Imidazol-2-and-4-ylidene by decarboxylation. Studies on the cross-conjugated mesomeric betaine-alkaloid norzooanemonine and its pseudo-cross-conjugated isomer

Article abstract of DOI:10.1039/b716508k

1,3-Dimethylimidazolium-2-carboxylate and -4-carboxylate (norzooanemonine), which belong to two distinct classes of heterocyclic mesomeric betaines, undergo thermal decarboxylations to the N-heterocyclic carbenes imidazol-2-ylidene and imidazol-4-ylidene, respectively. These carbenes can be detected by ESI mass spectrometry and can be trapped by isocyanates to imidazolium-amidates, the structure of which was proved by independent syntheses. We performed calculations to characterize the different types of conjugation in the imidazolium-carboxylates. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b716508k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Imidazol-2-and-4-ylidene by decarboxylation. Studies on the cross-conjugated
mesomeric betaine-alkaloid norzooanemonine and its pseudo-cross-conjugated
isomer
Andreas Schmidt,*a Ariane Beutler,a Marcel Albrecht,a Bohdan Snovydovycha and Francisco Javier Ram´ırezb
Received 26th October 2007, Accepted 19th November 2007
First published as an Advance Article on the web 5th December 2007
DOI: 10.1039/b716508k
1,3-Dimethylimidazolium-2-carboxylate and -4-carboxylate (norzooanemonine), which belong to two
distinct classes of heterocyclic mesomeric betaines, undergo thermal decarboxylations to the
N-heterocyclic carbenes imidazol-2-ylidene and imidazol-4-ylidene, respectively. These carbenes can be
detected by ESI mass spectrometry and can be trapped by isocyanates to imidazolium-amidates, the
structure of which was proved by independent syntheses. We performed calculations to characterize the
different types of conjugation in the imidazolium-carboxylates.
mesomeric betaines can be considered as precursors of N-
Introduction
heterocyclic carbenes. Related to the valence bond theory based
Currently considerable interest is focussed on the chemistry of
classification of mesomeric betaines, at least three distinct types
N-heterocyclic carbenes. They are utilized not only as ligands in
of N-heterocyclic carbenes can be seen. Wantzlick/Arduengo
metal-organic chemistry,1 but also as organocatalysts in Stetter
carbenes, which result in extrusion of heterocumulenes such as
reactions,2 benzoin condensations,3 transesterifications,4 enantios-
carbon dioxide from pseudo-cross-conjugated mesomeric betaines
elective acylations of secondary alcohols,5 hydroacylations of
can be represented either by polar all-octet or by nonpolar
activated ketones,6 trialkylsilylcyanations,7 redox esterifications
non-octet canonical formula. An example is the decarboxyla-
of aldehydes,8 and many other reactions. With few exceptions,
tion of the PCCMB 1,2-dimethylimidazolium-2-carboxylate 1
neither the structural nor the chemical relationship between N-
to the NHC 1,2-dimethylimidazol-2-ylidene 2 (Scheme 1). By
heterocyclic carbenes (NHC) and heterocyclic mesomeric betaines
contrast, on decarboxylation of the cross-conjugated mesomeric
(HMB) has been recognized to date. Representatives of the latter
mentioned class of compounds are neutral conjugated molecules
betaine 1,2-dimethylimidazolium-4-carboxylate 3 the NHC 1,2-
dimethylimidazol-4-ylidene 4 is formed which can exclusively be
which can exclusively be represented by dipolar canonical for-
represented by a dipolar all-octet structure. The same is true for
rNHC (r = remote heteroatom) which results from CCMB.16
mulae. They delocalize an even number of charges within a
common p-electron system. A first classification (1985) by Ollis
Molecule 4 is currently considered as “abnormal carbene”
(aNHC) in its behaviour in coordination chemistry.17
et al. divided HMB into four major groups, i.e. into conjugated
mesomeric betaines (CMB), conjugated heterocyclic N-ylides,
cross-conjugated mesomeric betaines (CCMB) and pseudo-cross-
conjugated mesomeric betaines (PCCMB).9 The characteristics
of these distinct types of conjugation10 and their occurrence
among natural products11—insofar investigated to date—have
been surveyed recently. Whereas conjugated mesomeric betaines,
which also include mesoions such as sydnones, mu¨nchnones,
isothiomu¨nchnones, N-ylides, and cross-conjugated mesomeric
betaines have been explored intensively as versatile key inter-
mediates in heterocyclic9,12 as well as natural product synthesis,13
pseudo-cross-conjugated mesomeric betaines obviously still con-
stitute an exceptional role among the different types of conju-
gated systems. Although originally classified somewhere between
CMB and CCMB, recent results show that they in fact do
have characteristic features which are not only of theoreti-
cal nature, but do also translate into chemistry.14,15 A priori,
cross-conjugated as well as pseudo-cross-conjugated heterocyclic
Scheme 1
The mesomeric betaine 3 is known as norzooanemonine and
was identified as alkaloid in marine sponges such as Pseudoptero-
gorgia americana, Cacospongia scalaris and Astrosclera willeyana
LISTER 1900.18
aClausthal University of Technology, Institute of Organic Chemistry, Leib-
nizstrasse 6, D-38678, Clausthal-Zellerfeld, Germany. E-mail: schmidt@
ioc.tu-clausthal.de; Fax: +49-(0)5323-722858; Tel: +49-(0)5323-723861
bUniversity of Ma´laga, Faculty of Sciences, Department of Physical Chem-
istry, 29071, Ma´laga, Spain
As part of an ongoing project dealing with N-heterocyclic
carbenes as well as mesomeric betaines from nature,19 we were
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interested in a detailed comparison of the PCCMB 1 and the
CCMB 3.
Results and discussion
Classifications and calculations
In the pseudo-cross-conjugated heterocyclic mesomeric betaine
1 the two parts of the molecule are combined by a “union
bond”, which we calculated to be 153.6 pm. In the valence
bond approach, the charges are “effectively, but not exclusively”
(Ollis et al.9) restricted to separate parts of the molecule, as
the dipolar canonical formula I exists in which the positive
charge is localized in the carboxylate group (Fig. 1). This is
an electron sextet structure without internal octet stabilization.
Undoubtedly, this canonical formula is no more than a means to
recognize pseudo-cross-conjugation, and to distinguish the three
types of conjugation of mesomeric betaines by their canonical
formulae. Furthermore, the dipole type II is characteristic of
PCCMB. Similar to the CCMB norzooanemonine 3, the anionic
partial structure is joined through an unstarred position (III),
i.e. through a nodal position of the HOMO (IV) to the cationic
portion of the betaine. The torsion angle between imidazole and
carboxylate group is 19.2◦ according to the calculation.
Fig. 3 Electrostatic potential surface of PCCMB 1.
In norzooanemonine 3 the charges are delocalized in separate
parts of the p-electron system, as exemplified by V in Fig. 4. The
charges are strictly separated by a “union bond”—which in contrast
to the rest of the molecule’s bonds has a single bond character. We
calculated the bond length to be 152.4 pm. The torsion angle was
determined to be 174.8◦. Furthermore, there exist specific dipole
increments for all types of conjugation in the betaines: This is
VI for CCMBs in betaine 3. The anionic part of the CCMB is
isoconjugate to an odd, alternant hydrocarbon anion (VII) which
is connected through a nodal position of the highest occupied
molecular orbital (HOMO) via the “union bond” (u) to the cationic
part of the molecule (VIII).
Fig. 1 Characteristics of pseudo-cross-conjugation.
Fig. 4 Characteristics of cross-conjugation.
The HOMO/LUMO topology of 1 and the electrostatic poten-
tial surface are displayed in Figs. 2 and 3, respectively. As can be
observed, all of them exhibit the C2v point-group symmetry of this
molecule.
The frontier orbital topology of norzooanemonine 3 is pre-
sented in Fig. 5. The HOMO is located in the carboxylate group;
Fig. 2 HOMO (left) and LUMO (right) of 1,3-dimethylimidazoli-
um-2-carboxylate 1.
Fig. 5 HOMO (left) and LUMO (right) of norzooanemonine.
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Table 1 Selected calculated bond lengths of 1 and 3
Table 2 Selected calculated bond angles of 1 and 3
Bond angles/◦
Atoms A–B–C
CCMB 3
PCCMB 1
C2–N3–C4
C2–N3–C8
C4–N3–C8
C2–N1–C5
C2–N1–C7
C5–N1–C7
C5–C4 -N3
C5–C4–C6
N3–C4–C6
N3–C2–N1
O10–C6–O9
O10–C6–C4
O9–C6–C4
109.08
123.74
127.15
108.50
125.51
125.98
105.76
126.65
127.57
108.71
128.98
113.48
117.54
109.57
126.92
123.51
109.65
126.83
123.47
107.13
128.04
125.24
106.72
130.01
115.89
114.10
˚
Bond length/A
Bond (atom A–B)
1
3
N1–C2–C6
N3–C2–C6
N1–C2
N1–C5
N3–C2
N3–C4
1.349
1.375
1.350
1.373
1.360
1.536
1.247
1.250
1.336
1.374
1.333
1.391
1.368
1.524
1.254
1.251
O10–C6–C2
O9–C6–C2
C5–C4
C4–C6/C2–C6 “union bonds”
C6–O9
C6–O10
Table 3 Torsion angles in the CCMB and PCCMB
Torsion angles/◦
the LUMO is essentially located in the imidazole ring as well as in
the union bond.
Atom A–B–C–D
CCMB 3
PCCMB 1
We then calculated the electrostatic potential surface which is
presented in Fig. 6.
C2–N3–C4–C8
C5–N1–C2–C7
C5–C4–N3–C6
C4–C6–O9–O10
N3–C4–C6–O9
C5–C4–C6–O10
C5–C4–C6–O9
N3–C4–C6–O10
−178.2
−179.5
178.8
−179.4
−3.7
177.8
−179.4
−0.1
N3–C2–N1–C6
C2–C6–O9–O10
N3–C2–C6–O9
N3–C2–C6 O10
C5–N1–C2–C6
C4–N3–C2–C6
179.5
19.2
−4.7
−161.2
179.9
179.8
−3.6
176.8
Fig. 6 Electrostatic surface of norzooanemonine 3.
Calculated bond lengths are presented in Table 1. The CN bond
distances within the 5-membered ring system are influenced by the
substitution. The calculated natural bond orders (NBO) showed
a good correlation with the corresponding bond lengths. They
localized the double bonds within the imidazole ring between the
C4–C5 and the C2–N3 bonds in both molecules. The obtained
values for the imidazolium-2-carboxylate 1 were 1.90 and 1.93,
respectively, while for norzooanemonine 3 they were 1.88 and 1.94.
As expected, the union bonds clearly show single bond character
(the NBO was 0.99 in both cases), which supports the two separate
p-electron systems in either molecule with double bond character
in the positive and negative fragment, respectively.
Selected calculated bond angles are presented in Table 2.
As expected, in either molecule the imidazolium ring in-
cluding the methyl groups is planar. The same is true for the
carboxylate group of norzooanemonine 3, whereas that of 1,3-
dimethylimidazolium-2-carboxylate adopts an angle of 19.2◦ with
respect to the imidazolium ring. Torsion angles are given in Table 3.
Fig. 7 presents the calculated permanent dipole moments of 1
(12.44 D) and 3 (17.12 D).
Fig. 7 Permanent dipole moments of 1 (left) and 3 (right).
imidazole reacted with dimethylcarbonate in an autoclave over a
◦
period of 10 h at 120 C to give imidazolium-2-carboxylate 1 or
imidazolium-4-carboxylate 3 (Scheme 2, procedure A), depending
on the reaction conditions.21 Conducting the reaction of 1-
methylimidazole with dimethylcarbonate at 120 ◦C yielded the
target compound, betaine 1. The 13C NMR spectrum displays four
signals, consistent with the assigned structure. As the yield of this
procedure is low, we tested alternative approaches. Methylation
of the ethyl imidazole-2-carboxylate with dimethylsulfate in the
presence of catalytic amounts of nitrobenzene in xylene yielded a
1,3-dimethylimidazolium salt which was subjected to a saponifi-
cation with diluted sulfuric acid. The isolated product proved to
be identical with an authentic sample (Scheme 2, procedure B).
Methylation of imidazole-4-carboxylic acid 6 in aqueous
sodium hydroxide with dimethylsulfate yielded norzooanemonine
3 (Scheme 3). Purification, however, met with difficulties, as inor-
ganic materials could not be removed due to the water-solubility
of norzooanemonine. The same was found to be true conducting
the reaction in nitrobenzene or in a two-phase system consisting
of nitrobenzene and aqueous sodium hydroxide. Conducting the
Syntheses
Some procedures have been described to date for the synthe-
sis of 1,3-disubstituted imidazolium-2-carboxylates.20 1-Methyl-
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imidazolium salts was observed.23 However, it decomposes in
MeOD at reflux temperature within 2 h, as evidenced by NMR
spectroscopy. Moreover, H/D-exchange took place for both C4-
H, and C5-H in an NMR-sample measured in MeOD. The
relation of the two aryl-Hs to the two methyl groups was 2 : 46
instead of 2 : 6 as showed the NMR of the same sample measured
in DMSO-d6.
Under ESIMS measurement conditions, the N-heterocyclic
carbene 2 was identified as sodium adduct at m/z = 119.0606
on spraying a sample of 1 with MeOH in the range of 0 V to 20 V
fragmentor voltage. On a preparative scale, heating in toluene
produced 2 which was reacted in-situ with heterocumulenes.
Examples of typical trapping reactions are presented in Scheme 4.
Scheme 2
Scheme 4
Thus, CS2 reacted to the dithiocarboxylate 8 in low yield, 3,5-
dichloroisothiocyanate to the thioamidate 9 in 89% yield, and
4-chlorophenylisocyanate to the amidate 10a in 80% yield. The
isocyanate moiety can also be exchanged via the NHC. As
an example, we performed an exchange reaction of the 4-
chlorophenylamidate in 10a to a 3,5-dichlorophenylamidate in
10b. The compounds 8, 9, and 10a,b are representatives of the
class of pseudo-cross-conjugated mesomeric betaines. Imidazol-
2-ylidenes were prepared earlier by reduction of imidazole-2(3H)-
thione with potassium as a pale yellow solid.23 Their reactions
Scheme 3
reaction in xylene with a small amount of nitrobenzene and using
3 eq of dimethylsulfate to methylate 6 lead to methyl imidazole-4-
carboxylate 7 which was then subjected to saponification.
The two isomers 1 and 3 can readily be distinguished by
their NMR spectra. Thus, in the 13C NMR spectra of 3, six
signals were detectable, proving a non-symmetric substitution
pattern. Application of HH-COSY, HSQC and HMBC techniques
allowed the unambiguous peak assignment as presented in the
Experimental. Accordingly, C5-H couples with C7-H3, and C7-H3
with C2-H as well as C5-H. Finally, a NOESY NMR experiment
proved the structure of 1,3-dimethylimidazolium-4-carboxylate, as
C2-H couples with either methyl group (cf. Fig. 8, Experimental).
24
25
with CO2 or CS2 to the PCCMBs imidazolium-2-carboxylate
and -2-dithiocarboxylate and other reactions26 have been studied
intensively by Kuhn and co-workers.
Chlorination of the PCCMB 1 with SOCl2 and subsequent
reaction with 3,5-dichloroaniline to 11b failed. As evidenced
1
by mass spectrometry and H NMR spectroscopy of the crude
Reactions of 1,3-dimethylimidazolium-2-carboxylate
reaction mixture, we obtained the demethylated product 12 and
yet unidentified by-products (Scheme 5). Thus, we were prevented
from deprotonation with the anion exchange resin Amberlite IRA-
402 in its hydroxy form.
1,3-Dimethylimidazolium-2-carboxylate 1 is known to be stable
at room temperature towards decarboxylation in most organic
solvents.22 In methanol in the presence of NaBF4 formation of
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sprayed from MeOH, under ESIMS conditions, and found the
molecular peak at m/z = 164.1. At higher fragmentor voltages
than approximately 30 V, a mass consistent to the 2-deuterio-
imidazol-4-ylidene 14 as sodium adduct was indeed detected at
m/z = 120.2 (40% at 80 V). Obviously, this carbene is stable under
these conditions. The corresponding monodeutero-imidazolium
salt 15 was found at m/z = 98.1 and only traces of 2 were detected.
In our experiments, the ratio of non-deuterated to deuterated
species in the peaks at m/z = 164.1 : 163.1 and 120.2 : 119.2 was
identical (1 : 0.45, respectively). Obviously, there are no exchange
reactions during the electrospray ionization process.
The formation of NHC 4 is also supported experimentally.
Norzooanemonine 3 reacted with 3,5-dichlorophenylisocyanate
in toluene at reflux temperature to the imidazolium-amidate 16b,
which is hygroscopic and forms the corresponding amide with
water (Scheme 8). Two methyl groups at 3.86 and 3.99 ppm in
the 1H NMR spectra lend support to the structure of the 4-
substituted imidazolium ring. This reaction can be interpreted
as trapping reaction of the imidazol-4-ylidene 4. Under anal-
ogous reaction conditions no reaction occurred, however, with
4-chlorophenylisocyanate which obviously gives a weaker union
bond between negatively and positively charged partial structures.
This is also reflected in the isocyanate exchange reaction depicted
in Scheme 4.
Scheme 5
Reactions of norzooanemonine 3
First, we studied H/D-exchange reactions. Norzooanemonine
readily exchanged 2-H with MeOD at rt to 13 (Scheme 6).
Scheme 6
In high resolution electrospray ionization mass spectrometry
of 3 at zero volt fragmentor voltage a mass was detected that
is in accord to the N-heterocyclic carbene 4 as sodium adduct
(m/z = 119.0595; Calcd. for C5H8N2Na: 119.0585) (Scheme 7).
In addition, the protonated species, i.e. the imidazolium cation
was found at m/z = 97.0765 (Calcd for C5H9N2: 97.0766). In
order to gain some knowledge about this species, and to exclude
the formation of carbene 2 from consideration, we sprayed
the 2-deuterio-norzooanemonine 13, dissolved in MeOD and
Scheme 8
To prove the structure independently, we chlorinated nor-
zooanemonine 3 with thionyl chloride and reacted the resulting
chloride with anilines to the imidazolium salts 17a,b. Deprotona-
tion yielded the imidazolium-4-amidates 16a,b as new represen-
tatives of cross-conjugated mesomeric betaines (Scheme 9). All
spectroscopic data of the sample thus obtained are identical to the
trapping adduct of imidazol-4-ylidene 4.
In summary, the distinct classes of heterocyclic mesomeric
betaines display their own characteristic chemistry depending
on the type of conjugation. Pseudo-cross-conjugated hetero-
cyclic mesomeric betaines, including 1,3-dimethylimidazolium-2-
carboxylate, undergo typical extrusion reactions of heterocumu-
lenes to N-heterocyclic carbenes. To the best of our knowledge,
however, we have also presented the first trapping reaction
Scheme 7
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this model the solute molecule is placed into a size-adapted cavity
formed from overlapping atom-centred van der Waals spheres,
while the solvent is assimilated to a continuum characterized by its
dielectric constant (78.4 for water). CAUTION: Dimethyl sulfate
is inter alia highly toxic, mutagenic, carcinogenic, and corrosive;
nitrobenzene and carbon disulfide are poisonous.
1,3-Dimethylimidazolium-2-carboxylate 1
Method A21. 30 mL (0.376 mol, 1 eq) of N-methylimidazole
and 44.4 mL (0.527 mol, 1.4 eq) of dimethyl carbonate were given
into an autoclave. The resulting clear solution was heated under
stirring at 120 ◦C for 50 h. Then, the solid was filtered off and
dried in vacuo, giving 2.4 g (5%) of 1,3-dimethylimidazolium-
2-carboxylate 1. All spectroscopic data are consistent to those
reported in the literature.21
Method B (two-step procedure). A sample of 0.4 g (2.854 mmol,
1 eq) of ethyl 1H-imidazole-2-carboxylate was suspended in 12 mL
of xylene. After addition of 0.35 mL (3.4 mmol, 1.19 eq) of
nitrobenzene a yellow solution resulted which was heated to reflux
temperature for 30 min. Then, 0.59 mL (6.279 mmol, 2.2 eq) of
dimethyl sulfate were added. The mixture was then heated to reflux
for 5 h. After cooling the resulting oil was separated, dried in vacuo,
and purified by flash chromatography (silica gel; MeOH) to give 2-
ethoxycarbonyl-1,3-dimethylimidazolium hydrogensulfate, yield
0.184 g (24%), mp > 245 ◦C; dH (DMSO-d6) 7.94 (2H, s, C4-
H, C5-H), 4.45 (2H, q, J = 7.2 Hz), 4.04 (6H, s; N-Me), 1.38 (3H,
t, J = 7.2 Hz); dC (DMSO-d6) 153.9, 132.9, 125.8, 63.5, 38.6, 13.7;
mmax (KBr)/cm−1: 3440, 1742, 1638, 1533, 1448, 1095, 787, 643;
MS: m/z = 169 (18%) [M], 141 (11%) [M-CH2–CH3 + 1].
A sample of 138 mg (0.518 mmol, 1 eq) of 2-ethoxycarbonyl-
1,3-dimethylimidazolium hydrogensulfate was dissolved in 10 mL
of 50% H2SO4 and heated to reflux temperature for 5 h. After
neutralization with NaOH, the solvent was evaporated. The
resulting solid was recrystallized from ethanol and dried in vacuo
to give 1 (0.065 g; 90% yield).
Scheme 9
of the N-heterocylic carbene 1,3-dimethylimidazolium-4-ylidene,
formed on decarboxylation of the alkaloid norzooanemonine
which belongs to the class of cross-conjugated heterocyclic me-
someric betaines.
Experimental
General remarks
The 1H (200 and 400 MHz) and 13C NMR spectra (50 and
100 MHz) were recorded on Bruker Digital FT-NMR Avance 400
and Avance DPX 200 spectrometers. Multiplicities are described
by using the following abbreviations: s = singlet, d = doublet,
m = multiplet. The numbering is defined in Fig. 8. FT-IR spectra
were obtained on a Bruker Vektor 22 in the range of 400 to
4000 cm−1 (2.5% pellets in KBr). The electrospray ionisation mass
spectra (ESIMS) were measured with an Agilent LCMSD Series
HP1100 with APIES, and EI mass spectra on a Hewlett Packard
HP 5989. Melting points are uncorrected. Quantum chemical
calculations were performed using the GAUSSIAN-03 package
of programs.27 We always used the split-valence 6-31G** basis
set,28,29 which includes six s-type and three p-type polarization
functions on all the atoms. Electron correlation energy was in-
troduced using the hybrid functional B3PW91, within the density
functional theory.30,31 The minimal energy geometry, the topology
of the frontier orbitals, the natural bond orders (NBO) and the
electrostatic surface potential were computed by simulating a polar
environment by means of a polarizable continuum model.32,33 In
Norzooanemonine 3
Method A21. 1-Methylimidazole (50 mL, 0.63 mol) and
dimethyl carbonate (75 mL, 0.89 mol) were placed in an autoclave.
The mixture was then heated under stirring to 120 ◦C. After 7 h,
the autoclave was allowed to cool to rt, the precipitate was filtered
off, washed with diethyl ether, and recrystallized from ethanol :
methanol (1 : 1). Yield: 19%.
Method B. A sample of 1.9 g (0.017 mol, 1 eq) of imidazole-4-
carboxylic acid was suspended in 40 mL H2O. Then, 7.5 mL of 20%
NaOH and subsequently 5 mL (0.051 mol, 3 eq) of dimethyl sulfate
were added. The mixture was heated for 5 h at reflux temperature.
After cooling, diluted NH3 solution was added and the mixture
was then neutralized with diluted HCl, and extracted twice with
150 mL of dichloromethane. The aqueous layer was evaporated to
dryness under Dean–Stark conditions with toluene. The resulting
solid was subsequently washed with diethyl ether and ethanol.
Norzooanemonine was obtained as a white solid in 68% yield.
Method C. A sample of 1.25 g (0.0112 mol) of imidazole-
4-carboxylic acid was suspended in a mixture of 18 mL of
nitrobenzene, 3 mL of 20% aqueous NaOH, and 15 mL of water.
Fig. 8 Results of an HH-COSY experiment.
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Then, 3.5 mL (0.037 mol) of dimethyl sulfate were added to the
two-phase system, which was heated at 160–170 ◦C for 20 h. After
cooling the reaction mixture was extracted with dichloromethane.
The aqueous layer was evaporated to dryness, and the resulting
precipitate was washed with ethanol to give norzooanemonine 3
as a colourless solid in 73% yield.
filtered off and driedin vacuo, yield0.43g (80%), mp 121 ◦C (found:
C, 53.51; H, 4.41; N, 15.96. C12H12N3OCl. H2O requires: C, 53.84;
H, 5.27; N, 15.70). dH (MeOD) 7.46 (2H, s; C4-H, C5-H), 7.42–
7.35 (2H, m, Har), 7.27–7.20 (2H, m, Har), 3.98 (6H, s, N-Me); dC
(MeOD) 155.2, 148.0, 129.3, 128.6, 126.5, 123.1, 107.2, 36.4 ppm;
mmax (KBr)/cm−1: 3424, 3109, 2960, 2215, 1596, 1561, 1513, 1482,
1453, 1398, 1341, 1249, 1235, 1097, 1010, 935, 897 cm−1; MS:
Method D/E. A sample of 1 g (8.92 mmol, 1 eq) of imidazole-
4-carboxylic acid was suspended in 20 mL of xylene. Then, 0.2 mL
(1.943 mmol, 0.22 eq) of nitrobenzene and subsequently 2.8 mL
(0.03 mol, 3.3 eq) of dimethyl sulfate were added, whereupon
all solids dissolved. The mixture was then refluxed for 3 h,
evaporated to dryness, and treated with 3 g (0.0535 mol) of
methanolic KOH. Stirring was continued for 24 h, and then
the solution was neutralized with diluted aqueous HCl. The
solvent was then evaporated to give a brownish solid which was
partially dissolved in ethanol. Evaporation to dryness followed by
column chromatography [silica gel; methanol/ethyl acetate = 1/1]
yielded a sample of norzooanemonine. All spectroscopic data are
consistent to those reported in literature.21
=
m/z = 249 (31%) [M], 153 (100%) [Cl–C6H4–N C–O].
1,3-Dimethylimidazolium-2-N-(3ꢀ,5ꢀ-dichlorophenyl)amidate 10b
A sample of 0.085 g (0.34 mmol, 1 eq) of 1,3-dimethylimidazolium-
2-N-(p-chlorophenyl)amidate 10a was suspended under inert
conditions in 8 mL of toluene. Then, 0.064 g (0.34 mmol, 1 eq)
of 3,5-dichlorophenylisocyanate were added. The mixture was
stirred for 20 min at rt, and then for 3 h at reflux temperature.
After evaporation of the solvent, a brown oil was obtained, yield
0.046 g (46%) (found: 284.0361. C12H12N3OCl2 requires 284.0357).
dH (MeOD) 7.55 (2H, s, C4-H, C5-H), 7.41–7.40 (3H, m, Har), 3.91
(6H, s, N-Me); dC (MeOD) 173.3, 172.4, 163.6, 134.1, 129.8, 123.7,
123.3, 36.6 ppm; mmax (KBr)/cm−1: 3333, 3216, 2961, 2361, 1598,
1563, 1512, 1494, 1430, 1342, 1306, 1241, 1173, 1092, 1009, 990,
941, 916, 892; ESI-MS: 308 (13%) [M + H+ + Na+].
1,3-Dimethylimidazolium-2-dithiolate 8
A 25 mL flask was subsequently filled with 0.070 g of 1,3-dimethyl-
1H-imidazolium-2-carboxylate 1, 10 mL of toluene and 1 mL
of CS2. The resulting orange coloured suspension was heated
to 100 ◦C under vigorous stirring. After 3.5 h the mixture was
cooled to rt, and the solvent was distilled off in vacuo. The
resulting residue was then chromatographed (silica gel, MeOH)
to give 1,3-dimethylimidazolium-2-dithiolate, yield 11 mg (16%),
and recovered starting material (13 mg; 18.6%), mp 227 ◦C (found:
173.0210. C6H9N2S2 requires 173.0207). dH (CDCl3) 6.86 (s, 2 H),
3.81 (s, 6 H) ppm; dC (CDCl3): 224.0, 149.9, 119.0, 35.1 ppm; mmax
(KBr)/cm−1 3107, 1512, 1242, 1060 (CS2), 705; MS (70 eV): m/z =
172 (M+, 100%), 95 (M-CS2, 49%).
2-Deuterio-1,3-dimethylimidazolium-4-carboxylate 13
Under nitrogen 0.020 g (0.143 mmol, 1 eq) of norzooanemonine
3 were dissolved in 1 mL of anhydrous MeOD and stirred for
1 h. The sample was directly analyzed by NMR-spectroscopy. dH
(MeOD) 7.70 (1H, s, C5-H), 4.08 (3H, s, C8-H), 3.89 (3H, s, C7-H)
ppm; dC (MeOD) = 162.9, 133.6, C2 not detectable, 126.9, 36.5,
36.3 ppm; ESI-MS: m/z = 164.1 (100%) [M + Na+], 120.2 (55%).
1,3-Dimethylimidazolium-4-N-(3ꢀ,5ꢀ-dichlorophenyl)amidate 16b
A sample of 0.5 g (3.56 mmol) of norzooanemonine 3 was
suspended in 10 mL of toluene. Then, 0.67 g (3.56 mmol) of 3,5-
dichlorophenyl isocyanate were added, the mixture was heated
to 100 ◦C for 1 h and then to reflux temperature for 10.5 h.
After cooling, the white solid was filtered off and dried in vacuo,
yield 0.13 g (13%), mp 230–240 ◦C (dec) (found: 284.0363.
C12H12N3OCl2 requires 284.0357); dH (DMSO-d6) 9.23 (1H, s,
C2-H), 8.35 (1H, s, Har), 7.56 (2H, s, Har), 7.18 (1H, s, C5-H),
3.99 (3H, s, C8-H), 3.85 (3H, s, C7-H); dC (DMSO-d6) 159.1,
152.0, 140.4, 134.1, 129.0, 125.0, 121.3, 116.5, 36.1, 36.0 ppm;
mmax (KBr)/cm−1: 3444, 3304, 3157, 3129, 3096, 3050, 2695, 2522,
2435, 1727, 1650, 1587, 1549, 1483, 1418, 1223, 1165, 1060, 848;
ESI-MS: m/z = 283 (10%)/285 (15%) [M].
1,3-Dimethylimidazolium-2-N-(3,5-dichlorophenyl)thioamidate 9
Under inert conditions 0.15 g (1.070 mmol, 1 eq) of 1,3-
dimethylimidazolium-2-carboxylate were suspended in 4 mL of
toluene, stirred for a short period of time, and treated with
0.22 g (1.070 mmol, 1 eq) of 3,5-dichlorophenylisothiocyanate
and another 4 mL of toluene. The resulting yellow suspension was
heated to reflux for 4.5 h. After cooling, the slightly brownish solid
was ◦filtered off and dried in vacuo, yield 0.2844 g (89%), mp 193–
194 C. dH (MeOD) 7.41 (2H, s; C4-H, C5-H), 7.25 (2H, d, J =
1.9 Hz; Har), 7.12 (1H, t, J = 1.9 Hz; Har), 3.89 (6H, s, N-Me); dC
(MeOD) 172.2, 154.1, 147.1, 135.7, 124.2, 122.2, 122.1, 35.5 ppm;
mmax (KBr)/cm−1: 3424, 3113, 1626, 1573, 1557, 1534, 1422, 1245,
1206, 1100, 1046, 994, 975, 899, 871; MS (70 eV): m/z = 300 (66%)
General procedure for the amide tetrafluoroborates 17a,b
=
[M], 203 (54%) [Cl2–Ph–N C–S].
Under an inert atmosphere, 1 eq of 1,3-dimethylimidazolium-
2-carboxylate 1 (0.15 g; 1.07 mmol) and norzooanemonine 3
(0.15 g, 1.07 mmol), respectively, was suspended in anhydrous
dichloromethane. Then, 9 eq of SOCl2 (1.15 g; 0.7 mL, 9.63 mmol)
as well as 1 eq of anhydrous pyridine (0.09 g, 0.09 mL 1.07 mmol)
were added, whereupon the mixture was stirred at reflux temper-
ature for 30–60 min. Then 3 eq of the corresponding aniline were
added carefully. After reflux for 3–6 h, the mixture was allowed
to cool, the solvent was evaporated and water was added. The
1,3-Dimethylimidazolium-2-N-(p-chlorophenyl)amidate 10a
0.3
g (2.141 mmol, 1 eq) of 1,3-dimethylimidazolium-2-
carboxylate 1 were suspended in 10 mL of toluene and treated
with 0.33 g (2.141 mmol, 1 eq) of 4-chlorophenylisocyanate. After
stirring for 10 min at rt the suspension was heated to reflux
temperature. After stirring at reflux temperature for 3 h, the
solution was cooled, the resulting slightly yellowish solid was
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resulting solid was dissolved in methanol and cooled to 0 ◦C. Then
a 50% HBF4-solution was added and the mixture was stirred at
0 C for 30 min. The resulting tetrafluoroborate was filtered off
Acknowledgements
◦
The Deutsche Forschungsgemeinschaft is greatfully acknowl-
edged for financial support. Dr Gerald Dra¨ger, University of
Hannover, Germany, is gratefully acknowledged for measuring
the high resolution electrospray ionization mass spectra.
and dried in vacuo.
1,3-Dimethylimidazolium-4-N-(4-chlorophenyl)amide
tetrafluoroborate 17a
References
The procedure described above yielded 412 mg (20%) of a brownish
solid, mp 175–176 C (found: C, 42.51%, H, 3.42%, N, 12.61%.
◦
¨
1 W. A. Herrmann, K. Ofele, D. von Preysing and S. K. Schneider,
C12H13BClF4N3O requires: C, 42.70%, H, 3.88%, N, 12.45%). dH
(MeOD) 8.90 (1H, s, C2-H, H/D exchangeable), 8.06 (1H, s, C5-
H), 7.58 (2H, m, Har), 7.27 (2H, m, Har), 4.02 (3H, s, N-Me), 3.88
(3H, s; N-Me); dC (MeOD) = 156.9, 137.7, 131.1, 130.0, 130.1,
129.0, 126.5, 123.2, 36.8, 36.7 ppm; mmax (KBr)/cm−1: 3349, 1684;
ESI-MS (0V): m/z = 250 (100%) [M].
J. Organomet. Chem., 2003, 687, 229; B. S. Yong and S. P. Nolan,
Chemtracts, 2003, 16, 205; W. A. Herrmann, Angew. Chem., Int. Ed.
Engl., 2002, 41, 1290.
2 H. Stetter, Angew. Chem., Int. Ed. Engl., 1976, 15, 639; H. Stetter and
H. Kuhlmann, Org. React., 1991, 40, 407; D. Enders, K. Breuer, J.
Runsink and J. H. Teles, Helv. Chim. Acta, 1996, 79, 1899; M. S. Kerr,
J. Read de Alaniz and T. Rovis, J. Am. Chem. Soc., 2002, 124, 10298;
M. S. Kerr and T. Rovis, Synlett, 2003, 1934; M. S. Kerr and T. Rovis,
J. Am. Chem. Soc., 2004, 126, 8876.
3 R. Breslow, J. Am. Chem. Soc., 1958, 80, 3719; D. Enders and U.
Kallfass, Angew. Chem., Int. Ed. Engl., 2002, 41, 1743; Y. Tachibana,
N. Kihara and T. Takata, J. Am. Chem. Soc., 2004, 126, 3438.
4 G. A. Grasa, R. M. Kissling and S. P. Nolan, Org. Lett., 2002, 4, 3583;
G. W. Nyce, J. A. Lamboy, E. F. Connor, R. M. Waymouth and J. L.
Hedrick, Org. Lett., 2002, 4, 3587; C. Burstein and F. Glorius, Angew.
Chem., Int. Ed. Engl., 2004, 43, 6205.
5 Y. Suzuki, K. Yamauchi, K. Muramatsu and M. Sato, Chem. Commun.,
2004, 2770; T. Kano, K. Sasaki and K. Maruoka, Org. Lett., 2005, 7,
1347.
6 A. Chan and K. A. Scheidt, J. Am. Chem. Soc., 2006, 128, 4558.
7 T. Kano, K. Saski, T. Konishi, H. Mii and K. Maruoka, Tetrahedron
Lett., 2006, 47, 4615.
8 A. Schmidt, T. Habeck, B. Snovydovych and W. Eisfeld, Org. Lett.,
2007, 9, 3515.
1,3-Dimethylimidazolium-4-N-(3,5-dichlorophenyl)amide
tetrafluoroborate 17b
The procedure described above gave 188 mg (25%) of a colour-
less solid, mp 170 ◦C (found: 284.0366. C12H12N3OCl2 requires
284.0357). dH (DMSO-d6) 10.93 (1H, bs; N-H), 9.26 (1H, s; C2-
H), 8.36 (1H, s; Har), 7.77 (2H, s; Har), 7.41 (1H, s; C5-H), 4.02
(3H, s; C8-H), 3.93 (3H, s, C7-H); dC (DMSO-d6) 156.0, 140.4,
140.3, 134.3, 126.1, 123.8, 118.4 (two overlapped signals), 36.3 (C-
8), 36.1 (C-7) ppm; mmax (KBr)/cm−1: 3129, 1697, 1594, 1541, 1444,
1271, 1084, 1003, 861 cm−1; ESI-MS: m/z = 284 (100%) [M].
9 W. D. Ollis, C. A. Ramsden and S. P. Stanforth, Tetrahedron, 1985, 41,
2239.
10 A. Schmidt, Curr. Org. Chem., 2004, 8, 653.
11 A. Schmidt, Adv. Heterocycl. Chem., 2003, 85, 67.
General procedure for the conversion of the amides 17a,b into the
amidates 16a,b
12 K. T. Potts, T. Rochanapruk, A. Padwa, S. J. Coats and L. Hadjiara-
poglou, J. Org. Chem., 1995, 60, 3795; A. Padwa, S. J. Coats and M. A.
Semones, Tetrahedron, 1995, 51, 6651; A. Padwa, S. J. Coats and M. A.
Semones, Tetrahedron Lett., 1993, 34, 5405; T. Kappe, Heterocycles,
1984, 21, 358.
13 S. M. Sheehan and A. Padwa, J. Org. Chem., 1997, 62, 438; C. S. Straub
and A. Padwa, Org. Lett., 1999, 1, 83; A. Padwa, S. M. Sheehan and C. S.
Straub, J. Org. Chem., 1999, 64, 8648; J. P. Marino, M. H. Osterhout
and A. Padwa, J. Org. Chem., 1995, 60, 2704; A. Padwa, M. A. Brodney,
J. P. Marino, Jr. and S. M. Sheehan, J. Org. Chem., 1997, 62, 78; A.
Padwa, T. M. Heidelbaugh and J. T. Kuethe, J. Org. Chem., 2000, 65,
2368; T. M. Heidelbaugh, B. Liu and A. Padwa, Tetrahedron Lett.,
1998, 39, 4757; A. Padwa, A. C. Flick and H. I. Lee, Org. Lett., 2005,
7, 2925.
An ion exchange resin, Amberlite IRA-402 was activated first
with conc. HCl in a chromatography column to fully achieve
the chloride form, then washed with water to pH 7. Conc.
NaOH was then left on the column to exchange the anion to
hydroxide. Then the resin was washed with water to pH 7–8. The
amides (0.505 mmol, respectively) were applied in a mixture of
MeOH/H2O (1/1) or EtOH/H2O (1/1) to the amberlite and
rinsed through the ion exchange resin with the same solvent to
give the corresponding amidates.
14 A. Schmidt, T. Habeck, A. S. Lindner, B. Snovydovych, J. C. Namyslo,
A. Adam and M. Gjikaj, J. Org. Chem., 2007, 72, 2236.
15 A. Schmidt, A. Beutler, T. Habeck, T. Mordhorst and B. Snovydovych,
Synthesis, 2006, 1882.
16 An example is the rNHC 1,2-dimethylpyrazolium-4-ylidene from 1,2-
dimethylpyrazolium-4-carboxylate.
17 C. E. Ellul, M. F. Mahon, O. Saker and M. K. Whittlesey, Angew.
Chem., Int. Ed. Engl., 2007, 46, 6343; S. Gru¨ndemann, A. Kovacevic,
M. Albrecht, J. W. Faller and R. H. Crabtree, J. Am. Chem. Soc., 2002,
124, 10473.
18 A. J. Weinheimer, E. K. Metzner and M. L. Mole, Jr., Tetrahedron,
1973, 29, 3135; T. Jahn, G. M. Ko¨nig, A. D. Wright, G. Wo¨rheide and
J. Reitner, Tetrahedron Lett., 1997, 3883; S. Tsukamoto, H. Kato, H.
Hirota and N. Fusetani, Tetrahedron, 1994, 50, 13583.
19 A. Schmidt, B. Snovydovych, T. Habeck, P. Dro¨ttboom, M. Gjikaj and
A. Adam, Eur. J. Org. Chem., 2007, 4909; A. Schmidt, M. Albrecht, T.
Mordhorst, M. Topp and G. Jeschke, J. Mater. Chem., 2007, 17, 2793;
A. Schmidt, M. Topp, T. Mordhorst and O. Schneider, Tetrahedron,
2007, 63, 1842; A. Schmidt, L. Merkel and W. Eisfeld, Eur. J. Org.
Chem., 2005, 2124.
1,3-Dimethylimidazolium-4-N-(4-chlorophenyl)amidate 16a
Yield: 390 mg (99%) of a white solid, mp 263–264 ◦C (found:
250.0744. C12H13N3OCl requires: 250.0747). dH (MeOD) 8.86
(1H, s, C2-H, exchangeable), 8.06 (1H, s, C5-H), 7.49 (2H, m,
Har), 7.13 (2H, m, Har), 3.90 (3H, s, C8-H), 3.77 (3H, s, C7-
H); dC (MeOD) = 157.0, 137.8, 131.0, 129.9, 128.9, 126.7, 123.2
(two overlapped signals), 37.0, 36.9 ppm; mmax (KBr)/cm−1: 3359,
−1
=
1679 cm ; MS: m/z = 249 (12%) [M], 153 (50%) [Cl–Ph–N C–
O], 127 (100%) [Cl–Ph–NH2].
1,3-Dimethylimidazolium-4-N-(3,5-dichlorophenyl)amidate 16b
Yield: 123 mg (86%) of a yellow solid. All spectroscopic data
are identical to those described as the trapping experiment for
NHC 4.
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View Article Online
20 W. Schossler and M. Regitz, Chem. Ber., 1974, 107, 1931; N. Kuhn,
M. Steinmann and G. Weyers, Z. Naturforsch., 1999, 54b, 427; H. A.
Duong, T. N. Tekavec, A. M. Arif and J. Louie, Chem. Commun., 2004,
112.
21 I. Tommasi and F. Sorrentino, Tetrahedron Lett., 2006, 47, 6453; J. D.
Holbrey, W. M. Reichert, I. Tkatchenko, E. Bouajila, O. Walter, I.
Tommasi and R. D. Rogers, Chem. Commun., 2003, 28.
22 I. Tommasi and F. Sorrentino, Tetrahedron Lett., 2005, 46, 2141.
23 N. Kuhn and T. Kratz, Synthesis, 1993, 561.
24 N. Kuhn, M. Steinmann and G. Weyers, Z. Naturforsch., 1998, 54b,
427.
25 N. Kuhn, H. Bohnen and G. Henkel, Z. Naturforsch., 1994, 49b, 1473;
N. Kuhn, E. Niquet, M. Steimann and I. Walker, Z. Naturforsch., 1999,
54b, 1181.
26 N. Kuhn, J. Fahl, R. Fawzi, C. Maichle-Mo¨ßmer and M. Steinmann,
Z. Naturforsch., 1998, 53b, 720; N. Kuhn, J. Fahl, R. Boese and G.
Henkel, Z. Naturforsch., 1998, 53b, 881; N. Kuhn, M. Steimann, G.
Weyers and G. Henkel, Z. Naurforsch., 1998, 54b, 434; N. Kuhn, M.
Steimann and M. Walker, Z. Naturforsch., 2001, 56b, 129; N. Kuhn,
C. Maichle-Mo¨ßmer, E. Niquet and I. Walker, Z. Naturforsch., 2002,
57b, 47; N. Kuhn, A. Abu-Rayyan, M. Go¨hner and M. Steimann,
Z. Anorg. Allg. Chem., 2002, 628, 1721; N. Kuhn, A. Abu-Rayyan, C.
Piludu and M. Steimann, Heteroatom Chem., 2005, 16, 316; N. Kuhn,
A. Al-Sheikh, S. Schwarz and M. Steimann, Z. Naturforsch., 2004, 59b,
129.
27 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A.
Robb, J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N.
Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone,
B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H.
Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa,
M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X.
Li, J. E. Knox, H. P. Hratchian, J. B. Cross, C. Adamo, J. Jaramillo,
R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi,
C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth,
P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D.
Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K.
Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S.
Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz,
I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y.
Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson,
W. Chen, M. W. Wong, C. Gonzalez, and J. A. Pople, Gaussian 03,
Revision B.0. Gaussian, Inc., Pittsburgh PA (2003).
28 T. Clark, J. Chandrasekhar, G. W. Spitznagel and P. Schleyer, J. Comput.
Chem., 1983, 4, 294.
29 P. C. Hariharan and J. A. Pople, Theor. Chim. Acta., 1973, 28,
213.
30 A. D. Becke, Phys. Rev., 1998, 38, 3098.
31 J. P. Perdew and Y. Wang, Phys. Rev. B., 1992, 45, 13244.
32 S. Miertus, E. Scrocco and J. Tomasi, Chem. Phys., 1981, 55, 117.
33 S. Miertus and J. Tomasi, Chem. Phys., 1982, 65, 239.
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The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 287–295 | 295
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