Mechanistic insight into the Staudinger reaction catalyzed by N-heterocyclic carbenes

Article abstract of DOI:10.1002/chem.201204428

Four zwitterions were prepared by treating 1,3-dimesitylimidazolin-2- ylidene (SIMes) or 1,3-dimesitylimidazol-2-ylidene (IMes) with either N-tosyl benzaldimine or diphenylketene. They were isolated in high yields and characterized by IR and NMR spectroscopy. The molecular structures of three of them were determined by using X-ray crystallography and their thermal stability was monitored by using thermogravimetric analysis. The imidazol(in)ium-2-amides were rather labile white solids that did not show any tendency to tautomerize into the corresponding 1,2,2-triaminoethene derivatives. They displayed a mediocre catalytic activity in the Staudinger reaction of N-tosyl benzaldimine with diphenylketene. In contrast, the imidazol(in)ium-2-enolates were orange-red crystalline materials that remained stable over extended periods of time. Despite their greater stability, these zwitterions turned out to be efficient promoters for the model cycloaddition under scrutiny. As a matter of fact, their catalytic activity matched those recorded with the free carbenes. Altogether, these results provide strong experimental insight into the mechanism of the Staudinger reaction catalyzed by N-heterocyclic carbenes. They also highlight the superior catalytic activity of the imidazole-based carbene IMes compared with its saturated analogue SIMes in the reaction under consideration. Catalysts caught in the act: The N-heterocyclic carbenes 1,3-dimesitylimidazolin-2- ylidene (SIMes) and 1,3-dimesitylimidazol-2-ylidene (IMes) react with N-tosyl benzaldimine or diphenylketene to afford the corresponding zwitterions in high yields (see scheme). The molecular structures of three of them were determined by X-ray crystallography and their thermal stability was monitored by thermogravimetric analysis. The NHC×ketene betaines were found to be key intermediates for the Staudinger reaction catalyzed by NHCs. Copyright

Full text of DOI:10.1002/chem.201204428

FULL PAPER
DOI: 10.1002/chem.201204428
Mechanistic Insight into the Staudinger Reaction
Catalyzed by N-Heterocyclic Carbenes
Morgan Hans,[a] Johan Wouters,[b] Albert Demonceau,[a] and Lionel Delaude*[a]
Abstract: Four zwitterions were pre-
pared by treating 1,3-dimesitylimidazo-
lin-2-ylidene (SIMes) or 1,3-dimesityl-
corresponding 1,2,2-triaminoethene de-
rivatives. They displayed a mediocre
catalytic activity in the Staudinger re-
action of N-tosyl benzaldimine with di-
phenylketene. In contrast, the imidazo-
l(in)ium-2-enolates were orange-red
crystalline materials that remained
stable over extended periods of time.
Despite their greater stability, these
zwitterions turned out to be efficient
promoters for the model cycloaddition
under scrutiny. As a matter of fact,
their catalytic activity matched those
recorded with the free carbenes. Alto-
gether, these results provide strong ex-
perimental insight into the mechanism
of the Staudinger reaction catalyzed by
N-heterocyclic carbenes. They also
highlight the superior catalytic activity
of the imidazole-based carbene IMes
compared with its saturated analogue
SIMes in the reaction under considera-
tion.
ACHTUNGTRENNUNGimidazol-2-ylidene (IMes) with either
N-tosyl benzaldimine or diphenylke-
tene. They were isolated in high yields
and characterized by IR and NMR
spectroscopy. The molecular structures
of three of them were determined by
using X-ray crystallography and their
thermal stability was monitored by
using thermogravimetric analysis. The
imidazol(in)ium-2-amides were rather
labile white solids that did not show
any tendency to tautomerize into the
Keywords: carbenes
·
lactams
·
organocatalysis · reaction mecha-
nisms · zwitterions
Introduction
tion, oxidation, or transesterification reactions, to name just
a few.[7]
Over the past two decades, stable N-heterocyclic carbenes
(NHCs) have become ubiquitous ligands in organometallic
chemistry and in homogeneous catalysis.[1] They have also
emerged as powerful nucleophilic organocatalysts for poly-
mer chemistry[2] and organic synthesis.[3] Initial research in
this field focused on their ability to invert the polarity of a
carbonyl group, thereby allowing the formation of acyl
anions from aldehydes through an “umpolung” process.[4]
Historically, the benzoin condensation and the Stetter reac-
tion were the first chemical transformations that took ad-
vantage of this mode of activation,[5] but recent years have
seen the development of an impressive range of enantiose-
lective enolate and homoenolate coupling reactions based
on chiral NHCs.[6] Stable carbenes or their immediate pre-
cursors were also successfully used to catalyze Michael addi-
First reported by Staudinger in 1907,[8] the [2+2] cycload-
dition of ketenes with imines to give b-lactams is a versatile
and efficient synthetic route to access an important class of
nitrogen heterocycles with outstanding biological and phar-
maceutical activities.[9] Although this reaction was dis-
AHCTUNGTREGcNNUN overed more than a century ago and has been extensively
studied ever since,[10] intimate details of its mechanism are
still heavily debated, especially those concerning the regio-
and the stereoselectivity of the transformation.[11]
In 2008, the groups of Ye[12] and Smith[13] reported almost
simultaneously the asymmetric synthesis of b-lactams by
using chiral NHC catalysts generated in situ by deprotona-
tion of imidazol(in)ium or triazolium salts (Scheme 1). Ye
et al. first carried out preliminary tests using the achiral
1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene carbene
before employing the (R)-pyroglutamic acid-derived precat-
AHCTUNGTREGaNNUN lyst 5 to perform the cycloaddition of unsymmetrical alkyl-
4
ACHTUNGTRENNUNG
[a] M. Hans, Prof. A. Demonceau, Prof. L. Delaude
Laboratory of Organometallic Chemistry
and Homogeneous Catalysis
AHCTUNGTREGaNNNU rylketenes 1 and N-protected aldimines 2 with excellent
enantio- and diastereoselectivities.[12] Smith and co-workers
devised a similar strategy starting from diphenylketene or
isobutylphenylketene and N-tosyl aldimines, with either tri-
Institut de chimie (B6a), Universitꢀ de Liꢁge
Sart-Tilman par 4000 Liꢁge (Belgium)
Fax : (+32)4-366-3497
AHCTUNGTREGaNNNU zolium 7 or imidazolinium salt 8 being the optimal precata-
E-mail: l.delaude@ulg.ac.be
lysts for obtaining b-lactams 3 in high enantiomeric excess-
es.[13] More recently, Feroci and Inesi et al. reported an elec-
trochemical process for the Staudinger reaction of an acyl
chloride 9 and a non-electrophilic N-aryl aldimine 10 in
1-butyl-3-methylimidazolium tetrafluoroborate (BMIM-
BF4).[14] The ionic liquid acted both as a solvent and a cata-
[b] Prof. J. Wouters
Department of Chemistry
Facultꢀs Universitaires N.-D. de la Paix,
61 Rue de Bruxelles, 5000 Namur (Belgium)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204428.
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azolium amide 14. This intermediate zwitterion then attacks
the ketene to form enolate 15, whose cyclization releases
the final product and regenerates the catalyst.
Experiments carried out by Smith et al. showed that the
addition of diphenylketene to a catalyst generated in situ
from triazolium salt 6 and potassium bis(trimethylsilyl)-
AHCTUNGTREGaNNNU mide, followed by N-tosyl benzaldimine led to the corre-
sponding b-lactam in high yield, whereas the reverse addi-
tion order did not result in any conversion even after 5 days,
thereby supporting the “ketene-first” mechanism.[13] How-
AHCTUNGTREGeNNUN ver, when Ye and co-workers used 1,3-bis(2,6-diisopropyl-
phenyl)imidazol-2-ylidene 4 as a catalyst, they were able to
isolate a zwitterion of type 14 rather than 12, which further
reacted with phenylethylketene to give a b-lactam.[12] In line
with earlier NMR studies from He and Bode,[16] the Chinese
team noted that the formation of betaine 14 was reversi-
ble[17] and that the cyclization of intermediate 15 was disfa-
vored according to Baldwinꢃs rules.[18] Nevertheless, their ex-
perimental data did not rule out entirely the possibility of
an “imine-first” mechanism. Theoretical calculations per-
formed by Liu et al., on the other hand, strongly suggested
that the NHC-catalyzed Staudinger reaction proceeded ex-
clusively through the “ketene-first” pathway and helped un-
derstand the stereoselectivities observed for some of the ex-
perimental systems investigated previously.[19]
Scheme 1. NHC-based catalytic systems investigated by the groups of Ye
(top frame) and Smith (bottom frame) for the synthesis of b-lactams.
Protecting group (PG)=tert-butoxycarbonyl (Boc), carbobenzyloxy
(Cbz), tosyl (Ts).
lyst precursor to afford the electrogenerated NHC active
species that catalyzed the formation of racemic, predomi-
nantly trans b-lactams 11 (Scheme 2).
Two possible mechanisms were proposed to account for
the catalytic activity of NHCs in Staudinger reactions
In light of our sustained interest for the betaines of
NHCs,[20] we decided to thoroughly investigate the interme-
diacy of NHC·imine or NHC·ketene zwitterions in the Stau-
dinger reaction. We reasoned that isolating and fully charac-
terizing both types of adducts would provide valuable infor-
mation about their physico-chemical properties and ease
their differentiation in mechanistic studies. In this contribu-
tion, we disclose the synthesis of four representative imida-
zol(in)ium amide or enolate inner salts and we probe their
catalytic activity in the [2+2] cycloaddition of diphenyl-
Scheme 2. Synthesis of b-lactams using an electrogenerated NHC in the
ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate (BMIM-BF4).
(Scheme 3).[12,15] In the “ketene-first” approach, the nucleo-
philic carbene initially attacks the ketene to generate a zwit-
terionic azolium enolate 12, which further reacts with the
imine in a Mannich-like reaction to form intermediate 13,
whose cyclization affords the final product and closes the
catalytic cycle. Alternatively, in the “imine-first” mechanism
the two reactants are added in reverse order: the imine is
first activated by the catalyst, leading to the formation of
ACHTUNGTRNEkNUNG etene and N-tosyl benzaldimine.
Results and Discussion
Synthesis of NHC·imine zwitterions: In a first series of ex-
periments, N-tosyl benzaldimine was treated with two of the
most common NHCs investigated so far, namely 1,3-dimesi-
tylimidazolin-2-ylidene (nick-
named SIMes) and its imida-
zole-based
cousin
IMes
(Scheme 4). These two carbenes
were generated in situ by de-
protonation of the correspond-
ing imidazol(in)ium salts with
potassium
bis(trimethylsilyl)-
AHCTUNGTERGaNNUN mide in THF. After filtration
of the inorganic byproducts, a
solution of the protected aldi-
mine in THF was added and
white precipitates appeared
within a few minutes. After 1 h,
Scheme 3. Possible mechanisms for the Staudinger reaction catalyzed by N-heterocyclic carbenes.
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Staudinger Reaction Catalyzed by N-Heterocyclic Carbenes
FULL PAPER
À
À
À
AHCTUNGTREGUNiNN um plane and forms a N1 C1 C6 N3 dihedral angle of
110.6(3)8.
Another important piece of information derived from the
À
crystal structure of compound 16 is that the C1 C6 bond
[24]
À
length of 1.518(5) ꢄ corresponds to a C C single bond.
This result nicely corroborates 1H and 13C NMR analyses
that showed the presence of a strongly deshielded aliphatic
CH group within the structures of adducts 16 and 17
(Scheme 5). Altogether, these data support the formulation
of both products as imidazol(in)ium-2-amide zwitterions in
the solid state and in solution. This observation is not trivial,
because when Berkessel and co-workers added benzalde-
hyde to SIMes, the sole product that they unambiguously
identified by using NMR spectroscopy was the neutral 2,2-
diamino enol 18 and not the tautomeric imidazolinium-2-
Scheme 4. Synthesis of imidazol(in)ium-2-amides 16 and 17.
they were filtered, rinsed with diethyl ether, and dried
under high vacuum to afford imidazol(in)ium-2-amides 16
and 17 isolated in 74 and 83% yields, respectively. Although
both zwitterions were better kept under an inert atmos-
phere, compound 17 showed a higher resistance to air and
moisture than 16 in the solid state. Moreover, solutions of
17 in CD2Cl2 remained stable overnight, whereas a rapid de-
composition occurred in the case of betaine 16. In some in-
stances, the latter salt precipitated as a THF solvate. When
this happened, heating under vacuum and washing with di-
ethyl ether allowed to release the solvent and to obtain the
pure NHC·imine compound.
1H NMR analysis confirmed the formation of 1:1 stoichio-
metric adducts between the two nucleophilic carbenes and
the N-tosyl imine. The characteristic highly deshielded form-
ACHTUNGTRENNUNGamidinium and aldimine protons of the starting materials lo-
cated between d=8.5 and 10 ppm were missing. They were
replaced by a diagnostic singlet at about d=5.5 ppm as-
À
À
signed to the Ph CH NTs methine unit linked to the azo-
ACHTUNGTRENNUNGlium moiety. This signal was clearly separated from the vari-
ous other aromatic and aliphatic resonances due to the
tosyl, phenyl, and mesityl groups. It is noteworthy that the
ortho-methyl substituents on the mesityl rings resonated as
two singlets integrated for 6H each and that the ethylene
backbone of the central heterocycle in 16 appeared as a
second-order multiplet. These observations reveal a lack of
symmetry and the absence of free rotation on the NMR
timescale for the three exocyclic substituents connected to
the central imidazol(in)ium core.
Figure 1. ORTEP diagram of imidazolinium-2-amide 16 with thermal el-
lipsoids drawn at 50% probability. Co-crystallized CH2Cl2 and H atoms
are omitted for clarity. Selected bond lengths [ꢄ] and angles [8]: C1–N1
1.324(4), C1–N2 1.322(2), C1–C6 1.518(5), C6–N3 1.448(5); N1-C1-N2
110.4(3), C1-N1-C4-C20 103.7(4), C1-N2-C5-C29 À98.8(4), N1-C1-C6-N3
110.6(3).
Crystals of 1,3-dimesitylimidazolinium-N-benzyl-N-tosyl-
ACHTUNGTRENNUNGamide 16 suitable for X-ray diffraction analysis were ob-
tained by slow diffusion of n-pentane into a dichlorome-
thane solution kept at À188C. Examination of their molecu-
lar structure showed that the tosyl and phenyl groups were
almost perpendicular (torsion angle 87.9(3)8), whereas they
are assumed to be trans to each other in the starting imine
À
À
(Figure 1). Within the heterocyclic ring, the C1 N1 and C1
N2 distances were almost identical and close to 1.32 ꢄ. This
indicates a significant C=N double bond character, which
can be easily rationalized by assuming equal contributions
+
+
À
À
of the N1 C2=N2 and N1=C1 N2 canonical forms, as
previously observed in the betaines formed between SIMes
and either CO2,[21] COS,[22] or CS2.[23] Contrastingly, the C6
À
N3 distance of 1.448(5) ꢄ is much closer to a typical single
C N bond (1.47 ꢄ) than to a C=N double bond (1.34 ꢄ),
in line with the transformation of the aldimine starting ma-
[24]
À
terial into a non-delocalized amide anion. For obvious steric
Scheme 5. Possible tautomers formed upon addition of aldehydes or
aldimines to NHCs.
À
reasons, this C N bond is twisted relative to the imidazolin-
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L. Delaude et al.
alkoxy zwitterion.[25] This difference of reactivity can be ex-
plained by a better stabilization of the negative charge by
the tosylamide anion compared with an alkoxy species. On
the other hand, Smith et al. recently disclosed that the addi-
tion of a range of 4-substituted benzaldehydes to an in situ-
generated triazolylidene carbene afforded the corresponding
3-(hydroxybenzyl)azolium products.[26] Although the yields
were very low, crystallization from DCl/D2O allowed them
to unambiguously determine the structure of chloride salt 19
and its p-methylbenzyl or p-fluorobenzyl analogues by using
X-ray diffraction analysis. This difference of behavior is
probably linked to the much greater acidity of triazolium
salts[27] compared with their imidazol(in)ium counterparts,[28]
but further investigations are needed to clarify this point.
8.8 ppm for IMes·HBF4 and the appearance of new aromatic
signals, which integrated for 10 hydrogen atoms, supported
the formation of a 1:1 adduct between an NHC and diphe-
nylketene. As observed for compounds 16 and 17, the ortho-
methyl substituents on the mesityl groups resonated as two
singlets integrated for 6H each in products 20 and 21. Like-
wise, the four imidazoline protons of SIMes or the two imi-
A
ACHTUNGTRENzNGNU ole protons of IMes located at about d=4 or 7 ppm, re-
a
second-order multiplet in 20 or a doublet in 21. These data
indicate a loss of symmetry within the imidazol(in)ium
moiety when it is associated to the ethenolate fragment.
The 13C NMR spectrum of betaine 20 featured a strongly
deshielded signal for the central carbon atom of the etheno-
late group (d=171.4 ppm), down from d=196.9 ppm in free
diphenylketene (Table 1). This signal was further lowered to
d=153.9 ppm in the imidazolium inner salt 21, in line with
Synthesis of NHC·ketene zwitterions: In a second series of
experiments, we have prepared two representative NHC·ke-
tene betaines by treating diphenylketene with either SIMes
or IMes in 1:1 molar proportions (Scheme 6). Once again,
the free carbenes were generated in situ by deprotonating
imidazol(in)ium salt precursors with potassium bis(trimeth-
Table 1. Evolution of 13C NMR chemical shifts upon reaction of diphe-
nylketene with SIMes or IMes.
Compound
d C1
[ppm]
d C2
[ppm]
N
ACHTUNGTRENNUNG
Ph2C2=C1=O
196.9[a]
171.4[b]
153.9[b]
57.9[a]
SIMes·Ph2C2=C1=O (20)
IMes·Ph2C2=C1=O (21)
111.9[b]
112.6[b]
[a] In CDCl3 at 298 K. [b] In CD2Cl2 at 298 K.
the greater donor ability of IMes versus SIMes.[31] Converse-
ly, in both adducts, the remote carbon atom of the etheno-
late functional group resonated at about d=112 ppm,
whereas the original signal was found at d=57.9 ppm in free
diphenylketene. We tentatively assign this downfield shift to
a greater delocalization of the C1=C2 electron density as it
participates to the stabilization of the negative charge in the
zwitterions.
Crystals suitable for X-ray diffraction analysis were easily
obtained by dissolving compounds 20 and 21 in acetonitrile,
followed by slow evaporation of the saturated solutions in
an open vessel at room temperature. Both zwitterions crys-
tallized in the same monoclinic Cc space group and dis-
played similar features. Only the molecular structure of imi-
dazolinium derivative 20 is depicted in Figure 2 and briefly
discussed here (see the Supporting Information for more de-
tails about imidazolium inner salt 21).
Scheme 6. Synthesis of imidazol(in)ium-2-enolates 20 and 21.
ACHTUNGTRENNUNGylsilyl)amide in THF under an inert atmosphere. Due to its
strong tendency to polymerize, the ketene was also synthe-
sized immediately prior to use following a well-established
procedure.[29] Thus, diphenylacetyl chloride was treated with
triethylamine in THF. The resulting bright-yellow suspen-
sion was stirred for 30 min at room temperature. It was then
filtered through Celite and added to the pale-yellow carbene
solution. An intense red color appeared within a few mi-
nutes, indicative of the formation of imidazol(in)ium-2-eth-
ACHTUNGTRENNUNGenACHTUNGTRENNUNGolate zwitterions. After work up, compounds 20 and 21
were isolated as bright-orange microcrystalline powders in
high yields. They were stable enough to be brought back to
air. The imidazolium inner salt 21 could be kept for more
than a year in a closed vial at room temperature without
any degradation, whereas its imidazolinium counterpart 20
had a much shorter shelf-life under the same conditions. To
the best of our knowledge, the only report on the synthesis
of NHC·ketene zwitterions prior to this work dates back to
1970 when Regitz et al. succinctly described the cleavage of
two enetetramines with diphenylketene to afford the corre-
sponding betaines.[30]
Apart from different tilt angles for the mesityl groups,
there was no significant deviation of geometry within the
imidazolinium moiety of enolate 20 compared to the amide
16 (cf., Figure 1, see also the Supporting Information, Fig-
À
ure S3). For both types of adducts, the C1 C6 distances be-
tween the anionic and cationic fragments were the same
(1.517(3) ꢄ in 20, 1.518(5) ꢄ in 16) and corresponded to a
[24]
À
C C single bond. These values sharply contrast with the
À
À
Various analytical techniques confirmed the identity and
lengths measured for the C6 C7 (1.386(3) ꢄ) and C6 O1
(1.266(2) ꢄ) bonds in compound 20, which matched those
recorded for typical C=C and C=O double bonds.[24] These
data indicate that the negative charge of the zwitterion is
1
the purity of zwitterions 20 and 21. On H NMR spectrosco-
py, the disappearance of the strongly deshielded imidazol-
ACHTUNGTRENNUNG(in)ium proton located at d=9.5 ppm for SIMes·HCl or d=
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Staudinger Reaction Catalyzed by N-Heterocyclic Carbenes
FULL PAPER
Imidazolinium-2-amide 16 began to lose weight at about
1008C to afford a stable pale-yellow solid that resisted fur-
1
ther degradation until about 1808C. H and 13C NMR analy-
sis of this product revealed that it was most likely 1,3-di-
ACHUTNGERNmNUG esiAHCTUNGTRNENtUGN ylimidazolinium tosylate 22 formed upon elimination
of benzaldimine (Scheme 7). Imidazolium-2-amide 17 dis-
Scheme 7. Possible degradation of imidazol(in)ium-2-amides 16 and 17.
Figure 2. ORTEP diagram of imidazolinium-2-enolate 20 with thermal
ellipsoids drawn at 50% probability. H atoms are omitted for clarity. Se-
lected bond lengths [ꢄ] and angles [8]: C1–N1 1.333(3), C1–N2 1.344(2),
C1–C6 1.517(3), C6–O1 1.266(2); N1-C1-N2 110.2(2), C1-N1-C4-C20
99.3(3), C1-N2-C5-C29 À122.2(2), N1-C1-C6-O1 48.5(3).
played a similar behavior, although its TGA curve was shift-
ed to higher temperatures. Thus, a first transition corre-
sponding to an 18.4% weight loss occurred at 1858C and
the residue was tentatively identified as 1,3-dimesitylimida-
zolium tosylate 23. Further thermolysis of this salt took
place around 2258C and left only a black tar. Additional ex-
perimental evidence supporting the formation of salt 23
came from failed attempts to slowly recrystallize compound
17 for X-ray diffraction analysis. Instead, the molecular
structure of imidazolium tosylate 23 was obtained (see the
Supporting Information for crystallographic details and an
ORTEP plot).
In sharp contrast with imidazol(in)ium-2-amides 16 and
17, which led to bimodal TGA curves, the thermolysis of
ethenolates inner salts 20 and 21 did not afford any stable
intermediate. The imidazolinium betaine 20 underwent a
steep transition at about 2208C, which took place at around
2608C for its imidazolium counterpart 21. In both cases, this
event corresponded to approximately 40% weight loss and
was assigned to the release of diphenylketene. It was fol-
lowed by a non-distinct part of the TGA curve that is typical
of the progressive break up of free NHCs at high tempera-
ture.
À
À
delocalized over the C7 C6 O1 motif, in the same way as
À
À
its positive charge is distributed over the N1 C1 N2 sub-
ACHTUNGTRENNUNGunit.
Thermogravimetric analyses: To complete their characteri-
zation and to probe their thermal stability, we have carried
out thermogravimetric analyses (TGA) of the four zwitter-
ions under investigation. Changing the nature of the anionic
or cationic moiety led to markedly different decomposition
profiles (Figure 3). As expected, the two NHC·imine ad-
ducts 16 and 17 were significantly less stable than the
NHC·ketene betaines 20 and 21. More surprisingly, replac-
Catalytic tests: To assess the role of NHC·imine and
NHC·ketene zwitterions in the Staudinger reaction, we have
carried out the [2+2] cycloaddition of diphenylketene and
N-tosyl benzaldimine by using various catalytic systems
(Table 2). In a first set of experiments, an imidazol(in)ium
salt (SIMes·HCl or IMes·HBF4) was deprotonated with
cesium carbonate (0.25 mmol each) in THF, whereas diphe-
nylacetyl chloride was dehydrochlorinated with triethyl-
Figure 3. TGA curves of the four zwitterions under investigation.
ing IMes with SIMes also dramatically reduced the thermal
stability of zwitterions 16 and 20 versus 17 and 21. This is a
rather unprecedented observation, as the presence or the
absence of a backbone C=C double bond in all the
NHC·CO2,[32] NHC·COS,[22] and NHC·CS2 zwitterions[23] ana-
lyzed so far by TGA altered only slightly the onset of their
thermolysis.
ACHTUNGTRENaNGNU mine (3.25 mmol each) in the same solvent. After 20 min,
triethylammonium chloride was filtered off and the solution
of diphenylketene was added to the suspension of free car-
bene, followed by
a solution of N-tosyl benzaldimine
(2.5 mmol) in THF. The reaction mixture was stirred for
24 h at room temperature before work up and 1H NMR
analysis. Under these conditions, the SIMes and IMes car-
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L. Delaude et al.
Table 2. Influence of the NHC catalyst on the Staudinger reaction of di-
phenylketene and N-tosyl benzaldimine.
Conclusion and Perspectives
In this study, two representative NHCs were treated with N-
tosyl benzaldimine or diphenylketene to afford four new
zwitterionic products. These were isolated in high yields and
fully characterized by various analytical techniques. Their
thermal stabilities were monitored by TGA and the molecu-
lar structures of three of them were determined by X-ray
crystallography. The imidazol(in)ium-2-amides 16 and 17
were rather labile white solids that did not show any tenden-
cy to tautomerize into the corresponding 1,2,2-triamino-
Entry
Catalyst [(mol%)]
Yield[a]
[%]
1
2
3
4
5
6
7
8
SIMes·HCl+Cs2CO3 (10)
IMes·HBF4 +Cs2CO3 (10)
SIMes·PhCH=NTs (16) (10)
IMes·PhCH=NTs (17) (10)
SIMes·Ph2C=C=O (20) (10)
IMes·Ph2C=C=O (21) (10)
IMes·Ph2C=C=O (21) (5)
IMes·Ph2C=C=O (21) (2.5)
47
71
10
57
AHCTUNGTREGeNNUN thene derivatives. They displayed a mediocre catalytic ac-
47
tivity in the Staudinger reaction of N-tosyl benzaldimine
with diphenylketene. Contrastingly, the imidazol(in)ium-2-
enolates 20 and 21 were orange-red crystalline materials
that remained stable over extended periods of time, proba-
bly due to the better delocalization of their negative charge
compared with the amide inner salts. Despite their greater
stability, these zwitterions turned out to be efficient promot-
ers for the model cycloaddition under scrutiny. As a matter
of fact, their catalytic activity matched exactly those record-
ed with free carbenes. Altogether, these results provide
strong experimental support in favor of the “ketene-first”
mechanism postulated by Ye et al. for NHC-promoted Stau-
dinger reactions.[12,15] They also highlight the superior cata-
lytic activity of the imidazole-based carbene IMes compared
with its saturated analogue SIMes in the reaction under con-
sideration.
Having identified imidazolium-2-enolate 21 as a stable,
crystalline key intermediate in the synthesis of racemic b-
lactam 24, we are now focusing our research efforts on the
synthesis and characterization of additional NHC·ketene
zwitterions derived from either chiral azolium salts or un-
symmetrical ketenes. We anticipate that determining the
molecular structures of these adducts will help us gain fur-
ther valuable insight into the regio- and stereoselectivity of
NHC-mediated Staudinger reactions and of related enantio-
selective cycloaddition processes.
71 (65)[b]
56
48
[a] Determined by comparing the integrals of the PhCHNTs proton in b-
lactam 24 (d=5.80 ppm) and in the aldimine starting material (d=
9.02 ppm). [b] Yield of the isolated product after chromatographic purifi-
cation.
benes afforded b-lactam 24 in 47 and 71% yields, respec-
tively (Table 2, entries 1 and 2).
Next, we turned our attention to the NHC·imine adducts
16 and 17. To take into account the incorporation of one of
the reagents in the catalyst precursor and to maintain the
same molar ratios between the various reaction partners, the
amount of N-tosyl benzaldimine added was reduced to
2.25 mmol. As observed when using a combination of base
and imidazol(in)ium salt, the reaction mixtures containing
zwitterions 16 and 17 were initially yellow and became pro-
gressively orange-red within the time course of the transfor-
mation, in line with the in situ-formation of enolate 20 or
21. Yields recorded after 24 h with the tosylamide inner salts
were significantly lower than those obtained with the free
NHCs and confirmed the superior catalytic activity of IMes
versus SIMes in the formation of b-lactam 24 (Table 2, en-
tries 3 and 4).
When NHC·ketene zwitterions 20 and 21 were employed
to promote the model cycloaddition under scrutiny, the
amount of diphenylketene was reduced to ensure that the
stoichiometry initially defined was preserved. The orange
color of the enolate inner salts was visible at the onset of
the reactions and gradually evolved into red and then brown
hues over time. Strikingly, the yields of product 24 obtained
with adducts 20 and 21 matched exactly those recorded with
the free carbenes generated in situ (Table 2, entries 5 and 6).
Thus, the desired b-lactam was formed in 71% yield after
24 h by using 10 mol% of compound 21 as a catalyst. Purifi-
cation of the crude product by column chromatography af-
forded pure (Æ)-3,3,4-triphenyl-1-tosylazetidin-2-one (24)
isolated as a white powder in 65% yield. When the catalyst
loading was decreased to 5 or 2.5 mol%, the yields dropped
down to 56 and 48%, respectively (Table 2, entries 7 and 8).
Experimental Section
General information: Unless otherwise specified, all the syntheses were
carried out under a dry argon atmosphere by using standard Schlenk
techniques. Solvents purchased from Labotec were distilled from appro-
priate drying agents and deoxygenated prior to use. Anhydrous triethyl-
AHCTUNGERTGaNNUN mine purchased from Aldrich was deoxygenated prior to use. Cesium
carbonate was kept in an oven at 808C. Silica gel 60 (60 ꢄ pore size,
0.063–0.2 mm particle size) supplied by Biosolve was used for column
chromatography. Petroleum ether refers to the fraction of b.p. 40–608C.
Diphenylacetyl
AHCTUNGTRENNUNG
chloride,[29]
N-benzylidene-4-methylbenzenesulfon-
amide,[13] N,N’-dimesitylethylenediimine,[33] and 1,3-dimesitylimidazolini-
um chloride (SIMes·HCl)[33] were prepared according to literature meth-
ods. All the other chemicals were obtained from Aldrich and used with-
out any further purification. Melting points were recorded with an Elec-
trothermal apparatus and are not corrected. 1H and 13C NMR spectra
were recorded at 298 K with a Bruker DRX 400 spectrometer operating
at 400.13 and 100.62 MHz, respectively. Chemical shifts are listed in parts
per million downfield from TMS and are referenced to solvent peaks or
TMS. Infrared spectra were recorded with a PerkinElmer Spectrum One
&
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Staudinger Reaction Catalyzed by N-Heterocyclic Carbenes
FULL PAPER
FT-IR spectrometer. Thermogravimetric analyses were performed under
nitrogen with a TA Q500 instrument by using a dynamic heating ramp.
Elemental analyses were carried out in the Laboratory of Pharmaceutical
Chemistry at the University of Liꢁge.
tered through Celite under an inert atmosphere into an oven-dried two-
necked 250 mL round-bottomed flask equipped with a magnetic stirring
bar and capped with a three-way stopcock. The filter cake was rinsed
with dry THF (2ꢅ5 mL). An oven-dried 50 mL round-bottomed flask
equipped with a magnetic stirring bar and capped with a three-way stop-
cock was charged with diphenylacetyl chloride (5 mmol, 1.1535 g) and
dry THF (20 mL). Triethylamine (5 mmol, 0.7 mL) was added with a sy-
ringe. The resulting yellow suspension was stirred for 30 min at room
temperature. It was filtered through Celite under an inert atmosphere
into the two-necked 250 mL round-bottomed flask containing the car-
bene solution. The filter cake was rinsed with dry THF (2ꢅ5 mL). The
reaction mixture turned red within a few minutes. After 30 min, the sol-
vent was removed under high vacuum and the resulting viscous oil was
brought back to air. It was dissolved in dichloromethane (20 mL) and
precipitated by slowly adding petroleum ether (50 mL) under vigorous
stirring. The solid product was filtered through a Bꢆchner funnel, washed
with petroleum ether (3ꢅ10 mL) and dried under high vacuum.
Synthesis of NHC·imine zwitterions: An oven-dried 100 mL round-bot-
tomed flask equipped with a magnetic stirring bar and capped with a
three-way stopcock was charged with an imidazol(in)ium salt (5 mmol)
and dry THF (15 mL). A 0.5m solution of potassium bis(trimethylsilyl)-
ACHTUNGTRENNUNGamide (1.20 g, 6 mmol) in dry THF (12 mL) was added with a cannula.
The resulting yellow suspension was stirred for 30 min at room tempera-
ture. It was allowed to settle and the supernatant solution was filtered
through Celite under an inert atmosphere into a two-necked 250 mL
round-bottomed flask equipped with a magnetic stirring bar and capped
with a three-way stopcock. The filter cake was rinsed with dry THF (2ꢅ
5 mL). Next, a solution of N-benzylidene-4-methylbenzenesulfonamide
(1.2966 g, 5 mmol) in dry THF (10 mL) was added with a cannula. A
white precipitate appeared within a few minutes. After 1 h, the suspen-
sion was brought back to air and filtered through a Bꢆchner funnel. The
precipitate was washed with diethyl ether (3ꢅ10 mL) and dried under
high vacuum.
1,3-Bis(2,4,6-trimethylphenyl)imidazolinium-2,2-diphenylethenolate
(SIMes·Ph2C=C=O, 20): Orange powder (1.86 g, 74% yield). 1H NMR
(400 MHz, CD2Cl2): d=7.19–7.11 (m, 5H, CHar), 6.95–6.92 (m, 4H,
3
CHar), 6.80 (s, 2H, CHar), 6.75 (t, 3JH-H =6.7 Hz, 1H, CHar), 6.60 (d, JH-
1,3-Bis(2,4,6-trimethylphenyl)imidazolinium-N-benzyl-N-tosylamide
(SIMes·PhCH=NTs, 16): White powder (2.08 g, 74% yield). M.p.: 146.2–
146.48C; 1H NMR (400 MHz, CD2Cl2): d=7.06–7.04 (m, 4H, CHar), 6.95
H =6.6 Hz, 2H, CHar), 4.15–3.97 (m, 4H, CH2), 2.70 (s, 6H, CH3), 2.26 (s,
6H, CH3), 1.90 ppm (s, 6H, CH3); 13C NMR (100 MHz, CD2Cl2): d=
171.4 (CO), 150.0 (C2), 144.7 (Car), 142.8 (Car), 139.3 (Car), 138.2 (Car),
135.7 (Car), 133.3 (CHar), 133.0 (Car), 129.9 (CHar), 129.6 (CHar), 128.7
(CHar), 128.4 (CHar), 127.2 (CHar), 125.8 (CHar), 122.7 (CHar), 111.9
((Ph)2C), 50.5 (CH2), 21.2 (CH3), 19.5 (CH3), 18.4 ppm (CH3); IR (KBr):
n˜ =3045 (w), 2919 (m), 2167 (m), 1598 (m), 1513 (s), 1486 (m), 1436 (m),
1371 (w), 1345 (m), 1324 (w), 1305 (w), 1279 (s), 1209 (w), 1171 (w), 1142
(w), 1071 (w), 1030 (m), 991 (w), 933 cmÀ1 (w); elemental analysis calcd
(%) for C35H36N2O (500.67): C 84.0, H 7.3, N 5.6; found C 83.8, H 7.0, N
5.6.
3
(t, JH-H =6.9 Hz, 1H, CHar), 6.79 (s, 2H, CHar), 6.76–6.70 (m, 4H, CHar),
6.51 (d, 3JH-H =6.5 Hz, 2H, CHar), 5.25 (s, 1H, CH), 4.12–3.89 (m, 4H,
CH2), 2.54 (s, 6H, Mes-CH3), 2.35 (s, 6H, Mes-CH3), 2.16 (s, 3H, Ts-
CH3), 1.89 ppm (s, 6H, Mes-CH3); 13C NMR (100 MHz, CD2Cl2): d=
170.0 (C2), 147.1 (Car), 140.4 (Car), 138.1 (Car), 137.5 (Car), 137.1 (Car),
136.9 (Car), 131.6 (Car), 130.0 (CHar), 130.0 (CHar), 129.3 (CHar), 128.1
(CHar), 127.6 (CHar), 127.4 (CHar), 125.9 (CHar), 58.5 (CH), 50.5 (CH2),
21.4 (Mes-CH3), 21.3 (Ts-CH3), 19.0 (Mes-CH3), 17.9 ppm (Mes-CH3);
IR (KBr): n˜ =3167 (w), 3158 (w), 2922 (m), 2860 (w), 1612 (s), 1568 (s),
1523 (w), 1492 (m), 1381(w), 1313 (w), 1281 (s),1238 (s), 1208 (w), 1184
(w), 1150 (s), 1118 (s), 1067 (m), 906 cmÀ1 (s); elemental analysis calcd
(%) for C35H39N3O2S (565.77): C 74.3, H 7.0, N 7.4, S 5.7; found: C 74.0,
H 6.8, N 7.2, S 5.6. Note: For some batches, NMR analysis of the product
1,3-Bis(2,4,6-trimethylphenyl)imidazolium-2,2-diphenylethenolate
(IMes·Ph2C=C=O, 21): Orange powder (2.18 g, 87% yield). 1H NMR
(400 MHz, CD2Cl2): d=7.30 (d, 3JH-H =7.3 Hz, 2H, CHar), 7.10–6.94 (m,
3
3
9H, CHar), 6.90 (s, 2H, CHar), 6.76 (t, JH-H =6.8 Hz, 1H), 6.55 (d, JH-H
=
6.5 Hz, 2 H CHar), 2.48 (s, 6H, CH3), 2.34 (s, 6H, CH3), 1.76 ppm (s, 6H,
CH3); 13C NMR (100 MHz, CD2Cl2): d=153.9 (CO), 149.9 (C2), 145.0
(Car), 143.2 (Car), 140.2 (Car), 137.6 (Car), 134.8 (Car), 133.6 (CHar), 133.0
(Car), 129.7 (CHar), 129.6 (CHar), 128.4 (CHar), 128.3 (CHar), 127.2 (CHar),
125.6 (CHar), 122.5 (CHar), 122.4 (CHar), 112.6 ((Ph)2C), 21.3 (CH3), 19.2
(CH3), 18.5 ppm (CH3); IR (KBr): n˜ =3159 (w), 3042 (w), 2919 (w), 1584
(m), 1528 (s), 1486 (s), 1444 (m), 1400 (m), 1325 (m), 1305 (m), 1227 (m),
1164 (w), 1030 (w), 938 cmÀ1 (w); elemental analysis calcd (%) for
C35H34N2O (498.66): C 84.3, H 6.9, N 5.6; found: C 84.6, H 6.8, N 5.7.
indicated that
a solvate with approximately 0.9 equiv of THF had
formed. When this happened, heating under vacuum and washing with
diethyl ether allowed to release the solvent and to obtain pure compound
16.
1,3-Bis(2,4,6-trimethylphenyl)imidazolium-N-benzyl-N-tosylamide
(IMes·PhCH=NTs, 17): After 1 h, no precipitate had formed in the reac-
tion mixture. The solvent was removed under high vacuum and the pale-
yellow oily residue was brought back to air. Crystallization was induced
by trituration with diethyl ether (10 mL). The precipitate was filtered
through a Bꢆchner funnel, washed with diethyl ether (3ꢅ10 mL), and
dried under high vacuum to afford the title compound as a white powder
(2.35 g, 83% yield). M.p.: 147–1488C. 1H NMR (400 MHz, CD2Cl2): d=
7.12–7.07 (m, 6H, CHar), 6.95 (t, 3JH-H =6.9 Hz, 1H, CHar), 6.87 (s, 2H,
Thermolysis of NHC·imine zwitterions: A platinum cell was charged with
about 15 mg of an NHC·imine zwitterion and heated in a TGA instru-
ment until the first plateau was reached. The residue was cooled to room
1
temperature and analyzed by H and 13C NMR spectroscopy.
3
CHar), 6.81–6.72 (m, 4H, CHar), 6.60 (d, JH-H =6.6 Hz, 2H, CHar), 5.62 (s,
1,3-Bis(2,4,6-trimethylphenyl)imidazolinium p-toluenesulfonate
(SIMes·TsOH, 22): Pale-yellow powder obtained upon heating compound
16 to 1708C. 1H NMR (400 MHz, CD2Cl2): d=10.16 (s, 1H, CH2 Im),
6.99–6.90 (m, 8H, CHar), 4.28 (s, 4H, CH2), 2.32 (s, 6H, p-CH3 Mes), 2.29
(s, 12H, o-CH3 Mes), 2.28 ppm (s, 3H, CH3 Ts); 13C NMR (100 MHz,
CD2Cl2): d=162.7 (CH2 Im), 140.8 (Cpara Mes), 137.7 (Car Ts), 135.6
(Cortho Mes), 131.1 (Cipso Mes), 130.3 (CHmeta Mes), 128.7 (CHar Ts), 124.3
(CHar Ts), 51.8 (CH2), 21.42 (CH3 Ts), 21.36 (p-CH3 Mes), 18.1 ppm
(o-CH3 Mes).
1H, CH), 2.40 (s, 6H, Mes-CH3), 2.32 (s, 6H, Mes-CH3), 2.16 (s, 3H, Ts-
CH3), 1.68 ppm (s, 6H, Mes-CH3); 13C NMR (100 MHz, CD2Cl2): d=
151.2 (C2), 146.9 (Car), 141.4 (Car), 138.8 (Car), 138.5 (Car), 136.5 (Car),
136.3 (Car), 131.7 (Car), 129.8 (CHar), 129.7 (CHar), 128.9 (CHar), 128.1
(CHar), 127.5 (CHar), 127.4 (CHar), 126.0 (CHar), 123.2 (CHar), 57.7 (CH),
21.5 (Mes-CH3), 21.3 (Ts-CH3), 18.8 (Mes-CH3), 17.7 ppm (Mes-CH3);
IR (KBr): n˜ =3137 (w), 3084(m), 3025 (m), 2965 (w), 2920 (m), 2861 (w),
1608 (w), 1562 (w), 1495 (s), 1451 (m), 1383 (w), 1330 (w), 1289 (w), 1233
(s), 1160 (s), 1149 (s), 1117 (s), 1080 (s), 1066 (s), 1035 (m), 967 (w),
905 cmÀ1 (s); elemental analysis calcd (%) for C35H37N3O2S (563.75): C
74.6, H 6.6, N 7.5, S 5.7; found: C 74.3, H 6.5, N 7.3, S 5.6.
1,3-Bis(2,4,6-trimethylphenyl)imidazolium p-toluenesulfonate
(IMes·TsOH, 23): Dark-brown oil obtained upon heating compound 17
to 1958C. 1H NMR (400 MHz, CD2Cl2): d=10.98 (s, 1H, CH2 Im), 7.48
(s, 2H, CH4,5 Im), 7.03 (s, 4H, m-CH Mes), 7.01 (d, 2H, 3JH-H =7.6 Hz,
CH Ts), 6.92 (d, 3JH-H =7.6 Hz, 2H, CH Ts), 2.37 (s, 6H, p-CH3 Mes),
2.28 (s, 3H, p-CH3 Ts), 2.10 ppm (s, 12H, o-CH3 Mes); 13C NMR
(100 MHz, CD2Cl2): d=157.3 (Car Ts), 141.7 (Cpara Mes), 137.6 (CH2 Im),
134.8 (Cortho Mes), 131.4 (Cipso Mes), 130.2 (CHmeta Mes), 128.7 (CHar Ts),
124.7 (CH4,5 Im), 124.4 (CHar Ts), 21.5 (p-CH3 Mes), 21.4 (CH3 Ts),
17.8 ppm (o-CH3 Mes).
Synthesis of NHC·ketene zwitterions: An oven-dried 100 mL round-bot-
tomed flask equipped with a magnetic stirring bar and capped with a
three-way stopcock was charged with an imidazol(in)ium salt (5 mmol)
and dry THF (50 mL). A 0.5m solution of potassium bis(trimethylsilyl)-
ACHTUNGTRENNUNGamide (1.20 g, 6 mmol) in dry THF (12 mL) was then added with a can-
nula. The resulting yellow suspension was stirred for 30 min at room tem-
perature. It was allowed to settle and the supernatant solution was fil-
Chem. Eur. J. 2013, 00, 0 – 0
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L. Delaude et al.
Typical procedure for the Staudinger reaction: An oven-dried two-
necked 50 mL round-bottomed flask equipped with a magnetic stirring
bar and capped with a three-way stopcock was charged with IMes·Ph2C=
C=O (21) (0.1247 g, 0.25 mmol). An oven-dried 25 mL round-bottomed
flask equipped with a magnetic stirring bar and capped with a three-way
stopcock was charged with diphenylacetyl chloride (0.6921 g, 3 mmol)
and dry THF (10 mL). Triethylamine (0.42 mL, 3 mmol) was added with
a syringe. The resulting yellow suspension was stirred for 20 min at room
temperature. It was filtered through Celite under an inert atmosphere
into the flask containing the NHC·ketene zwitterion. The filter cake was
rinsed with dry THF (2ꢅ5 mL). Next, a solution of N-benzylidene-4-
methylbenzenesulfonamide (0.6483 g, 2.5 mmol) in dry THF (5 mL) was
added with a cannula. The reaction mixture was stirred for 24 h at room
temperature and the solvent was removed on a rotary evaporator. The
residue was dissolved in THF (10 mL). Water (10 mL) and two drops of
concentrated HCl were added. The resulting suspension was stirred for
20 min at room temperature. Water (20 mL) was added and the precipi-
tate was filtered through a Bꢆchner funnel. It was washed with water (2ꢅ
10 mL) and cold diethyl ether (2ꢅ10 mL). This crude product was puri-
fied by passing through a short plug of silica gel using dichloromethane
as eluent. Pure (Æ)-3,3,4-triphenyl-1-tosylazetidin-2-one (24) was isolated
as a white solid (0.737 g, 65% yield). 1H and 13C NMR data matched
those reported in the literature.[13]
1617–1639; h) J. Douglas, G. Churchill, A. D. Smith, Synthesis 2012,
44, 2295–2309.
[7] For selected examples, see: a) G. A. Grasa, T. Gꢆveli, R. Singh, S. P.
Nolan, J. Org. Chem. 2003, 68, 2812–2819; b) B. E. Maki, A. Chan,
E. M. Phillips, K. A. Scheidt, Tetrahedron 2009, 65, 3102–3109; c) T.
Boddaert, Y. Coquerel, J. Rodriguez, Chem. Eur. J. 2011, 17, 2266–
2271; d) Q. Kang, Y. Zhang, Org. Biomol. Chem. 2011, 9, 6715–
6720; e) Y.-M. Zhao, Y. Tam, Y.-J. Wang, Z. Li, J. Sun, Org. Lett.
2012, 14, 1398–1401.
[8] a) H. Staudinger, Ber. Dtsch. Chem. Ges. 1907, 40, 1145–1148; b) H.
Staudinger, Justus Liebigs Ann. Chem. 1907, 356, 51–123.
[9] a) Chemistry and Biology of b-Lactam Antibiotics (Eds.: R. B.
Morin, M. Gorman), Academic Press, New York, 1982; b) Heterocy-
clic Scaffolds. I b-Lactams, Vol. 22 of Topics in Heterocyclic Chemis-
try (Ed.: B. K. Banik), Springer, Heidelberg, 2010.
[10] For a recent review, see: N. Fu, T. T. Tidwell, Tetrahedron 2008, 64,
10465–10496.
[11] F. P. Cossꢇo, A. Arrieta, M. A. Sierra, Acc. Chem. Res. 2008, 41,
925–936.
[12] Y.-R. Zhang, L. He, X. Wu, P.-L. Shao, S. Ye, Org. Lett. 2008, 10,
277–280.
[13] N. Duguet, C. D. Campbell, A. M. Z. Slawin, A. D. Smith, Org.
Biomol. Chem. 2008, 6, 1108–1113.
[14] a) M. Feroci, I. Chiarotto, M. Orsini, A. Inesi, Chem. Commun.
2010, 46, 4121–4123; b) M. Feroci, Int. J. Org. Chem. 2011, 1, 191–
201.
[15] For a related duality in mechanism, see: E. C. Lee, B. L. Hodous, E.
Bergin, C. Shih, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 11586–
11587.
[16] M. He, J. W. Bode, Org. Lett. 2005, 7, 3131–3134.
[17] L. He, T.-Y. Jian, S. Ye, J. Org. Chem. 2007, 72, 7466–7468.
[18] J. E. Baldwin, L. I. Kruse, J. Chem. Soc. Chem. Commun. 1977, 233–
235.
Acknowledgements
The authors would like to thank Mr. Guillaume Guiho and Mrs. Berna-
dette Norberg for their technical assistance, and the members of COST
action CM0905 “Organocatalysis” for stimulating discussions.
[19] a) K. Tang, J. Wang, X. Cheng, Q. Hou, Y. Liu, Eur. J. Org. Chem.
2010, 6249–6255; b) K. Tang, J. Wang, Q. Hou, X. Cheng, Y. Liu,
Tetrahedron: Asymmetry 2011, 22, 942–947.
[20] For a review, see: L. Delaude, Eur. J. Inorg. Chem. 2009, 1681–
1699.
[21] B. Bantu, G. M. Pawar, K. Wurst, U. Decker, A. M. Schmidt, M. R.
Buchmeiser, Eur. J. Inorg. Chem. 2009, 1970–1976.
[22] M. Hans, J. Wouters, A. Demonceau, L. Delaude, Eur. J. Org.
Chem. 2011, 7083–7091.
[1] For monographs, see: a) N-Heterocyclic Carbenes in Synthesis (Ed.:
S. P. Nolan), Wiley-VCH, Weinheim, 2006; b) N-HetACTHNUTRGENNeGU roACHUTNGTRENcNNGU yclic Car-
benes in Transition Metal Catalysis, Vol. 21 of Topics in Organome-
tallic Chemistry (Ed.: F. Glorius), Springer, Berlin, 2007; c) N-Het-
ACHTUNGTRENNUNGeroACHTUNGTRENNUNGcyclic Carbenes: From Laboratory Curiosities to Efficient Synthet-
ic Tools, Vol. 6 of RSC Catalysis Series (Ed.: S. Dꢇez-Gonzꢈlez),
Royal Society of Chemistry, Cambridge, 2010; d) N-Heterocyclic
Carbenes in Transition Metal Catalysis and Organocatalysis, Vol. 32
of Catalysis by Metal Complexes (Ed.: C. S. J. Cazin), Springer, Dor-
drecht, 2011.
[23] L. Delaude, A. Demonceau, J. Wouters, Eur. J. Inorg. Chem. 2009,
1882–1891.
[2] a) N. E. Kamber, W. Jeong, R. M. Waymouth, R. C. Pratt, B. G. G.
Lohmeijer, J. L. Hedrick, Chem. Rev. 2007, 107, 5813–5840;
b) M. K. Kiesewetter, E. J. Shin, J. L. Hedrick, R. M. Waymouth,
Macromolecules 2010, 43, 2093–2107; c) M. Fꢁvre, J. Pinaud, Y.
Gnanou, J. Vignolle, D. Taton, Chem. Soc. Rev. 2013, 42, 2142–2172.
[3] a) D. Enders, O. Niemeier, A. Henseler, Chem. Rev. 2007, 107,
5606–5655; b) N. Marion, S. Dꢇez-Gonzꢈlez, S. P. Nolan, Angew.
Chem. 2007, 119, 3046–3058; Angew. Chem. Int. Ed. 2007, 46, 2988–
3000.
[4] X. Bugaut, F. Glorius, Chem. Soc. Rev. 2012, 41, 3511–3522.
[5] For seminal contributions, see: a) R. Breslow, J. Am. Chem. Soc.
1958, 80, 3719–3726; b) H. Stetter, Angew. Chem. 1976, 88, 695–
704; Angew. Chem. Int. Ed. Engl. 1976, 15, 639–647; c) J. H. Teles,
J.-P. Melder, K. Ebel, R. Schneider, E. Gehrer, W. Harder, S. Brode,
Helv. Chim. Acta 1996, 79, 61–83; d) R. L. Knight, F. J. Leeper, Tet-
rahedron Lett. 1997, 38, 3611–3614.
[6] For recent reviews, see: a) V. Nair, S. Vellalath, B. P. Babu, Chem.
Soc. Rev. 2008, 37, 2691–2698; b) E. M. Phillips, A. Chan, K. A.
Scheidt, Aldrichimica Acta 2009, 42, 55–66; c) H. U. Vora, T. Rovis,
Aldrichimica Acta 2011, 44, 3–11; d) A. T. Biju, N. Kuhl, F. Glorius,
Acc. Chem. Res. 2011, 44, 1182–1195; e) V. Nair, R. S. Menon, A. T.
Biju, C. R. Sinu, R. R. Paul, A. Jose, V. Sreekumar, Chem. Soc. Rev.
2011, 40, 5336–5346; f) A. Grossmann, D. Enders, Angew. Chem.
2012, 124, 320–332; Angew. Chem. Int. Ed. 2012, 51, 314–325;
g) H. U. Vora, P. Wheeler, T. Rovis, Adv. Synth. Catal. 2012, 354,
[24] a) F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G.
Orpen, R. Taylor, J. Chem. Soc. Perkin Trans. 2 1987, S1–S19;
b) F. H. Allen, D. G. Watson, L. Brammer, A. G. Orpen, R. Taylor
in International Tables for Crystallography, Vol C (Ed.: E. Prince),
Springer, Berlin 2006, pp. 790–811.
[25] A. Berkessel, S. Elfert, V. R. Yatham, J.-M. Neudçrfl, N. E. Schlçrer,
J. H. Teles, Angew. Chem. 2012, 124, 12537–12541; Angew. Chem.
Int. Ed. 2012, 51, 12370–12374.
[26] C. J. Collett, R. S. Massey, O. R. Maguire, A. S. Batsanov, A. C.
OꢃDonoghue, A. D. Smith, Chem. Sci. 2013, 4, 1514–1522.
[27] R. S. Massey, C. J. Collett, A. G. Lindsay, A. D. Smith, A. C. OꢃDo-
noghue, J. Am. Chem. Soc. 2012, 134, 20421–20432.
[28] a) R. W. Alder, P. R. Allen, S. J. Williams, J. Chem. Soc. Chem.
Commun. 1995, 1267–1268; b) Y.-J. Kim, A. Streitwieser, J. Am.
Chem. Soc. 2002, 124, 5757–5761; c) T. L. Amyes, S. T. Diver, J. P.
Richard, F. M. Rivas, K. Toth, J. Am. Chem. Soc. 2004, 126, 4366–
4374; d) A. M. Magill, K. J. Cavell, B. F. Yates, J. Am. Chem. Soc.
2004, 126, 8717–8724; e) Y. Chu, H. Deng, J.-P. Cheng, J. Org.
Chem. 2007, 72, 7790–7793; f) E. M. Higgins, J. A. Sherwood, A. G.
Lindsay, J. Armstrong, R. S. Massey, R. W. Alder, A. C. OꢃDonog-
hue, Chem. Commun. 2011, 47, 1559–1561.
[29] a) E. C. Taylor, A. McKillop, G. H. Hawks, Org. Synth. 1972, 52,
36–38; b) E. C. Taylor, A. McKillop, G. H. Hawks, Org. Synth. Coll.
Vol. 1988, 6, 549–551.
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Staudinger Reaction Catalyzed by N-Heterocyclic Carbenes
FULL PAPER
[30] M. Regitz, J. Hocker, B. Weber, Angew. Chem. 1970, 82, 394;
Angew. Chem. Int. Ed. Engl. 1970, 9, 375.
[33] M. Hans, L. Delaude, Org. Synth. 2010, 87, 77–87.
[31] T. Drçge, F. Glorius, Angew. Chem. 2010, 122, 7094–7107; Angew.
Chem. Int. Ed. 2010, 49, 6940–6952.
[32] a) A. Tudose, A. Demonceau, L. Delaude, J. Organomet. Chem.
2006, 691, 5356–5365; b) B. R. Van Ausdall, J. L. Glass, K. M. Wig-
gins, A. M. Aarif, J. Louie, J. Org. Chem. 2009, 74, 7935–7942.
Received: December 12, 2012
Revised: April 11, 2013
Published online: && &&, 2013
Chem. Eur. J. 2013, 00, 0 – 0
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L. Delaude et al.
Organocatalysis
M. Hans, J. Wouters, A. Demonceau,
L. Delaude* ................... &&&& — &&&&
Mechanistic Insight into the Stau-
dinger Reaction Catalyzed by N-
Heterocyclic Carbenes
Catalysts caught in the act: The N-het-
erocyclic carbenes 1,3-dimesitylimida-
zolin-2-ylidene (SIMes) and 1,3-dime-
sitylimidazol-2-ylidene (IMes) react
with N-tosyl benzaldimine or diphenyl-
ketene to afford the corresponding
zwitterions in high yields (see scheme).
The molecular structures of three of
them were determined by X-ray crys-
tallography and their thermal stability
was monitored by thermogravimetric
analysis. The NHC·ketene betaines
were found to be key intermediates for
the Staudinger reaction catalyzed by
NHCs.
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ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!