An Environment-friendly and efficient method for aldol condensation catalyzed by L-Lysine in pure water

Article abstract of DOI:10.2174/157017810790533995

This is a new example of a nonmetallic small-molecule catalyst for direct intermolecular aldol reactions. We found L-lysine is an effective catalyst for this condensation between unmodified acetone and a variety of aldehydes in the presence of pure water. This green catalyst system could be reused.

Full text of DOI:10.2174/157017810790533995

Letters in Organic Chemistry, 2010, 7, 27-31
27
An Environment-Friendly and Efficient Method for Aldol Condensation
Catalyzed by L-Lysine in Pure Water
Yan Zhang, Man Gang Wang, Jun Liang and Zhi Cai Shang*
Department of chemistry, Zhejiang University, Hangzhou 310027, P. R. China
Received October 23, 2009: Revised November 13, 2009: Accepted November 16, 2009
Abstract: This is a new example of a nonmetallic small-molecule catalyst for direct intermolecular aldol reactions. We
found L-lysine is an effective catalyst for this condensation between unmodified acetone and a variety of aldehydes in the
presence of pure water. This green catalyst system could be reused.
Keywords: L-lysine, organo-catalysis, aldol reaction, green chemistry.
Green chemistry, which is defined as the design of
chemical products and processes that reduce or eliminate the
use and generation of hazardous substances, generated
extensive interest in both industrial and academic research
years ago. In this regard, synthetic chemists have great
interest to develop highly efficient transformations for the
preparation of organic compounds. One of the main themes
of contemporary synthetic organic chemistry is using
environmentally benign solvent and catalysts. Obviously, the
use of water with positive effects in terms of cost, safety, and
environmental impact as reaction solvent instead of organic
solvent is preferred to decrease environmental contamination
[1]. Organo-catalysis became a new research area in
synthetic chemistry several years ago, which is one of the
most important contents for green chemistry. Driven by
environmental concerns, there is great interest and need for
cheap and readily available, recyclable and reusable
organocatalysts that promote reactions in pure water to
expand the scope of organocatalysis as part of an
environmentally benign approach to fine chemical synthesis,
especially large scale reactions.
which are present but the yield is low [10]. To our delight, L-
lysine, which is very cheap, was found to have at least
equally good catalytic activity in water as compared to
proline. The relevant reactions proceeded very smoothly in
pure water with no need to add surfactant or organic solvent.
To achieve the best results for this reaction (Scheme 1),
we select the reaction between acetone and p-
nitrobenzaldehyde as a model to optimize the reaction
conditions. For each reaction condition, conversion of
acetone (0.8ml) and p-nitrobenzaldehyde (1mmol) to 4-
Hydroxyl-4-(4-nitrophenyl)-2-butanone was measured by
HPLC. As is shown in Table 1, with the amount of catalyst
increased, the yield will get the best and don’t increase any
more, though the reaction time reduces a little.
OH
O
O
O
O
+
+
L-lysine 20 mol%
H2O
R
R
R
H
Scheme 1.
Table 1. Effect of Catalyst on the Reaction of 4-
Nitrobenzaldehyde with Acetone
Aldol condensation plays an important role in nature as a
source of carbohydrates and is used for the synthesis of
chiral ꢀ-hydroxy carbonyl compounds or ꢁ, ꢀ-unsaturated
ketones, which in turn have great potential and valuable
intermediates in organic synthesis [2]. This powerful and
atom-economic C-C bond forming reaction is usually carried
out in organic solvents catalyzed by strong acids, bases [3],
or some metal salts [4]. Recently ionic liquid was used as the
solvent [5]. Yet, the application of ionic liquids in the
industrial syntheses of fine chemicals is still problematic
because of the relatively high cost of these solvents. L-
proline was first reported as the organocatalyst in aldol
reactions [6]. Since then many papers have been published
on this topic [7]. However, it should be noted that among all
the reported systems most catalysts work in organic solvent
[8] or mixed aqueous organic solvent [9], and there is also a
method in the both secondary amine and mesoporous silica,
Entry
Amount of Catalyst
Time
Yieldꢀ
1
5 mol%
20 mol%
40 mol%
60 mol%
80 mol%
24 h
15 h
15 h
15 h
13 h
31%
79%
79%
79%
75%
2
3
4
5
ꢁHPLC yield.
A series of aromatic aldehydes was studied instead of p-
nitrobenzaldehyde under the same conditions. The results are
presented in Table 2. Despite the extremely low solubility of
aldehydes in water, the lysine-catalyzed aldol reactions
proceeded efficiently at ambient temperature (30-37ꢂC). The
electron-deficient aldehydes proceeded much faster than the
electron-rich ones. In some cases, dehydration occurred and
in other cases the hydroxyketone was isolated. Perhaps this
is because the products formed by the electron-deficient
*Address correspondence to this author at the Department of chemistry,
Zhejiang University, Hangzhou 310027, P. R. China; Fax: (+86) 571-
87951895; E-mail: shangzc@zju.edu.cn
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

28
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
Zhang et al.
Table 2. L-Lysine Catalyzed Aldol Reactions between Acetone and Arylaldehydes in Pure Water
Yielda,b (%)
Aldehyde
Main product
OH
Entry
Time (h)
O
O2N
1
CHO
19
86
88
O2N
OH
O
O2N
CHO
O2N
2
3
20
20
NO2
NO2
88
CHO
OH
O
H3C
H3CO
Cl
O
4
5
6
H3C
H3CO
Cl
CHO
48
45
24
62
79
81
O
CHO
O
CHO
Cl
O
7
8
24
22
83
83
CHO
Cl
O
Cl
CHO
Cl
O
Br
CHO
Br
9
22
24
84
85
H3CO
H3CO
CHO
O
10
H3CO
H3CO
O
11
12
CHO
26
24
83
83
NC
CHO
NC
O

An Environment-Friendly and Efficient Method
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
29
(Table 2). Contd…..
Yielda,b (%)
Aldehyde
Entry
Main product
Time (h)
OH
O
Br
13
24
81
CHO
Br
14
22
84
Br
CHO
Br
O
OH
OH
OH
OH
O
H3CO
CHO
H3CO
15
16
50
28
79
76
O
CHO
O
O
OH
aIsolated yields after column chromatography.
bA mixture of an aldehyde (1.0mmol), acetone(0.5mL), and L-lysine(20 mol%) in 4 mL of water was stirred in a 10 ml, round-bottomed flask at ambient temperature. The reaction
was followed and monitored by TLC. When the reaction was completed, ethyl acetate (10mLꢀ3) was added into the flask to extract the product. Then the reaction mixture was
partitioned between aqueous and ethyl acetate. The organic layer was separated and concentrated, then the residue was purified by column chromatography eluting with
petroleum/ethyl acetate to give aldol product.
aldehydes are easier to form a carbanion. Or they are more
likely to carry out E1cB elimination. The experimental
results also show that there will be more beta elimination
product, if we extend the reaction time. In addition, different
sensitivity of the products to temperature changes may also a
factor. We didn’t pay attention to the optical activity at a
specific reaction temperature. Vigorous stirring was required
for the success of the reaction. Both electron-deficient and
electron-rich aldehydes can react with acetone, giving
excellent yields. Our findings reflect the wide applicability
and usefulness of the method.
environmentally benign synthetic methodology can be
regarded as a goal in modern organic chemistry.
The spectra data of the compounds Entry 1-16 are as
follows.
Entry 1
Rf 0.30 (1:3 EtOAc/Petroleum); IR (KBr) 3455, 2907,
-1
1714, 1600, 1521, 1341, 1241, 1165, 1079, 858, 839 ㎝ ;
1H-NMR(500MHz, CDCl3): ꢁ 2.23(s, 3H, COCH3), 2.86(t,
J=5.6 Hz, 2H, CH2), 3.58(br s, 1H, OH), 5.27(t, 1H, J=6.2
Hz, CH), 7.54(d, 2H, J=8.6 Hz, Ar-H), 8.19(d, 2H, J=8.7 Hz,
Ar-H).
We also investigated the reusability of this system of
water and L-lysine. After the reaction was completed, the
product was extracted out by filling in ethyl acetate.
Amazingly, the aqueous solution could be reused without
any loss of its activity even after five runs. (Table 3).
Entry 2
Rf 0.32 (1:3 EtOAc/Petroleum); 1H-NMR(500MHz,
CDCl3): ꢁ 2.15(s, 3H, COCH3), 2.83(t, 2H, J=8.6 Hz, CH2),
4.03(s, 1H, OH), 5.19(q, 1H, J=3.6 Hz, CH), 7.44(t, 1H,
J=7.9 Hz, Ar-H), 7.63(d, 1H, J=7.7 Hz, Ar-H), 8.0(q, 1H,
J=1.4 Hz, Ar-H), 8.14(s, 1H, Ar-H).
In conclusion, we choose L-lysine as organocatalyst,
which can promote the direct aldol reaction of aldehydes and
acetone in large amount of water. And this catalytic amount
of lysine is reusable, nonmetallic small-molecule catalyst.
From a green chemistry perspective, this highly effective and
Table 3. Recycling Experiments with L-Lysinea
OH
O
O
L-lysine 20 mol%
H2O 19 h
O2N
CHO
O2N
Run
1
2
3
4
5
Yield(%)b
86
85
86
86
85
aReactions performed with p-nitrobenzaldehyde (1.0 mmol), acetone(0.5 mL), and L-lysine (20mol%) in pure water (4 mL) and stirred for 19 h at r.t. bIsolated yields after column
chromatography.

30
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
Zhang et al.
Entry 3
Rf 0.31 (1:3 EtOAc/Petroleum); 1H-NMR(500MHz,
CDCl3): ꢀ 2.24(s, 3H, COCH3), 2.74(dd, 1H, J=9.4, 9.4 Hz,
one H of CH2CO), 3.12(dd, 1H, J=2.0, 2.0 Hz, the other one
H of CH2CO), 3.76(br s, 1H, OH), 5.68(dd, 1H, J=1.8, 1.8
Hz, CH), 7.42-7.46(m, 1H, Ar-H), 7.67(t, 1H, J=7.4 Hz, Ar-
H), 7.89(d, 1H, J=7.8 Hz, Ar-H), 7.94(t, 1H, J=7.6 Hz, Ar-
H).
6H, CH3O), 6.51(s, 1H, Ar-H), 6.66-6.69(m, 3H, one H of
CH and Ar-H), 7.42(d, 1H, J=16.2 Hz, the other one H of
CH)); MS（ESI）m/z 228.9 ([M+Na])+.
Entry 11
Rf 0.66 (1:3 EtOAc/Petroleum); 1H-NMR(500MHz,
CDCl3): ꢀ 2.31(s, 3H, COCH3), 6.65(d, 1H, J=16.3 Hz, one
H of CH), 7.33(q, 3H, J=3.3 Hz, Ar-H), 7.44(s, 1H, the other
one H of CH), 7.48(q, 2H, J=2.8 Hz, Ar-H).
Entry 4
Rf 0.60 (1:4 EtOAc/Petroleum); 1H-NMR(500MHz,
CDCl3): ꢀ 2.31(d, 6H, J=4.9 Hz, six H of the two CH3),
6.62(d, 1H, J=16.3 Hz, one H of CH), 7.14(d, 2H, J=8.0 Hz,
Ar-H), 7.38(d, 2H, J=8.1Hz, Ar-H), 7.43(d, 1H, J=16.3Hz,
the other one H of CH); 13C-NMR(125MHz, CDCl3): ꢀ 21.4,
27.3, 126.2, 128.3, 129.7, 131.7, 140.9, 143.4, 198.3.
Entry 12
Rf 0.37 (1:2 EtOAc/Petroleum); IR (KBr) 2225, 1673,
1624, 1481, 1365, 1225, 1209, 975, 835, 814 ㎝ ; 1H-
-1
NMR(500MHz, CDCl3): ꢀ 2.41(s, 3H, COCH3), 6.78(d, 1H,
J=16.2 Hz, one H of CH), 7.49(d, 1H, J=16.3 Hz, the other
one H of CH ), 7.63(d, 2H, J=8.2 Hz, Ar-H), 7.69(t, 2H,
J=6.6 Hz, Ar-H).
Entry 5
Rf 0.51 (1:4 EtOAc/Petroleum); IR (KBr) 1656, 1633,
1601, 1574, 1511, 1423, 1360, 1245, 1177, 1029, 836, 806
Entry 13
Rf 0.58 (1:2 EtOAc/Petroleum); 1H-NMR(500MHz,
CDCl3): ꢀ 2.15(s, 3H, COCH3), 2.61(dd, 1H, J=9.7, 9.7 Hz,
one H of CH2CO), 2.87(dd, 1H, J=2.1, 2.1 Hz, the other one
H of CH2CO), 3.91(s, 1H, OH), 5.40(d, 1H, J=9.7 Hz, CH),
7.05-7.08(m, 1H, Ar-H), 7.28(q, 1H, J=0.8 Hz, Ar-H),
7.43(q, 1H, J=1.0 Hz, Ar-H), 7.56(t, 1H, J=1.3 Hz, Ar-H).
-1
㎝ ; 1H-NMR(500MHz, CDCl3): ꢀ 2.36(s, 3H, COCH3),
3.84(s, 3H, CH3O), 6.60(d, 1H, J=16.3 Hz, one H of CH ),
6.91(d, 2H, J=8.8 Hz, Ar-H), 7.46-7.50(m, 3H, the other one
H of CH and Ar-H).
Entry 6
Rf 0.50 (1:4 EtOAc/Petroleum); 1H-NMR(500MHz,
CDCl3): ꢀ 2.37(s, 3H, COCH3), 6.67(d, 1H, J=16.3 Hz, one
H of CH ), 7.35(d, 2H, J=8.5 Hz, Ar-H), 7.44(d, 1H, J=16.3
Hz, the other one H of CH), 7.46(d, 2H, J=2.1 Hz, Ar-H).
Entry 14
Rf 0.50 (1:2 EtOAc/Petroleum); 1H-NMR(500MHz,
CDCl3): ꢀ 2.15(s, 3H, COCH3), 2.73(dd, 1H, J=3.4, 3.3 Hz,
one H of CH2CO), 2.81(dd, 1H, J=9.1, 9.1 Hz, the other one
H of CH2CO), 3.71(s, 1H, OH), 5.06(q, 1H, J=3.0 Hz, CH),
7.19(d, 2H, J=8.4 Hz, Ar-H), 7.44(d, 2H, J=8.4 Hz, Ar-H);
13C-NMR(125MHz, CDCl3): ꢀ 30.8, 51.9, 69.2, 121.4, 127.5,
131.6, 142.1, 208.8.
Entry 7
Rf 0.60 (1:3 EtOAc/Petroleum); 1H-NMR(500MHz,
CDCl3): ꢀ 2.42(s, 3H, COCH3), 6.67(d, 1H, J=16.4 Hz, one
H of CH), 7.26-7.34(m, 2H, Ar-H), 7.43(q, 1H, J=0.8 Hz,
Ar-H), 7.63(q, 1H, J=1.6 Hz, Ar-H), 7.93(d, 1H, J=16.4 Hz,
the other one H of CH).
Entry 15
Rf 0.50 (1:2 EtOAc/Petroleum); 1H-NMR(500MHz,
CDCl3): ꢀ 2.19(s, 3H, COCH3), 2.93(t, 2H, J=4.6 Hz, CH2),
3.72(s, 1H, OH), 3.89(s, 3H, CH3O), 5.39(q, 1H, J=5.2 Hz,
CH), 6.48(s, 1H, OH), 6.79-6.92(m, 3H, Ar-H). MS（ESI）
m/z 232.8 ([M+Na])+.
Entry 8
Rf 0.61 (1:3 EtOAc/Petroleum); 1H-NMR(500MHz,
CDCl3): ꢀ 2.38(s, 3H, COCH3), 6.70(d, 1H, J=16.3 Hz, one
H of CH), 7.26-7.52(m, 5H, the other one H of CH and Ar-
H).
Entry 16
Rf 0.39 (1:2 EtOAc/Petroleum); 1H-NMR(500MHz,
CDCl3): ꢀ 2.20(s, 3H, COCH3), 2.91(dd, 1H, J=3.5, 3.5 Hz,
one H of CH2CO), 3.04(dd, 1H, J=8.9, 8.9 Hz, the other one
H of CH2CO), 3.49(br s, 1H, OH), 5.16(q, 1H, J=3.5 Hz,
CH), 6.25(d, 1H, J=3.2 Hz), 6.32(q, 1H, J=1.9 Hz), 7.36(d,
1H, J=1.1 Hz).
Entry 9
Rf 0.50 (1:2 EtOAc/Petroleum); 1H-NMR(500MHz,
CDCl3): ꢀ 2.38(s, 3H, COCH3), 6.70(d, 1H, J=16.3 Hz, one
H of CH), 7.27(q, 1H, J=3.2 Hz, Ar-H), 7.41-7.52(m, 3H,
Ar-H), 7.68(s, 1H, the other one H of CH).
REFERENCES AND NOTES
Entry 10
[1]
(a) Narayan, S.; Muldoon, J.; Finn, M.G.; Fokin, V.V.; Kolb, H.C.;
Sharpless, K.B. Enhanced effect of mesoporous silica on base-
catalyzed aldol reaction. Angew. Chem. Int. Ed. Engl., 2005, 44,
3275-3279. (b) Chen, X.; She, J.; Shang, Z.-C.; Wu, J.; Zhang, P.
Rf 0.55 (1:2 EtOAc/Petroleum); IR (KBr) 1674, 1650,
-1
1597, 1468, 1432, 1358, 1270, 1165, 1067, 977, 836 ㎝ ;
1H-NMR(500MHz, CDCl3): ꢀ 2.38(s, 3H, COCH3), 3.82(s,

An Environment-Friendly and Efficient Method
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
31
Z. Synthesis of pyrazoles, diazepines, enaminones, and enamino
esters using 12-Tungstophosphoric acid as a reusable catalyst in
water. Synthesis, 2008, 21, 3478-3486. (c) Li, C.-J. Organic
reactions in aqueous media with a focus on carbon-carbon bond
formations: a decade update. Chem. Rev., 2005, 105, 3095-3165.
(d) Shiraishi, Y.; Tsukamoto, D.; Hirai, T. Highly efficient methyl
ketone synthesis by water-assisted C-C coupling between olefins
and photoactivated acetone. Org. Lett., 2008, 10, 3117-3120. (e)
Azizi, N.; Torkian L.; Saidi, M. R. Highly efficient synthesis of
bis(indolyl)methanes in water. J. Mol. Catal. A Chem., 2007, 275,
109-112.
[7]
(a) Peng, Y. Y.; Ding, Q. P.; Li, Z. C.; Wang, P. G.; Cheng, J. P.
Proline catalyzed aldol reactions in aqueous micelles: an
environmentally friendly reaction system. Tetrahedron Lett. 2003,
44, 3871-3875. (b) Gruttadauria, M.; Riela, S.; Meo, P. L.; D’Anna,
F.; Noto, R. Supported ionic liquid asymmetric catalysis. A new
method for chiral catalysts recycling: the case of proline-catalyzed
aldol reaction. Tetrahedron Lett. 2004, 45, 6113-6116. (c)
Kucherenko, A. S.; Struchkova, M. I.; Zlotin, S. G. The (S)-
proline/polyelectrolyte system: an efficient, heterogeneous,
reusable catalyst for direct asymmetric aldol reactions. Eur. J. Org.
Chem., 2006, 2000-2004.
[2]
[3]
(a) Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S.
The art and science of total synthesis at the dawn of the twenty-first
century. Angew. Chem. Int. Ed. Engl., 2000, 39, 44. (b) Mukaiyama,
T. The unexpected and the unpredictable in organic synthesis.
Tetrahedron, 1999, 55, 8609.
(a) Paul, S.; Gupta, M. A simple and efficient method for selective
single aldol condensation between arylaldehydes and acetone.
Synth. Commun., 2005, 35, 213-222. (b) Fuentes, A.; Marinas, J.
M.; Sinisterra, J. V. Catalyzed synthesis of chalcones under
interfacial solid-liquid conditions with ultrasound. Tetrahedron
Lett., 1987, 28, 4541.
[8]
(a) (Amy) Tong, S. T.; Harris, P. W. R.; Barker, D.; Brimble, M. A.
Use of (S)-5-(2-methylpyrrolidin-2-yl)-1H-tetrazole as a novel and
enantioselective organocatalyst for the aldol reaction. Eur. J. Org.
Chem., 2008, 164-170. (b) Odedra, A.; Seeberger, P. H. 5-
(Pyrrolidin-2yl) tetrazole-catalyzed aldol and mannich reactions:
Acceleration and lower catalyst loading in a continuous-flow
reactor. Angew. Chem. Int. Ed. Engl., 2009, 48, 2699-2702. (c) Wu.
F. C.; Da, C. S.; Du, Z. X.; Guo, Q. P.; Li, W. P.; Yi, L.; Jia, Y. N.;
Ma, X. N-Primary-Amine-Terminal beta-Turn tetrapeptides as
organocatalysts for highly enantioselective Aldol reaction. J. Org.
Chem., 2009, 74, 4812-4818.
[4]
[5]
Deng, G. S.; Ren, T. G. Indium trichloride catalyzes aldol-
condensations of aldehydes and ketones. Synth. Commun., 2003, 33,
2995.
(a) Gruttadauria, M.; Riela, S.; Aprile C.; Meo, P. L.; D’Anna, F.;
Noto, R. Supported ionic liquids. New recyclable materials for the
L-proline-catalyzed aldol reaction. Adv. Synth. Catal., 2006, 348,
82-92. (b) Yang, S. D.; Wu, L. Y.; Yan, Z. Y.; Pan, Z. L.; Liang, Y.
M. A novel ionic liquid supported organocatalyst of pyrrolidine
amide: synthesis and catalyzed Claisen-Schmidt reaction. J. Mol.
Catal. A Chem., 2007, 268, 107-111.
[9]
(a) Amedjkouh, M. Primary amine catalyzed direct asymmetric
aldol reaction assisted by water. Tetrahedron Asymmetry, 2005, 16,
1411-1414. (b) Font, D.; Jimeno, C.; Pericàs, M. A. Polystyrene-
supported hydroxyproline: an insoluble, recyclable organocatalyst
for the asymmetric aldol reaction in water. Org. Lett., 2006, 8,
4653-4655.
Kubota, Y.; Goto, K.; Miyata, S.; Goto, Y.; Fukushima, Y.; Sugi, Y.
Enhanced effect of mesoporous silica on base-catalyzed aldol
reaction. Chem. Lett., 2003, 32, 234-235.
[10]
[6]
List, B.; Lerner, R. A.; Barbas, C. F. Proline-catalyzed direct
asymmetric aldol reactions. J. Am. Chem. Soc., 2000, 122, 2395-
2396.