A solid-supported organocatalyst for continuous-flow enantioselective aldol reactions

Article abstract of DOI:10.1002/cssc.201100570

Asymmetric aldol reactions catalyzed by a novel polystyrene-immobilized proline derivative occur in short reaction times with excellent diastereo- and enantioselectivity. The catalyst can be recovered by simple filtration and shows very high reusability.

Full text of DOI:10.1002/cssc.201100570

DOI: 10.1002/cssc.201100570
A Solid-Supported Organocatalyst for Continuous-Flow
Enantioselective Aldol Reactions
[a]
[a]
[a, b]
Carles Ayats, Andrea H. Henseler, and Miquel A. Pericꢀs*
Asymmetric aldol reactions catalyzed by a novel polystyrene-
immobilized proline derivative occur in short reaction times
with excellent diastereo- and enantioselectivity. The catalyst
can be recovered by simple filtration and shows very high re-
usability. The high activity depicted by the supported catalyst
and its chemical and mechanical stability have allowed its ap-
plication in packed-bed reactors for continuous flow process-
ing. This system can produce enantio- and diastereomerically
pure aldol adducts under continuous flow conditions with a
residence time of 26 min. Furthermore, the reactor allowed
processing of four different aldol products in sequence without
any decrease in both catalytic activity and optical purity. The
effective catalyst loading could be reduced to 1.6% (six-fold re-
duction of catalyst loading compared to the corresponding
batch process).
Introduction
In recent years, the development of sustainable and environ-
mentally friendly processes for chemical synthesis has attracted
lysts in continuous flow systems have been reported in the lit-
erature. Massi and coworkers described the use of proline-
functionalized silica packed-bed microreactors for the continu-
[
1]
a growing interest. The use of organocatalysts offers several
advantages towards this objective because of their non-toxic
nature, the air- and water-tolerating reaction conditions, and
[22]
ous reaction of cyclohexanone with p-nitrobenzaldehyde.
Sels and coworkers, in turn, immobilized primary amino acid-
derived diamines in a non-covalent fashion onto solid acids
and used these catalysts in the asymmetric aldol reaction of
2-butanone with 4-(trifluoromethyl)benzaldehyde under flow
[
2–4]
simple reaction set-ups.
However, organocatalytic methods
often require catalyst loadings as high as 30 mol% for the
achievement of high conversions in reasonable reaction
[
5,6]
[23]
times.
To overcome this problem, immobilization of organo-
conditions. However, only low levels of productivity and dia-
catalysts represents an attractive technique, which allows
simple recovery and reuse of the catalysts leading to a sub-
stantial reduction of the effective catalyst loading. Additionally,
the immobilization of organocatalysts onto solid supports
allows a simplified workup by direct filtration of the catalytic
stereoselectivity could be achieved in both cases.
We have recently reported the preparation and utilization of
polystyrene (PS)-supported proline derivatives
1 and 2
(Figure 1) as highly efficient catalysts in aldol reactions under
[24,25]
batch conditions.
We showed that resin 1 can also catalyze
[
7–13]
[14]
species.
supported organocatalysts are particularly suitable for continu-
Because of their stability and recyclability, solid-
highly stereoselective Mannich reactions and the a-aminoxyla-
tion of aldehydes under batch conditions as well as in a con-
[
15–18]
[26–28]
ous flow systems,
which allow large-scale synthesis usually
tinuous flow process.
In both reactions, stereoselectivity
accompanied by higher turnover numbers (TONs).
and activity appears to be improved by the presence of a
1,2,3-triazole moiety initially designed as a linker in the catalyst
The aldol reaction is one of the most powerful methods to
form carbonÀcarbon bonds. Control of the absolute configura-
tion of the newly formed stereogenic centers is of particular
importance for the synthesis of biologically active com-
[29,30]
structure.
through
The triazole linker in resin 2, implemented
copper-mediated Huisgen cycloaddition (click
plays the double role of grafting the mono-
a
[
31–33]
chemistry),
[
19,20]
pounds.
The implementation of asymmetric aldol reactions
meric proline unit onto the polystyrene backbone and allowing
the formation of a hydrogen bond network between the tri-
azole moiety and the amine and carboxylic acid functional
in flow systems is of utmost interest because aldol products
are important building blocks for pharmaceuticals and natural
products and, therefore, a continuous production of large
quantities of these materials is highly desirable. The first exam-
ple of a homogeneous organocatalytic asymmetric aldol reac-
tion conducted in a microreactor device utilizing 5-(pyrroli-
dine-2-yl)tetrazole as the catalyst was reported by Seeberger
[
a] Dr. C. Ayats, A. H. Henseler, Prof. Dr. M. A. Pericꢀs
Institute of Chemical Research of Catalonia (ICIQ)
Avda. Paꢁsos Catalans, 16. E-43007, Tarragona (Spain)
Fax: (+34)977-920-222
[
21]
E-mail: mapericas@iciq.es
and coworkers. In this way, catalyst loadings could be re-
duced and reaction times were significantly shortened; howev-
er, the catalyst was co-eluted with the reaction product, so pu-
rification was still necessary. Only recently, two examples of
stereoselective aldol reactions catalyzed by immobilized cata-
[
b] Prof. Dr. M. A. Pericꢀs
Departament de Quꢂmica Orgꢀnica
Universitat de Barcelona, 08028 Barcelona (Spain)
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201100570.
3
20
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ChemSusChem 2012, 5, 320 – 325

Organocatalyst for Continuous-Flow Aldol Reactions
operation. Therefore, a Merrifield
resin containing 8% DVB was
[34–36]
prepared
port for catalysts 2 and 3. Resin
was functionalized with 4-
as the solid sup-
3
ethynylbenzyl alcohol (5) under
basic conditions followed by a
Huisgen cycloaddition with
[25]
Figure 1. Polystyrene-supported catalysts.
azide derivative 8, which was
catalyzed by tris(triazolyl)methyl
[37]
copper complex (7), and sub-
sequent trifluoroacetic acid
(
(
TFA)-mediated
Scheme 1).
deprotection
Catalysts 2 and 3 containing a
triazole linker, but different
spacers (Figure 1), were initially
tested under batch conditions
to compare activity, selectivity,
and recyclability, to determine
the resin with optimal catalytic
performance and the suitable
conditions for the planned con-
tinuous flow process. First, the
resins were evaluated in a test
reaction between cyclohexa-
none and benzaldehyde in dif-
Scheme 1. Preparation of the immobilized catalyst 3.
ferent solvent systems (Table 1).
The reaction worked nicely in
different solvents yielding the
groups of proline. This is probably correlated with water gela-
tion in the presence of 2 and with aldol reactions taking place
at a higher rate and improved stereoselectivity in the resulting
aqueous microenvironment. Thus, the combination of the hy-
drophobic polystyrene backbone, proline as the active center
of the catalyst, and the triazole linker gives rise to the forma-
tion of a highly stereoselective catalytic system operating
anti aldol product in both, high diastereo- and enantioselectivi-
[24,25]
ty. As anticipated from previous results,
the presence of
water was crucial for high levels of stereoselectivity. The ab-
sence of significant amounts of water in the reaction media
[
10,25]
through a simplified enzyme-like mechanism.
Table 1. Solvent effects on the aldol reaction of cyclohexanone with
Herein, we present the preparation of a novel, polystyrene-
supported proline derivative as a highly active and stereoselec-
tive catalyst for aldol reactions, and its use for the implementa-
tion of a single-pass continuous flow process for the produc-
tion of diastereo- and enantiomerically pure aldol products.
[a]
benzaldehyde catalyzed by resin 2 and 3 under batch conditions.
[
b]
[b]
[c]
Entry
Catalyst Solvent
Conversion
%]
anti:syn
ee
[
[%]
Results and Discussion
[
d]
1
2
3
4
5
6
7
8
2
2
2
2
3
3
3
3
CH
CH
H O
2
2
Cl
Cl
2
2
47
47
75
77
85
82
81
92
80:20
89:11
93:7
79:21
85:15
95:5
77
94
96
93
85
95
97
97
Polystyrene-supported proline derivatives 2 and 3 were pre-
2
/H
2
O (50:50)
pared from home-made Merrifield resins following modified lit-
[
25,29]
erature procedures.
The synthesis of resin 2 containing a
DMF/H
2
d]
O (50:50)
[
CH
CH
2
Cl
Cl
2
2
low level of cross-linking [1% 1,4-divinylbenzene (DVB)] was re-
[
25]
2
2
/H O (50:50)
cently reported by our group. As mentioned above, this cat-
alyst showed a high level of enantio- and diastereoselectivity
in aldol reactions under batch conditions. However, as the aim
of this research was the use of the catalytic resins in a continu-
ous flow process, we reasoned that a higher degree of cross-
linking of the resins should enhance its mechanical stability,
making them more robust under the pressure applied for flow
H
2
O
95:5
95:5
DMF/H O (50:50)
2
[
1
a] Reactions were performed with resin 2 or 3 (10 mol%), benzaldehyde
0a (0.4 mmol), and cyclohexanone 11 a (5 equiv) in different solvents.
[b] Determined by performing H NMR spectroscopy on the crude mix-
ture. [c] Determined by performing HPLC using a chiral stationary phase
of the crude mixture. [d] Synthesis grade.
1
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321

C. Ayats, A. H. Henseler, and M. A. Pericꢀs
led to important decreases in stereoselectivity (Table 1, en-
tries 1 and 5).
Table 2. Substrate scope in the aldol reaction catalyzed by resin 3 under
batch conditions.
[a]
In all the solvent systems tested, catalyst 3 showed a higher
activity and diastereoselectivity than 2. The beneficial role of
the p-phenylene spacer was observed in Michael reactions cat-
alyzed by a PS-supported pyrrolidine reported previously by
[
29]
our group. We presume that the p-phenylene group enhan-
ces the stereoselectivity of the catalyst because of the in-
creased separation between the hydrophilic, catalytically active
moiety and the hydrophobic polymer backbone.
[b]
[c]
[d]
Run
Product
t
[h]
Yield
[%]
anti:syn
ee
[%]
As catalysts 2 and 3 led to similar results in different sol-
vents, recycling experiments were conducted with both resins
to determine and compare their lifetimes in three different sol-
vent systems (see the Supporting Information). After each run,
the catalyst was recovered by performing simple filtration and
reused. The optimal performance regarding yield, selectivity,
and recyclability was achieved in a mixture of dimethylforma-
1
2
24
24
74
96:4
98
[e]
84
85:15
96
3
4
5
6
5
24
13
72
5
91
41
96
28
85
96:4
98:2
97:3
90:10
98:2
98
>99
98
mide (DMF)/H O (50:50) with resin 3 (Figure 2). Resin 3 was re-
2
cycled seven times affording the aldol product with constant
or even improved stereoselectivity and with only moderate de-
crease of catalytic activity in every cycle. Under batch condi-
tions, the results in water were almost equally good (see the
Supporting Information), but could be problematic for solubili-
ty issues under flow conditions. Therefore, a mixture of DMF/
[
38]
H O was the best choice.
2
98
[
f]
7
97
[
(
(
a] Reactions were performed with resin
0.4 mmol), and cyclic ketone 11 (5 equiv.) in a mixture of DMF/H
50:50). [b] Isolated yield. [c] Determined by performing H NMR spectros-
3 (10 mol%), aldehyde 10
2
O
1
copy of the crude mixture. [d] Determined by performing HPLC using a
chiral stationary phase. [e] In this experiment, formation of dehydrated
product in 5% yield was obtained. [f] Reaction with p-nitrobenzaldehyde
was repeated to compare conversion and stereoselectivity with the same
substrate after three interjacent runs.
Figure 2. Recycling experiments of the test reaction under optimized batch
conditions. Bright bars: conversion (%); black bars: dr; gray bars: ee (%).
reactions of these substrates to continuous flow conditions ap-
[26,28,39–42]
peared as a promising alternative.
For this purpose,
To investigate the scope of the reaction, a representative set
of aromatic aldehydes and cyclic ketones was examined under
optimized conditions in the presence of resin 3 (10 mol%) in a
the instrument set-up represented in Figure 3 was used (see
the Supporting Information for more details). The packed-bed
reactor consisted of a vertically mounted and fritted low-pres-
sure Omnifit glass chromatography column (10 mm pore size
and up to maximal 70 mm of adjustable bed height) loaded
with the swollen resin 3 (600 mg, ꢀ20 mm bed height), assem-
bled to a microflow system based on the microSyn equipment
developed by MiKroglas. The reactor inlet was connected to a
syringe pump, into which a solution of both reagents (no reac-
tion occurs in the absence of catalyst) in a mixture of DMF/
mixture of DMF/H O (50:50). The different aldol products could
2
be obtained in good yields with excellent enantio- and diaste-
reoselectivities. The results are summarized in Table 2.
It is worth pointing out that the same sample of catalyst 3
was reused seven times with different substrates after simple
filtration and washing with ethyl acetate (Table 2). Repetition
of the same experiment after three interjacent runs led to only
marginally lower yields and to the same stereoselectivity
[43]
H O (60:40) was placed, to continuously feed the reactor.
2
(
Table 2, entries 3 and 7).
The reactor outlet was connected to a receiving flask, where
the product was collected. Conversion and diastereoselectivity
of the formed product were determined by performing
In view of the excellent results (moderate reaction time and
high stereoselectivity) recorded with electron-deficient alde-
hydes under batch conditions, the possibility of adapting the
1
H NMR spectroscopy of periodically collected samples.
3
22
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ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2012, 5, 320 – 325

Organocatalyst for Continuous-Flow Aldol Reactions
batch process as a reference, the continuous-flow
process allows for a six-fold reduction of the catalyst
amount without any deterioration of its performance
[47]
(
see the Supporting Information). According to the
these excellent results, we assume that resin 3 is
more resistant to collapse under continuous-flow
conditions because of the higher level of cross-link-
ing of the PS support (8% DVB), but still retains the
characteristics (swellability, high catalytic activity) as-
sociated with microporous behavior.
Bearing in mind the excellent results obtained in
the continuous production of 12ba, we attempted
to use a single reactor to prepare different aldol ad-
ducts by repeatedly using the same sample of resin.
Operation between two different, sequentially used
aldehydes only involved washing the resin by circula-
tion of a mixture of DMF, water, and cyclohexanone
for a brief period of time. The reactions were per-
Figure 3. The experimental set-up for the continuous-flow experiments. EWG=electron
withdrawing group.
After optimization of the parameters for the continuous-flow
formed with the same catalyst loading and under the same
conditions as in the previous flow experiment; the results are
summarized in Table 3. Aldol products 12ba, 12da, 12 fa, and
12ga were obtained in high diastereo- and enantiomeric
purity in 8 h runs, with productivities ranging from 1.39–2.35
for 7 h collection times. Conversion remained constant within
individual cycles, so that productivity with individual aldehydes
purely reflects differences in reactivity between the substrates.
To compare results under flow and batch conditions, the
same sequence of experiments and cycles using the same sub-
[
44]
process, operation of this device at room temperature with
a loading of swollen resin 3 (600 mg, functionalization f=
À1
0
.54 mmolg ) led to optimal conversion when a solution of p-
nitrobenzaldehyde and cyclohexanone in a mixture of DMF/
H O (60:40) was passed through the system with a flow rate of
2
À1
[45]
2
5 mLmin (equivalent to ꢀ26 min residence time). The ex-
periment showed that the conversion decreased after 30 h,
but diastereoselectivity remained constant for more than 45 h
(
Scheme 2 and Figure 4). Notably, the process produced ste-
reochemically pure 12ba (4.87 g, 19.54 mmol, diastereomeric
strates and solvent ratios was performed under batch condi-
[
46]
[48]
ratio dr=96:4, 97% ee) in a 30 h run without any deteriora-
tion of stereoselectivity, with comparable results to those re-
corded under batch conditions (Table 2, entry 3). Taking the
tions (Table 3).
Stereoselectivities under both operation
modes were essentially identical. Importantly, this demonstrat-
ed that the supported proline derivative 3 can be advanta-
geously used for continuous-flow processes and that it can be
repeatedly used with different substrates. This system can be
considered as a “machine” for the simple and continuous pro-
duction of optically pure aldol products suitable for integration
into more complex machinery for the total synthesis of enan-
tiomerically pure complex molecules under flow conditions.
Conclusions
Scheme 2. Continuous production of 12ba.
A catalytic system for highly stereoselective aldol reactions in
continuous operation has been developed. The applicability to
different substrates and the suitability of the flow system for
repeated reuse allowing the medium-scale preparation of a
series of aldol adducts under a single set of reaction conditions
has been demonstrated. With respect to previous isolated ex-
[22,23]
[22,23]
amples,
diastereo-,
very important improvements in productivity,
[22,23]
[22]
and enantioselectivity
have been achieved.
Studies aimed at the extension of the continuous-flow process
to the aldol reaction of non-activated aldehydes are currently
underway in our laboratory.
Experimental Section
Figure 4. Continuous-flow aldol reaction between p-nitrobenzaldehyde and
General procedure for the asymmetric aldol reaction under batch
conditions catalyzed by resin 2 and 3: Polystyrene-supported pro-
cyclohexanone running for 45 h.
: dr; ^: conversion (%).
&
ChemSusChem 2012, 5, 320 – 325
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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323

C. Ayats, A. H. Henseler, and M. A. Pericꢀs
Table 3. Continuous-flow enantioselective aldol reaction of four different adducts and comparison to those obtained in batch conditions.
[
a]
[b]
Run Aldehyde
Product
Flow conditions
product
mmol]
Batch conditions
[
c]
[d]
[e]
[e]
[f]
[g]
[e]
[d]
[e]
[f]
productivity
conversion
[%]
anti:syn
ee
t
conversion
yield
[%]
anti:syn
ee
[
[%] [h] [%]
[%]
1
2
3
4
10d, X=CN
10 f, X=CO
10b, X=N
10g, X=CF
12da, X=CN
2.23
1.70
2.35
1.39
5.06
3.85
5.34
3.15
71
57
86
56
97:3
97:3
96:4
97:3
95
98
96
97
13 >99
20 >99
16 >99
97
86
94
95
96:4
97:3
97:3
97:3
94
98
98
99
2
Me 12 fa, X=CO
12ba, X=N
12ga, X=CF
2
Me
2
O
2
O
3
3
16
97
À1
[
a] Reactions were performed with 600 mg of resin 3 (0.32 mmol), 25 mLmin flow (ꢀ26 min residence time), 0.79m concentration of aldehyde 10 in a
mixture of DMF/H
2
O/cyclohexanone 11 a (1.5:1:1.7) and running the experiment for 8 h. [b] Reactions were performed with resin 3 (10 mol%), aldehyde 10
À1
À1
(0.4 mmol), and cyclohexanone 11 a (5 equiv.) in a mixture of DMF/H
2
O (60:40). [c] In mmol of pure isolated product (mmol
tained after performing flash chromatography on silica gel for 7 h collection time. [e] Determined by performing H NMR spectroscopy on the crude mix-
ture. [f] Determined by performing HPLC using a chiral stationary phase. [g] Reaction time for full conversion.
h
). [d] Pure product ob-
resin
1
line (10 mol% 2 or 3) was swollen in a mixture of DMF/H O (50:50
tion of p-nitrobenzaldehyde (10b, 53.32 mmol) in a mixture of
2
or 60:40, 150 mL). Aldehyde 10 (0.4 mmol) and ketone 11 (5 equiv.)
were added, and the reaction mixture was shaken at room temper-
ature. After the indicated time, the resin was filtered off, washed
with ethyl acetate, and dried under vacuum. The combined liquid
phases were dried over anhydrous magnesium sulfate and concen-
trated under reduced pressure. Purification was achieved by using
column chromatography (eluting with hexane/ethyl acetate gave
the corresponding aldol product 12). Conversion and diastereo-
DMF, H
2
O, and 11 a (67.5 mL), filled in the syringe pump prior to
À1
the experiment, was pumped with a flow rate of 1000 mLmin
through the system until the solution filled the column. Then, the
flow rate was reduced to 25 mLmin , and the system was run for
45 h. Samples were collected from 2 h (when the experiment was
stabilized) to 30 h (showing constant conversion and diastereose-
À1
1
lectivity as determined by using H NMR spectroscopy). The sol-
vents from the collected samples were removed under reduced
pressure to give a yellow oil, which was submitted to flash silica
gel column chromatography (hexane/ethyl acetate=2:1) to give
pure product 12ba (4.87 g, 19.54 mmol, dr=96:4, 97% ee) as a
white solid.
1
meric ratio (dr) were determined by performing H NMR spectros-
copy on the crude samples after removal of the resin. The enantio-
meric excess (ee) was determined by HPLC on a chiral stationary
phase, after purification by flash silica gel column chromatography,
unless stated otherwise.
Experimental setup for the continuous-flow process: The packed-
bed reactor consisted of a vertical mounted and fritted low-pres-
sure Omnifit glass chromatography column (10 mm pore size and
up to maximal 70 mm of adjustable bed height) loaded with the
swollen resin 3 (600 mg, ꢀ20 mm bed height), assembled to a mi-
croflow system based on the microSyn equipment developed by
MiKroglas. The reactor inlet was connected to a syringe pump, into
Acknowledgements
This work was funded by MICINN (CTQ2008-00947/BQU), Consol-
ider Ingenio 2010 (CSD2006-0003), DIUE (2009SGR623), and ICIQ
Foundation. C.A. thanks MICINN for a Juan de la Cierva postdoc-
toral fellowship. The authors gratefully acknowledge P. Llanes for
the preparation of the home-made Merrifield resin.
which a solution with both reagents in a mixture of DMF/H O
2
(
60:40) was placed to continuously feed the reactor. The reactor
outlet was connected to a receiving flask, where the product was
collected. Under these conditions, the dead volume was deter-
mined to be 1.05 mL when the process was slow enough to allow
maximal swelling of the resin. Conversion and diastereoselectivity
Keywords: aldol reaction · continuous flow · heterogeneous
catalysis · organocatalysis · supported catalysts
1
of the formed product were determined by performing H NMR
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3
24
www.chemsuschem.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2012, 5, 320 – 325

Organocatalyst for Continuous-Flow Aldol Reactions
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2
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À1
[
[
[
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[
[
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À1
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[
Received: September 10, 2011
2
Published online on January 2, 2012
ChemSusChem 2012, 5, 320 – 325
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemsuschem.org
325