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Research Article
pubs.acs.org/acscatalysis

Translating the Enantioselective Michael Reaction to a Continuous
Flow Paradigm with an Immobilized, Fluorinated Organocatalyst
Irina Sagamanova,† Carles Rodríguez-Escrich,† István Gábor Molnár,§ Sonia Sayalero,†
Ryan Gilmour,*,§,∥ and Miquel A. Pericàs*,†,‡
†

Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology,
Avinguda Països Catalans 16, 43007 Tarragona, Spain
‡
Departament de Química Orgànica, Universitat de Barcelona, 08080 Barcelona, Spain
§
Institut für Organische Chemie, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany
∥
Excellence Cluster EXC 1003 “Cells in Motion”, Westfälische Wilhelms-Universität Münster, Münster, Germany
S
* Supporting Information

ABSTRACT: A novel polymer-supported fluorinated organocatalyst has been prepared and benchmarked in the
enantioselective Michael addition of aldehydes to nitroalkenes.
The system has proven to be highly efficient and displays
excellent selectivities (er and dr) with a wide variety of
substrates. Detailed deactivation studies have given valuable
insights, thus allowing the lifespan of this immobilized
aminocatalyst to be significantly extended. These data have
facilitated the implementation of enantioselective, continuous
flow processes allowing either the multigram synthesis of a single
Michael adduct over a 13 h period or the sequential generation of
a library of enantiopure Michael adducts from different combinations of substrates (13 examples, 16 runs, 18.5 h total operation). A customized in-line aqueous workup, followed by liquid−liquid
separation in flow, allows for product isolation without the need of chromatography or other separation techniques.
KEYWORDS: fluorinated organocatalyst, continuous flow, polystyrene-supported catalysts, enantioselective catalysis, Michael reaction

1. INTRODUCTION
Sustainability concerns have resulted in a change of paradigm in
which not only cost reduction but also waste minimization and
catalyst recovery are crucial issues in process design. In this
context, continuous flow chemistry is one of the technologies
expected to facilitate process intensification, reducing the
footprint of chemical plants while increasing their productivity,
modularity, and flexibility.1 Despite the potential of immobilized catalysts for enantioselective flow processes, the fine
chemical industry still shows some reluctance to apply these
techniques because of the often limited lifespan of the reference
homogeneous species. Designing more stable homogeneous
catalysts and successfully translating their corresponding batch
processes to an immobilized platform is therefore essential to
further validate the potential of this approach. Consequently,
the preparation of supported catalysts with high activity and
improved stability holds great potential for both the industrial
and academic chemical communities.
Since the pioneering reports by List, Lerner, Barbas,2 and
MacMillan3 laid the foundations of modern organocatalysis,
efforts to develop effective metal-free small molecule catalysts
have intensified.4 One of the most successful organocatalysts
is the diarylprolinol trimethylsilyl ether, commonly known as
the Jørgensen−Hayashi catalyst.5 Given the versatility of this
© XXXX American Chemical Society

species, which is able to exploit both the enamine and iminium
ion activation mode, several groups have tried to harness
its potential by developing immobilized analogues.6 With the
aim of enhancing the sustainability profile of this catalyst,
this laboratory has reported the preparation of a set of solidsupported derivatives7 whose robustness was established through
recycling and implementation of enantioselective continuous
flow processes.8 These studies revealed that the reusability of
the catalyst was often compromised by the lability of the
trimethylsilyl ether; this has also been investigated spectroscopically in the homogeneous paradigm.9
Several approaches have been employed to address this issue.
First, it was demonstrated that resilylation is indeed possible,7a
although this has obvious drawbacks from an operational point
of view, and it precludes continuous flow applications. The
analogous methyl ether10 (rather than silyl) was also prepared,
but the polymer-supported version proved to be less active and
selective than the parent system.7b Although catalysts with bulkier
silyl ethers display increased stability,7d,e significant structural
changes can compromise reactivity, and they tend to deactivate
Received: August 10, 2015
Revised: September 10, 2015

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Scheme 1. Strategy for the Preparation of a Polymer-Supported Analog of 1

reactively inert C−F bond, ensures that any concerns regarding
stability of this site are mitigated.
It was therefore envisaged that compound 2, a polymersupported analog of 1, would display increased robustness
when compared with the structurally related silyl ethers. In
addition, because the active site of 1 (the pyrrolidine moiety) is
not involved in the polymerization of 3 and the pyrrolidine
moiety can freely rotate in polymer 2, we anticipated that the
performance of 1 would be preserved in the polymer. To test
the validity of this hypothesis, compound 2 was prepared by
copolymerization of the divinylated derivative 3 with styrene
(Scheme 1).

over time. With these data in hand, efforts to immobilize the
fluorinated compound 111 were initiated; this system was introduced in asymmetric organocatalysis by Gilmour et al. in 2009.12
The pyrrolidine derivative, designed to validate the gauche effect
hypothesis for molecular preorganization,13 has proven to be
highly effective in the enantioselective epoxidations12a,14 and
aziridinations15 of enals with great success, outperforming the
Jørgensen−Hayashi catalyst in some cases.16 Moreover, the
low steric demand of the fluorine substituent, coupled with the
Scheme 2. Preparation of the Monomer 3

2. RESULTS AND DISCUSSION
The synthesis of the target catalyst (Scheme 2) started with
the addition of 4-vinylphenyl magnesium bromide (prepared
in situ) to the proline derivative 4,17 which furnished 5 in
87% yield.18 The Boc group was then cleaved in basic media,
presumably via the corresponding oxazolidinone, to generate
amino alcohol 6.19 Deoxyfluorination of this amino alcohol,
achieved by treatment with diethylaminosulfur trifluoride20
(DAST), provided 3 in a concise three-step sequence and 68%
overall yield. Immediate fluorination of compound 6 was
essential to avoid spontaneous self-polymerization.
Polymer 2 was obtained by suspension polymerization of the
chiral monomer 3 with styrene in water following a modification of the procedure reported by Itsuno for the related amino
alcohol21 (Scheme 3). Because the monomeric species has two
vinyl units, a cross-linking agent (e.g., DVB) was not required.
Up to 65% of the functional monomer was incorporated to the
polymer, giving rise to resin batches with functionalization levels

Scheme 3. Preparation of Resin 2 by Copolymerization of 3

Table 1. Effect of Additives for the Addition of Propanal to β-Nitrostyrenea

entry

additive

pKa in H2Ob

t (h)

1
2
3
4
5
6
7
8

CF3COOH
2-FC6H4COOH
(R)-mandelic acid
(S)-mandelic acid
PhCOOH
CH3CH2COOH
4-nitrophenol

0.52
3.27
3.37
3.37
4.20
4.887
7.15

11
5
3.5
5
5
3.5
4
1.5

convc (yieldd)
100
14
100
81
81
100
98
100

(99)
(n.d.)
(97)
(n.d.)
(n.d.)
(98)
(n.d.)
(99)

drc

eee (%)

96:4
67:33
93:7
85:15
83:17
95:5
96:4
95:5

94
95
94
94
94
94
95

a
General conditions: (E)-β-nitrostyrene (22.4 mg, 0.15 mmol), propanal (33 μL, 0.45 mmol), catalyst 2 (10 mol %), additive (10 mol %) in 300 μL
of CH2Cl2 at room temperature. bpKa values taken from literature sources.24 cConversion (%) and diastereomeric ratio (dr) determined by 1H NMR
spectroscopy of the crude reaction mixture. dIsolated yield. eDetermined by chiral HPLC analysis using a Chiralpak IC column.

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ranging between 0.80 and 1.15 mmol g−1. This polymer was
characterized by IR, elemental analysis, and SEM (see
Supporting Information for details). Moreover, it was possible
to confirm the presence of the fluorine substituent at the surface
of the catalyst by EDX analysis
To characterize the behavior of this polymer further, the
swelling ability with different solvents was determined in CH2Cl2,
toluene, and water. As expected for a polystyrene derivative,
greater swelling was observed in CH2Cl2 than in water, whereas
toluene led to an average result (see Supporting Information for
details).

To evaluate the catalytic activity and recyclability of this
system, the well-established catalytic addition of aldehydes to
nitroalkenes22 was selected as the benchmark reaction for this
study. It is worth mentioning that there are no reports of 1
acting as a catalyst for this reaction. Indeed, this study constitutes the first report of its application in the enamine activation mode.
As a model substrate set, propanal and (E)-β-nitrostyrene
were selected. An initial screening of the addition reaction
catalyzed by 2 is summarized in Tables 1 and 2. Gratifyingly,
the reaction in CH2Cl2 without any additives was complete
within 11 h and gave excellent stereoselectivities (entry 1).
Consistent with literature reports on the homogeneous reaction,
the addition of organic acids increased the reaction rate23 while
maintaining the high levels of enantioselectivity (entries 2−8).
As illustrated in Table 1, relatively strong acids, such as TFA,
proved detrimental (entry 2), but several carboxylic acids
were tested with good results. Finally, it was observed that
4-nitrophenol (the weakest of the acids examined) as an
additive23a,d provided the desired product with excellent levels
of enantioselectivity (95% ee) within 1.5 h. Good levels of diastereocontrol (up to 96:4 syn/anti) were observed throughout
this optimization process.
The organocatalytic Michael addition reaction was then
optimized in batch mode using catalyst 1 to provide a data
set for comparison with the immobilized system (Table 2).
The initial reaction in CH2Cl2 reached completion in only 1 h
furnishing the desired product 9aa in quantitative yield and
with excellent levels of both diastereo- and enantioselectivity
(dr 97:3 syn/anti and ee 97%. Table 2, entry 1). Indeed, the
selectivity of the transformation was essentially unaffected
by changes in reaction medium (entries 4−7) and temperature
variations (entries 2 and 3).
Next, the influence of reaction medium on the organocatalytic
Michael reaction with resin 2 was examined using several

Table 2. Organocatalytic Michael Addition in Batch Modea

catalyst/additive
entry
(mol %)
1
2
3
4
5
6
7
8
9

10
10
10
10
10
10
10
5
5

solvent

t (h)

CH2Cl2
CH2Cl2e
CH2Cl2f
CH2Cl2 (dry)g
toluene
EtOAc
THF
CH2Cl2
toluene

1
3
0.5
1
2.5
16
24
1.5
8

convb
(yieldc)
(%)
>99
>99
>99
>99
>99
>99
93
>99
>99

(99)
(98)
(97)
(98)
(95)
(97)
(86)
(98)
(95)

drb

eed
(%)

96:4
97:3
84:16
96:4
95:5
94:6
94:6
96:4
96:4

95
95
97
96
95
92
90
95
95

a
General conditions: (E)-β-nitrostyrene (22.4 mg, 0.15 mmol), propanal (33 μL, 0.45 mmol), catalyst 1, and 4-nitrophenol in 300 μL of
solvent at room temperature. bConversion (%) and diastereomeric
ratio (dr) determined by 1H NMR spectroscopy of the crude reaction
mixture. cIsolated yield (%). dDetermined by chiral HPLC analysis.
e
Reaction temperature: 0 °C. fReaction temperature: 40 °C. gDry
solvent, stored over 4 Å molecular sieves.

Scheme 4. Scope of the Aldehyde Reaction Partnera

Table 3. Examining the Effect of Solvent on the Addition of
Propanal to β-Nitrostyrene in the Presence of 4-Nitrophenol
and Catalyst 2a

entry

solvent

t (h)

1
2
3
4
5
6

CH2Cl2
toluene
EtOAc
THF
H2O
CH2Cl2e

1.5
5
16
16
1.5
5

convb (yieldc)
100
100
99
65
100
100

(99)
(98)
(n.d.)
(n.d.)
(99)
(98)

drb

eed (%)

95:5
95:5
95:5
93:7
95:5
95:5

95
96
93
92
95
95

a
General conditions: (E)-β-nitrostyrene (22.4 mg, 0.15 mmol),
propanal (33 μL, 0.45 mmol), catalyst 2 (10 mol %), 4-nitrophenol
(10 mol %) in 300 μL of solvent at room temperature. bConversion
(%) and diastereomeric ratio (dr) determined by 1H NMR spectroscopy of the crude reaction mixture. cIsolated yield. dDetermined by
chiral HPLC analysis using a Chiralpak IC column. e5 mol % of
catalyst 2 and 5 mol % of 4-nitrophenol were used.

a
General conditions: (E)-β-nitrostyrene (22.4 mg, 0.15 mmol), aldehyde
(0.45 mmol), catalyst 2 (10 mol %), 4-nitrophenol (10 mol %) in 300 μL
of CH2Cl2 at room temperature. bIsolated yield (%). cDiastereomeric
ratio (dr) determined by 1H NMR spectroscopy of the crude reaction
mixture. dDetermined by chiral HPLC analysis.

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Scheme 5. Scope of the Nitroalkenea

aldehydes bearing longer alkyl chains gave rise to the corresponding Michael adducts in short reaction times with
excellent enantioselectivities (9aa−9fa). In the case of
3-phenylpropionaldehyde, longer reaction times were required
to drive the reaction to completion (9ga).
Variation of the nitroalkene partner was then investigated
(Scheme 5). It was generally noted that using aromatic nitro
olefins (9ab−9ag) led to short reaction times, regardless of
the nature of the substituents (<2.5 h). Nitroalkenes with
heterocyclic aromatic groups, such as the 2-furyl or 2-thienyl
systems, proved to be excellent Michael acceptors for this
reaction, providing the desired compounds in 1 h (9ah−9ai).
Employing nitro olefins with an aliphatic side chain (adduct
9aj) led to longer reaction times (5.5 h), and although the dr
slightly decreased, high enantioselectivities were recorded
(97%). The characteristically high yields obtained throughout
(95−99%) are due to the simplified isolation procedure, made
possible by the immobilization of the catalyst: filtration, washing
with 0.1 M NaOH to remove the additive and evaporation
rendered the pure products. Michael adduct 9ag is the sole
exception to this, in which the phenol-containing product had to
be further purified by flash chromatography on silica gel.
To further establish the scope and limitations of the present
methodology, catalytic reactions of more challenging substrates
mediated by 2 were also examined (Scheme 6). To this end, we
Scheme 6. Scope of α- and β-Branched Aldehydesa

a
General conditions: nitroalkene (0.15 mmol), propanal (33 μL,
0.45 mmol), catalyst 2 (10 mol %), 4-nitrophenol (10 mol %) in 300 μL
of CH2Cl2 at room temperature. bIsolated yield (%). cDiastereomeric
ratio (dr) determined by 1H NMR spectroscopy of the crude reaction
mixture. dDetermined by chiral HPLC analysis (GC for 9ag).

Conditions A: nitroalkene (0.15 mmol), isovaleraldehyde (45 μL,
0.45 mmol), catalyst 2 (10 mol %), 4-nitrophenol (10 mol %) in
300 μL of CH2Cl2 at room temperature. Conditions B: 20 mol % of
4-nitrophenol. Conditions C: 20 mol % of 2 and 20 mol % PhCOOH.
Conditions D (for α-branched aldehydes): nitroalkene (0.21 mmol),
isobutyraldehyde (96 μL, 1.05 mmol), catalyst 2 (30 mol %),
4-nitrophenol (60 mol %) in 420 μL of CH2Cl2 at room temperature.
b
Isolated yield (%). cDiastereomeric ratio (dr) determined by
1
H NMR spectroscopy of the crude reaction mixture. dDetermined
by chiral HPLC analysis.
a

solvents while retaining 4-nitrophenol as an additive. In all cases,
excellent diastereo- and enantioselectivities were recorded (up
to 95:5 and 96%, respectively; see Table 3). Of the organic
solvents investigated, CH2Cl2 proved to be beneficial in terms
of reaction rate, leading to full conversions in less than 1.5 h
(Table 3, entry 1). Use of toluene also led to efficient reactions
(5 h, entry 2), whereas EtOAc and THF resulted in more
sluggish processes (entries 3 and 4). To our delight, the reaction
worked well in water (entry 5), affording the desired compound
in only 1.5 h and with enantioselectivities that were comparable
to those in CH2Cl2, irrespective of the low swelling ability of 2
in this solvent. Finally, lowering the catalyst loading to only
5 mol % was well tolerated, and the reaction reached completion
in 5 h (entry 6).
An important conclusion of these studies is that immobilization of 1 (in polymer 2) does not lead to any decrease in
catalytic performance under the optimized set of reaction
conditions. This being secured, the scope of the reaction was
next studied. Initially, variation of the donor quickly revealed that
a wide variety of aldehydes reacted smoothly with β-nitrostyrene
(Scheme 4). This result sharply contrasts with a similar catalytic
resin previously prepared in our group,7a which was extremely
selective in the case of propanal.25 Using catalyst 2, linear

started with the β-branched donor isovaleraldehyde. Although
the reaction proved to be sluggish, full conversions resulting
in the formation of 9ha were observed after 20 h using the
standard conditions (10 mol % 2, 10 mol % 4-nitrophenol).
Whereas doubling the amount of additive had a remarkable
effect on the reaction rate, the optimal results were obtained
with 20 mol % catalyst loading in the presence of 20 mol %
benzoic acid. Isovaleraldehyde was also found to react smoothly
with both 2-bromo- and 4-bromonitrostyrene. After fine-tuning
the reaction conditions, the desired products 9hb and 9hc were
obtained in quantitative yield after simple extraction with 0.1 M
NaOH or saturated NaHCO3 without additional purification.
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As for α-branched aldehydes, it was found that isobutyraldehyde can be employed as the Michael donor with nitrostyrene
and 4-bromonitrostyrene, giving rise to products 9ia and 9ib,
respectively, which bear quaternary centers. Despite the severe
steric hindrance of the corresponding trisubstituted enamine,
full conversions were achieved after 28 h using 30 mol % catalyst

and 60 mol % of 4-nitrophenol. Extraction with 0.1 M NaOH
gave the Michael adducts in good yields, but with moderate
enantioselectivities (66 and 72% ee, respectively). Unfortunately, trisubstituted nitroalkenes such as α-methylnitrostyrene
or β-ethoxycarbonylnitrostyrene proved unreactive, even after
42 h with 20 mol % catalyst and 4-nitrophenol.
Having established the generality of the reaction, it was
essential to demonstrate the stability of the catalytic resin 2
upon reuse. To that end, a standard reaction was successively
run in the presence of 4-nitrophenol, and after each cycle, the
mixture was simply filtered off and washed to remove all of the
soluble materials. The remaining material 2 was then dried and
used in the subsequent cycle. The filtrate was extracted with
0.1 M NaOH, and provided pure compound when full conversions
were achieved. We were pleased to find that this polymer
remained active for at least eight runs (Table 4), although some
progressive loss of activity was observed in the last cycles. Despite
this, even in the eighth run, the desired Michael adduct could
be obtained in 68% isolated yield after 24 h. Importantly, the
stereoselectivity remained constant throughout the whole process.
As outlined in the introduction, the major contributing factor
to the deactivation of the Jørgensen−Hayashi catalyst (i.e.,
desilylation) is no longer a risk owing to the installation of
the C−F unit. Consequently, the slow decay observed in
reaction efficiency can be attributed to several factors, including
mechanical degradation of the polymer or irreversible oxidation
of reaction intermediates, as demonstrated by Zlotin et al.26 On
the basis of these precedents, a series of recycling experiments
were carried out under glovebox conditions to study the effect of
oxygen exclusion on catalyst stability. It was quickly noted that,
after only a few reaction cycles in the glovebox, the catalytic
activity decreased; however, performing another run with the
same immobilized catalyst outside the glovebox immediately
led to improved performance. This suggests that the absence of
water results in sluggish reactions. Three additional recycling
experiments were carried out to gain further insight into the
factors responsible for catalyst deactivation: performing the
reaction under a nitrogen atmosphere (oxygen exclusion with
0.5 and 2.0 equiv of water) and under air with 2.0 equiv of
water; in these experiments, dry CH2Cl2 was used. The results
indicate that trace amounts of water are beneficial for catalyst
turnover, whereas oxygen is detrimental (Table 5).
These conditions that have allowed catalytic activity to be
retained for longer periods of time were then translated into a

Table 4. Recycling Experimentsa

run

t (h)

convb (%)

yieldc (%)

1
2
3
4
5
6
7
8

1.5
2
2.5
4
6
12
24
24

100
100
100
100
100
84
100
70

99
98
97
98
97
83
97
68

a

General conditions: (E)-β-nitrostyrene (41.0 mg, 0.275 mmol), propanal (60 μL, 0.83 mmol), catalyst 2 (10 mol %), additive (10 mol %)
in 550 μL of CH2Cl2 at room temperature. bConversion (%) and
diastereomeric ratio (dr) determined by 1H NMR spectroscopy of the
crude reaction mixture. cIsolated yield (%).

Table 5. Recycling Experiments in the Presence of Watera

run

t (h)

convb (%) (under
N2, 0.5 equiv H2O)

1
2
3

1.5
2
2

convb (%) (under convb (%) (under
N2, 2.0 equiv H2O) air, 2.0 equiv H2O)

100
94
79

100
96
81

93
89
80

a
General procedure: (E)-β-nitrostyrene (41.0 mg, 0.275 mmol), propanal (60 μL, 0.83 mmol), catalyst 2 (10 mol %), additive (10 mol %)
in 550 μL of CH2Cl2 at room temperature. bConversion (%) and
diastereomeric ratio (dr) determined by 1H NMR spectroscopy of the
crude reaction mixture. cDetermined by chiral HPLC analysis.

Figure 1. Continuous flow setup.
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continuous flow process.27 An overview of the setup used,
in which 500 mg of resin 2 was packed in a glass column (1 cm
diameter), is shown in Figure 1.
Upstream of the column, two channels were connected to a
three-way valve that determined which one would feed the
catalytic column. Dry, degassed CH2Cl2 was passed through the
first channel, its purpose being to swell the resin prior to the
reaction and also to rinse any remaining organic material from
the column when the reagents have passed through. The
second channel was fed with a solution of 4-bromonitrostyrene,
propanal, and 4-nitrophenol in dry, degassed CH2Cl2 with
2.0 equiv of water.
Downstream, a back-pressure regulator was mounted to avoid
bubble formation with volatile solvents such as CH2Cl2, and
then further, a third pump with 0.1 M NaOH was assembled to
allow for the aqueous workup and removal of 4-nitrophenol.
The biphasic mixture was then separated in-line using a Zaiput
liquid−liquid separator, which gave rise to a yellow aqueous
phase (due to the presence of 4-nitrophenolate) and an organic
phase with the desired Michael adduct and excess aldehyde (plus
remaining nitrostyrene if the conversions were not complete). In
most cases, simply evaporating the organic outstream furnished
pure product where no further purification was necessary.
Using this setup, full conversions were obtained during the
first 10 h running the flow process at 100 μL min−1 (Figure 2).

Figure 2. Continuous flow process for polymer-supported catalyst in
the formation of 9ab.

Figure 3. Continuous flow process with polymer-supported catalyst 2 applied to the preparation of a compound library.
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yields were obtained in both reactions for the two Michael
adducts tested.

Over the following 3 h, a slight decrease in conversion was
observed, but remained above 97%. Overall, the desired Michael
adduct was obtained in 95% yield, and the effective catalyst
loading for the whole operation period was determined to be
1.6%; this corresponds to an overall turnover number (TON)
slightly above 60. The turnover frequency (TOF) remained
essentially constant at 4.6 h−1 over the considered 13 h operation
period.
The importance of correctly handling the packed catalyst
columns is illustrated by the following fact: when a still fully
active column used in a flow experiment was dried, stored in
contact with the atmosphere, and then attempted to recycle
after reswelling, it was found that catalytic activity was lost to a
high degree. This behavior can be easily understood when the
conditions of use of the catalytic column in-flow are considered.
Because an excess of aldehyde reactant is employed, when flow
is arrested, most of the active sites in the column will be in the
active, enamine form. If the column is then dried and allowed
to be in contact with air, oxidation of the labile enamine units26
will lead to irreversible deactivation. As shown below, simply
keeping the catalytic column wet with dichloromethane when
not in use efficiently suppresses this problem.
The possibility of using this continuous flow setup to
generate a library of compounds was then explored. With a new
batch of catalyst, a similar flow process was run with different
reagent combinations. Each pair of starting materials was
circulated through the system for 30 min, rinsing with solvent
for 1 h afterward. At the end of each day and to avoid catalyst
deactivation, CH2Cl2 was passed at a rate of 25 μL min−1 before
continuing the flow experiments the next day. Eight different
combinations were run the first day, and five more, the second.
On the third day, the first three examples were rerun for 4 h
each, thus demonstrating that the catalytic activity was retained
after several changes of substrates and an extended operation
time. The compounds synthesized and the results obtained
during the generation of this library are summarized in Figure 3.
In total, 16 consecutive runs were carried out, with high yields
and stereoselectivities observed in all cases. Remarkably, the last
run produced the desired Michael adduct in 90% conversion,
thus demonstrating the robustness of the catalyst. The overall
TON for this set of experiments was 72.
To demonstrate the synthetic utility of the process, two
different Michael adducts were further derivatized to the
corresponding 3,4-disubstituted pyrrolidines 10 by a one-pot
operation involving reduction of the nitro group and reductive
amination of the corresponding amino aldehyde28 (Scheme 7).
The process was carried out on a gram scale, and the corresponding products were transformed into the N-tosylated
derivatives 11 before determining the optical purity. Excellent

3. CONCLUSIONS
In summary, an immobilized analog of the fluorinated aminocatalyst 1 has been developed and showcased in a model
transformation. Key to the success of this approach has been
a polymer design that does not affect the active site in 1 and,
hence, maintains its catalytic performance. The catalytic resin 2
shows great potential for the Michael addition of aldehydes to
nitroalkenes in batch and flow: this is the first example of this
catalytic system in enamine activation. Catalyst deactivation
studies have delineated the conditions responsible for degradation, thus allowing the process to be streamlined to extend the
lifespan of the catalyst. Applying this resin in a carefully designed
continuous flow setup has allowed for the facile isolation of the
desired Michael adducts without chromatographic purification.
This catalyst system has proved to be extremely active, both in
experiments that were run for extended periods of time and in
the preparation of a complex library of analogs. Importantly,
the immobilized system shows activity comparable with that of
the batch process. This, together with the stability profile of this
novel polymer-supported catalyst, is a powerful endorsement for
the use of flow chemistry as an enabling synthesis technology.
Application of this catalytic resin to other synthetically valuable
transformations is in progress and will be reported in due course.

■

ASSOCIATED CONTENT

S
* Supporting Information

The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.5b01746.
Experimental procedures, compound and polymer
characterization, NMR spectra and HPLC chromatograms (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: ryan.gilmour@uni-muenster.de.
*E-mail: mapericas@iciq.es.
Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS
Financial support from the Institute of Chemical Research of
Catalonia (ICIQ) Foundation, MINECO (Grant CTQ201238594-C02-01), and DEC Generalitat de Catalunya (Grant
2014SGR827) is gratefully acknowledged. We also thank
MINECO for support through Severo Ochoa Excellence
Accreditation 2014−2018 (SEV-2013-0319). C.R.-E. thanks
the AGAUR (Generalitat de Catalunya) for a Beatriu de Pinós
B fellowship. R.G. and I.G.M. thank the WWU Münster, and
the Deutsche Forschungsgemeinschaft (SFB 858 and DFG
EXC 1003 “Cells in Motion − Cluster of Excellence”, Münster)
for generous financial support.

Scheme 7. Derivatization of the Adducts 9aa and 9ab to
Pyrrolidines 10

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