Indium (III) mediated Markovnikov addition of malonates and β-ketoesters to terminal alkynes and the formation of Knoevenagel condensation products

Article abstract of DOI:10.1016/j.tet.2005.05.065

The indium(III) triflate mediated addition of active methylene compounds to terminal alkynes has been expanded to use malonates and low boiling terminal alkynes to form the Markovnikov addition products. Indium(III) chloride and indium(III) bromide were also found to be efficient catalysts. Knoevenagel condensation products were isolated when reactions involved a simple malonate or β-ketoester.

Full text of DOI:10.1016/j.tet.2005.05.065

Tetrahedron 61 (2005) 7807–7813
Indium (III) mediated Markovnikov addition of malonates and
b-ketoesters to terminal alkynes and the formation of
Knoevenagel condensation products
*
Ji Zhang, Peter G. Blazecka, Paul Angell, Mark Lovdahl and Timothy T. Curran
Chemical Research and Development, Pfizer Global Research & Development, Michigan Laboratories, Pfizer, Inc., 2800 Plymouth Road,
Ann Arbor, MI 48105, USA
Received 28 March 2005; revised 17 May 2005; accepted 18 May 2005
Available online 22 June 2005
Abstract—The indium(III) triflate mediated addition of active methylene compounds to terminal alkynes has been expanded to use
malonates and low boiling terminal alkynes to form the Markovnikov addition products. Indium(III) chloride and indium(III) bromide were
also found to be efficient catalysts. Knoevenagel condensation products were isolated when reactions involved a simple malonate or
b-ketoester.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
question of our ability to prepare densely functionalized
olefins using metal catalysis. Although the classic Wittig
olefination10 or Horner–Emmons reaction11 has been used
frequently to prepare terminal olefins, the Wittig reaction
suffers from the generation of a notorious side-product,
phosphine oxide. Indeed developing a green, simple and
efficient method to prepare functionalized, terminal olefins,
reducing our dependence on the Wittig reaction is extremely
significant.
Developing environmentally friendly, or green and atom
efficient processes is becoming more and more important in
modern organic chemistry.1 Indium(III) salts, such as
indium(III) triflate and indium(III) chloride, are efficient
green Lewis acids2 and have become the focus of attention
in several organic reactions.3 A particularly powerful
application of this Lewis acid in the preparation of terminal
olefins was recently reported by Nakamura and co-workers.4
The indium triflate (0.5–5%) promoted addition of
b-ketoester and 1,3-diketone to terminal alkynes described
therein attracted our attention. Compounds 1 and 2 (Fig. 1)
are important intermediates in Pfizer’s drug research and
development program, and we envisioned that these
molecules could be accessed through intermediates 3 and
4, products of an indium(III) promoted addition employing
malonates as the active methylene species.
2. Results and discussion
There were several issues to address at the beginning of our
study. First, could malonate be one of the starting materials?
Secondly, could low boiling alkynes, such as 1-pentyne (bp
39–41 8C) and 1-hexyne (bp 71–72 8C) be employed under
neat conditions involving temperatures of 100–140 8C?
Finally, although it was reported that other Lewis acids are
not efficient and only indium triflate works well,4 would
Moreover, terminal olefins comprise one of the most
important classes of compounds vis a vis functional group
transformation, giving alcohols, amines, aldehydes car-
boxylic acid derivatives, ethers and epoxides as products of
various catalytic reactions.5 The recent revolution in olefin
metathesis and ring-closing metathesis (RCM) led by
Grubbs,6 Schrock,7 Hoveyda8 and others9 also raises the
Keywords: Indium (III); Active methylene; Alkyne; Markovnikov;
Knoevenagel.
*
Corresponding author. Tel.: C1 734 622 3940; fax: C1 734 622 3294;
e-mail: ji.zhang@pfizer.com
Figure 1. Some useful compounds potentially from the reaction of
malonate and 1-alkynes mediated by indium(III).
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.065

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J. Zhang et al. / Tetrahedron 61 (2005) 7807–7813
observed that as the heating continued, the reaction became
self-heating causing the temperature to rise quickly in a very
short time. This is a potential safety concern for large scale
application.
Thus, we decided to dilute the neat mixture with a high
boiling, non-polar solvent, such as toluene. The reaction
proceeded very well under these conditions. On 20 mmol
scale the desired product was isolated in 98% yield. A 1.2
mole scale reaction afforded product in 98% yield, isolated
by simple vacuum distillation. This reaction proceeded
without the previously described exotherm.
Figure 2. Possible mechanism of In(III) mediated addition of b-ketoester to
terminal alkyne.
A solvent screen (Table 1) revealed o-xylene (bp 143–
145 8C) to be an ideal solvent in which to run the reaction at
higher temperature with excellent yield when phenylacety-
lene was the reactant. Indeed, neat conditions also provided
the desired product in excellent yield on this scale. Addition
of an amine base such as N-methylmorpholine, reported to
promote formation of the enolate,16 had a deleterious effect.
other indium salts be effective? Furthermore, by what
mechanism does the reaction proceed? In light of some
related reports using allylindiums in the allylation of
unactivated alkynes12 and an indium(III) catalyst in the
Friedel–Crafts alkenylation of arenes using alkynes,13 as
well as indium triflate as an alkyne activator to catalyze a
double addition of heterocyclic arenes to alkyne,13 we
believe the mechanistic rationale proposed by Nakamura4
might be incomplete. Since other Lewis acids that favored
the formation of the enolate anion14 did not promote this
reaction, we therefore postulate that activation of alkyne is
required in order for the reaction to proceed (Fig. 2).15
A screen of various Lewis acids was then conducted using
the reaction between phenylacetylene and diethyl methyl-
malonate as the model. The study (Table 2) revealed that
other indium(III) salts could promote the reaction as
efficiently as In(OTf)3. However, the unique nature of
indium was once again illustrated by the lack of reactivity
exhibited by other Lewis acids.
The low boiling point of 1-pentyne and the desired reaction
temperature of 100–140 8C necessitated performing the
reaction in a sealed tube. Employing Nakamura’s con-
ditions, a neat mixture of nearly stoichiometric amounts of
1-pentyne and diethyl methylmalonate and 5% In(OTf)3
was heated to 100–140 8C for 10 h (Scheme 1). Surpris-
ingly, it gave only a low yield of desired product, as well as
at least two other significant side-products. We also
We then turned our attention to other alkynes (Table 3).
Unlike phenylacetylene, 3-phenyl-1-propyne and 4-phenyl-
1-butyne gave products 8 and 9 in 58 and 54% yield. If
activation of the alkyne by In(OTf)3 occurs, it will form the
carbocation intermediate suggested by Shirakawa.13 The
phenyl group is much better at stabilizing the cation than an
alkyl group. Since this is a highly regioselective reaction,
giving the Markovnikov addition product (branched
product) even under the high temperature/sealed tube
conditions, it strongly suggests that electronic effects are
much more important than steric effects in governing the
regiochemistry. Otherwise one might expect the reaction
Scheme 1. Addition of malonate to low boiling alkyne.
a
Table 1. Solvent screen using InCl3
Entry
Solvent
Temperature (8C)
Additiveb
Conversion (%)c
4 h
20 h
1
2
3
4
5
6
7
o-Xylene
o-Xylene
Toluene
Toluene
Dioxane
Neat
135
135
110
110
100
140
140
—
NMM
—
NMM
—
—
35
0
2
0
0
94
1
53
0
0
98
34
61
7
Neat
NMM
a Reaction conditions: 1 equiv (2.0 mmol) of diethyl methylmalonate, 1.2 equiv of phenylacetylene, 0.02 equiv of InCl3, neat or with desired solvent, 20 h at
desired temperature.
b 0.10 equiv N-methylmorpholine (NMM).
c Amount of product relative to malonate. Determined by HPLC analysis of reaction mixture after desired reaction time.

J. Zhang et al. / Tetrahedron 61 (2005) 7807–7813
7809
Table 2. Lewis acid screena
4. Experimental
4.1. General
All reactions were carried out under nitrogen atmosphere
unless otherwise noted. All solvents and reagents used were
from commercial sources and no further purification was
performed. Reactions were monitored by mass spectrometry
(MS) on a Micromass Platform LC and by thin-layer
chromatography on 0.25 mm E. Merck silica gel 60 plates
(F254) using UV light and aqueous potassium permanga-
nate–sodium bicarbonate as visualizing agents. E. Merck
silica gel 60 (0.040–0.063 mm and 0.063–0.200 mm
particle sizes) was used for column chromatography. Proton
nuclear magnetic resonance (1H NMR) spectra were
recorded at 400 MHz on a Varian UNITY INOVA AS400.
Chemical shifts are reported as delta (d) units in parts per
million (ppm) relative to the singlet at 7.26 ppm for
deuteriochloroform. Coupling constants (J) are reported in
Hertz (Hz). Carbon-13 nuclear magnetic resonance (13C
NMR) spectra were recorded at 100 MHz on a Varian
UNITY Plus INOVA 400. Chemical shifts are reported as
delta (d) units in parts per million (ppm) relative to the
center line of the triplet at 77.3 ppm for deuteriochloroform.
Elemental analyses were performed out-of-house by
Quantitative Technologies Inc.
Entry
Catalyst
Yield (%)b
1
2
3
4
5
6
7
8
9
10
La(OTf)3
Mg(OTf)2
Sc(OTf)3
Sn(OTf)2
Zn(OTf)2
Yb(OTf)3
InCl3
InBr3
In(OAc)3
InF3
Trace
NDc
Trace
8
ND
ND
88
92
ND
ND
a Reaction conditions: 1 equiv (10 mmol) of diethyl methylmalonate,
1.2 equiv of phenylacetylene, 0.05 equiv of desired Lewis acid, o-xylene,
16 h at 125–130 8C. The reaction time was not optimized.
b Isolated yield after purification by silica gel chromatography. Products
1
estimated to be O95% pure by H NMR and elemental analysis.
c NDZnot detected.
would provide the anti-Markovnikov addition product
(linear product).
The classic Knoevenagel reaction is the condensation of an
aldehyde or ketone with an activated methylene compound
in the presence of ammonia or amine.17 Recently, it was
reported that the reaction is catalyzed by Lewis acid.18 The
Knoevenagel acceptors are versatile intermediates for
Michael addition,19 Diels–Alder reaction20 and Pinner
reaction.21 When an unsubstituted malonate was used in
this indium(III) mediated reaction, a mixture of conjugated
and unconjugated products was formed (Table 4). In some
cases, only the Knoevenagel condensation products or
alkylidenemalonates were observed. When a b-ketoester
was used, it also afforded a mixture of conjugated and
unconjugated products, which was inconsistent with
Nakamura’s study.4 It is generally accepted that the
Knoevenagel condensation between ketones and malonate
is often unachievable by using conventional methodology.22
Thus, this indium (III) mediated highly regioselective
Markovnikov addition of malonates and other activated
methylene compounds to terminal alkynes, giving high
yield of Knoevenagel condensation products, provides an
alternative approach.
4.2. General procedure for indium(III) mediated
Markovnikov addition of diethyl methylmalonate to
phenylacetylene (Table 1). Compound 5
Diethyl methylmalonate (0.348 g, 2.00 mmol) was com-
bined with phenylacetylene (0.245 g, 2.40 mmol,
1.20 equiv) and InCl3 (9 mg, 0.04 mmol, 0.02 equiv), with
or without N-methylmorpholine (20 mg, 0.20 mmol,
0.10 equiv), in the desired solvent (10 mL), or in the
absence of solvent, and heated at a few degrees below reflux
for 20 h. Relative amounts of product and malonate starting
material in the reaction mixtures were determined by HPLC
analysis.
4.3. General procedure for metal mediated
Markovnikov addition of diethyl methylmalonate
to phenylacetylene (Table 2). Compound 5
Diethyl methylmalonate (1.74 g, 10.0 mmol) was combined
with phenylacetylene (1.23 g, 12.0 mmol, 1.20 equiv) and
the desired Lewis acid catalyst (0.50 mmol, 0.05 equiv) in
o-xylene (10 mL) and stirred at 125–130 8C for 16 h. The
reaction mixture was concentrated under reduced pressure,
and the residue was purified by silica gel column
chromatography (ethyl acetate/heptane).
3. Conclusion
In summary, the indium triflate mediated addition of
activated methylene compounds to terminal alkynes has
been expanded to use malonates and low boiling terminal
alkynes to form Markovnikov addition products. Other
indium(III) salts, such as indium chloride and indium
bromide were also found to be efficient catalysts. When an
unsubstituted malonate or b-ketoester was used, Knoeven-
gel condensation product was formed. Further investi-
gations, including extension of the use of this reaction will
be reported in due course.
4.4. General procedure for indium(III) mediated
Markovnikov addition of malonates and b-ketoesters
to terminal alkynes (reagents with bp !130 8C).
Compounds 4, 6, 17 and 19
The desired malonate or b-ketoester (10.0 mmol) was
combined with the desired alkyne (12.0 mmol, 1.2 equiv)
and the desired indium (III) catalyst (0.05–0.20 mmol,
0.005–0.02 equiv) in toluene or o-xylene (10 mL) and
heated at 140 8C in a sealed tube for 10–20 h. The reaction

7810
J. Zhang et al. / Tetrahedron 61 (2005) 7807–7813
Table 3. Addition of different 1-alkynes to branched malonates and b-ketoestersa
Entry
Product
Catalyst/Rxn
temperature (8C)
Yield (%)b
6
1
2
In(OTf)3/110
In(OTf)3/110c
95
98
4
7
3
4
InCl3/130
58
In(OTf)3/110
InCl3/130
84
88
5
InBr3/130
InCl3/130
InBr3/130
92
58
30
8
5
6
InCl3/130
InBr3/130
54
35
9
10
11
7
8
InCl3/140
InCl3/130
81
82
12
9
InCl3/130
InCl3/130
InCl3/130
50
41
96
13
10
11
14
15
12
InCl3/130
43
a Reaction conditions: 1 equiv (10–20 mmol) of malonate or b-ketoester, 1.2–1.5 equiv of desired alkyne, 0.005–0.05 equiv of desired indium(III) salt, o-
xylene or toluene, 10–24 h at 110–140 8C. The reaction time was not optimized.
1
b Isolated yield after purification by silica gel chromatography. Products estimated to be O95% pure by H NMR and elemental analysis.
c Reaction repeated on 0.6 and 1.2 mol scales with identical results.
mixture was concentrated under reduced pressure, and the
residue was purified by silica gel column chromatography
(ethyl acetate/heptane).
5.05–5.07 (m, 1H). 13C NMR (CDCl3): d 12.9, 14.2, 21.0,
25.7, 60.8, 61.6, 111.6, 148.6, 171.5. Anal. Calcd for
C12H20O4: C, 63.14; H, 8.83. Found: C, 63.12; H, 8.36.
4.4.1. 2-Methyl-2-(1-methylenebutyl)malonic acid
diethyl ester (4). H NMR (CDCl3): d 0.90 (t, JZ7.3 Hz,
4.4.3. 2-(1-Methylbutylidene)malonic acid diethyl ester
(17). H NMR (CDCl3): d 0.92 (t, JZ7.4 Hz, 3H), 1.26 (t,
1
1
3H), 1.23 (t, JZ7.1 Hz, 6H), 1.44–1.53 (m, 2H), 1.56 (s,
3H), 2.01–2.05 (m, 2H), 4.17 (q, JZ7.2 Hz, 4H), 4.96–4.98
(m, 1H), 5.02–5.04 (m, 1H). 13C NMR (CDCl3): d 14.2,
21.0, 21.9, 35.1, 60.8, 61.6, 112.2, 147.0, 171.5. Anal. Calcd
for C13H22O4: C, 64.44; H, 9.15. Found: C, 64.54; H, 8.82.
JZ7.1 Hz, 3H), 1.27 (t, JZ7.1 Hz, 3H), 1.52 (m, 2H), 2.04
(s, 3H), 2.30 (m, 2H), 4.20 (q, JZ7.1 Hz, 2H), 4.21 (q, JZ
7.1 Hz, 2H). 13C NMR (CDCl3): d 14.2, 20.8, 21.4, 38.8,
60.9, 61.0, 124.8, 166.0, 158.8, 165.7. Anal. Calcd for
C10H20O4: C, 63.14; H, 8.83. Found: C, 63.14; H, 8.75.
4.4.2. 2-Methyl-2-(1-methylenepropyl)malonic acid
diethyl ester (6). H NMR (CDCl3): d 1.08 (t, JZ7.5 Hz,
4.4.4. 2-(1-Methylpentylidene)malonic acid diethyl ester
(19). H NMR (CDCl3): d 0.90 (t, JZ7.3 Hz, 3H), 1.27 (t,
1
1
3H), 1.25 (t, JZ7.1 Hz, 6H), 1.59 (s, 3H), 2.12 (q, JZ
7.2 Hz, 2H), 4.19 (q, JZ7.1 Hz, 4H), 4.98–5.01 (m, 1H),
JZ7.1 Hz, 3H), 1.27 (t, JZ7.1 Hz, 3H), 1.33 (m, 2H), 1.47
(m, 2H), 2.05 (s, 3H), 2.33 (m, 2H), 4.21 (q, JZ7.1 Hz, 2H),

J. Zhang et al. / Tetrahedron 61 (2005) 7807–7813
Table 4. Addition of 1-alkynes to simple malonates or b-ketoestersa
7811
Entry
1
S.m.
Alkyne
Products (%yield)b
16 (0%)
17 (75%)
18 (0%)
19 (82%)
2
3c
20 (8%)
20 (9%)
21 (71%)
21 (82%)
4d
22 (22%)
24 (22%)
23e (60%)
25e (53%)
5
6
a Reaction conditions: 1 equiv (10 mmol) of malonate or b-ketoester, 1.2–1.5 equiv of desired alkyne, 0.01–0.05 equiv of InCl3, o-xylene, 16–20 h at 130–
140 8C. The reaction time was not optimized.
1
b Isolated yield after purification by silica gel chromatography. Products estimated to be O95% pure by H NMR and elemental analysis.
c Used 1.2 equiv of alkyne. Compounds 20 and 21 isolated as 1:9 mixture.
d Used 1.5 equiv of alkyne. Compounds 20 and 21 isolated as 1:9 mixture.
e Compounds 23 and 25 isolated as mixtures of E and Z isomers.
4.22 (q, JZ7.1 Hz, 2H). 13C NMR (CDCl3): d 14.0, 14.2,
20.9, 22.9, 30.2, 36.7, 60.9, 61.0, 124.6, 159.1, 165.7, 166.0.
Anal. Calcd for C13H22O4: C, 64.44; H, 9.15. Found: C,
64.70; H, 8.94.
2.03–2.10 (m, 2H), 4.19 (q, JZ7.16 Hz, 4H), 4.98–5.00 (m,
1H), 5.05–5.07 (m, 1H). 13C NMR (CDCl3): d 14.2, 14.3,
21.0, 22.9, 28.8, 29.5, 29.8, 32.1, 33.0, 60.8, 61.6, 112.1,
147.3, 171.5. Anal. Calcd for C18H32O4: C, 69.19; H, 10.32.
Found: C, 69.21; H, 10.39.
4.5. General procedure for indium(III) mediated
Markovnikov addition of malonates and b-ketoesters to
terminal alkynes (reagents with bp O130 8C). Com-
pounds 5, 7–15 and 20–25
4.5.3. 2-(1-Benzylvinyl)-2-methylmalonic acid diethyl
ester (8). H NMR (CDCl3): d 1.27 (t, JZ7.1 Hz, 6H),
1.66 (s, 3H), 3.47 (s, 2H), 4.19 (q, JZ7.1 Hz, 4H), 4.72–
4.79 (m, 1H), 5.10–5.16 (m, 1H), 7.15–7.31 (m, 5H). 13C
NMR (CDCl3): d 14.2, 21.2, 39.7, 60.4, 61.8, 115.9, 126.4,
128.5, 129.8, 139.5, 146.8, 171.4. Anal. Calcd for
C17H22O4: C, 70.32; H, 7.64. Found: C, 70.59; H, 7.79.
1
The desired malonate or b-ketoester (10.0 mmol) was
combined with the desired alkyne (12.0–15.0 mmol, 1.20–
1.50 equiv) and the desired indium (III) catalyst (0.10–
0.50 mmol, 0.01–0.05 equiv) in toluene or o-xylene
(10 mL), and heated at 110–140 8C for 16–24 h. The
reaction mixture was concentrated under reduced pressure,
and the residue was purified by silica gel column
chromatography (ethyl acetate/heptane).
4.5.4. 2-Methyl-2-(1-methylene-3-phenylpropyl)malonic
1
acid diethyl ester (9). H NMR (CDCl3): d 1.27 (t, JZ
7.1 Hz, 6H), 1.62 (s, 3H), 2.38–2.46 (m, 2H), 2.78–2.86 (m,
2H), 4.21 (q, JZ7.2 Hz, 4H), 5.09 (br s, 1H), 5.18 (br s, 1H),
7.14–7.30 (m, 5H). 13C NMR (CDCl3): d 14.2, 21.1, 34.9,
35.2, 60.8, 61.7, 112.9, 126.1, 128.6, 128.6, 142.1, 146.6,
171.4. Anal. Calcd for C18H24O4: C, 71.03; H, 7.95. Found:
C, 71.34; H, 8.18.
4.5.1. 2-Methyl-2-(1-phenylvinyl)malonic acid diethyl
1
ester (5). H NMR (CDCl3): d 1.20 (t, JZ7.1 Hz, 6H),
1.59 (s, 3H), 4.14–4.21 (m, 4H), 5.34 (d, JZ0.7 Hz, 2H),
7.23–7.28 (m, 5H). 13C NMR (CDCl3): d 14.1, 22.5, 60.3,
61.9, 118.3, 127.6, 128.1, 128.5, 141.0, 148.0, 171.6. Anal.
Calcd for C16H20O4: C, 69.55; H, 7.30. Found: C, 69.68; H,
7.29.
4.5.5.
2-Methoxy-2-(1-phenylvinyl)malonic
acid
1
dimethyl ester (10). H NMR (CDCl3): d 3.49 (s, 3H),
3.73 (s, 6H), 5.52 (s, 1H), 5.76 (s, 1H), 7.28 (m, 3H), 7.42
(m, 2H). 13C NMR (CDCl3): d 53.1, 54.3, 87.8, 121.6,
127.2, 128.1, 128.4, 138.7, 142.4, 168.2. Anal. Calcd for
C14H16O5: C, 63.63; H, 6.10. Found: C, 64.01; H, 6.12.
4.5.2. 2-Methyl-2-(1-methylenenonyl)malonic acid
1
diethyl ester (7). H NMR (CDCl3): d 0.87 (t, JZ7.1 Hz,
3H), 1.21–1.33 (m, 16H), 1.41–1.52 (m, 2H), 1.59 (s, 3H),

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J. Zhang et al. / Tetrahedron 61 (2005) 7807–7813
4.5.6. 2-Acetyl-2-methyl-3-phenylbut-3-enoic acid ethyl
ester (11). H NMR (CDCl3): d 1.19 (t, JZ7.1 Hz, 3H),
1.51 (s, 3H), 2.28 (s, 3H), 4.16 (dq, JZ7.1 Hz, 0.6, 2H),
5.27 (br s, 1H), 5.42 (br s, 1H), 7.16–7.31 (m, 5H). 13C
NMR (CDCl3): d 14.1, 21.5, 27.6, 61.8, 66.0, 119.0, 127.8,
128.0, 128.3, 140.6, 148.2, 172.0, 205.5. Anal. Calcd for
C15H18O3: C, 73.15; H, 7.37. Found: C, 73.20; H, 7.03.
(d, JZ1.7 Hz, 1H), 5.75 (d, JZ1.5 Hz, 1H), 7.22–7.41 (m,
5H), 12.99–13.06 (m, 1H). 13C NMR (CDCl3): d 14.1, 19.8,
60.6, 103.9, 117.8, 126.1, 127.7, 128.5, 141.0, 142.7, 172.7,
174.3. Anal. Calcd for C14H16O3: C, 72.39; H, 6.94. Found:
C, 72.63; H, 6.77.
1
4.5.14. 2-Acetyl-3-phenylbut-2-enoic acid ethyl ester
1
(23). H NMR (CDCl3): d 0.91 (dt, JZ7.1, 1.5 Hz, 1.3H),
4.5.7. 2-Acetyl-3-benzyl-2-methylbut-3-enoic acid ethyl
1.30 (dt, JZ7.1, 1.3 Hz, 1.7H), 1.85 (d, JZ1.5 Hz, 1.7H),
2.32 (d, JZ1.2 Hz, 1.3H), 2.34 (d, JZ1.2 Hz, 1.3H), 2.39
(d, JZ1.2 Hz, 1.7H), 3.93 (dq, JZ7.1, 1.3 Hz, 0.8H), 4.26
(dq, JZ7.1, 1.3 Hz, 1.2H), 7.16–7.39 (m, 5H). 13C NMR
(CDCl3): d 13.7, 14.3, 23.1, 23.3, 30.6, 31.2, 61.2, 61.3,
126.8, 127.5, 128.5, 128.5, 128.9, 129.1, 133.7, 134.4,
141.1, 142.3, 152.4, 154.3, 165.7, 167.4, 198.4, 201.9. Anal.
Calcd for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.57; H,
6.93.
1
ester (12). H NMR (CDCl3): d 1.26 (t, JZ7.2 Hz, 3H),
1.56 (s, 3H), 2.24 (s, 3H), 3.37 (s, 2H), 4.17 (q, JZ7.2 Hz,
2H), 4.80–4.89 (m, 1H), 5.06–5.14 (m, 1H), 7.16–7.31 (m,
5H). 13C NMR (CDCl3): d 14.2, 20.2, 27.3, 39.7, 61.7, 66.2,
116.7, 126.6, 128.6, 129.8, 139.0, 147.0, 171.9, 205.4. Anal.
Calcd for C16H20O3: C, 73.82; H, 7.74. Found: C, 74.02; H,
7.63.
4.5.8. 2-Acetyl-2-methyl-3-methylene-5-phenylpentanoic
1
acid ethyl ester (13). H NMR (CDCl3): d 1.27 (t, JZ
4.5.15. 3-Hydroxy-2-(1-phenylvinyl)hex-2-enoic acid
ethyl ester (24). H NMR (CDCl3): d 0.89 (t, JZ7.5 Hz,
1
7.2 Hz, 3H), 1.53 (s, 3H), 2.20 (s, 3H), 2.29–2.36 (m, 2H),
2.77–2.84 (m, 2H), 4.21 (q, JZ7.2 Hz, 2H), 5.01–5.11 (m,
1H), 5.22–5.28 (m, 1H), 7.13–7.31 (m, 5H). 13C NMR
(CDCl3): d 14.3, 19.9, 27.3, 34.9, 35.0, 61.7, 66.6, 113.9,
126.2, 128.5, 128.6, 141.8, 146.8, 172.0, 205.5. Anal. Calcd
for C17H22O3: C, 74.42; H, 8.08. Found: C, 74.76; H, 7.84.
3H), 1.01 (t, JZ7.2 Hz, 3H), 1.57–1.68 (m, 2H), 2.25–2.33
(m, 2H), 4.07 (q, JZ7.1 Hz, 2H), 5.15 (d, JZ1.5 Hz, 1H),
5.75 (d, JZ1.7 Hz, 1H), 7.21–7.42 (m, 5H) 13.05–13.09 (s,
1H). 13C NMR (CDCl3): d 14.1, 14.2, 20.5, 34.9, 60.6,
103.6, 117.6, 126.2, 127.7, 128.4, 141.1, 142.5, 172.9,
177.3. Anal. Calcd for C16H20O3: C, 73.82; H, 7.74. Found:
C, 73.90; H, 7.69.
4.5.9. 2-(1-Biphenyl-4-ylvinyl)-2-methylmalonic acid
diethyl ester (14). 1H NMR (CDCl3): d 1.23 (t, JZ
7.1 Hz, 6H), 1.65 (s, 1H), 4.17–4.25 (m, 4H), 5.40 (d, JZ
15.6 Hz, 2H), 7.35 (m, 1H) 7.32–7.60 (m, 9H). 13C NMR
(CDCl3): d 14.1, 22.6, 60.3, 61.9, 118.3, 126.8, 127.2, 127.6,
128.9, 129.0, 140.0, 140.4, 140.9, 147.7, 171.6. Anal. Calcd
for C22H24O4: C, 74.98; H, 6.86. Found: C, 74.63; H, 6.78.
4.5.16. 3-Oxo-2-(1-phenylethylidene)hexanoic acid ethyl
1
ester (25). H NMR (CDCl3): d 0.63 (t, JZ7.5 Hz, 1.7H),
0.88–0.99 (m, 2.6H), 1.28 (t, JZ7.1 Hz, 1.7H), 1.34 (q, JZ
7.1 Hz, 1.2H), 1.69 (q, JZ7.1 Hz, 0.8H), 2.06 (t, JZ7.2 Hz,
1.2H), 2.26 (s, 1.2H), 2.41 (s, 1.8H), 2.60 (t, JZ7.2 Hz,
0.8H), 3.93 (q, JZ7.2 Hz, 0.8H), 4.24 (q, JZ7.1 Hz, 1.2H),
7.15–7.37 (m, 5H). 13C NMR (CDCl3): d 13.6, 13.8, 13.9,
14.3, 17.2, 17.4, 22.9, 23.3, 44.7, 45.7, 61.1, 126.8, 127.7,
128.4, 128.4, 128.7, 128.9, 133.8, 134.2, 141.2, 142.3,
152.0, 153.4, 165.6, 167.0, 201.5, 204.7. Anal. Calcd for
C16H20O3: C, 73.82; H, 7.74. Found: C, 73.84; H, 7.83.
4.5.10. 2-[1-(4-Methoxyphenyl)-vinyl]-2-methylmalonic
1
acid diethyl ester (15). H NMR (CDCl3): d 1.21 (t, JZ
7.1 Hz, 6H), 1.58 (s, 3H), 3.78 (s, 3H), 4.14–4.22 (m, 4H),
5.28 (d, JZ10.0 Hz, 2H), 6.77–6.83 (m, 2H) 7.16–7.22 (m,
2H). 13C NMR (CDCl3): d 14.1, 22.5, 55.4, 60.4, 61.8,
113.4, 117.6, 129.6, 133.3, 147.5, 159.1, 171.7. Anal. Calcd
for C17H22O5: C, 66.65; H, 7.24. Found: C, 67.06; H, 7.22.
4.5.11. 2-(1-Phenylvinyl)malonic acid diethyl ester (20).
1H NMR (CDCl3): d 1.23 (t, JZ7.1 Hz, 6H), 4.20 (dq, JZ
7.1, 1.7 Hz, 4H), 4.60 (d, JZ1.0 Hz, 1H), 4.51 (d, JZ
0.7 Hz, 1H), 5.63 (s, 1H), the phenyl protons of 20 not
distinguishable from those of 21. 13C NMR (CDCl3): d 14.2,
57.4, 62.0, 117.9, 126.4, 126.4, 140.4, 140.9. Anal. Calcd
for C15H18O4: C, 68.69; H, 6.92. Found: C, 68.95; H, 6.85.
Data from analysis of 1:9 mixture of 20:21.
References and notes
1. For recent examples, see: (a) Uozumi, Y.; Nakai, Y. Org. Lett.
2002, 4, 2997. (b) Choi, E.; Lee, C.; Na, Y.; Chang, S. Org.
Lett. 2002, 4, 2369. (c) Skyler, D.; Heathcock, C. H. Org. Lett.
2001, 3, 4323.
2. (a) Fu, N.-Y.; Pang, M.-L.; Yuan, Y.-F.; Wang, J.-T. Youji
Huaxue 2003, 23, 1085. (b) Kobayashi, S.; Manabe, K. Acc.
Chem. Res. 2002, 35, 209. (c) Kobayashi, S.; Manabe, K. Pure
Appl. Chem. 2000, 72, 1373.
4.5.12. 2-(1-Phenylethylidene)malonic acid diethyl ester
1
(21). H NMR (CDCl3): d 0.95 (t, JZ7.1 Hz, 3H), 1.31 (t,
JZ7.1 Hz, 3H), 2.43 (s, 3H), 3.95 (q, JZ7.1 Hz, 2H), 4.28
(q, JZ7.1 Hz, 2H), 7.28 (m, 5H). 13C NMR (CDCl3): d
13.8, 14.3, 23.0, 61.1, 61.3, 126.8, 128.5, 128.6, 141.8,
155.9, 165.0, 166.4, 168.1. Anal. Calcd for C15H18O4: C,
68.69; H, 6.92. Found: C, 68.95; H, 6.85. Data from analysis
of 1:9 mixture of 20:21.
3. Zhang, J.; Li, C.-J. J. Org. Chem. 2002, 67, 3969. See also:
Nguyen, R.-V.; Yao, X.-Q.; Bohle, D. S.; Li, C.-J. Org. Lett.
2005, 7, 673.
4. Nakamura, M.; Endo, K.; Nakamura, E. J. Am. Chem. Soc.
2003, 125, 13002. See also: Nakamura, M.; Fujimoto, T.;
Endo, K.; Nakamura, E. Org. Lett. 2004, 6, 4837.
5. Borman, S. Chem. Eng. News 2004, 82, 42.
4.5.13. 3-Hydroxy-2-(1-phenylvinyl)but-2-enoic acid
ethyl ester (22). H NMR (CDCl3): d 1.01 (t, JZ7.1 Hz,
3H), 2.03 (d, JZ1.0 Hz, 3H), 4.07 (q, JZ7.1 Hz, 2H), 5.16
6. (a) Chatterjee, A. K.; Sanders, D. P.; Grubbs, R. H. Org. Lett.
2002, 4, 1939. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res.
2001, 34, 18. (c) Chatterjee, A. K.; Grubbs, R. H. Org. Lett.
1

J. Zhang et al. / Tetrahedron 61 (2005) 7807–7813
7813
1999, 1, 1751. (d) Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413. (e) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992,
114, 7234.
13. (a) Tsuchimoto, T.; Hatanaka, K.; Shirakawa, E.; Kawakami,
Y. Chem. Commun. 2003, 2454. (b) Tsuchimoto, T.; Maeda,
T.; Shirakawa, E.; Kawakami, Y. Chem. Commun. 2000, 1573.
14. Barnes, D. M.; Ji, J.; Fickes, M. G.; Fitzgerald, M. A.; King,
S. A.; Morton, H. E.; Plagge, F. A.; Preskill, M.; Wagaw, S. H.;
Wittenberger, S. J.; Zhang, J. J. Am. Chem. Soc. 2002, 124,
13097.
7. (a) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2003, 42, 4592. (b) Schrock, R. R. Tetrahedron 1999, 55,
8141.
8. (a) Dolman, S. J.; Schrock, R. R.; Hoveyda, A. H. Org. Lett.
2003, 5, 4899. (b) Teng, X.; Cefalo, D. R.; Schrock, R. R.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 10779. (c)
Dolman, S. J.; Sattely, E. S.; Hoveyda, A. H.; Schrock, R. R.
J. Am. Chem. Soc. 2002, 124, 6991. (d) Van Veldhuizen, J. J.;
Garber, S. B.; Kingsbury, J. S.; Hoveyda, A. H. J. Am. Chem.
Soc. 2002, 124, 4954. (e) Hoveyda, A. H.; Schrock, R. R.
Chem. Eur. J. 2001, 7, 945.
15. Takita, R.; Fukuta, Y.; Tsuji, R.; Ohshima, T.; Shibasaki, M.
Org. Lett. 2005, 7, 1363.
16. (a) Yang, D.; Li, J.-H.; Gao, Q.; Yan, Y.-L. Org. Lett. 2003, 5,
2869. (b) Yang, D.; Gao, Q.; Lee, C.-S.; Cheung, K.-K. Org.
Lett. 2002, 4, 3271.
17. Jones, G. Org. React. 1967, 15, 204.
18. For Lewis acid catalyzed Knoevenagel reactions, see: (a)
Narsaiah, A. V.; Nagaiah, K. Synth. Commun. 2003, 33, 3825.
(b) Harjani, J. R.; Nara, S. J.; Salunkhe, M. M. Tetrahedron
Lett. 2002, 43, 1127. (c) Rao, P. S.; Venkataratnam, R. V.
Tetrahedron Lett. 1991, 32, 5821.
9. (a) For an account of olefin metathesis, see: Rouhi, A. M.
Chem. Eng. News 2002, 80, 29. (b) Rouhi, A. M. Chem. Eng.
News 2002, 80, 34. (c) For recent examples of olefin
metathesis, see: Ratnayake, A. S.; Hemscheidt, T. Org. Lett.
2002, 4, 4667. (d) Deiters, A.; Martin, S. F. Org. Lett. 2002, 4,
3243. (e) Takao, K.-i.; Watanabe, G.; Yasui, H.; Tadano, K.-i.
Org. Lett. 2002, 4, 2941. (f) Creighton, C. J.; Reitz, A. B. Org.
Lett. 2001, 3, 893. (g) Smulik, J. A.; Diver, S. T. Org. Lett.
2000, 2, 2271.
19. (a) Sabitha, G.; Reddy, G. S. K. K.; Rajkumar, M.; Yadav,
J. S.; Ramakrishna, K. V. S.; Kunwar, A. C. Tetrahedron Lett.
2003, 44, 7455. (b) Kaupp, G.; Naimi-Jamal, M. R.;
Schmeyers, J. Tetrahedron 2003, 59, 3753. (c) Tedeschi, L.;
Enders, D. Org. Lett. 2001, 3, 3515.
10. (a) Wittig, G.; Haag, W. Ber. 1955, 88, 1654. (b) Wittig, G.;
¨
Schollkopf, U. Ber. 1954, 87, 1318. (c) For reviews, see: Kelly,
20. (a) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III
Synlett 2003, 1910. (b) Ramachary, D. B.; Chowdari, N. S.;
Barbas, C. F., III Angew. Chem., Int. Ed. 2003, 42, 4233. (c)
Tietze, L. F.; Evers, H.; Topken, E. Helv. Chim. Acta 2002, 85,
4200. (d) Tietze, L. F.; Zhou, Y. Angew. Chem., Int. Ed. 1999,
38, 2045. (e) Tietze, L. F.; Bachmann, J.; Schul, W. Angew.
Chem., Int. Ed. Engl. 1988, 100, 983.
S. E. Comp. Org. Synth. 1991, 1, 755. (d) Maryanoff, B. E.;
Reitz, A. B. Chem. Rev. 1989, 89, 863. (e) Gosney, I.; Rowley,
A. G. In Organophosphorus Reagents in Organic Synthesis;
Cadogan, J. I. G., Ed.; Academic: New York, 1979; pp 17–153.
(f) Wadsworth, W. S., Jr. Org. React. 1977, 25, 73. (g)
Vollhardt, K. P. C. Synthesis 1975, 765. (h) Maercker, A. Org.
React. 1965, 14, 270.
21. (a) Fringuelli, F.; Piermatti, O.; Pizzo, F. Synlett 2003, 2331.
(b) Bigi, F.; Chesini, L.; Maggi, R.; Sartori, G. J. Org. Chem.
1999, 64, 1033.
11. Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc.
1961, 83, 1733.
22. (a) Davis, A.; Bhattarai, K. M. Tetrahedron 1995, 51, 8033. (b)
´
Brillon, D.; Sauve, G. J. Org. Chem. 1992, 57, 1838. (c) Hein,
12. (a) Fujiwara, N.; Yamamoto, Y. J. Org. Chem. 1999, 64, 4095.
(b) Ranu, B. C.; Majee, A. Chem. Commun. 1997, 1225. (c)
Fujiwara, N.; Yamamoto, Y. J. Org. Chem. 1997, 62, 2318.
R. W.; Astle, M. J.; Shelton, J. R. J. Org. Chem. 1961, 26,
4874. (d) Cope, A. C. J. Am. Chem. Soc. 1937, 59, 2327.