N-heterocyclic carbene-catalyzed conjugate additions of alcohols

Article abstract of DOI:10.1021/ja1061196

An efficient intermolecular conjugate addition of alcohols to activated alkenes catalyzed by N-heterocyclic carbenes has been developed. With 5 mol % of the free carbene derived from IMes?HCl, unsaturated ketones and esters are competent substrates, and a variety of primary and secondary alcohols can be employed as the nucleophile. No oligomerization is observed under these mild conditions for effective hydroalkoxylation. In addition to reactions with activated alkenes, IMes catalyzes the formation of vinyl ethers through the 1,4-addition of alcohols to ynones and promotes tandem conjugate addition/Michael cascade reactions. Preliminary data support a Bronsted base mechanism with the free carbene.

Full text of DOI:10.1021/ja1061196

Published on Web 09/01/2010
N-Heterocyclic Carbene-Catalyzed Conjugate Additions of Alcohols
Eric M. Phillips, Matthias Riedrich, and Karl A. Scheidt*
Department of Chemistry, Center for Molecular InnoVation and Drug DiscoVery, Chemistry of Life Processes
Institute, Northwestern UniVersity, SilVerman Hall, 2145 Sheridan Road, EVanston, Illinois 60208
Received July 10, 2010; E-mail: scheidt@northwestern.edu
only just emerging.8 Nolan, as well as Waymouth and Hedrick,
Abstract: An efficient intermolecular conjugate addition of alco-
hols to activated alkenes catalyzed by N-heterocyclic carbenes
has been developed. With 5 mol % of the free carbene derived
from IMes ·HCl, unsaturated ketones and esters are competent
substrates, and a variety of primary and secondary alcohols can
be employed as the nucleophile. No oligomerization is observed
under these mild conditions for effective hydroalkoxylation. In
addition to reactions with activated alkenes, IMes catalyzes the
formation of vinyl ethers through the 1,4-addition of alcohols to
ynones and promotes tandem conjugate addition/Michael cas-
cade reactions. Preliminary data support a Brønsted base mech-
anism with the free carbene.
independently demonstrated that NHCs catalyze transesterification
reactions,9 but new processes that capitalize on this Brønsted base
characteristic of NHCs remain limited. In this Communication, we
report an efficient carbene-catalyzed intermolecular conjugate
addition of alcohols to activated alkenes.
We began our investigation with 5 mol % loading of azolium
salt A (IMes ·HCl) and then surveyed different bases in a 1:1 ratio
relative to A.10 Aryl ketone 1 was employed as the conjugate
acceptor, with benzyl alcohol as the nucleophile in toluene. A weak
base such as triethylamine provided no product (entry 1), but
KHMDS generated a 70% yield (GC) of ꢀ-benzyloxy ketone (2,
entry 2). Employing NaH led to a decrease in yield, but n-BuLi in
combination with A led to a measurable increase in reaction
efficiency (88%). To probe the impact of lithium counterion further,
The carbon-oxygen bond is a key component of biologically
active compounds. Classical synthetic approaches to these prevalent
linkages include substitution reactions employing a highly nucleo-
philic alkoxide (e.g., Williamson ether synthesis).1 The direct
formation of these bonds through intermolecular 1,4-addition of
alcohols to conjugate acceptors is a logical approach but remains
challenging due to potential oligomerization of the acceptor and
the inherent energetic aspects of this process.2 A catalytic approach
to this important structural motif (a) is desirable due to the reduction
of potential waste and (b) opens possibilities to control the overall
stereochemistry by means other than traditional approaches. While
the addition of metal alkoxides (generated with a full equivalent
of base) to related nitroalkenes has been successful,3 the catalytic
addition of alcohols to R,ꢀ-unsaturated ketones in a bimolecular
process is much more unusual.4
the addition of 1 equiv of 12-crown-4 was accompanied with an
observed decrease in yield (74%). Based on this result, 1 equiv of
LiCl was added (entry 6), which resulted in a 95% yield of the
desired ꢀ-alkoxy ketone (2).11
Table 1. Conjugate Addition Optimizationa
entry
base
additive
GC yield (%)c
1
2
3
4
5
6
Et3N
KHMDS
NaH
NR
70
60
88
74
95
n-BuLib
n-BuLib
n-BuLib
12-crown-4
LiCl (1 equiv)
Scheme 1. NHC-Catalyzed Conjugate Additions
a Reactions run on 0.4 mmol scale. b A and base were combined in
THF at -78 °C and warmed to 20 °C. THF was then removed under
vacuum. c Determined by gas chromatography with dodecane as an
internal standard.
With efficient reaction conditions in hand, we surveyed a variety
of alcohols in combination with ketone 1. A variety of primary
and secondary alcohols are competent nucleophiles in this carbene-
catalyzed reaction. The addition of allyl alcohol affords the product
in excellent yield. p-Methoxybenzyl alcohol and 2-(trimethylsi-
lyl)ethanol were also well tolerated. Addition of the N-BOC serine
tert-butyl ester at the hydroxyl group is successful in the presence
of the carbamate (entry 8). Addition of the secondary alcohol
1-(naphthalen-1-yl)ethanol to the parent enone is successful (75%
yield) but with no diastereoselectivity observed to date. To date,
tertiary alcohols are not competent nucleophiles under the current
conditions.
Verkade has shown that proazaphosphatranes promote this
transformation, and Toste and Bergman have reported a mechanisti-
cally intriguing phosphine-catalyzed hydroalkoxylation of simple
activated olefins.5 A broader scope for this process with the
possibility of stereocontrol and/or chemoselectivity would allow
for direct and catalytic access to a wide variety of useful ꢀ-alkoxy
carbonyl compounds. Recently, N-heterocyclic carbenes (NHCs)
have emerged as powerful Lewis bases, and our program in this
area continues to explore new possibilities with these highly
versatile catalysts.6,7 While the Lewis basic properties of NHCs
are firmly established, their potential as Brønsted base catalysts is
We then set out to determine the substrate scope with respect to
conjugate acceptors (Table 3). Replacing the phenyl ring on the
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J. AM. CHEM. SOC. 2010, 132, 13179–13181 13179

C O M M U N I C A T I O N S
Table 2. Alcohol Addition Scope
with selectivity favoring one olefin geometry would be a useful
transformation.12 Gratifyingly, benzyl alcohol underwent 1,4-
addition to ynone 18 in good yield and excellent selectivity (eq 1).
Further exploration found that the initial conjugate addition of
alcohol 20 can be coupled to an intramolecular Michael reaction
to generate tetrahydropyran 21 with excellent diastereoselectivity
(eq 2).
Our current understanding of this reaction is illustrated in Scheme
2. While NHCs are known to undergo additions to activated alkenes
via a conjugate addition manifold,13 we currently favor a Brønsted
base-catalyzed process. Consideration of previous work by Movas-
saghi14 in combination with our own studies prompted us to invoke
an NHC-alcohol complex as a key intermediate (I, Scheme 2).15
This complex facilitates the 1,4-addition of the alcohol to the
conjugate acceptor, generating an imidazolium ion and the corre-
sponding enolate (II), presumably stabilized by the addition of a
lithium counterion. Subsequent protonation of the enolate affords
the ꢀ-alkoxy ketone and regenerates the NHC.16,17 In contrast to
reactions performed under anionic conditions, these mild conditions
attenuate unwanted side reactions such as oligomerization of the
enone or aldol condensations at ambient temperature.18
a See Supporting Information for details. b Isolated yields. c CH2Cl2
used as solvent. 1.2:1 dr (determined by H NMR spectroscopy).
d
1
ketone with a more electron-deficient aryl ring provided the desired
alcohol in good yield (73%, entry 1). Alkyl ketones are also
accommodated under the reaction conditions (entry 2), as are highly
reactive conjugate acceptors such as methyl vinyl ketone (entry
3). This particular example underscores the unusual and useful
aspects of this reaction, given that no polymerization is observed
with this highly reactive conjugate acceptor. Additions to esters
also proceed in moderate yield, but substrates with aryl substituents
in the ꢀ-position do not afford desired products (not shown). Based
on this profile, a differentially substituted divinyl ketone was
subjected to the reaction conditions and provided a regioselective
addition in 82% yield (entry 6). Cyclohexenone and cyclopentenone
provided ∼50% conversion under the reaction conditions (not
shown). The differential reactivity exhibited by acyclic and cyclic
substrates is currently under investigation.
Scheme 2. Proposed Pathway
Table 3. Survey of Conjugate Acceptorsa
An enantioselective version of this reaction would be useful but
is challenging, given the control of the stereochemistry and potential
reversibility. To date, all studies with intermolecular variants of
this process with chiral NHC catalysts have afforded racemic
products. However, we then surveyed a variety of azolium
precatalysts (A-C) with a substrate capable of intramolecular
cyclization (22). While all the yields for this reaction are high
(>85%), reaction with azolium B19 produces a modest, but
reproducible, 10-11% ee at -30 °C for this NHC-catalyzed
conjugate addition (eq 3).20 Reducing the reaction temperature to
-78 °C provided much lower levels of conversion and did not
improve the enantioselectivity of the process. While this observed
selectivity is not synthetically practical yet, these results do support
a pathway involving the NHC-alcohol complex depicted in Scheme
2. Further exploration and development of this catalytic asymmetric
conjugate addition is underway.
a See Supporting Information for reaction details. b Isolated yields.
With the reaction components of this reaction initially charted,
we sought to capitalize on the unusual aspects of this NHC-alcohol
combination and expand the scope beyond general enones. The
addition of alcohols to ꢀ-substituted ynones to generate vinyl ethers
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C O M M U N I C A T I O N S
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In summary, we have discovered a novel conjugate addition of
alcohols that demonstrates carbenes as efficient Brønsted base
catalysts. A free carbene with the addition of lithium chloride allows
for the addition of alcohols to enones in good to excellent yields at
ambient temperature and with no oligomerization of the substrates.
This new carbene-alcohol combination does not require stoichio-
metric amounts of strong base and also extends beyond additions
to enones. The formation of vinyl ethers is possible through the
1,4-addition of alcohols to ynones, and a tandem conjugate addition/
Michael reaction occurs to generate a tetrahydropyran with good
selectivity. Studies directed toward enhancing asymmetric induction
and exploring further the mechanism are currently ongoing. This
particular development of N-heterocyclic carbenes as efficient and
unusual Brønsted base catalysts creates new opportunities for future
direct bond-forming processes.
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(10) Additional imidazolium and triazolium salts were evaluated as catalysts
but provided lower yields of 2 than IMes · HCl (A).
(11) More LiCl did not improve the yield. One equivalent of LiCl without the
free NHC or azolium salt resulted in no conjugate addition reaction. The
combination of 5 mol % n-BuLi with BnOH in toluene followed by the
addition of 1 afforded <30% of desired product 2, as observed by GC,
along with multiple additional peaks compared to the NHC-catalyzed
process.
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D.; Santos-Exposito, A.; Mendez-Abt, G.; Ruiz-Perez, C.; Garcia-Tellado,
F. Synlett 2009, 8, 1223–1226, and references cited therein.
(13) (a) Fischer, C.; Smith, S. W.; Powell, D. A.; Fu, G. C. J. Am. Chem. Soc.
2006, 128, 1472–1473. (b) He, L.; Jian, T. Y.; Ye, S. J. Org. Chem. 2007,
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(14) Movassaghi, M.; Schmidt, M. A. Org. Lett. 2005, 7, 2453–2456.
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derived from IMes is a competent Brønsted base:
Acknowledgment. This work was supported by NIGMS
(GM73072-01 and P50 GM086145-01), AstraZeneca, Amgen, and
GlaxoSmithKline. E.M.P. thanks the ACS Division of Organic
Chemistry for a fellowship sponsored by Organic Reactions
(2008-2009). Funding for the NU Integrated Molecular Structure
Education and Research Center (IMSERC) has been furnished in
part by the NSF (CHE-9871268). We thank Sigma-Aldrich and
FMCLithium for generously providing reagents and Prof. Dean
Tantillo (University of California, Davis) for helpful discussions.
Supporting Information Available: Experimental procedures and
spectral data for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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