)3O BF4
N
N
N
N
N
N
EtOAc
O
(4 oC- r.t.)
O
OH
4
2keto
2enol
Scheme 1. Synthesis of 1,3-dimethyl-5-imidazolium-carbaldehyde and 1,3-dimethyl-2-imidazolium-carbaldehyde and their tautomerism. 1keto
1
+
enol, yield À95%; 2keto + 2enol, yield À91%.
and the alkylation occurs either at the surface of the sus-
pended alkyloxonium salt or in the dilute solution
phase.17
O
O
N
O
+ HOCl
+
HClO2
N
N
A or B
N
1
9 (norzooanemonin)
Upon alkylation, the insoluble 1,3-dimethyl-5-imidazo-
lium-carbaldehyde 1 (Scheme 1) is precipitated from
the reaction mixture as the tetrafluoroborate salt. Side-
products were not detected, thereby eliminating the need
for a further work-up. The reaction was fast, quantita-
tive and only required mixing the reaction mixture and
collecting the desired compound on a filter. In contrast,
alkylation with MeI under the same conditions
described above did not give the desired compound,
leaving the starting material intact. To demonstrate
the generality of the alkylation method, 1,3-dimethyl-
2-imidazolium-carbaldehyde 2 was also prepared in the
same manner (Scheme 2). Although 2 has been reported
previously,21 the literature description of its synthesis
and usage is sketchy.19,20
Scheme 2. Synthesis of norzooanemonin by the oxidation of dimethyl-
imidazolium-carbaldehyde. Reagents and conditions: (A) NaClO2,
KH2PO4, water, DMSO, rt, 20 min; (B) resin-ClO2, resin-H2PO4,
water, DMSO, rt, 1 h, 89%.
for 1 and 6.05 ppm for 2). In methanol, dimethylated
imidazoliums 1 and 2 exist exclusively in the enol form,
suggesting their stabilization by proton transfer while in
aprotic DMSO the keto form is favored. The starting
material mono-methylated 5-imidazole 3 does not show
solvent dependent tautomeric properties, remaining
exclusively in a keto-form. The mono-methylated 2-
imidazole 4 demonstrates only some degree of tautomer-
ism. In the solid form, 1 and 2 are in the keto form, as
evidenced by the characteristic band of carbonyls at
1700 cmÀ1 in the IR spectra and in the absence of peaks
corresponding to alcohols (see Supplementary data).
Despite the structural similarities between 1 and 2,
the compounds have drastically different physical
properties, such as melting points: 1 ꢀ57 °C and 2
ꢀ180 °C.
Analyses of the 1H NMR spectra showed that com-
pounds 1 and 2 exhibit interesting solvent dependent
tautomeric properties (Table 1). This is indicated by
the disappearance of the signals corresponding to alde-
hyde protons (9.86 ppm for 1 and 9.93 ppm for 2) and
appearance of enol proton signals upfield (5.60 ppm

M. Berezin, S. Achilefu / Tetrahedron Letters 48 (2007) 1195–1199
Table 1. Keto–enol tautomer composition in different solvents determined by 1H NMR
1197
Compound
Solvent
da (2-H)
da (4-H)
da (5-H)
da (6-H)
Enol (%)
Keto (%)
1
1
2
2
3
3
4
4
DMSO-d6
Methanol-d4
DMSO-d6
Methanol-d4
DMSO-d6
Methanol-d4
DMSO-d6
9.26
8.75
—
8.53
7.54
7.89
7.48
7.88
7.84
7.61
—
—
7.89
7.48
—
9.86
5.60
9.93
6.05
9.76
9.76
9.71
0
100
0
100
0
0
0
28
100
0
100
0
100
100
100
72
—
8.01
7.91
—
—
7.27
7.24keto
6.83enol
Methanol-d4
—
7.41keto
7.00enol
9.72keto
5.62enol
a ppm, relative to TMS.
The versatility of 1 as a synthon was demonstrated by its
utility in a variety of classical organic reactions, such as
Knoevenagel condensation, Wittig reaction, Schiff base
formation, and base-mediated electrophilic substitution
(Table 2). Knoevenagel condensation was conducted in
water at room temperature following a recently pub-
lished procedure22 by simply adding a stoichiometric
amount of barbituric acid to an aqueous solution of 1.
After 4 h, the solid formed was filtered, washed with a
small amount of cold water and dried. Solubility of
the formed compound 5 in water resulted in a relatively
low yield (54%). Higher yields could be obtained by
recovering the portion of 1 in the filtrate. Wittig reaction
was performed in DCM at room temperature. Although
1 is not soluble in non-polar solvents, its low melting
point allowed us to generate a biphasic liquid solution
in DCM by heating to 60 °C in a closed reaction vessel.
After cooling the biphasic solution, (triphenylphosphor-
anylidene)acetaldehyde was added to the reaction mix-
ture, which was vigorously stirred for 20 h. The
precipitate was washed with DCM and methanol and
dried. Spectroscopic studies (1H NMR, DMSO-d6)
showed desired aldehyde 6 was obtained in a high
purity.
Table 2. Reactivity of 1,3-dimethyl-5-imidazolium-carbaldehyde 1 in different reactions
X
O
X
N
N
N
N
1
5-8
Reaction and conditions
Knoevenagela
X
Product
Yield (%)
54
O
BF4
H
HN
NH
O
O
N
O
N
O
O
HN
N
5
BF4
N
N
Wittigb
50
95
O
PPh3
O
6
BF4
Schiff base formationc
N
N
NH2
N
7
BF4
N
Base-mediated electrophilic substitutiond
60
N
N
N
OH
O
O
8
OH
a Water, rt 30 min.
b DCM, rt 20 h.
c DCM, rt 4 h.
d MeOH, NaOAc, rt 20 h.

1198
M. Berezin, S. Achilefu / Tetrahedron Letters 48 (2007) 1195–1199
Schiff base formation was achieved in DCM by adding a
stoichiometric amount of aniline (1.05 equiv) to a sus-
pension of 1 in DCM at room temperature. Product 7
slowly crystallized out of DCM at À20 °C (overnight),
providing the desired compound in an excellent yield.
For spectroscopic studies, the Schiff base was further
recrystallized from DCM.
ful incorporation of a permanent cationic imidazolium
moiety into diverse molecules (Table 2) or opening a
new route to synthesis of the natural compound norzoo-
anemonin. Considering that dialkylated imidazolium
constitute a major class in the rapidly expanding area
of ionic liquids and ionic liquid crystals,31 extension of
the use of 1 in material science is conceivable. Similarly,
1 could be used to incorporate dimethylated imidazoles
into N-heterocyclic carbenes, which are good chelating
groups for a variety of metals used in organometallic
catalysis and general organic synthesis.32 Thus, the
availability of a suitable building block for the incorpo-
ration of di-N-methyl-imidazolium would allow comple-
menting a variety of compound libraries with important
functionality.
Fluorescent compound 8 was synthesized via base-med-
iated electrophilic substitution of 3-(2-carboxyethyl)-
1,1,2-trimethyl-1H-benzo[e]indolium23 in methanol in
the presence of NaOAc. The large Stoke’s shift of the
fluorescent compound24 would improve the sensitivity
of fluorescence microscopy studies, where the bleeding
of excitation light into the detection source can be
problematic.
In conclusion, we demonstrated an efficient synthesis
of novel 1,3-dimethyl-5-imidazolium-aldehyde and a
known 1,3-dimethyl-2-imidazolium-aldehyde. Both
compounds were found to be non-hydroscopic and air
stable. We demonstrated the solvent dependent tautom-
erism of both compounds and showed their utility (using
1,3-dimethyl-5-imidazolium-aldehyde 1 as an example)
as synthons for incorporating imidazolium functionality
into molecules through a variety of reactions: Knoeve-
nagel condensation, Wittig reaction, Schiff base forma-
tion and base-mediated electrophilic substitution. We
also demonstrated that 1 can be used for direct synthesis
of norzooanemonin via oxidation.
We further demonstrated the oxidation of 1 to a natural
product norzooanemonin 9 (Fig. 1). To our knowledge
there are only two publications regarding norzooanem-
onin synthesis. In one of them, the synthesis of 9 was
achieved by treating imidazole-4-carboxylic acid with
dimethylsulfate.25 Long reaction times (several days),
harsh conditions (100 °C) and a tedious product isola-
tion procedure limit the practical utility of the method.
In the second publication, norzooanemonin was pre-
pared by treatment of 1-methylimidazole with dimethyl
carbonate.26 However, attempts to reproduce this meth-
od by other investigators yielded 1,3-dimethyl-imid-
azolium-2-carboxylate instead of the expected 1,3-
dimethyl-imidazolium-4-carboxylate.27 In our method,
we found that the reaction of 1 with a relatively mild
oxidation reagent chlorite selectively oxidized the alde-
hyde to the corresponding carboxylic acid. An initial
attempt to conduct the reaction in aqueous KH2PO4
buffer did not yield the expected product after 24 h. In
contrast, the addition of 20 vol % of DMSO to the reac-
tion mixture resulted in 100% conversion within 10 min
(Scheme 1, A). The role of DMSO could be rationalized
in two ways. First, DMSO could interact with the hypo-
chlorite ion formed in the oxidation process (DMSO is a
known hypochlorite ion scavenger28), thereby driving
the reaction equilibrium to the right. Second, in the pres-
ence of DMSO, 1 tautomerizes to its keto-form (Table
1) which is more reactive toward oxidation than the cor-
responding enol-form. In aqueous solution, 1 is predom-
inantly in its unreactive enol form. Further study to
delineate the role of DMSO in this reaction is in pro-
gress. Although our approach gave 100% conversion,
isolation of the product from salt mixtures was cumber-
some and required numerous cycles of methanol–etha-
nol triturations (inorganic salts are less soluble in
methanol–ethanol mixture than 9). To minimize the
presence of inorganic salts and simplify the work-up,
we optimized the reaction by conducting the oxidation
with chlorite and phosphate immobilized on a solid sup-
port29 (Scheme 1, B). As in method A, the formation of
the product in method B was fast (less than 1 h) and
quantitative. The NMR spectra of the product matched
published data.25,30
Acknowledgments
We thank Dr. Yunpeng Ye for providing the 3-(2-carb-
oxyethyl)-1,1,2-trimethyl-1H-benzo[e]indolium used for
this work. This work was supported in part by the
NIH (R01 CA109754).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2006.
12.051.
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