Natural α-amino acid l-lysine-catalyzed knoevenagel condensations of α,β-unsaturated aldehydes and 1,3-dicarbonyl compounds

Article abstract of DOI:10.1080/00397911.2010.490626

Knoevenagel condensations of α,β-unsaturated aldehydes and 1,3-dicarbonyl compounds were catalyzed by primary natural amino acid L-lysine. The reactions were carried out at room temperature in dimethylsulfoxide. It provides a facile entry to a wide variety of α,β,γ,δ- unsaturated dicarbonyl compounds. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2010.490626

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Natural α-Amino Acid L-Lysine–Catalyzed
Knoevenagel Condensations of α,β-
Unsaturated Aldehydes and 1,3-
Dicarbonyl Compounds
Yan-Hong He a , Ying Hu a & Zhi Guan a
a School of Chemistry and Chemical Engineering, Southwest
University, Chongqing, China
Version of record first published: 20 Apr 2011.
To cite this article: Yan-Hong He , Ying Hu & Zhi Guan (2011): Natural α-Amino Acid L-
Lysine–Catalyzed Knoevenagel Condensations of α,β-Unsaturated Aldehydes and 1,3-Dicarbonyl
Compounds, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 41:11, 1617-1628
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Synthetic Communications1, 41: 1617–1628, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.490626
NATURAL a-AMINO ACID L-LYSINE–CATALYZED
KNOEVENAGEL CONDENSATIONS OF a,b-
UNSATURATED ALDEHYDES AND 1,3-DICARBONYL
COMPOUNDS
Yan-Hong He, Ying Hu, and Zhi Guan
School of Chemistry and Chemical Engineering, Southwest University,
Chongqing, China
GRAPHICAL ABSTRACT
Abstract Knoevenagel condensations of a,b-unsaturated aldehydes and 1,3-dicarbonyl
compounds were catalyzed by primary natural amino acid L-lysine. The reactions were
carried out at room temperature in dimethylsulfoxide. It provides a facile entry to a wide
variety of a,b,c,d-unsaturated dicarbonyl compounds.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords 1,3-Dicarbonyl compound; Knoevenagel condensation; L-lysine; a,b-
unsaturated aldehyde
INTRODUCTION
Knoevenagel condensation is the reaction between an aldehyde or ketone and
an active methylene compound.[1,2] It has been widely used to form C-C bonds.[3]
Especially, the Knoevenagel condensations between a,b-unsaturated aldehydes and
1,3-dicarbonyl compounds generate useful a,b,c,d-unsaturated dicarbonyl com-
pounds,[4] which are versatile synthons[5–7] and significant substrates for Diels–Alder
reactions and 1,4-additions.[8–13] However, there are only a few examples of
Knoevenagel condensations involving a,b-unsaturated aldehydes, and most of them
either gave poor yields[14–16] or required drastic temperatures.[17,18] Furthermore, the
Knoevenagel condensations involving 1,3-diketones often face the drawbacks of
longer reaction times or lesser yields than other methylene active compounds[3,19,20]
because 1,3-diketones have an inherent tendency to form stable cyclic enols.
Received October 18, 2009.
Address correspondence to Zhi Guan, School of Chemistry and Chemical Engineering, Southwest
University, Chongqing 400715, China. E-mail: guanzhi@swu.edu.cn
1617

1618
Y.-H. HE, Y. HU, AND Z. GUAN
Therefore, development of a mild and high-yielding Knoevenagel condensation of
a,b-unsaturated aldehydes with 1,3-dicarbonyl compounds is still a desirable and
challenging goal.
On the other hand, a-amino acids as cheap and environmentally benign cata-
lysts have been widely used in organic synthesis.[21–26] However, amino acid–
catalyzed Knoevenagel condensations are relatively few, and among them L-proline
is the most used acid. With regard to the great success of secondary amino acid
L-proline,[8,27] it is somewhat surprising that the primary amino acids remain
largely unexplored. Therefore, the potential of primary amino acids as catalysts in
Knoevenagel condensation still deserves exploration. We recently reported primary
amino acid L-tryptophan as a catalyst in Knoevenagel condensations of aldehydes
with acetylacetone and ethyl acetoacetate.[28] Herein, we report another primary
natural amino acid, L-lysine, as a catalyst in Knoevenagel condensations between
various a,b-unsaturated aldehydes and a wide range of 1,3-dicarbonyl compounds.
The reaction is operationally simple, mild, and high yielding. A wide variety of
a,b,c,d-unsaturated dicarbonyl compounds were prepared using this method, and
among them there are 12 new compounds. X-ray crystal analysis was used to
determine the structures.
RESULTS AND DISCUSSION
In our initial study, to examine the solvent effect on amino acid–catalyzed
Knoevenagel condensation, the reaction between cinnamaldehyde and acetyl acetone
catalyzed by 30 mol% L-proline was selected as a model reaction (Table 1). The
excess of cinnamaldehyde and long reaction time (24 h) were provided to guarantee
relatively good yields. The reaction in H2O gave a poor yield of 26% (Table 1,
entry 1). It is probably because of the insolubility of cinnamaldehyde and acetyl acet-
one in H2O. Both tetrahydrofuran (THF) and CH2Cl2 were found to give poor yields
(Table 1, entries 2 and 3). Dimethylformamide (DMF) and solvent-free conditions
gave modest yields (Table 1, entries 4 and 5). The reaction in dimethylsulfoxide
Table 1. Knoevenagel condensation between cinnamaldehyde and acetyl acetone in different solvents
Entry
Solvent
Yield (%)a
1
2
3
4
5
6
H2O
THF
26
31
48
58
60
97
CH2Cl2
DMF
Solvent-free
DMSO
aRefers to yield of isolated product after flash chromatography.

L-LYSINE–CATALYZED KNOEVENAGEL CONDENSATION
1619
(DMSO) provided the best yield of 97% (Table 1, entry 6). Therefore, DMSO was
chosen as the optimized solvent for the Knoevenagel condensation.
Next, to find out the proper catalyst loading, 10, 20, 30, and 40 mol% of
L-proline were used to catalyze the condensation between cinnamaldehyde and
acetyl acetone (Table 2). A loding of 20 mol% of L-proline was determined as
optimal.
With the chosen solvent and catalyst loading in hand, we screened 20 natural
a-amino acids (Table 3). We found that several amino acids can catalyze the
Knoevenagel condensation efficiently. L-Proline gave a good yield of 89%, which
ranked second (Table 3, entry 19). Basic amino acid L-lysine showed the best result
of 93% yield (Table 3, entry 20), and basic amino acid L-arginine gave a moderate
yield of 64% (Table 3, entry 17). The results of L-lysine and L-arginine led us to
assume that the alkalinity of the amino acid is essential for good catalytic activity.
However, basic amino acid L-histidine, which contains an imidazole, gave a yield
of only 6% (Table 3, entry 5). Meanwhile, L-tryptophan, which contains an indole,
gave a good yield of 72% (Table 3, entry 18). As we all know, the imidazole is more
alkaline than indole. Those results convinced us that the alkalinity of amino acid
should not be the factor of catalytic activity. Interestingly, the structurally similar
amino acids L-asparagine and L-glutamine showed enormously different activities
(Table 3, entries 16 and 7). No better results were obtained for other tested amino
acids. The reaction without catalyst was also carried out, which gave only 7% yield
(Table 3, entry 21). The experiments showed that some amino acids are indeed
catalysts, and among them L-lysine is the most efficient one.
Based on this investigation, a series of a,b-unsaturated aldehydes and 1,3-
dicarbonyl compounds were catalyzed by L-lysine (20 mol%) in DMSO (Table 4).
The reactions gave the corresponding a,b,c,d-unsaturated dicarbonyl compounds
in moderate to excellent yields. It was observed that electronic factors of aromatic
a,b-unsaturated aldehydes played a crucial role. Better yields were obtained in the
presence of electron-donating substituents (Table 4, entries 7–16) than the
electron-withdrawing substituents (Table 4, entries 17–27), and some by-products
were observed for the latter. This is probably due to the further Michael or
Knoevenagel reactions of the products (a,b,c,d -unsaturated dicarbonyl compounds)
Table 2. Effect of catalyst loading on the Knoevenagel condensation
Entry
L-proline (mol%)
Yield (%)a
1
2
3
4
10
20
30
40
76
89
90
90
aRefers to yield of isolated product after flash chromatography.

1620
Y.-H. HE, Y. HU, AND Z. GUAN
Table 3. Various amino acids used as catalysts for Knoevenagel condensation
Entry
Amino acid
Yield (%)a
1
2
L-Isoleucine
L-Tyrosine
L-Aspartate
L-Glutamate
L-Histidine
L-Alanine
2
3
3
4
4
5
5
6
6
7
7
L-Glutamine
L-Leucine
L-Valine
8
8
9
9
10
12
13
15
33
34
35
58
64
72
89
93
7
10
11
12
13
14
15
16
17
18
19
20
21
L-Phenylalanine
L-Threonine
Glycine
L-Methionine
L-Cysteine
L-Serine
L-Asparagine
L-Arginine
L-Tryptophan
L-Proline
L-Lysine
No amino acid
aRefers to yield of isolated product after flash chromatography.
with 1,3-dicarbonyl compounds. The electron-withdrawing groups increase the
activity of the a,b,c,d-unsaturated dicarbonyl compounds, which facilitates these
side reactions. We tried to identify some by-products but failed to purify them.
Besides the effect of aldehydes, 1,3-dicarbonyl compounds also played an important
role. Knoevenagel condensations of diethyl malonate with p-methylcinnamaldehyde
or p-fluorocinnamaldehyde (Table 4, entries 14 and 25) and p-nitrobenzoylacetic acid
ethyl ester with p-chlorocinnamaldehyde or p-fluorocinnamaldehyde (Table 4,
entries 22 and 27) gave relatively poor yields because of the incomplete reactions.
Prolonged reaction times did not improve the yields. The Meldrum’s acid progressed
with poor yields because of the instability of the products (Table 4, entries 4 and 20).
Ethyl acetoacetate gave all products as E and Z configuration isomers. Z and E refer
to the newly formed double bond between a-C and b-C (Table 4). The configurations
were determined by NMR in comparison with reported cinnamaldehyde pro-
ducts.[29] To our surprise, Z isomers were received as the major products, and the
ratio of Z and E was shown in the note of Table 4. However, all the products of
p-nitrobenzoylacetic acid ethyl ester and benzoylacetic acid ethyl ester were obtained
selectively as E isomers. The structure of product p16 was further confirmed by
single-crystal x-ray analysis as depicted in Fig. 1.

L-LYSINE–CATALYZED KNOEVENAGEL CONDENSATION
1621
Table 4. L-Lysine–catalyzed Knoevenagel condensations of a,b-unsaturated aldehydes and 1,3-dicarbo-
nyl compounds
Entry
1
a
b
Time (h) Yield (%)a Product number
2.5
1
97
97b
97
p1
p2a, p2b
p3
2
3
2
4
3
55
p4
5
6
2
2
90
80
p5
p6
7
8
9
4
3
98
92b
89
p7
p8a, p8b
p9
12
10
11
21
8
70
90
p10
p11
(Continued )

1622
Y.-H. HE, Y. HU, AND Z. GUAN
Table 4. Continued
Entry
12
a
b
Time (h) Yield (%)a Product number
4
96
79b
77
p12
p13a, p13b
p14
13
24
18
14
15
16
24
18
86
96
p15
p16
17
18
19
18.5
6
95
72b
90
p17
p18a, p18b
p19
23
20
21
6
47
72
p20
24
p21
p22
22
23
18
2
60
79
p23
(Continued )

L-LYSINE–CATALYZED KNOEVENAGEL CONDENSATION
1623
Table 4. Continued
Entry
24
a
b
Time (h) Yield (%)a Product number
3
56b
79
p24a, p24b
P25
25
26
24
12
24
76
51
p26
p27
27
28
29
5
4
88
96
p28
p29
30
31
4
4
80
33
p30
p31
32
4
52
p32
aRefers to yield of isolated product after flash chromatography.
bRefers to the total yield of two isomers. The ratio of two isomers: Z=E ¼ 2.1 for entries 2 and 8; Z=
E ¼ 2.2 for entries 13 and 18; Z=E ¼ 3.2 for entry 24. Z and E refer to the newly formed double bond
between a-C and b-C.
In addition, aliphatic a,b-unsaturated aldehyde crotonaldehyde also performed
well. Crotonaldehyde reacting with acetyl acetone, ethyl acetoacetate, and diethyl
malonate respectively furnished good yields (Table 4, entries 28–30), but when it
reacted with benzoylacetic acid ethyl ester (Table 4, entry 31), poor yield was
obtained and a side reaction was observed. The possible reason may be that the
d-carbon (Table 4) of the product from crotonaldehyde is less hindered than the
product from aromatic a,b-unsaturated aldehyde, which makes it easy to further
react with benzoyl acetic acid ethyl ester. However, crotonaldehyde reacting with
p-nitrobenzoylacetic acid ethyl ester (Table 4, entries 32) also gave poor yield

1624
Y.-H. HE, Y. HU, AND Z. GUAN
Figure 1. X-ray crystal structure of (2E,4E)-ethyl(2-p-nitrobenzoyl-5-p-tolyl)-2,4-pentadienoate (p16).
because of the incomplete reaction. This reaction gave two isomers, but we could not
distinguish them by column chromatography. The ratio of two isomers was about
3.3:1 by NMR.
CONCLUSION
In summary, the present procedure provides a convenient and efficient method
for the synthesis of a,b,c,d-unsaturated dicarbonyl compounds by Knoevenagel con-
densations of aliphatic and aromatic a,b-unsaturated aldehydes with 1,3-dicarbonyl
compounds. The reaction was carried out at room temperature. It employs amino
acid L-lysine as a green and efficient catalyst. This report also successfully expanded
the use of primary amino acids in Knoevenagel condensations. With those significant
advantages, this method has great potential for future application.
EXPERIMENTAL
General Procedure for L-Lysine-Catalyzed Knoevenagel
Condensation
A catalytic amount of L-lysine (0.2 mmol, 20 mol%) was added to a vial contain-
ing a,b-unsaturated aldehyde (1 mmol), 1,3-dicarbonyl compounds (1 mmol) and
DMSO (2 mL). The mixture was stirred at room temperature and monitored by
thin-layer chromatography (TLC). After completion, the mixture was diluted with
CH2Cl2 (20 ml) and washed with H2O (10 ml ꢀ 2). The mixture was concentrated in
vacuo and purified by silica-gel column chromatography (EtOAc=petrol mixtures).
Data of New Compounds
(2E,4E)-Ethyl(2-(p-nitrobenzoyl)-5-phenyl)-2,4-pentadienoate (p6). Yel-
1
low solid, mp 94–98 ꢁC. H NMR spectrum, d, ppm: 8.33 d (2H, p-nitrophenyl,
=
J ¼ 8.6 Hz), 8.04 d (2H, p-nitrophenyl, J ¼ 8.6 Hz), 7.79 d (1H, R3CH CR4R5,

L-LYSINE–CATALYZED KNOEVENAGEL CONDENSATION
1625
=
J ¼ 11.7 Hz), 7.41 d (2H, Ph, J ¼ 1.9 Hz), 7.34–7.33 m (3H, Ph), 7.14 d (1H, PhCH ,
=
J ¼ 15.4 Hz), 6.90 dd (1H, PhCH CH-CH, J1 ¼ 11.8 Hz, J2 ¼ 15.3 Hz), 4.18 q (2H,
OCH2, J ¼ 7.1 Hz), 1.13 t (3H, CH3, J ¼ 7.1 Hz). 13C NMR spectrum, dC, ppm:
192.7, 164.7, 150.3, 146.1, 145.8, 142.1, 135.1, 130.1, 129.8, 129.6, 128.8, 127.8,
123.8, 122.3, 61.4, 13.9. HRMS-ESI: m=z [M þ Na]þ calcd. for C20H17NO5Na
374.0999; found 374.1001.
(2E,4E)-Ethyl(2-(p-nitrobenzoyl)-5-(p-methoxyphenyl))-2,4-pentadieno-
1
ate (p11). Yellow solid, mp 143–145 ꢁC. H NMR spectrum, d, ppm: 8.32 d (2H,
p-nitrophenyl, J ¼ 8.1 Hz), 8.02 d (2H, p-nitrophenyl, J ¼ 8.2 Hz), 7.78 d (1H,
=
R3CH CR4R5, J ¼ 11.8 Hz), 7.38 d (2H, p-methoxyphenyl, J ¼ 8.2 Hz), 7.10 d
=
=
(1H, PhCH , J ¼ 15.3 Hz), 6.87–6.77 m (3H, p-methoxyphenyl and PhCH CH-
CH), 4.17 q (2H, OCH2, J ¼ 6.9 Hz), 3.82 (3H, s, OCH3), 1.12 t (3H, CH3,
J ¼ 7.0 Hz). 13C NMR spectrum, dC, ppm: 192.9, 165.0, 161.4, 150.3, 147.0, 145.9,
142.5, 129.8, 129.6, 128.1, 123.8, 123.6, 120.4, 114.4, 61.3, 55.4, 14.0. HRMS-ESI:
m=z [M þ Na]þ calcd. for C21H19NO6Na 404.1105; found 404.1107.
Diethyl-2-((E)-3-p-tolylallylidene) malonate (p14). Yellow solid, mp
1
ꢁ
=
61–66 C. H NMR spectrum, d, ppm: 7.53 d (1H, R3CH CR4R5, J ¼ 11.5 Hz),
=
7.40 d (2H, p-tolyl, J ¼ 7.8 Hz), 7.34–7.22 m (1H, p-tolylCH CH-CH), 7.18 d (2H,
=
p-tolyl, J ¼ 7.2 Hz), 7.02 d (1H, p-tolylCH , J ¼ 15.4 Hz), 4.37 q (2H, OCH2,
J ¼ 7.1 Hz), 4.28 q (2H, OCH2, J ¼ 7.0 Hz), 2.37 s (3H, p-tolylCH3), 1.38 t (3H,
CH3, J ¼ 7.1 Hz), 1.33 t (3H, CH3, J ¼ 7.0 Hz). 13C NMR spectrum, dC, ppm:
165.4, 164.8, 145.6, 144.7, 140.2, 132.9, 129.5, 127.8, 124.2, 122.3, 61.2, 21.4, 14.2.
HRMS: m=z [M þ Na]þ calcd. for C17H20O4Na 311.1254; found 311.1255.
(2E,4E)-Ethyl(2-benzoyl-5-p-tolyl)-2,4-pentadienoate (p15). Yellow solid,
1
mp 71–75 ꢁC. H NMR spectrum, d, ppm: 7.91 d (2H, phenyl, J ¼ 8.0 Hz), 7.70 d
=
(1H, R3CH CR4R5, J ¼ 11.7 Hz), 7.59–7.45 m (3H, phenyl), 7.28 d (2H, p-tolyl,
=
J ¼ 8.1 Hz), 7.11 d (2H, p-tolyl, J ¼ 7.7 Hz), 7.02 d (1H, p-tolylCH , J ¼ 15.4 Hz),
=
6.78 dd (1H, p-tolylCH CH-CH, J1 ¼ 11.8 Hz, J2 ¼ 15.1 Hz), 4.18 q (2H, OCH2,
J ¼ 7.1 Hz), 2.32 s (3H, p-tolylCH3), 1.13 t (3H, CH3, J ¼ 7.1 Hz). 13C NMR spec-
trum, dC, ppm: 194.4, 165.2, 144.4, 144.1, 140.0, 137.2, 133.5, 132.7, 130.6, 129.5,
129.1, 128.6, 127.6, 121.9, 61.0, 21.4, 13.9. HRMS-ESI: m=z [M þ Na]þ calcd. for
C21H20O3Na 343.1305; found 343.1307.
(2E,4E)-Ethyl(2-p-nitrobenzoyl-5-p-tolyl)-2,4-pentadienoate (p16). Yel-
1
low solid, mp 131–134 ꢁC. H NMR spectrum, d, ppm: 8.32 d (2H, p-nitrophenyl,
=
J ¼ 8.5 Hz), 8.03 d (2H, p-nitrophenyl, J ¼ 8.4 Hz), 7.78 d (1H, R3CH CR4R5,
J ¼ 11.7 Hz), 7.32 d (2H, p-tolyl, J ¼ 7.8 Hz), 7.13 d (2H, p-tolyl, J ¼ 7.3 Hz), 7.09
=
=
(1H, p-tolylCH ), 6.87 dd (1H, p-tolylCH CH-CH, J1 ¼ 11.9 Hz, J2 ¼ 14.9 Hz),
4.17 q (2H, OCH2, J ¼ 7.0 Hz), 2.34 s (3H, p-tolylCH3), 1.12 t (3H, CH3, J ¼ 7.1 Hz).
13C NMR spectrum, dC, ppm: 192.8, 164.8, 150.2, 146.6, 146.0, 142.2, 140.6, 132.4,
129.7, 129.6, 128.8, 127.8, 123.8, 121.4, 61.3, 21.4, 13.9. HRMS-ESI: m=z [M þ Na]þ
calcd. for C21H19NO5Na 388.1155; found 388.1148.
Diethyl-2-((E)-3-p-chlorophenylallylidene)malonate (p19). White solid,
1
ꢁ
=
mp 75–76 C. H NMR spectrum, d, ppm: 7.50 d (1H, R3CH CR4R5, J ¼ 11.5 Hz),
7.43 d (2H, p-chlorophenyl, J ¼ 8.4 Hz), 7.34 d (2H, p-chlorophenyl, J ¼ 8.4 Hz), 7.23

1626
Y.-H. HE, Y. HU, AND Z. GUAN
=
dd (1H, p-chlorophenylCH CH-CH, J1 ¼ 11.6 Hz, J2 ¼ 15.3 Hz), 6.98 d (1H, p-
=
chlorophenylCH C, J ¼ 15.4 Hz), 4.37 q (2H, OCH2, J ¼ 7.1 Hz), 4.28 q (2H,
OCH2, J ¼ 7.1 Hz), 1.38 t (3H, CH3, J ¼ 7.1 Hz), 1.33 t (3H, CH3, J ¼ 7.1 Hz). 13C
NMR spectrum, dC, ppm: 165.1, 164.5, 144.7, 142.8, 135.5, 134.0, 129.0, 128.8,
125.4, 123.7, 61.3, 14.1. HRMS-ESI: m=z [M þ Na]þ calcd. for C16H17ClO4Na
331.0708; found 331.0708.
(2E,4E)-Ethyl(2-benzoyl-5-p-chlorophenyl)-2,4-pentadienoate
(p21).
Yellow solid, mp 99–102 ꢁC. 1H NMR spectrum, d, ppm: 7.90 d (2H, phenyl,
=
J ¼ 7.8 Hz), 7.68 d (1H, R3CH CR4R5, J ¼ 11.6 Hz), 7.62–7.58 m (1H, phenyl),
7.51–7.46 m (2H, phenyl), 7.32–7.28 m (4H, p-chlorophenyl), 6.99 d (1H, p-chloro-
=
=
phenylCH C, J ¼ 15.4 Hz), 6.83–6.78 m (1H, p-chlorophenylCH CH-CH), 4.18 q
(2H, OCH2, J ¼ 7.1 Hz), 1.13 t (3H, CH3, J ¼ 7.1 Hz). 13C NMR spectrum, dC,
ppm: 194.1, 165.0, 143.5, 142.2, 137.2, 135.4, 134.0, 133.6, 131.9, 129.1, 129.0,
128.7, 128.7, 123.4, 61.2, 13.9. HRMS-ESI: m=z [M þ Na]þ calcd. for C20H17ClO3Na
363.0758; found 363.0753.
(2E,4E)-Ethyl(2-p-nitrobenzoyl-5-p-chlorophenyl)-2,4-pentadienoate (p22).
Yellow solid, mp 151–153 ꢁC. 1H NMR spectrum, d, ppm: 8.33 d (2H, p-nitrophenyl,
=
J ¼ 8.5 Hz), 8.03 d (2H, p-nitrophenyl, J ¼ 8.5 Hz), 7.76 d (1H, R3CH CR4R5,
J ¼ 11.6 Hz), 7.36 d (2H, p-chlorophenyl, J ¼ 8.4 Hz), 7.30 d (2H, p-chlorophenyl,
=
J ¼ 8.4 Hz), 7.08
d
(1H, p-chloroCH , J ¼ 15.4 Hz), 6.87 dd (1H, p-
=
chlorophenylCH CH-CH, J1 ¼ 11.7 Hz, J2 ¼ 15.1 Hz), 4.18
q (2H, OCH2,
J ¼ 7.1 Hz), 1.13 t (3H, CH3, J ¼ 7.1 Hz). 13C NMR spectrum, dC, ppm: 192.6,
164.6, 150.4, 145.8, 144.2, 142.0, 136.0, 133.7, 130.2, 129.8, 129.1, 129.0, 123.9,
122.9, 61.5, 13.9. HRMS: m=z [M þ Na]þ calcd. for C20H16ClNO5Na 408.0609;
found 408.0607.
Diethyl-2-((E)-3-p-fluorophenylallylidene)malonate (p25). White solid,
1
mp 63–65 ꢁC. H NMR spectrum, d, ppm: 7.52–7.45 m (3H, p-fluorophenyl and
=
=
R3CH CR4R5), 7.19 dd (1H, p-fluorophenylCH CH-CH, J1 ¼ 11.6 Hz,
=
J2 ¼ 15.3 Hz), 7.09–6.97 m (3H, p-fluorophenyl and p-fluorophenylCH ), 4.37 q
(2H, OCH2, J ¼ 7.1 Hz), 4.28 q (2H, OCH2, J ¼ 7.1 Hz), 1.38 t (3H, CH3, J ¼ 7.1 Hz),
1.33 t (3H, CH3, J ¼ 7.1 Hz). 13C NMR spectrum, dC, ppm: 165.3, 164.7, 163.5 d
(J ¼ 249.6 Hz), 145.0, 143.1, 131.8, 129.5 d (J ¼ 8.2 Hz), 125.0, 123.0, 115.9 d
(J ¼ 21.8 Hz), 61.3, 14.2. HRMS-ESI: m=z [M þ Na]þ calcd. for C16H17FO4Na
315.1003; found 315.1005.
(2E,4E)-Ethyl(2-benzoyl-5-p-fluorophenyl)-2,4-pentadienoate (p26). White
1
solid, mp 107–108 ꢁC. H NMR spectrum, d, ppm: 7.91 d (2H, phenyl, J ¼ 7.2 Hz),
=
7.70–7.66 m (1H, phenyl), 7.59 d (1H, R3CH CR4R5, J ¼ 7.2 Hz), 7.48 dd (2H, phe-
nyl, J1 ¼ 7.2 Hz, J2 ¼ 7.3 Hz), 7.35 d (2H, p-flurophenyl, J ¼ 5.4 Hz), 7.02–6.97 m
=
(3H, p-flurophenyl and p-flurophenylCH ), 6.78–6.73 m (1H, p-fluorophe-
=
nylCH CH-CH), 4.18 q (2H, OCH2, J ¼ 7.1 Hz), 1.13 t (3H, CH3, J ¼ 7.1 Hz).
13C NMR spectrum, dC, ppm: 194.2, 165.0, 163.3 d (J ¼ 250.3 Hz), 143.8, 142.5,
137.1, 133.6, 131.7, 131.3, 129.4 d (J ¼ 8.2 Hz), 129.1, 128.6, 122.6, 115.8 d
(J ¼ 21.8 Hz), 61.1, 13.9. HRMS-ESI: m=z [M þ Na]þ calcd. for C20H17FO3Na
347.1054; found 347.1051.

L-LYSINE–CATALYZED KNOEVENAGEL CONDENSATION
1627
(2E,4E)-Ethyl(2-p-nitrobenzoyl-5-p-fluorophenyl)-2,4-pentadienoate (p27).
Yellow solid; mp 121–123 ꢁC. 1H NMR spectrum, d, ppm: 8.32 d (2H, p-nitrophenyl,
=
J ¼ 8.1 Hz), 8.03 d (2H, p-nitrophenyl, J ¼ 8.0 Hz), 7.76 d (1H, R3CH CR4R5,
J ¼ 11.7 Hz), 7.44–7.39 m (2H, p-fluorophenyl), 7.13–7.00 m (3H, p-fluorophenyl
=
=
and p-fluorophenylCH ), 6.83 dd (1H, p-fluorophenylCH CH-CH, J1 ¼ 12.0 Hz,
J2 ¼ 15.0 Hz), 4.18 q (2H, OCH2, J ¼ 7.0 Hz), 1.13 t (3H, CH3, J ¼ 7.0 Hz).
13C NMR spectrum, dC, ppm: 192.7, 164.7, 163.7 d (J ¼ 250.3 Hz), 150.4, 146.1,
144.4, 142.1, 131.5, 129.8, 129.7, 123.9, 122.2, 116.2, 115.9, 61.4, 14.0. HRMS-ESI:
m=z [M þ Na]þ calcd. for C20H16FNO5Na 392.0905; found 392.0907.
(4E)-Ethyl(2-p-nitrobenzoyl)-2,4-hexadienoate (p32). The spectroscopy
showed that the product is a mixture of two isomers. Data of the major isomer
are listed. Yellow oil. 1H NMR spectrum, d, ppm: 8.31 d (2H, p-nitrophenyl,
=
J ¼ 8.5 Hz), 8.01 d (2H, p-nitrophenyl, J ¼ 8.6 Hz), 7.58 d (1H, R3CH CR4R5,
=
J ¼ 11.6 Hz), 6.43 dd (1H, methylCH CH-CH, J1 ¼ 7.1 Hz, J2 ¼ 19.7 Hz),
=
6.37–6.15 m (1H, methylCH ), 4.16 q (2H, OCH2, J ¼ 7.2 Hz), 1.86 d (3H, methyl,
J ¼ 6.7 Hz), 1.11 t (3H, CH3, J ¼ 7.1 Hz). 13C NMR spectrum, dC, ppm: 192.8, 164.8,
149.0, 147.8, 146.1, 145.8, 141.9, 129.8, 126.5, 123.8, 61.3, 19.1, 13.9. HRMS: m=z
[M þ Na]þ calcd. for C15H15NO5Na 312.0842; found 312.0837.
Supplementary Material: The 1H NMR, 13C NMR and HRMS spectra of new
compounds are given as Supplementary Material (available online).
ACKNOWLEDGMENT
Financial support from the Natural Science Foundation Project of CQ CSTC
(CSTC, 2009BA5051) is gratefully acknowledged.
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