N-heterocyclic carbene catalyzed umpolung of Michael acceptors for intermolecular reactions

Article abstract of DOI:10.1002/anie.201103555

leahciM! The N-heterocyclic carbene catalyzed umpolung of Michael acceptors proceeds through the formation of a deoxy-Breslow intermediate (see scheme; EWG=electron-withdrawing group). This nucleophilic species can react with other Michael acceptors in an intermolecular fashion, thereby resulting in the formation of homo- or heterodimeric olefins. This "Michael umpolung" should become a valuable method for the formation of densely functionalized olefins.

Full text of DOI:10.1002/anie.201103555

Communications
DOI: 10.1002/anie.201103555
Organocatalysis
N-Heterocyclic Carbene Catalyzed Umpolung of Michael Acceptors
for Intermolecular Reactions**
Akkattu T. Biju, Mohan Padmanaban, Nathalie E. Wurz, and Frank Glorius*
Dedicated to Dr. Vijay Nair on the occasion of his 70th birthday
The benzoin reaction, the coupling of two aromatic aldehydes
[Eq. (1)], is one of the most important transformations
catalyzed by N-heterocyclic carbenes (NHCs).[1] It proceeds
through a unique umpolung strategy, which is widely used to
provide unconventional access to various target molecules.[2]
Intriguingly, however, in most cases this strategy is limited to
aldehydes,[3] and the umpolung of other electrophiles in this
realm of NHC organocatalysis is very rare. In 2006, Fu and co-
workers developed an elegant NHC-catalyzed umpolung of
Michael acceptors and applied this strategy in an intra-
molecular b-alkylation of Michael acceptors, the equivalent of
a Heck reaction.[4] Although the coupling of an activated
olefin/latent enolate with a second Michael acceptor to create
À
a new C C bond at the a position of the former is well
documented [Rauhut–Currier reaction, Eq. (2); EWG =
electron-withdrawing group],[5] the analogous transformation
for the b functionalization of Michael acceptors is less
developed,[6] and an organocatalytic approach that utilizes
an umpolung strategy remains to be explored.[7] Herein, we
report the NHC-catalyzed umpolung of Michael acceptors,
followed by an intermolecular addition to activated olefins
that leads to the b-selective formation of linear dimers, which
are potential precursors for the synthesis of fine chemicals
and polymer intermediates [Eq. (3)].[8]
In the context of our sustained interest in developing
organocatalytic transformations using NHCs,[3b–d,9] we
recently initiated a research program on the NHC-catalyzed
umpolung of activated alkenes followed by intermolecular
addition reactions. The underlying principle behind this
program is to extend NHC catalysis beyond the umpolung
of aldehydes. Our current study commenced with the NHC-
catalyzed umpolung of the b position of n-butyl methacrylate
(1a) to give dibutyl 2,5-dimethylhex-2-enedioate (2a;
Table 1). After extensive investigation, we found that treat-
ment of 1a with the carbene generated by deprotonation of
the 1,3,4-triphenyltriazolium salt 3[10] with DBU resulted in
the smooth formation of hex-2-enedioate 2a in 71% yield and
1
an excellent E/Z ratio of 97:3 (based on H NMR spectros-
copy; Table 1, entry 1). Remarkably, other common NHCs
derived from the precursors 4–7 are ineffective (Table 1,
entries 2–5). Control experiments showed that no umpolung
reactivity is observed if the carbene precursor 3 or DBU is
omitted (Table 1, entries 6 and 7). Additionally, a variety of
phosphines and amines are essentially inactive as catalysts
(Table 1, entries 8 and 9), thus emphasizing the essential role
of NHCs in the umpolung of Michael acceptors.[11] Bases such
as KOtBu, K2CO3, and K3PO4 furnished the desired product
in reduced yields (Table 1, entries 10–12), and solvents other
than 1,4-dioxane resulted in inferior reactivity (Table 1,
entries 13–15). The reaction is sluggish at lower temperatures
(Table 1, entry 16), and the yield of the product was reduced
considerably when the amount of DBU was halved (Table 1,
entry 17). Delightfully, increasing the amount of DBU led to
full conversion, which led to the formation of 2a in 96% yield
and an excellent diastereoselectivity of 96:4 (Table 1,
entry 18).[12]
[*] Dr. A. T. Biju
Organic Chemistry Division
National Chemical Laboratory (CSIR)
Dr. Homi Bhabha Road, Pune—411008 (India)
M. Padmanaban, N. E. Wurz, Prof. Dr. F. Glorius
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster, NRW Graduate School
of Chemistry, Organisch-Chemisches Institut
Corrensstrasse 40, 48149 Mꢁnster (Germany)
E-mail: glorius@uni-muenster.de
[**] Generous financial support by the Deutsche Forschungsgemein-
schaft, the Fonds der Chemischen Industrie, the Alexander von
Humboldt Foundation (A.T.B.), the International NRW Graduate
School of Chemistry (M.P.), and the Deutsche Telekom Stiftung
(N.E.W.) is gratefully acknowledged. The research of F.G. has been
supported by the Alfried Krupp Prize for Young University Teachers
of the Alfried Krupp von Bohlen und Halbach Foundation.
With these optimized reaction conditions in hand, we
examined the scope of this unique NHC-organocatalyzed
umpolung/dimerization reaction (Scheme 1). A variety of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103555.
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Angew. Chem. Int. Ed. 2011, 50, 8412 –8415

Table 1: Optimization of the reaction conditions.[a]
Entry
Variation of the standard conditions[a]
Yield [%][b]
E/Z[c]
1
2
3
4
5
6
7
8
none
4 instead of 3
5 instead of 3
6 instead of 3
7 instead of 3
no 3, 40 mol% DBU
no DBU
10 mol% PPh3 instead of 3 and DBU
10 mol% DMAP instead of 3 and DBU
KOtBu instead of DBU
K2CO3 instead of DBU
K3PO4 instead of DBU
THF instead of 1,4-dioxane
toluene instead of 1,4-dioxane
DME instead of 1,4-dioxane
run at 408C, 1.0 equiv of DBU
10 mol% 3 and 10 mol% DBU
10 mol% 3 and 1.0 equiv of DBU
71(70)[d]
<1
<1
<1
<1
<1
<1
<1
<1
<1
6
97:3
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
96:4
98:2
97:3
94:4
97:3
n.d.
97:3
96:4
9
Scheme 1. NHC-catalyzed umpolung of Michael acceptors: Substrate
scope. General conditions: 1 (1.0 mmol), 3 (10 mol%), DBU
(1.0 equiv), 1,4-dioxane (2.0 mL), 808C, and 24 h. Yields of isolated
products are given. E/Z ratio determined by 1H NMR spectroscopic
analysis of crude products is given in parentheses. Bn=benzyl.
[a] 0.25 mmol scale. [b] Using 20 mol% of 3 on 0.5 mmol scale.
10
11
12
13
14
15
16
17
18
17
57
50
64
<1
31
98(96)[d]
treated with methyl methacrylate in the presence of 3 and
DBU no cross-over product 8 or its isomer was detected, and
2a was recovered quantitatively [Eq. (5)].[11] These observa-
tions indicate that the dimerization occurs irreversibly under
the optimized conditions. It is noteworthy in this context that
the NHC-catalyzed formation of benzoin is reversible in most
cases.[13]
[a] Standard conditions: 1a (0.25 mmol), NHC·HX 3 (10 mol%), DBU
(20 mol%), 1,4-dioxane (0.5 mL), 808C, and 24 h. [b] The yields were
1
determined by H NMR spectroscopic analysis of crude products using
CH2Br2 as the internal standard. [c] Determined by 1H NMR spectros-
copy. [d] Yield of isolated product in parentheses. DBU=1,8-
diazabicyclo[5.4.0]undec-7-ene, DMAP=4-dimethylaminopyridine,
DME=1,2-dimethoxyethane, Mes=mesityl, 2,4,6-trimethylphenyl.
methacrylate derivatives showed superb reactivity and led to
the formation of hex-2-enedioates in 66–96% yield and
excellent diastereoselectivities (2a–e). Moreover, 2-phenyl
acrylate underwent smooth dimerization to afford 2 f in 90%
yield. Electron-donating and electron-withdrawing groups on
the aromatic ring of the 2-aryl acrylates were well tolerated
(2g–i). Furthermore, 2-alkyl acrylates furnished the desired
products in good yields and excellent diastereoselectivities
(2j–l). It is important to note, however, that in preliminary
experiments, a,b-unsaturated aldehydes such as 2-ethylacro-
lein and cinnamaldehyde failed to undergo this transforma-
tion under the standard reaction conditions, presumably
because of irreversible binding of the carbene with these
substrates, as evident from our inhibition experiments.[11]
We carried out a series of experiments to probe the
mechanism of this unique transformation. To get insight into
the reversibility of the reaction and to test the stability of the
product 2a under the reaction conditions, 2a was treated with
triazolium salt 3 and DBU [Eq. (4)]. The reaction returned 2a
quantitatively without the formation of any detectable
amount of butyl methacrylate. Moreover, when 2a was
The mechanistic rationale for this transition-metal-free
transformation is shown in Scheme 2. The reaction is likely
initiated by the conjugate addition of the NHC generated
from 3 to the activated alkene 1 to form the ester enolate 9,
which undergoes proton transfer to form the enamine
intermediate 10. It is noteworthy that similar enamines have
been isolated by the 1:1 addition of the NHC derived from 3
to activated alkenes, including dimethyl maleate, dimethyl
fumarate, and fumaric dinitrile.[14] Intermediate 10 bears a
strong resemblance to the Breslow intermediate,[15] which is
usually formed by the addition of an NHC to aldehydes and is
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Communications
Scheme 3. NHC-catalyzed cross-coupling of Michael acceptors. Gen-
eral conditions: 1 (1.0 mmol), 12 (2.0 mmol), 3 (20 mol%), DBU
(40 mol%), 1,4-dioxane (2.0 mL), 808C, and 24 h. Yields of isolated
products are given. E/Z ratio determined by GC-MS analysis of crude
reaction mixture is given in parentheses.
Scheme 2. Proposed mechanism of the reaction.
the cross-coupling products 13a and 13a’ in 70% yield.[18] In
addition, phosphoryl acrylate can also be employed as the
coupling partner, which leads to the formation of 13b and 13c
in moderate yields but excellent diastereoselectivities.
In conclusion, we have developed a transition-metal-free
NHC-organocatalyzed umpolung of Michael acceptors
(“Michael umpolung”) and their addition to Michael accept-
ors. It is conceivable that the present study will trigger
increased interest in the umpolung of Michael acceptors.
Further elucidation of the mechanism of this transformation,
expanding the scope to challenging cross-coupling reactions,
and the development of an asymmetric variant seem to be
rewarding goals.
nucleophilic at the b-carbon atom (umpolung). This deoxy
Breslow intermediate[16] 10 adds to another molecule of 1 to
form the ester enolate 11, which undergoes proton transfer
and elimination of the NHC to form the observed product 2.
A strong indication for the presence of 10 comes from the fact
that the stoichiometric reaction of NHC precursor 3, DBU,
and butyl methacrylate 1a in a 1:1:1 ratio resulted in the
smooth formation of the corresponding protonated species
10·HClO4 [Eq. (6)].[17] Moreover, adding more DBU and 1a
to 10·HClO4 and heating the mixture to 808C resulted in full
conversion to the desired coupling product 2a [Eq. (7)].
Experimental Section
Triazolium salt 3 (39.7 mg, 0.1 mmol) was added to a Schlenk tube
with a teflon screw cap inside a glovebox. Dry 1,4-dioxane (2.0 mL)
was then introduced into the tube by syringe outside of the glovebox
but under a positive pressure of argon, and the mixture was stirred at
RT. The Michael acceptor 1 (1.0 mmol) followed by DBU (152 mg,
149 mL, 1.0 mmol) were then added. The resulting mixture was then
stirred in a preheated oil bath at 808C for 24 h, and then cooled to RT.
Evaporation of the solvent followed by column chromatography
afforded the corresponding products 2.
Received: May 24, 2011
Published online: July 21, 2011
Monitoring the kinetics of the reaction on varying the
amount of DBU indicated that in addition to shifting the
equilibrium towards the generation of more free NHC, the
base may also be involved in the deprotonation events in the
catalytic cycle.[11] This is in accordance with the observation of
Fu and co-workers,[4a] where the base is involved in the
catalytic cycle and is also supported by computational
mechanistic studies.[4b]
Encouraged by the NHC-catalyzed homocoupling of
Michael acceptors by using the umpolung strategy, we then
focused our attention on the cross-coupling of two different
Michael acceptors (Scheme 3). Gratifyingly, treatment of
butyl methacrylate with methacrylonitrile under modified
reaction conditions resulted in the formation of a mixture of
Keywords: carbenes · Michael acceptors ·
nitrogen heterocycles · organocatalysis · umpolung
.
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[18] Two experiments support the notion that 13a’ is formed from the
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was not found to be suitable for this umpolung, not providing
any homocoupling product. Moreover, resubjecting isolated
product 13 to the reaction conditions (without additional olefin
12a) resulted in the formation of double bond isomerization
product 13a’.
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