Recyclable enamine catalysts for asymmetric direct cross-aldol reaction of aldehydes in emulsion media

Article abstract of DOI:10.1039/c1gc15473g

Highly diastereo- and enantioselective cross-aldol reactions of aldehydes (>20:1 dr, 99% ee), catalyzed by chiral diamine-polyoxometalate acid combined enamine catalysts in emulsion media, are reported. This type of catalysts can be recycled several times

Full text of DOI:10.1039/c1gc15473g

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Green Chemistry
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COMMUNICATION
Recyclable enamine catalysts for asymmetric direct cross-aldol reaction of
aldehydes in emulsion media†
Qiang Gao,a,b Yan Liu,a Sheng-Mei Lu,a Jun Lia and Can Li*a
Received 28th April 2011, Accepted 31st May 2011
DOI: 10.1039/c1gc15473g
Highly diastereo- and enantioselective cross-aldol reactions
of aldehydes (>20 : 1 dr, 99% ee), catalyzed by chiral
diamine-polyoxometalate acid combined enamine catalysts
in emulsion media, are reported. This type of catalysts can
be recycled several times without significant deterioration
of activity and selectivity.
examples of highly diastereo- and enantio-selective cross-aldol
reactions of aliphatic aldehydes with aromatic aldehydes were
reported.4d,7 The original version of this reaction carried out
in organic solvent was reported by MacMillan.7c After that,
the Hayashi group reported the same reaction catalyzed by
4-substituted proline in the presence of water.4d And then, a
diastereoselectivity reversed type of cross-aldol reaction was
achieved by the Marouka group7l,7m and Luo group separately.7n
However, there were very few recyclable heterogeneous catalytic
systems to achieve the highly diastereo- and enantioselec-
tive cross-aldol reaction of aliphatic aldehydes with aromatic
aldehydes.7e,7j So it is highly desired to explore readily available
and recyclable catalysts to achieve efficient asymmetric cross-
aldol reaction in emulsion media.
In this paper, we report highly diastereo- and enantioselective
asymmetric cross-aldol reactions of aldehydes in the presence of
water, using recyclable chiral diamine-POM combined enamine
catalysts. Our study indicates that a metastable emulsion formed
in the organic-aqueous biphasic systems is mainly responsible
for the high reactivity and enantioselectivity.
Over the past few decades, asymmetric catalysis has been devel-
oped into a powerful methodology to obtain chiral compounds
with a broad scope of catalytic reactions, high enantioselectivity
and activity.1 Despite this remarkable success, only a few
examples of asymmetric catalytic processes have been developed
in industry, which is partly due to the high cost of chiral
catalysts. Therefore, the development of heterogeneous catalytic
systems to achieve the separation and the efficient recycling
of expensive chiral catalysts is highly desirable.2 Recently,
catalysis in emulsion systems has attracted much attention as
a promising strategy to improve the mass-diffusion limitation
in liquid multiphase systems.3 Various catalytic systems were
designed to promote the formation of an emulsion system
for the organocatalytic asymmetric direct aldol reactions in
water.4 The previous work in this group reported surfactant-type
catalysts, based on quaternary ammonium polyoxometalates
(POMs), which can be assembled in emulsion droplets, and
showed remarkably high selectivity and activity in the oxidation
of organic molecules.5 The POM anion acting as a novel chiral
catalyst support was reported by Luo and coworkers,4k,6 and
the biphasic catalysts afforded the desired products with high
yields and enantioselectivities in the aldol reaction of simple
ketones with aromatic aldehydes and the Michael addition of
cyclohexanone to nitroalkene.
Several enamine catalysts composed of the POM acid
(H3PW12O40) and chiral diamines with different lengths of alkyl
chain (Scheme 1) were prepared. The quaternary ammonium
group with different alkyl chains in these amphiphilic catalysts
have different hydrophilic-lipophilic balance values and could
Asymmetric cross-aldol reactions of aldehydes provide an at-
tractive strategy for the construction of a-substituted b-hydroxy
aldehydes, which are important synthons in the synthesis of
polypropionate and polyacetate products. Despite all that, few
aState Key Laboratory of Catalysis, Dalian Institute of Chemical
Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian,
116023, China. E-mail: canli@dicp.ac.cn; Fax: +86-411-84694447;
Tel: +86-411-84379070
bGraduate School of Chinese Academy of Sciences, Beijing, 100049,
China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1gc15473g
Scheme 1 Chiral diamine-POM combined enamine catalysts with
different length of alkyl chain.
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Table 2 Direct cross-aldol reaction in the emulsion media promoted
by catalyst 5a
perform as surfactants in the formation of an emulsion. So,
whether an emulsion formed or not in the real reaction
conditions was then investigated. The mixtures with catalysts 1
and 2 carrying short alkyl chains cannot form the emulsion, even
after stirring overnight. However, when catalyst 3 was added, the
mixture can form an unstable emulsion (Fig. S2, see ESI†). The
mixture using catalyst 4 or 5 with a longer alkyl chain formed
much more stable emulsions, which was confirmed by the light
microscopic image. The emulsion droplets were observed to be
spherical particles with an average size below 50 mm (Fig. 1).
Entry R1
Time (h) Yieldb (%) Anti/Sync eed (%)
1
2
3
4
5
6
7
8
9
4-Nitrophenyl
3-Nitrophenyl
2-Nitrophenyl
2-Methoxyphenyl 80
Phenyl
1-Naphtyl
4-Tolyl
4-Fluorophenyl
4-Chlorophenyl
24
24
24
92
83
94
73
80
43
70
61
79
>20 : 1
>20 : 1
>20 : 1
14 : 1
>20 : 1
>20 : 1
16 : 1
99
98
98
95
99
99
98
99
96
80
80
80
120
120
>20 : 1
>20 : 1
a Reaction conditions: 360 mL propionaldehyde, 1.0 mmol aromatic
aldehyde, 2.5 mol% catalyst 5, 162 mL water, 0 ◦C. b Isolated yield.
c Determined by 1H NMR spectroscopy of crude products. d Determined
by chiral HPLC after conversion into the corresponding benzoyl ester
(see ESI†).
and a metastable emulsion can efficiently mix the organic phase
and aqueous phase.8 The amounts of water were also optimized
using catalyst 5 (entries 6–8). If the reaction was performed
under neat conditions, the cross-aldol product with 73% yield
and slightly decreased diastereo- and enantioselectivities was
obtained (entry 8). When 4.5 equivalents of water were added,
the activity of the cross-aldol reaction was enhanced (entry 7 vs.
entry 8). The adding of more water decreased the activity and
selectivity of the reaction (entry 6). When 9 equivalents of water
were added to the reaction mixture, the reaction could afford the
corresponding anti-product 8 in 97% ee and nearly quantitative
yield.
The scope of cross-aldol reactions of aldehydes using the
catalyst 5 was expanded to a series of aromatic aldehyde
acceptors. In all the cases, cross-aldol products with excellent
diastereo- and enantioselectivities were attained. The substituent
of the aromatic aldehyde has great effect on the yield of the
products. With the nitro group substituent, no matter at which
(2-, 3- or 4-) position of the benzaldehyde, the reaction proceeded
smoothly, giving the product in high yield (Table 2, entries
1–3). For the 1-naphthaldehyde, the cross-aldol product with
only moderate yield was obtained, even prolonging the reaction
time to 80 h (entry 6). When the other aromatic aldehydes
carrying either an electron-withdrawing group or electron-
donating group were selected as acceptors, the reactions could
afford the corresponding products with moderate reactivities
and excellent enantioselectivities by prolonging the reaction time
(entries 4, 5, 7–9).
Fig. 1 Light microscopic image was taken after the mixture of 360 mL
propionaldehyde, 112 mL 2-chlorobenzaldehyde (1.0 mmol), 2.5 mol%
catalyst 5 and 162 mL water (9 mmol) was stirred for 1 h.
Catalysts 1–5 were then tested for the cross-aldol reaction of
aldehydes in the aqueous phase. The propionaldehyde (6) and
2-chlorobenzaldehyde (7) were selected as the model substrates,
and the reactions were carried out under 0 ◦C with a 2.5 mol%
catalyst loading. The results were shown in Table 1. All the
catalysts could catalyze the reaction and achieve excellent
enantioselectivities. However, the reactivities for the cross-aldol
reaction of aldehydes were dramatically enhanced from 36%
to 98% with the different lengths of alkyl chain from the
shortest (1) to the longest (5) (Table 1, entries 1–5). The results
clearly indicate that the emulsion state is critically important for
achieving high reactivity in the cross-aldol reaction of aldehydes,
Table 1 Screening the catalysts and amount of water for the cross-aldol
reaction of propionaldehyde 6 and 2-chlorobenzaldehyde 7a
Entry
Catalyst
Yieldb (%)
Anti/Sync
ee (%)d
1
2
3
4
1
2
3
4
5
5
5
5
36
40
48
78
98
57
90
73
9 : 1
97
99
98
98
97
90
94
96
>20 : 1
11 : 1
16 : 1
>20 : 1
15 : 1
19 : 1
20 : 1
Recycling of the present catalyst 5 was also investigated
(Table 3). Using 2-nitrobenzaldehyde and propionaldehyde as
substrates, catalyst 5 can be easily precipitated and recycled by
adding methanol, and we did not observe significant deteriora-
tion of activity and selectivity in the recovered catalyst after three
times of use (entries 1–3). From the 4th recycle, reactivity and
enantioselectivity of the reaction began to drop slowly, this may
be attributed to the loss of catalyst while recycling (entries 4–6).
Though the catalyst 5 was carefully recycled, the catalyst could
not be recycled completely because of its solubility in methanol
and its loss while recycling.
5
6e
7f
8g
a Reaction conditions: 360 mL propionaldehyde (5.0 mmol), 1.0 mmol
2-chlorobenzaldehyde, 2.5 mol% catalyst, 162 mL water (9 eq.), 0
◦C, 72 h. b Isolated yield. c Determined by 1H NMR spectroscopy of
crude products. d Determined by chiral HPLC after conversion into the
monobenzoyl ester (see ESI†). e 18 eq. of water was added. f 4.5 eq. of
water was added. g No water was added.
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Table 3 The recyclability of the catalyst 5a
reactions in water, see: (b) M. Raj and V. K. Singh, Chem. Commun.,
2009, 6687 (c) M. Gruttadauri, F. Giacalone and R. Notoa, Adv.
Synth. Catal., 2009, 351, 33.
4 For reviews on organocatalytic reactions in water, see: (a) M. Raja
and V. K. Singh, Chem. Commun., 2009, 6687; (b) M. Gruttadauria,
F. Giacalone and R. Noto, Adv. Synth. Catal., 2009, 351, 33; (c) N.
Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F. Tanaka and C.
F. Barbas III, J. Am. Chem. Soc., 2006, 128, 734; (d) Y. Hayashi, S.
Aratake, T. Okano, J. Takahashi, T. Samiya and M. Shoji, Angew.
Chem., Int. Ed., 2006, 45, 5527; (e) L. Zhong, Q. Gao, J. B. Gao, J. L.
Xiao and C. Li, J. Catal., 2007, 250, 360; (f) N. Mase, N. Noshiro, A.
Mokuya and K. Takabea, Adv. Synth. Catal., 2009, 351, 2791; (g) Y.
Wu, Y. Zhang, M. Yu, G. Zhao and S. Wang, Org. Lett., 2006, 8, 4417;
(h) T. Miura, K. Imai, M. Ina, N. Tada, N. Imai and A. Itoh, Org.
Lett., 2010, 12, 1620; (i) C.-M. Lo and H.-F. Chow, J. Org. Chem.,
2009, 74, 5181; (j) M. Gruttadauria, F. Giacalone, A. M. Marculescu,
P. L. Meo, S. Riela and R. Noto, Eur. J. Org. Chem., 2007, 4688; (k) J.
Li, S. Hu, S. Luo and J.-P. Cheng, Eur. J. Org. Chem., 2009, 132; (l) M.
Gruttadauria, F. Giacalone, A. M. Marculescu and R. Noto, Adv.
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Xiao, Green Chem., 2009, 11, 1750; (n) F. Giacalone, M. Gruttadauria,
A. M. Marculescu and R. Noto, Tetrahedron Lett., 2007, 48, 255.
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Entry
Recycle
Yieldb (%)
Anti/Syn
ee (%)c
1
2
3
4
5
6
1st
93
90
92
87
73
61
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
97
97
98
93
91
90
2nd
3rd
4th
5th
6th
a Reaction conditions: 360 mL propionaldehyde, 1.0 mmol 2-
nitrobenzaldehyde, 2.5 mol% catalyst 5, 162 mL water, 0 ◦C, 24 h.
b Isolated yield. c Determined by chiral HPLC.
In conclusion, we realized the highly diastereo- and enan-
tioselective cross-aldol reaction of aldehydes in the presence
of water (>20 : 1 dr, 99% ee), using recyclable chiral diamine-
POM combined enamine catalysts. Organic co-solvents were not
neceassary in the reaction. The emulsion formed in the reactions
is proposed to be critical for the enhanced reactivity, diastereo-
and enantioselectivity. Our findings may provide a general and
efficient approach for asymmetric synthesis using emulsion as
reaction media.
This work was supported by the National Natural Science
Foundation of China (No. 20921092), the Program for Strate-
gic Scientific Alliances between China and Netherlands (No.
2008DFB50130). The authors also thank Professor Qi-Hua
Yang for her useful discussion.
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3675; (b) J. Li, X. Li, P. Zhou, L. Zhang, S. Luo and J.-P. Cheng, Eur.
J. Org. Chem., 2009, 4486.
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Reactions, Wiley-VCH, Weinheim, 2004; (b) R. Mahrwald, Aldol
Reactions, Springer, Heidelberg, 2009. For examples of asymmetric
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Am. Chem. Soc., 2002, 124, 6798; (d) Y. Hayashi, T. Itoh, S. Aratake
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1 For books on asymmetric catalysis, see: (a) I. Ojima, Catalytic
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3 For reviews on organic reactions in aqueous media, see: (a) C.-J.
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This journal is
The Royal Society of Chemistry 2011
Green Chem., 2011, 13, 1983–1985 | 1985
©