Conversion of α,β-unsaturated aldehydes into saturated esters: An umpolung reaction catalyzed by nucleophilic carbenes

Article abstract of DOI:10.1021/ol050100f

(Chemical Equation Presented) N-Heterocyclic carbenes derived from benzimidazolium salts are effective catalysts for generating homoenolate species from α,β-unsaturated aldehydes. These nucleophilic intermediates can be protonated, and the resulting activated carbonyl unit is trapped with an alcohol nucleophile, thereby promoting a highly efficient conversion of an α,β-unsaturated aldehyde into a saturated ester. A kinetic resolution of secondary alcohols can be achieved using chiral imidazoylidene catalysts.

Full text of DOI:10.1021/ol050100f

ORGANIC
LETTERS
2005
Vol. 7, No. 5
905-908
Conversion of
r,â-Unsaturated
Aldehydes into Saturated Esters:
An Umpolung Reaction Catalyzed by
Nucleophilic Carbenes
Audrey Chan and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, EVanston, Illinois 60208
scheidt@northwestern.edu
Received January 18, 2005
ABSTRACT
N-Heterocyclic carbenes derived from benzimidazolium salts are effective catalysts for generating homoenolate species from
aldehydes. These nucleophilic intermediates can be protonated, and the resulting activated carbonyl unit is trapped with an alcohol nucleophile,
thereby promoting a highly efficient conversion of an -unsaturated aldehyde into a saturated ester. A kinetic resolution of secondary
r,â-unsaturated
r,â
alcohols can be achieved using chiral imidazoylidene catalysts.
The inversion of standard functional group polarity, or
Umpolung, is a powerful strategy in chemistry that facilitates
the construction of organic molecules in unusual ways.1
Established catalytic reactions that employ this unorthodox
strategy include the benzoin2 and Stetter3 reactions in which
carbonyl units of aldehydes are converted into nucleophiles
upon the addition of a nucleophilic catalyst. Although the
development of these carbonyl anion reactions has received
significant attention, a related strategy to access catalytic
“vinylogous” carbonyl anions has received considerably less
attention.4 As part of our efforts focused on the development
of new nucleophile-catalyzed processes,5 we envisioned that
under appropriate organocatalytic conditions, R,â-unsaturated
aldehydes could be converted into unique homoenolate
nucleophiles with subsequent electrophilic characteristics at
the carbonyl carbon.6 Herein, we report the conversion of
R,â-unsaturated aldehydes into homoenolates catalyzed by
nucleophilic carbenes generated from ammonium salts A-C
(eq 1).
(1) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239-258.
(b) Eisch, J. J. J. Organomet. Chem. 1995, 500, 101-115. (c) Pohl, M.;
Lingen, B.; Muller, M. Chem. Eur. J. 2002, 8, 5289-5295.
(2) Hassner, A. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 1, pp 541-577.
(3) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407-496.
(4) For a review, see: Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004,
37, 534-541.
(5) (a) Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem.
Soc. 2004, 126, 2314-2315. (b) Mattson, A. E.; Scheidt, K. A. Org. Lett.
2004, 6, 4363-4366. (c) A. E.; Bharadwaj, A. R.; Scheidt, K. A Org. Lett.
2004, 6, 2465-2468. (d) Clark, C. T.; Lake, J. F.; Scheidt, K. A. J. Am.
Chem. Soc. 2004, 126, 84-85.
Homoenolates are important nucleophiles that are es-
sentially the Umpolung equivalent of conjugate addition
reactions (Scheme 1).7 Although this uncommon reactivity
(6) (a) List, B. Synlett 2001, 1675-1686. (b) Dalko, P. I.; Moisan, L.
Angew. Chem., Int. Ed. 2004, 43, 5138-5175 and references therein.
10.1021/ol050100f CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/04/2005

should produce enol IV. After tautomerization of IV to
activated ester V, the attack of a suitable nucleophile
completes the catalytic cycle.10,11
Scheme 1. General Umpolung Strategy
We began our investigations of this intriguing strategy by
employing the simplest electrophile, a proton (Table 1). The
Table 1. Investigation of Homoenolate Reactivitya
pattern has significant utility in organic synthesis, establishing
the requisite nucleophilic character at the â-position of a
carbonyl compound is challenging.
Inspired by the proposed catalytic cycle for the thiazolium-
catalyzed benzoin reaction,8 we hypothesized that the exten-
sion of carbonyl anion reactivity to a â-position could be
achieved by use of an alkene in the form of R,â-unsaturation
(Scheme 2). The addition of a nucleophilic carbene catalyst9
entry
ROHb
catalyst (mol %)
additivec
yield (%)
1
2
3
4
5
EtOH
PhOH
BnOH
BnOH
BnOH
A (30 mol %)
A (30 mol %)
B (10 mol %)
C (20 mol %)
C (5 mol %)
57 (2)
55 (3)
47 (4)
82 (4)
82 (4)
PhOH
PhOH
PhOH
a Reactions performed with a 1:1 molar ratio of catalyst to DBU at reflux
temperature. b Performed with 5 equiv of nuclephilic alcohol. c Performed
with 2 equiv of proton additive.
Scheme 2. Proposed Mechanism to Generate Homoenolate
Equivalents from R,â-Unsaturated Aldehydes
use of the optimal alcohol would presumably serve a double
purpose as the electrophile source and subsequent nucleo-
phile. To probe this possibility, cinnamaldehyde (1) and
various alcohols were heated in toluene in the presence of
catalytic quantities of ammonium salts A-C and DBU. With
ethanol and ammonium salt A, we were pleased to isolate
the desired ester (57%), but clearly the system required
improvement. Initially, we pursued a moderate-yielding
approach that utilized a single reagent as the potential proton
donor and subsequent nucleophile required for catalyst
turnover (entries 1 and 2).
Fortuitously, while using PhOH as the alcohol in chloro-
form subjected to Al2O3 filtration, but not distillation, a
substantial amount of ethyl ester was observed. Our initial
hypothesis for this result was that the putative activated
acylation agent (i.e., V) was being trapped by the ethanol
typically added to stabilize chloroform (not shown). Armed
with the knowledge that the electrophile and nucleophile can
be decoupled in this manner, we discovered that the use of
imidazolium salt C (5 mol %) with phenol as the proton
source and a second alcohol as the nucleophile affords the
best yields for the reaction. This process is noteworthy since
no self-condensation (benzoin) products are observed, and
combinations of acids and bases in the reaction still generate
effective concentrations of catalyst I. The combination of
DBU and imidazolium salts in the presence of phenolic
functionality seems to be uniquely suited for this reaction.
Encouraged by these interesting results, we proceeded to
examine the ability of other alcohols to act as nucleophiles
to the carbonyl compound should generate tetrahedral
intermediate II, and subsequent hydrogen migration would
generate the reactive dienamine III. The normal nucleophilic
character of the carbonyl carbon is then extended to the
â-position and, in the presence of an electrophile (E-X),
(7) For reviews on homoenolate equivalents, see: (a) Hoppe, D.;
Kraemer, T.; Schwark, J.; Zschage, O. Pure Appl. Chem. 1990, 62, 1999-
2006. (b) Ahlbrecht, H.; Beyer, U. Synthesis 1999, 365-390. For recent
examples, see: Seppi, M.; Kalkofen, R.; Reupohl, J.; Frohlich, R.; Hoppe,
D. Angew. Chem., Int. Ed. 2004, 43, 1423-1427. (c) Reuber, J.; Frohlich,
R.; Hoppe, D. Org. Lett. 2004, 6, 783-786. (d) Hilgenkamp, R.; Zercher,
C. K. Org. Lett. 2001, 3, 3037-3040. (e) Whisler, M. C.; Beak, P. J. Org.
Chem. 2002, 68, 1207-1215.
(8) (a) Breslow, R.; Schmuck, C. Tetrahedron Lett. 1996, 37, 8241-
8242. (b) White, M. J.; Leeper, F. J. J. Org. Chem. 2001, 66, 5124-5131.
(9) (a) Bourissou, D.; Guerret, O.; Gabbai, F. P.; Bertrand, G. Chem.
ReV. 2000, 100, 39-91. (b) Herrmann, W. A. Angew. Chem., Int. Ed. 2002,
41, 1291-1309.
(10) Similar activated esters have been implicated in the reactions
between N-heterocyclic carbenes and R-halo aldehydes (Reynolds, N. T.;
de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 9518-9519) or
epoxy-aldehydes (Chow, K. Y. K.; Bode, J. W. J. Am. Chem. Soc. 2004,
126, 8126-8127).
(11) For recent and related approaches accessing homoenolates from R,â-
unsaturated aldehydes for the synthesis of γ-butyrolactones, see: (a) Sohn,
S. S.; Rosen, J. W.; Bode, J. J. Am. Chem. Soc. 2004, 126, 14370-14371.
(b) Glorius, F., Burstein, C. Angew. Chem., Int. Ed. 2004, 43, 6205-6208.
906
Org. Lett., Vol. 7, No. 5, 2005

The overall reaction can successfully accommodate various
R,â-unsaturated aldehyde structures (Table 3). Electron-rich
Table 2. Examination of Nucleophiles in Homoenolate
Reactiona
Table 3. Survey of R,â-Unsaturated Aldehydesa
a Reactions performed at 0.5 M at 100 °C. b Performed with 5 equiv of
ROH.
in the presence of a Brønsted acid such as phenol (Table 2).
Primary and secondary alcohols afford good to high yields
of the corresponding esters when using cinnamaldehyde (1).
Not surprisingly, the use of sterically demanding tert-butyl
alcohol only afforded phenyl ester (56% yield, not shown).
The generation of the phenyl ester is the default product
observed when the potential nucleophile does not undergo
addition. Usually with standard alcohols, this competition
is not problematic. When chiral secondary alcohols are
employed, the carbon stereocenter remains intact (entries 5
and 6).
a Performed with 5 equiv of PhCH2OH. See Supporting Information for
general experimental details.
The use of typical nitrogen-based nucleophiles in this
general tranformation such as sulfonamides, amides, azide,
and anilines did not afford desired products. The results from
this intense reaction screening underscore the crucial, and
currently not well undestood, balance of acids and bases
present in this process. However, during the examination of
many of these potential nucelophiles, we did identify that
â-amino alkylidene malonate 8 affords a modest yield of
the corresponding bis-ester amide product (Scheme 3). The
or electron-deficient cinnamaldehydes are good substrates
for the reaction (entries 2 and 3). The use of unbranched
â-alkyl substituents affords fully saturated esters in good
yield (entry 4). Interestingly, the extended dienylic system
of sorbaldehyde is disrupted in the reaction to afford the γ,δ-
unsaturated ester in moderate yield (entry 5).
Disubstitution at the â-positions of unsaturated aldehydes
leads to divergent reactivity depending on the substituents.
For example, aldehydes with at least one â-aryl substituent
are competent substrates (entries 6-8), but surprisingly, â,â-
dialkyl compounds afford no product (entry 9). Efforts are
currently underway to understand this differing reactivity.
Although phenols have the best level of acidity for this
Umpolung process to date, various amounts of phenyl ester
can be observed when employing sterically demanding
alcohol nucleophiles such as cyclohexanol when just phenol
is used as the proton source. This competition between
phenol or hindered secondary alcohols as the nucelophile
prompted us to examine more hindered proton donors with
Scheme 3
success and application of this unusual class of nitrogen-
delivering nucleophile is currently being investigated in the
context of this reaction.
Org. Lett., Vol. 7, No. 5, 2005
907

Scheme 4
Table 4. Impact of Phenol Structure on Homoenolate
Reactiona
cycle of this reaction such as VII has sufficient facial
selectivity to undergo preferential reaction with the (R)-
stereoisomer of 1-phenylethanol.
a Reactions performed at 0.5 M at 100 °C with 5 equiv of cyclohexanol.
In summary, the combination of R,â-unsaturated aldehydes
and N-heterocyclic carbenes accesses unusual homoenolate
reactivity under catalytic conditions. These unique nucleo-
philic species possess subsequent electrophilic character at
the carbonyl carbon that can be trapped by a secondary
nucleophile such as an alcohol. The combination of a proton
donor and a separate nucleophile affords the highest yields
of the resulting saturated esters. The use of a chiral
imidazoylidene carbene as a catalyst in the reaction allows
for the kinetic resolution of chiral secondary alcohols, thereby
implicating a chiral activated ester as an intermediate in this
process. Further investigations and applications of these
unusual homoenolate species are being actively pursued in
our laboratory and will be reported in due course.
similar levels of acidity (Table 4, eq 4). By additional
substitution at the 2- and 6-positions of the phenol archi-
tecture, the generation of phenyl ester 17 can be minimized
in the reaction of 5 mol % catalyst C and DBU with
cinnamaldehdye (1). By increasing the size of the substituents
from 2,6-dimethylphenol (entry 2) to 2,6-di-tert-butyl-4-
methylphenol (entry 3), the level of phenyl ester can be
suppressed completely.
We hypothesized that the use of a chiral imidazolium
would generate chiral activated esters capable of enantio-
discrimination. This transformation would be synthetically
useful in the organocatalytic kinetic resolution of secondary
alcohols while also lending credence to the participation of
V (Scheme 4) as a viable intermediate along the catalytic
cycle. To probe this possibility, chiral imidazolium salt D12
was employed as the catalyst in the reaction of racemic
1-phenylethanol (18) and cinnamaldehyde (Scheme 3).
Gratifyingly, the average s factor for this transformation at
40% conversion is 4.8 when using D as the catalyst.13
Presumably, a chiral intermediate present in the catalytic
Acknowledgment. This work has been supported by
Northwestern University, the NSF (CAREER Award), and
a New Faculty Award from Amgen. We thank Ms. Anita
Mattson and Mr. Christopher Graves (NU) for assistance with
preparing this manuscript. A.C. thanks Dow Chemical
Company for a graduate fellowship.
(12) For the synthesis of D, see: (a) Rivas, F. M.; Giessert, A. J.; Diver,
S. T. J. Org. Chem. 2002, 67, 1708-1711. (b) Rivas, F. M.; Riaz, U.;
Giessert, A.; Smulik, J. A.; Diver, S. T. Org. Lett. 2001, 3, 2673-2676.
(13) For information on selectivity factors (s) in kinetic resolutions,
see: (a) Kagan, H. B.; Fiaud, J. C. In Topics in Stereochemistry; Eliel, E.
L., Ed.; Wiley: New York, 1988; Vol. 18, pp 249-330. (b) Chen, C. S.;
Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294-
7299. See Supporting Information for details.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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Org. Lett., Vol. 7, No. 5, 2005