Proline catalyzed aldol reactions in aqueous micelles: An environmentally friendly reaction system

Article abstract of DOI:10.1016/S0040-4039(03)00692-0

The proline catalyzed aldol reactions of nitrobenzaldehydes with various ketones in aqueous anionic micelles were investigated. Both the selectivities and reaction yields were observed to be higher than those of the corresponding reactions in organic solv

Full text of DOI:10.1016/S0040-4039(03)00692-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3871–3875
Proline catalyzed aldol reactions in aqueous micelles:
an environmentally friendly reaction system
a,b
b
a
c
a,
Yi-Yuan Peng, Qiu-Ping Ding, Zucheng Li, Peng George Wang and Jin-Pei Cheng *
a
Department of Chemistry, Nankai University, Tianjin 300071, China
b
Department of Chemistry, Jiangxi Normal University, Nanchang 330027, China
Department of Chemistry, Wayne State University, Detroit, MI 48202, USA
c
Received 4 December 2002; revised 28 February 2003; accepted 28 February 2003
Abstract—The proline catalyzed aldol reactions of nitrobenzaldehydes with various ketones in aqueous anionic micelles were
investigated. Both the selectivities and reaction yields were observed to be higher than those of the corresponding reactions in
organic solvents. A reaction mechanism is proposed that is somewhat different from that in organic solvents. © 2003 Elsevier
Science Ltd. All rights reserved.
Since the discovery of its roles as a good small-organic-
product, 4-hydroxy-4-(4-nitrophenyl)-2-butanone (3),
was obtained in only 15% yield (Table 1, entry 1).
When an anionic surfactant, sodium dodecyl sulfate (20
mol% SDS), was added to the reaction system, 87%
yield of aldol product 3 was obtained in only 24 h
1,2
molecule catalyst in intramolecular aldol reactions,
3
proline has drawn considerable attention in synthetic
4
chemistry due to its similarity to the type I aldolases.
Recently, List and others have reported some new
direct asymmetric intermolecular reactions catalyzed by
(
entry 2). This yield is substantially higher than that of
5
6
7
proline, including aldol, Mannich, Michael, and
the corresponding reaction in organic solvents
(
8
other analogous reactions. Additionally, some non-
5a,b
68%).
This reaction is very efficient, with only one
proline catalyzed aldol reactions in aqueous media have
been reported due to the increasing concerns regarding
environmental issues. In most cases, these reactions
require Lewis acid activation of the acceptors and the
by-product formed, the a,b-unsaturated ketone, in a
12
trace amount. When only SDS was used (no proline,
entry 3), the yield of 3 was only 12%. The above results
indicate that both proline and anionic surfactant SDS
play important roles in this reaction.
9
use of silyl enol ethers as aldol donors. In one case,
aldol reactions were catalyzed by
molecule in a buffer solution with 10% DMSO.
Except for one recent example, proline catalyzed aldol
a proline-like
10
To examine the effects of different surfactants on the
reaction, several other micelles, including anionic, non-
ionic, and cationic systems, were applied under com-
parable conditions. The results are shown in Table 1.
11
reactions in aqueous micelles have not been reported.
Herein we wish to present our recent results regarding
environmentally benign aldol reactions catalyzed
directly by proline in aqueous anionic micelles.
As shown in Table 1, satisfactory yields were observed
with anionic surfactant micelles, e.g. SDS (entry 2,
Initially, the aqueous aldol reaction of acetone (1a)
with 4-nitrobenzaldehyde (2a) in the absence of surfac-
tant was studied by mixing 1a (20 mmol), 2a (4 mmol)
and proline (0.16 mmol, 40 mol%) in pure water (15
ml). After five days at 40°C, the anticipated aldol
8
7%), SDBS (entry 4, 87%), and SLS (entry 5, 63%).
Other surfactants, including nonionic (entry 6) and
cationic (entries 7–10) did not efficiently promote the
reaction and the observed yields were much lower.
*
0
Corresponding author. Tel.: 0086-22-23504445; fax: 0086-10-68514074; e-mail: jpcheng@nankai.edu.cn, chengjp@mail.most.gov.cn
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00692-0

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Y.-Y. Peng et al. / Tetrahedron Letters 44 (2003) 3871–3875
Table 1. Proline catalyzed aldol reactions in different aqueous surfactants micelles
Entry
Surfactant
T (h)
Yield (%)a
Entry
Surfactant
Trtion-100
T (h)
Yield (%)
c
1
2
3
4
5
H O
120
24
120
5
15
87
12
87
63
6
7
8
9
10
120
120
120
120
120
Trace
7
Trace
29
2
c
SDS
SDS(only)
CTAB
OTAC
b
c
c
c
SDBS
DDBAC
DTAC
SLSc
60
c
Trace
a
Yields based on isolation with column chromatography (petroleum/ethyl acetate (2:1)).
Proline was not added.
b
c
SDBS denotes
;
SLS, C12H25OSO Na; Trtion-100,
; CTAB, C16H33N(CH ) Br; OTAC,
3 3
3
C18H37N(CH ) Cl; DDBAC, C12H25N(CH ) (CH C H )Cl and DTAC, C12H25N(CH ) Cl.
3 3
3 2
2
6
5
3 3
In order to explore the generality of this reaction, a
range of substrates was examined. The results of these
reactions are presented in Table 2. Inspection of Table
2
shows that among the aldehydes examined, only
nitrobenzaldehydes performed well (entries 1–3). The
reactions of 3- and 2-nitrobenzaldehydes gave the cor-
responding aldol products 4 (74%, entry 2) and 5 (52%,
entry 3) in reasonable yields.
Figure 1. Proposed iminium and enamine intermediates.
In contrast to the reaction of benzyl methyl ketone,
where no reaction was observed (entry 13), moderate to
excellent yields of the aldol products were obtained for
aliphatic ketones and activated aromatic substrates
such as nitrobenzaldehyde (Table 2). Among substrate
On the basis of these observations, we extended the
study to the reactions of nitrobenzaldehydes with other
ketones in SDS micelles (Table 2 entries 4–13). First,
the reactions of cyclopentanone and cyclohexanone
were investigated. The results indicate that both of
these cyclic ketones underwent the desired cross-
aldolization with 2, and afforded syn/anti-mixtures of
the aldol products 12–17 in reasonable yields. The
diastereoselectivity of these reactions is quite good. The
anti-products are favored, as indicated by the anti/syn
ratios of about 80:20 (entries 7–11) and 97:3 (entry 12).
These results are much better than those of the corre-
sponding reactions in organic solvent, where the anti/
syn ratios of the reactions of 4-nitrobenzaldehyde with
cyclohexanone and cyclopentanone were found to be
2
, the yields of the reactions of 2a are the highest,
followed those by 2b and then 2c. The differences in
reaction yields and in required reaction times (Table 2,
column 4) may be accounted for by the steric effect of
the nitro substituent. Importantly, the diastereoselectiv-
ity and the chemical yields of these aldol reactions in
micelles are much better than those of the correspond-
5b
ing reactions in organic solvent.
In organic solvent, the reaction was proposed to pro-
ceed by an amine base and Brønsted acid co-catalyzed
5b
only 41/24 and 46/27, respectively.
mechanism, where both the pyrrolidine ring (in L-pro-
5b
line) and carboxylic acid group are required. The
Next, reactions of 2-butanone were investigated. An
interesting feature of these reactions is that this sub-
strate resulted in two regioisomeric forms, one of which
gave syn/anti isomers. Upon stirring an aqueous mix-
ture of nitrobenzaldehyde 2-butanone, proline, and
SDS at 40°C, the corresponding aldol products 6, 8,
and 10 (from nucleophilic attack of the methyl group)
were formed in yields of 23, 17 and 7%, respectively.
Products 7, 9 and 11 (from nucleophilic attack of the
methylene group) were also formed, but in higher yields
hydrogen bonds in the complexes 21 and 25 (Scheme 1)
5a,b
were found to be the reaction driving force.
However, we found that only the pyrrolidine ring (in
L
-proline) was required in micelles, so the carboxylic
acid group (in
experiments, we found that
-hydroxyproline can catalyze the same aldol reaction
in micelles, giving the aldol product 3 with yields of 82
and 70%, respectively. Most other natural -amino and
some -amino acids were also examined, only giving
L
-proline) may not be involved. In other
L
-proline methyl ester and
L
L
(
66, 42 and 13%). This is in contrast to the previous
D
observation that only products 6, 8, and 10 were
trace or no aldol products. The above results imply that
the reaction mechanism in micelle may be different
from that in organic solvents. On this basis, an amine
catalyzed mechanism for the aldol reaction in micelles
was proposed (Scheme 1). The hydrogen bond between
the carboxylic acid and substrates in organic solvent
5
b
observed in organic solvent. The higher yields of the
methylene aldol products yields indicate that in this
reaction the thermodynamically more stable enamine 20
is favored over the kinetically more stable enamine 19
(
Fig. 1). It should be noted that the yields of the
(
vide supra) may be substituted by a stronger hydrogen
anti-products are higher than those of the correspond-
ing syn products (39/27 for 7, 22/20 for 9, and 10/3 for
bond between water and substrate in the micelles. The
reaction driving force in micelles may be related to the
10).

Y.-Y. Peng et al. / Tetrahedron Letters 44 (2003) 3871–3875
Table 2. Aldol reactions of ketones with nitrobenzaldehydes in SDS micelle
3873
a
b
c
Yields based on isolation with column chromatography (petroleum/ethyl acetate (2:1)).
anti/syn ratio detected by NMR.
anti/syn ratio based on isolation with column chromatography.

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Y.-Y. Peng et al. / Tetrahedron Letters 44 (2003) 3871–3875
Scheme 1. A proline directly catalyzed aldol reaction mechanism in micelles.
13
hydrophobic force which compresses the reactants
together in a highly compact arrangement of complexes
Engl. 2001, 40, 529–532; (c) List, B. Tetrahedron 2002, 58,
5573–5590.
2
1 and 25. The strong substituent steric effect of the
4. (a) Lai, C. Y.; Nakai, N.; Chang, D. Science 1974, 183,
1204–1206; (b) Morris, A. J.; Tolan, D. R. Biochemistry
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5. (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am.
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compressed compact substrates in a restricted hydro-
phobic domain. The detailed reaction mechanism is
currently under investigation.
2001, 123, 5260–5267; (c) Benaglia, M.; Celentano, G.;
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Acknowledgements
(
e) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem.
We are grateful to the support of the Natural Science
Foundation of China (NSFC No. 29928004) and the
Natural Science Foundation of Jiangxi province (No.
Soc. 2002, 124, 6798–6799.
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