N-Heterocyclic Carbenes as Key Intermediates in the Synthesis of Fused, Mesoionic, Tricyclic Heterocycles

Article abstract of DOI:10.1002/chem.201903242

Coupling between 5-bromoimidazo[1,5-a]pyridinium salts and malonate or arylacetate esters leads to a facile and straightforward access to the new mesoionic, fused, tricyclic system of imidazo[2,1,5-cd]indolizinium-3-olate. Mechanistic studies show that the reaction pathway consists of nucleophilic aromatic substitution on the cationic, bicyclic heterocycle by an enolate-type moiety and in the nucleophilic attack of a transient free N-heterocyclic carbene (NHC) species on the ester group; the relative order of these two steps depends on the nature of the starting ester. This work highlights the valuable implementation of free NHC species as key intermediates in synthetic chemistry, beyond their classical use as stabilizing ligands or organocatalysts.

Full text of DOI:10.1002/chem.201903242

A Journal of
Accepted Article
Title: N-Heterocyclic Carbenes as key intermediates in the synthesis of
fused mesoionic, tricyclic heterocycles
Authors: Idir Benaissa, Lenka Pallova, Marie-Emilie Morantin, Thomas
Lafitte, Mathieu Huynh, Cécile Barthes, Laure Vendier, Noël
Lugan, Stéphanie Bastin, and Vincent César
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To be cited as: Chem. Eur. J. 10.1002/chem.201903242
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N-Heterocyclic Carbenes as key intermediates in the synthesis of
fused mesoionic, tricyclic heterocycles
Idir Benaissa,‡ Lenka Pallova,‡ Marie-Emilie Morantin, Thomas Lafitte, Mathieu Huynh, Cécile Barthes,
Laure Vendier, Noël Lugan, Stéphanie Bastin,* Vincent César*,[a]
Abstract: The coupling between 5-bromoimidazo[1,5-a]pyridinium
salts and malonate or arylacetate esters leads to a facile and
straightforward access to the new mesoionic, fused tricyclic system
imidazo[2,1,5-cd]indolizinium-3-olate. Mechanistic studies show that
the reaction pathway consists in a nucleophilic aromatic substitution
(SNAr) on the cationic, bicyclic heterocycle by an enolate-type moiety
and in a nucleophilic attack of a transient free N-Heterocyclic Carbene
(NHC) species on the ester group, the relative order of those two steps
depending on the nature of the starting ester. This work highlights the
valuable implementation of free NHC species as key intermediates in
synthetic chemistry, beyond their classical use as stabilizing ligands
or organocatalysts.
reductive elimination to form C2-substituted imidazolium salts and
palladium black.[13] Building on this specific reactivity, the Ni- or
Pd-catalyzed C2-alkylation and arylation of imidazol-2-ylidenes
were further developed (Scheme 1A).[14],[15]
A) Pd-and Ni-catalyzed arylation/alkylation of imidazolium cycles
Ar
X
R
N
N
N
N
N
N
R
R'
R
R'
R
R'
[Pd] or [Ni]
[Ni]
H
Ar
R
B) Rh(III)-catalyzed
annelation on an NHC platform
C) Cu-catalyzed nitrene insertion
R
R
N
X
X
R2
N
R2
R1
N
N
CuX
N
R1
N
N
N3
Y
R
base
Introduction
[RhCp*Cl2]2
Y
R
oxidant, base
R
Since the seminal discoveries of
a
stable singlet
R
X = NR or S
Y = CH or N
(phosphino)(silyl)carbene by Bertrand,[1] and of the first stable
imidazol-2-ylidene by Arduengo,[2] the chemistry of N-
Heterocyclic Carbenes (NHCs) has been fascinating chemists
and attracted great research interest.[3],[4] Being singlet,
nucleophilic carbenes generated from versatile, highly modular
nitrogen-heterocycles,[5] NHCs have been mainly employed as
strong donating and sterically protecting ancillary ligands in
organometallic chemistry[6] with important applications in
homogeneous catalysis,[7] materials,[8] or medicinal chemistry.[9]
In addition, NHCs have shown outstanding aptitudes to
coordinate and stabilize main-group element compounds and to
form adducts with small molecules,[10] and they constitute on their
own highly efficient nucleophilic organocatalysts.[11]
D) Intermediacy of a "masked" free NHC
N
N
BR3
N
O
N
OH
O
N
B
N
R
R
H
R
R
R
mesomeric betaine / free NHC tautomerism
E) Formal 1,3-dipole from 5-bromoimidazo[1,5]pyridinium
(this work)
formal 1,3-dipole
O
R1
N R
base
R
OR2
N
N
N
R
N
N
+
Br
O
Br
+
R1
A
(
H)
Conversely, besides the use of NHCs as partners for the
activation of small molecules,[12] there are very few examples of
synthetic protocols, which occur through the intermediacy of a
NHC as one of the key reactive substrates or intermediates. In a
seminal contribution, Cavell and co-workers reported on the
decomposition of alkyl- and aryl-NHC Pd(II) complexes through
A
B
Scheme 1. Examples of previously reported synthetic procedures involving a
NHC as key reactive intermediate and general depiction of the cyclization
strategy developed in this study.
More recently, Choudhury’s group reported a versatile protocol for
the Rh(III)-catalyzed C-H activation-annelation on a NHC platform
from N-(hetero)aryl-azolium salts, in which the in situ generated
NHC serves as directing group for the C-H activation and as
coupling partner in a further reductive elimination step (Scheme
1B).[16] Analogously to the Staudinger reaction, NHCs rapidly
react with organic azides to form 1,3-triazenes, which can further
be interconverted into cyclic guanidine or guanidinium salts by
loss of dinitrogen upon heating or acidic treatment.[17] This
coupling reaction was recently extended to nitrous oxide[18] and to
[a]
I. Benaissa,‡ L. Pallova,‡ M.-E. Morantin, T. Lafitte, M. Huynh, C.
Barthes, Dr. L. Vendier, Dr. N. Lugan, Dr. S. Bastin, Dr. V. César
LCC-CNRS
Université de Toulouse, CNRS, Toulouse, France
E-mail: stephanie.bastin@lcc-toulouse.fr
vincent.cesar@lcc-toulouse.fr
[‡]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/chem.201903242
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nitric oxide.[19] Fused nitrogen-containing heterocycles were also
accessed from N-(2-azidophenyl)azolium salts through a key
insertion step of a nitrene/amido ligand into a Cu-NHC bond
(Scheme 1C).[20]
In recent years, mesomeric betaines – defined as conjugated
molecules, in which the positive and negative charges are
moiety. This resonance behavior suggests negligible 10-electron
aromaticity around the three rings, which is confirmed by the very
long connecting C4-C12 [1.4367(17) Å] and especially C5-C6
[1.4964(17) Å] bonds.
RO
OR
N
Mes
O
O
N
N Mes
Br
N
delocalized within
a common π-system and that can be
K2CO3, DMF
100°C
exclusively described using a dipolar canonical form[21] – were
shown to be in equilibrium with the corresponding free carbenic
form through a proton shift (Scheme 1D).[22],[23] As this equilibrium
is strongly shifted toward the more stable mesoionic compounds,
the latter can be viewed as “masked” free NHC sources.
Nevertheless, addition of a reaction partner usually results in full
conversion of the NHC, thanks to its high reactivity.
O
Br
RO
O
1
2a
(R = Me, 86%)
2b (R = Et, 69%)
K
RO
OR
DMF, RT
N Mes
O
O
(2.2 equiv)
We recently reported on 5-functionalized imidazo[1,5-a]pyridin-3-
ylidene (IPy) ligands, whose precursors were efficiently accessed
through a key nucleophilic aromatic substitution (SNAr) on the 5-
bromoimidazo[1,5-a]pyridinium cation (A·H)+.[24],[25] While the pre-
carbenic imidazolium ring was here unaffected, we speculate on
the possibility to access – at least transiently – the corresponding
carbene A (or an analogue) and thus to generate a formal 1,3-
dipole composed of the nucleophilic carbenic center and of the
electrophilic bromo-substituted pyridinic position. We report
herein the efficient annelation of 5-bromoimidazo[1,5-a]pyridinium
salts (A·H)+ with 2-substituted acetate esters to yield new
mesoionic, fused, tricyclic heterocycles B, and demonstrate the
intermediacy of NHC species.
N
N Mes
N
H
MeO
O
MeO
OMe
S
S8
O
O
N
4 (81%)
OMe
3 (63%)
O
CH2Cl2, 40°C
DMF
N Mes
N Mes
N
100°C
MeO
O
O
RO
H
O
2a
(54%)
OMe
O
3'
Scheme 2. Reactivity of 5-bromoimidazo[1,5-a]pyridinium bromide
1 with
malonic esters. Mes = 2,4,6-trimethylphenyl.
Results and Discussion
In the course of our study on the scope of the above-mentioned
SNAr reaction, we focused our attention on malonate esters as
coupling partners as they constitute acyclic analogues of the
hexapyrimidinetrione, which was successfully grafted onto the IPy
scaffold. Thus, heating 5-bromoimidazo[1,5-a]pyridinium bromide
1 with dimethyl or diethyl malonate in presence of an excess of
potassium carbonate at 100°C led to a highly fluorescent crude
mixture, from which the mesoionic heterotricyclic compounds 2a-
b were isolated in good yields (86%, and 69%, respectively). 2a-
b were fully characterized by spectroscopic and analytical
techniques, and their molecular formulation was firmly
established by an X-Ray diffraction experiment on a single crystal
of 2b (Figure 1).[26] The main core of 2b is a novel type of fused
mesoionic heterocycle, namely an imidazo[2,1,5-cd]indolizinium-
3-olate, which appears to be completely flat. Noteworthy, related
neutral and cationic four-ring system benzo[a]imidazo[2,1,5-
cd]indolizine fluorophores were recently developed by Charette
and co-workers.[27] The perfect planarity of the central nitrogen
atom environment [ΣN2 = 359.95°] speaks for a sp2 hybridization
of that atom, and indicates that the 10-electron aromaticity of the
imidazopyridine bicycle is conserved. Moreover, the almost
perfect coplanarity of the ester and tricyclic planes [torsion angle
(O1-C3-C4-C5) = 2.64°] associated with rather long and identical
bond distances for the inner-ring C4-C5 [1.4497(17) Å] and
exocyclic C3-C4 [1.4459(17) Å] bonds are testimony of the
existence of a mesomeric resonance within the acetylacetate
Figure 1. Molecular structure of 2b (ellipsoids drawn at 30% probability level).
Two independent molecules are present in the unit cell, differing only by a 180°
rotation of the ester moiety around the C3-C4 bond. Hydrogen atoms and
solvent molecule were omitted for clarity. Selected bond lengths (Å) and angles
(deg): C6-N1 1.3543(16), C6-N2 1.3330(16), N1-C17 1.3840(15), C13-C17
1.3909(18), C13-C14 1.4180(18), C14-C15 1.3781(19), C15-C16 1.4330(18),
C12-C16 1.3761(17), C4-C12 1.4367(17), C4-C5 1.4497(17), C5-C6
1.4964(17), C5-O3 1.2403(15), C3-C4 1.4459(17), C3-O1 1.3646(15), C3-O2
1.2147(15), O1-C3-C4-C5 2.64.
Intrigued by this somewhat unexpected reactivity and final
structure, we decided to study in more details the mechanism of
this annelation reaction. Reacting the bromo derivative 1 with the
potassium salt of the dimethyl malonate anion under milder
conditions, i.e. at room temperature, allowed isolation of the
zwitterionic compound 3, in which the malonate unit is grafted on
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the position 5 of the cationic heterobicycle. The C-C bond
formation between the two parts occurred through an SNAr
pathway, as we reported previously for related nucleophiles.[24],[25]
Two equivalents of the potassium malonate reagent were
required in this case, since the second equivalent served as a
base to trap the acidic proton on the central malonate carbon
atom in the intermediate after the SNAr reaction. The zwitterionic
formulation of 3 was in particular inferred from its 1H and 13C NMR
spectra at 298K, in which the signals for the imidazolium N2CH
moiety were detected at δH 9.06 ppm, and δC 129.1 ppm,
respectively, and the central sp2-hybridized malonate carbon
atom was identified at δC 72.7 ppm. Upon cooling down to 193 K,
the signals of the hydrogen atoms on the IPy bicycle broadened
and the N2CH signal vanished (Figure S1), indicating the
occurrence of a fast proton shift between the imidazolyl N2C
carbon atom of the major mesoionic species 3 and the central
malonate carbon atom of the elusive free NHC species 3’. This
tautomeric equilibrium was also reflected by the 13C NMR data
with the disappearance of the peaks corresponding to the
imidazolyl N2C and carbonyl carbon atoms at 193 K (Figure S2).
Further evidence of the tautomeric equilibrium between 3 and 3’
was provided upon reacting 3 with sulfur to yield the thiourea 4 in
81% yield. The imidazolium proton was shifted to the central
malonate position, as indicated by the corresponding singlets at
enolates.[29] After changing the solvent for DMF, the
bromoimidazopyridinium salt 1 was added at room temperature,
inducing an immediate color change to dark red. The tricyclic
mesoion 5a was isolated as a red solid and KHMDS was found to
lead to a better yield than NaHMDS. Compound 5a was fully
characterized by spectroscopic and analytical techniques,
including by an X-Ray diffraction experiment (Figure 2). The
tricyclic skeleton in 5a is fully planar and displays about the same
metrical features as in 2b, i.e. a 10 electron aromatic imidazo[1,5-
a]pyridinium bicycle, on which the enolate-type O1-C2-C3 moiety
is grafted through the two quite long C2-C12 [1.4847(15)] and C3-
C10 [1.4321(15)] bonds.
Scheme 4. Formation of compound 5a from 5-bromoimidazo[1,5-a]pyridinium
bromide 1 and ethyl phenylacetate.
1
δH 8.53 ppm and δC 52.6 ppm in the H and 13C NMR spectra.
Likewise, heating a solution of compound 3 in DMF at 100°C led
to the formation of the tricyclic mesoionic compound 2a in 54%
isolated yield, evidencing the intermediacy of compound 3 in the
annelation reaction between 1 and potassium malonates. A
suitable mechanism for the transformation of 3 into 2a could also
be drawn, which highlighted the crucial role of the tautomeric
equilibrium between 3 and 3’ (Scheme 3). Indeed, the proximity
of the nucleophilic carbene center and one the two ester moieties
in the minor free NHC tautomer 3’ would favor the intramolecular
reaction between both entities,[28] generating the tetrahedral
intermediate 3’’, which would interconvert into 2a by loss of
methanol.
Figure 2. Molecular structure of 5a (ellipsoids drawn at 30% probability level).
Hydrogen atoms and solvent molecule were omitted for clarity. Selected bond
lengths (Å) and angles (deg): C12-N2 1.3565(14), C12-N1 1.3288(14), N2-C23
1.3853(14), C23-C24 1.3909(16), C24-C25 1.4130(16), C25-C26 1.3774(17),
C26-C27 1.4255(17), C27-C10 1.3792(16), C3-C10 1.4321(15), C2-C3
1.4411(15), C2-C12 1.4847(15), C2-O1 1.2519(12).
Scheme 3. Proposed mechanism for the transformation of 3 into 2a.
At that point, we turned our attention on the extension of this
methodology to other types of substituted acetate esters and we
first selected ethyl phenylacetate as coupling partner (Scheme 4).
Using the previous one-pot protocol, i.e. with an excess of K2CO3
at 100°C, an intractable mixture was obtained arising from the
decomposition of compound 1. Decreasing the reaction
temperature to room temperature led to no reaction at all, the two
reagents being recovered intact. We thus decided to first generate
quantitatively the corresponding enolate using a strong base.
Hence, ethyl phenylacetate was deprotonated with NaHMDS or
KHMDS in toluene to yield the corresponding metallated
The scope of the annelation reaction was then investigated and
the results are displayed in scheme 5. Using the previous
procedure involving the pre-generation of the ester enolate
(procedure A), the ortho-, meta- and para-tolylacetate esters gave
the corresponding products 5b-d in good isolated yields, without
any noticeable effect of the methyl position. However, only
decomposition products were observed when using the highly
hindered ethyl mesitylacetate as coupling partner and the
expected product 5e could not be detected in the crude mixture.
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as coupling partner, the dark purple, fused tricyclic product 5j was
isolated in 23% yield, along with the dark blue by-product 6 in 8%
yield after column chromatography. While such an intense navy
blue band had been previously observed from time to time with
some of the previous substrates, the amount was too small to
allow isolation and characterization of the compound. Luckily here,
the isolated amount of compound 6 was sufficient to allow its
complete characterization and structural determination by a
thorough multinuclear, multidimensional NMR study.[30]
Compound 6 was obtained through the coupling of compound 1
with two equivalents of p-anisylacetate esters and was shown to
be composed of a mesoionic 1-iminopyrrolo[1,2-a]pyridinium-2-
olate core. While its formation involved the opening of the
imidazolyl ring of the imidazo[1,5-a]pyridinium bicycle, it was
shown not to arise from a subsequent attack of an ester enolate
on compound 5j, since no reaction was observed when mixing the
two compounds. Eventually, the N-substituent in the starting 5-
bromoimidazo[1,5-a]pyridinium salt 1 was also changed for 2,6-
diisopropylphenyl and 1-adamantyl groups and compounds 5k
and 5l were isolated in 52% and 34% yields respectively.
N
R1
OEt
procedure A or B
N
R1
N
R2
N
+
O
Br
Br
O
R2
5a-l
(yield, procedure)
1
N
Mes
N
Mes
N
Mes
N Mes
N
N
N
N
O
O
O
O
5a
(81%, A)
5b
(65%, A)
5c
(78%, A)
5d
(60%, A)
N
N
Mes
N
Mes
N
Mes
N
N
Mes
N
N
O
O
O
O
Mes
N
The quite different relative reactivities and conditions between the
previous malonate and the 2-arylacetate esters prompted us to
explore in more details the mechanism of the latter annelation
reaction, by carrying out some additional experiments. As the
O2N
5e
(0%)
5f
(72%, A)
5g
(61%, A)
5h
(0%, A), (60%, B)
OMe
reaction between
1 and the potassium enolate of ethyl
MeOOC
N
N
Mes
N Mes
phenylacetate occurred really quickly and no intermediate could
be characterized during the reaction, we decided to block the
inherent reactivity of the position 5 of the bicyclic heterocycle by
replacing the bromine atom by a methyl group. Thus, the
imidazo[1,5-a]pyridinium 7·HCl instantaneously reacted with the
ester enolate 8 in THF-d8 at room temperature through an acid-
base reaction to yield free NHC 7 and ethyl phenylacetate
(Scheme 6A). This result is consistent with the relative pKa values
of the different reagents. Indeed, considering that the acidity of
imidazo[1,5-a]pyridinium is within the range of those of
imidazolium salts [pKa ~19-24 in DMSO],[31] a malonate anion is
not enough basic [pKa(malonate) = 16.4 in DMSO] to induce its
deprotonation and generation of the free NHC, when the basicity
of the ester enolate [pKa(ethyl phenylacetate) = 22.7 in DMSO] is
sufficient to fully deprotonate 1 or 7·HCl.[32] The resulting mixture
of 7 and ethyl phenylacetate did not evolve further even under
heating to 60°C. In a second step, we studied the generation and
stability of the free NHC 9 deriving from 1. While reaction of 1 with
potassium bis(trimethylsilyl)amide (KHMDS) at room temperature
only led to decomposition products, the free NHC 9 could be
cleanly generated at – 50°C and trapped with BH3·SMe2 to form
the borane adduct 10 in 80% yield after purification (Scheme 6B).
Noteworthy, the molecular structure of 10 was firmly established
by an X-ray diffraction experiment (Figure 3). The C1-B1 bond
distance of 1.604(3) Å falls within the standard range of NHC-BH3
adducts [1.58-1.62 Å].[33] The peri positioning of the bromine and
the borane moieties induces a steric repulsion between them,
which is reflected by the dihedral angle B1-C1-C7-Br1 of 23.99°.
Going back to the reaction conditions, we were prompted to prove
that free NHC 9 is effectively produced as first intermediate in the
reaction between 1 and potassium enolate 8. Thus the two latter
reagents were mixed under the standard conditions of the
N
N
+
O
O
N
Mes
O
NC
MeO
5i
5j
6
(7%, A), (13%, B)
(23%, A)[b]
(8%, A)[b]
MeO
N
N
N
N
O
O
5k
(52%, A)
5l
(34%, A)
Scheme 5. Scope of the annelation reaction to generate tricyclic, mesoionic
compounds 5a-l. [a] Procedure A: ) Ethyl 2-arylacetate (2.22 equiv.), KHMDS
(2.2 equiv.), toluene, RT, 2) 1 (1 equiv.), DMF, RT; Procedure B: 1 (1 equiv.),
ethyl 2-arylacetate (1.1 equiv.), K2CO3 (3.5 equiv.), DMF, 100°C 1. [b] Methyl
(4-methoxyphenyl)acetate used instead of ethyl (4-methoxyphenyl)acetate.
While good yields were also observed with the extended 2-
naphthyl group (5f) and the 2-pyridinyl heterocycle (5g), the
electronic effects were shown to play a critical role on the outcome
of the reaction (products 5h-j). The two-step procedure A failed to
yield any trace of the desired 4-nitrophenyl-substituted 5h.
Fortunately, when using the previous one-pot procedure involving
excess of potassium carbonate at 100°C (procedure B),
compound 5h was smoothly and cleanly produced in 60% yield.
4-Cyanophenylacetate ester appeared to be a much more
reluctant substrate, since the best isolated yield in 5i was 13%
using procedure B. Using the electron-rich methyl p-anisylacetate
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10.1002/chem.201903242
Chemistry - A European Journal
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annelation reaction (DMF, RT) but in presence of a small excess
of sulfur. After 15 min of reaction, no tricyclic product 5a was
detected and only the thiourea 11 was observed in the crude
mixture. Compound 11 was then isolated in 52%, demonstrating
our hypothesis that free NHC 9 is the actual first intermediate in
Conversely, if the coupling between 1 and arylacetate esters
proceeded through the same SNAr/cyclization pathway as with the
malonate esters, the last cyclization step would occur from the
phenylacetate-substituted analogue of mesoion 3 and through a
tautomeric equilibrium similar to the one observed for 3. In order
to access this mesoionic compound, we devised to first graft a
phenylmalonate moiety on the position 5 of the imidazo[1,5-
a]pyridinium skeleton through the SNAr reaction as developed in
the first part followed by a decarboxylation reaction. Unfortunately,
the annelation reaction.
A. Reaction between imidazo[1,5-a]pyridinium 7.HCl and ester enolate
N
Mes
N
THF-d8
OEt
K
N
Mes
7
Ph
+
N
RT, 5 min
no coupling was observed between 1 and di(tert-butyl)
+
O
phenylmalonate even under drastic conditions.[34] Releasing
some steric pressure on the malonate by removing the central
phenyl group allowed the clean formation of the zwitterionic
compound 12 in 94% yield (Scheme 6C). Acidic treatment of 12
by triflic acid followed by addition of methanol led to a
decarboxylation reaction and esterification of the remaining
carboxylic acid group to yield the imidazo[1,5-a]pyridinium triflate
13 in average yield. The mesoionic compound 14 was then
quantitatively obtained by deprotonation of 12 with 1 equivalent of
KHMDS. While no definite conclusion about a tautomeric
equilibrium could be drawn from the VT NMR experiment, no
OEt
Cl
HCl
Ph
7
8
O
B. Generation and trapping of the free NHC 9 derived from 1
BH3.SMe2
KHMDS
- 50°C
N
Mes
N
Mes
Br
N Mes
N
N
N
BH3
Br
Br
Br
1
10 (80%)
9
C. Trapping of transient free NHC 9 generated during the annelation reaction
S8
N
Mes
OEt
K
N
Mes
N
Ph
N
DMF
RT, 15 min
O
tricyclic compound similar to
5 was detected by heating
Br
S
Br
Br
1
8
compound 14, and adding sulfur to 14 led a complexed mixture.[29]
Even if the latter does not possess an aryl group on the α-position
of the carboxylate group, it appeared unlikely that the annelation
reaction between 1 and arylacetate esters proceeds through such
an intermediate.
11
(52%)
D. Generation of zwitterionic compound 13
Na
Br
Mes
tBu-O
O-tBu
N
Mes
N
O
N
O
O
N
tBu-O
O-tBu
Altogether, based on the latter experiments, the formation of
compounds 5 could be explained by the proposed mechanism
described in scheme 7. In a first fast reaction, potassium enolate
deprotonates the imidazolium 1 to generate transiently the free
carbene 9, which would attack the ester moiety to form the
tetrahedral intermediate Int1. Evolution by loss of ethanol would
lead to the imidazolium enolate Int2,[28d],[35] which would undergo
a facile intramolecular SNAr reaction generating the intermediate
Int3, and then the final mesoionic tricycle 5 in a final aromatization
reaction.
DMF, RT
Br
N
O
1
12
(80%)
1) TfOH
N
Mes
N
Mes
N
CH2Cl2, RT
KHMDS
O
2) MeOH
O
TfO
OMe
13 (56%)
OMe
14
(quant.)
Scheme 6. Additional test reactions for establishing the mechanism of the
reaction between compound 1 and arylacetate esters.
Scheme 7. Proposed mechanism for the formation of the fused mesoionic
tricycle 5 from 1 and arylacetate esters enolates.
Figure 3. Molecular structure of compound 10 (ellipsoids drawn at 30%
probability level). Hydrogen atoms and solvent molecule were omitted for clarity.
Selected bond lengths (Å) and angles (deg): C1-B1 1.604(3), C7-Br1 1.874(2),
B1-C1-C7-Br1 23.99.
Conclusions
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straightforward and efficient manner starting from readily
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aromatic substitution • tautomerism
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Entry for the Table of Contents (Please choose one layout)
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Idir Benaissa,‡ Lenka Pallova,‡ Marie-
Emilie Morantin, Thomas Lafitte, Cécile
Barthes, Laure Vendier, Noël Lugan,
Stéphanie Bastin,* Vincent César**
Page No. – Page No.
N-Heterocyclic Carbenes as key
intermediates in the synthesis of
fused mesoionic, tricyclic
heterocycles
Synthetic NHC intermediates: The condensation of 2-substituted acetate esters
on 5-bromoimidazo[1,5-a]pyridinium salts leads to the formation of a new class of
fused, mesoionic heterocycles, and is shown to proceed through the intermediacy
of transient free NHC species as key synthetic intermediates.
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