A simple method for the preparation of functionalized trisubstituted alkenes and α,β,γ,δ-unsaturated carbonyl compounds by using natural amino acid l-tryptophan

Article abstract of DOI:10.1016/j.catcom.2010.01.016

Primary natural amino acid l-tryptophan was used, for the first time, as a catalyst in Knoevenagel condensations of aliphatic, aromatic, hetero-aromatic and α,β-unsaturated aldehydes with less reactive acetylacetone and ethyl acetoacetate. The reactions were carried out at room temperature and gave good yields. It is a convenient entry for preparation of functionalized trisubstituted alkenes and α,β,γ,δ-unsaturated carbonyl compounds.

Full text of DOI:10.1016/j.catcom.2010.01.016

Catalysis Communications 11 (2010) 656–659
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Catalysis Communications
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A simple method for the preparation of functionalized trisubstituted alkenes and
a,b,
c,d-unsaturated carbonyl compounds by using natural amino acid L-tryptophan
*
Ying Hu, Yan-Hong He, Zhi Guan
School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Primary natural amino acid
densations of aliphatic, aromatic, hetero-aromatic and
L
-tryptophan was used, for the first time, as a catalyst in Knoevenagel con-
,b-unsaturated aldehydes with less reactive ace-
tylacetone and ethyl acetoacetate. The reactions were carried out at room temperature and gave good
Received 8 September 2009
Received in revised form 16 January 2010
Accepted 18 January 2010
Available online 25 January 2010
a
yields. It is a convenient entry for preparation of functionalized trisubstituted alkenes and
urated carbonyl compounds.
a,b,c,d-unsat-
Ó 2010 Elsevier B.V. All rights reserved.
Keywords:
L-tryptophan
Knoevenagel condensation
Aldehyde
Acetylacetone
Ethyl acetoacetate
1. Introduction
perfumes and pharmaceuticals [18]. On the other hand, the cata-
lysts for Knoevenagel condensations usually were Lewis acids
[18], bases [19–21], zeolites [22] and heterogeneous catalysts
[23–25]. However, most catalysts lacked general applicability,
and only few could entirely catalyze Knoevenagel condensations
The natural a-amino acids have been elegantly used to catalyze
many kinds of reactions such as the direct asymmetric aldol reac-
tion [1], Mannich reaction [2], Michael reaction [3], Knoevenagel
condensation [4] and Ullmann-type coupling reaction [5]. Among
of aliphatic, aromatic, hetero-aromatic and
hydes. In the present method, -tryptophan successfully catalyzed
Knoevenagel condensations of aromatic, aliphatic, hetero-aromatic
and ,b-unsaturated aldehydes with less reactive acetylacetone
and ethyl acetoacetate. The products, trisubstituted alkenes and
,b, ,d-unsaturated carbonyl compounds, are good Michael accep-
a,b-unsaturated alde-
these natural
based -proline has attracted considerable attention [6]. It was
found to be a good bifunctional organocatalyst for enantioselective
Michael [7], Mannich [8] and aldol reactions [1]. Recently, -proline
catalyzed Knoevenagel condensation has also been reported [9,10].
With regard to the great success of secondary amino acid -proline,
a
-amino acids, the secondary cyclic pyrrolidine-
L
L
a
L
a
c
L
tors, and also can be used directly in the Diels–Alder reactions for
further transformations, which provides wide applications in phar-
maceuticals [26–28].
it is somewhat surprising that the use of primary natural amino
acids as catalysts still remains largely unexplored. So development
of highly efficient primary amino acids with a broad spectrum of
substrates is desired. We initially focused on L-tryptophan. Since
it could catalyze aldol reaction [11], we expected to use it as a cat-
alyst in Knoevenagel condensation which is a modification of aldol
reaction.
Knoevenagel condensation is one of the most useful carbon–
carbon bond forming reactions in organic synthesis [12,13]. The
condensation of aldehydes with active methylene compounds
has been commonly employed to synthesize speciality chemicals
and chemical intermediates [14] such as carbocyclic as well as het-
erocyclic compounds of biological significance [15], calcium antag-
onists [16], polymers [17], coumarin derivatives, cosmetics,
2. Results and discussion
Initially, to evaluate the catalytic efficiency, six catalysts were
used in reaction between p-methoxy cinnamaldehyde and acetyl-
acetone (Table 1). All the reactions were performed by using
20 mol% of catalyst in 1 mL of DMSO at room temperature for
2 h. The primary amino acid
82% (entry 1). The secondary amino acid
yield of 65% (entry 2), and side reactions were observed. Taking
into account that -tryptophan has an indole segment, indole was
also tested as a catalyst (entry 6), but it only gave poor yield of
2%. This implied that the efficiency of -tryptophan may not be
solely determined by indole substituent. Moreover, the simplest
L
-tryptophan gave the best yield of
L
-proline gave moderate
L
L
* Corresponding author. Tel./fax: +86 23 68254091.
E-mail address: guanzhi@swu.edu.cn (Z. Guan).
1566-7367/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2010.01.016

Y. Hu et al. / Catalysis Communications 11 (2010) 656–659
657
Table 1
Table 3
The catalytic activities of different catalysts in Knoevenagel condensation between p-
methoxy cinnamaldehyde and acetylacetone.
Effects of solvent volume and catalyst loading on the yield of Knoevenagel
condensation.
H3CO
H3CO
H3CO
O
H3CO
O
O
O
O
O
catalyst (0.2 mmol),
DMSO (1 mL), rt (2h)
L-tryptophan, DMSO, rt
+
+
CHO
CHO
O
(1 mmol)
(1 mmol)
(1 mmol)
(1 mmol)
O
Entry DMSO
(mL)
Time
(h)
Conversion
(%)
Yield
(%)a
L
-tryptophan
Entry
Catalyst
Yield (%)a
(mol%)
1
2
82
65
L
L
-tryptophan
-proline
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2
2
2
2
2
2
1
1
1
1
1
1
1
1
5
10
15
20
25
30
5
10
10
10
15
20
25
30
48
48
48
6
3
1
18
18
24
48
17
3
37
64
73
27
51
64
64
89
95
34
60
61
59
66
91
94
98
3
4
5
Glycine
Pyridine
14
10
4
78
L
-histidine
100
100
50
76
79
80
76
100
100
100
6
Indole
2
a
Refers to yield of isolated product after flash chromatography.
primary amino acid glycine only gave yield of 14% (entry 3). Other
catalysts pyridine and -histidine did not show better results
(entries and 5). Therefore, we chose unexplored primary
natural amino acid
condensation.
L
2
1
4
L-tryptophan as a catalyst in Knoevenagel
a
Refers to yield of isolated product after flash chromatography.
Next, to choose a suitable solvent, the model reaction of p-
methoxy cinnamaldehyde and acetylacetone catalyzed by
30 mol% L-tryptophan was carried out in various solvents (2 mL)
loading to achieve the satisfied yield by extending the reaction
(Table 2). It can be seen that there is a remarkable solvent depen-
dency for this reaction. The best yield of 95% was obtained in
DMSO after 1 h (entry 1), and the solvent-free reaction gave the
moderate yield of 52% after 24 h (entry 2). Reactions in 1,2-dichlo-
roethane, H2O, THF gave low yields (entries 3–5). However, no
products were observed when the reactions were performed in
CH2Cl2 and cyclohexane even after 24 h (entries 6 and 7). The ma-
jor reason of the solvent dependency may be related to the solubil-
ity of the reactants and catalyst in the solvents. Thus, DMSO was
chosen as the optimal solvent.
time. However, the condensation of p-methoxy cinnamaldehyde
and acetylacetone using 10 mol% of
showed no obvious differences in yields among the reaction times
of 18, 24 and 48 h (entries 8–10). From Table 3, 20 mol% of -tryp-
L-tryptophan in 1 mL of DMSO
L
tophan loading in 1 mL of DMSO was the optimal conditions for the
reaction of p-methoxy cinnamaldehyde and acetylacetone. More-
over, in consideration of some less reactive substrates, the solubil-
ity of wide range of reactants and cheapness of
30 mol% of -tryptophan in 2 mL of DMSO was also chosen as an-
other suitable reaction conditions.
L-tryptophan,
L
We further investigated the effects of solvent volume and cata-
lyst loading on the yield of Knoevenagel condensation of p-meth-
oxy cinnamaldehyde and acetylacetone (Table 3). When 2 mL of
DMSO was used, the good yields of 89% and 95% were obtained
With the optimized conditions in hand, some other aldehydes
and active methylene compounds were used to expand upon this
primary amino acid-catalyzed Knoevenagel condensation to show
the generality and scope of this reaction. The reaction conditions
with 25 and 30 mol% of
6). When 1 mL of DMSO was used, the excellent yields of 91–98%
were achieved with 20–30 mol% of -tryptophan (entries 12–14).
L-tryptophan respectively (entries 5 and
of 30 mol% of
of 20 mol% of
L
-tryptophan in 2 mL of DMSO, as well as conditions
-tryptophan in 1 mL of DMSO, were used (Table 4).
L
L
Generally, the condensations catalyzed by 20 mol% of catalyst re-
quired longer reaction times, and gave slightly lower yields (except
Generally, the catalyst loading less than 20 mol% in 2 mL of DMSO
and less than 15 mol% in 1 mL of DMSO only gave low to moderate
yields (entries 1–4, and 7–11). Moreover, by comparison of
entries 2–4, 17 and 18) than by 30 mol%
some similar features for the reactions catalyzed by both condi-
tions. ,b-Unsaturated aromatic and aliphatic aldehydes swiftly re-
L-tryptophan. There are
20 mol% of L-tryptophan loading in 2 mL of DMSO (64% yield after
a
6 h) (entry 4) with in 1 mL of DMSO (91% yield after 3 h) (entry 12),
it can be seen that the volume of DMSO had obviously impact on
the reaction rate. In addition, we attempted to use lower catalyst
acted with 1 equivalent of acetylacetone and ethyl acetoacetate
(entries 1–12). However, longer reaction times were required for
aromatic aldehydes, and 2 equivalents of acetylacetone and ethyl
acetoacetate were used in most cases (entries 15–26). This is prob-
ably because the aldehyde groups are more hindered in aromatic
aldehydes than in
a,b-unsaturated aromatic aldehydes. The con-
Table 2
densations between aromatic aldehydes and acetylacetone took
much longer reaction times than corresponding aromatic alde-
hydes and ethyl acetoacetate (entries 15–26). It indicated that ace-
tylacetone is less reactive than ethyl acetoacetate, which may be
because the six-membered enolate formed by acetylacetone is
more stable than the enolate of ethyl acetoacetate. In addition,
the electronic nature of substituents on the aromatic aldehydes
also had an effect on the reaction rate. Aromatic aldehydes bearing
an electron-withdrawing substituent favored this reaction (entries
17–24). In contrast, aromatic aldehydes containing an electron-
donating group required much longer reaction times to give the
corresponding products (entries 25 and 26). This is because elec-
tron-withdrawing groups enhance the electrophilicity of carbonyl
carbons in aldehydes which facilitates the reaction, while
Solvent effects on L-tryptophan catalyzed Knoevenagel condensation.
H3CO
H3CO
O
O
O
L-tryptophan (0.3 mmol)
solvent (2 mL), rt
+
CHO
O
(1 mmol)
(1 mmol)
Entry
Solvent
DMSO
Time (h)
Yield (%)a
1
2
3
4
5
6
7
1
24
24
24
24
24
24
95
52
34
29
26
0
Solvent-free
1,2-Dichloroethane
H2O
THF
CH2Cl2
Cyclohexane
0
a
Refers to yield of isolated product after flash chromatography.

658
Y. Hu et al. / Catalysis Communications 11 (2010) 656–659
Table 4
Knoevenagel condensations of various aldehydes with acetylacetone and ethyl acetoacetate.
EWG
R
H
EWG
EWG
L-tryptophan, DMSO, rt
R
CHO
+
EWG
a (1 mmol)
For entries 1-16, b (1 mmol); for entries 17-30, b (2 mmol)
b
Entry
a
b
L
-tryptophan (0.3 mmol); DMSO (2 mL)
L-tryptophan (0.2 mmol); DMSO (1 mL)
Time (h)
0.3
Yield (%)a (Z:E)b
94
Time (h)
3
Yield (%)a (Z:E)b
91
H3CO
H3CO
H3C
1
2
3
O
O
O
O
CHO
CHO
0.3
0.5
97 (1.8)
85
1
5
98 (2.0)
90
O
O
O
O
CHO
CHO
4
H3C
0.5
97 (2.2)
2
98 (1.7)
O
O
O
O
5
6
O
O
O
O
O
O
0.5
0.5
96
1
1
91
CHO
CHO
97 (3.6)
89 (2.1)
Cl
Cl
F
7
0.5
0.5
0.5
0.5
96
1
89
CHO
8
88 (1)
86
0.5
0.5
0.5
81 (3.1)
75
O
O
O
O
O
O
CHO
CHO
CHO
9
F
10
81 (1.7)
80 (1.8)
O
11
12
O
O
O
O
1
90
2
79
CHO
0.2
98 (45)
1.5
83 (22.5)
CHO
O
O
O
O
13
14
O
O
16
8
96
18
14
89
O
O
O
O
CHO
CHO
88 (6.7)
80 (5.4)
15
16
O
O
O
O
16
8
82
64
18
72
CHO
CHO
93 (4.4)
78 (3)
17
18
O
O
O
O
12
2
95
24
5
96
NC
NC
CHO
CHO
97 (19.4)
98 (3.9)
19
20
21
22
12
6
94
64
20
65
6
83
O
O
O
O
O
O
O
O
CHO
CHO
Cl
Cl
81 (4.9)
98
80 (3.6)
83
O
O
35
2.5
CHO
Cl
92 (4.5)
88 (1.5)
CHO
Cl
Cl
23
24
O
O
O
O
35
2
91
72
18
85
CHO
CHO
91 (3.9)
82 (3.7)
Cl
O
O
O
O
25
26
120
36
69
137
72
62
O
O
O
O
H3C
H3C
CHO
CHO
95 (4.5)
77 (4.1)
27
28
CHO
CHO
O
O
O
O
1
1
92
3
3
83
97 (3.7)
85 (3.1)
29
30
1
1
82
3
3
74
O
O
O
O
CHO
CHO
92 (1.3)
83 (2)
a
Refers to yield of isolated product after flash chromatography.
Numbers in parenthesis refer to Z:E ratio.
b
electron-donating groups render it less electrophilic. Moreover,
hetero-aromatic aldehyde 2-furaldehyde also provided good yields
with acetylacetone and ethyl acetoacetate (entries 13 and 14).
efficiently participated the reaction with acetylacetone and ethyl
acetoacetate, and the products were received with relatively short
reaction times (entries 11, 12 and 27–30). It is probably due to the
less hindered aldehyde group in aliphatic aldehydes. Furthermore,
Besides, both aliphatic and
a,b-unsaturated aliphatic aldehydes

Y. Hu et al. / Catalysis Communications 11 (2010) 656–659
659
all the products from ethyl acetoacetate had both Z and E isomers
Appendix A. Supplementary data
according to the newly formed double bonds. The different degrees
of Z selectivity were observed for all the reactions, and their ratios
were given in Table 4.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.catcom.2010.01.016.
References
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a,b,c,d-unsaturated carbonyl compounds.
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General procedure for
densation (the specified quantity was shown in Table 4):
L
-tryptophan catalyzed Knoevenagel con-
L
-Trypto-
phan was added to a flask containing aldehyde, active methylene
compound and DMSO. The reaction mixture was stirred at room
temperature and monitored by thin layer chromatography (TLC).
After completion, the mixture was diluted with CH2Cl2 (10 mL)
and washed with water (5 mL Â 2). The aqueous phase was ex-
tracted with CH2Cl2 (10 mL Â 2). Combined organic phase was
washed with water (30 mL) and concentrated in vacuo. The crude
product was purified by flash column chromatography (EtOAc/
petroleum ether).
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Financial support from the Selected Project in Scientific and
Technological Activities in 2007 for Returned Scholars by the State
Personnel Ministry is gratefully acknowledged.