Synthesis of β-and β,β-substituted Morita-Baylis-Hillman adducts using a two-step protocol

Article abstract of DOI:10.1139/v2012-017

The synthesis of a large number of β-and β,β-substituted keto esters was successful by the use of the Knoevenagel condensation reaction. The stereoselectivity of these reactions was improved by alteration of various substituent groups. Although there were

Full text of DOI:10.1139/v2012-017

450
Synthesis of β- and β,β-substituted Morita–Baylis–
Hillman adducts using a two-step protocol
David I. Magee, Same Ratshonka, Jessica McConaghy, and Maggie Hood
Abstract: The synthesis of a large number of b- and b,b-substituted keto esters was successful by the use of the Knoevena-
gel condensation reaction. The stereoselectivity of these reactions was improved by alteration of various substituent groups.
Although there were few examples of complete Z selectivity, the use of tert-butyl acetoacetate with either aromatic or ali-
phatic aldehydes afforded Z selectivity. The selective reductions of these substituted keto esters was successfully achieved
by using a combination of NaBH4 and CeCl3·7H2O or Yb(OTf)3, which allowed a facile synthesis of a large number of ster-
eochemically pure substituted Morita–Baylis–Hillman adducts, including b,b-substituted adducts.
Key words: Morita–Baylis–Hillman, Knoevenagel, reduction, b,b-substituted.
Résumé : On a effectué avec succès la synthèse d’un grand nombre d’esters b- et b,b-substitués en faisant appel à la
condensation de Knoevenagel. On a amélioré la stéréosélectivité de ces réactions en procédant à l’altération de divers substi-
tuants. Même s’il n’y a que peu d’exemples de sélectivité Z complète, l’utilisation de l’acétoacétate de tert-butyle avec des
aldéhydes aromatiques ou aliphatiques conduit à la formation de produits avec une sélectivité Z. On a effectué avec succès
les réductions sélectives de ces cétoesters substitués en utilisant une combinaison de NaBH4 et de CeCl3·7H2O ou de
Yb(OTf)3; ceci a permis de réaliser une synthèse facile d’un grand nombre d’adduits de Morita-Baylis-Hillman substitués et
stéréochimiquement purs, y compris des adduits b,b-substitués.
Mots‐clés : Morita–Baylis–Hillman, Knoevenagel, réduction, b,b-substitué.
[Traduit par la Rédaction]
Fig. 1. Sarcodonin A.
Introduction
OH
There is significant interest in the field of natural product
synthesis for the purpose of developing methodology for the
synthesis of compounds with medicinal properties. Sarcodo-
nin A (1) is a natural product found in the fungus Sarcodon
scabrosus, which has been found to possess antibacterial and
anti-inflammatory properties.1 The cyanthane diterpenes are
characterized by a fused 5,6,7-tricyclic array (Fig. 1), with
most containing a C-3 isopropyl group that is not functional-
ized. Sarcodonin A is an exception, as it has an alcohol func-
tionality at C-19, which generates a chiral centre at C-18.
This increased level of oxidation makes the synthesis of sar-
codonin A significantly more difficult than other members of
the cyanthane family, since it requires controlling the config-
uration of a stereogenic centre on a pendant side chain rela-
tive to which it is attached. Since this particular type of
stereochemical arrangement has been proven to be particu-
larly troublesome to handle synthetically, this compound pro-
vides an interesting target to address this challenge.
CHO
H
1
OH
from the [3.2.1]-bicyclic diketone 4 (Scheme 1), thus, com-
pounds like 2 became the lynchpin for our proposed synthe-
sis.
There appeared to be several approaches for the construc-
tion of this type of structure; these included: (1) addition of
an allyl cation, or equivalent, to a conjugated diene;3 (2)
[3 + 3] carbocyclization of a nitroallylic ester and an enam-
ine;4 and (3) an a,a′-annulation strategy5 involving reaction
between a cyclic enamine and a biselectrophile (i.e., a com-
pound that could serve as both an alkylation and Michael ad-
dition agent) (Fig. 2). For our purposes, however, each
Recently, the MaGee group2 demonstrated that enantiose-
lective deprotonation can be used to help address this prob-
lem. To implement this strategy for the synthesis of
sarcodonin A, a potential symmetry in the molecule had to
be delineated. Upon close examination it was envisioned that
the left-hand portion of sarcodonin A could be constructed
Received 27 October 2011. Accepted 25 January 2012. Published at www.nrcresearchpress.com/cjc on 10 April 2012.
D.I. Magee, S. Ratshonka, J. McConaghy, and M. Hood. Department of Chemistry, P.O. Box 4400, University of New Brunswick,
Fredericton, NB E3B 5A3, Canada.
Corresponding author: David I. MaGee (e-mail: dmagee@unb.ca).
Can. J. Chem. 90: 450–463 (2012)
doi:10.1139/V2012-017
Published by NRC Research Press

Magee et al.
451
Scheme 1. Retrosynthetic analysis of sarcodonin A.
O
OH
Me
O
CHO
H
1
2
Me
OH
Fig. 2. Various approaches to construct [3.2.1]-bicyclic ketones.
OCH3
H3CO
OCH3
[1]
O
Me
OCH3
O
Me
O
N
O2N
[2]
Me
NO2
OPv
Me
O
N
MeO2C
[3]
CO2Me
Br
approach had limitations. For instance, oxyallyl cation addi-
tion to 1,1-diethoxycyclopentadiene proceeds in very poor
yield, which is unacceptable as the first step in a total synthe-
sis. The [3 + 3]-carbocyclization route using nitroallylic es-
ters proceeds in acceptable yields and is easily scaled up,
however, all attempts to perform a Nef reaction failed.6 Fi-
nally, the a,a′-annulation strategy efficiently generates com-
pounds such as [3.2.1]-bicyclic ketones, however, it is
underfunctionalized, and the ability to synthesize and use
more highly substituted derivatives to participate in the annu-
lation reaction has not been demonstrated.
To solve the issue of underfunctionalization, compounds
like 4 (Scheme 2) were required, and it was felt that these
can potentially be accessed from Morita–Baylis–Hillman
(MBH) adducts.7 Unfortunately, b-branched MBH adducts
are difficult to obtain using classical conditions, therefore,
several chemical solutions have been reported.8–15 Although
each has their own advantages, they all have the limitation in
Scheme 2. An a,b-unsaturated compound suitably substituted for
use in an a,a′-annulation sequence for sarcodonin A synthesis.
EWG
EWG
X
X
X
TEA
4
3
requiring reactive organometallic and (or) toxic reagents and
not being very amenable to scale up.
Given these limitations, an alternative route for the synthe-
sis of the targeted annulation agent was sought. It was felt
that the Knoevenagel reaction16 between an aldehyde and
ethyl acetoacetate would give rise to an a,b-unsaturated keto
ester like 7, and that upon reduction with an appropriate re-
ducing agent would provide the MBH adduct 8 (Scheme 3).
Although there was precedent for this approach,17 in our
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452
Can. J. Chem. Vol. 90, 2012
Scheme 3. Synthesis of Morita–Baylis–Hillman (MBH) adducts
Fig. 3. Different quadrants of the Knoevenagel condensation pro-
duct.
using the Knoevenagel condensation/reduction two-step protocol.
O
O
O
O
O
O
Y
OEt
OEt
H
X
7
5
6
R1
R2
the formation of substituted [3.2.1]-bicyclic diketones, but
also a variety of other natural products. With this in mind,
18 different Knoevenagel products were synthesized follow-
ing general procedures (Tables 1 and 2).
HO
O
AcO
O
OEt
OEt
8
It was decided to first investigate what effect, if any, aro-
matic and aliphatic aldehydes had on the E and Z stereose-
lectivity when condensed with 1,3-dicarbonyl compounds.
Thus, condensation of different acetoacetates with various
aliphatic aldehydes (Table 1, entries 1–6) showed that regard-
less of whether a methyl, isopropyl, pentyl, or cyclohexyl
group was on the terminus of the double bond, all condensa-
tions afforded roughly the same mixture of isomers (1.5–
2.3:1) with Z being favoured over the E isomer in most
cases. The exception to this was entry 6 where a tert-butyl
group was able to confer complete stereochemical control,
albeit in low chemical yield.
Other notable results obtained are entries 7–9 (Table 1),
where the ester functionality was varied from methyl to tert-
butyl to benzyl. It was found that increasing the bulk of the
EWG group also increased the selectivity of the reaction in
favour of the Z isomer. This was surprising, since it was ex-
pected that E stereoselectivity would be preferred as one in-
creased the size of the ester group.18 However, Tanikaga et
al.19 demonstrated that the stereoselectivity of the Knoevena-
gel product is affected by slight differences in steric require-
ments between the two EWGs and when the differences
between X, Y, and R2 (Fig. 3) are rather small then selectiv-
ity in favour of the Z isomer is preferred.
The effect of EWGs other than esters was also investi-
gated. In entry 11 (Table 1), a sulfone was used for compar-
ison and, as reported by Tanikaga et al.,20 an overwhelming
preference for the E-isomer was observed. However, as ex-
pected,21 use of a cyano group (Table 1, entry 14) in place
of an ester preferentially gave the Z-isomer.
Continuing with this survey of different combinations, var-
ious alkyl groups were substituted on the ketone (Table 1,
entries 10, 12, and 13) to assess if improved selectivity could
be obtained and if the reduction would tolerate increased
steric hindrance near the ketone. Not surprisingly, as the
steric hindrance around the ketone increased there was an im-
provement in the stereochemical purity. This increase in ster-
eoselectivity came at a price as the yield of Knoevenagel
product decreased substantially as the acetoacetate became
bulkier.
9
hands we routinely obtained low yields (>30%). If more sub-
stituted examples were used (e.g., Ph substituted on the al-
kene rather than methyl) then a much slower reduction
occurred and did not have complete conservation of stereo-
chemistry. Given these difficulties, we decided to investigate
the breadth and scope of this reaction focusing on different
substitution patterns, electron-withdrawing groups, and re-
duction conditions. Herein we report our study on the prepa-
ration of MBH adducts by this two-step protocol and show
that it is rapid and generally applicable to the formation of
b- and b,b-disubstituted MBH compounds.
Results and discussion
The first step was the synthesis of the intermediate keto
esters via a Knoevenagel condensation reaction. Literature re-
ports have demonstrated this method to be appropriate for re-
actions between aromatic and aliphatic aldehydes, as well as
different 1,3-dicarbonyl compounds16 such as acetoacetates.
The breadth of this reaction was attractive, since it would al-
low for the construction of a wide variety of adducts and thus
permit the exploration of the scope of this two-step process.
In deciding what compounds should be generated, consid-
eration was given to each quadrant of the alkene (Fig. 3). For
instance, if Y were an ester then it could be easily varied
from tert-butyl to methyl or benzyl to probe the sterics. It
was also envisaged that electron-withdrawing groups (EWGs,
Y) other than esters could be explored, such as a SO2Ph, a
ketone, or a cyano group. The ketone (X) could also be var-
ied from a methyl to a branched or long-chain aliphatic ke-
tone or to an aromatic ketone. Altering this quadrant allowed
one to explore the effect of sterics on both the E:Z ratios ob-
tained in the Knoevenagel condensations, as well as the ease
of hydride reduction. Moving to the other quadrants of the
double bond, R1 and (or) R2 could be replaced with branched
or long-chain aliphatic or aromatic units. Finally, if both R1
and R2 were replaced with carbons then this would provide
access to b,b-substituted adducts that could then be trans-
formed into b,b-substituted MBH adducts; these are little
known or studied compounds.
With a large number of aldehydes screened, a decision was
made to look at the possibility of doing the condensation
with a number of ketones ranging from straight-chain ali-
phatic (symmetric and unsymmetric), to cyclic aliphatic, to
heterocyclic. These were condensed with ethyl acetoacetate
to form b,b-substituted Knoevenagel products (Table 2).
It is important to note that all of these alterations were im-
portant for obtaining a variety of substituted symmetrical and
unsymmetrical compounds that have the potential to be very
useful a,a′-annulation agents (biselectrophiles) for not only
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Magee et al.
453
Table 1. Synthesis of b-substituted unsaturated keto esters by the Knoevenagel condensation reaction.
O
O
Y
+ R1CHO
Y
X
X
R1
Isomer ratio
Entry
1
2
3
4
5
6
7
8
X
Y
R′
Me
i-Pr
(CH2)4CH3
C6H11
(CH2)4CH3
t-Bu
Ph
Ph
Ph
Ph
Ph
Ph
Ph
C6H11
Time (h)
Product
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Yield (%)
83
70
80
84
20
14
80
77
50
70
78
60
18
50
(E:Z)
1:2.3
1:2.3
2:3
2:3
1:2
Z
1:1
2:3
Z
Z
E
1.8:1
Z
Z
Method
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2Me
CO2Me
CO2Et
CO2Me
CO2Bn
CO2t-Bu
CO2Et
SO2Ph
CO2Me
CO2Me
CN
12
12
10
4
4
12
3
3
10
3
12
3
10
48
A
A
A
A
B
B
B
B
B
B
B
B
B
C
9
10
11
12
13
14
Ph
i-Pr
t-Bu
Ph
Note: Reagents: (A) CH3COCH2–Y; RCHO; piperidine; EtOH; 0 °C; (B) X–COCH2–Y; RCHO; piperidine; AcOH; benzene;
reflux; (C) PhCOCH2CN; RCHO; proline; EtOH; room temperature (RT).
Table 2. Synthesis of b,b-substituted unsaturated keto esters by the Knoevenagel con-
densation reaction using the Lewis acids ZnCl2 or TiCl4.
O
O
O
Y
+
Y
X
R1
R2
X
R1
R2
Entry
X
Y
R′, R″
Me, Me
(CH2)5
(CH2)4
C(C2H4)2NCO2CH3
Me, C7H15
Time (h)
Product
24
25
26
27
Yield (%)
1
2
3
4
5
Me
Me
Me
Me
Me
OEt
OEt
OEt
OEt
OEt
72
16
16
16
16
42
28
38
32
27
28
methanol at 0 °C and room temperature (to assess the influ-
ence of temperature on the yield) to provide allylic alcohols
29 and 30 in 34%–80% overall yield (Table 3). From these
results it was clear that effecting the reduction at room tem-
perature gave the best results.
With a number of Knoevenagel condensation products in
hand, the stage was set to look at the critical 1,2-hydride re-
duction. Upon examination of the literature there appeared to
be several approaches. The first method to be studied was re-
duction using Luche conditions.22 The advantage of this
method was that selective 1,2-reduction could be obtained
under conditions that did not affect other functional groups
such as carboxylic acids, esters, amides, or nitro groups.19
Furthermore, the reaction could be conducted at room tem-
perature without the special exclusion of air or moisture.
Even though there was a lot of precedent literature that con-
sistently showed that Luche conditions were the appropriate
choice for the selective 1,2-reduction of a-enones, it was not
clear how it was going to perform on keto esters like 7, as
there were few reports of its use for the reduction of b′-oxo-
carbonyl compounds.23 Regardless, following the procedure
outlined by Luche, compounds 16 and 17 were treated with
1 mol equiv of sodium borohydride and cerium trichloride in
Of note in this preliminary investigation was the fact that,
even though the reaction was started with a 1:1 mixture of
isomers, the final stereoisomeric ratio of the products was
found to be 2:3. There were several possibilities to account
for this. Firstly, if the reduction of one isomer was faster
than the other and the rate of isomerization of the starting
materials was approximately the same as the reduction, then
this would lead to a preponderance of one isomer. A second
possibility was that there was some isomerization that took
place after the reduction had occurred, presumably this
would lead to a predominance of the thermodynamic product.
Finally, it is possible that the reduction of one isomer was
much more efficient than the other.
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Can. J. Chem. Vol. 90, 2012
Table 3. Reduction of Knoevenagel condensation products 16 and
17 to allylic alcohols 29 and 30 using Luche conditions.
Table 4. Reduction of selected Knoevenagel products with tri-tert-
butoxyaluminium hydride (LATB-H), borane methyl sulfide com-
plex (BMS), and Yb(OTf)3.
Starting material
(E:Z isomer
ratio)
16 (1:1)
16 (1:1)
17 (2:3)
17 (2:3)
Isomer
ratio
(E:Z)
2:3
2:3
2:3
2:3
Temp. Time
Yield
(%)
50
80
34
77
Starting material
(E:Z isomer
ratio)
Isomer
ratio
(E:Z)
Reducing
agents
Time
(h)
Yield
Product (%)
(°C)
(h)
Product
29
29
30
30
0
2
LATB-H
16 (1:1)
19 (0:1)
16 (1:1)
17 (2:3)
18 (0:1)
19 (0:1)
21 (2:1)
16 (1:1)
17 (2:3)
18 (0:1)
19 (0:1)
2
2
3
3
3
3
3
2
2
2
2
29
43
29
30
42
43
45/46
29
30
nr
nr
—
—
2:3
2:3
Z
—
2:3
2:3
2:3
Z
25
0
2
2
BMS
40
27
10
nr
10
20
10
40
nr
25
2
With the optimal conditions for the Luche reduction ob-
tained, other reducing agents were investigated to see if
greater success could be realized; these included lithium tri-
tert-butoxyaluminium hydride (LATB-H),24 borane methyl
Yb(OTf)3
42
43
sulfide complex (BMS),25 and Yb(OTf)3 (Table 4). Of
26
—-
these, only Yb(OTf)3 consistently reduced the ketone; how-
ever, the yields were substantially inferior to the yields under
Luche conditions.
Note: nr, no reaction.
bromide 55 was obtained in 48% yield as a 1:1 mixture of
E- and Z-isomers. Alternatively, 31 could be efficiently acy-
lated with acetyl chloride, pivaloyl chloride, and methyl
chloroformate in 71%, 65%, and 73% yields, respectively.4,17
Treatment of each of these biselectrophiles with 1-pyrroli-
dino-1-cyclopentene (56) with and without triethylamine in
refluxing ethanol or acetonitrile provided variable success,
with the desired cycloadducts, 57a and 57b, being most effi-
ciently produced in 43% yield as a 1:1 mixture of isomers
using bromide 55.
Based on the optimized conditions, all of the compounds
in Tables 1 and 2 were reduced using the Luche method,
and the results are summarized in Table 5. It was observed
that as the substituent on the terminus of the alkene increased
in size, the yield of the reduction product improved (Table 5,
entries 1–7). This was presumably due to a diminution of
competing side reactions such as Michael addition, self-
condensation, or 1,4-reduction. This was especially true for
the methyl-substituted compound (Table 5, entries 1 and 2)
where it was observed that good yields could only be real-
ized if the reduction was allowed to run for only a few sec-
onds. It was also observed that in most cases it was
possible to obtain pure isomers when starting with either
pure E or Z starting material. The exception to this was
the phenyl ketone 16, for which the same isomer ratio of
products was obtained after reduction regardless of the iso-
mer ratio of the starting ketones.
Another notable result was the reduction of the cyano
compound (Table 5, entry 18). It was found that the desired
reduction product (Z-isomer) along with the fully reduced
product, in which the double bond was also reduced, was ob-
tained in approximately a 1:1 ratio. Although the desired
product was present, the two compounds were found to be
inseparable by column chromatography; thus, pure MBH ad-
duct could not be achieved by this method.
The isolated products were determined to be an approxi-
mately 50:50 mixture of symmetric and asymmetric esters
1
based on an analysis of the H and 13C NMR spectra. The
stereochemistries of the esters were assigned on the basis of
correlations observed in the NOESY spectrum of the mix-
ture. For the symmetric ester, the methine hydrogens on the
carbons bearing the methyl groups were assigned as equato-
rial based on NOESY correlations observed between these
hydrogens and the axial methylene hydrogens. The ester was
assigned as axial based on NOESY correlations observed be-
tween the axial methyl hydrogens and the methine hydrogen
on the carbon bearing the ester group (Fig. 4, 57a).
A similar analysis for the asymmetric ester determined the
ester group to be axial. For the side of the molecule with the
methyl group axial, NOESY correlations similar to those for
the symmetric ester were observed, with an additional NOESY
correlation observed between the methyl hydrogens and the
axial methine hydrogen on the carbon bearing the equatorial
methyl group. In addition, NOESY correlations were ob-
served between the equatorial methyl hydrogens and one of
the axial methylene hydrogens (Fig. 4, 57b).
Having succeeded with the reduction of the b-substituted
Knoevenagel condensation products, the reduction of the
b,b-substituted 1,3-dicarbonyl compounds was examined (Ta-
ble 5). All the ketones (24–28) reduced very efficiently and in
a short period of time (15 min) to produce the b,b-substituted
MBH adducts in good to excellent yields. Of particular note
is entry 23 (Table 5) where compound 52 was obtained in
71%; this result shows that additional functional groups may
be present without adversely affecting the reduction.
Conclusion
In conclusion, a large number of b- and b,b-substituted
a,b-unsaturated keto esters were synthesized using the Knoe-
venagel condensation. For the synthesis of the b-keto esters,
it was demonstrated that the stereoselectivity of the reaction
was improved by alteration of various substituents on the ke-
tone, ester group, and various aldehydes. From our results, a
Z-selective Knoevenagel condensation can be achieved by the
use of tert-butyl acetoacetate with either aromatic or aliphatic
a,a′-Annulation strategy for construction of the [3.2.1]-
bicyclic ketone
With a suitable method available to generate amounts of
alcohol 31 in hand, investigation into transforming it to the
targeted annulation agent 57 was undertaken (Scheme 4).
Fortunately, when alcohol 31 was treated with triphenylphos-
phine and N-bromosuccinimide (NBS)27 at –30 °C, allylic
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Magee et al.
455
Table 5. Reduction of the Knoevenagel condensation products using Luche conditions.
O
OH
Y
Y
X
.
CeCl3 7H2O
X
NaBH4
R1
R2
MeOH, rt
R1
R2
Isomer
ratio
(E:Z)
E
Z
E
Z
E
Z
Z
E
Z
E
Z
Z
Z
E
E
Z
—
Z
—
—
—
—
Z
Yield
(%)
Entry
1
2
3
4
5
6
7
X
Y
R1, R2
Me, H
H, Me
i-Pr, H
H, i-Pr
(CH2)4CH3, H
H, (CH2)4CH3
t-Bu, H
(CH2)4CH3, H
H, (CH2)4CH3
C6H11, H
H, C6H11
Ph, H
Ph, H
Ph, H
Ph, H
H, Ph
Ph, H
C6H11, H
Me, Me
(CH2)5
(CH2)4
Time
Product
31
32
33
34
35
36
37
38
∫39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2Et
CO2Me
CO2Me
CO2Me
CO2Me
CO2t-Bu
CO2Et
0.5 min
1 min
3 min
3 min
5 min
5 min
3 min
2 h
66
68
79
66
75
72
92
40
49
52
56
60
77
40
65
71
nr
52
91
91
90
71
82
82
8
9
2 h
10
11
12
13
14
15
16
17
18
19
21
22
23
24
25
5 min
5 min
2 h
2 h
15 min
2 h
Ph
SO2Ph
i-Pr
i-Pr
t-Bu
Ph
Me
Me
Me
Me
Me
Me
CO2Me
CO2Me
CO2Me
CN
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
2 h
2 h
5 min
15 min
15 min
15 min
15 min
15 min
15 min
(C2H4)2NCO2CH3
CH3, nC7H15
nC7H15, CH3
E
Note: nr, no reaction.
Scheme 4. Synthesis of a [3.2.1]-bicyclic ketone using a Morita–Baylis–Hillman (MBH) adduct as a biselectrophile.
Br
O
HO
O
N
OtBu
OtBu
NBS, PPh3,
+
CH2Cl2,, - 30 °C
31
55
56
EtOH, ?
O
O
Me
Me
CO2tBu
CO2tBu
57a
57b
Me
Me
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Can. J. Chem. Vol. 90, 2012
Fig. 4. Partial NOESY correlations observed for the (A) symmetric ester and (B) asymmetric ester.
O
O
CH3
CH3
H
H
CH3
H
H
H
H
H
H
CH3
CO2tBu
CO2tBu
57a
57b
1H NMR spectroscopic data are presented in parts per million
(d) relative to tetramethylsilane as an internal standard. All
proton–proton NMR coupling constants (J) are expressed in
Hertz (Hz). 13C NMR data are presented in parts per million
(d) relative to CDCl3 (77.16 ppm) as an internal standard un-
less otherwise stated. Infrared spectra (IR) were recorded on
a NEXUS 470 FTIR. Main peaks are reported as wavenum-
bers in cm–1. High-resolution mass spectra (HRMS) were re-
corded using a Waters Xevo Q-Tof mass spectrometer.
Samples were dissolved into a mixture of acetonitrile / deion-
ized water / formic acid (50%:50%:0.1% composition), filtered
on a 0.2 µm membrane filter, and then immediately intro-
duced into the instrument by infusion at a rate of 10 µL/min.
The ionization mode was electrospray positive (ESI+), which
predominantly produced protonated cations ([M + H]+ spe-
cies). High-resolution spectra were acquired using a sodium
formate solution as a lock mass reference solution and used
as a mass correction when acquiring the sample spectra. ESI+
conditions were optimized with a capillary voltage between
2 kV, a sample cone of 30, an extraction cone of 3.0, a
source temperature of 120 °C, a desolvation temperature of
200 °C, a desolvation gas flow of 500 L/h, and a cone gas
flow of 10 L/h. The MS data were acquired over a range of
20–1000 m/z with a scan duration of 1 s. Melting points were
measured on a Gallenkamp melting point apparatus and all
melting points are uncorrected.
aldehydes. An added advantage of the tert-butyl ester deriva-
tives was that it allowed for easy chromatographic separation
of the stereoisomers. Although there were a few examples of
complete Z selectivity, for the most part ratios of approxi-
mately 70:30 were routinely obtained. A number of b,b-
substituted Knoevenagel condensation products were also
obtained by the use of various symmetrical and unsymmet-
rical ketones with TiCl4 or zinc chloride. In the case of an
unsymmetrical ketone a 1:1 mixture of isomers was obtained.
These b- and b,b-substituted keto ester compounds were
subjected to a variety of different reducing conditions to gen-
erate substituted MBH products, many of them previously
unknown and inaccessible via traditional MBH methods. It
was found that the reduction of these b-oxoesters was most
successful using Luche conditions with good to excellent
yields (40%–92%) being obtained within a few minutes at
room temperature. In most cases, it was determined that there
was no scrambling of the stereochemistry when either pure
E- or Z-isomers were reduced. Since it is well-documented
that Knoevenagel products are readily isomerized by simple
heating,28 this is important because, coupled with the ability
to separate them by chromatography, it offers the potential of
cycling both b-oxoester compounds to either MBH product in
a stereochemically pure fashion.
Studies aimed at using these substituted MBH adducts for
a variety of different synthetic endeavors are currently under-
way and results will be communicated in due course.
General procedure for the synthesis of a,b-unsaturated
dicarbonyl compounds 10–13
General experimental procedures
To a cooled (0 °C) mixture of aldehyde (50 mmol) and
acetoacetate (15 mmol) was added a mixture of piperidine
(0.03 mL) and EtOH (0.025 mL). The mixture was stirred at
0 °C for 12 h, and the reaction was quenched with cold aque-
ous 20% tartaric acid. The products were extracted with ethyl
acetate, and the extracts were washed with brine, dried
(MgSO4), and concentrated under reduced pressure. The
crude product was purified by column chromatography
(SiO2, hexane–AcOEt 10:1).
All reactions were carried out in flame-dried round bottom
flasks (RBF) or in oven-dried glassware (pyrex) (140 °C,
1 h) unless stated otherwise. Temperatures indicated refer to
an external bath. All reactions were magnetically stirred, un-
less stated otherwise. Standard techniques were used for sol-
vent purifications. Anhydrous reaction solvents were
available via the use of Grubbs-type columns. Air- and mois-
ture-sensitive reagents were handled via standard techniques.
Reagents were purchased from common suppliers and used
as received unless stated otherwise. SiO2 flash chromatogra-
phy was performed using Silicycle silica gel (30–60 µm par-
ticle size). Nuclear magnetic resonance (NMR) spectroscopy
was performed on a Varian INOVA 300 MHz or on a Varian
UNITY 400 MHz (referred to proton resonance frequency).
Preparation of tert-butyl (E)- and (Z)-2-acetyl-but-2-enoate
(10)
Following the general procedure, esters 10a and 10b were
formed in 83% yield (2.2 g) as a 1.2:3 mixture of E- and Z-
isomers.16
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Magee et al.
457
Preparation of tert-butyl (E)- and (Z)-2-acetyl-4-
methylpent-2-enoate (11)
Preparation of benzyl (E)- and (Z)-2-benzylidene-3-
oxobutanoate (17)
Following the general procedure, esters 11a and 11b were
formed in 70% yield (2.23 g) as a 1.2:3 mixture of E- and Z-
isomers.16
Following the general procedure, esters 17a and 17b were
formed in 77% yield as a 2:3 mixture of E- and Z-isomers.30
Preparation of tert-butyl 2-benzylidene-3-oxobutanoate (18)
Following the general procedure, ester 18 was formed in
50% yield as a single Z-isomer.31
Preparation of tert-butyl (E)- and (Z)-2-acetyloct-2-enoate (12)
Following the general procedure, esters 12a and 12b were
formed in 80% yield as a 2:3 mixture of E- and Z-isomers.
(Z)-Isomer 12a: IR (neat, cm–1): 2985, 1724, 1657, 1625,
1577, 1497, 1448, 1394, 1234, 1213, 1043, 949, 890, 757,
695. 1H NMR (CDCl3, 300 MHz) d: 0.93 (t, 3H, J =
7.0 Hz), 1.21–1.51 (m, 8H), 1.52 (s, 9H), 2.31 (s, 3H), 6.82
(t, 1H, J = 9.5 Hz). 13C NMR (CDCl3, 300 MHz) d: 22.0,
29.8, 52.0, 70.0, 126.0, 128.7, 129.6, 130.5, 133.3, 135.8,
139.9, 168.6. HRMS (M+ + H) calcd for C14H25O3:
241.1801; found: 241.1803. (E)-Isomer 12b: IR (neat, cm–1):
2985, 1724, 1657, 1625, 1577, 1497, 1448, 1394, 1234,
1213, 1043, 949, 890, 757, 695. 1H NMR (CDCl3,
300 MHz) d: 0.89 (t, 3H, J = 6.8 Hz), 1.21–1.40 (m, 8H),
1.50 (s, 9H), 2.33 (s, 3H), 6.80 (t, 1H, J = 7.8 Hz). 13C
NMR (CDCl3, 400 MHz) d: 13.9, 22.3, 28.0, 29.1, 31.0,
31.4, 81.8, 137.2, 147.6, 163.7, 201.6. HRMS (M+ + H)
calcd for C14H25O3: 241.1804; found: 241.1804.
Preparation of ethyl (Z)-2-benzoyl-3-phenylacrylate (19)
Following the general procedure, ester 19 was formed in
70% yield as a single Z-isomer.16,32
Preparation of (E)-1,3-diphenyl-2-(phenylsulfonyl)prop-2-
en-1-one (20)
Following the general procedure, ester 20 was formed as a
brown solid that was recrystalized from ethanol to give 2.7 g
(78% yield) of the E-isomer.7 mp 135–136.5 °C (lit.7 136 °C).
Preparation of methyl (E)- and (Z)-2-isobutyryl-3-
phenylacrylate (21)
Following the general procedure, ester 21 was formed in
60% yield as an 1.8:1 mixture of E- and Z-isomers.16,33
Preparation of methyl 2-benzylidene-4,4-dimethyl-3-
oxopentanoate (22)
Preparation of methyl (E)- and (Z)-2-
(cyclohexylmethylene)-3-oxobutanoate (13)
Following the general procedure, ester 22 was formed in
18% yield as a Z-isomer.34
Following the general procedure, esters 13a and 13b were
formed in 84% yield as a 2:3 mixture of E- and Z-isomers.23
Preparation of (Z)-3-cyclohexyl-2 (benzo)acrylonitrile (23)
In a RBF under argon was added benzoylacetonitrile
(1.45 g 10.0 mmol) and ethanol (30 mL). To this, L-proline
(0.23 g, 2.0 mmol) and cyclohexane carboxaldehyde
(1.21 mL, 10.0 mmol) were added. The mixture was allowed
to stir at room temperature for 48 h. It was then concentrated
in vacuo and purified via SiO2 chromatography (15:1 hexane –
ethyl acetate) to give 1.19 g (50% yield) of 23 as a clear
yellow oil.35
General procedure for the synthesis of a,b-unsaturated
dicarbonyl compounds 14–22 using the Knoevenagel
condensation reaction
1,3-Dicarbonyl compound (10 mmol), benzene (50 mL),
aldehyde (10 mmol), glacial acetic acid (1 mmol), and piper-
idine (1 mmol) were placed in an oven-dried RBF equipped
with a Dean–Stark apparatus. The mixture was heated to re-
flux and maintained there until TLC showed the complete
consumption of starting material. Upon cooling to room tem-
perature, the solution was diluted with diethyl ether (50 mL)
and water (25 mL). The organic layer was separated and
washed with water (25 mL), 1 mol/L HCl solution (2 ×
25 mL), and then sodium hydrogen carbonate solution until
neutrality was reached. The organic layer was dried
(Na2SO4), filtered, and the solvent evaporated in vacuo. The
crude product was purified by flash chromatography (hex-
ane – diethyl ether).
Preparation of ethyl a-isopropylidine acetoacetate (24)
Ethyl acetoacetate (13.0 g, 0.100 mol), acetone (8.7 g,
0.15 mol), acetic anhydride (12.8 mL), and fused zinc chlor-
ide (1.9 g) were heated under reflux for 72 h. After cooling,
diethyl ether (25 mL) was added and the resulting solution
was washed with water (4 × 25 mL). The combined water
washings were extracted with Et2O (50 mL), and the com-
bined organic extracts were dried with MgSO4, filtered, and
the solvent evaporated under reduced pressure. The oily resi-
due was purified via SiO2 chromatography (10:1 hexane –
AcOEt) to give 7.42 g (42%) of 17 as a yellow oil.36
Preparation of methyl (E)- and (Z)-2-acetyloct-2-enoate
(14)
Following the general procedure, esters 14a and 14b were
formed in 70% yield as a 1:2 mixture of E- and Z-isomers.16
General procedure for the synthesis of a,b-unsaturated
dicarbonyl compounds 25–28 using TiCl4
Preparation of ethyl (Z)-2-acetyl-4,4-dimethylpent-2-enoate
(15)
CH2Cl2 (20 mL) and THF (20 mL) were placed in a RBF
cooled to 0 °C. To this TiCl4 (2.2 mL, 20 mmol) was care-
fully added dropwise, followed by ketone (10 mmol) and
ethyl acetoacetate (1.08 mL, 10 mmol) in THF (5 mL). After
complete addition, pyridine (3.2 mL, 40 mmol) was added
and the solution was allowed to slowly warm to room tem-
perature and stir for 16 h. The reaction mixture was diluted
with H2O and ethyl acetate (1:1, 100 mL) and the aqueous
Following the general procedure, ester 15 was formed in
24% yield as a single Z-isomer.29
Preparation of methyl (E)- and (Z)-2-benzylidene-3-oxo-
butanoate (16)
Following the general procedure, esters 16a and 16b were
formed in 80% yield as a 1:1 mixture of E- and Z-isomers.16
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458
Can. J. Chem. Vol. 90, 2012
phase was separated. The organic phase was washed with
H2O (3 × 50 mL), NaHCO3, and brine and then dried over
MgSO4, filtered, and the solvent removed under reduced
pressure. The oily residue was purified via SiO2 chromatog-
raphy (7:1 hexane – ethyl acetate).
and 29b were formed in 80% yield as a 2:3 mixture of E-
and Z-isomers.40
Preparation of benzyl (E)- and (Z)-2-benzylidene-3-
hydroxybutanoate (30)
Following the general procedure (15 min), alcohols 30a
and 30b were formed in 77% yield as a 2:3 mixture of E-
and Z-isomers. Z-Isomer 30a: IR (neat, cm–1): 3421, 3031,
2974, 1718, 1497, 1455, 1385, 1212, 1142, 1014, 921, 751,
697. 1H NMR (CDCl3, 300 MHz) d: 1.44 (d, 3H, J =
6.5 Hz), 2.35 (d, 1H, J = 6.2 Hz), 4.64 (q, 1H, J = 6.3 Hz),
5.16 (s, 2H) 6.85 (s, 1H), 7.23–7.60 (m, 10H). 13C NMR
(CDCl3, 400 MHz) d: 22.4, 66.8, 69.9, 128.1, 128.2, 128.4,
128.5, 132.7, 135.0, 135.4, 137.5, 168.8. HRMS (M+ + H)
calcd for C18H19O3: 283.1334; found: 283.1334. E-Isomer
30b: IR (neat, cm–1): 3421, 3031, 2974, 1718, 1497, 1455,
1385, 1212, 1142, 1082, 1014, 921, 751, 697. 1H NMR
(CDCl3, 300 MHz) d: 1.48 (d, 3H, J = 6.5 Hz), 2.20 (s, 1H,
J = 6.3 Hz), 4.84 (q, 1H, J = 5.9 Hz), 5.16 (s, 2H), 7.21–
7.43 (m, 10H), 7.85 (s, 1H). 13C NMR (CDCl3, 400 MHz)
d: 23.3, 65.0, 66.8, 128.3, 128.5, 128.6, 128.7, 128.9, 129.2,
134.5, 135.6, 140.0, 167.5. HRMS (M+ + H) calcd for
C18H19O3: 283.1334; found: 283.1334.
Preparation of ethyl a-cyclohexylidine acetoacetate (25)
Following the general procedure, ester 18 was formed in
38% yield (0.75 g) as a pale yellow oil.37
Preparation of ethyl a-cyclopentylidine acetoacetate (26)
Following the general procedure, ester 19 was formed in
28% yield (0.55 g) as a pale yellow oil.38
Preparation of methyl 4-(1-(ethoxycarbonyl)-2-
oxopropylidine)piperdine-1-carboxylate (27)
Following the general procedure, ester 20 was formed in
32% yield (0.8 g) as a pale yellow oil.39
Preparation of ethyl (E)- and (Z)-2-acetyl-3-methyldec-2-
enoate (28)
Following the general procedure, esters 28a and 28b were
formed in 27% yield (0.64 g) as colourless oils in a 1.25:1
mixture of E- and Z-isomers. Z-Isomer 28a: IR (neat, cm–1):
2954, 2929, 2857, 1725, 1700, 1624, 1466, 1354, 1225,
Preparation of tert-butyl (E)-2-(1-hydroxyethyl)-but-2-
enoate (31)
1
1119, 1053. H NMR (CDCl3, 300 MHz) d: 0.88 (t, 3H, J =
7.1 Hz), 1.22–1.38 (m, 8H), 1.30 (t, 3H, J = 7.0 Hz), 1.42–
1.55 (m, 2H), 1.95 (s, 3H), 2.28 (s, 3H), 2.34–2.42 (m, 2H),
4.24 (q, 2H, J = 7.2 Hz). 13C NMR (CDCl3, 300 MHz) d:
14.3, 21.3, 22.8, 28.2, 29.2, 29.9, 30.8, 31.8, 31.9, 36.8,
60.9, 132.1, 157.4, 166.3, 200.3. HRMS (M+ + H) calcd for
C15H27O3: 255.1961; found: 255.1960. E-Isomer 28b: IR
(neat, cm–1): 2928, 2857, 1725, 1722, 1625, 1466, 1355,
1273, 1225, 1118, 1056. 1H NMR (CDCl3, 300 MHz) d:
0.87 (t, 3H, J = 7.0 Hz), 1.18–1.35 (m, 8H), 1.29 (t, 3H,
J = 7.2 Hz), 1.42–1.60 (m, 2H), 2.08 (s, 3H), 2.14–2.21 (m,
2H), 2.28 (s, 3H), 4.22 (q, 2H, J = 7.0 Hz). 13C NMR
(CDCl3, 300 MHz) d: 14.26, 14.3, 20.8, 22.8, 28.3, 29.2,
29.9, 31.2, 31.9, 37.1, 60.9, 132.2, 157.4, 165.9, 201.0.
HRMS (M+ + H) calcd for C15H27O3: 255.1961; found:
255.1960.
Following the general procedure (15 s), E-alcohol 31 was
formed in 66% yield as a colourless oil. IR (neat, cm–1):
3508, 2977, 2932, 1683, 1645, 1456, 1368, 1322, 1291,
1
1149, 1060, 988, 897, 761. H NMR (CDCl3, 300 MHz) d:
1.39 (d, 3H, J = 6.7 Hz), 1.51 (s, 9H), 1.80 (d, 3H, J =
7.4 Hz), 3.80 (b, 1H), 4.70 (q, 1H, J = 6.7 Hz), 6.69 (q, 1H,
J = 7.4 Hz). 13C NMR (CDCl3, 300 MHz) d: 13.7, 23.4,
28.4, 64.9, 81.5, 136.2, 136.8, 166.9. HRMS (M+ + H) calcd
for C10H19O3: 187.1334: found: 187.1332.
Preparation of tert-butyl (Z)-2-(1-hydroxyethyl)-but-2-
enoate (32)
Following the general procedure (15 s), Z-alcohol 32 was
formed in 68% yield as a colourless oil. IR (neat, cm–1):
1
3462, 2977, 1684, 1645, 1456, 1368, 1291, 1148, 1104. H
NMR (CDCl3, 300 MHz) d: 1.34 (d, 3H, J = 6.5 Hz), 1.53
(s, 9H), 1.95 (d, 3H, J = 7.2 Hz), 4.40 (q, 1H, J = 6.5 Hz),
6.15 (q, 1H, J = 7.2 Hz). 13C NMR (CDCl3, 300 MHz) d:
15.5, 22.5, 28.5, 70.3, 81.8, 134.7, 137.4, 167.4. HRMS (M+ +
H) calcd for C10H19O3: 187.1334; found: 187.1332.
General procedure for the reduction of Knoevenagel
adducts using Luche conditions
Adducts 10–28 (1 mmol) and CeC13·7H2O (1 mmol) were
dissolved in methanol (2.5 mL) and NaBH4 (38 mg, 1 mmol)
was added in one portion with stirring. A vigorous gas evolu-
tion occurred and then stirring was continued for the speci-
fied time before the pH was adjusted to neutrality with dilute
aqueous HCl. The mixture was extracted with diethyl ether
(3 × 15 mL), the combined organic extracts were dried over
MgSO4, and the solvent evaporated under reduced pressure.
The crude product was analyzed for quantitative isomer de-
termination by 1H NMR. It was then purified by column
chromatography and identified by the usual spectroscopic
methods.
Preparation of tert-butyl (E)-2-(1-hydroxyethyl)-4-
methylpent-2-enoate (33)
Following the general procedure (1 min), E-alcohol 33 was
formed in 79% yield as a colourless oil. IR (neat, cm–1):
3514, 2969, 2932, 2871, 1684, 1641, 1457, 1368, 1324,
1276, 1153, 1120, 1065, 900, 773. 1H NMR (CDCl3,
300 MHz) d: 0.98 (d, 3H, J = 6.7 Hz), 1.03 (d, 3H, J =
6.7 Hz), 1.38 (d, 3H, J = 6.7 Hz), 1.50 (s, 9H), 2.60–2.75
(m, 1H), 3.71 (d, 1H, J = 10.9 Hz), 4.61–4.72 (m, 1H), 6.35
(d, 1H, J = 10.3 Hz). 13C NMR (CDCl3, 300 MHz) d: 22.4,
22.5, 24.0, 27.3, 28.4, 65.3, 81.5, 133.1, 148.5, 167.3.
HRMS (M+ + H) calcd for C12H23O3: 215.1647; found:
215.1647.
Preparation of methyl (E)- and (Z)-2-benzylidene-3-
hydroxybutanoate (29)
Following the general procedure (15 min), alcohols 29a
Published by NRC Research Press

Magee et al.
459
Preparation of tert-butyl (Z)-2-(1-hydroxyethyl)-4-
methylpent-2-enoate (34)
128.2, 129.0, 134.4, 135.4, 141.5, 167.0. HRMS (M+ + H)
calcd for C11H21O3: 201.1491; found: 201.1491.
Following the general procedure (1 min), Z-alcohol 34 was
formed in 66% yield as a colourless oil. IR (neat, cm–1):
3514, 2969, 2932, 2871, 1684, 1641, 1457, 1368, 1324,
1276, 1153, 1120, 1065, 900, 773. 1H NMR (CDCl3,
300 MHz) d: 1.03 (d, 3H, J = 6.7 Hz), 1.38 (d, 3H, J =
6.7 Hz), 1.50 (s, 9H), 2.70 (d, 1H, J = 6.2 Hz), 3.00–3.06
(m, 1H), 4.61–4.72 (m, 1H), 6.35 (d, 1H, J = 10.3 Hz). 13C
NMR (CDCl3, 300 MHz) d: 22.65, 22.78, 22.79, 28.39,
28.44, 65.3, 81.8, 134.4, 146.0, 167.6. HRMS (M+ + H)
calcd for C12H23O3: 215.1647; found: 215.1647.
Preparation of methyl (Z)-2-(1-hydroxyethyl)oct-2-enoate
(39)
Following the general procedure (15 min), Z-alcohol 39
was formed in 49% yield as a colourless oil. IR (neat, cm–1):
3447, 2959, 1718, 1496, 1436, 1367, 1226, 1139, 1012, 753,
697. 1H NMR (CDCl3, 300 MHz) d: 0.85 (t, 3H, J =
7.0 Hz), 1.51–1.60 (m, 6H), 1.39 (d, 3H, J = 6.5 Hz), 2.40
(q, 1H, J = 7.4 Hz), 2.59 (bs, 1H), 3.80 (s, 3H), 4.52 (t, 2H,
J = 6.4 Hz), 6.19 (t, 1H, J = 7.7 Hz). 13C NMR (CDCl3,
300 MHz) d: 13.0, 20.2, 33.5, 52.0, 74.8, 128.6, 129.0,
134.0, 135.2, 141.5, 167.4. HRMS (M+ + H) calcd for
C11H21O3: 201.1491; found: 201.1491.
Preparation of tert-butyl (E)-2-(1-hydroxyethyl)oct-2-enoate
(35)
Following the general procedure (5 min), E-alcohol 35 was
formed in 75% yield as a colourless oil. IR (neat, cm–1):
3471, 2960, 2930, 2857, 1686, 1454, 1368, 1277, 1148,
1066, 850. H NMR (CDCl3, 300 MHz) d: 0.91 (t, 3H, J =
7.0 Hz), 1.30–1.51 (m, 8H) 1.62 (s, 9H), 2.80 (bs, 1H) 2.28
(s, 3H), 4.41 (q, 1H, J = 6.5 Hz), 6.61 (t, 3H, J = 6.7 Hz).
13C NMR (CDCl3, 300 MHz) d: 13.9, 22.5, 28.1, 28.3, 32.0,
82.2, 137.7, 146.9, 148.0, 163.1, 166.1, 195.0. HRMS (M+ +
H) calcd for C14H27O3: 243.1961; found: 243.1961.
Preparation of methyl (E)-2-cyclohexzylidene-3-
hydroxybutanoate (40)
Following the general procedure (5 min), E-alcohol 40 was
formed in 52% yield as a colourless oil. IR (neat, cm–1):
3447, 2959, 1718, 1496, 1436, 1367, 1226, 1139, 1012,
753, 697. 1H NMR (CDCl3, 300 MHz) d: 0.80–1.38 (m,
10H), 1.40 (d, 3H, J = 6.7 Hz), 1.41–1.80 (m, 1H), 2.50
(bs, 1H) 3.80 (s, 3H), 4.71 (t, 1H, J = 9.9 Hz), 6.53 (d, 1H,
J = 9.2 Hz). 13C NMR (CDCl3, 400 MHz) d: 24.3, 25.6,
25.8, 26.0, 32.5, 37.4, 52.0, 65.5, 132.3, 148.6, 168.4.
HRMS (M+ + H) calcd for C12H21O3: 213.1491; found:
213.1491.
1
Preparation of tert-butyl (Z)-2-(1-hydroxyethyl)oct-2-enoate
(36)
Following the general procedure (5 min), Z-alcohol 36 was
formed in 72% yield as a colourless oil. IR (neat, cm–1):
3430, 2960, 2930, 2859, 1713, 1458, 1368, 1250, 1153,
846. 1H NMR (CDCl3, 300 MHz) d: 0.91 (t, 3H, J =
6.5 Hz), 1.20–1.51 (m, 8H) 1.52 (s, 9H), 2.28 (s, 3H), 2.80
(d, 1H, J = 6.3 Hz), 4.41 (q, 1H, J = 7.0 Hz) 6.10 (t, 1H,
J = 6.7 Hz). 13C NMR (CDCl3, 300 MHz) d: 13.9, 22.4,
26.9, 28.3, 32.0, 82.2, 138.2, 146.9, 148.0, 163.1, 165.1,
195.0. HRMS (M+ + H) calcd for C14H27O3: 243.1961;
found: 243.1961.
Preparation of methyl (Z)-2-cyclohexzylidene-3-
hydroxybutanoate (41)
Following the general procedure (5 min), Z-alcohol 41 was
formed in 56% yield as a colourless oil. IR (neat, cm–1):
3447, 2959, 1718, 1496, 1436, 1367, 1226, 1139, 1012,
753, 697. 1H NMR (CDCl3, 300 MHz) d: 0.80–1.38 (m,
10H, J = 6.5 Hz), 1.39 (d, 3H, J = 6.5 Hz), 1.40–1.80 (m,
1H), 2.50 (bs, 1H) 3.80 (s, 3H), 4.71 (t, 1H, J = 9.7 Hz),
5.93 (d, 1H, J = 9.7 Hz). 13C NMR (CDCl3, 400 MHz) d:
22.6, 25.5, 26.0, 26.1, 32.5, 37.9, 51.3, 69.5, 133.0, 146.4,
168.1. HRMS (M+ + H) calcd for C12H21O3: 213.1491;
found: 213.1491.
Preparation of ethyl (Z)-2-(1-hydroxyethyl)-4,4-
dimethylpent-2-enoate (37)
Following the general procedure (1 min), Z-alcohol 37 was
formed in 66% yield as a colourless oil. IR (neat, cm–1):
3441, 2959, 2872, 1725, 1661, 1464, 1380, 1271, 1235,
1194, 1140, 1071, 1028. 1H NMR (CDCl3, 300 MHz) d:
1.15 (s, 9H), 1.35 (t, 2H, J = 7.2 Hz), 2.28 (s, 3H), 4.23 (q,
3H, J = 6.7 Hz), 5.65 (s, 1H). 13C NMR (CDCl3, 300 MHz)
d: 14.3, 22.5, 29.6, 33.3, 60.0, 61.0, 134.7, 141.3, 169.1.
HRMS (M+ + H) calcd for C11H21O3: 201.1491; found:
201.1491.
Preparation of tert-butyl (Z)-2-benzylidene-3-
hydroxybutanoate (42)
Following the general procedure (15 min), Z-alcohol 42
was formed in 50% yield.41
Preparation of ethyl (Z)-2-(hydroxyl(phenyl)methyl)-3-
phenylacrylate (43)
Following the general procedure (15 min), (Z)-alcohol 43
was formed in 64% yield.28
Preparation of methyl (E)-2-(1-hydroxyethyl)oct-2-enoate
(38)
Preparation of (E)-1,3-diphenyl-2-(phenylsulfonyl)prop-2-
en-1-ol (44)
Following the general procedure (15 min), E-alcohol 38
was formed in 40% yield as a colourless oil. IR (neat, cm–1):
3447, 2959, 1718, 1496, 1436, 1367, 1226, 1139, 1012, 753,
697. 1H NMR (CDCl3, 300 MHz) d: 0.85 (t, 3H, J =
6.9 Hz), 1.52–1.60 (m, 6H, J = 6.7 Hz), 1.39 (d, 3H, J =
6.5 Hz), 2.40 (q, 1H, J = 7.3 Hz), 2.59 (bs, 1H) 3.80 (s,
3H), 4.52 (t, 2H, J = 6.4 Hz), 6.79 (t, 1H, J = 7.4 Hz). 13C
NMR (CDCl3, 300 MHz) d: 13.0, 22.0, 33.0, 51.8, 80.5,
Following the general procedure (15 min), with the excep-
tion that a 4 mol equiv excess of sodium borohydride and ce-
rium trichloride were used, alcohol 44 was formed in 40%
yield as a colourless solid based on reacted starting material.
mp 145–147 °C. IR (neat, cm–1): 3478, 1619, 1493, 1446,
1
1298, 12589, 1142, 1089, 1049, 1029, 773, 698, 611. H
NMR (CDCl3, 300 MHz) d: 4.03 (bs, 1H), 6.09 (s, 1H),
7.02–7.14 (m, 4H), 7.25–7.32 (m, 3H), 7.38–7.54 (m, 8H),
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Can. J. Chem. Vol. 90, 2012
8.14 (s, 1H). 13C NMR (CDCl3, 300 MHz) d: 69.6, 126.0,
127.5, 127.6, 128.3, 129.0, 129.1, 129.6, 130.3, 132.7,
132.9, 139.2, 141.3, 143.0, 143.5. HRMS (M+ + H) calcd
for C21H19O3S: 351.1055; found: 351.1055.
3456, 2980, 2931, 2856, 1718, 1656, 1448, 1367, 1300,
1
1263, 1210, 1146, 1108, 1025, 916, 733. H NMR (CDCl3,
300 MHz) d: 1.32 (d, 3H, J = 7.2 Hz), 1.36 (t, 3H, J =
6.8 Hz), 1.53–1.71 (m, 6H), 2.20–2.35 (m, 4H), 2.49 (d, 1H,
J = 7.3 Hz), 4.26 (q, 2H, J = 7.2 Hz), 4.80 (p, 1H, J =
6.7 Hz). 13C NMR (CDCl3, 300 MHz) d: 14.4, 23.0, 26.5,
28.0, 28.1, 30.4, 33.4, 60.6, 65.9, 129.6, 145.1, 169.8.
HRMS (M+ + H) calcd for C12H21O3: 213.1491; found:
213.1491.
Preparation of methyl (E)-2-benzylidene-3-hydroxy-4-
methylpentanoate (45)
Following the general procedure (15 min), E-alcohol 45
was formed in 65% yield as a colourless oil. IR (neat, cm–1):
3447, 2959, 1718, 1496, 1436, 1367, 1226, 1139, 1012, 753,
697. 1H NMR (CDCl3, 300 MHz) d: 0.69 (d, 3H, J =
6.7 Hz), 1.04 (d, 3H, J = 6.7 Hz), 2.03 (m, 1H), 3.22 (d,
1H, J = 2.7 Hz), 3.85 (s, 3H), 4.22 (t, 1H, J = 9.9 Hz),
7.26–7.43 (m, 5H), 7.80 (s, 1H). 13C NMR (CDCl3,
300 MHz) d: 18.0, 19.5, 33.0, 51.8, 80.5, 128.2, 129.0,
134.4, 135.4, 141.5, 167.4. HRMS (M+ + H) calcd for
C14H19O3: 235.1334; found: 235.1334.
Preparation of ethyl 2-cyclopentylidene-3-hydroxybutanoate
(51)
Following the general procedure (15 min), alcohol 51 was
formed in 94% yield as a pale yellow oil. IR (neat, cm–1):
3447, 2976, 2931, 2856, 1717, 1448, 1367, 1300, 1263,
1
1210, 1146, 1108, 916, 733. H NMR (CDCl3, 300 MHz) d:
1.32 (t, 3H, J = 7.2 Hz), 1.39 (d, 3H, J = 6.7 Hz), 1.60–1.78
(m, 4H), 2.28–2.40 (m, 2H), 2.66–2.72 (m, 2H), 3.64 (d, 1H,
J = 10.4 Hz), 4.24 (q, 2H, J = 7.0 Hz), 4.6 (p, 1H, J =
6.6 Hz). 13C NMR (CDCl3, 300 MHz d): 14.2, 25.9, 26.1,
30.3, 34.8, 34.82, 60.8, 128.1, 166.4, 169.2, 199.2. HRMS
(M+ + H) calcd for C11H19O3: 199.1334; found: 199.1334.
Preparation of methyl (Z)-2-benzylidene-3-hydroxy-4-
methylpentanoate (46)
Following the general procedure (15 min), Z-alcohol 46
was formed in 71% yield as a colourless oil. IR (neat, cm–1):
3447, 2959, 1718, 1496, 1436, 1367, 1226, 1139, 1012, 753,
697. 1H NMR (CDCl3, 300 MHz) d: 0.86 (d, 3H, J =
6.7 Hz), 1.02 (d, 3H, J = 6.7 Hz), 1.92 (m, 1H, J =
2.7 Hz), 2.10 (s, 1H), 3.63 (s, 3H), 4.06 (d, 1H, J =
9.9 Hz), 6.83 (s, 1H), 7.23–7.40 (m, 5H). 13C NMR (CDCl3,
300 MHz) d: 19.6, 33.5, 52.0, 74.8, 128.6, 128.67, 129.0,
133.2, 134.0, 141.5, 167.4. HRMS (M+ + H) calcd for
C14H19O3: 235.1334; found: 235.1334.
Preparation of methyl 4-(1-(ethoxycarbonyl)-2-
hydroxypropylidene)piperidine-1-carboxylate (52)
Following the general procedure, alcohol 52 was formed in
71% yield as a pale yellow oil. IR (neat, cm–1): 3455, 2980,
2873, 1684, 1456, 1412, 1371, 1213, 1132, 1095, 1071,
1
1024, 862, 769. H NMR (CDCl3, 300 MHz) d: 1.32 (t, 3H,
J = 7.0 Hz), 1.37 (d, 3H, J = 6.7 Hz), 2.54–2.46 (m, 5H),
3.46–3.58 (m, 4H), 3.70 (s, 3H), 4.26 (q, 2H, J = 7.2 Hz),
4.75 (p, 1H, J = 6.5 Hz). 13C NMR (CDCl3, 300 MHz) d:
14.5, 23.1, 29.6, 32.0, 44.1, 44.4, 52.9, 61.0, 65.4, 132.2,
140.8, 156.0, 168.9. HRMS (M+ + H) calcd for C13H22NO5:
272.1498; found: 272.1498.
Preparation of (Z)-3-cyclohexyl-2-(hydroxy(phenyl)methyl)
acrylonitrile (48)
Following the general procedure (5 min), alcohol 48 and
its saturated analogue were formed in 52% yield as a yellow
oil that was inseparable by SiO2 chromatography. IR
(neat, cm–1): 3444, 3063, 3031, 2926, 2853, 2221, 1450,
Preparation of ethyl (Z)-2-(1-hydroxyethyl)-3-methyldec-2-
enoate (53)
1
1047, 701. H NMR (CDCl3, 400 MHz) d: 1.67–1.76 (m,
Following the general procedure (15 min), Z-alcohol 53
was formed in 82% yield as a pale yellow oil. IR (neat, cm–1):
3509, 3419, 2929, 2857, 1720, 1624, 1465, 1366, 1272,
1164, 1117, 1056, 967, 779, 722. 1H NMR (CDCl3,
300 MHz) d: 0.88 (t, 3H, J = 7.2 Hz), 1.24–1.48 (m,
10H), 1.33 (t, 3H, J = 7.2 Hz), 1.35 (d, 3H, J = 6.7 Hz),
1.80 (s, 3H), 2.14–2.22 (m, 2H), 2.67 (d, 1H, J = 8.4 Hz),
4.25 (q, 2H, J = 7.2 Hz), 4.71 (p, 1H, J = 7.4 Hz). 13C
NMR (CDCl3, 300 MHz) d: 14.3, 14.5, 18.6, 22.6, 22.8,
28.4, 29.4, 29.8, 32.0, 37.1, 60.6, 66.3, 76.5, 132.0, 143.7,
169.4. HRMS (M+ + H) calcd for C15H29O3: 257.2117;
found: 257.2118.
10H), 2.17 (d, 1H, J = 4.0 Hz), 2.51–2.62 (m, 1H), 5.27 (d,
1H, J = 4.0 Hz), 6.37 (d, 1H, J = 10.0 Hz), 7.25–7.41 (m,
5H). 13C NMR (CDCl3, 400 MHz) d: 25.4, 25.8, 32.1, 40.7,
74.6, 126.4, 126.5, 126.7, 128.9, 128.95, 129.0, 153.2.
HRMS (M+ + H) calcd for C16H20NO: 242.1546; found:
242.1545.
Preparation of methyl 2-(1-hydroxyethyl)-3-methylbut-2-
enoate (49)
Following the general procedure (15 min), alcohol 49 was
formed in 91% yield as pale yellow oil. IR (neat, cm–1):
3450, 2970, 2931, 2856, 1715, 1448, 1372, 1300, 1253,
1
1210, 1146, 1108, 916, 733. H NMR (CDCl3, 300 MHz) d:
Preparation of ethyl (E)-2-(1-hydroxyethyl)-3-methyldec-2-
enoate (54)
1.34 (t, 3H, J = 7.1 Hz), 1.35 (d, 3H, J = 6.6 Hz), 1.83 (s,
3H), 1.9 (s, 3H), 2.80 (d, 1H, J = 1.4), 4.28 (q, 2H, J =
7.0 Hz), 4.74 (p, 1H, J = 6.9 Hz). 13C NMR (CDCl3,
300 MHz) d: 14.4, 20.8, 22.5, 23.2, 60.5, 66.1, 131.9, 140.0,
169.3. HRMS (M+ + H) calcd for C8H15O3: 159.1021;
found: 159.1021.
Following the general procedure (15 min), E-alcohol 54
were formed in 82% yield as a pale yellow oil. IR (neat, cm–1):
3515, 3419, 2929, 2857, 1720, 1700, 1624, 1465, 1354,
1
1224, 1172, 1118, 1052, 970, 859, 781, 668, 646, 563. H
NMR (CDCl3, 300 MHz) d: 0.88 (t, 3H, J = 6.8 Hz), 1.32
(t, 3H, J = 7.0 Hz), 1.35 (d, 3H, J = 6.5 Hz), 1.88 (s, 3H),
2.04–2.22 (m, 2H), 2.81 (d, 1H, J = 8.0 Hz), 4.27 (q, 2H,
J = 7.2 Hz), 4.72 (p, 1H, J = 6.3 Hz). 13C NMR (CDCl3,
300 MHz) d: 14.3, 14.5, 21.4, 22.8, 28.4, 29.3, 29.9, 31.9,
Preparation of ethyl 2-cyclohexylidene-3-hydroxybutanoate
(50)
Following the general procedure (15 min), alcohol 50 was
formed in 69% yield as a pale yellow oil. IR (neat, cm–1):
Published by NRC Research Press

Magee et al.
461
35.0, 60.7, 65.9, 131.6, 144.8, 169.6. HRMS (M+ + H)
calcd for C15H29O3: 257.2117; found: 257.2117.
20.8 mmol) and CH2Cl2 (30 mL). The solution was cooled
to –30 °C and triphenylphosphine (5.8 g, 22.1 mmol) was
added, followed by NBS (3.9 g, 21.9 mmol). When the reac-
tion was deemed complete using TLC, ~4 h at –30 °C, the
solution was diluted with CH2Cl2, washed with NaHCO3
(2×), brine, and then dried over MgSO4. It was then filtered
and solvent was removed in vacuo. The product was then pu-
rified via column chromatography using hexane – ethyl ace-
tate (10:1) as eluent to yield bromide 55 as a yellow oil
(2.2 g, 48%) that was immediately used in the next reaction.
IR (neat, cm–1): 2981, 2927, 1720, 1640, 1445, 1387, 1262,
1153, 1095, 1033, 913, 763, 734. 1H NMR (CDCl3,
300 MHz) d: 6.92 (q, 0.33 H, J = 7.4 Hz) and 6.35 (qd,
0.66 H, J = 0.9, 7.2 Hz), 5.23 (q, 0.33H, J = 7.1 Hz), 5.11
(qt, 0.66 H, J = 0.9, 7.1 Hz), 4.29 (m, 2H), 2.05–1.85 (m,
6H), 1.32 (m, 3H). 13C NMR (CDCl3, 300 MHz) d: 166.2,
140.3, 136.4, 60.8, 37.9, 24.3, 15.7, 14.2.
General procedure for the reduction of Knoevenagel
adducts using BMS
In a 50 mL three-neck flask equipped with a magnetic stir-
ring bar and a reflux condenser, THF (3 mL) and b-keto ester
(0.5 mmol) were added. To this well-stirred solution under an
argon atmosphere was added BMS (0.50 mmol). After stir-
ring for 75 min, excess hydride was quenched by the addition
of methanol (0.5 mL), and the solution was diluted with
water (25 mL) and extracted with diethyl ether (6 × 10 mL).
The combined organic extracts was dried over MgSO4 and,
after filtration and evaporation of solvent, the crude product
was purified by silica gel chromatography.
Preparation of methyl 2-benzylidene-3-hydroxybutanoate (29)
Two isomers were obtained: E and Z (2:3); 40% yield.
Preparation of 2,4-dimethyl-8-oxo-bicyclo[3.2.1]octane-3-
carboxylic acid tert-butyl ester (57)
Preparation of tert-butyl 2-benzylidene-3-hydroxybutanoate
(42)
To a RBF, under argon, was added enamine 56 (1.36 g,
9.95 mmol), CH3CN (15 mL), and triethylamine (1.2 g,
11.9 mmol). To this solution was then added bromoalkene
55 (2.2 g, 9.95 mmol) in CH3CN (10 mL). After complete
addition, the solution was heated at reflux for 20 h, cooled,
and then water (15 mL) was added and heating at reflux was
continued for 1.5 h. After cooling to room temperature, the
solution was extracted with CH2Cl2 (4×). The combined or-
ganic phases were washed with brine, dried over MgSO4,
and filtered. The solvent was removed in vacuo to yield a
brown oil that was purified via column chromatography us-
ing hexane – ethyl acetate (4:1) as eluent to yield ketone 57
as a yellow oil (0.79 g, 36%). IR (neat, cm–1): 2975. 1H
NMR (CDCl3, 300 MHz) d: 2.76 (m, 0.5H), 2.63 (dp, J =
2.9, 7.4 Hz, 0.5H), 2.45 (m, 1H), 2.26 (dd, J = 2.6, 7.7 Hz,
0.5H), 2.16–1.94 (m, 3H), 1.92–1.78 (m, 2.5H), 1.71 (t, J =
8.4 Hz, 1H), 1.48 (s, 4.5H), 1.47 (s, 4.5H), 1.17 (d, J =
7.3 Hz, 1.5H), 1.08 (d, J = 7.1 Hz, 4.5H). 13C NMR
(CDCl3, 300 MHz) d: 220.1, 219.6, 174.7, 173.4, 81.0, 80.8,
52.2, 49.9, 49.5, 48.8, 48.4, 45.8, 43.0, 39.0, 28.23, 28.2,
25.1, 22.6, 22.0, 21.5, 17.7, 17.4. HRMS (M+ + H) calcd
for C15H25O3: 253.1804; found: 253.1805.
1,2- and 1,4-addition products and two isomers (E and Z)
were obtained in 10% yield.
Preparation of ethyl (Z)-2-(hydroxyl(phenyl)methyl)-3-
phenylacrylate (43)
No reduction.
Preparation of methyl (E)- and (Z)-2-isobutyryl-3-
phenylacrylate (45)
Two isomers were obtained (E and Z in a ratio of 2:3) in
10% yield, but they were not separable.
General procedure for the reduction of Knoevenagel
adducts with sodium borohydride and Yb(OTf)3
The keto ester (0.05 g, 1 mmol), MeOH (3 mL), and
Yb(OTf)3 (1.1 equiv) were added to a RBF and stirred at
room temperature for 30 min. The solution was cooled to
–78 °C and then NaBH4 (1.1 equiv) was added slowly. The
resulting mixture was stirred for 30 min at this temperature
and then quenched by the addition of saturated aqueous am-
monium chloride (10 mL). The reaction mixture was ex-
tracted with CH2Cl2 (3 × 5 mL), and the combined organic
extract was dried over anhydrous MgSO4. After filtering,
the solvent was evaporated under reduced pressure and the
product purified by flash column chromatography.
Acknowledgments
Financial support from the Natural Sciences and Engineer-
ing Research Council of Canada (NSERC) for a Discovery
Grant and the University of New Brunswick (UNB), Freder-
icton, New Brusnwick, is gratefully acknowledged. S.R.
would like to thank the Botswana International University of
Science and Technology (BIUST) for supporting her studies
in Canada. Helpful discussions with Dr. Larry Calhoun
(UNB) are gratefully acknowledged. We would like to thank
Gilles Vautour for his assistance in running the mass specs
and Elena McIntyre for her assistance in making some start-
ing materials.
Preparation of methyl 2-benzylidene-3-hydroxybutanoate
(29)
Two isomers were obtained: E and Z (2:3); 20% yield.
Preparation of tert-butyl 2-benzylidene-3-hydroxybutanoate
(42)
The Z-isomer was obtained in 40% yield.
Preparation of ethyl (Z)-2-(hydroxyl(phenyl)methyl)-3-
phenylacrylate (43)
No reduction.
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