"This is the peer reviewed version of the following article: Catalytic Enantioselective Flow Processes with Solid-Supported Chiral Catalysts,
which has been published in final form at https://doi.org/10.1002/tcr.201800097. This article may be used for non-commercial purposes
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Catalytic Enantioselective Flow Processes with Solid-Supported
Chiral Catalysts
Carles Rodríguez-Escrich*[a] and Miquel A. Pericàs*[a],[b]
Abstract: Sustainability concerns are the wind in the sails for the
development of novel, more selective catalytic processes. Hence,
chiral catalysts play a crucial role in the green production of
enantioenriched compounds. To further increase the green profile
of this approach, the use of solid-supported catalytic species is
appealing due to the reduced generation of waste, as well as the
possibility of reusing the precious catalyst. Even more attractive
is the implementation of flow processes based on these
immobilized catalysts, a flexible strategy that allows to generate
from milli- to multi-gram amounts of chiral product with a reduced
footprint set-up. Herein, we will present the efforts devoted in our
laboratory towards the immobilization of chiral catalysts and their
use in single-pass, highly enantioselective, flow processes.
Proline, diarylprolinols, other aminocatalysts, squaramides,
thioureas, phosphoric acids and even chiral ligands and metalbased catalysts constitute our current toolkit of supported species
for enantioselective catalysis.

1. Introduction
Sustainability is a transversal concept that stems from the notion
that resources are finite and the human footprint in the planet has
to be as faint as possible.[1] Albeit it was industrial development
that generated the current scenario, we must be aware that
technological solutions represent the best way out of this spiraling
situation. Countless initiatives are proposing ways to minimize the
impact of human activity over Nature. Chemistry, despite its
perceived association with pollution and poisoning of natural
resources, is undoubtedly going to play a key role in fighting
climate change and preserving the environment. The big question
that arises is: how do we revert this situation in a global context
that involves a growing demand of fine chemicals for technical,
agricultural or health-related applications? Our dependence on
the end-products of the chemical industry is more important than
society thinks, so the solution has to come from changing the way
these are produced. Sustainable chemistry is the attempt to adapt
[a]

[b]

Dr. Carles Rodríguez-Escrich, Prof. Dr. Miquel A. Pericàs.
Institute of Chemical Research of Catalonia (ICIQ)
The Barcelona Institute of Science and Technology (BIST)
Avinguda Països Catalans 16, 43007, Tarragona (Spain)
Fax: (+34) 977-920-243
E-mail: mapericas@iciq.es
Prof. Dr. Miquel A. Pericàs, Departament de Química Orgànica,
Universitat de Barcelona, 08080 Barcelona (Spain)

the chemical practice to this idea. The answer to such a complex,
multi-faceted problem cannot be a straightforward one; along
these lines, Anastas and Warner introduced the 12 principles of
Green Chemistry,[2] a set of basic guidelines to light the way for a
sustainable evolution of chemical practice.
The implementation of catalytic processes usually allows working
under mild reaction conditions, using less elaborated materials
and generating less waste. Consequently, it is perfectly aligned
with many of the above-mentioned 12 principles. The demand of
enantiopure compounds is also growing as a consequence of
their use in advanced materials and the increasingly restrictive
pharmaceutical regulations.[3] In this scenario, the advantages of
developing new catalytic enantioselective transformations[4]
become more evident, as the alternatives are hampered by
substrate availability (chiral pool approach) or excessive
substrate specificity (biocatalysis). The most important drawback
of asymmetric catalysis is perhaps the cost of the chiral species
required, which is one of the main bottlenecks for its full
deployment in industrial environments. Upon immobilization,
chiral catalysts can be easily recovered after the reaction is
complete, which opens the possibility of reusing them. The
efficiency of this approach is therefore subject to the robustness
of the catalytically active species: the less off-cycle reactions that
can kill the catalyst, the more advantageous this immobilization
approach will be.[5] The classical way to reuse these solidsupported catalysts has been lately challenged by an alternative
method: the use of flow techniques to carry out what is nothing
more than an in-line recycling.[6] The benefits associated to this
change of regime may be less than obvious to those not familiar
with the field. However, the implementation of flow processes with
immobilized catalysts entails savings in terms of solvent required
to separate the catalyst, the direct translation of reaction
conditions for the scale up and the possibility to produce big
amounts of product with a reduced reactor volume. In two words,
the process intensification[7] inherent to this approach makes it a
fundamental asset of green chemistry. In this context, it is
important to mention that a recent report by the US Government
Accountability Office (GAO) concluded that three categories of
technology can make chemical production more sustainable:[8]
catalysts, which reduce the energy needed for chemical
processes; solvents that are derived from renewable materials or
are less hazardous than those currently employed; and
continuous processing rather than batch processing.

The design of a suitable immobilization strategy is crucial to obtain
a heterogenized catalyst that replicates the behavior of its
homogeneous counterpart. In this regard, two premises are to be
considered for an optimal outcome: (a) ensuring enough distance
between the active site and the solid support and (b) choosing a
support material, a linker and a spacer that do not interfere with
the catalytic process. A few years ago, we identified the coppercatalyzed azide-alkyne cycloaddition[9] (CuAAC hereafter) as an
extremely valuable tool for this purpose.[10] Indeed, this has often
been our first choice to immobilize chiral catalysts because it is a
clean, orthogonal reaction that takes place under mild reaction
conditions and can be followed by IR spectroscopy even on the
resin beads. However, it will become evident that in other cases
(especially with catalysts bearing H-bond donors or Brønsted
acids) the triazole plays a negative role and is best avoided.
This manuscript is divided in three main sections: first, a brief
historical discussion will be given, followed by our approaches to
immobilized organocatalysts suitable for operation in flow. Finally,
a few examples of supported metal catalysts will also be
discussed and compared to their metal-free counterparts.

Carles Rodríguez-Escrich (Barcelona, 1980)
obtained his PhD from the University of
Barcelona in 2008, after completing the total
synthesis of Amphidinolide X under the
supervision of Profs. Vilarrasa and Urpí.
Afterwards,

he

moved

to

the

Pericàs

laboratory at the ICIQ, Tarragona to work in
polystyrene-supported (organo)catalysts and
flow chemistry. He then spent two years
(2010-2012) in the group of Prof. Karl Anker
Jørgensen at the University of Aarhus,
developing new organocatalytic enantioselective methods. In September
2012 he returned to the ICIQ where he is currently group coordinator of the
Pericàs laboratory.

Miquel A. Pericàs (Ciutat de Mallorca, 1951)
obtained his doctorate in 1979 under the
guidance of Prof. Fèlix Serratosa at the

2. Precedents and practical considerations
2.1. Early years and usual suspects
The pioneering work of Robert B. Merrifield on solid-phase
organic synthesis[11] established a strategy that bisected
homogeneous and heterogeneous chemistry, combining the
advantages of both. Based on this premise, some authors
decided to explore the possibility of anchoring a catalyst onto a
solid support to establish whether the resulting catalytic material
could be reused.[5a, 5g] Later on, the interest in obtaining
enantiopure compounds spurred the development of supported
chiral catalysts, which mainly involved transition metal complexes.
The first example of a metal-free, supported chiral catalyst used
in flow was reported in 1996, when Itsuno an co-workers used a
boron-based Lewis acid to promote the Diels–Alder addition of
methacrolein to cyclopentadiene.[12] However, the first example of
what we would nowadays label as flow organocatalysis came by
Lectka et al., who reported a few examples of a supported
Cinchona alkaloid that was able to mediate the reaction between
an allene and an imine to produce b-lactams in good yields and
excellent enantioselectivities.[13]
The conceptualization of organocatalysis that followed the
ground-breaking works of List, Lerner and Barbas on enamine
catalysis[14] and MacMillan on iminium ion catalysis[15] paved the
way for the extension of these simple (yet hitherto elusive)
concepts to hundreds of related reactions.[16] This fever also
arrived to the main players in the field of solid-supported catalysts,
allured by the fact that these species would not suffer the problem
of metal leaching.[5c-e, 5i, 17]
Nevertheless, the implementation of flow processes based on this
solid-supported organocatalysts faces a significant challenge: in
most cases, the batch reaction requires high catalyst loadings and
long reaction times, which hampers the transition to flow in a
single pass experiment. Thus, identifying a suitable
heterogenized organocatalyst that works with favorable kinetics is
often the bottleneck in this endeavor. Among the several authors
that have been successful in this task it is worth highlighting the
groups of Benaglia/Puglisi,[18] Massi,[19] Fülop,[20] Sóos[21] or
Wennemers.[22]

Universitat de Barcelona. After postdoctoral
studies at the Spanish research council

2.2. Flexibility of the flow strategy

(CSIC) with Prof. Francesc Camps, he joined
the Universitat de Barcelona as Assistant
Professor in 1980 and was promoted to Full
Professor in 1991. In June 2000, he was
appointed to found the Institute of Chemical
Research of Catalonia (ICIQ) where he now
serves as Director and Group Leader. His major research interest is focused
on asymmetric catalysis with immobilized species for the development of

An advantage of using solid-supported catalysts in flow is the
flexibility of this approach. Indeed, whereas in batch the scale
determines the set-up to be used, with a packed bed reactor the
production of a few milligrams or multi-gram amounts of
compound can be easily carried out with the same set-up, simply
extending the operation time. This flexibility also enables the
possibility to generate libraries of enantioenriched analogues with

flow processes allowing the continuous production of enantiomerically pure
compounds.

the same set-up. Sequentially pumping different combinations of
starting materials and rinsing for a given time before the next run
one can achieve compound libraries in a straightforward manner.
In comparison to the classical approach, where different products
are prepared in different reaction flasks (spatial separation), flow
processes allow to use a small footprint set-up to do this (temporal

separation). Indeed, many of the examples summarized hereafter
entail a long flow experiment (to prove robustness and scalability)
as well as sequential experiments where libraries of analogues
are prepared.

LIQUID-LIQUID SEPARATOR. A piece of equipment that
enables the separation of a biphasic mixture in flow regime by
virtue of their different polarities. It is a crucial gadget to perform
in-line work-ups.

2.3. What we speak about when we speak about flow

RESIDENCE TIME. For a given set-up, operated at a given
overall flow rate, it is the time the reactants are inside the column,
in contact with the catalyst. The interesting parameter is the
residence time for complete conversion in single-pass operation.
Residence time is not equivalent to reaction time in batch
operation, although both parameters provide an indication of the
efficiency of the catalyst under a given set of reaction conditions.

Those not familiar with flow techniques might find the jargon
confusing,[23] but the underlying concepts are in general so simple
that it is worth taking some time to get acquainted with the devices
most commonly used. A brief list, that must be taken as a short
introduction mostly related to our own work, rather than a
comprehensive one, is given below. Given the importance of
pictorial representations, a possible reaction set-up with the
symbols of all the components is also provided (Figure 1).
pump
Reagent A
Y-mixer
(with valves)
Reagent B

liquid-liquid
coil separator
aqueous
waste

aqueous
quench

catalyst

L-L
Product C

packed
bed
reactor

T-mixer
(without
valves)

back-pressure
regulator (BPR)

ACCUMULATED TON vs. YIELD. In flow operation the amount
of product generated in a given catalytic experiment is best
expressed by the accumulated TON rather than by yield (a
parameter best suited for batch operation). In the case of a nondeactivating catalyst, accumulated TON is simply given by the
product of catalyst TOF by operation time. Then, the molar
amount of catalyst in the packed bed reactor provides direct
information on the expected production in a given period of
operation.

3. Immobilized Organocatalysts for Work in
Flow

Figure 1. Schematic representation of a flow set-up with some of the devices.

3.1. Proline-based
PUMPS. Despite the examples by Lectka, in which the flow was
forced by pressure[13] the vast majority of flow processes require
the use of pumps, which ensures a steady flow rate. There are
several choices, but we tend to use regular syringe pumps or
HPLC-like piston pumps.
TUBING. Most commonly PTFE tubing of 1/16” is used. For
photochemical applications PFA tubing has to be employed.
PACKED BED REACTOR. This is simply a way to refer to a
cylindrical piece of labware filled with the resin that has been
swollen with solvent. This can be made of any material, PTFE,
glass or steel. Our most common choice is a 1 cm Ø glass column,
due to the fact that we do not usually require very high pressures.
CHECK VALVE. This gadget ensures that flow is unidirectional,
avoiding back flow situations that can, for instance, damage the
catalyst inside the packed bed reactor.

The proline-catalyzed direct aldol reaction was a big breakthrough
in asymmetric catalysis: suddenly, a reaction that required preformation of an enolate equivalent and most likely a chiral
auxiliary, could be carried out with proline in exceedingly high
enantioselectivities. The rationalization behind the work of List,
Lerner and Barbas,[14] that finally gave rise to the Houk-List
model,[24] established a solid yet simple theoretical base that
could be translated to many other reaction partners. Given our
previous experience in solid-supported ligands for organozinc
addition to aldehydes,[25] we were curious to see how this concept
would embrace organocatalysis. Thus, we anchored a
hydroxyproline derivative onto a Merrifield-type resin using three
different strategies: direct substitution using the free hydroxy
group, or the two possible combinations of azide and alkyne via
CuAAC (1–3, Figure 2).[26]

N

N

N

O
O

O

N

N
N

BACK-PRESSURE REGULATOR. Commonly abbreviated as
BPR, this is a device that allows to build some pressure on every
part of the system that is found upstream. This allows working with
gases and avoiding bubble formation with low boiling point
solvents. It also enables stabilizing the flow rate of HPLC-type
pumps, that are usually designed to work at high pressures.

Figure 2. Early polystyrene-supported proline derivatives developed in our
group.

FLOW IR. A device, with its associated software, that allows to
obtain real-time information of the system by recording periodical
samples of the flow stream without having to stop or open the
system.

Not surprisingly, the simplest approach (1) rendered a system that
was too close to the polymer backbone, which significantly
affected the catalytic activity. On the other hand, the two

N
H

COOH
1

N
H

COOH
2

N
H

COOH
3

alternative triazole-based supported catalysts showed a good
catalytic profile. To our surprise, 3 turned out to swell in water, a
pretty uncommon feature for a polystyrene resin. Calculations
point to a hydrogen bond network between the triazole and the
carboxylate as the responsible for this unexpected behavior.[26b]
After testing the performance of 2 and 3 in the aldol reaction in
batch, we turned our attention to other electrophiles. In particular,
imines proved very convenient and the resulting Mannich adducts
were produced in very good results, both with aldehydes and
ketones as donors. The fast reaction rates prompted us to
consider the implementation of a flow experiment (Figure 3). To
this end, we packed 2 in a simple ¼” PTFE tube and pumped a
mixture of both reagents at 0.2 mL min–1. Two separate
experiments provided the corresponding products with very good
results, replicating the batch process but with higher
productivities.[27]

O
+

Cat. 2: 1.0 g, 0.46 mmol
Flow rate: 0.2 mL/min
Residence time: 6 min

NPMP
OEt
O

R
N

N

R

N
O
2

NHPMP
OEt

O

cat. 2

N
H

COOH

O

R = i-Pr
R = Me
5.5 h
5.5 h
90%
76%
dr > 97:3
dr > 97:3
99% ee
99% ee
Prod.* 3.1 Prod.* 2.6
* in mmol mmolcat-1 h-1

Figure 3. Polystyrene-supported proline for the Mannich reaction in flow.

Not long before, Seeberger had published a related paper dealing
with the homogeneous, proline-catalyzed asymmetric aldol
reaction in a microreactor. In that case, however, the catalyst
loading was set from the beginning, whereas using supported
catalysts the TON is a function of time: the longer the system is
running, the lower the overall catalyst loading and the higher the
accumulated TON.[28] The conclusion drawn from comparing both
strategies is clear: to compensate for the cost of immobilization,
supported catalysts must be very robust and allow for prolonged
operation time.
Encouraged by these results, we decided to explore the generality
of the concept, so we moved to the a-oxidation of aldehydes using
nitrosobenzene[29] as the electrophile. A related packed bed
reactor filled with 2[30] turned out to be very active and in 5 min
residence time the desired products were obtained in good
conversions[31] (Figure 4). However, the practicality of this process
was hampered by a side reaction of the catalyst that led to
deactivation of the resin.

Cat. 2: 300 mg, 0.144 mmol
Flow rate: 0.24 mL/min
Residence time: 5 min

O
R

cat. 2

Ph

O

R
ONHPh

O
N

N

N

R = Et, i-Pr, n-Bu, 9-decenyl, n-Pr
5 h operation each substrate
94-96% ee
Prod. 6.5-2.5 mmol mmolcat-1 h-1

N
O
2

N
H

COOH

Figure 4. Immobilized proline for the flow aminoxylation of aldehydes.

Whereas aldehydes performed very well in the example of flow
aldol reaction described above,[32] ketones could be used in batch
but reacted too slow to be adapted to flow. Accordingly, we set
out to find a system that would be able to admit ketones as the
donor component in the aldol reaction. To increase the reaction
rate, an analogue of 3 with a longer linker was prepared; a higher
degree of cross-linking was also used to prevent possible
mechanical degradation of the resin. The resulting catalyst 4
proved competent in the aldol addition of cyclohexanone to
benzaldehydes. Due to its resemblance with 3, we assessed the
impact of water as the solvent, finding that a DMF/H2O mixture
was the ideal choice.
It has been proven that proline has some tendency to
decarboxylate in water-free environments.[33] Thus, we envisaged
that these reaction conditions would give rise to a flow experiment
that would remain active for a long time. The sluggish kinetics
imposed a rather slow flow rate of 25 µL min–1, but with only 600
mg of 4 the continuous production of the aldol derivative was
running for 45 h, with good conversions and 97% ee, which
remained constant for the whole process.[34] With the same
system, four different aldehydes were reacted in a sequential
manner, replicating the enantioselectivities recorded in batch
(Figure 5).

O

Cat. 4: 600 mg, 0.32 mmol
Flow rate: 25 µL/min
Residence time: 26 min
O

O

OH

cat. 4

+
EWG

O
N

N
N

4

EWG

EWG = NO2
45 h operation
19.54 mmol
96:4 dr, 97% ee
Prod. 1.36
mmol mmolcat-1 h-1

N
H

EWG = CN, COOMe, NO2, CF3
8 h operation each
3.15-5.34 mmol
97:3 dr, 95-98% ee
Prod. 1.23-2.01
mmol mmolcat-1 h-1

COOH

Figure 5. Continuous aldol reaction of ketones and aldehydes.

3.2. Diarylprolinol Derivatives

O

Cat. 6: 300 mg, 13 mmol
Flow rate: 0.15 mL/min
cooling
Residence time: 6 min
bath at 0 ºC
O
Me
cat. 6

Me

Formally related to proline, but with their own reactivity profile, are
the diarylprolinol organocatalysts[35] developed by the groups of
Jørgensen[36] and Hayashi.[37] Whereas proline is mainly restricted
to the enamine activation mode, diarylprolinols are also
competent in the iminium ion pathway, which makes them ideal
candidates for cascade reactions:[38] one must bear in mind that
the Michael addition to an a,b-unsaturated iminium ion gives rise
to an enamine, that may continue to react in the presence of a
proper electrophile.
These appealing features encouraged us to study the
heterogenization of a Jørgensen-Hayashi diarylprolinol catalyst
onto polystyrene, as well as its catalytic behavior. The first
examples involved the reaction between Michael addition of
aldehyde to nitroalkenes in batch promoted by 5.[39]
Later on, we studied the cascade process between enals and
oxodiesters that produced cyclohexanols after a reductive
treatment.[40] The fast reactions observed in batch called for the
implementation of a flow process, that is depicted in Figure 6.[41]

R

CHO PhCOOH
O
MeOOC
COOMe
N

N

Cat. 5: 900 mg, 2.38 mmol
Flow rate: 0.12 mL/min
(collected at -40 ºC)
Residence time: 10 min
COOMe

cat. 5
R

N
O
5

N
H

Ph
Ph
OTMS

R = (MeO)C6H4
72 h operation
27.0 mmol
97% ee
R
Prod. 0.16
mmol mmolcat-1 h-1

O
COOMe
NaBH4
COOMe
OH
COOMe

Figure 6. Supported diarylprolinol silyl ether for a flow cascade reaction.

In this case, a final reduction step was necessary to install the full
array of 4 consecutive stereocentres. Owing to the inconvenience
of working with NaBH4 in flow,[42] this step was carried out in batch,
after collecting the outstream over a cooling bath.
Due to concerns regarding the stability of the labile TMS group on
the oxygen, and with the aim of increasing the robustness of the
supported diarylprolinol, alternative silyl groups were
considered.[43] Catalyst 6, bearing a tert-butyldimethylsilyl (TBS)
group showed a good compromise between reactivity,
enantioselectivity and stability, so it was applied to the aamination of aldehydes with azodicarboxylates.[44] In batch, this
reaction gave problems due to the addition of catalyst 6 onto the
azodicarboxylate, which could be solved by slow addition of the
electrophile. In flow, however, this technical solution was not
possible, so we had to increase the concentration of aldehyde (5fold excess) to favour the enamine formation pathway over the
addition to the azodicarboxylate. With this premise, the flow
experiment was carried out at 0.15 mL min–1 for a total operation
time of 8 h, the residence time being as low as 6 min[45] (Figure 7).

AcOH

Cbz

N

N

N

N

Cbz

Cbz
8 h operation
>95% conv. for 6 h
87% conv. at 8 h
83-91% ee

N
O
6

NHCbz
NaBH4
Me

HO
Cbz

N
H

N

N

NHCbz

Ph
Ph
OTBS

Figure 7. a-Amination in flow promoted by an immobilized diarylprolinol catalyst.

While not strictly speaking a diarylprolinol, the fluorinated
analogue known as the Gilmour catalyst[46] has proven an
interesting alternative to the Jørgensen-Hayashi type catalysts.
On our quest for more stable supported aminocatalysts, we
reasoned that this would make an ideal candidate due to the
sturdy C–F bond. This time, instead of using a commercially
available Merrifield-type resin, we evaluated an alternative that
consisted of preparing a vinyl-substituted precursor and
copolymerizing it with styrene (no DVB was required, as the
monomer played the role of the cross-linker as well). The resulting
immobilized catalyst 7 was tested in the Michael addition of
aldehydes to nitroalkenes[47] in a project carried out in
collaboration with the group of Gilmour. After finding the optimal
reaction conditions, which involved the use of 4-nitrophenol as an
acidic additive, we found that trace amounts of water were
beneficial, while oxygen contributed to catalyst degradation. With
this knowledge, we focused on the batch-to-flow transition, that
was carried out with 500 mg of 7 and a flow rate of 0.1 mL min–1.
A long experiment spanning 13 h proved the robustness of 7, that
recorded full conversion for the first 10 h, slightly decaying after
that (Figure 8).
Another benefit of working in flow is the possibility of carrying out
in-line work-up procedures. In this case, the 4-nitrophenol additive
was efficiently removed by adding an extra pump with an aqueous
NaOH solution downstream of the column. In the resulting plug
flow situation, with tiny aqueous and organic phases successively
passing through the coil, the base deprotonated 4-nitrophenol,
giving the aqueous layer a distinctive yellow colour. To separate
this mixture, that traditionally would have been poured onto an
extraction funnel and decanted, a liquid-liquid separator was
employed (vide supra). This small device efficiently removed the
aqueous stream, leaving the organic one so clean that if the
aldehyde (only reagent in excess) was volatile, simple
evaporation of the mixture furnished the pure product.

Cat. 7: 500 mg, 0.58 mmol
Flow rate: 0.1 mL/min
O
NO2
R2
R1
O2N
OH

N
H

F

7

NaOH
(0.1 M)

cat. 7

aqueous
waste

N

N
H

R2
NO2

13 examples @ 30 min
3 examples @ 4 h
18.5 h operation
60-99% yield
94-97% ee

Figure 8. A co-polymerized version of the Gilmour catalyst for the continuous
Michael addition of aldehydes to nitroalkenes.

To further prove the advantages of the flow system, the same setup was used to prepare a library of 13 different analogues, by
sequentially pumping the corresponding reagent combination for
30 minutes and rinsing for 1 h with solvent. Since the packed bed
reactor was still fully active after this, larger amounts of three of
the substrates were prepared in 4-h experiments. This is a good
example of the flexibility of flow processes: with the same set-up
one can easily change the scale of the reaction without having to
bother about technical issues.
Another point worth emphasizing is that, in line with the previous
finding that oxygen was detrimental for the reaction, we found that
drying the column between runs severely affected its reusability.
Therefore, during the three days it took to run the sequential
generation of the library, the flow was not stopped, but kept
overnight under a stream of CH2Cl2 (25 µL min–1).

OTBS

N
H

Ph
Ph
OTBS

N
H

9R (resin)
9M (monolith)

OTBS
10R (resin)
10M (monolith)

Figure 9. Immobilized catalysts prepared for the asymmetric cyclopropanation.

Catalysts 8–10 were thus tested in batch in the above-mentioned
cyclopropanation reaction; the results show that the parameters
under study significantly affect the performance of the resin. The
most successful ones, resin 8R and monolith 9M, were evaluated
in long flow experiments spanning more than 24 h. Whereas 9M
experienced a catalytic decay after 24 h, the flow process with
resin 8R (lacking the triazole group) was running for 48 h, the ee’s
remaining constant through the whole process. The same packed
bed reactor was then used to react dimethyl bromomalonate with
12 different a,b-unsaturated aldehydes in a sequential manner.
Each example was run for 6 h, before rinsing the column with
solvent and moving to the next run (Figure 10). Perhaps the most
remarkable feature of 8R is the robustness displayed: the
sequential library generation was carried out with the same
packed bed reactor over a period of one year.
Cat. 8R: 200 mg, 0.23 mmol (long exp.)
500 mg, 0.58 mmol (library)
Flow rate: 0.10 mL/min
Residence time: 12 min (long exp.)
R
MeOOC

So far, we have seen how the immobilization strategy can affect
the reaction outcome. The presence of a triazole group, for
instance, can either improve the results, expand the solvent
choice or shut down the reactivity, depending on the reaction
being studied (vide infra, as well). However, the selection of the
solid support rarely undergoes a casting aimed at identifying the
most suitable alternative. In order to dig into this issue, we
selected the diarylprolinol-catalyzed cyclopropanation of a,bunsaturated aldehydes[48] as a touchstone. Thus, a library of
supported catalysts (8–10) was prepared with two points of
diversity: the type of resin and the immobilization strategy.[49] For
the resin, we chose a microporous polystyrene resin (low crosslinking) or a macroporous monolith; the three immobilization
strategies to be compared were (a) a hydroxyproline with a
benzylic linker (8), (b) a triazole-based 9 and (c) a copolymerization approach analogous to the one followed for 10, [47]
(Figure 9).

Ph
Ph

8R (resin)
8M (monolith)

R1

N

O

O

L-L
O

R1 = Me
R2 = 4-BrC6H4
13 h operation
31.0 mmol
95% yield 96% ee
Prod. 4.63
mmol mmolcat-1 h-1

N

NH4Cl
(sat.)

CHO
+

COOMe

Br

N

cat. 8R

N

aqueous
waste
L-L
CHO

Me
MeOOC
MeOOC

O
8R

N
H

Ph
Ph
OTBS

R = Ph
49 h operation
31.0 mmol
56% yield, 93% ee
Prod. 2.75
mmol mmolcat-1 h-1

R

12 examples @ 6 h
70 h operation
24-60% yield
89-96% ee
Prod. 0.58-1.87
mmol mmolcat-1 h-1

Figure 10. Continuous flow asymmetric cyclopropanation.

3.3. Other Aminocatalysts
Even if they might be the most paradigmatic examples, there is
much more to aminocatalysis beyond proline and diarylprolinols.
Therefore, other successful primary and secondary amines have
been immobilized and evaluated in asymmetric flow processes.
Along these lines, we developed pyrrolidine derivative 11 in our
laboratories and applied it to the anti-selective Mannich addition
of aldehydes and ketones to imines.[50] The modularity of this

catalyst facilitated the preparation of 12, a solid-supported version
that resorted once more to a triazole-based linker.[51] The
outstanding activities recorded with 12 (low catalyst loadings,
short reaction times and high enantioselectivities) called upon the
implementation of a flow process. A set of aldehydes/ketones and
imines was circulated through the system depicted in Figure 11,
giving rise to a small library of anti-Mannich adducts. In this case,
however, it is worth highlighting two experiments in particular, that
were operative for more than two days each, reaching TONs close
to 300 and producing up to 21 g of a Mannich adduct.

O
+

R1

NPMP
OEt

R2

cat. 12

N

NHPMP
OEt

O

R1

O

N

R2
O

O

N

Design based on:

N
H

NHTf

N
11
H
R = Me, TBS, TBDPS

O
4 aldehydes
2 ketones

NHTf

O

12

RO

Cat. 12: 500 mg, 0.23 mmol
Flow rate: 0.2 mL/min
Residence time: 12 min

4-8 h each
61-97% conv.
87-97% ee

N
Me
48 h
53 h
97% conv.
97% conv.
68.1 mmol
66.1 mmol
dr 95:5
dr 94:6
98% ee
96% ee
Prod.* 6.2
Prod.* 5.4
* in mmol mmolcat-1 h-1

O
Ar

Figure 11. anti-Selective Mannich reaction in flow promoted by a polystyrenesupported pyrrolidine derivative.

Primary amino acids have also been shown to make good
catalysts, albeit whereas secondary ones (e.g. proline and
derivatives) work better with aldehydes, these are more prone to
ketone activation.[52] In 2014, we reported on the three-component
Mannich reaction between hydroxyacetone and glyoxylate imines,
that gives an aminohydroxylated compound.[53] To promote this
transformation, we immobilized six primary amino acids, of which
threonine derivative 13 resulted the most promising one. Even if
the flow rates were rather low, the three-component reaction
could be translated to a continuous regime as depicted in Figure
12. Two different anilines were tested in long experiments (6 and
4 h) giving the desired Mannich adducts in up to 3.13 mmol. After
that, a library of five analogues was prepared in a succession of
one-hour experiments with good productivities.
Cat. 13: 300 mg, 0.31 mmol
Flow rate: 30-50 µL/min
Residence time: 10-17 min

NH2
O
R1

cat. 13
OH
CHO

R2

N N
N

HN

Me
OH

NH2
O
13

R1
O

Me

COOH
Me

R1 = H
R2 = NO2
6h
3.13 mmol
dr 88:12
89% ee
Prod.* 1.7

R1 = Cl
R2 = NO2
4h
2.78 mmol
dr 92:8
96% ee
Prod.* 2.2

Cinchona alkaloids derivatives occupy a central position amongst
primary amine organocatalysts, as demonstrated by several
authors.[54] Their ability to form enamines with ketones and the
presence of other functional groups (quinuclidine and quinoline)
make them very versatile catalysts with broad applicability.
However, this array of functionalities makes the anchoring of such
scaffolds far from straightforward. We decided to use the
quinuclidine vinyl group for that purpose, which gave rise to the
triazole-linked resin 14 in four synthetic steps.[55] The reaction of
choice this time was the Michael addition of a-nitroesters to
enones,[56] given the already mentioned ketone preference of
primary amines. The high acidity of the nucleophile entailed low
diastereoselectivities, but the enantiomeric excesses were
usually very good. Following the usual test to prove robustness
and versatility, 450 mg of 14 were packed in a column and the two
reagents were pumped in a single stream at 50 µL min–1. In this
manner, 12.9 mmol of the Michael adduct were isolated in 98/97%
ee in a total of 21 h operation time (Figure 13). The sequential
library generation in flow was carried out for 5 different analogues
(1 h each, 1 h rinsing in between runs) giving the corresponding
products in 85-99% ee.

R2
5 combinations
1 h each
69-94% yield
dr 81:19-92:8
80-96% ee
Prod.* 1.6-2.1

* in mmol mmolcat-1 h-1

Figure 12. Three-component Mannich reaction with an immobilized threonine.

Me

EWG1

EWG2

Cat. 14: 450 mg, 0.39 mmol
Flow rate: 50 µL/min
Residence time: 40 min
EWG1

cat. 14
Ar

EWG2
O
Me

PhCOOH
N N
N
OMe
N
NH2
N

5 combinations
EWG1 = COOEt
1 h each
EWG2 = NO2
85-99% ee
21 h
Prod.* 1.4-3.2
12.9 mmol
dr 1:1
98/97% ee
Prod.* 1.58
* in mmol mmolcat-1 h-1

14

Figure 13. Supported Cinchona-derived primary amine for flow conjugate
addition.

The Robinson annulation[57] is a classic reaction that has been
broadly applied to the synthesis of countless natural products and
steroid derivatives. Despite the classic reports on prolinecatalyzed, asymmetric Robinson annulation by the groups of
Hajos/Parrish[58] and Eder/Sauer/Wiechert,[59] that are a landmark
in organocatalysis, a recyclable catalyst that works at reasonable
rates remained elusive. Motivated by a report where Luo and coworkers applied their diamine 15 to this reaction,[60] we embarked
in a project aimed at immobilizing this catalyst onto a solid support
and apply it to the enantioselective Robinson annulation. A
synthetic sequence that hinged on the preparation of a chiral
aziridine furnished 17 (without triazole linker in this case) in six
steps from tert-leucine. To our delight, going from room
temperature to 55 ºC with resin 17, did not affect the ee’s, but the
reaction times were reduced by a 10-fold.[61] Strikingly, its
homogeneous analogue 16 did not show such a significant
improvement when heating up, indicating that the interplay of
polymer and temperature generates a special situation.

These fast kinetics, together with its proven recyclability, enabled
the deployment of 17 in a continuous flow experiment with a
jacketed packed bed reactor heated at 60 ºC. A couple of
adjustments had to be done before. Firstly, the low solubility of
some substrates in 2-methyltetrahydrofuran forced us to use DMF
instead. Secondly, methyl vinyl ketone was found to react with the
catalyst, so the first step of the reaction had to be carried
beforehand. This was solved by using a polymer-supported DBU,
which yielded the clean meso-compound that could be directly
pumped in the system after filtration. With these precautions, a
24-h flow experiment allowed the preparation of 11.7 g of the
Wieland-Miescher ketone in 91% ee, for an overall TON of 117.
A similar set-up was used to prepare a library of eight chiral biand tricyclic cylohexenones in up to 94% ee (Figure 14).

enantioselectivity remained constant during the whole process
(96% ee) and 6.6 g of the desired product were isolated, which
corresponds to an accumulated TON of 200 and a productivity of
10.7 mmol mmolcat–1 h–1. Resin 18 also proved amenable for the
production of libraries of compounds, as demonstrated by a
sequential experiment in which 500 mg of this supported
squaramide catalyst were used to prepare six different analogs in
high yields and enantiomeric excesses.
O

t-Bu

Me

18
N

O
+

H 2N

O

Cat. 17: 800 mg, 0.56 mmol
Flow rate: 50-125 µL/min
Jacket @ 60 ºC
O

Me
O

R

Me

cat. 17
BPR
1.3 bar

COOH

NO2

Cat. 18: 250-500 mg
0.095-0.171 mmol
Flow rate: 200 µL/min

N

O
OH

cat. 18

15 R = H (Luo diamine)
16 R = OBn (homogeneous analogue of 17)

filter
Me

N
H

NO2

O

(in batch)

PS-DBU

O

R

Me

O

O

OH
·TfOH
N

O
N
H

N
N

O
O

CF3

O

t-Bu

H 2N
17

·TfOH
N

O

As depicted
24 h
11.7 g
65.5 mmol
91% ee
Prod.* 4.9

O
8 combinations
30 min each
62-87% yield
78-94% ee
Prod.* 6.7-9.3

* in mmol mmolcat-1 h-1

Figure 14. Immobilized chiral diamine catalyst for the flow Robinson annulation.

3.4. Squaramides
The term organocatalyst encompasses much more than amines.
Hydrogen bond donors, for instance, have proven extremely
successful, especially when they are integrated in a bifunctional
catalyst bearing an additional basic center. A good example of
this are the chiral squaramide catalysts,[62] originally described by
Rawal and co-workers.[63] We postulated that Brønsted acids and
H-bond donors would be ideal candidates for immobilization,
given the fact that they do not establish covalent bonds with the
substrates, thus reducing the possible pathways for catalyst
deactivation.[64] On this basis, we prepared the polystyrenesupported bifunctional squaramide 18, that proved highly active
and selective in the Michael addition of active carbonyl
compounds to nitroalkenes.[65] Even more importantly, it was a
very robust material that could be recycled at least ten times. The
low catalyst loadings and short reaction times encouraged us to
test this immobilized squaramide in flow. After optimizing the
reaction between hydroxynaphthoquinone and a set of
nitroalkenes in batch, we packed 250 mg of 18 (<0.1 mmol) in a
glass column and pumped a mixture of both reagents at 0.2 mL
min–1 flow rate[66] (Figure 15). This minute amount of catalyst
allowed to maintain a flow experiment active for 20 h. The

NO2

O

R

R1 = Ph
6 combinations
R2 = H
1 h each
69-93% yield
20 h
94-97% ee
75% yield
Prod.* 5.4-6.6
6.6 g (20.4 mmol)
96% ee
Prod.* 10.7
* in mmol mmolcat-1 h-1

Figure 15. Supported squaramide catalyst for the continuous conjugate addition
of hydroxynaphthoquinones to nitroalkenes.

Concerned by the tedious and costly preparation of 18, we
embarked in a project aimed at determining how much we could
simplify its synthesis. Using the reaction between
hydroxynaphthoquinone and a-acetoxymethylnitroalkenes[67] as
the benchmark reaction, we could establish that the
trifluoromethyl group in 18 did not play any particular role,
whereas the triazole was merely a spacer. These studies allowed
the preparation of 19, a much simpler squaramide catalyst that
proved even more active and selective than 18. In contrast to the
original reports in homogeneous,[67] we had to add base to
complete the cyclization reaction. Thus, a telescoped flow system
consisting of a column packed with 400 mg of 19, followed by an
additional pump with NaHCO3 (aq.) and a 10-mL coil, was
assembled. While the role of 19 was to promote the
enantioselective Michael addition, the basic in-line work-up
effected the elimination–oxa-Michael cyclization that gives rise to
the final product. Working at a flow rate of 0.2 mL min–1, a library
of seven analogues could be prepared in good yields and
excellent enantioselectivities[68] (Figure 16).

O

Cat. 19: 400 mg, 0.23 mmol
Flow rate: 200 µL/min
0.45 mL/min
Residence time: 30 min
NaHCO3
(sat. aq.)
O

Ar

O

OAc

aqueous
waste

NO2

7 combinations
50 min each
(1 mmol of nitroalkene)
62-83% yield
96-98% ee
Prod. 3.2-4.3
mmol mmolcat-1 h-1

O
OH OAc
NO2
O

Ar

Wang resin

O

O

COOt-Bu

COOEt
N COOt-Bu
HN COOt-Bu

cat. 20

N
H

N
H

O

Et3N
periodic washing
at 200 µL/min

CF3
S

O
N
H

7.5 h
71% yield
1.81 g (4.68 mmol)
93% ee
Prod. 4.88 mmol mmolcat-1 h-1

N
H

N

20

Figure 17. Immobilized thiourea for the enantioselective amination of ketoesters.

O

O
O

t-BuOOC

N
N

Cat. 20: 300 mg, 0.128 mmol
Flow rate: 50 µL/min
Residence time: 21 min
O

L-L

cat. 19

Ar

COOEt

NO2

OH

O

O

O

3.6. Phosphoric Acids
N

19

Figure 16. Flow synthesis of pyranonaphthoquinones with a simplified
supported squaramide catalyst.

3.5. Thioureas
Formally related to squaramides, ureas and thioureas were the
first H-bond donors to be used in asymmetric catalysis, thanks to
the pioneering works by Jacobsen[69] and Takemoto.[70] The ability
of thioureas to coordinate to carbonyl compounds or nitro groups,
and to abstract anions, has been exploited in several catalytic
asymmetric transformations. Lured by the anticipated robustness
of the thiourea moiety, we set out to study the immobilization of a
bifunctional thiourea–cyclohexandiamine derivative, while trying
to evaluate the influence of the linker. Indeed, the presence of a
triazole handle led to poorly reproducible results, arguably due to
trace amounts of copper remaining from the immobilization step.
Consequently, we prepared 20, devoid of triazole, that was
anchored by simple nucleophilic displacement of the chloride by
a carboxylate. While anchoring the monomer as late as possible
is generally a safer strategy to safeguard the identity of the
supported species, in this case the reliability of the reaction
sequence allowed the solid phase synthesis of 20.[71] This was
employed in the amination of b-dicarbonylic compounds
(ketoesters and diketones) with azodicarboxylates.[72] Resin 20
turned out to be fairly active for 7- and especially 5-membered
cyclic substrates, but cyclohexanone derivatives and aliphatic
ones were reluctant to participate in the reaction. For the flow
experiment, 300 mg of 20 were packed in the reactor and the
mixture of reagents was circulated at 50 µL min–1. On the basis of
the batch experiments, where loss of activity could be deterred by
treatment with base, every 2 h of operation we performed a reconditioning procedure consisting of washing the reactor with
Et3N in CH2Cl2. Under these conditions, 7.5 h of effective
operation were enough to produce 1.81 g of the amination product
in 71% yield and 93% ee (Figure 17).

Guided again by the hypothesis that the lack of covalent
interactions between substrate and catalyst increases the lifetime
of the latter we turned our attention to chiral phosphoric acids.
These, independently developed by Akiyama[73] and Terada[74] in
2004 for the activation of imines, have proven very versatile,
displaying a significantly broad scope.[75] Previous reports in the
literature had either relied on co-polymerization of vinylated
intermediates or exploited the innate ability of thiophene residues
to polymerize.[76] In contrast, our first attempt hinged in the
preparation of a BINOL derivative functionalized in position 6,
which
allowed
anchoring
through
etherification
of
chloromethylpolystyrene. Formation of the phosphoric acid gave
rise to the desired catalyst 21,[77] that was evaluated in the azaFriedel–Crafts addition of indoles to N-tosylimines.[78] Working in
batch, the addition products were isolated in good yields and ee’s
and 21 could be repeatedly re-used. During these recycling
studies, we found the most remarkable feature of 21: the catalytic
activity lost upon recycling could be restored by simply reconditioning the resin with HCl in EtOAc.
These results prompted us to pack 360 mg of 21 (<0.1 mmol) to
study the related flow process. Up to 3.6 g of the addition product
were isolated after six hours at 0.2 mL min–1; the conversion and
yield remained constant during the whole process and the
productivity reached as high as 17.0 mmol mmolcat–1 h–1.
Afterwards, the same packed bed reactor was applied to the
sequential production of five analogues with similarly high
productivities (Figure 18). It is worth emphasizing that the use of
a flow IR device allowed to collect information of the system in
real time. The use of in-line analysis, together with the in-line
work-ups previously discussed, is deemed crucial for the
implementation of flow chemistry in industrial environments. This
strategy has a direct impact on the footprint of the reactors,
allowing significant reduction of their overall volume.

NSO2R1

Cat. 21: 360 mg, 0.09 mmol
Flow rate: 200 µL/min
Residence time: 9 min
R1O2SHN
cat. 21
R3

R2

R3
N
H

CF3
CF3

O
O
O
P
OH
O

Cat. 22: 500 mg, 0.11 mmol
Flow rate: 200 µL/min
400 µL/min
NaHSO3
O
(2.0 M)
OH
R2

cat. 22

N
H
6h
5 analogs
80%
1 h each
3.6 g
3 points of diversity
9.2 mmol
80-94% yield
94% ee
86-92% ee
Prod.* 17.0
Prod.* 17.2-20.0
* in mmol mmolcat-1 h-1

Bpin

i-Pr
O
O
P
OH
O
i-Pr

CF3

Figure 18. Solid-supported chiral phosphoric acid-catalyzed Friedel–Crafts
addition of indoles to sulfonylimines.

The robustness of 21 motivated us to study the immobilization of
TRIP catalyst developed by List,[79] perhaps the most versatile
phosphoric acid derivative reported to date. The synthesis of a
polystyrene-supported version of TRIP proved more troublesome,
but co-polymerizing a conveniently functionalized BINOL
derivative gave the desired catalytic material in an easy manner
that required only three more steps than the homogeneous
counterpart. The reaction of choice to evaluate the performance
of resin 22 was the allylboration of aldehydes, reported in
homogeneous by Antilla et al.[80] The batch experiments worked
smoothly to generate 18 different allylated products re-using the
same sample of 22. Basic substrates deactivated the catalyst
(presumably by acid-base reaction) but, as with 21, the activity
could be restored by washing the resin with HCl in EtOAc.[81]
The flow process was carried out with two independent pumps
due to the incompatibility of the aldehyde and the allylboronate.
Downstream of the column, a third pump fed the system with
aqueous NaHSO3 to scavenge the remaining aldehyde; otherwise,
a background process took place, drastically reducing the
recorded enantioselectivities (Figure 19). In these conditions, the
flow process spanned 28 h at a combined flow rate of 0.2 mL min–
1
, furnishing the chiral alcohol in 92% yield and 91% ee with high
productivities (10.1 mmol mmolcat–1 h–1) and an accumulated TON
of 282.

i-Pr

i-Pr

CF3

21

(biphasic
mixture)

22

i-Pr

28 h
92% yield
4.60 g
31.0 mmol
91% ee
Prod. 10.1
mmol mmolcat-1 h-1

i-Pr

Figure 19. Polystyrene-supported TRIP for the asymmetric allylboration of
aldehydes in flow.

3.7. Isothioureas
The chemistry of enolates is a time-honoured strategy for the
construction of C–C bonds. However, the classic methods are
hampered by the need to pre-generate stoichiometric amounts of
an activated intermediate, often employing strong bases. Several
alternatives have been recently developed to circumvent the need
to pre-form enolates, which allows working under much milder
reaction conditions. In addition to the aminocatalysts, already
discussed in Sections 3.1-3.3, chiral Lewis bases such as Nheterocyclic carbenes[82] (NHCs) or isothioureas[83] provide an
interesting solution, enabling the generation of enolate
equivalents in situ from simple precursors.
The pioneering use of chiral isothioureas in catalysis by Birman[84]
and Okamoto,[85] has established a useful approach for kinetic
resolution and asymmetric creation of C–C bonds[86] that has
been exploited by other authors like Smith[87] and Romo,[88] among
others. Thus, we decided to immobilize these isothioureas to
assess if the associated benefits compensate the synthetic cost.
Starting from enantiopure phenylglycidol, we prepared in five
steps an analog of benzotetramisole that was subsequently
anchored to azidomethylpolystyrene by means of a click reaction.
The resulting supported catalyst 23[89] was found to efficiently
promote the asymmetric [4+2] addition of chiral enolates
(generated in situ from the acid) to chalcone-derived sulfonyl
imines.[87c] The scope of the reaction was very broad, tolerating
substitution on both ends of the imine, as well as on the acid. We
found that saccharin-derived tosylimines also participated in the
reaction, leading to tricyclic molecules. After securing the
recyclability of 23 in batch we assembled a flow system consisting
of (a) two syringe pumps connected to a coil to generate in situ
the mixed anhydride, (b) a second pump feeding the system with
the a,b-unsaturated tosylimine, (c) a packed bed reactor with 600
mg of 23, (d) downstream of the column, another pump with water
to quench the excess anhydride and finally (e) a liquid-liquid
separator to remove the aqueous waste (Figure 20). Under these

conditions, more than 4 g of the resulting dihydropyridone were
obtained in an enantiopure manner.
O
Ph
HOOC
i-Pr2NEt

Cat. 23: 600 mg, 0.54 mmol
Flow rate: 110 µL/min
Residence time 7.5 min

Cl

120 µL/min
H 2O

O
PivO

aqueous
waste

●

Ph

the application of 24 in the kinetic resolution of alcohols in flow.[91]
(Figure 22). In batch, 24 displayed a very broad substrate scope
and remarkable robustness, allowing for 15 cycles with essentially
the same results. The implementation of the related flow process
gave rise to a long experiment (24 h) and the generation of nine
analogs by sequential experiments. All the examples run in flow
were carried out with the same packed bed reactor, proving once
more the significant stability of 24 for this reaction.
OH
R1

NTs

O

N N
N

O
Ph
N

23

Ph

TsN
11 h
70% yield
Ph
4.44 g
9.3 mmol
>99.9% ee
Prod. 1.6
mmol mmolcat-1 h-1

N

S

at 0 ºC

i-Pr
Ph

R1

+

R3

O

R2 R1

R2

R3

O
Et3N

Ph

O

N
N

S

24

N

N
N

24 h
55% conv.
28.8 mmol
94/76% ee
s factor: 28

9 analogs
4 mmol each
49-63% conv.
84-98% ee (alc.)
s factor: 11-200

Figure 22. Isothiourea-mediated kinetic resolution of alcohols in flow.

Figure 20. Immobilized isothiourea for the asymmetric synthesis of lactams in
flow.

Later, we expanded the scope of 23 to accommodate exocyclic
alkylidene pyrazolones or thiazolones as heterodienophiles,
giving rise to the corresponding bicyclic products bearing two
contiguous stereocentres.[90] A single continuous flow experiment
was carried out, using a similar set-up as in the previous case,
where the mixed anhydride was produced in situ. The system was
operated for 18 h to produce 2.74 g of the resulting
pyranopyrazolone (Figure 21).
O
Ph
HOOC
i-Pr2NEt

R3

O

O
OH

cat. 24

O
Ph

R2

L-L

cat. 23

Ph

Cat. 24: 600 mg, 0.54 mmol
Flow rate: 100 µL/min
Residence time: 30 min

Cl

4. Immobilized Ligands and Metal-Based
Catalysts for Work in Flow
By now it must be quite obvious that the group expertise revolves
around solid-supported organocatalysts. Nevertheless, we have
also worked with immobilized ligands and metallic catalysts,
which were actually our entrance door to flow chemistry. The main
issue related with the use of supported metal species in flow is
the leaching, which can be hard to control.[17] In addition, the need
to exclude air or moisture can hamper the implementation of such
flow processes. In spite of these pitfalls, we have successfully
developed a few examples of the use of immobilized metalcontaining species in continuous flow.
4.1. Amino Alcohol Ligands

Cat. 23: 600 mg, 0.54 mmol
Flow rate: 100 µL/min
Residence time 7.5 min
O
Ph

PivO

●

Me

cat. 23

N
Ph

Ph
N
Ph

O

N N
N

O
Ph
N

23

S

Ph

N

Me
N

Ph

N

O

O

18 h
67% yield
2.74 g
7.20 mmol
99% ee
Prod. 0.74
mmol mmolcat-1 h-1

Figure 21. Flow synthesis of chiral pyranopyrazolones with a supported
isothiourea.

More recently, a collaboration with the group of Andrew D. Smith
form the University of Saint Andrews (Scotland) has given rise to

The use of ligands to promote the alkylation and arylation of
aldehydes with organozinc species is a classic strategy that
allows the generation of enantiopure alcohols in a straightforward
fashion.[92] For several years our laboratory worked on this topic,
developing new ligands and synthetic strategies;[93] intrigued by
the possibility of recycling the chiral ligand, we considered their
heterogenization on polymer- or silica-based supports.[25] The
high levels of activity and selectivity of these materials
encouraged us to study for the first time in our laboratory their
deployment in a flow process.
To this end, resin-bound amino alcohol 25 was packed in a glass
column and the aldehyde and diethylzinc solutions were
circulated through the system with two independent pumps
(Figure 23). In this manner, seven independent experiments gave
rise to a library of benzylic alcohols using flow rates of 0.24 mL
min–1 (3 h each run); in one remarkable case, though, 4cyanobenzaldehyde could be ethylated at an astonishing 0.72 mL
min–1, full conversion being recorded. To prove the robustness of

the resin, three consecutive runs were carried out on the same
sample of 25, only a slight decrease in conversion being
observed.[94]

supported amino alcohol that would disfavor this C–C bond
cleavage.
Ph

Ligand 25: 1.5 g, 0.975 mmol
Flow rate: 0.24 mL/min
Residence time: 9.8 min

O
R

Me

25

Et2Zn
Ph

five exp. @ 0.24 mL/min
3 h each
76-97% yield
82-93% ee
Prod.* 5.03-6.6

OH
Ph
Ph

N

R

(collected
under N2)
three consecutive runs
6 h overall
85-99% yield
86-93% ee

one exp. @ 0.72 mL/min
3h
99% yield
87% ee
* in mmol mmolcat-1 h-1
Prod.* 19.9

N
25

Ph
Ph

N
OH

jacketed at 10 ºC

Figure 23. Aldehyde ethylation in flow.

Ph

OH
base

X

Six different flow experiments were carried out with the set-up
depicted in Figure 24, each run spanning 3-4 h. The resulting
diarylmethanols were isolated, after collecting the outstream over
aqueous NH4Cl and chromatographic purification, in up to 93%
yield.[95]
O

OH

jacketed at 10 ºC

25

ArZnEt
Ph
B
O

O
B
Ar

Ar
B
Et2Zn
O +

N
X

O

X = CH2 or NCH2-PS

Ph

Ph

Scheme 1. Fragmentation of triphenylethylene oxide-derived amino alcohols.

Thus, 26 was prepared as an immobilized analogue of MIB,[96]
proving to be very active and recyclable, provided that oxygen
was completely excluded from the system. The robustness of
catalyst 26 was confirmed by a related flow process that was
running for as long as 30 h. Only a slight decrease in conversion
was observed and the accumulated TON reached 251[97] (Figure
25).
Ligand 26: 500 mg, 0.39 mmol
Flow rate: 0.24 mL/min
Residence time: 6 min
jacketed at 0 ºC

26

Et2Zn
N
N
OH

26

OH
Me
(collected
under N2)

30 h
13.0 g
95.5 mmol
quant. yield
98% ee
Prod. 8.2 mmol mmolcat-1 h-1
Overall TON 251

Figure 25. Aldehyde ethylation in flow with a supported piperazinoisoborneol
ligand.

4.2. A Phosphinooxazoline Ligand
Ligand 25: 1.1 g, 0.51 mmol
Flow rate: 0.24 mL/min

R

Ar

[M]

Ph
Ph

X

O

In 2008 we published that triarylboroxins undergo a scrambling
process with Et2Zn that generates in situ the corresponding
arylzinc species. This strategy greatly simplified the arylation of
aldehydes, avoiding the use of expensive and difficult to prepare
diarylzinc derivatives.[93e] Hence, we reasoned that integrating this
approach with the knowledge acquired on the previous work with
ligand 25 would allow to carry out the enantioselective continuous
arylation of aldehydes with triarylboroxins as the ultimate source
of aryl groups.

N

Ph

O [M]

OH
Ph
Ph

N

R

Ar
(collected
over NH4Cl)

six aldehydes
3-4 h each
78-93% yield
55-81% ee
Prod. 7.7-9.2 in mmol mmolcat-1 h-1

N
25

Figure 24. Aldehyde arylation in flow.

Despite the good results shown recorded, 25 proved to be
unsuitable for long-term operation due to a fragmentation that
took place in the presence of strong base (Scheme 1). After
making the hypothesis that the presence of an aromatic group
could stabilize the developing negative charge, we designed a

The Tsuji-Trost reaction, which involves the activation of allylic
substrates with palladium complexes, followed by the interception
of the resulting p-allyl intermediates with a suitable nucleophile, is
a common strategy in organic synthesis.[98] Several ligands have
been developed to control the enantioselectivity of the process,
and bidentate phosphinooxazolines (PHOX) are amongst the
most successful. After optimizing the ligand structure, the
anchoring strategy via CuAAc and the length of the linker, the flow
experiment depicted in Figure 26 was carried out with 27.[99]
Based on the observation made in batch that use of low-power
microwave irradiation significantly improved the results, the whole
set-up was assembled without metallic pieces and placed inside
the MW cavity in open-vessel mode. Thus, working at 0.12 mL
min–1, the system was running for 3 h, in which the conversion
decreased from the initial 85% to 54%, probably pointing out to
palladium leaching.[100]

Cat. 27: 240 mg, 0.12 mmol
Flow rate: 0.12 mL/min
Residence time: 8.5 min

Ph

Ph

+

NH2

N2

HN
Ph

NTMS

OEt +

Ph

cat. 27

OTMS
Me

O

1W MW
irradiation

Ph

OAc

Cat. 28: 300 mg, 0.117 mmol
Flow rate: 0.5 mL/min
Residence time: 1 min Y CH2COOEt
or
cat. 28
H COOEt

Y H
or

Me

Ph
Me
O

O
Ph P Pd
Ph

N

O

4

Ph
N

Cl

N

N

Ph

Ph

3h
1.95 g
6.5 mmol
68% yield
83% ee
Prod. 18.1 mmol mmolcat-1 h-1

27

Bn

Bn N
N N

PF6

N
N N
N Bn
N
N
Cu
N

28

Y-H = EtOH
48 h
12.6 g
95.8 mmol
90% yield
Prod.* 17.1
Overall TON 820

Y-H = THF, Cy, PhNH2
2 h each
0.54-4.10 mmol
41-93% yield
Prod.* 2.3-17.5
Accumulated TON 915
(including 48-h exp.)

* in mmol mmolcat-1 h-1

Me
Figure 26. Continuous flow asymmetric allylic amination.
Figure 27. Cationic copper complex for the ethyl diazoacetate insertion in flow.

4.3. A tris-Triazolyl Ligand for Copper
4.4. Flow processes with metal organic frameworks (MOFs)
In contrast to all the examples described above, the last project
to be discussed does not deal with enantioselective catalysis. The
ligand used in this case, the tris-triazolylmethanol[101] (TTM), was
designed in our laboratories for the CuAAC, a reaction that in turn
was crucial in its preparation. Despite the previous instances
where this ligand had been immobilized,[101b] high levels of copper
leaching had precluded implementation of flow processes. We
reasoned that, if the complex was formed from a cationic coper
species rather than with CuCl, the chances of leaching would
diminish. Consequently, solid-supported TTM was treated with
[Cu(MeCN)4]PF6 and the resulting cationic complex 28 was
benchmarked with the ethyl diazoacetate insertion onto ethanol,
in the framework of a collaboration with the group of Díaz-Requejo
and Pérez from the University of Huelva.[102] The system was
incredibly robust, allowing for a flow process that spanned 48 h
working at flow rates as high as 500 µL min–1. The only issue was
that the resin had to be re-swollen every few hours due to the
presence of ethanol, but 90% yield was still obtained, and the
TON for this experiment alone reached an amazing 820 (Figure
27).
After this result, the same packed bed reactor with 28 was applied
to an array of substrates including THF, cyclohexane or aniline,
which furnished the C-H and N-H insertion products, and an
alkyne, that gave rise to the cyclopropene. Overall, an
accumulated TON of 915 was recorded, thanks to the stability of
the cationic complex and the fast flow rates employed (500 µL
min–1), which entailed a residence time as short as 1 min.

In a fruitful collaboration with Prof. Belén Martin-Matute
(Stockholm University) we have demonstrated that Pd
nanoparticles supported on functionalized mesoporous MOFs
can also be used in flow. To this end, the broad-scope SuzukiMiyaura synthesis of highly functionalized biaryls and the aerobic
oxidation of alcohols were studied.[103] These are, however, nonenantioselective applications involving achiral catalysts and will
not be discussed in detail here.

5. Summary and Outlook
The implementation of continuous flow processes based on solidsupported chiral catalysts is a key enabling technology for the
green production of enantiopure compounds. Catalyst design is
critical to obtain a material that is robust under the reaction
conditions, while allowing for high activities required for a singlepass operation. In this sense, the CuAAC-mediated installation of
a triazole linker has proven a versatile approach, but the
anchoring strategy will be eventually dictated by the reagents,
solvent or even by-products that come in close contact with the
catalytically active species. If the right buttons are pressed, one
can generate a packed bed reactor that, much like a HPLC
column, can be stored and used at the user’s convenience.
The lessons learnt from the examples described herein (as well
as many others described in the literature) are certain to improve
the next generation of immobilized chiral catalysts, leading to a
new scenario where flow chemistry becomes an alternative to
batch processes thanks to the associated benefits in terms of
process intensification. In the current scenario, sustainability
issues are critical to decide the processes to be deployed in an
industrial environment. Hence, we should not be surprised to see
flow processes being adopted for the production of (enantiopure)
fine chemicals, as they have been in the petrochemical and bulk
chemicals industry.

Acknowledgements

[13]

We would like to thank all the members of the Pericàs Lab at ICIQ
who, with their dedication and effort, have made possible the
research described herein. Their names appear in the
corresponding references, and they deserve full credit for the
work. Financial support from CERCA Programme/Generalitat de
Catalunya, MINECO (CTQ2015-69136-R, AEI/MINECO/FEDER,
UE and Severo Ochoa Excellence Accreditation 2014–2018,
SEV-2013-0319) and DEC Generalitat de Catalunya (Grant
2014SGR827) is gratefully acknowledged.

[14]

Keywords: flow chemistry • immobilized catalysts • solidsupported catalysts • asymmetric catalysis • organocatalysis
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Entry for the Table of Contents (Please choose one layout)
Layout 1:

PERSONAL ACCOUNT
The flexibility, reduced footprint and
minimization of waste products
associated with flow techniques
constitutes a perfect match for solidsupported chiral catalysts. The efforts
made in our group to identify ever
more active, robust and selective
heterogenized catalysts and the
subsequent applications in
asymmetric flow processes are
summarized here.

Carles Rodríguez-Escrich* and Miquel
A. Pericàs*
Page No. – Page No.
Title