A novel simple bifunctional catalyst for the direct aldol reaction

Article abstract of DOI:10.1016/j.cclet.2010.12.025

Direct aldol reactions of aldehydes and ketones can proceed smoothly in the presence of a catalytic amount of naphthol/sodium naphtholate (5 mol%) to afford the corresponding products with yields up to 98%. Such a bifunctional catalyst is more moderate than strong acid or base employed in direct aldol reactions.

Full text of DOI:10.1016/j.cclet.2010.12.025

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 651–654
www.elsevier.com/locate/cclet
A novel simple bifunctional catalyst for the direct aldol reaction
a
a
Chang Lu Liu b, , Hao Zhang , Ning Wang
*
a School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
b Department of Chemistry, Sichuan University of Arts and Sciences, Dazhou 635000, China
Received 20 September 2010
Abstract
Direct aldol reactions of aldehydes and ketones can proceed smoothly in the presence of a catalytic amount of naphthol/sodium
naphtholate (5 mol%) to afford the corresponding products with yields up to 98%. Such a bifunctional catalyst is more moderate
than strong acid or base employed in direct aldol reactions.
# 2010 Chang Lu Liu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Aldol reactions; Naphthol; Sodium naphtholate; Bifunctional catalyst; Acid–base
The aldol reaction is one of key C–C bond forming reactions [1]. This reaction creates the b-hydroxy carbonyl
compounds with great potential in organic synthesis [2]. Lots of emphasis recently has been given to nonmetallic small
molecule catalysts as they are more efficient and friendly [3]. Barbas and List [4] have proved L-proline to be a
powerful catalyst in the intramolecular direct aldol reaction and paved the way for the development of small organic
molecules as catalysts. Since then, so many new organic catalysts containing both Lewis acid and Brønsted base sites
in itself, called bifunctional catalysts, have been developed due to their higher selectivities as compared to acid or base
alone [5]. This topic has been extensively reviewed by Shibasaki et al. [6]. We have found that the match of the acidity
and basicity is very important to such reactions [7]. The discovery of a small single molecule used to catalyze aldol
reaction is challenge [8]. In this letter, however, we will report the use of catalytic amount of the mixture of naphthol
for acid sites and sodium naphtholate for basic sites as a novel simple and readily available bifunctional catalyst for the
direct aldol reaction performed under moderate conditions.
1. Experimental
Typical experimental procedure: Ketone (5 mL) was added to a dried vial charged with aldehyde (1 mmol) and
naphthol(0.05 mmol)/sodiumnaphtholate(0.05 mmol). ThereactionwasstirredatRTforthetimeinTable5followedby
theextractionofthemixturewithethylacetate.Organiclayerwaswashedwithbrineanddriedoveranhydrousmagnesium
sulfate. After filtration and evaporation of the solvent, the residuewas purified through column chromatography on silica
gel to give the corresponding aldol products. The products from our direct aldol reactions have been confirmed by NMR
* Corresponding author.
E-mail address: dzliuchanglu@163.com (C.L. Liu).
1001-8417/$ – see front matter # 2010 Chang Lu Liu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.12.025

6[()TD$FIG] 52
C.L. Liu et al. / Chinese Chemical Letters 22 (2011) 651–654
CHO
O
OH
O
OH
O
OH
O
Bronsted acid
Bronsted base
+
+
+
O2N
O2N
O2N
NO2
NO2
I
III
II
IV
V
OH
OH
ONa
O2N
OH
O2N
ONa
ONa
1a
1b
2a
2b
ONa
OH
3a
3b
4a
4b
Scheme 1. The catalysts evaluated in this study.
withBruker-300spectrometer.Onerepresentativespectroscopicdataispresenthere:Entry6:anti-diastereomer,1HNMR
(CDCl3,300 MHz):d8.21–7.47(m,4H,Ar–H),4.91–4.87(m,1H,OCH),4.10(s,1H,OH),2.63–2.54(m,1H,CH),2.51–
1.25 (m, 8H, CH2). 13C NMR (CDCl3, 300 MHz): d 24.6, 27.6, 30.7, 42.6, 57.1, 73.9, 123.5, 127.8, 147.5, 148.3, 214.6.
2. Results and discussion
The reaction of acetone with p-nitrobenzaldehyde in excess of acetone (Scheme 1) was studied. When phenolates
such as 1b, 3b and 4b were used, the total yields of aldol products III and IV were between 66% and 94% as shown in
Table 1. Surprisingly, only trace amount of aldol product (less than 1%) was observed for 2b. Almost the same yields
were obtained for 3b and 4b, but the reactivity of 4b was higher than that of 3b as shown the reduction of reaction time
Table 1
The effect of catalysts on the direct aldol reactionsa.
Entry
Catalyst
Catalyst (eq)
Time (h)
III (%)
IV (%)
Total yield (%)b
1
2
1b
2b
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
12
12
12
4
49
17
66
Trace
93
3
3b
4b
93
91
89
3
4
3
7
94
5
1a,1b
2a,2b
2a,1b
2a,4b
3a,3b
4a,4b
NaOH
12
12
12
12
12
2
96
6
3
7
62
47
82
94
25
13
10
12
2
75
8
57
9
94
10
11
96
12
33
58
a
The reactions were carried out at room temperature.
Isolated yield.
b
Table 2
The influence of time on the reactionsa.
Entry
4a,4b (eq)
Time (h)
III (%)
IV (%)
V (%)
Total yield (%)b
1
2
3
4
5
0.3
0.3
0.3
0.3
0.3
1
2
88
94
94
92
90
2
2
3
3
5
90
96
98
99
99
4
1
4
4
8
12
a
The reactions were carried out at room temperature.
Isolated yield.
b

C.L. Liu et al. / Chinese Chemical Letters 22 (2011) 651–654
653
Table 3
The influence of catalyst amount on the reactionsa.
Entry
Catalyst
Catalyst (eq)
Time (h)
III (%)
IV (%)
Total yield (%)b
1
4a,4b
4a,4b
4a,4b
4a,4b
4a,4b
4a,4b
4a,4b
0.3
2
2
2
2
2
2
2
94
94
93
90
78
86
65
2
3
96
97
97
96
94
93
83
2
0.2
3
0.1
4
4
5c
0.05
0.05
0.025
0.01
6
16
7
6
7
18
a
The reactions were carried out at room temperature.
Isolated yield.
b
c
The reaction was carried out at 0 8C.
Table 4
The influence of catalysts components on the reactionsa.
Entry
Catalyst (eq)
Time (h)
III (%)
IV (%)
Total yield (%)b
4a
4b
1
2
3
0.025
0.05
0.075
0.05
2
2
2
90
90
85
1
6
91
96
98
0.075
0.025
13
a
The reactions were carried out at room temperature.
Isolated yield.
b
from 12 h to 4 h. With the addition of 0.3 equivalents phenol 1a–4a as co-catalysts, the reactivity was enhanced (Table
1, entries 5, 7, and 10). The use of the mixture of naphthol and sodium naphtholate brought the yield up to 96% in 2 h
with the distinct chemoselectiveiy (Table 1, entry 10). Such results are very impressive as compared to sodium
hydroxide alone (Table 1, entry 11).
The best solvent for this direct aldol reaction was acetone among those investigated solvents such as acetone, DMF,
THF, MeOH, EtOH, C6H5CH3, and CH2Cl2. The influence of reaction time, temperature, quantity and ratio of catalyst
components on the reaction was investigated (Tables 2–4). The satisfied yield of the desired product III could be
achieved within 2 h (Table 2, entries 1 and 2). With an increase in reaction time, the aldol product III was translated
into product IV slowly and IV (Table 2, entries 3–5). The chemoselectivity of the reaction decreased with a decrease in
temperature (Table 3, entries 4 and 5). The catalyst loading can be reduced to 0.05 equiv. without compromising the
yield (Table 3, entry 4) and the best ratio for catalyst components was 1:1 (Table 4, entry 2).
Currently, we assume this reaction occurs through a bifunctional conjugated acid–base mechanism as shown in
Scheme 2. With this type of bifunctional acid–base catalyst, compounds without modification are able to undergo the
reaction with much higher yields than those obtained on strong acid or base as catalysts. The reason for this might be
due to the synergic function from the conjugated acid–base or the existences of more equilibriums as compare to acid
or base alone as a catalyst. We further evaluated the reactivity of different substrates under the optimal conditions
(Table 5). The aldol reaction of aromatic aldehydes with ketones proceeded very well with reasonable yields (76–98%,
Table 5). Interestingly, few dialdol products were observed.
[()TD$FIG]
O
NaO
R1
H
R1
O
OH
O
H
O
ONa
R
H
+
R1
R
+
OH
H
O Na
+
O
R
Scheme 2. Proposed mechanism of this aldol reaction.

654
C.L. Liu et al. / Chinese Chemical Letters 22 (2011) 651–654
Table 5
Direct aldol reactions of aldehydes with ketones catalyzed by naphthol (4a)/sodium naphtholate (4b)a
Entry
I
II
Time (h)
III (%)
IV (%)
Total yield (%)b
1
2
Acetone
Acetone
Acetone
Acetone
Acetone
4-Nitrobenzaldehyde
2-Nitrobenzaldehyde
3-Nitrobenzaldehyde
Benzaldehyde
2
90
6
96
97
91
76
93
98
93
90
92
92
2
87
10
3
2
91
4
2
76
5
2,4-Dichlorobenzaldehyde
4-Nitrobenzaldehyde
4-Nitrobenzaldehyde
4-Nitrobenzaldehyde
3-Nitrobenzaldehyde
2-Nitrobenzaldehyde
2
93
6
Cyclohexanone
2-Butanone
1.5
1.5
1
98c
34/59d
90
7
8
Acetophenone
Acetophenone
Acetophenone
9
1
92
10
1
92
a
The reactions were carried out at room temperature with 0.05eq catalysts.
Isolated yield.
b
c
d
Yield represents the combined yield of diastereomers, and the anti:syn = 1:1.
Methylene/methyl. Reaction at the methyl, and the anti:syn = 48:52.
3. Conclusions
In summary, the combination of naphthol/sodium naphtholate as a simple and readily available bifunctional
catalyst has been developed to facilitate the direct aldol reaction. Through this catalyst, the direct aldol reaction can be
performed at room temperature with yield up to 98% and trace level of side products. In addition, no prior modification
of the carbonyl substrates such as deprotonation or silylation is required.
Acknowledgments
This work is supported by the Natural Science Foundation of China (Nos. 20872120 and 20572087), the Municipal
Science Foundation of Chongqing City (No. 2003-8118), the Ministry of Education, PR of China (No. 106141) and the
Fundamental Research Funds for the Central Universities.
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