Protonation of homoenolate equivalents generated by N-heterocyclic carbenes

Article abstract of DOI:10.1055/s-2008-1072516

Homoenolate equivalents are generated by Lewis basic N-heterocyclic carbene catalysts and then protonated to generate efficiently saturated esters from unsaturated aldehydes. This reactivity is extended to the generation of β-acylvinyl anions from alkynyl aldehydes. The asymmetric protonation of a homoenolate equivalent generated from a β,β-disubstituted aldehyde can be accomplished with a chiral N-heterocyclic carbene. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072516

1306
FEATURE ARTICLE
Protonation of Homoenolate Equivalents Generated by N-Heterocyclic
Carbenes
Protonation of
N
H
r
C
-Gene
o
rate
d
H
omo
o
enolate Equi
k
valents s E. Maki, Audrey Chan, Karl A. Scheidt*
Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, USA
Fax +1(847)4672184; E-mail: scheidt@northwestern.edu
Received 22 February 2008
benes (NHCs) have attracted a growing interest as cata-
Abstract: Homoenolate equivalents are generated by Lewis basic
N-heterocyclic carbene catalysts and then protonated to generate ef-
ficiently saturated esters from unsaturated aldehydes. This reactivi-
ty is extended to the generation of b-acylvinyl anions from alkynyl
lysts or reagents for an expanding set of reactions.4–6 This
unique class of Lewis basic catalyst7 has long been known
to catalyze the benzoin8,9 and Stetter10,11 reactions by con-
aldehydes. The asymmetric protonation of a homoenolate equiva- verting an electrophilic carbonyl functional group, such as
an aldehyde,12–14 a-keto acid,15,16 or acylsilane,17–19 into
lent generated from a b,b-disubstituted aldehyde can be accom-
plished with a chiral N-heterocyclic carbene.
nucleophilic acyl anion equivalents.
Key words: carbenes, umpolung, protonations, asymmetric cataly-
In a key study reported in 1958,9 Breslow proposed that
sis, esters
the intermediate in the thiazolium-catalyzed benzoin reac-
tion was an unusually substituted alkene A (Scheme 1) re-
sulting from the addition of the azolium to the aldehyde.
After proton migration, what was the carbonyl carbon of
this neutral species is rendered nucleophilic. Our hypo-
thesis in 2004 was that this electron density could be
transported to a distal position by virtue of unsaturation
(i.e., an alkene or alkyne).20 If successful, this would gen-
erate a homoenolate B (Scheme 1) or b-acylvinyl anion
reactivity pattern, respectively. Since that time, it has been
shown that these unusual nucleophiles can react with a va-
riety of electrophiles.21–30
Introduction
The discovery and understanding of unconventional reac-
tivity patterns for the construction of organic molecules is
an important goal. These advances can greatly facilitate
the rapid access to a wide range of molecular targets. Re-
search to promote or catalyze the reversal of a functional
group’s polarity, known as umpolung,1–3 has undergone a
renaissance, and can provide unusual routes to desirable
compounds. Over the last decade, N-heterocyclic car-
OH
O
O
O
S
E
NHC
R1
δ–
R1
H
R1
R1
E
N
R2
A
Breslow intermediate
HYPOTHESIS:
extend electron density
R2
OH
R3
R2
O
R3
R3
R2
O
NHC
N
N
R1
R1
δ–
Z
Z
R1
H
N
N
R3
B
homoenolate equivalent
R4OH, H
R2
O
π-bond reduced
H
R1
aldehyde oxidized
OR4
Scheme 1 Homoenolate generation and protonation with NHC catalysis
SYNTHESIS 2008, No. 8, pp 1306–1315
x
x
.
x
x
.2
0
0
8
Advanced online publication: 18.03.2008
DOI: 10.1055/s-2008-1072516; Art ID: E20908SS
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Protonation of NHC-Generated Homoenolate Equivalents
1307
Here we describe the development of our first NHC-cata- likely deprotonating the conjugate acid of the base gener-
lyzed process, namely the protonation of homoenolate ated through deprotonation of the carbene precursor (in
equivalents. This protonation accomplishes an internal re- this case DBU, pKa = 13.9 in DMSO).34 The optimal con-
dox reaction, wherein the carbon–carbon p-bond of an ditions for this reaction demonstrate an important balance
a,b-unsaturated aldehyde is reduced and the carbonyl is of the ability to generate the NHC catalyst through depro-
oxidized to yield a saturated ester. To further our initial tonation of the benzimidazolium salt (pKa = 18.6 in
examination of this interesting reactivity pattern, our ef- DMSO)35 and the acidity needed to protonate the homo-
forts to render this protonation enantioselective are also enolate equivalent.
described.
Separate reports by Glorius and co-workers and Bode and
co-workers in 2004 described the dimerization of alde-
hydes in the presence of NHCs through homoenolate
Homoenolate Equivalents Generated by N-Hetero-
cyclic Carbenes (NHCs)
addition to form g-butyrolactones.21,22 Under our homo-
enolate protonation conditions, none of these undesired
products are observed, and formation of the saturated es-
Our investigation of this reactivity began with the proto-
ter is the dominant reaction pathway. Variation of the nu-
nation of the homoenolate equivalent obtained from
cleophilic alcohol allows practical access to a variety of
cinnamaldehyde31 catalyzed by the carbene derived from
esters (Table 1). Primary, secondary, and aromatic alco-
hols are all competent nucleophiles in the NHC-catalyzed
benzimidazolium salt 1 (Table 1). Although unnecessary
for the generation of the protonated product,32 higher
reaction. Not surprisingly, stereochemical information is
yields were observed with the addition of a Brønsted acid,
preserved in the case when a chiral secondary alcohol is
such as phenol (pKa = 18.0 in DMSO),33 as an additional
used as the nucleophile to form the ester product 6
proton source in conjunction with a nucleophilic alcohol
(Table 1, entry 5).
to form the ester and regenerate the carbene catalyst. Al-
Several unsaturated aldehydes are also functional sub-
though phenol is ostensibly the proton source, it is inter-
strates in this reaction, and a variety of benzyl esters can
esting to note that the homoenolate equivalent is most
Biographical Sketches
Brooks Maki received a ate research, at Northwest- ate studies have been funded
Bachelor of Arts degree in ern University under the in part by a GAANN fellow-
chemistry and mathematics direction of K. A. Scheidt, is ship from the U.S. Depart-
from Gustavus Adolphus focused on NHC-catalyzed ment of Education.
College in 2004. His gradu- redox reactions. His gradu-
Audrey Chan obtained her Her graduate research is di- enolate aminations, and
degree in chemistry from rected toward the discovery carbene-catalyzed hydro-
Cornell University in 2002. of new NHC-catalyzed re- acylations. She is currently
After working at Merck, actions, including homo- the Dow Chemical Compa-
Rahway under Dr. Sheryl enolate protonation, homo- ny fellow at Northwestern.
Devenham, she joined the enolate annulations with
Scheidt laboratory in 2003. azomethine imines, homo-
Professor Karl Scheidt joined the faculty of North- Foundation Fellow and No-
obtained his Ph.D. with western University (Evan- vartis Lecturer as well as the
William Roush from Indi- ston, IL, USA) in 2002. His recipient of awards from
ana University in 1999. Af- research focuses on the de- Abbott Laboratories, Amgen,
ter an NIH postdoctoral velopment of new organic AstraZeneca, Boehringer-
fellowship under the direc- methodology and the syn- Ingelheim,
tion of David A. Evans thesis of bioactive mole- Kline, and 3M.
(Harvard University), he cules. He is a recent Sloan
GlaxoSmith-
Synthesis 2008, No. 8, 1306–1315 © Thieme Stuttgart · New York

1308
B. E. Maki et al.
FEATURE ARTICLE
Table 1 Internal Redox Leading to Saturated Estersa
tures and longer reactions times (2 days) are required.
Notably, b,b-disubstituted unsaturated aldehydes
(Table 2, entries 5, 6) are also capable of being protonated
under these conditions, which provides a natural inspira-
tion for asymmetric variants of this reaction (vide infra).
Me
1
N
I
(5 mol%)
N
Me
A plausible pathway for this reaction is to proceed first by
the addition of the carbene to the carbonyl of the unsatur-
ated aldehyde system (Scheme 2). After intermolecular
proton transfer, the homoenolate equivalent III is formed.
The b-position, which is now nucleophilic by virtue of be-
ing electronically coupled to the benzimidazole ring sys-
tem, is protonated, most likely by the conjugate acid of the
base (DBU). Tautomerization produces an acyl-azolium
intermediate IV, which acts as an acylating agent for the
nucleophilic alcohol within the reaction. This acylation
gives the ester product and regenerates the carbene cata-
lyst. The proton from the acylated alcohol regenerates the
protonated base, which is then available to protonate an-
other homoenolate equivalent.
O
H
O
PhOH (2 equiv)
+
ROH
DBU, toluene
100 °C
Ph
H
Ph
OR
2–6
Entry
1
Product
Yieldb (%)
72
O
2
3
Ph
Ph
O
O
Me
Ph
2
3
82
57
O
O
4
Ph
O
O
Evidence for the acyl-azolium intermediate IV as the acy-
lating agent is provided through the kinetic resolution of
racemic 1-phenylethanol (Scheme 3). The chiral benzim-
idazolium salt 12 first described by Diver et al.36 creates a
chiral acylating agent similar to intermediate IV. Selec-
tive acylation of one enantiomer of the secondary alcohol
is accomplished, resulting in an s factor of 4.8 at 40% con-
version.31 This selective reactivity induced by the use of a
chiral NHC demonstrates the ability of these catalysts to
create a chiral environment in their reactions with alde-
hydes.
4
5
5
6
56
77
Ph
Ph
O
O
Me
O
Ph
a Reaction conditions: 1 (0.04 mmol), DBU (0.04 mmol), cinnamal-
dehyde (0.79 mmol), PhOH (1.6 mmol), ROH (4.0 mmol), toluene
(1.6 mmol), 100 °C, 2–6 h.
b Isolated yields.
be synthesized by this method (Table 2). Unsaturated al-
dehydes with alkyl or electron-rich aryl substituents suc-
cessfully undergo the protonation/acylation sequence.
Despite concerns about steric interactions of substituents
in the a-position of the aldehyde with the NHC catalyst
upon addition to the carbonyl, no significant decrease in
yield is observed when an a-substituted aldehyde is em-
ployed (Table 2, entry 3). However, elevated tempera-
Generation of b-Acylvinyl Anions
Through a similar pathway, the partial reduction of a triple
bond can be conceived. Investigations into this internal re-
dox reaction were carried out by the generation of b-
R2
O
Me
R2
O
N
R1
OR3
R1
H
N
R3OH
Me
I
R2
O
Me
H
R1
R2
O
Me
N
II
N
R1
N
H
IV
Me
N
Me
B
H
R2
OH
III
R1
R2
OH
Me
Me
N
R1
N
N
N
Me
Me
Scheme 2 Reaction pathway for homoenolate protonation
Synthesis 2008, No. 8, 1306–1315 © Thieme Stuttgart · New York

FEATURE ARTICLE
Protonation of NHC-Generated Homoenolate Equivalents
1309
Table 2 Reaction of Various Aldehydes with Benzyl Alcohola
1 (5 mol%)
PhOH (2 equiv)
R2
O
R2
O
H
R1
+
BnOH
R1
H
DBU, toluene
100 °C
OBn
Entry
1
Aldehyde
Product
Yield (%)
82
O
O
3
7
Ph
H
Ph
OBn
O
O
2
76
OBn
H
MeO
Me
MeO
Me
O
O
3
4
5
8
9
90
H
OBn
O
O
O
O
82b
86
Ph
Me
Ph
H
Ph
OBn
Me
Ph
10
Ph
OBn
Ph
Ph
H
O
Ph
O
6
11
82
OBn
H
Cl
Cl
a Reaction conditions: 1 (0.04 mmol), DBU (0.04 mmol), cinnamaldehyde (0.79 mmol), PhOH (1.6 mmol), BnOH (4.0 mmol), toluene (1.6
mmol), 100 °C, 2–6 h.
b 100 °C, 2 d.
O
Me
12 (5 mol%)
DBU (5 mol%)
Ph
H
Ph
OH
O
+
+
PhOH, toluene
s = 4.8
Me
O
Me
6
( )
@ 40% conversion
Ph
OH
Ph
Ph
Me
N
Ph
Me
H
O
I
H
H
N
N
C
RCHO
DBU
Ph
H
N
H
Me
Me
12
Ph
selective
acylating agent
Scheme 3 Kinetic resolution of 1-phenylethanol
acylvinyl anions through the reaction of NHC catalysts through judicious choice of catalyst precursor. In the pres-
with alk-2-ynals. In this manner, alk-2-ynals can be con- ence of 2,6-di-tert-butyl-4-methylphenol (BHT), with
verted into a,b-unsaturated esters (Table 3), compounds 1,8-diazabicyclo[5.4.0]undec-7-ene as the base, the benz-
that hold further potential for functionalization through imidazolium salt 1 employed in the initial investigations
conjugate addition or other synthetic manipulations. Ex- of this reactivity gives a mixture of isomers (Table 3, en-
periments in our laboratories demonstrated this reactivity tries 1, 3, 5) at 100 °C, while the imidazolium salt, 1,3-
to be feasible, although limited to aryl substrates or alk-2- bis(2,4,6-trimethylphenyl)imidazolium chloride (IMes,
ynals with no enolizable protons (Table 3). These results 13] catalyzes the reaction at lower temperatures (45 °C)
are congruous with those reported in 2005 by Zeitler.37 than previously observed by Zeitler, and selectively af-
Control over the double bond stereochemistry is possible fords the E-isomer (Table 3, entries 2, 4). This marked
Synthesis 2008, No. 8, 1306–1315 © Thieme Stuttgart · New York

1310
B. E. Maki et al.
FEATURE ARTICLE
Table 3 Protonation of b-Acylvinyl Anionsa
1 or 13 (5 mol%)
O
H
O
R
O
BHT (2 equiv)
BnOH
+
+
R
DBU, toluene
R
OBn
H
OBn
H
Me
Mes
N
N
N
I
Cl
N
Me
Mes
1
13
Entry
Aldehyde
Catalyst
Yieldb (%)
Ratioc E/Z
O
H
1
2
1
13
65
67
3:1
>20:1
O
H
3
4
1
13
56
59
3:1
>20:1
Cl
O
5
6
1
1
10
0
4:1
–
MeO
H
O
H
TBSO
a Reaction conditions: step 1: 1 or 13 (0.04 mmol), DBU (0.04 mmol), toluene, 23 °C, 10 min, step 2: addition of aldehyde (0.43 mmol), BHT
(0.85 mmol), BnOH (2.2 mmol), 100 °C (for 1) or 45 °C (for 13), 12–36 h.
b Isolated yields.
c Determined by 500 MHz 1H NMR spectroscopy.
difference in reactivity and selectivity underscores the sources (e.g., BINOL48 or TADDOL49) were not selective
profound effect that subtle changes to the balance of acids when combined with an achiral catalyst such as IMes (13)
and bases can have in this catalytic system [the pKa of im- or 1. Thus, our attempts to render this protonation of
idazolium salts similar to IMes (13) have been determined NHC-generated homoenolates stereoselective turned to
through theoretical calculations to be ~17.0 in DMSO].38
chiral NHC catalysts (Figure 1). We began with a survey
of chiral triazolium precatalysts. A range of selectivities
are observed (Table 4) in the protonation of b-methylcin-
namaldehyde (14), with the best catalysts 18 and 19 being
derived from geminal diphenyl-substituted derivatives of
the amino acids phenylalanine and tryptophan (Table 4,
Stereoselective Protonation of Homoenolate
Equivalents
One of the significant advantages of the use of NHC cata- entries 4, 5).
lysts over traditional Lewis base catalysts, such as cya-
The relative success of these catalysts demonstrates the
nide,39–41 is the availability of enantiopure chiral NHC
precursors for stereoselective reactions.42–45 Chiral NHCs
have been successfully applied to the asymmetric proto-
nation of the a-position of a,a-dichloroaldehydes,46 but to
date we are unaware of any asymmetric protonation of ho-
moenolate equivalents generated by NHCs. The protona-
tion of these reactive intermediates appeared to be a
challenging manifold for asymmetric synthesis due to (a)
the small nature of the electrophile (i.e., proton) and (b)
the distance between the catalyst’s reactive site (the car-
bonyl) and the newly formed stereogenic center at the b-
position.
remote nature of the newly formed stereogenic center. As
the size of the sidearm group of the NHC is increased,
greater selectivity is observed (Table 4, entries 1, 4, 5).
Geminal disubstitution with larger groups (entries 2–4)
restricts the rotation of the blocking group and also
projects it into the vicinity of the protonation site, increas-
ing the selectivity.
The reaction yields two inseparable products, the desired
saturated ester 22 and the unsaturated ester 23 resulting
from the oxidation of the aldehyde. We were initially sur-
prised to observe this oxidation product 23, which results
from the Cannizzaro-like generation of a hydride equiva-
lent from the aldehyde50–54 (Scheme 4, V to VII). The
generation of a reducing equivalent oxidizes the NHC-
aldehyde adduct to an acyl-azolium intermediate VII,
which then acylates ethanol to generate the undesired side
product. While we have utilized this type of reactivity in
a beneficial manner for the reductions of activated ke-
Due to this anticipated difficulty in projecting asymmetric
induction to the b-position, several chiral bases [cinchona
alkaloid derivatives, (–)-sparteine, or alkylated Simpkins’
base derivatives47] were employed with the goal that their
conjugate acids would enantioselectively protonate the
homoenolate equivalent. These and other chiral proton
Synthesis 2008, No. 8, 1306–1315 © Thieme Stuttgart · New York

FEATURE ARTICLE
Protonation of NHC-Generated Homoenolate Equivalents
1311
Me
Me
Me
Me
Me
N
N
N
N
O
O
O
O
N
N
Me
15
N
Me
N
Me
16
N
Me
17
Ph
N
N
Me
Me
N
Me
Ph
Me
18
Me
Ph
Ph
Ph
BF4
BF4
BF4
BF4
Me
N
O
Ph
Ph
Ph
N
Me
19
O
O
N
21
Me
Ph
Me
Ph
20
Me
Ph
N
N
Me
NH
N
N
Me
BF4
OTf
Me
Me
Cl
Figure 1 Chiral NHC precursors
tones,51 the minimization of this pathway in these enantio- ton source yields a lower ratio of homoenolate reactivity
selective protonations has been problematic.
to oxidation without any improvement in enantioselectiv-
ity. N,N-Diisopropylethylamine (Hünig’s base) is used to
generate the active carbene catalyst. Chiral imidazolium
catalysts 2055 and 2156 were also surveyed but gave no ho-
moenolate reactivity with this substrate.
The most detrimental aspect of this reduction pathway is
that the NHC-catalyzed oxidation reduces another equiv-
alent of the starting aldehyde. For this undesired reaction,
two full equivalents of starting material aldehyde are con-
sumed for every equivalent of the unsaturated ester gener- Since our previous studies indicated that reactivity varied
ated. The inability thus far to eliminate this side reaction significantly with minor manipulation of the acid/base
is the primary cause of the observed low yields. The par- balance in the reaction, the role of the base was investigat-
titioning of tetrahedral intermediates such as V between ed in an effort to suppress the oxidation side product. A
homoenolate equivalents (such as VI) and acyl azoliums range of bases was surveyed with 10 mol% of NHC pre-
(VII) is a fascinating aspect of carbene catalysis. The cursor 18 (Table 5). Using N,N-diisopropylethylamine at
modulation of these outcomes by tuning the electronic and 25 mol% yields the best results (Table 5, entry 4), but still
steric properties of potential catalysts should open new contains a significant amount of the undesired oxidation
avenues of discovery using N-heterocyclic carbenes for product. Although not the only factor determining the di-
both new bond-forming reactions and redox processes.
vergent reactivity, the pKa of the base in this reaction is
clearly very important. Stronger bases yield more oxida-
tion product (Table 5, entries 5, 6), while bases with a pKa
in the range of 9 to 11 yield the best ratios of homoenolate
to oxidation reactivity.
The protonation reactions using chiral azolium precata-
lysts are carried out using ethanol without an additional
proton source. The use of phenol or other exogenous pro-
Table 4 Asymmetric Protonation of Homoenolate Equivalentsa
azolium salt (10 mol%)
DIPEA (25 mol%)
Me
O
Me
O
Me
O
+
Ph
H
Ph
OEt
Ph
OEt
EtOH, THF
r.t.
14
22
23
Entry
Azolium salt
Yieldb (%) of 22 + 23
ee (%) of 22
1
2
3
4
5
6
7
15
16
17
18
19
20
21
51
33
9d
23d
55
59
–
c
–
c
–
58
45
0
0
–
a Reaction conditions: 15–21 (0.02 mmol), DIPEA (0.05 mmol), 14 (0.20 mmol), EtOH (0.41 mmol), THF (1.0 mL), r.t., 12–24 h.
b Isolated yields.
c Not isolated.
d Assessed by HPLC of crude reaction mixture.
Synthesis 2008, No. 8, 1306–1315 © Thieme Stuttgart · New York

1312
B. E. Maki et al.
FEATURE ARTICLE
22
Me
O
Me
O
*R
Mes
N
N
Ph
OEt
Ph
H
N
14
EtOH
addition
nucleophilic
attack
Me
O
Mes
Me
X
O
R
Mes
Me
O
H
N
Me
O
Mes
Ph
V
N
EtOH
Ph
N
N
X
N
Ph
N
Ph
OEt
N
* R
N
N
*
VII
23
R
*
H-migration
tautomerization
hydride donation
VI
Me
OH
Me
OH
Mes
Mes
Me
N
N
Me
O
Ph
Ph
Ph
OH
N
N
X
N
N
protonation
Ph
H
R
R
*
*
Scheme 4 Generation of oxidized side product 23
Table 5 Variation of Base in Asymmetric Protonation of Homoenolatesa
Entry
Base
pKa
7.0
Equiv or mol%
1
Ratiob 22/23
23 only
1:1
ee (%) of 22
1
2
3
4
5
6
1-methyl-1H-imidazole
N,N,a-trimethylbenzylamine
(–)-sparteine
–
8.9
40 mol%
40 mol%
25 mol%
40 mol%
40 mol%
50
52
55
40
–
10.1
11.0
12.0
17.0
1.5:1
DIPEA
3.4:1
DBU
1:3
t-BuOK
23 only
a Reaction conditions: 18 (0.02 mmol), base, 14 (0.20 mmol), EtOH (0.4 mmol), THF (1.0 mL), r.t., 12–24 h.
b Ratios determined by 1H NMR of purified mixtures.
It is interesting to note that minimal variation in enantio-
selectivity is observed, even with the use of chiral bases
Conclusion
such as (–)-sparteine. The weakest bases, such as 1-meth- The internal redox reaction resulting from the protonation
yl-1H-imidazole (Table 5, entry 1), may be unable to gen- of homoenolate equivalents catalyzed by N-heterocyclic
erate the catalytic carbene in meaningful quantities, as carbenes is a useful transformation with significant poten-
these reactions were extremely sluggish and low yielding. tial. In addition to the synthesis of saturated esters without
These results reinforce the delicate nature of the balance using activating reagents or acid chlorides, this umpolung
of acids and bases involved in the generation of these reactivity can be extended to the generation of b-acylvinyl
homoenolate equivalents.
anions in select cases. The enantioselective protonation of
these intermediates is also possible, but under current con-
ditions, its development is hampered by the generation of
an oxidation side product through a Cannizzaro-like path-
way. This promising reaction is also limited in selectivity
(up to 59% ee) by the remote nature of the newly formed
stereocenter. Current efforts are directed toward accessing
new NHC precursors that will attenuate the generation of
the undesired oxidized product, as well as the develop-
ment of NHC-catalyzed oxidations and reductions in-
spired by this unexpected side reaction. From its
biochemical origins and early benzoin and Stetter applica-
tions, the field of carbene catalysis is rapidly expanding
Efforts to eliminate the oxidation side product 23 by ma-
nipulating the electronic nature of intermediate I through
the use of different substrates and NHC catalysts have not
yet achieved an optimal process. However, we report the
first asymmetric protonation of NHC-generated homo-
enolate equivalents in up to 59% ee with the use of chiral
triazolium precatalyst 19 and b-methylcinnamaldehyde
(14).
Synthesis 2008, No. 8, 1306–1315 © Thieme Stuttgart · New York

FEATURE ARTICLE
Protonation of NHC-Generated Homoenolate Equivalents
IR (film): 3448, 3033, 2951, 2835, 1734, 1247 cm–1.
1313
and in doing so provides new avenues for reaction devel-
opment.
1H NMR (500 MHz, CDCl3): d = 7.40–7.30 (m, 5 H), 7.10 (d,
J = 7.94 Hz, 2 H), 6.82 (d, J = 7.63 Hz, 2 H), 5.11 (s, 2 H), 3.79 (s,
3 H), 2.92 (t, J = 7.63 Hz, 2 H), 2.65 (t, J = 7.63 Hz, 2 H).
All reactions were carried out under an N2 atmosphere in flame-
dried glassware with magnetic stirring. THF, Et2O, CH2Cl2, DMF,
and toluene were purified by passage through a bed of activated alu-
mina.57 Reagents were purified prior to use unless otherwise stated
following the guidelines of Perrin and Armarego.58 Purification of
reaction products was carried out by flash chromatography using
EM Reagent silica gel 60 (230–400 mesh). Analytical TLC was per-
formed on EM Reagent 0.25 mm silica gel 60-F plates. Visualiza-
tion was accomplished with UV light and anisaldehyde, CAN,
KMnO4, or phosphomolybdic acid stain followed by heating. IR
spectra were recorded on a Perkin Elmer 1600 series FT-IR spectro-
photometer. 1H NMR spectra were recorded on a Varian Inova 500
(500 MHz) or Mercury 400 (400 MHz) spectrometer and are report-
ed using solvent as an internal standard (CDCl3 at d = 7.26). Proton-
decoupled 13C NMR spectra were recorded on a Varian Inova 500
(125 MHz) or Mercury 400 (100 MHz) spectrometer and are report-
ed using solvent as an internal standard (CDCl3 at d = 77.0). MS
data were obtained on a Varian 1200 Quadrupole Mass Spectrome-
ter.
13C NMR (125 MHz, CDCl3): d = 173.3, 158.5, 136.4, 132.9, 129.7,
129.0, 128.7, 128.6, 114.3, 66.7, 55.7, 36.7, 30.6.
LR-MS (APCI): m/z [M + H]+ calcd for C17H19O3: 271.3; found:
271.4.
Benzyl 2-Benzylpropanoate (9)
Light tan oil; yield: 150 mg (82%); Rf = 0.71 (EtOAc–hexanes, 1:4).
IR (film): 3448, 3064, 3030, 3974, 2936, 1735, 1245 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.35–7.14 (m, 10 H), 5.07 (s, 2 H),
3.04 (dd, J = 13.3, 7.0 Hz, 1 H), 2.80 (q, J = 7.3 Hz, 1 H), 2.69 (dd,
J = 13.4, 7.3 Hz, 1 H), 1.18 (d, J = 6.7 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 176.4, 139.7, 136.5, 129.5, 129.0,
128.8, 128.6, 128.5, 126.8, 66.6. 42.0, 40.2, 17.3.
LRMS (APCI): m/z [M + H]+ calcd for C17H19O2: 255.3; found:
255.3.
Benzyl 3,3-Diphenylpropanoate (10)
Light yellow oil; yield: 113 mg (82%); Rf = 0.70 (Et2O–hexanes,
1:4).
IR (film): 3448, 3061, 3030, 2953, 2921, 1735, 1258 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.38–7.14 (m, 15 H), 5.02 (s, 2 H),
4.56 (t, J = 8.2 Hz, 1 H), 3.12 (d, J = 7.9 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 172.1, 143.8, 136.2, 129.6, 129.0,
128.9, 128.8, 128.7, 128.6, 128.5, 128.4, 128.1, 127.0, 66.8, 47.5,
41.3.
Homoenolate Equivalents Generated by NHCs
3-(4-Chlorophenyl)cinnamaldehyde was prepared according to
Kirsch and co-workers.59,60 4-Chlorocinnamaldehyde was prepared
according to a procedure analogous to Moloney and co-workers.61
4-Methoxycinnamaldehyde was purchased from Acros and the re-
maining aldehydes and IMes (13) were commercially available
from Sigma-Aldrich and purified before use.
Benzyl 3-Phenylpropanoate (3); Typical Procedure
A screw-capped tube was charged with the benzimidazolium salt 1
(11 mg, 0.04 mmol) in a N2-filled dry box. The tube was removed
from the box and placed under a positive pressure of N2. The tube
was charged with toluene (1.0 mL), DBU (6 mL, 0.04 mmol), and
lastly, distilled cinnamaldehyde (104 mg, 0.79 mmol). The mixture
was allowed to stir for 5 min after which PhOH (150 mg, 1.6 mmol)
in toluene (0.6 mL) was added via syringe followed by the addition
of BnOH (429 mg, 4 mmol). The mixture was heated at 100 °C for
2–6 h until cinnamaldehyde was consumed (GC). The mixture was
cooled to r.t., diluted with CH2Cl2 (20 mL) and washed with H2O
(20 mL). The aqueous layer was washed with CH2Cl2 (3 × 30 mL)
and the combined organic extracts were dried (anhyd Na2SO4), fil-
tered, and concentrated in vacuo. The resulting residue was purified
by flash column chromatography (silica gel).
Benzyl 3-(4-Chlorophenyl)-3-phenylpropanoate (11)
Light yellow oil; yield: 94 mg (86%); Rf = 0.85 (CH2Cl2–hexanes,
5:1).
IR (film): 3449, 3030, 2955, 1735, 1254 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.31–7.14 (m, 14 H), 5.02 (s, 2 H),
4.54 (t, J = 7.9 Hz, 1 H), 3.08 (d, J = 7.7 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 171.9, 143.3, 142.2, 136.1, 132.8,
129.5, 129.2, 129.0, 128.7. 128.6, 128.0, 127.2, 114.6, 66.9, 46.9,
41.2.
Generation of b-Acylvinyl Anions
Phenylpropynal and 5-(tert-butyldimethylsiloxy)pent-2-ynal were
prepared according to a procedure analogous to that of Kuroda et
al.67 (4-Chlorophenyl)propynal and (4-methoxyphenyl)propynal
were synthesized by a procedure analogous to that of Roy and
Banerjee.68
Spectral data for compounds 2,62 3,63 4,64 5,65 and 866 matched those
found in the literature.
(S)-1-Phenylethyl 3-Phenylpropanoate (6)
Yellow oil; yield: 155 mg (77%); Rf = 0.70 (Et2O–hexanes, 1:4).
IR (film): 3446, 3030, 2981, 2868, 1732, 1248 cm–1.
Benzyl Prop-2-enoates (Table 3); General Procedure
A screw-capped tube was charged with IMes (13, 15 mg, 0.04
mmol) or benzimidazolium salt 1 (12 mg, 0.04 mmol) in an N2-
filled dry box. The tube was removed from the box and placed under
a positive pressure of N2. The tube was charged with toluene (1.5
mL) and DBU (6 mL, 0.04 mmol) and the mixture was allowed to
stir at 23 °C for 10 min after which the aldehyde (0.43 mmol) and
BHT (187 mg, 0.85 mmol, 2 equiv) were added, followed by the ad-
dition of BnOH (227 mL, 2.2 mmol, 5 equiv). The mixture was heat-
ed at 100 °C or 45 °C for 12–36 h until the aldehyde was consumed
(TLC). The mixture was cooled to r.t., diluted with CH2Cl2 (20 mL)
and washed with H2O (20 mL). The aqueous layer was washed with
CH2Cl2 (3 × 20 mL) and the collected organic layers were dried
(anhyd Na2SO4), filtered and concentrated in vacuo. The resulting
residue was purified by flash column chromatography (silica gel).
1H NMR (500 MHz, CDCl3): d = 7.36–7.17 (m, 10 H), 5.89 (q,
J = 6.7 Hz, 1 H), 2.96 (t, J = 7.3 Hz, 2 H), 2.66 (t, J = 5.7 Hz, 2 H),
1.51 (d, J = 6.7 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 172.4, 141.8, 140.7, 129.6, 128.8,
128.7, 128.5, 128.0, 126.4, 126.3, 36.3, 31.1, 22.4.
LR-MS (ACPI): m/z [M + H]+ calcd for C17H19O2: 255.3; found:
255.4.
Benzyl 3-(4-Methoxyphenyl)propanoate (7)
Light yellow oil; yield: 127 mg (76%); Rf = 0.6 (Et2O–hexanes,
1:4).
Synthesis 2008, No. 8, 1306–1315 © Thieme Stuttgart · New York

1314
B. E. Maki et al.
FEATURE ARTICLE
Spectral data for benzyl cinnamate69 and benzyl 4-methoxy-
cinnamate70 matched those found in the literature.
(11) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. Helv. Chim.
Acta 1996, 79, 1899.
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88, 3666.
Benzyl 4-Chlorocinnamate
Orange solid; yield: 68 mg (59%); Rf = 0.64 (EtOAc–hexanes, 1:4).
IR (film): 3056, 3041, 2953, 1715, 1165, 822, 697 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.67 (d, J = 16.1 Hz, 1 H), 7.34–
7.46 (m, 9 H), 6.46 (d, J = 16.1 Hz, 1 H), 5.26 (s, 2 H).
13C NMR (125 MHz, CDCl3): d = 166.7, 143.9, 136.4, 136.1, 133.0,
129.4, 129.3, 128.8, 128.5, 118.6, 66.7.
(13) Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem. Int.
Ed. 2006, 45, 1463.
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Chem. Soc. 2004, 126, 2314.
LRMS (APCI): m/z [M + H]+ calcd for C16H14ClO2: 272.1; found:
272.3.
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Stereoselective Protonation of Homoenolate Equivalents
b-Methylcinnamaldehyde (14) was prepared according to Oh and
co-workers.71 Triazolium catalysts were prepared by a route analo-
gous to that of Rovis and co-workers.72 Imidazolium salts 2055 and
2156 were prepared according to procedures of Glorius and
Hermann and co-workers.
(20) Our preliminary studies of generating homoenolates using
N-heterocyclic carbenes and the protonation of these
unusual intermediates was first described in a lecture by
K.A.S. at the 2004 Natural Products Gordon Research
Conference (Tilton, NH) on Thursday, July 29, 2004.
(21) Burstein, C.; Glorius, F. Angew. Chem. Int. Ed. 2004, 43,
6205.
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2004, 126, 14370.
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(24) Burstein, C.; Tschan, S.; Xie, X. L.; Glorius, F. Synthesis
2006, 2418.
(25) Nair, V.; Poonoth, M.; Vellalath, S.; Suresh, E.; Thirumalai,
R. J. Org. Chem. 2006, 71, 8964.
(26) Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, E. J. Am. Chem.
Soc. 2006, 128, 8736.
(27) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 5334.
(28) Phillips, E. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem.
Soc. 2008, 130, 2416.
(29) Seayad, J.; Patra, P. K.; Zhang, Y.; Ying, J. Y. Org. Lett.
2008, 10, 953.
Ethyl 3-Methylbutanoate (22) and Ethyl 3-Methylbut-2-enoate
(23) (Table 4); General Procedure
A triazolium salt (0.02 mmol) was dissolved in THF (1.0 mL) fol-
lowed by sequential addition of DIPEA (9 mL, 0.05 mmol), b-meth-
ylcinnamaldehyde (14, 30 mg, 0.20 mmol), and abs EtOH (24 mL,
0.41 mmol). The mixture was stirred at r.t. for 12–24 h and moni-
tored (TLC, 30% Et2O–hexanes). Upon consumption of starting al-
dehyde, the mixture was diluted with CH2Cl2 and washed with H2O
and brine. The organic layer was dried (Na2SO4) and evaporated.
The residue was purified by flash chromatography (silica gel, 5%
Et2O–hexanes) to give 22 as well as unsaturated ester 23 as an in-
separable mixture. Enantioselectivity was assessed by chiral HPLC
(OD-H column). Spectral data for both 22 and 23 were identical to
those previously reported.
(30) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2008, 130, 2740.
(31) Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905.
(32) Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7, 3873.
(33) Bordwell, F. G.; Mccallum, R. J.; Olmstead, W. N. J. Org.
Chem. 1984, 49, 1424.
(34) Lepore, S. D.; Khoram, A.; Bromfield, D. C.; Cohn, P.;
Jairaj, V.; Silvestri, M. A. J. Org. Chem. 2005, 70, 7443.
(35) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(36) Diver, S. T.; Rivas, F. M.; Giessert, A. J. J. Org. Chem.
2002, 67, 1708.
Acknowledgment
Financial support for this work was provided by NIGMS (RO1
GM73072), Abbott Laboratories, Amgen, AstraZeneca, Glaxo-
SmithKline, the Sloan Foundation, and Boehringer-Ingelheim.
B.E.M. was supported by a GAANN Fellowship and A.C. thanks
Dow Chemical Company for a graduate fellowship. FMCLithium
and Sigma-Aldrich provided generous reagent support. Funding for
the NU Integrated Molecular Structure Education and Research
Center (IMSERC) has been furnished in part by the NSF (CHE-
9871268). We thank Dr. Steve Wittenberger, Professor Regan
Thomson, and Eric M. Phillips for helpful discussions.
(37) Zeitler, K. Org. Lett. 2006, 8, 637.
(38) Magill, A. M.; Cavell, K. J.; Yates, B. F. J. Am. Chem. Soc.
2004, 126, 8717.
(39) Wöhler, F.; Liebig, J. Ann. Pharm. (Lemgo, Ger.) 1832, 3,
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