N-heterocyclic carbene catalyzed umpolung of styrenes: Mechanistic elucidation and selective tail-to-tail dimerization

Article abstract of DOI:10.1021/ol501256d

The reaction between N-heterocyclic carbenes (NHCs) and styrenes yields alkyl-substituted azolium salts, which are able to form nucleophilic deoxy Breslow intermediates by simple deprotonation. This hitherto unknown reaction of NHCs represents a new way to generate deoxy Breslow intermediates and paves the way for the selective NHC-catalyzed tail-to-tail homodimerization of styrenes. This reaction significantly broadens the scope of the Michael umpolung and provides a new method to generate 1,4-diaryl compounds.

Full text of DOI:10.1021/ol501256d

Letter
pubs.acs.org/OrgLett
N‑Heterocyclic Carbene Catalyzed Umpolung of Styrenes:
Mechanistic Elucidation and Selective Tail-to-Tail Dimerization
Michael Schedler, Nathalie E. Wurz,† Constantin G. Daniliuc, and Frank Glorius*
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster, Corrensstraße 40, 48149 Munster, Germany
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S
* Supporting Information
ABSTRACT: The reaction between N-heterocyclic carbenes (NHCs)
and styrenes yields alkyl-substituted azolium salts, which are able to
form nucleophilic deoxy Breslow intermediates by simple deprotona-
tion. This hitherto unknown reaction of NHCs represents a new way to
generate deoxy Breslow intermediates and paves the way for the
selective NHC-catalyzed tail-to-tail homodimerization of styrenes. This
reaction significantly broadens the scope of the Michael umpolung and
provides a new method to generate 1,4-diaryl compounds.
he use of NHCs1 as organocatalysts2 is mainly founded on
their ability to attack the electrophilic aldehyde moiety and
limited scope of the cross-coupling of two different Michael
acceptors. The combination of NHCs with Michael acceptors
also led to further interesting reactions, similar to the Morita−
Baylis−Hillman reaction.10 In addition, the group of Scheidt has
shown that NHCs add to vinyl sulfones, turning these into
reactive nucleophiles.10,11
T
form the so-called Breslow intermediate,3 a nucleophilic acyl
anion equivalent, which leads to an umpolung of this moiety.4
This umpolung of aldehydes led to extensive research on the
benzoin condensation and the Stetter reaction.5 While the
electrophilic reaction partner of the Breslow intermediate has
been widely varied, only limited variation of the aldehyde has
been yet realized. The scope was significantly extended by the
introduction of α,β-unsaturated aldehydes and the “conjugate
umpolung” in 2004.6 Recently, the area of conjugate umpolung
was further broadened by the group of Y. R. Chi, who introduced
saturated esters as suitable substrates with the β-position of these
compounds being rendered nucleophilic.7 Additionally, Fu and
co-workers showed in 2005 that NHCs are also able to add to
α,β-unsaturated esters and to perform an umpolung of this
Michael acceptor, which they used in an intramolecular reaction
to form cyclopentenones (Scheme 1a).8 Six years later, the
In a recent communication we presented the first inter-
molecular NHC-catalyzed hydroacylation of unactivated alkenes,
namely, styrenes,12 demonstrating the feasibility of a reaction of
the Breslow intermediate13 with styrenes. Adding to our previous
research, we now report the ability of NHCs to add directly to
styrenes, turning them into transient nucleophiles and enabling
the homocoupling of styrenes as well as the cross-coupling of
different styrenes (Scheme 1c). In order to investigate the
reactivity of NHCs toward styrenes, we conducted a stoichio-
metric reaction of the NHC precursor 1a, which was the most
potent catalyst for the acrylate dimerization,9a with the electron-
poor styrene 2a under basic conditions (Scheme 2a). At a
temperature of 80 °C, only the adduct of the NHC to styrene was
formed and could be isolated in a good yield of 78%. Motivated
by this successful reaction of 2a, we repeated the same reaction
with unsubstituted styrene 2b, which surprisingly also gave the
addition product 3b in a yield of 45%, but only at an increased
temperature of 160 °C and using a slight excess of styrene. The
structure of this adduct 3b could be confirmed by X-ray
crystallography (Scheme 2). This reaction shows for the first
time that NHCs are capable of adding to unactivated double
bonds and even to an electron-rich double bond, a reaction
typically known for carbenes or metal-bound carbenoids, which
add readily to alkenes to form cyclopropanes.14
Scheme 1. NHC-Catalyzed Reactions of Acrylates and
Styrenes
When repeating the stoichiometric reaction of p-cyanostyrene
2a with other NHCs, only traces of the NHC-styrene adduct
were observed. Notably, the reaction of IMes 1b with p-
cyanostyrene 2a yielded a mixture of the NHC-styrene adduct
intermolecular Michael umpolung of acrylates was independ-
ently reported by Matsuoka and our group, leading to a tail-to-tail
homocoupling of two Michael acceptors (Scheme 1b).9 These
first intermolecular Michael umpolung reactions constitute a
groundbreaking proof of principle but suffered from the fact that
only α-substituted acrylates were suitable substrates and the
Received: May 1, 2014
Published: May 14, 2014
© 2014 American Chemical Society
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Letter
electron-poor styrenes led selectively to the tail-to-tail dimers
(6a−d) in moderate yields, whereas the adducts were formed as
approximately 1:1 mixtures of the two shown double-bond
regioisomers (Scheme 3). Encouraged by these remarkable
Scheme 2. Stoichiometric Reactions of NHCs with Styrenes
and Molecular Structure of 3b (Counterion Omitted for
Clarity)
a
Scheme 3. Stoichiometric Cross-Coupling of Styrenes
and a 2:1 adduct of styrene and NHC (Scheme 2b). Using an
excess of 2a, the 2:1 adduct became the main product, which
could be isolated and identified as 4. The formation of 4 can be
explained by deprotonation of the methylene group adjacent to
the azolium salt and the formation of a so-called deoxy Breslow
intermediate,15 which then acts as a nucleophile and attacks
another molecule of 2a. In order to confirm this hypothesis, we
mixed the adducts 3a and 3b with 1.5 equiv of NaH in d8-THF in
an NMR tube, which led to full deprotonation of the CH2 group,
which is directly connected to the triazolium moiety and the
expected formation of the deoxy Breslow intermediates, which
were stable under O2- and H2O-free conditions. These
intermediates were fully characterized by 1D and 2D NMR
spectroscopy, showing that a mixture of (E)- and (Z)-deoxy
Breslow intermediates was formed, in a ratio of about 1:3 in favor
of the (Z)-intermediate. The formation of the two deoxy Breslow
intermediates could be followed by 1H and 13C NMR
spectroscopy, and the assignment of the (E)- and (Z)-geometry
was achieved by NOE experiments (Figure 1).16 Previous
a
Standard conditions: 1 equiv ≙ 0.1 mmol, 2 equiv of DBU, 1,4-
dioxane (0.25 M, 0.4 mL), 16 h, 160 °C. Yields of isolated products.
b
Contains another inseparable isomer (about 5%).
stoichiometric reactions, we focused on the possibility of a
catalytic dimerization of styrenes and investigated the homo-
dimerization of 2a with 1a as the catalyst. Under the previously
established conditions for the Michael umpolung of acrylates9a
the dimer 7a could not be observed (Table 1, entry 1), but
increasing the temperature to 120 °C (21% yield, entry 2) and
subsequently to 140 °C (77%, entry 4) facilitated the product
formation. Using an increased amount of base was helpful to a
Table 1. Optimization of the Catalytic Dimerization of
Styrenes
a
b
entry
catalyst
DBU (equiv)
temp (°C)
yield (%)
1
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
1
1
2
1
2
2
2
2
2
2
2
80
120
120
140
140
140
140
140
140
140
140
0
2
21
81
77
78
61
0
3
4
5
Figure 1. 1H NMR spectrum of deoxy Breslow intermediate 5a.
6
7
8
5
research on the structures of deoxy Breslow intermediates was
based on the reaction of NHCs with activated alkyl halides,
leading to compounds similar to 5, and deprotonation of these
compounds also led to the formation of deoxy Breslow
intermediates.15 The isolation of these intermediate 3 allowed
us to investigate the reactivity of the deoxy Breslow intermediates
5 toward electrophilic styrenes. Under basic conditions and at
high temperatures, a reaction of the adduct 3a with four different
9
0
10
11
0
c
1g
99 (87)
a
Standard conditions: 1 equiv ≙ 0.1 mmol, 10 mol % NHC·HX, DBU,
b
1,4-dioxane (0.5 M, 400 μL), 16 h. Yield was determined by 1H NMR
c
spectroscopy with CH2Br2 as the internal standard. Yield of isolated
product, 2 equiv of 2a (1 mmol).
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Letter
degree (entries 3 and 5), but full conversion was achieved only
after a screening of carbenes. IMes 1b, which had earlier been
shown to be capable of adding to styrenes, gave only a reduced
yield of 61% (Entry 6). Variations of IMes, such as the more
electron-rich NHC precursor 1c17 or the phenyl-substituted
imidazolium salt 1d, gave no or a very low yield (entries 7 and 8).
The same can be said for other triazolium-based catalysts, such as
1e and 1f (entries 9 and 10). Only a more electron-rich variation
of the previously used NHC 1a gave a better yield, and its use in
fact led to full conversion into the dimer 2a (99%, entry 11).
Having established these conditions, we were curious about
the scope and the functional group tolerance of this dimerization
and hence tested different styrenes with electron-withdrawing
substituents. A carbonyl-based electron-withdrawing group as a
ketone was well tolerated and gave the corresponding dimer 7c in
a good yield (Scheme 4). However, for most of the other styrenes
trifluoromethyl-styrene 2h in good and moderate yields,
respectively. The structure of 7g, especially the E-configuration
of the double bond, could be confirmed by X-ray crystallog-
raphy.18 However, a strongly electron-withdrawing group is
essential for the reactivity, which can be seen by the low yield of
the ester-substituted styrene 2i, which yielded only 36% of the
dimer 7i even with increased catalyst loading. Furthermore, the
amide-substituted styrene 2j did not give any product.
Surprisingly, the acetyl-substituted styrene 7k yielded 79% of
the dimer, showing that acidic protons, such as the ones in the
acetyl moiety, are well tolerated under the harsh and basic
conditions. For most substrates, nearly full conversion of the
styrene, even at a low yield of 7, was observed, indicating a
decomposition of the styrene, probably via oligo- or polymer-
ization, as a competing process.
Based on the stoichiometric reactions and the characterization
of the deoxy Breslow intermediates, the following mechanism for
the dimerization of styrenes is proposed (Scheme 5). Addition of
a
Scheme 4. Scope of the Catalytic Dimerization of Styrenes
Scheme 5. Proposed Mechanism for the Dimerization of 2a
the NHC to the β-position of the styrene leads to a first adduct I,
which was isolated and characterized in its protonated form. A
1,2-migration of a proton transforms the zwitterionic adduct into
the deoxy Breslow intermediate 5a, which performs a
nucleophilic attack on a second molecule of styrene, forming
the adduct II. Now, another proton shift is needed to generate an
anionic charge in the β-position of the NHC, enabling the
elimination of the NHC and the formation of 7a. While the
addition of the NHC to the styrene already proceeds smoothly at
80 °C (Scheme 2a), the attack of the deoxy Breslow intermediate
on a second molecule of styrene also happens for the challenging
substrates at 140 °C (vide supra). Therefore, only the elimination
of the NHC from II requires the high temperature of 160 °C,
indicating that this last step is the turnover-limiting step of the
catalytic cycle. Finally, we also performed preliminary experi-
ments concerning the coupling of two different styrenes.
Submitting a 1:1 mixture of styrenes 2a and 2d to the established
conditions yielded 36% of the cross-coupled product 6d
alongside the products of homocoupling. Product 6d was
isolated as an approximately 1:1 mixture of two double-bond
regioisomers. Preliminary experiments on combining the styrene
umpolung with acrylates revealed the formation of the cross-
coupled product 9 in a yield of 35%, while remaining starting
materials formed the homocoupling products. In this case, the
two double-bond isomers were formed in a 2.5:1 ratio and could
be separated by column chromatography (Scheme 6).
a
Standard conditions: 1 equiv ≙ 0.5 mmol, 10 mol % 1g, 2 equiv of
DBU, 1,4-dioxane (0.5 M, 2 mL), 16 h. Yields of isolated products.
b
Reaction performed at 160 °C in 1,4-dioxane (2 M, 0.5 mL).
c
d
Contains an inseparable isomer (about 5%). Reaction performed
with 20 mol % 1g at 160 °C.
that were tested, the conversion into the dimer was quite low; we
thus optimized the conditions again and found that an increased
temperature of 160 °C and an increased concentration (2 M
instead of 0.5 M) were beneficial.18 Under these conditions,
heteroaromatic compounds, such as 4-vinylpyridine 2d, 2-
vinylpyridine 2e, and 5-vinylpyrimidine 2f, could be used as
substrates and gave the corresponding products in good to
moderate yields. When the reaction was performed at 140 °C, no
product was formed at all, but the adduct of the NHC to the
product could be detected by ESI mass spectrometry, indicating
that the final elimination of the carbene to liberate the product is
not proceeding at 140 °C and only occurs, as is typical for an
elimination, at sufficiently high temperatures and at high
concentrations of a base. The same is true for trifluoromethyl-
substituted styrenes, and the high-temperature conditions gave
the dimers of 3,5-bis(trifluoromethyl)-styrene 2g and of 4-
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Letter
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heterocyclic carbenes with styrenes and demonstrated that
NHCs are capable of adding to these comparatively electron-
neutral alkenes. Furthermore, we showed that the deprotonation
of these adducts yielded nucleophilic deoxy Breslow inter-
mediates, which enabled the previously unknown tail-to-tail
dimerization of styrenes. This surprising expansion of the
Michael umpolung provides a new synthetically useful method to
generate 1,4-diaryl compounds.
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ASSOCIATED CONTENT
* Supporting Information
■
(8) Fischer, C.; Smith, S. W.; Powel, D. A.; Fu, G. C. J. Am. Chem. Soc.
2006, 128, 1472.
S
Experimental data on formation of the stoichiometric adducts,
their reactions, and the catalytic reactions. NMR spectra and
information on the single crystal X-ray structures. This material is
available free of charge via the Internet at http://pubs.acs.org.
(9) (a) Biju, A. T.; Padmanaban, M.; Wurz, N. E.; Glorius, F. Angew.
Chem., Int. Ed. 2011, 50, 8412. (b) Matsuoka, S.-i.; Ota, Y.; Wahio, A.;
Katada, A.; Ichioka, K.; Tagaki, K.; Suzuki, M. Org. Lett. 2011, 13, 3722.
(c) Matsuoka, S.-i.; Namera, S.; Wahio, A.; Tagaki, K.; Suzuki, M. Org.
Lett. 2013, 15, 5916. (d) Kato, T.; Matsuoka, S.-i.; Suzuki, M. J. Org.
Chem. 2014, DOI: 10.1021/jo500514e.
(10) (a) Atienza, R. L.; Roth, H. R.; Scheidt, K. A. Chem. Sci. 2011, 2,
1772. (b) Atienza, R. L.; Scheidt, K. A. Aust. J. Chem. 2011, 64, 1158.
(11) For a review on NHC-catalyzed reactions with C−C multiple
bonds, see: Chen, X.-Y.; Ye, S. Org. Biomol. Chem. 2011, 11, 7991.
(12) Schedler, M.; Wang, D.-S.; Glorius, F. Angew. Chem., Int. Ed. 2013,
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: glorius@uni-muenster.de.
Present Address
†Wiley-VCH, Boschstrasse 12, 69469 Weinheim, Germany.
Notes
(13) For recent studies on the properties of the Breslow intermediate,
see: (a) Berkessel, A.; Elfert, S.; Yatham, V. R.; Neudorfl, J.-M.; Schlorer,
N.; Teles, J. H. Angew. Chem., Int. Ed. 2012, 51, 12370. (b) Berkessel, A.;
̈
̈
The authors declare no competing financial interest.
Yatham, V. R.; Elfert, S.; Neudorfl, J.-M. Angew. Chem., Int. Ed. 2013, 52,
11158.
̈
ACKNOWLEDGMENTS
■
Generous financial support by the Fond der Chemischen
Industrie (M.S.), the Deutsche Forschungsgemeinschaft and
the Deutsche Telekom Stiftung (N.E.W.) is gratefully acknowl-
edged. Dr. Mohan Padmanaban (Inst. fur Org. Chem./
University of Vienna) is acknowledged for the synthesis of
NHC precursors. Karin Gottschalk (Org.-Chem. Inst./WWU
(14) For a review on the addition of carbenes to alkenes
(cyclopropanation), see: (a) Davies, H. M. L.; Antoulinakis, E. G. Org.
React. 2001, 57, 1. For the more typical addition of NHCs to electron-
poor double bonds, see: (b) Enders, D.; Breuer, K.; Raabe, G.; Runsink,
J.; Teles, J. H.; Melder, J. P.; Ebel, K.; Brode, S. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1021. For a recent work on the reaction of
diamidocarbenes with olefins, see: (c) Moerdyk, J. P.; Bielawski, C.
W. Nat. Chem. 2012, 4, 275.
̈
Munster) is acknowledged for skillful technical support.
̈
(15) For recent work on the properties of deoxy Breslow
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