Catalytic microwave-promoted direct aldol condensation using resin-bound secondary amine

Article abstract of DOI:10.1080/00397911.2013.793775

A series of polystyrene-supported imino group-bearing catalysts were prepared. A highly efficient combination of recyclable catalysts and microwave irradiation was developed as a green protocol for the direct aldol reaction. Notably, microwaves greatly shorten the reaction times to only 20 min and improve the yield significantly. Catalyst loading was reduced as well. Different aromatic aldehydes as aldol donors were subjected to our catalyst system and afforded the corresponding products in satisfactory yields. Additionally, the polymer-supported catalysts could be recovered by simple filtration and were reusable for at least four times without significant loss of reactivity. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.793775

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Catalytic Microwave-Promoted Direct Aldol
Condensation Using Resin-Bound Secondary Amine
Fu Xu Liao a , Yu Guang Wang a & Qing Zhu a
a College of Biological and Environmental Engineering, Zhejiang University of Technology ,
Hangzhou , Zhejiang , P. R. of China
Accepted author version posted online: 15 Aug 2013.
To cite this article: Synthetic Communications (2013): Catalytic Microwave-Promoted Direct Aldol Condensation Using Resin-
Bound Secondary Amine, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, DOI: 10.1080/00397911.2013.793775
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Catalytic Microwave-Promoted Direct Aldol Condensation Using Resin-Bound
Secondary Amine
Fu Xu Liao1, Yu Guang Wang1, Qing Zhu1,
1College of Biological and Environmental Engineering, Zhejiang University of
Technology, Hangzhou, Zhejiang, P. R. of China
Address correspondence to Qing Zhu, College of Biological and Environmental
Engineering, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, P. R. of
China. Tel.: +86-571-88320781; E-mail: zhuq@zjut.edu.cn
Abstract
A series of polystyrene-supported imino group-bearing catalysts were prepared. Highly
efficient combination of recyclable catalysts and microwave was developed as a green
protocol for the direct aldol reaction. Notably, MW greatly shorten the reaction times to
only 20 min and improved the yield significantly，meanwhile, catalyst loading was
reduced as well. Different aromatic aldehydes as aldol donors were subjected to our
catalyst system and afforded the corresponding products in satisfactory yields.
Additionally, the polymer-supported catalysts could be recovered by simple filtration and
were reusable for at least four times without significant loss of reactivity.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
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KEYWORDS: Aldol reaction; polymer-supported reagents; imino group; microwave;
recyclability
INTRODUCTION
The aldol reaction, one of the most important carbon-carbon bond-forming reactions, was
widely employed in synthetic organic chemistry.[1–4] Its products, β-hydroxyl carbonyl
compounds or α, β-unsaturated carbonyl compounds, had served as important building
blocks for the synthesis of polyfunctional compounds and natural products.[5] In recent
years, studies of organocatalysts for the aldol reaction, such as proline and its derivatives
or analogues, have attracted great attentions due to their simple structures and being free
of metals.[6–12] For example, List and Barbas reported that the direct intermolecular aldol
reaction could be performed under mild catalysis of proline.[13] More recently, secondary
amines were found to have distinct or better catalytic abilities in direct aldol reaction and
Michael addition due to the formation of enamine, whereas proline-based catalysts
showed no activity.[14–17] This mechanism proposed that the imino group plays an
indispensable role in promoting the condensation with an aldol acceptor.[6,18–22] However,
these homogeneous catalysts were not beneficial to the purification process.[23,24] Few
years ago, K. Sakthivel et al. developed a heterogeneous catalyst by the immobilization
of proline on silica gel, which offered good yield and purity.[6] Unfortunately, the major
disadvantages of these heterogeneous catalysts included the long reaction times, high
catalyst loading but delivering varied yields,[25] and the large amount addition of
additives (such as acetic acid,[26] DiMePEG,[27] diols or diphenols[28]). Moreover, this
class of catalysts was not robust for the direct aldol condensation due to low stability
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caused by the non-covalent bond between the catalysts and solid support.[29] To overcome
these shortcomings, herein, we investigated a microwave-assisted direct aldol
condensation catalyzed by resin-bound secondary amine.
RESULTS AND DISCUSSION
A series of cross-linked PS resin-supported secondary amines were prepared according to
the synthetic route outlined in Scheme 1. Four kinds of amine were attached to the
polymer via a simple two-step reaction to give heterogeneous catalysts. The loadings
were determined by gravimetry.
Secondary Amine Resin-Catalyzed Aldol Reaction Under The Enhancement Of MW
Irradiation
Microwave irradiation has become a useful tool in organic synthesis. It is reported that
the MW irradiation could shorten the reaction time and increase the product yield
compared to conventional thermal approach.[30,31] To optimize the MW conditions, we
initially studied the model reaction of p-nitrobenzaldehyde with cyclohexanone catalyzed
by the four kinds of resin (20 mol%) in methanol. Firstly, the reaction was carried out
with a temperature-controlled program. In methanol, only 20% of conversion was
achieved after 20 min at 70℃ with 20 mol% resin 2a (entry 1, Table 1). For other groups,
the temperature was increased to 90℃ or 110℃, and 46% or 92% yields were obtained
after 20 min (entry 2 and 3, Table 1). Once the temperature was above 130℃, p-
nitrobenzaldehyde was totally consumed after 20 min. However, a large amount of bis-
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aldol and by-products (methylal) were detected (entry 4, Table 1). Moreover, at the
temperature of 110 ℃, a comparable yield could be obtained by using half amount of the
resin-catalyst (entry 5, Table 1). The catalytic performances of other three kinds of resin
were also investigated under the same conditions (entries 6, 7, 8, Table 1), in general, the
yields obtained were not as good as that obtained by resin 2a. Based on these results
further examinations were made using resin 2a.
Substrate Scope And The Resin Reusability Studies
After the optimization of microwave conditions, the substrate scope was extended to
other aldehydes and ketones. As shown in Table 2, both of the results with and without
the assistance of MW were listed. As for the trials without MW enhancement,
benzaldehydes with strong electron-withdrawing groups, such as p-fluorobenzaldehyde
(entry 6, Table 2), p-nitrobenzaldehyde (entry 11, Table 2), p-chlorobenzaldehyde (entry
8, Table 2) could be converted to the corresponding aldol products in good yields. On the
other hand, benzaldehydes with electron-donating groups such as methoxyl group, gave a
relatively poor conversion (entry 10, Table 2). Different substitutent positions on benzene
ring also affected the yields of Aldol reactions. For example, p-tolualdehyde with smaller
steric hindrance compared to o-tolualdehyde and m-tolualdehyde, gave the highest yield
(entries 3~5, Table 2). It is also interesting to note that cyclohexanone offered β-hydroxyl
ketone rather than the corresponding α, β-unsaturated carbonyl compound, which may
result from the great steric hindrance on the ring (entry 1, Table 2). However, this time-
consuming and relatively less efficient method was far from ideal, though the reusablity
of the catalyst. Once the MW irradiation was applied, the results were totally improved.
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Most of the substrates gave yields of more than 82% in only 20 min. Under this
innovative catalyst system, most kinds of aldehydes were transformed into the
corresponding aldol products with higer conversion and yield, and only 20 min was
required compared with that by means of conventional heating. Thus, the use of the MW
technique offered a great advantage in the secondary amine resin-catalyzed aldol
condensation reaction.
Next, the recycling of these resin-catalysts was investigated. As shown in Table 2, the
recovered resin 2a could catalyze the aldol reaction of p-nitrobenzaldehyde with
cyclohexanone in good yields even after five consecutive trials (entries 12~15, Table 2).
A Possible Mechanism For Direct Aldol Condensation
Based on the above results, we proposed the following enamine-mediated mechanism
(Scheme 2). Firstly, the imino group launched a nucleophilic attack, and the consequent
dehydration and deprotonation of the corresponding intermediates led to the formation of
another crucial intermediate enamine (a, Scheme 2). Next, the carbon-carbon bond-
forming reaction between acetone enamine and aldehydes occurred and resulted in
intermediate c. After the subsequent effect of water, it was converted to d, which was
transformed to β-hydroxyl-ketone (e) quickly. The α, β-unsaturated carbonyl compound
(f) was generated after the release of one molecule of water. Obviously, MW irradiation
could promote the secondary amine-catalyzed aldol reactions probably due to the specific
interaction of the electric field with the polar reaction species. [32, 33]
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CONCLUSION
A novel kind of catalyst system has been established by the use of MW and recyclable
resin catalyst. Reaction times and the required catalysts loading were reduced
significantly after the assistance of the MW irradiation. The combination of MW energy
and secondary amine resin-bound catalysts could constitute a new type of highly reliable
and recyclable catalyst system, which, as far as we know, has not been reported
previously. This approach is potentially applicable to a number of reactions catalyzed by
proline and its analogues as organocatalysts.
EXPERIMENTAL
All the Aldol products were known compounds and identified by using a combination of
their NMR and mass spectra, and compared with data given in the literature and from the
data library of Agilent GC-MS workstation.
The full experimental details and characterization data for the preparation of reusable
catalysts are provided in the Supplementary Information.
General Procedure For Aldol Reaction (Conventional Method).
Resin was added to a suspension of aldehyde (0.5 mmol), ketone (1.0 mmol) in 4 mL
solvent in a sealed tube. The reaction mixture was stirred for 72 h at 50℃, and HPLC or
GC-MS were employed to determine the conversions and yields.
Typical Procedure For Aldol Reaction Under MW Irradiation.
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To a 10 mL vessel were introduced resin, aldehyde (0.5 mmol), solvent (4 mL) and
finally ketone (1.0 mmol). The vessel was sealed with a septum and placed into the
microwave cavity. The microwave source was then turned on. After the time was out,
HPLC or GC-MS were employed to determine the conversions and yields.
Recycling Of The Catalytic System.
After the reaction was completed, the organic reaction solution was vacuum-filtered
through a sintered-glass funnel. The small balls were washed successively with THF,
water and methanol until there were no residual compounds. After the recovered catalyst
was dried under vacuum for four hours, it was directly used in the next cycle without
further purification.
Characterization Of Typical Compounds.
2-(Hydroxy(4-Nitrophenyl)Methyl)Cyclohexanone(5a):[34]
1H NMR (400 MHz, CDCl3) δ8.13 (s, 2H), 7.41 (s, 2H), 4.82 (d, J = 8.4 Hz, 1H), 2.54 (s,
1H), 2.31 (dd, J = 14.7, 4.5 Hz, 2H), 1.77 (s, 3H), 1.63 (d, J = 9.4 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 212.3, 151.3, 147.1, 128.5, 123.3, 76.4, 56.6, 39.4, 29.2, 25.6, 23.6.
HPLC: tR: 9.75 min. MS(EI): m/z 250[M++H]. Anal. Calcd. For: C13H15NO4: C 62.64, H
6.07, N 5.62, O 25.67, found: C 62.61, H 6.08, N 5.66, O 25.65.
The Full experimental detail, data of 1H, 13C NMR spectra, retention time in HPLC or GC
and ESI-MS characterization of products 5b-l together with the IR spectra of prepared
catalysts(1a-d) are available in the Supplementary Information.
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Table 1. MW-assisted aldol reactions under the catalysis of solid-phase
calysts
Entry
Catalyst t/min mol%
Con./%a Y./%b
T/℃
1
2
3
4
5
6
7
8
9c
2a
2a
2a
2a
2a
2b
2c
2d
2a
20
20
20
20
20
20
20
20
20
20
20
20
10
10
10
10
70
90
23
55
19
46
92
45
90
74
69
58
75
110 96
130 99
110 94
110 79
110 75
110 75
4320 20
50
78
aConversion based on 5, and determined by HPLC;
bYields were determined by HPLC.
cIn comparison with the performance without the assistance of MW irradiation.
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Table 2. Comparison of the direct aldol reactions between microwave irradiation and
conventional heating
Entry
Product
Conventional methoda
Microwave methodb
t/min Con./%c Y./%d t/min Con.% c Y./%d
1
4320 53
47
20
89
86
2
3
4
4320 66
4320 63
4320 44
62
60
38
20
20
20
93
86
88
90
85
84
5
6
4320 39
4320 82
32
69
20
20
83
98
80
94
7
4320 53
46
20
86
83
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8
4320 74
69
10
20
20
93
83
89
80
9
4320 18
10
11
4320 32
4320 73
28
66
20
20
85
87
84
82
12
13
14
15
First reuse of resin 1
4320 74
70
66
65
67
20
20
20
20
92
89
88
83
90
86
87
82
Second reuse of resin 1 4320 72
Third reuse of resin 1
Fourth reuse of resin 1
4320 75
4320 69
aentries 1~15, 20mol% of resin 2a;
bentries 1~15, 10mol% of resin 2a, MW 110°C;
cConversion based on the aldehyde and determined by HPLC or GC-MS;
ddetermined by HPLC or GC-MS;
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Scheme 1. Synthesis of the resin-catalysts. Reagents and conditions: (a):ClCH2COCl,
AlCl3, CH2Cl2, r.t.; (b): piperazine, K2CO3, DMF, 80℃; (c): benzylamine, DBU, DMSO,
r.t. ; (d): aniline, DBU, DMSO, r.t. ; (e): glycine, DBU, DMSO, r.t.
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Scheme 2. Proposed enamine mechanism of aldol reaction catalyzed by imino group-
bearing organocatalysts
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