Indium(III)-catalyzed knoevenagel condensation of aldehydes and activated methylenes using acetic anhydride as a promoter

Article abstract of DOI:10.1021/acs.joc.5b00011

The combination of a catalytic amount of InCl₃ and acetic anhydride remarkably promotes the Knoevenagel condensation of a variety of aldehydes and activated methylene compounds. This catalytic system accommodates aromatic aldehydes containing a variety of electron-donating and -withdrawing groups, heteroaromatic aldehydes, conjugate aldehydes, and aliphatic aldehydes. Central to successfully driving the condensation series is the formation of a geminal diacetate intermediate, which was generated in situ from an aldehyde and an acid anhydride with the assistance of an indium catalyst.

Full text of DOI:10.1021/acs.joc.5b00011

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Article
Indium(III)-Catalyzed Knoevenagel Condensation of Aldehydes
and Activated Methylenes Using Acetic Anhydride as a Promoter
Yohei Ogiwara, Keita Takahashi, Takefumi Kitazawa, and Norio Sakai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00011 • Publication Date (Web): 17 Feb 2015
Downloaded from http://pubs.acs.org on February 18, 2015
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Indium(III)-Catalyzed Knoevenagel Condensation of Aldehydes and Activated
Methylenes Using Acetic Anhydride as a Promoter
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Yohei Ogiwara, Keita Takahashi, Takefumi Kitazawa, and Norio Sakai*
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of
Science (RIKADAI), Noda, Chiba 278-8510, Japan
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E-mail: sakachem@rs.noda.tus.ac.jp
cat. InCl3
Ac2O
E
R
E
E = ester, ketone, amide
O
carboxylic acid, nitrile
+
E
E
R
H
toluene
R = aryl, heteroaryl, alkenyl,
alkyl
OAc
up to 98% yield
34 examples
R
OAc
key intermediate
Abstract
We demonstrated how the combination of a catalytic amount of InCl3 and acetic anhydride remarkably
promotes the Knoevenagel condensation of a variety of aldehydes and activated methylene compounds.
This catalytic system accommodated aromatic aldehydes containing a variety of electron-donating and
-withdrawing groups, heteroaromatic aldehydes, conjugate aldehydes, and aliphatic aldehydes. The
central key to successfully driving the condensation series was the formation of the geminal diacetate
intermediate, which was in situ-generated from an aldehyde with an acid anhydride with the assistance of
an indium catalyst.
Introduction
The Knoevenagel reaction is a condensation between activated methylene compounds with carbonyl
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compounds in the presence of a weak base, such as an amine; it is a powerful and practical tool for the
formation of a carbon–carbon double bond.1 Because the multi-substituted alkenes that are produced can
be further used for a variety of molecular transformations, such as Michael additions and Diels-Alder
reactions, a number of organic chemists have continuously improved this useful conversion.1d In a
typical Knoevenagel condensation, a catalytic amount of primary or secondary amines, along with their
ammonium salts, acts as an effective promoter, in which the formation of the iminium intermediate
derived from the amine and a carbonyl compound plays a central role in promoting condensation.2
During the past two decades, several Lewis acid catalysts have been used to promote Knoevenagel
condensations.3 In general, however, aldehydes with coordinating functional groups—such as methoxy,
nitro, or cyano groups—and heterocyclic aldehydes are unsuitable for use as a substrate in a
Lewis-acid-catalyzed Knoevenagel condensation with an activated methylene that has a relatively low
degree of acidity, such as dimethyl malonate (pKa = 15.9 in DMSO).4 This is probably due to
deactivation of the acidic catalyst by coordination rather than by activation of the carbonyl compound
that is used.
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Indium compounds are known to display a high tolerance to functional groups.5 We have joined several
other researchers in reporting the indium-catalyzed conversions of various carbonyl compounds with a
variety of functional groups.6 Based on these reports, we anticipated that the indium compound that
shows unique activation of typical carbonyl compounds will effectively promote a Knoevenagel
condensation with a weak carbonyl compound that includes a coordinating functional group.7 Herein, we
report a novel catalytic system composed of indium chloride and acetic anhydride that effectively
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promotes the Knoevenagel condensation of aromatic/aliphatic/heteroaromatic aldehydes with a variety of
activated methylene compounds leading to the preparation of substituted alkene derivatives. We also
describe how the condensation series proceeds via the indium-promoted formation of a geminal diacetate
intermediate that is derived from an aldehyde with acetic acid anhydride.
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Results and Discussion
On the basis of conventional Knoevenagel reactions, we initially investigated reaction conditions using
benzaldehyde (1a) and dimethyl malonate (2a) as a model substrate (Table 1). When a reaction was
performed with 10 mol % of InBr3 in toluene at 60 °C for 8 h, only 3% of Knoevenagel product 3aa was
detected (entry 1). Thus, to promote the initial abstraction of the activated proton, the addition of 1 equiv
of several bases to the reaction mixture was examined. Consequently, when a primary amine,
2-aminoethanol, was added, the yield was remarkably increased to 61% (entry 2). The additions of a
secondary and a tertiary amine, however, were ineffective for the present condensation (entries 3 and 4).
After further screenings of several additives for the condensation reaction,8 1 equiv of acetic anhydride
showed the best additive effect to afford the corresponding product 3aa in an 89% yield (entry 5). Then,
a counteranion effect of the indium catalyst was investigated in the presence of Ac2O. InCl3 produced the
best yield of Knoevenagel product 3aa in a 94% NMR yield (86% isolated yield) along with the
formation of a small amount (4%) of geminal diacetate 4a. Stronger Lewis acids, InI3 and In(OTf)3,
showed a similar catalytic effect and provided alkene 3aa in 79% (involving an 8% of diacetate 4a) and
82% yields, respectively (entries 7 and 8), although In(OH)3 and In(OAc)3 produced neither the
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corresponding alkene 3aa nor diacetate 4a (entries 9 and 10). Without an indium salt, Ac2O did not
undergo the expected condensation to yield Knoevenagel products (entry 11). When the reaction was
conducted with other solvents, such as CHCl3, CH3CN, CH3OH and THF, a remarkable improvement in
the yield of 3aa was not observed.9
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Table 1. Knoevenagel Condensation of Aromatic Aldehyde 1a with Dimethyl Malonate (2a)a
InX3 (10 mol %)
additive (1 equiv)
E
E
O
OAc
OAc
4a
+
+
E
E
toluene, 60 °C
8 h
Ph
H
Ph
Ph
E = CO2Me
1a
2a
3aa
1.1 equiv
NMR yields (%)
entry InX3
additive
3aa
4a
―
―
―
―
ndb
4
1
InBr3
InBr3
InBr3
InBr3
InBr3
InCl3
InI3
―
3
2
HOCH2CH2NH2 61
3
piperidine
Et3N
48
4
6
5
Ac2O
89
6
Ac2O
94 (86)c
79
7
Ac2O
8
8
In(OTf)3 Ac2O
In(OH)3 Ac2O
In(OAc)3 Ac2O
Ac2O
82
ndb
ndb
ndb
ndb
9
ndb
ndb
ndb
10
11
―
a Reaction conditions: 1a (0.60 mmol), 2a (0.66 mmol), InX3 (0.060 mmol), additive (0.60 mmol),
toluene (0.60 mL), 60 °C, 8 h. bNot detected. cIsolated yield.
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The general application of aromatic aldehydes 1 for a Knoevenagel condensation with dimethyl
malonate (2a) was next investigated in toluene at 60 °C for 8 h (Table 2). Aldehydes containing a strong
electron-donating group, such as either Me2N or MeO groups, on the benzene ring afforded the
corresponding products 3ba−3ea in good yields (entries 1−4). During the condensation series, neither the
amino nor the methoxy groups, which generally deactivate a typical Lewis acid via coordination, had an
effect on the activation by InCl3. Similarly, 4-methyl- or 4-phenyl-substituted aromatic aldehyde also
undertook the condensation, and produced alkenes 3fa and 3ga in 80 and 84% yields, respectively,
within 5−7 h (entries 5 and 6). The catalytic condensation of halogen-substituted benzaldehydes 1h−1l
with malonate 2a proceeded successfully to isolate adducts 3ha−3la in excellent yields (entries 7−11).
Benzaldehyde derivatives bearing an electron-withdrawing groups, such as a methoxycarbonyl, a
trifluoromethyl, a cyano, or a nitro group, generally showed a slightly higher reactivity than
benzaldehydes with an electron-donating group to give the Knoevenagel products 3ma−3ra in 80−98%
yields (entries 12−17). When salicylaldehyde (1s) was used as a substrate, the expected Knoevenagel
alkene product was not detected. Instead, further O-acetylated product 5 and an intramolecular
cyclization product, coumarin derivative 6, were obtained in 40 and 7% yields, respectively (entry 18).
For the substrates shown in Table 2, a small amount of the corresponding diacetate 4 was detected by 1H
NMR analysis.
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Table 2. Indium-Catalyzed Knoevenagel Condensation of Aromatic Aldehydes 1a
4
5
6
7
InCl3 (10 mol %)
Ac2O (1 equiv)
E
E
O
OAc
Ar
OAc
+
+
E
E
toluene, 60 °C
8 h
Ar
H
Ar
E = CO2Me
2a
1.1 equiv
1
3
4
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yields (%)
entry
1
substrate 1
product 3
3b
4c
O
O
O
MeO
OMe
ndd
H
69
Me2N
1b
Me2N
3ba
O
O
O
MeO
OMe
H
MeO
MeO
2
3
4
1c, 4-MeO
1d, 3-MeO
1e, 2-MeO
3ca
3da
66
59
71
ndd
2
3ea
ndd
O
O
O
MeO
OMe
5e
6f
7
80
84
87
8
7
4
H
1f
3fa
O
O
O
MeO
OMe
H
Ph
1g
Ph
3ga
O
O
O
MeO
OMe
H
F
1h
F
3ha
O
O
O
MeO
OMe
H
Cl
Cl
8
9
1i, 4-Cl
1j, 3-Cl
1k, 2-Cl
3ia
3ja
3ka
94
87
95
5
2
10
ndd
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O
O
O
MeO
OMe
11f
12
86
98
10
H
Br
1l
Br
3la
O
O
O
MeO
OMe
ndd
H
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MeO2C
1m
MeO2C
3ma
O
O
O
MeO
OMe
H
F3C
F3C
13
14
15
1n, 4-CF3
1o, 3-CF3
1p, 2-CF3
3na
3oa
88
80
92
6
ndd
ndd
3pa
O
O
O
MeO
OMe
ndd
ndd
H
16
17
92
92
NC
1q
NC
3qa
O
O
O
MeO
OMe
H
O2N
1r
O2N
3ra
O
O
O
O
O
MeO
OMe
O
OMe
H
18
40 (7)g
ndd
OH
OAc
1s
5
6
aReaction conditions: 1 (0.6 mmol), 2a (0.66 mmol), InCl3 (0.06 mmol), Ac2O (0.6 mmol), toluene 0.6
mL, 60 °C, 8 h. bIsolated yield. cNMR yield. dNot detected. e7 h. f5 h. gYield of coumarin derivative 6.
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To expand the scope of an activated methylene derivative, InCl3-catalyzed Knoevenagel condensation of
benzaldehyde (1a) with several methylene compounds 2 was next conducted in the presence of Ac2O
(Table 3). For example, the reaction of benzaldehyde with β-ketoesters methyl acetoacetate (2b) and
ethyl benzoylacetate (2c) efficiently gave the Knoevenagel products 3ab (E:Z = 42:58) and 3ac (E:Z =
10:90), respectively.10 β-Ketoamide 2d afforded the desired product 3ad in a rather low yield,11 but
extended the reaction time to 30 h possibly because a decrease in the electrophilicity of the methylene
moiety by a strong electron-donating effect of the amino group hindered the initial condensation of the
methylene with acetic anhydride. It was remarkable, however, that when the condensation was carried
out with malonic acid (2e), 2-benzylidene-malonic acid (3ae) was obtained in a 79% yield without a
Doebner-type decarboxylation.12 Also, when the reaction of malononitrile (2f) was carried out in toluene,
only 15% (NMR yield) of the product was obtained. It was interesting that the use of
N,N-dimethylformamide (DMF) as a solvent instead of toluene successfully improved the chemical yield
of alkene 3af to 86%. When the condensation of 1a with a cyclic 1,3-diketone, dimedone (2g), was
conducted under the optimal conditions, 1:2 adduct 7 (a xanthenedione derivative) was isolated as the
sole product, which otherwise would have been produced via a further Michael addition of 2g to the first
Knoevenagel adduct and a subsequent intramolecular cyclodehydration.7g
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Table 3. Indium-Catalyzed Knoevenagel Condensation of Several Activated Methylenes 2a,b
4
5
6
7
InCl3 (10 mol %)
Ac2O (1 equiv)
E1
E2
+
O
OAc
OAc
4a
E1
E2
+
toluene, 60 °C
8 h
Ph
H
Ph
Ph
1a
2
3
8
1.1 equiv
9
O
O
O
O
O
O
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MeO
EtO
Ph
Me2N
Ph
Ph
Ph
3ab
79% (E:Z = 42:58)
3ac
84% (E:Z = 10:90)
3ad
17%c
O
O
O
NC
Ph
CN
HO
OH
Ph
O
Ph
7
O
3ae
78%
3af
86%d
54%
aReaction conditions: 1a (0.6 mmol), 2 (0.66 mmol), InCl3 (0.06 mmol), Ac2O (0.6 mmol), toluene 0.6
mL, 60 °C, 8 h. bIsolated yield (E:Z ratio was determined by 1H NMR). c30 h. dDMF was used instead of
toluene.
Further application of the indium-catalyzed condensation to a variety of aldehydes 8, with the exception
of benzaldehyde with dimethyl malonate (2a), was then investigated in the presence of Ac2O (Table 4).
When 4-formylpyridine (8a) was used as a substrate, the corresponding alkene product 9aa was obtained
in a 65% yield (entry 1). In this case, InCl3 was unnecessary for the condensation based on the fact that
alkene 9aa (68% NMR yield) was obtained in the absence of InCl3. When the reactions of either a
pyridyl aldehyde, which have a more sterically hindered portion around the nitrogen atom,
2-bromo-6-formylpyridine (8b), or 2-thiophenyl aldehyde (8c) with malonate ester 2a were treated with
our optimal conditions, the extended π-conjugate heteroaromatic compounds 9ba and 9ca were obtained
in good yields (entries 2 and 3). Also, the present Knoevenagel condensation could be applied to either a
conjugated or an aliphatic aldehyde in addition to an aromatic aldehyde. For example, a conjugated
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aldehyde, (E)-cinnamaldehyde (8d), reacted with the malonate ester to afford α, β, γ, δ-unsaturated
carbonyl compound 9da in a 79% yield, which retained the double-bond geometry (entry 4). The
reactions of linear aliphatic aldehydes 8e and 8f were completed within 24 h to give the corresponding
products 9ea and 9fa in good yields (entries 5 and 6). Moreover, when α-branched aldehydes 8g−8j were
reacted with malonate 2a, the expected alkenes 9ga-9ja were produced in 68−72% yields (entries 7−10).
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Table 4. Indium-Catalyzed Knoevenagel Condensation of Various Aldehydes 8a
InCl3 (10 mol %)
Ac2O (1 equiv)
E
R
E
O
OAc
R
OAc
+
+
E
E
toluene, 60 °C
8 h
R
H
E = CO2Me
8
2a
9
10
1.1 equiv
yields (%)
10c
entry
1f
substrate 8
product 9
9b
O
O
O
MeO
N
OMe
65
nde
nde
nde
nde
H
(68)c,d
N
8a
9aa
O
O
O
MeO
OMe
Br
N
2g
83
64
H
Br
N
8b
9ba
O
O
O
MeO
OMe
S
H
3
S
8c
9ca
O
O
O
MeO
OMe
4
79h
Ph
H
Ph
8d
9da
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O
O
O
MeO
Ph
OMe
4
5
6
7
8
9
5i
60
70
71
71
72
68
nde
Ph
H
8e
9ea
O
O
O
MeO
OMe
6i
8
10
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H
3
8f
3
9fa
O
O
O
MeO
OMe
7i
2
H
Ph
8g
Ph
9ga
O
O
O
MeO
OMe
8i,j
nde
H
8h
9ha
O
O
O
MeO
OMe
9i
3
H
8i
9ia
O
O
O
MeO
OMe
10i,k
nde
H
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8j
9ja
aReaction conditions: 8 (0.6 mmol), 2a (0.66 mmol), InCl3 (0.06 mmol), Ac2O (0.6 mmol), toluene 0.6
mL, 60 °C, 8 h. bIsolated yield. cNMR yield. dWithout InCl3. eNot detected. f15 h. g13 h. hOnly (E)-isomer
was obtained. i24 h. j2 equiv (1.2 mmol) of 2a was used. k2 equiv (1.2 mmol) of 2a, and 20 mol % (0.12
mmol) of InCl3 were used in toluene (0.3 mL) at 80 °C.
As control experiments, the reactions of benzaldehyde (1a) with 1 equiv of Ac2O were conducted both
with and without InCl3 (eq 1 in Scheme 1). In the former reaction, the corresponding geminal diacetate
4a was quickly obtained in a 91% yield at room temperature, but in the latter reaction no formation of
diacetate 4a nor any other by-products were observed. Moreover, in order to find out whether geminal
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diacetate 4a would be an intermediate in the Knoevenagel reaction series,13 the reactions of 4a with
dimethyl malonate 2a were next examined both with and without InCl3. Consequently, Knoevenagel
adduct 3aa was obtained in a 79% yield in the presence of a catalytic amount of InCl3, but the reaction
without the indium catalyst did not produce the corresponding product along with the recovery of a
starting diacetate 4a (eq 2 in Scheme 1). These results indicated that geminal diacetate 4a is one of the
intermediates in the Knoevenagel condensation and proved that the indium catalyst is necessary for both
stages involving the generation of 4a from aldehyde and Ac2O, as well as a subsequent reaction of 4a
with malonate 2a.
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Scheme 1. Control Experiments for Clarification of the Condensation Path
cat. InCl3
Ac2O (1 equiv)
O
OAc
Ph
OAc
(1)
toluene 0.6 mL
rt, 0.5 h
Ph
H
1a
4a
0.6 mmol
OAc
InCl3 (10 mol %) : 91% GC yield
InCl3 (none)
: not detected
E
E
cat. InCl3
toluene 0.6 mL
E
E
+
(2)
Ph
OAc
E = CO2Me 60 °C, 16 h
Ph
4a
0.6 mmol
2a
3aa
0.66 mmol
InCl3 (10 mol %) : 79% GC yield
InCl3 (none)
: not detected
Based on the results obtained by the control experiments, a plausible reaction mechanism of the present
condensation is shown in Scheme 2. When aldehyde 1 is activated by an indium catalyst, it is initially
reacted with Ac2O to form geminal diacetate 4,14 the formation of which facilitates a subsequent
nucleophilic attack of an enolizable activated methylene compound in the presence of the indium
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catalyst,15 which produces intermediate A. Finally, an intramolecular elimination of acetic acid occurs to
afford substituted alkene 3 along with the regeneration of the indium catalyst.
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Scheme 2. Possible Mechanism of an Indium-Catalyzed Knoevenagel Condensation
[In]
O
Ac2O
– [In]
AcO
Ar
[In]
O
Ar
H
OAc
O
Ar
H
1
4
[In]
OH
O
E
E
H
[In]
E
Z
Z
O
Z
– AcOH
– [In]
– AcOH
Ar
O
Ar
A
3
Conclusions
In conclusion, we have demonstrated an indium-catalyzed Knoevenagel condensation between aldehydes
with activated methylene compounds in the presence of acetic acid anhydride leading to the preparation
of polysubstituted alkenes. Also, we have clarified that in order to drive the Knoevenagel condensation
series forward, the in situ formation of the geminal diacetate intermediate derived from an aldehyde and
acetic anhydride is essential. Thus far, several examples involving the conversion of aldehydes into the
geminal diacetates or the synthesis of Knoevenagel products from the geminal diacetates, have been
reported. This novel procedure presents one-pot access to Knoevenagel products from various aldehydes
via the geminal diacetate as a key intermediate. Also, in conventional Lewis acid-catalyzed Knoevenagel
condensations, substrates were limited to mainly either aldehydes bearing a non-coordinating functional
group or activated methylenes with relatively high acidic hydrogen. With the present catalytic system in
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hand, therefore, the carbonyl compounds used in the Knoevenagel condensation could be extensively
expanded to a heteroaromatic aldehyde, a conjugate aldehyde, and an aliphatic aldehyde, including a
variety of benzaldehydes. Moreover, we disclosed that the present method could be applied to various
activated methylenes besides a malonate ester. The use of an indium compound with a unique and high
tolerance to various functional groups allowed the extension of the substrate and new entry to the
preparation of valuable substituted alkenes. Further attempts to elucidate the reaction mechanism and
extend the substrate scope are now in progress.
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Experimental Section
General Information. All reactions were carried out under a N2 atmosphere. Toluene and
N,N-dimethylformamide (DMF) were freshly distilled from CaH2, and aldehydes were also purified via
the distillation of commercially available products. Indium salts, methylene compounds, and acid
anhydrides were purchased and used without further purification. 1H, 13C NMR spectra were recorded on
a 500 or 300 MHz spectrometer. Chemical shifts in the 1H and 13C NMR spectra were reported in ppm
relative to the internal reference for tetramethylsilane (δ 0.00 for 1H) and to the residual solvent peaks (δ
77.0 for 13C) in CDCl3, and the residual solvent peaks (δ 2.50 for 1H, and δ 39.52 for 13C) in DMSO-d6.
High-resolution mass spectra were measured using NBA (3-nitrobenzylalcohol) as a matrix.
General Procedure for the InCl3-Catalyzed Knoevenagel Condensation. To a screw-capped vial,
InCl3 (0.0600 mmol, 13.3 mg), toluene (0.6 mL), aldehyde (1 or 8; 0.60 mmol), methylene (2; 0.66
mmol), and acetic anhydride (0.600 mmol, 61.3 mg) were added in succession. After the vial was sealed
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with a cap that contained a PTFE septum, the mixture was heated at 60 °C. The progress of the reaction
was monitored by thin-layer chromatography (TLC) analysis, which was performed on silica gel 60 F254.
A saturated aqueous solution of NaHCO3 was added to the resultant mixture, which was then extracted
with EtOAc. The combined organic phase was dried over anhydrous Na2SO4, filtered, and then
evaporated under reduced pressure. The crude material was purified by a column chromatography (silica
gel 60 F254, 95/5 = hexane/EtOAc) to give the corresponding Knoevenagel product 3 or 9 (followed by
recrystallization, if necessary).
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Dimethyl 2-benzylidenemalonate (3aa). The general procedure was followed with benzaldehyde (1a;
63.7 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol) for 8 h, with the exception of
performing recrystallization from hexane following column chromatography to yield a colorless solid
(3aa; 113.6 mg, 86%): mp 40−41 °C; 1H NMR (300.5 MHz, CDCl3) δ 3.84 (s, 6 H, OCH3), 7.38−7.43
(m, 5 H, ArH), 7.78 (s, 1 H, C=CH); 13C NMR (75.6 MHz, CDCl3) δ 52.6, 125.4, 128.8, 129.3, 130.6,
132.7, 142.8, 164.4, 167.0; LRMS (FAB) m/z (% relative intensity) 221 ([M+H]+, 77), 189 (100). The
spectroscopic data of 3aa were in good agreement with that reported in the literature.16
Dimethyl 2-[4-(dimethylamino)benzylidene]malonate (3ba). The general procedure was followed
with 4-(dimethylamino)benzaldehyde (1b; 89.5 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg,
0.660 mmol) for 8 h to yield a yellow-green solid (3ba; 109.0 mg, 69%): mp 86−87 °C; 1H NMR (300.5
MHz, CDCl3) δ 3.00 (s, 6 H, N(CH3)2), 3.80 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 6.62 (d, J = 8.7 Hz, 2
H, ArH), 7.32 (d, J = 8.7 Hz, 2 H, ArH), 7.66 (s, 1 H, C=CH); 13C NMR (75.6 MHz, CDCl3) δ 39.8, 52.1,
52.4, 111.4, 118.8, 119.7, 131.7, 143.4, 151.8, 165.3, 168.3; HRMS (FAB-Magnetic Sector) calcd for
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[M]+ (C14H17NO4) m/z 263.1158, found 263.1166. The spectroscopic data of 3ba were in good
agreement with that reported in the literature.17
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Dimethyl 2-(4-methoxybenzylidene)malonate (3ca). The general procedure was followed with
4-methoxybenzaldehyde (1c; 81.7 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol)
for 8 h to yield a colorless oil (3ca; 99.1 mg, 66%): 1H NMR (297.6 MHz, CDCl3) δ 3.83 (s, 6 H, OCH3),
3.87 (s, 3 H, OCH3), 6.89 (d, J = 8.6 Hz, 2 H, ArH), 7.39 (d, J = 8.6 Hz, 2 H, ArH), 7.71 (s, 1 H, C=CH);
13C NMR (74.8 MHz, CDCl3) δ 52.5, 52.6, 55.3, 114.3, 122.7, 125.2, 131.5, 142.6, 161.7, 164.8, 167.6;
HRMS (EI-Quadrupole) calcd for [M]+ (C13H14O5) m/z 250.0841, found 250.0855. The spectroscopic
data of 3ca were in good agreement with that reported in the literature.17
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Dimethyl 2-(3-methoxybenzylidene)malonate (3da). The general procedure was followed with
3-methoxybenzaldehyde (1d; 81.7 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol)
for 8 h to yield a pale yellow solid (3da; 88.6 mg, 59%): mp 81−82 °C; 1H NMR (500.2 MHz, CDCl3) δ
3.80 (s, 3 H, OCH3), 3.85 (s, 6 H, OCH3), 6.94−7.00 (m, 2 H, ArH), 7.01 (d, J = 5.0 Hz, 1 H, ArH), 7.29
(t, J = 5.0 Hz, 1 H, ArH), 7.74 (s, 1 H, C=CH); 13C NMR (125.8 MHz, CDCl3) δ 52.6, 52.7, 55.2, 114.2,
116.7, 121.9, 125.7, 129.9, 134.0, 142.7, 159.7, 164.4, 167.0; HRMS (EI-Quadrupole) calcd for [M]+
(C13H14O5) m/z 250.0841, found 250.0849. The spectroscopic data of 3da were in good agreement with
that reported in the literature.17
Dimethyl 2-(2-methoxybenzylidene)malonate (3ea). The general procedure was followed with
2-methoxybenzaldehyde (1e; 81.7 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol)
for 8 h, with the exception that recrystallization from hexane was performed after column
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chromatography to yield a colorless solid (3ea; 106.6 mg, 71%): mp 53−54 °C; H NMR (297.6 MHz,
CDCl3) δ 3.78 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 6.92 (t, J = 5.0 Hz, 2 H, ArH),
7.32−7.39 (m, 2 H, ArH), 8.12 (s, 1 H, C=CH); 13C NMR (74.8 MHz, CDCl3) δ 52.4, 55.4, 110.8, 120.5,
122.1, 125.2, 129.0, 132.1, 139.0, 158.0, 164.7, 167.1; HRMS (EI-Quadrupole) calcd for [M]+
(C13H14O5) m/z 250.0841, found 250.0842. The spectroscopic data of 3ea were in good agreement with
that reported in the literature.17
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Dimethyl 2-(4-methylbenzylidene)malonate (3fa). The general procedure was followed with
4-methylbenzaldehyde (1f; 72.1 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol) for
1
7 h to yield a colorless oil (3fa; 112.4 mg, 80%): H NMR (500.2 MHz, CDCl3) δ 2.37 (s, 3 H, CH3),
3.84 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 7.18 (d, J = 8.0 Hz, 2 H, ArH), 7.32 (d, J = 8.0 Hz, 2 H, ArH),
7.74 (s, 1 H, C=CH); 13C NMR (125.8 MHz, CDCl3) δ 21.4, 52.5, 52.6, 124.3, 129.5, 129.6, 129.9, 141.3,
142.9, 164.6, 167.3; HRMS (EI-Quadrupole) calcd for [M]+ (C13H14O4) m/z 234.0892, found 234.0889.
The spectroscopic data of 3fa were in good agreement with that reported in the literature.18
Dimethyl 2-(4-phenylbenzylidene)malonate (3ga). The general procedure was followed with
4-phenylbenzaldehyde (1g; 109.3 mg, 0.6000 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol)
for 5 h to yield a colorless solid (3ga; 149.3 mg, 84%): mp 75−76 °C; 1H NMR (297.6 MHz, CDCl3) δ
3.86 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 7.37 (t, J = 8.9 Hz, 1 H, ArH), 7.45 (t, J = 8.9 Hz, 2 H, ArH),
7.50 (d, J = 8.9 Hz, 2 H, ArH), 7.59 (d, J = 8.9 Hz, 2 H, ArH), 7.62 (d, J = 8.9 Hz, 2 H, ArH), 7.81 (s, 1
H, C=CH); 13C NMR (74.8 MHz, CDCl3) δ 52.6, 52.7, 125.1, 127.0, 127.5, 128.0, 128.9, 130.0, 131.5,
139.8, 142.4, 143.4, 164.5, 167.2; IR (neat) 1731 s, 1632 w, 1434 w, 1270 m, 1223 m, 1196 m, 1070 w,
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765 w cm−1; HRMS (EI-Quadrupole) calcd for [M]+ (C18H16O4) m/z 296.1049, found 296.1039.
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Dimethyl 2-(4-fluorobenzylidene)malonate (3ha). The general procedure was followed with
4-fluorobenzaldehyde (1h; 74.5 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol) for
8 h, with the exception that recrystallization from hexane was performed after column chromatography
to yield a colorless solid (3ha; 124.3 mg, 87%): mp 38−39 °C; 1H NMR (297.6 MHz, CDCl3) δ 3.85 (s,
6 H, OCH3), 7.08 (t, J = 8.3 Hz, 2 H, ArH), 7.42 (d, J = 8.3 Hz, 1 H, ArH), 7.45 (d, J = 8.3 Hz, 1 H,
ArH) , 7.73 (s, 1 H, C=CH); 13C NMR (74.8 MHz, CDCl3) δ 52.6, 52.7, 116.0 (d, J = 22.4 Hz), 125.2,
128.9 (d, J = 3.7 Hz), 131.5 (d, J = 9.0 Hz), 141.5, 163.9 (d, J = 252.8 Hz), 164.3, 166.9; HRMS
(EI-Quadrupole) calcd for [M]+ (C12H11FO4) m/z 238.0641, found 238.0638. The spectroscopic data of
3ha were in good agreement with that reported in the literature.17
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Dimethyl 2-(4-chlorobenzylidene)malonate (3ia). The general procedure was followed with
4-chlorobenzaldehyde (1i; 84.3 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol) for
8 h, with the exception that recrystallization from hexane was performed after column chromatography
to yield a colorless solid (3ia; 143.6 mg, 94%): mp 36−37 °C; 1H NMR (500.2 MHz, CDCl3) δ 3.85 (s, 6
H, OCH3), 7.36 (s, 4 H, ArH), 7.72 (s, 1 H, C=CH); 13C NMR (125.8 MHz, CDCl3) δ 52.7, 125.9, 129.1,
130.5, 131.2, 136.7, 141.4, 164.2, 166.8; HRMS (EI-Quadrupole) calcd for [M]+ (C12H11ClO4) m/z
254.0346, found 254.0344. The spectroscopic data of 3ia were in good agreement with that reported in
the literature.17
Dimethyl 2-(3-chlorobenzylidene)malonate (3ja). The general procedure was followed with
4-chlorobenzaldehyde (1j; 84.3 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol) for
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8 h to yield a colorless solid (3ja; 132.9 mg, 87%): mp 65−66 °C; 1H NMR (500.2 MHz, CDCl3) δ 3.86
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5
6
13
(s, 6 H, OCH3), 7.29−7.34 (m, 2 H, ArH), 7.37−7.40 (m, 2 H, ArH), 7.70 (s, 1 H, C=CH); C NMR
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(125.8 MHz, CDCl3) δ 52.7, 52.8, 126.9, 127.3, 129.1, 130.1, 130.5, 134.5, 134.8, 141.1, 164.0, 166.5;
IR (neat) 1724 s, 1624 w, 1433 m, 1373 w, 1258 m, 1200 s, 1068 w, 783 w cm−1; HRMS
(EI-Quadrupole) calcd for [M]+ (C12H11ClO4) m/z 254.0346, found 254.0328.
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Dimethyl 2-(2-chlorobenzylidene)malonate (3ka). The general procedure was followed with
4-chlorobenzaldehyde (1k; 84.3 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol) for
8 h to yield a colorless oil (3ka; 145.2 mg, 95%): 1H NMR (500.2 MHz, CDCl3) δ 3.75 (s, 3 H, OCH3),
3.87 (s, 3 H, OCH3), 7.25 (t, J = 10.0 Hz, 1 H, ArH), 7.33 (t, J = 10.0 Hz, 1 H, ArH), 7.40 (d, J = 10.0 Hz,
1 H, ArH), 7.44 (d, J = 10.0 Hz, 1 H, ArH), 8.07 (s, 1 H, C=CH); 13C NMR (125.8 MHz, CDCl3) δ 52.5,
52.7, 126.9, 127.9, 129.0, 129.9, 131.3, 131.8, 134.7, 139.9, 164.0, 166.2; HRMS (EI-Quadrupole) calcd
for [M]+ (C12H11ClO4) m/z 254.0346, found 254.0330. The spectroscopic data of 3ka were in good
agreement with that reported in the literature.17
Dimethyl 2-(4-bromobenzylidene)malonate (3la). The general procedure was followed with
4-bromobenzaldehyde (1l; 111 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol) for
5 h to yield a colorless oil (3la; 154.3 mg, 86%): 1H NMR (297.6 MHz, CDCl3) δ 3.84 (s, 3 H, OCH3),
3.85 (s, 3 H, OCH3), 7.28 (d, J = 8.3 Hz, 2 H, ArH), 7.51 (d, J = 8.3 Hz, 2 H, ArH), 7.70 (s, 1 H, C=CH);
13C NMR (74.8 MHz, CDCl3) δ 52.7, 125.2, 126.1, 130.7, 131.6, 132.1, 141.5, 164.2, 166.8; IR (neat)
1729 s, 1630 w, 1489 w, 1437 m, 1261 s, 1221 s, 1069 m cm−1; HRMS (EI-Quadrupole) calcd for [M]+
(C12H11BrO4) m/z 297.9841, found 297.9862.
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Dimethyl 2-[4-(methoxycarbonyl)benzylidene]malonate (3ma). The general procedure was followed
with 4-(methoxycarbonyl)benzaldehyde (1m; 98.5 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3
mg, 0.660 mmol) for 8 h, with the exception that recrystallization from hexane was performed after
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column chromatography to yield a colorless solid (3ma; 163.6 mg, 98%): mp 114−115 °C; H NMR
(500.2 MHz, CDCl3) δ 3.84 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 3.93 (s, 3 H, OCH3), 7.48 (d, J = 8.0
Hz, 2 H, ArH), 7.80 (s, 1 H, C=CH), 8.04 (d, J = 8.0 Hz, 2 H, ArH); 13C NMR (125.8 MHz, CDCl3) δ
52.3, 52.7, 52.8, 127.5, 129.0, 129.9, 131.5, 137.0, 141.4, 164.0, 166.1, 166.5; HRMS (EI-Quadrupole)
calcd for [M]+ (C14H14O6) m/z 278.0790, found 278.0798. The spectroscopic data of 3ma were in good
agreement with that reported in the literature.17
Dimethyl 2-[4-(trifluoromethyl)benzylidene]malonate (3na). The general procedure was followed
with 4-(trifluoromethyl)benzaldehyde (1n; 104.5 mg, 0.6000 mmol) and dimethyl malonate (2a; 79.3 mg,
1
0.660 mmol) for 8 h to yield a colorless solid (3na; 152.2 mg, 88%): mp 43−44 °C; H NMR (500.2
MHz, CDCl3) δ 3.85 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 7.53 (d, J = 8.0 Hz, 2 H, ArH), 7.65 (d, J = 8.0
13
Hz, 2 H, ArH), 7.79 (s, 1 H, C=CH); C NMR (125.8 MHz, CDCl3) δ 52.8, 52.9, 123.6 (q, J = 272.5
Hz), 125.8 (q, J = 3.9 Hz), 127.9, 129.4, 132.0 (q, J = 32.6 Hz), 136.2, 141.0, 164.0, 166.4; IR (neat)
1732 s, 1724 s, 1721 s, 1635 w, 1439 w, 1326 s, 1265 s, 1226 m, 1166 m, 1117 s, 1067 s, 849 w cm−1;
HRMS (EI-Quadrupole) calcd for [M]+ (C13H11F3O4) m/z 288.0609, found 288.0604.
Dimethyl 2-[3-(trifluoromethyl)benzylidene]malonate (3oa). The general procedure was followed
with 3-(trifluoromethyl)benzaldehyde (1o; 104.5 mg, 0.6000 mmol) and dimethyl malonate (2a; 79.3 mg,
1
0.660 mmol) for 8 h to yield a colorless solid (3oa; 138.3 mg, 80%): mp 52−53 °C; H NMR (500.2
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MHz, CDCl3) δ 3.85 (s, 3 H, OCH3), 3.87 (s, 6 H, OCH3), 7.53 (t, J = 10.0 Hz, 1 H, ArH), 7.60 (d, J =
10.0 Hz, 1 H, ArH), 7.66 (d, J = 10.0 Hz, 1 H, ArH), 7.68 (s, 1 H, ArH), 7.79 (s, 1 H, C=CH); 13C NMR
(125.8 MHz, CDCl3) δ 52.7, 52.8, 123.6 (q, J = 272.5 Hz), 125.7 (q, J = 3.9 Hz), 126.9 (q, J = 3.9 Hz),
127.4, 129.4, 131.3 (q, J = 32.6 Hz), 132.3, 133.5, 140.9, 164.0, 166.4; IR (neat) 1728 s, 1635 w, 1439 w,
1366 w, 1336 m, 1253 m, 1227 m, 1196 m, 1159 w, 1117 s, 1071 m, 809 w, 698 w cm−1; HRMS
(EI-Quadrupole) calcd for [M]+ (C13H11F3O4) m/z 288.0609, found 288.0597.
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Dimethyl 2-[2-(trifluoromethyl)benzylidene]malonate (3pa). The general procedure was followed
with 2-(trifluoromethyl)benzaldehyde (1p; 104.5 mg, 0.6000 mmol) and dimethyl malonate (2a; 79.3 mg,
0.660 mmol) for 8 h to yield a colorless oil (3pa; 159.1 mg, 92%): 1H NMR (500.2 MHz, CDCl3) δ 3.67
(s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 7.44 (d, J = 7.5 Hz, 1 H, ArH), 7.50 (t, J = 7.5 Hz, 1 H, ArH), 7.54
(t, J = 7.5 Hz, 1 H, ArH), 7.72 (d, J = 7.5 Hz, 1 H, ArH), 8.10 (s, 1 H, C=CH); 13C NMR (125.8 MHz,
CDCl3) δ 52.5, 52.8, 123.7 (q, J = 273.4 Hz), 126.1 (q, J = 5.8 Hz), 128.7 (q, J = 30.7 Hz), 129.1, 129.5,
129.6, 131.8, 132.1 (q, J = 1.9 Hz), 140.2, 163.7, 165.8; IR (neat) 1733 s, 1438 m, 1316 s, 1306 m, 1296
m, 1263 s, 1225 m, 1168 s, 1123 s, 1067 s, 1036 m, 771 m cm−1; HRMS (EI-Quadrupole) calcd for [M]+
(C13H11F3O4) m/z 288.0609, found 288.0617.
Dimethyl 2-(4-cyanobenzylidene)malonate (3qa). The general procedure was followed with
4-cyanobenzaldehyde (1q; 78.7 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol) for
8 h to yield a colorless solid (3qa; 135.4 mg, 92%): mp 97−98 °C; 1H NMR (300.5 MHz, CDCl3) δ 3.85
(s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 7.53 (d, J = 8.1 Hz, 2 H, ArH), 7.69 (d, J = 8.1 Hz, 2 H, ArH), 7.76
13
(s, 1 H, C=CH); C NMR (75.6 MHz, CDCl3) δ 52.8, 113.6, 117.9, 128.5, 129.4, 132.4, 137.0, 140.2,
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163.6, 166.0; HRMS (EI-Quadrupole) calcd for [M]+ (C13H11NO4) m/z 245.0688, found 245.0716. The
spectroscopic data of 3qa were in good agreement with that reported in the literature.18
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Dimethyl 2-(4-nitrobenzylidene)malonate (3ra). The general procedure was followed with
4-nitrobenzaldehyde (1r; 90.7 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol) for 8
h to yield a pale yellow solid (3ra; 146.4 mg, 92%): mp 135−136 °C; 1H NMR (500.2 MHz, CDCl3) δ
3.86 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3), 7.59 (d, J = 9.0 Hz, 2 H, ArH), 7.81 (s, 1 H, C=CH), 8.24 (d, J
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= 9.0 Hz, 2 H, ArH); C NMR (125.8 MHz, CDCl3) δ 52.9, 123.9, 129.1, 129.8, 139.0, 139.8, 148.4,
163.6, 165.9; HRMS (EI-Quadrupole) calcd for [M]+ (C12H11NO6) m/z 265.0586, found 265.0572. The
spectroscopic data of 3ra were in good agreement with that reported in the literature.18
Dimethyl 2-(2-acetoxybenzylidene)malonate (5). The general procedure was followed with
4-hydroxybenzaldehyde (1s; 73.3 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol)
1
for 8 h to yield a colorless oil (5; 66.8 mg, 40%): H NMR (300.5 MHz, CDCl3) δ 2.33 (s, 3 H, CH3),
3.76 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 7.15 (d, J = 7.8 Hz, 1 H, ArH), 7.23 (t, J = 7.8 Hz, 1 H, ArH),
13
7.42 (t, J = 7.8 Hz, 2 H, ArH), 7.83(s, 1 H, C=CH); C NMR (75.6 MHz, CDCl3) δ 20.8, 52.5, 52.7,
122.8, 126.06, 126.09, 127.6, 128.8, 131.4, 137.7, 149.0, 164.1, 166.3, 168.8; IR (neat) 1768 m, 1730 s,
1632 w, 1437 m, 1370 m, 1261 s, 1176 s, 1103 m, 1067 m, 910 w, 763 w cm−1; HRMS (FAB-Magnetic
Sector) calcd for [M+H]+ (C14H15O6) m/z 279.0869, found 279.0872.
3-(Methoxycarbonyl)coumarin (6). The general procedure was followed with 4-hydroxybenzaldehyde
(1s; 73.3 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol) for 8 h to yield a colorless
solid (6; 8.6 mg, 7%): mp 115−116 °C; 1H NMR (500.2 MHz, CDCl3) δ 3.96 (s, 3 H, OCH3), 7.35 (t, J =
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7.5 Hz, 1 H, ArH), 7.37 (d, J = 7.5 Hz, 1 H, ArH), 7.63 (d, J = 7.5 Hz, 1 H, ArH), 7.67 (t, J = 7.5 Hz, 1 H,
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ArH), 8.58 (s, 1 H, C=CH); C NMR (125.8 MHz, CDCl3) δ 52.9, 116.7, 117.8, 117.9, 124.9, 129.5,
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134.4, 149.1, 155.2, 156.7, 163.7; HRMS (EI-Quadrupole) calcd for [M]+ (C11H8O4) m/z 204.0423,
found 204.0404. The spectroscopic data of 6 were in good agreement with that reported in the
literature.19
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Methyl 2-benzylidene-3-oxobutanoate (3ab). The general procedure was followed with benzaldehyde
(1a; 63.7 mg, 0.600 mmol) and methyl acetoacetate (2b; 76.6 mg, 0.660 mmol) for 8 h to yield a pale
1
yellow oil ((Z)-3ab; 56.4 mg, 46%): H NMR (500.2 MHz, CDCl3) δ 2.42 (s, 3 H, CH3), 3.84 (s, 3 H,
13
OCH3), 7.39–7.44 (m, 5 H, ArH), 7.58 (s, 1 H, C=CH); C NMR (125.8 MHz, CDCl3) δ 26.4, 52.5,
128.9, 129.4, 130.8, 132.8, 134.2, 141.6, 168.2, 194.6; LRMS (FAB) m/z (% relative intensity) 205
([M+H]+, 49%), 173 (100), 131 (52), 73 (54). The spectroscopic data of (Z)-3ab were in good agreement
with that reported in the literature.20
A pale yellow-green oil ((E)-3ab; 40.4 mg, 33%): 1H NMR (500.2 MHz, CDCl3) δ 2.35 (s, 3 H, CH3),
13
3.84 (s, 3 H, OCH3), 7.39 (s, 5 H, ArH), 7.70 (s, 1 H, C=CH); C NMR (125.8 MHz, CDCl3) δ 31.2,
52.5, 128.9, 129.6, 130.5, 132.8, 133.6, 140.8, 164.9, 203.4; LRMS (FAB) m/z (% relative intensity) 205
([M+H]+, 100), 173 (35), 147 (25), 73 (38). The spectroscopic data of (E)-3ab were in good agreement
with that reported in the literature.20
Ethyl 2-benzoyl-3-phenylacrylate (3ac). The general procedure was followed with benzaldehyde (1a;
63.7 mg, 0.600 mmol) and ethyl benzoylacetate (2c; 126.9 mg, 0.6600 mmol) for 8 h to yield a colorless
solid (3ac; 141.3 mg, 84%, E:Z = 10:90): mp 94−95 °C; 1H NMR (297.6 MHz, CDCl3, Z isomer) δ 1.17
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(t, 3 H, CH3), 4.21 (q, 2 H, OCH2), 7.20–7.27 (m, 3 H, ArH), 7.35 (d, J = 7.4 Hz, 2 H, ArH), 7.42 (t, J =
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7.4 Hz, 2 H, ArH), 7.55 (t, J = 7.4 Hz, 1 H, ArH), 7.94–7.97 (m, 3 H, C=CH, ArH); C NMR (74.8
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MHz, CDCl3 Z isomer) δ 13.9, 61.5, 128.7, 128.8, 129.0, 130.1, 130.3, 131.2, 132.7, 133.8, 136.0, 142.5,
164.9, 195.6; LRMS (EI) m/z (% relative intensity) 280 (M+, 100), 251 (18), 235 (20), 178 (42), 105
(100). The spectroscopic data of 3ac were in good agreement with that reported in the literature.21
2-Benzylidene-N,N-dimethyl-3-oxobutanamide (3ad). The general procedure was followed with
benzaldehyde (1a; 63.7 mg, 0.600 mmol) and N,N-dimethylacetoacetamide (2d; 85.2 mg, 0.660 mmol)
for 30 h to yielod a pale yellow-green oil (3ad; 22.2 mg, 17%): 1H NMR (500.2 MHz, CDCl3) δ 2.44 (s,
3 H, CH3), 2.77 (s, 3 H, NCH3), 3.09 (s, 3 H, NCH3), 7.39–7.40 (m, 3 H, ArH), 7.48–7.50 (m, 2 H, ArH),
7.51 (s, 1 H, C=CH); 13C NMR (125.8 MHz, CDCl3) δ 26.5, 34.5, 37.4, 129.0, 129.6, 130.6, 133.1, 136.1,
139.3, 168.4, 195.7; IR (neat) 1662 m, 1620 s, 1497 w, 1407 w, 1242 w, 1210 w, 1155 w, 763 w cm−1;
LRMS (FAB) m/z (% relative intensity) 218 ([M+H]+, 100), 173 (59), 131 (36), 73 (22).
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2-Benzylidenemalonic acid (3ae). The general procedure was followed with benzaldehyde (1a; 63.7 mg,
0.600 mmol) and malonic acid (2e; 68.7 mg, 0.660 mmol) for 8 h, with the exception of using H2O
instead of aq. NaHCO3 for the reaction work-up, which was followed by isolation via recrystallization
1
from CHCl3 to yield a colorless solid (3ae; 89.9 mg, 78%): mp 193−194 °C; H NMR (297.6 MHz,
DMSO-d6) δ 7.43 (t, J = 8.0 Hz, 3 H, ArH), 7.54 (s, 1 H, C=CH), 7.56 (d, J = 3.3 Hz, 1 H, ArH), 7.58 (d,
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J = 3.3 Hz, 1 H, ArH), 13.2 (s, 2 H, COOH); C NMR (74.8 MHz, DMSO-d6) δ 128.5, 129.0, 129.3,
130.5, 132.9, 138.7, 165.3, 168.1; HRMS (FAB-Magnetic Sector) calcd for [M+H]+ (C10H9O4) m/z
193.0501, found 193.0504. The spectroscopic data of 3ae were in good agreement with that reported in
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2-Benzylidenemalononitrile (3af). The general procedure was followed with benzaldehyde (1a; 63.7
mg, 0.600 mmol) and malononitrile (2f; 39.6 mg, 0.660 mmol) for 8 h, with the exception of using DMF
instead of toluene, to yield a colorless solid (3af; 79.6 mg, 86%): mp 83−84 °C; 1H NMR (500.2 MHz,
CDCl3) δ 7.55 (t, J = 7.5 Hz, 2 H, ArH), 7.64 (t, J = 7.5 Hz, 1 H, ArH), 7.79 (s, 1 H, C=CH) , 7.91 (d, J =
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7.5 Hz, 2 H, ArH); C NMR (125.8 MHz, CDCl3) δ 82.6, 112.5, 113.6, 129.5, 130.6, 130.8, 134.5,
159.9; HRMS (FAB-Magnetic Sector) calcd for [M+H]+ (C10H9O4) m/z 193.0501, found 193.0504. The
spectroscopic data of 3af were in good agreement with that reported in the literature.3e
3,3,6,6-Tetramethyl-9-phenyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (7). The general
procedure was followed with benzaldehyde (1a; 63.7 mg, 0.600 mmol) and
5,5-dimethyl-1,3-cyclohexanedione (2g; 92.5 mg, 0.660 mmol) for 8 h to yield a colorless solid (7; 113.5
mg, 54%): mp 203−205 °C; 1H NMR (297.6 MHz, CDCl3) δ 0.98 (s, 6 H, CH3), 1.09 (s, 6 H, CH3), 2.15
(d, J = 16.1 Hz, 2 H, CH2), 2.23 (d, J = 16.1 Hz, 2 H, CH2), 2.47 (s, 4 H, CH2), 4.75 (s, 1 H, CH), 7.08 (t,
J = 7.7 Hz, 1 H, ArH), 7.20 (t, J = 7.7 Hz, 2 H, ArH), 7.29 (d, J = 7.7 Hz, 2 H, ArH); 13C NMR (74.8
MHz, CDCl3) δ 27.2, 29.1, 31.7, 32.1, 40.7, 50.6, 115.5, 126.2, 127.9, 128.2, 144.0, 162.2, 196.3; LRMS
(FAB) m/z (% relative intensity) 351 ([M+H]+, 95), 350 (M+, 40), 273 (100). The spectroscopic data of 7
were in good agreement with that reported in the literature.22
Dimethyl 4-pyridylmethylenemalonate (9aa). The general procedure was followed with
4-formylpyridine (8a; 64.3 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol) for 15 h
to yield a pale brown solid (9aa; 86.3 mg, 65%): mp 72−73 °C; 1H NMR (500.2 MHz, DMSO-d6) δ 3.79
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(s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 7.38 (d, J = 6.0 Hz, 2 H, ArH), 7.78 (s, 1 H, C=CH) 8.66 (d, J = 6.0
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Hz, 2 H, ArH); C NMR (125.8 MHz, DMSO-d6) δ 52.96, 53.03, 122.7, 129.0, 139.6, 139.8, 150.5,
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163.3, 165.5; IR (neat) 1722 s, 1597 w, 1441 w, 1266 m, 1221 m, 1068 w, 811 w cm−1; HRMS
(FAB-Magnetic Sector) calcd for [M+H]+ (C11H12NO4) m/z 222.0766, found 222.0796.
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Dimethyl 2-(6-bromo)pyridylmethylenemalonate (9ba). The general procedure was followed with
2-bromo-6-formylpyridine (8b; 111.6 mg, 0.6000 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660
1
mmol) for 13 h to yield a pale brown solid (9ba; 149.5 mg, 83%): mp 105−106 °C; H NMR (500.2
MHz, CDCl3) δ 3.87 (s, 3 H, OCH3), 4.00 (s, 3 H, OCH3), 7.34 (d, J = 5.0 Hz, 1 H, ArH), 7.45 (d, J = 5.0
Hz, 1 H, ArH), 7.55 (s, 1 H, C=CH), 7.58 (t, J = 5.0 Hz, 1 H, ArH); 13C NMR (125.8 MHz, CDCl3) δ
52.7, 52.9, 125.0, 129.1, 129.6, 137.5, 139.0, 141.9, 151.7, 164.0, 166.3; IR (neat) 1726 s, 1637 w, 1438
w, 1411 w, 1376 w, 1274 m, 1248 m, 1218 m, 1207 m, 1163 w, 1063 w, 788 w cm−1; HRMS
(EI-Quadrupole) calcd for [M]+ (C11H10BrNO4) m/z 298.9793, found 298.9789.
Dimethyl 2-(thien-2-ylmethylene)malonate (9ca). The general procedure was followed with
2-formylthiophene (8c; 67.3 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol) for 8 h,
with the exception of performing recrystallization from hexane following column chromatography to
yield a colorless solid (9ca; 86.9 mg, 64%): mp 43−44 °C; 1H NMR (297.6 MHz, CDCl3) δ 3.84 (s, 3 H,
OCH3), 3.94 (s, 3 H, OCH3), 7.09 (dd, J = 4.5, 4.8 Hz, 1 H, ArH), 7.37 (d, J = 4.5 Hz, 1 H, ArH), 7.54 (d,
J = 4.8 Hz, 1 H, ArH), 7.90 (s, 1 H, C=CH); 13C NMR (74.8 MHz, CDCl3) δ 52.6, 52.8, 121.5, 127.8,
131.9, 134.7, 135.5, 135.9, 164.7, 166.6; HRMS (EI-Quadrupole) calcd for [M]+ (C10H10O4S) m/z
226.0300, found 226.0300. The spectroscopic data of 9ca were in good agreement with that reported in
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(E)-Dimethyl 2-(3-phenylallylidene)malonate (9da). The general procedure was followed with
(E)-cinnamaldehyde (8d; 79.3 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol) for 8
h to yield a yellow solid (9da; 116.7 mg, 79%): mp 64−65 °C; 1H NMR (500.2 MHz, CDCl3) δ 3.81 (s, 3
H, OCH3), 3.90 (s, 3 H, OCH3), 7.04 (d, J = 16.0 Hz, 1 H, PhCH), 7.27 (dd, J = 15.0, 15.5 Hz, 1 H,
PhCH=CH), 7.32–7.38 (m, 3 H, ArH), 7.50 (d, J = 6.0 Hz, 2 H, ArH), 7.56 (d, J = 11.5 Hz, 1 H,
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PhCH=CH−CH=C); C NMR (125.8 MHz, CDCl3) δ 52.2, 52.3, 123.1, 123.9, 127.8, 128.8, 129.8,
135.4, 145.1, 146.1, 165.0, 165.6; HRMS (EI-Quadrupole) calcd for [M]+ (C14H14O4) m/z 246.0892,
found 246.0881. The spectroscopic data of 9da were in good agreement with that reported in the
literature.24
Dimethyl 2-(3-phenylpropylidene)malonate (9ea). The general procedure was followed with
3-phenylpropanal (8e; 80.5 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol) for 24 h
to yield a colorless oil (9ea; 89.4 mg, 60%): 1H NMR (300.5 MHz. CDCl3) δ 2.63 (q, J = 7.9 Hz, 2 H,
CH2CH2CH), 2.80 (t, J = 7.2 Hz, 2 H, PhCH2), 3.78 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 7.07 (t, J = 7.5
Hz, 1 H, C=CH), 7.17−7.19 (m, 3 H, ArH), 7.26−7.30, (m, 2 H, ArH); 13C NMR (74.8 MHz, CDCl3) δ
31.5, 34.3, 52.2, 52.3, 126.3, 128.29, 128.32, 128.5, 140.2, 149.2, 164.3, 165.7. The spectroscopic data
of 9ea were in good agreement with that reported in the literature.25
Dimethyl 2-hexylidenemalonate (9fa). The general procedure was followed with hexanal (8f; 60.1 mg,
0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol) for 24 h to yield a colorless oil (9fa;
1
90.0 mg, 70%): H NMR (500.2 MHz, CDCl3) δ 0.89 (t, J = 6.6 Hz, 3 H, CH3), 1.28−1.33 (m, 4 H,
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CH3CH2CH2CH2CH2), 1.44−1.54 (m, 2 H, CH3CH2), 2.30 (q, J = 7.4 Hz, 2 H, CHCH2) 3.78 (s, 3 H,
OCH3), 3.82 (s, 3 H, OCH3), 7.04 (t, J = 7.7 Hz, 1 H, C=CH); 13C NMR (74.8 MHz, CDCl3) δ 13.9, 22.3,
27.9, 29.8, 31.3, 52.2, 52.3, 127.8, 150.6, 164.4, 166.0; IR (neat) 2956 m, 2862 w, 1729 s, 1646 w, 1437
m, 1370 w, 1259 m, 1225 m, 1144 w, 1062 m cm−1; HRMS (EI-Quadrupole) calcd for [M]+ (C11H18O4)
m/z 214.1205, found 214.1208.
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Dimethyl 2-(2-phenylpropylidene)malonate (9ga). The general procedure was followed with
2-phenylpropionaldehyde (8g; 80.5 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660 mmol)
for 24 h to yield a colorless oil (9ga; 116 mg, 71%): 1H NMR (500.2 MHz, CDCl3) δ 1.45 (d, J = 6.9 Hz,
3 H, CH3), 3.76 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 3.88−3.92 (m, 1 H, ArCH), 7.04 (d, J = 10.8 Hz, 1
H, C=CH), 7.24 (d, J = 8.0 Hz, 3 H, ArH), 7.32 (t, J = 7.7 Hz, 2 H, ArH); 13C NMR (125.8 MHz, CDCl3)
δ 20.2, 39.6, 52.3, 52.4, 126.0, 127.0, 127.1, 128.8, 142.2, 152.8, 164.4, 165.8. The spectroscopic data of
9ga were in good agreement with that reported in the literature.26
Dimethyl 2-(2-methylpropylidene)malonate (9ha). The general procedure was followed with
isobutyraldehyde (8h; 43.3mg, 0.600 mmol) and dimethyl malonate (2a; 158.5 mg, 1.200 mmol) for 24 h
1
to yield a colorless oil (9ha; 79 mg, 71%): H NMR (297.6 MHz, CDCl3) δ 1.06 (d, J = 6.5 Hz, 6 H,
CH3), 2.62−2.75 (m, 1 H, CH3CHCH3), 3.78 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 6.81 (d, J = 10.7 Hz, 1
13
H, C=CH); C NMR (125.8 MHz, CDCl3) δ 21.8, 29.5, 52.2, 52.3, 125.7, 155.9, 164.5, 166.0. The
spectroscopic data of 9ha were in good agreement with that reported in the literature.27
Dimethyl 2-(cyclohexylmethylene)malonate (9ia). The general procedure was followed with
cyclohexanecarboxaldehyde (8i; 67.3 mg, 0.600 mmol) and dimethyl malonate (2a; 79.3 mg, 0.660
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The Journal of Organic Chemistry
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mmol) for 24 h to yield a colorless oil (9ia; 97.7 mg, 72%): 1H NMR (297.6 MHz, CDCl3) δ 1.11−1.35
(m, 5H, CyH), 1.70−1.73 (m, 5H, CyH), 2.33−2.45 (m, 1 H, CH2CHCH2), 3.78 (s, 3 H, OCH3), 3.84 (s, 3
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H, OCH3), 6.84 (d, J = 10.4 Hz, 1 H, C=CH); C NMR (74.8 MHz, CDCl3) δ 25.1, 25.6, 31.6, 39.1,
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52.2, 52.3, 126.0, 154.6, 164.6, 166.1. The spectroscopic data of 9ia were in good agreement with that
reported in the literature.25
Dimethyl 2-(2,2-dimethylpropylidene)malonate (9ja). The general procedure was followed with
pivalaldehyde (8j; 51.7 mg, 0.600 mmol) and dimethyl malonate (2a; 158.5 mg, 1.200 mmol) for 24 h to
yield a colorless oil (9ja; 81.7 mg, 68%): 1H NMR (297.6 MHz, CDCl3) δ 1.14 (s, 9 H, CH3), 3.77 (s, 3
H, OCH3), 3.82 (s, 3 H, OCH3), 6.92 (s, 1 H, C=CH); 13C NMR (74.8 MHz, CDCl3) δ 28.7, 34.2, 52.2,
52.4, 124.5, 155.8, 164.8, 167.3; IR (neat) 2959 m, 1734 s, 1642 w, 1436 m, 1368 w, 1251 s, 1232 s,
1197 m, 1070 m, 1002 w cm−1; HRMS (EI-Quadrupole) calcd for [M−CH3]+ (C9H13O4) m/z 185.0814,
found 185.0814.
Acknowledgement
This work was partially supported by a grant from the Japan Private School Promotion Foundation
supported by MEXT.
Supporting Information
1
Copies of the H and 13C NMR spectra of the products produced by this method. This material is
available free of charge via the Internet at http://pubs.acs.org/.
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