The synthesis of cyclohexenone using l-proline immobilized on a silica gel catalyst by a continuous-flow approach

Article abstract of DOI:10.1039/c4ra01231c

A facile and convenient method for the synthesis of cyclohexenone compounds was developed using an l-proline immobilized silica gel catalyst combined with a continuous-flow approach. Because of the mild reaction conditions, ease of catalyst recyclability, and product isolation, this reaction approach can potentially be used in a facile scale-up reaction or in industrial applications. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra01231c

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The synthesis of cyclohexenone using L-proline
immobilized on a silica gel catalyst by a
continuous-flow approach†
Cite this: RSC Adv., 2014, 4, 15036
Received 12th February 2014
Accepted 14th March 2014
*
Cong Zhi, Jiaqing Wang, Bin Luo, Xinming Li, Xueqin Cao, Yue Pan and Hongwei Gu
DOI: 10.1039/c4ra01231c
www.rsc.org/advances
A facile and convenient method for the synthesis of cyclohexenone acetone for C–C bond formation and Michael reactions under
compounds was developed using an L-proline immobilized silica gel homogeneous conditions.10 However, because of the inherent
catalyst combined with a continuous-flow approach. Because of the drawbacks of homogeneous catalysts (e.g., short catalyst life-
mild reaction conditions, ease of catalyst recyclability, and product time, large amount of organic solvent, and difficulties in cata-
isolation, this reaction approach can potentially be used in a facile lyst separation and recovery), as well as practical difficulties,11
scale-up reaction or in industrial applications.
heterogeneous catalysts based on L-proline immobilized on
different solid supports (e.g., organic polymers,12 zeolites,13
mesoporous silica14 and iron oxide nanoparticles15) have been
studied.
Cyclohexenone and cyclohexanone derivatives, as high-value
molecules, serve as a common structural motif for many natural
products and important intermediates of organic compounds
such as dihydrojunenol, faurinone, b-cadinene and other
natural products1 because of their wide range of applications in
pharmaceuticals, pesticides, photographic lm materials,
drugs and other important chemicals.2 Traditionally,
substituted cyclohexenones are prepared using the well-known
Robinson annulation, which combines three reactions: Michael
addition, intramolecular aldol reaction, and dehydration.3 For
example, Fuchs et al. introduced a multistep process starting
with enantiopure epoxyvinyl sulfones for the preparation of
chiral 4-alkylcycloalkenones and enantiopure 2,5-cyclo-
hexadienone synthons.4 Both Baran and Nicolaou's groups used
Robinson annulations to produce dihydrojunenol and ent-7-
epizingiberene, respectively.5 Recently, Zhao et al.6 and Lu et al.7
separately used primary–secondary diamine and primary amino
acid catalysts for the generation of a, b-unsaturated ketones
with outstanding results.
In addition, continuous-ow technologies have recently
emerged as new strategies for the sustainable generation of ne
chemicals and pharmaceuticals,16 because of a number of
advantages over traditional batch procedures such as a shorter
reaction time, efficient mixing, and faster heat and mass
transfer.17 Although many research groups have used proline
organocatalysts in continuous-ow approaches for aldol reac-
tions,18 a number of drawbacks still exist19 such as (i) long
processing times, (ii) difficulties in product separation, and (iii)
low yields that restrict their applications.
Therefore, the development of a more sustainable and
industrially reliable catalytic procedure for the aldol reaction is
still of continuing interest and a signicant challenge for
synthetic chemists. Herein, we report a simple, green and effi-
cient method for the aldol reaction by a continuous-ow
approach in which L-proline was immobilized on silica gel to
produce a heterogenous catalyst that triggered the aldol reac-
tion in a silica-packed chromatographic column upon the ow
of eluent. The described technique has many merits such as
catalyst reclability, ease of product isolation, and mild reaction
conditions.
L-Proline and its derivatives, as well-known asymmetric
organocatalysts,8 have found wide application in the catalysis of
enantioselective aldol reactions9 between aldehydes and
Because of its thermal and kinetic stability as well as its
chemical inertness, we chose silica as a solid support for proline
immobilisation. The silica gel-supported proline catalyst was
prepared by following the reaction conditions and procedures
reported previously20 and as illustrated in Scheme 1. These were
divided into three steps. Firstly, silica gel powder was activated
by sodium hydroxide to create hydroxyl groups on its surface,
and it was reacted with aminopropyl triethoxysilane to afford
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123,
China. E-mail: hongwei@suda.edu.cn; Fax: +86-65880905; Tel: +86-65880905
† Electronic supplementary information (ESI) available: Experimental procedures
include a synthetic protocol for the construction of Si-LP, the synthesis of
cyclohexenones from corresponding aldehydes. And also, the FTIR, TGA spectra
of Si-LP and full spectroscopy data for all compounds. See DOI:
10.1039/c4ra01231c
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Table 1 a, b-unsaturated cyclohexenones prepared from their cor-
responding aldehydes and acetone using the Si-LP catalysta
Entry
Aldehydes
Unsaturated cyclohexenones
Yieldb (%)
1
2
55.7
50.5
3
4
79.3
82.1
Scheme 1 Illustration of proline functionalized silica gel.
silica gel (Si-L) with amino group modication on its surface.
Upon activation by ethyl chloroformate, N-Boc-L-proline reacted
with Si-L to form Si-LP (Boc). Aer removing the protecting
groups from proline by triuoroacetic acid (TFA) we obtained a
silica gel-supported catalyst (Si-LP) as the nal product. From
the FTIR spectra of the Si-LP and the bare silica gel presented in
Fig. S1,† we found that the two spectra had similar character-
istics for most of the peaks except for three additional bands
around 2832 cmÀ1, 1640 cmÀ1 and 3200 cmÀ1 in the spectrum
of Si-LP. These come from the stretching vibrations of the
–CH2–, –NHCO– and –NH-groups from proline, respectively,
indicating the successful attachment of proline onto the surface
of the silica gel.
The catalytic performance of Si-LP in the aldol reaction was
evaluated in a model reaction between benzaldehyde and
acetone, and this is shown in Scheme 2. First, the Si-LP powder
(35 mL) was packed into an upright chromatographic column of
22 mm in diameter and 0.3 m in length. It was then rinsed with
a sufficient amount of ethanol to remove the physically absor-
bed N-Boc-L-proline or L-proline on the surface of the silica gel.
Then, an appropriate amount of benzaldehyde (102 mL, 1 mmol)
5
6
88.9
>99
7
97.1
85.7
65.4
73.8
69.1
8
9
10
11
12
13
72.5
74.1
14
15
88.9
86.6
Scheme 2 Illustration of the aldol reaction triggered by Si-LP in a
silica-packed chromatographic column.
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Table 1 (Contd.)
highest yields of around 99 and 97.1%, respectively (Table 1,
entries 4 and 5). Other para-substituted substrates as well as
benzaldehyde that contain methoxy, ethoxy, propoxy, phenyl,
hydroxy or chloro groups exhibited a relatively high conversion
with acceptable yields (Table 1 entries 8–12 and 5). The yields
for heterocyclic aldehydes (Table 1, entries 13–16) were still
attractive at 74.1% to 88.9%. In the control, when the synthesis
was performed as a batch reaction, under the same conditions,
the yield was obviously lower than that from the continuous-
ow approach (Table S1†).
Entry
Aldehydes
Unsaturated cyclohexenones
Yieldb (%)
76.6
16
a
All the reactions were carried out at room temperature and under
atmospheric pressure. b GC yield.
Electron-withdrawing effects have a great impact on these
reactions. The substrates containing chloro, bromo or cyano
and acetone (100 mL, 1362 mmol) was charged and eluted with groups enhanced the electron-withdrawing effects of the
dehydrated ethanol (250 mL) at room temperature and at benzene rings, which resulted in a higher yield (Table 1, entries
atmospheric pressure at a ow rate of around 0.1 mL minÀ1
.
5–7) compared with substrates containing methoxy, ethoxy or
The reaction solution relied on gravity downow. The collected propoxy groups (Table 1, entries 9–11). Additionally, substrates
solution was recharged into the chromatography column and containing obvious electron-donating groups such as formal-
this procedure was repeated 10 times. The resultant product dehyde, butyraldehyde, p-biphenylaldehyde and p-hydroxy-
mixture was subjected to GC, GC-MS and NMR analysis. The benzaldehyde gave yields of 50.5, 55.7, 72.5 and 85.7% (Table 1,
chemical structure of the product was veried by NMR spec- entries 1, 2, 8 and 12), respectively.
troscopy (Fig. S3†) and the yield was about 82.1%, as deter-
To obtain more information about the mechanism of this
mined by GC measurement (Table 1, entry 4). In the above catalytic process, GC measurements were carried out to study
reaction process we observed that the a, b-unsaturated ketones the model reaction between p-cyanobenzaldehyde and acetone
were generated as intermediates (Scheme 2), which further with Si-LP as the catalyst over time. The kinetic curve of the
reacted with acetone to afford the nal a, b-unsaturated cyclo- transformation from p-cyanobenzaldehyde to cyclohexenone is
hexenones via Michael addition and Robinson cyclization.
shown in Fig. 1. During the reaction, the concentration of a
Under the conditions used for the formation of a, b-unsat- appeared to increase over the rst 18 h and then decreased
urated cyclohexenone from benzaldehyde and acetone, we upon its conversion to the cyclohexenone compound b. The
further examined the catalytic ability of Si-LP using other reaction is complete in 60 h. a, b-unsaturated ketone a was
aldehyde substrates that contain aromatic, aliphatic or hetero- observed to be an intermediate in the reaction between the
cyclic subgroups (Table 1). As shown in Table 1, almost all the aldehyde and acetone, and it can further react with acetone to
aldehyde substrates were quantitatively converted to their cor- afford cyclohexenone b via Michael addition and Robinson
responding cyclohexenone products (Table 1, entries 2–16). For cyclization.
example, aromatic aldehydes such as p-bromobenzaldehyde
In summary, we successfully developed an efficient, envi-
and p-cyanobenzaldehyde (Table 1, entries 6 and 7) gave the ronmentally friendly method for the generation of cyclo-
hexenone using a L-proline immobilized silica gel catalyst by a
continuous-ow approach. Because of the many advantages
exhibited by our system such as catalyst recyclability, ease of
product isolation and mild reaction conditions, this system may
be a useful guideline for the design of more efficient methods of
cyclohexenone production with industrial application possibil-
ities. Further investigations into the L-proline immobilized
silica gel catalyst for wider applications are ongoing in our
laboratory.
H. W. G. acknowledges the nancial support from NSFC (no.
21003092, no. 21373006), the Key Project of Chinese Ministry of
Education (no. 211064), and the Priority Academic Program
Development of Jiangsu Higher Education Institutions.
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