A family of thiazolium salt derived N-heterocyclic carbenes (NHCs) for organocatalysis: Synthesis, investigation and application in cross-benzoin condensation

Article abstract of DOI:10.1002/ejoc.201100870

A family of thiazolium salt derived N-heterocyclic carbenes (NHCs) bearing sterically demanding aryl substituents on the nitrogen and with varying backbone substitution patterns have been synthesized. Investigation of the catalytic activity of these NHCs in a number of benzoin-type coupling reactions revealed markedly different levels of reactivity and selectivity. To elucidate the underlying factors leading to differences in reactivity, a study of the electronic and steric properties of these NHC catalysts was conducted. By using the best catalyst in this study, the intermolecular cross-benzoin condensation reaction was explored in more detail.

Full text of DOI:10.1002/ejoc.201100870

FULL PAPER
DOI: 10.1002/ejoc.201100870
A Family of Thiazolium Salt Derived N-Heterocyclic Carbenes (NHCs) for
Organocatalysis: Synthesis, Investigation and Application in Cross-Benzoin
Condensation
Isabel Piel,[a][‡] Marius D. Pawelczyk,[a][‡] Keiichi Hirano,[b] Roland Fröhlich,[a] and
Frank Glorius*[a]
Keywords: Organocatalysis / Nitrogen heterocycles / Carbenes / Umpolung / Cross-benzoin condensation
A family of thiazolium salt derived N-heterocyclic carbenes
(NHCs) bearing sterically demanding aryl substituents on
the nitrogen and with varying backbone substitution patterns
have been synthesized. Investigation of the catalytic activity
of these NHCs in a number of benzoin-type coupling reac-
tions revealed markedly different levels of reactivity and
selectivity. To elucidate the underlying factors leading to dif-
ferences in reactivity, a study of the electronic and steric
properties of these NHC catalysts was conducted. By using
the best catalyst in this study, the intermolecular cross-
benzoin condensation reaction was explored in more detail.
sation reported by Stetter in the 1970s.[5,6] Since then, tri-
azolium-[7] and imidazolium-derived NHCs (B and C,
respectively) have become more prominent organocatalysts,
with each of them having preferred fields of application,[8]
whereas only a very few examples have been reported of
imidazolinylidenes D acting as organocatalysts.[8n] However,
the sulfur atom renders thiazolylidenes (A) to be a unique
class of NHCs: Whereas the steric demand of the N substit-
uent can be varied over a wide range, sulfur does not even
have a substituent, rendering the carbene environment
highly unsymmetrical (Figure 2). In addition, the electronic
properties and carbene stabilization are also greatly influ-
enced by the very small π character of the carbene C–S
bond, which may be responsible for the specific reactivity
of this class of NHCs.[8m]
Introduction
The first coupling of benzaldehyde to benzoin was re-
ported by Wöhler and Liebig in the course of their investi-
gation of bitter almond oil in 1832.[1] More than 100 years
later, Ukai et al., inspired by coenzyme thiamine (Fig-
ure 1),[2] reported on the thiazolium ion mediated process
in basic media.[3] Ever since, N-heterocyclic carbene (NHC)
organocatalysis has attracted considerable attention, espe-
cially during the last decade. In addition to facile reaction
handling, environmental friendliness, and low cost and tox-
icity compared with transition-metal catalysts, it also pro-
vides new types of reactivity that have become unique and
powerful synthetic tools by virtue of umpolung.[4]
Figure 1. Coenzyme thiamine (vitamin B1).
Figure 2. Common NHC organocatalysts.
In the beginning, thiazolium salt derived NHCs (A) were
the most popular class of NHC in organocatalytic transfor-
mations, such as the intermolecular cross-benzoin conden-
Despite the intensive investigation of the thiazolylidene-
catalyzed enantioselective benzoin condensation[5,6] and the
Stetter reaction[9] in the 20th century, other transformations
have hardly been reported. This has changed in the last dec-
ade when exciting thiazolylidene-catalyzed transformations
were reported, such as the conversion of epoxy aldehydes
into activated carboxylates (Chow and Bode),[10] the forma-
tion of α-amido ketones from acylimines (Murry, Frantz
and co-workers),[11] oxidative esterifications (Connon and
co-workers),[12] or the sila-Stetter reaction using acylsilanes
[a] Organisch-Chemisches Institut, Westfälische Wilhelms-Universität
Münster,
Corrensstr. 40, 48149 Münster, Germany
Fax: +49-251-83-33202
E-mail: glorius@uni-muenster.de
[b] Chemistry Department, Stanford University,
CA 94305-5080, USA
[‡] These two authors contributed equally to this work.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100870.
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Scheme 1. Applications of Isa-NHC, a versatile thiazolylidene organocatalyst.[18–23]
as aldehyde surrogates (Scheidt and co-workers).[13] A few In addition, interesting results were obtained when the cata-
recent studies have reported on the differences in the reac- lytic activities of the NHCs were compared in four different
tivity and asymmetric induction of triazolium salts com- umpolung transformations.
pared with thiazolium salts, which demonstrates the general
interest in this class of compounds.[14] In addition, a dia-
Results and Discussion
stereoselective synthesis of trifluoromethylated γ-butyro-
lactones using thiazol-2-ylidenes as optimal catalysts has
been reported.[15] A first breakthrough in terms of the com-
patibility of NHCs with transition-metal catalysts was re-
ported by Hamada and co-workers, the one-pot sequential
multi-catalytic Pd-catalyzed allylic amination/NHC-cata-
lyzed Stetter reaction cascade using activated olefins.[16]
Moreover, an investigation by Rose and Zeitler clearly dem-
onstrated the great potential of the compatibility of thiazol-
ylidenes with organic oxidants such as azobenzene in en-
abling oxidative lactonization chemistry.[17]
Synthesis of N-Arylthiazolium Salts with Variable
Backbone Architectures
The N-aryl substitution as well as the backbone architec-
ture of the thiazolium salts can be easily varied by em-
ploying different arylamines and α-bromo ketones follow-
ing a two-step synthesis developed by Bach and co-
workers.[24] Starting from 3-bromobutan-2-one (1) and ani-
lines with N-aryl substituents known to work well in NHC
We have recently developed a sterically demanding N-
mesityl-substituted thiazolylidene with
a cycloheptane
backbone, Isa-NHC, which has allowed a number of chal-
lenging transformations (Scheme 1).[18–23] Most promi-
nently, the unprecedented organocatalyzed intramolecular
hydroacylation of unactivated alkenes and alkynes was real-
ized (Scheme 1).[19,20] In this surprising transformation, the
NHC is most likely involved in dual activation leading to
a concerted but highly asynchronous mechanism.[19b] Most
likely, the Breslow intermediate not only acts as a C-nucleo-
phile, but its hydroxy group also functions as a Brønsted
acid catalyst, activating the alkene for the attack of the en-
amine moiety.
Because in each NHC-catalyzed transformation, the
proper choice of NHC was found to be crucial for success,
the development of structurally related families of NHCs
with slightly different properties and the investigation of
their activity is of great interest. In addition, elucidation of
the underlying factors leading to the reactivity differences
of the NHC catalysts would be a valuable achievement.
Herein, we report the preparation and electronic and steric
analyses of a family of structurally related thiazolium salts. Scheme 2. Synthesis of thiazolium salts 3 and 6.
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Thiazolium Salt N-Heterocyclic Carbenes for Organocatalysis
organocatalysis, such as mesitylamine or 2,6-diisopro- Table 1. Buried volumes [%VBur] determined for selected thiazol-
ium salts 3 and 6.[a]
pylaniline, the reaction with aqueous NaOH and carbon
disulfide in DMSO followed by condensation with HCl af-
forded the desired thiones 2 (Scheme 2). Oxidative desulfur-
ization with hydrogen peroxide and anion exchange yielded
the thiazolium perchlorate salts 3a and 3b. Furthermore,
thiazolium salts bearing different cyclic alkyl backbones
were prepared to fine-tune the reactivity of the correspond-
ing NHCs. Starting from the corresponding cyclic ketones,
NBS bromination followed by the previously described syn-
thetic pathway afforded the salts 6a–6j in moderate-to-good
yields.[25]
Steric and Electronic Properties of Selected Thiazolium
Salts
To address the question of the reactivity of thiazolium
salt derived NHCs, we embarked on a study of their steric
and electronic properties. Interestingly, although methods
for the investigation of NHC ligands exist, good methods
for the evaluation of these properties of NHC organocata-
lysts are lacking. Thus, we used the methods established
for investigating NHC ligands[8k] and will point out their
limitations. To quantify the steric demand, we applied the
buried volume concept introduced and recently refined by
Nolan and Cavallo and co-workers.[26] This concept was put
forward to describe the steric demand of ligands, however,
in the case of NHCs this should also correlate with the rel-
evant steric demand of the carbene itself. Single-crystal X-
ray structures[27] were obtained of selected thiazolium salts
and this data allowed the calculation of the buried vol-
ume.[28]
[a] Based on modified CIF files from X-ray crystal structure deter-
minations of the corresponding thiazolium perchlorate salts.[27]
of different azole-2-ylidene ligands is possible. However, al-
though TEPs have been reported for many imidazolylidene
ligands, to the best of our knowledge, there is only one re-
port of an N-propylbenzothiazolin-2-ylidene ligand.[32] This
piqued our interest and we decided to prepare the required
[(NHC)Ir(CO)2Cl] complexes 8 of selected thiazolylidenes
(Scheme 3). They were prepared by a two-step sequence
starting from thiazolium salts 3a,b and 6c,e. After depro-
As depicted in Table 1, the buried volume (%VBur) calcu-
lated from the crystal structures of the corresponding salts
increases with increasing size of the N substituent. Thus,
throughout, and as expected, the N-diisopropylphenyl-sub-
stituted NHCs were found to be more sterically demanding
than their N-mesityl-substituted counterparts by 4–9%VBur
(Table 1). Regarding the effect of ring size of the thiazolium Scheme 3. Synthesis of [(NHC)Ir(CO)2Cl] complexes 8.
backbone, generally, only very small deviations of the bur-
ied volume were observed. Even though a good model for
the determination of the steric characteristics of NHC or-
ganocatalysts is still missing, we feel that these buried vol-
ume values are similarly important for the application of
the NHC as an organocatalyst.
One of the most characteristic properties of NHCs is
their pronounced electron-richness. Surprisingly, the com-
plete elucidation of the electronic properties of NHC organ-
ocatalysts poses a challenge. The characterization of the
electronic properties of NHC ligands for transition metals
using one of several different methods is well established.[29]
The most widely applied method is the IR spectroscopic
analysis of the CO stretching frequencies of [(L)Ni(CO)3],
Figure 3. X-ray crystal structure of [(NHC)Ir(CO)2Cl] complex 8a.
[(L)Rh(CO)2Cl], [(L)Ir(CO)2Cl], or related complexes, re-
Selected bond lengths [Å] and angles [°]: Ir20–C4 2.075(7), Ir20–
sulting in Tolman’s electronic parameter (TEP).[8k,29–31]
C21 1.826(11), Ir20–C23 1.895(9), Ir20–Cl25 2.351(2); C4–Ir20–
A significant amount of reference data is now available
C21 93.2(3), C4–Ir20–C23 175.0(3), C4–Ir20–Cl25 86.7(2), C21–
and therefore a quantitative comparison of the TEP values Ir20–C23 91.8(4), C21–Ir20–Cl25 179.9(3), C23–Ir20–Cl25 88.3(3).
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tonation of the salts with KOtBu and reaction with [Ir- equivocally characterized by crystal structure analysis (Fig-
(cod)Cl]2 to form the [(NHC)Ir(cod)Cl] complexes 7, the ure 3). The structure of 8a clearly shows a square-planar
latter were subjected to gaseous CO to afford the corre- geometry around the iridium metal center. The TEP values
sponding carbonyl complexes in yields of 61–94% after col- resulting from IR studies of the complexes 8 reveal that, as
umn chromatographic purification. Complex 8a was un- ligands, all of the NHCs have comparable electronic proper-
ties (Table 2). In addition, all of them were found to be
rather electron-rich thiazolylidenes. However, among all
NHCs, this family of thiazolylidenes are the least electron-
rich. NHCs such as IMes, one of the most prominent imid-
azol-2-ylidene ligands in transition-metal catalysis (TEP =
2049.6 cm–1), and IPr (TEP = 2050.2 cm–1), are more elec-
tron-rich.[33]
Table 2. Carbonyl stretching frequencies for NHCs in [(NHC)Ir-
(CO)2Cl] complexes 8.[a]
However, it is clear that the performance of an NHC as
organocatalyst will not only rely on its σ-donating property
and the nucleophilicity of the free NHC, but also on the π-
donating properties relevant to the nucleophilicity of the
Breslow intermediate. This latter issue is difficult to analyze,
either experimentally or theoretically, but might be affected
by the backbone substitution and orbital overlap between
the σ orbital of the “benzylic” alkyl C–H bond of the back-
bone and the π* orbital of the heterocycles (Figure 4). It is
hoped that tools will be developed in the near future that
allow the (stereo)electronic classification of NHC organo-
catalysts.
[a] NHCs given in order of descending TEP value (increasing elec-
tron-richness). [b] Values calculated according to the expression
TEP [cm–1] = 0.8475x + 336.2, in which x = ν [cm–1]).
av
co
Comparative Investigation of The NHCs in Intramolecular
Hydroacylation, Homobenzoin, Cross-Acyloin, and Cross-
Benzoin Condensation
With these catalyst precursors in hand we compared this
family of catalysts in four umpolung reactions. Our study
commenced with the investigation of the aforementioned
intramolecular hydroacylation of electron-neutral olefins
(A, Table 3).[18a] When using thiazolium salts with a cyclic
backbone, the N-mesityl substituent generally gave better
yields of the chromanone 10 (57–69%), with the exception
of the five-membered ring, which seems to be special for an
unknown reason (entry 1). Clearly, the steric demand of the
N-Dipp substituent renders attack on the 2-allyloxy-substi-
tuted aldehyde 9 unfavorable. Interestingly, among the salts
with an acyclic backbone, the dimethyl-substituted N-mes-
itylthiazolium salt gave good results (61%, entry 11),
whereas the Stetter salt gave almost no conversion (en-
try 13). Commonly used imidazolium and triazolium salts
such as IMesHCl (entry 14), benzimidazolium iodide (en-
try 15), Rovis’ pentafluorophenyltriazolium salt (entry 16),
and Enders’ TPT perchlorate (entry 17) proved to be un-
suitable for this transformation.
Furthermore, we explored the potential of these NHCs
in more classical umpolung reactions, like the homobenzoin
condensation of 4-chlorobenzaldehyde (11a; B, Table 3).[34]
Remarkably, among the catalysts bearing a cyclic backbone
architecture, the five-membered ring thiazolium salt again
proved to be unreactive, again for an unknown reason (en-
try 1), whereas the seven-membered-ring thiazolium salts
bearing N-mesityl-, N-2,6-diisopropylphenyl (Dipp), or N-
2-tBu-C6H4 substitution afforded the homobenzoin 12a in
Figure 4. Single-crystal X-ray structures of thiazolium salts 3a, 6c,
and 6e. The perchlorate anion has been omitted for clarity. Dihe-
dral angles for salt 3a: H7A–C7–C5–N1 74.7°, H7B–C7–C5–N1
–45.3°, H7C–C7–C5–N1 –165.3°. Dihedral angles for salt 6c:
H8A–C8–C9–N1 47.4°, H8B–C8–C9–N1 –71.6°. Dihedral angles
for salt 6e: H4A–C4–C3A–N3 117.0°, H4B–C4–C3A–N3 –0.3°.
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Thiazolium Salt N-Heterocyclic Carbenes for Organocatalysis
Table 3. Performance of the thiazolium salt catalyst precursors in four different umpolung reactions.[a]
1
[a] Yields based on H NMR integration using 1,2-dibromomethane or mesitylene as an internal standard for reactions B–D. Yields of
reaction A determined by calibrated GC–FID. GC–FID calibration and determination of response factors were carried out independently
with pure product 16 and mesitylene as reference. Isolated yields are given in brackets; n.d. = not determined. [b] Standard conditions:
9 (0.25 mmol), NHC·HX (10 mol-%), DBU (20 mol-%), 1,4-dioxane (0.5 mL), 120 °C, 1 h. [c] Standard conditions: 11a (0.5 mmol),
NHC·HX (10 mol-%), DBU (20 mol-%), THF (2.0 mL), 60 °C, 14 h. [d] Standard conditions: 11a (0.25 mmol), 13 (0.75 mmol), NHC·HX
(10 mol-%), Et3N (20 mol-%), EtOH (0.5 mL), 80 °C, 22 h. Ratio of both regioisomers determined by 1H NMR spectroscopy. [e] Standard
conditions: 11 (0.25 mmol), 15a (0.25 mmol), NHC·HX (10 mol-%), Et3N (20 mol-%), THF (0.65 mL), 60 °C, 22 h. [f] Isolated yield
obtained on a 1.0 mmol scale after a reaction time of 2 h.
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moderate yields of around 55% (entries 5–7). Increasing the test reaction, 2-chlorobenzaldehyde (15a) was treated with
ring size to an 8- or 12-membered ring led to diminished PhCHO (11) to selectively obtain the cross-product 16a
yields (entries 8–10). the fact that a cycloheptane ring in (Table 3). Again, marked differences were obtained by using
the backbone is optimal is in agreement with our previous different catalyst precursors: IMes·HCl, benzimidazolium
findings.[14,16–19,21,22] However, further screening of the cat- iodide, and also the thiazolium salts 6a and 6b gave only
alysts bearing the dimethyl backbone showed the Dipp-sub- low yields (entries 1, 2, and 14–16). Remarkably, the best
stituted NHC derived from 3b to be the most active, result was obtained by using thiazolium salt 3b, which pro-
whereas other commonly known carbene precursors like the vided the cross-benzoin product selectively and in very
Stetter thiazolium salt (entry 13) and Enders triphenyltria- good yield (entry 12).
zolium perchlorate (entry 17) showed only moderate reac-
tivity, and IMes·HCl gave no product at all (entry 14).
Chemoselective Cross-Benzoin Condensation
However, the synthetic use of homocoupling reactions is
rather limited. Therefore the more versatile NHC-catalyzed
acyloin condensation was investigated following Stetter’s
chemoselective cross-acyloin reaction between an aliphatic
and aromatic aldehyde.[5] More recently, Zeitler and co-
workers[35] were able to evaluate the relative performance
of thiazolium and triazolium precatalysts in cross-acyloin
condensation reactions. An excellent set of experiments was
performed to rationalize the interplay between catalyst and
substrate control. Similar to Stetter’s original report, in the
acyloin reaction (C) we employed a three-fold excess of the
aliphatic aldehyde. The examination of the cross-acyloin
condensation carried out with our thiazolium salts revealed
similar results concerning ring-size tendency, and em-
ploying N-Dipp substitution generally gave either no reac-
tivity or lower conversion to the cross-acyloin products 14a
and 14aЈ. The five-membered-ring thiazolium salts 6a and
6b gave low yield with good selectivity or no reactivity,
respectively (entries 1 and 2), whereas the seven- and eight-
membered-ring catalysts with mesityl substitution afforded
the acyloin in good yields of up to 91% (entries 5 and 8).
Again, the dimethyl backbone with N-mesityl substitu-
tion[37] showed the best reactivity with quantitative conver-
sion and a ratio of isomers of 44:56 (entry 11). The best
ratio of isomers of 90:10 was obtained with Enders’ tri-
phenyltriazolium perchlorate (entry 17), albeit with poor
conversion. With thiazolium precatalysts, in general, the
preferred formation of regioisomer 14aЈ can be rationalized
by a preferred nucleophilic attack of the NHC on 4-chloro-
benzaldehyde (9a) rather than isobutyraldehyde (13) to
form the most resonance-stabilized Breslow intermediate
and later on release the thermodynamically more stable iso-
mer 14aЈ. A general switch of regioselectivity occurs when
triazolium precatalysts are used. The more sterically de-
manding carbene environment leads to a preferred first at-
tack on the isobutyraldehyde (13) to furnish the regioisomer
14a. To the best of our knowledge there are only a few
reports in the literature that evoke an intermolecular cross-
benzoin condensation of two different aromatic aldehydes,
catalyzed by either cyanide or thiamine-derived enzymes.[38]
The generality of this cross-benzoin reaction D with ef-
ficient chemocontrol was explored by using the carbene pre-
cursor 3b. First, several aromatic aldehydes were cross-cou-
pled with 2-chlorobenzaldehyde (15a; Table 4). By using
10 mol-% of thiazolium catalyst 3b and 20 mol-% of NEt3
in THF at 60 °C, good yields were obtained with several
electron-poor, electron-neutral, and electron-rich benzalde-
hyde derivatives (entries 1–6). Annulated and heterocyclic
aldehydes also gave the desired products (entries 7–9), with
thiophene-2-carbaldehyde providing 80% yield.
Table 4. Variation of the aldehyde moiety.[a]
[a] Standard conditions: 11 (1.0 mmol), 15a (1.0 mmol), NHC·HX
3b (10 mol-%), Et3N (20 mol-%), THF (0.65 mL), 60 °C, 22 h. [b]
Isolated yields.
Regarding the ortho-substituted aldehyde, different
Regarding the cross-acyloin condensation described by chemoselectivity directing groups are tolerated (Table 5).
Zeitler and co-workers, which uses an ortho-substituted re- Similar to the 2-chloro substitution, which allows modula-
action partner to improve chemoselectivity,[35] an NHC-cat- tion of the electrophilicity of the substrate and furthermore
alyzed intermolecular cross-benzoin condensation seemed is a versatile handle for further functionalization, 2-bromo-
to be very attractive as cross-benzoin formation has not yet and 2-iodobenzaldehyde are equally suited to providing
been reported by NHC organocatalysis and cross-benzoins only one cross-benzoin isomer, with yields in the range of
clearly are an important class of substrates. In the fourth 69–82% (entries 1–3). Incorporating a pharmaceutically im-
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Thiazolium Salt N-Heterocyclic Carbenes for Organocatalysis
portant 2-trifluoromethyl group provided the product in a 2-substituted aldehydes serve as better electrophiles for the
moderate 46% yield, together with a significant amount Breslow intermediate, which itself is more electron-donating
(14%) of the benzoin homodimer (entry 4). 2-Methoxy- without a halide ortho-substitution, therefore rendering a
and 2-methylbenzaldehyde afforded the products in even selective cross-process feasible.
lower yields and homodimer formation was observed in
both cases as well (entries 5 and 6).
Table 5. Variation of the ortho-substituted aldehyde.[a]
[a] Standard conditions: PhCHO (11; 1.0 mmol), 15 (1.0 mmol),
NHC·HX (10 mol-%), Et3N (20 mol-%), THF (0.65 mL), 60 °C,
22 h. [b] Isolated yields. [c] 14% of benzaldehyde homodimer was
observed (based on 1H NMR). [d] A mixture of the desired product
(80%) and the 2-methylbenzaldehyde homodimer (20%) was ob-
Scheme 4. Proposed mechanistic pathway for the selective cross-
benzoin condensation.
1
tained (based on H NMR integration).
Conducted crossover experiments should demonstrate
the influence of a retro-benzoin condensation taking place
as a background reaction (Table 6). Surprisingly, treating 2-
chlorobenzaldehyde (15a) with 0.5 equiv. of unsubstituted
benzoin under our optimized conditions led to the forma-
To gain some mechanistic insight, the reaction was care-
fully monitored by H NMR analysis of the crude reaction
1
mixture using mesitylene as internal standard. A first ex-
amination of the homocoupling rate of unsubstituted benz-
aldehyde (11) catalyzed by 3b under our optimized condi-
tions revealed only 26% formation of 12b after 22 h, which
demonstrates a relatively low homocoupling rate.
Table 6. Crossover experiments under optimized conditions.[a]
Furthermore, this result is supported by a more careful
monitoring of the cross-benzoin reaction of 11 and 15a by
1
1H NMR analysis. H NMR analysis after reaction times
of 10 min, 1 h, and 5 h, showed a maximum of only 2%
homobenzoin formation. In contrast, the cross-benzoin
product was formed in 1, 5, and 27% yields, respectively.
In general, the chemoselectivity associated with the use
of 2-substituted aldehydes is primarily based on the steric
requirements essential for both the formation of the Bres-
low intermediate II and for the nucleophilic attack[35] of the
Breslow intermediate II on the second aldehyde (Scheme 4).
For the initial attack of the carbene, the non-ortho-substi-
tuted aldehyde is preferred for steric reasons and a relatively
nucleophilic (and therefore more reactive) Breslow interme-
diate II is formed. The Breslow intermediate II sub-
sequently faces two possible reaction partners. This second
attack is intriguing because II seems to prefer the ortho-
substituted aldehyde, most likely due to electronic effects. It
[a] Standard conditions: 15a (0.25 mmol), 12b (0.125 mmol),
NHC·HX (10 mol-%), Et3N (20 mol-%), THF (0.65 mL), 60 °C,
22 h. [b] Based on 1H NMR integration using mesitylene as an
is reasonable to assume that (mostly) electron-withdrawing internal standard.
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of the conversion and characterization of the products, only one
method was used. The initial injection temperature was T0 = 50 °C,
after holding this temperature for 3 min, the column was heated
to the temperature T1 = 280 °C (ramp: 40 °C/min), and the final
temperature was held for 3 min.
tion of only 3% of the cross-benzoin product 16a, which
shows that the reversible homobenzoin formation/retro-
benzoin reaction does not play a significant role in our cata-
lytic system. The use of catalyst precursor 6f instead af-
forded the cross-product in 8% yield and switching to the
analogous N-mesityl catalyst 6e led to the product in 28%
yield. This shows the responsibility of the sterically less de-
manding mesityl group for the ability of the carbene to cat-
alyze a retro-benzoin reaction, in contrast to the Dipp sub-
stituent, which mostly restricts the system towards the at-
tack of a benzoin formed during the course of the reac-
tion.[39]
No significant formation of the homodimer could be ob-
served (Ͻ5%) and, as shown by the crossover experiments
(Table 6), retro-benzoin condensation does not take place
in significant amounts with catalyst 3b. Therefore a differ-
ence in the thermodynamic stability of both the homo- and
the cross-benzoin product might be responsible for the de-
gradation of the more labile homobenzoin, resulting in a
selective cross-benzoin formation step that liberates the
NHC and completes the catalytic cycle.
Typical Procedure for the Intermolecular Cross-Benzoin Reaction to
Afford Benzoin 16a:[40] In a flame-dried screw-capped test-tube
equipped with a magnetic stirring bar and equal amounts of 2-
chlorobenzaldehyde (15a; 112.5 μL, 1.0 mmol, 1.0 equiv.) and benz-
aldehyde (11; 101.0 μL, 1.0 mmol, 1.0 equiv.), thiazolium salt 3b
(37.4 mg, 0.1 mmol, 0.1 equiv.) and Et3N (27.5 μL, 0.2 mmol,
0.2 equiv.) were added and dissolved in absolute THF (0.65 mL).
After stirring for 22 h in a 60 °C preheated oil bath, the reaction
mixture was pre-adsorbed on silica and purified by flash
chromatography on silica gel (n-pentane/EtOAc = 20:1) to yield 2-
(2-chlorophenyl)-2-hydroxy-1-phenylethanone (16a) as a white so-
lid (202 mg, 0.82 mmol, 82%). Rf (n-pentane/EtOAc = 20:1) = 0.26.
1H NMR (300 MHz, CDCl3): δ = 7.95–7.89 (m, 2 H, 2 Ar-H),
7.56–7.49 (m, 1 H, Ar-H), 7.44–7.36 (m, 3 H, 3 Ar-H), 7.22 (dt, J
= 7.2, 2.1 Hz, 1 H, Ar-H), 7.17 (dt, J = 7.2, 1.5 Hz, 1 H, Ar-H),
7.14–7.09 (m, 1 H, Ar-H), 6.38 (s, 1 H, CH), 4.58 (br. s, 1 H,
OH) ppm. 13C NMR (100 MHz, CDCl3): δ = 198.8, 136.9, 134.3,
133.8, 133.3, 130.5, 130.2, 129.3, 129.0, 128.9, 127.8, 73.0 ppm.
FTIR (ATR): ν = 3480, 2917, 1671, 1596, 1577, 1477, 1440, 1364,
˜
1311, 1289, 1239, 1196, 1181, 1161, 1127, 1094, 1046, 1034, 1000,
972, 853, 803, 762, 716, 658, 633, 596, 559, 530, 507 cm–1. GC–MS:
Rt = 9.18 min. MS (EI): m/z (%) = 141.0 (13), 139.0 (27), 111.0
(10), 106.0 (8), 105.1 (100), 77.1 (39), 75.0 (8), 51.1 (12), 50.1 (5).
MS (ESI): calcd. for [C14H11ClO2Na]+ 269.0345; found 269.0331.
Conclusions
In previous studies we have developed and successfully
employed a new thiazolylidene, Isa-NHC. In this study we
have reported the synthesis of a whole family of structurally
closely related thiazolylidenes. By using tools developed for
the analysis of NHC ligands, we explored the electronic
properties and the steric demand of these NHCs. However,
it is important to note that new powerful tools, either exper-
imental or theoretical, need to be developed for the investi-
gation of the electronic and steric properties of NHC
organocatalysts. In addition, we have shown that these
thiazolium salt derived NHCs are effective organocatalysts
for promoting a chemoselective intermolecular cross-
benzoin condensation leading to unsymmetrically substi-
tuted benzoins. This family of NHCs might enable new or
improved organocatalytic processes and the results of this
study might assist the design of new and more efficient
NHC catalysts.
Supporting Information (see footnote on the first page of this arti-
cle): Synthesis, full characterization and NMR spectra of all com-
pounds.
Acknowledgments
We are grateful to Ms. Karin Gottschalk for skillful technical as-
sistance and to Ms. Claudia Lohre for helpful discussions. Gener-
ous financial support by the Deutsche Forschungsgemeinschaft
(DFG) (SPP 1179), the Fonds der Chemischen Industrie, Astra-
Zeneca, the International NRW Graduate School of Chemistry (to
I. P.) and the Deutsche Akademische Austauschdienst (DAAD) (to
K. H.) are gratefully acknowledged. The research of F. G. was sup-
ported by the Alfried Krupp Prize for Young University Teachers
of the Alfried Krupp von Bohlen und Halbach Foundation.
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Experimental Section
General Methods: All reactions were carried out in flame-dried re-
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5482
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Eur. J. Org. Chem. 2011, 5475–5484

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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5483

I. Piel, M. D. Pawelczyk, K. Hirano, R. Fröhlich, F. Glorius
FULL PAPER
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methylthiazolylidene is not as efficient in terms of selectivity,
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homoacyloin and 12% of the homobenzoin product; b) as
demonstrated recently, this triazolylidene is both efficient and
selective for the studied reaction, giving a ratio of 12a/12aЈ of
63:12 with 7% of the homobenzoin product; see ref.[35a] for
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[40] See the Supporting Information for further details of the syn-
thesis, full characterization and NMR spectra for all com-
pounds.
[35] For three recent examples of a chemoselective acyloin conden-
sation, see: a) C. A. Rose, S. Gundala, S. J. Connon, K. Zeitler,
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Received: June 15, 2011
Published Online: August 22, 2011
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