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Letter
pubs.acs.org/acscatalysis

Polystyrene-Supported TRIP: A Highly Recyclable Catalyst for Batch
and Flow Enantioselective Allylation of Aldehydes
Lidia Clot-Almenara,‡ Carles Rodríguez-Escrich,*,‡ Laura Osorio-Planes,‡ and Miquel A. Pericàs*,‡,§
‡

Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països Catalans, 16,
43007 Tarragona, Spain
§
Departament de Química Orgànica, Universitat de Barcelona (UB), 08028 Barcelona, Spain
S
* Supporting Information

ABSTRACT: The widely applicable TRIP phosphoric acid
catalyst has been immobilized on polystyrene using a
copolymerization-based strategy. The resin (PS-TRIP) has
proven to be highly active and enantioselective in the
asymmetric allylboration of aldehydes. Moreover, it has
shown to be extremely robust, as it can be reused for 18
times, after which it still retained its activity. Lastly, to further
prove the benefits of the immobilization, a continuous flow
experiment spanning 28 h has been carried out with very high
yields and ee’s.
KEYWORDS: enantioselective catalysis, chiral phosphoric acids, polystyrene-supported catalysts, flow chemistry, organocatalysis

1. INTRODUCTION
Since the pioneering works of Akiyama1 and Terada,2 chiral
phosphoric acids have proven to be extremely successful and
versatile enantioselective catalysts.3 Indeed, these Brønsted
acids (which can be regarded as a metal-free alternative to chiral
Lewis acids) have been used in a wide variety of asymmetric
catalytic transformations including transfer hydrogenation,4
addition to imines,5 multicomponent reactions,6 or (trans)acetalization,7 to name just a few. With BINOL-derived
phosphoric acids, the substituents in the 3,3′ positions have
been found to exert a dramatic effect on both the catalytic
activity and enantioselectivity.8 Among all the reported
structures, the 2,4,6-tris-isopropyl derivative commonly
known as TRIP (introduced by List et al. in 20054a) has
been the most successful, judging by the recent literature. This
catalyst has been applied to a vast range of enantioselective
reactions with unprecedented levels of stereocontrol,9 either as
a Brønsted acid catalyst or in ACDC catalysis.10 However,
TRIP presents some important drawbacks, mainly associated
with its tedious preparation (reflected in a high cost), the
adventitious formation of the related sodium or calcium salts,11
and the usually high catalyst loadings required.
Thus, even if it might entail a somewhat longer sequence, we
thought it could be interesting to study the immobilization12 of
TRIP onto a solid support as it would allow us to (a) recover
and reuse the catalyst, thus reducing its effective cost and (b)
preclude the formation of calcium or sodium salts by skipping
any chromatographic purification. On the basis of the few
previous works involving solid-supported phosphoric acids,13,14
(including our own experience15), we expected that a
polystyrene-supported TRIP (PS-TRIP) would fulfill these
conditions while retaining the excellent enantiocontrol and
© 2016 American Chemical Society

wide applicability of its homogeneous counterpart (Figure 1).
However, to the best of our knowledge, the only reported

Figure 1. TRIP catalyst and an immobilized version thereof.

attempt to immobilize TRIP had given rise to a nonactive
catalyst,16 and thus, the immobilization strategy was deemed to
be crucial.
We report herein the development of a simple and effective
strategy for the incorporation of TRIP in a slightly cross-linked
polystyrene network without compromising the excellent
catalytic activity and enantioselectivity displayed by the
monomer. The resulting functional polymer (PS-TRIP) has
been used as an abundantly recyclable catalyst for the highly
enantioselective allylboration of aldehydes in batch and flow.
Received: September 13, 2016
Revised: October 6, 2016
Published: October 6, 2016
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DOI: 10.1021/acscatal.6b02621
ACS Catal. 2016, 6, 7647−7651

Letter

ACS Catalysis
Scheme 1. Preparation of PS-TRIP

Table 1. Screening of Reaction Conditionsa

2. RESULTS AND DISCUSSION
The preparation of PS-TRIP (Scheme 1) is common to that of
its homogeneous analogue11 until diol 1. At that point, instead
of the direct phosphorylation reported by List and co-workers,
we carried out a dibromination in 6,6′, followed by Suzuki
coupling with 4-vinylphenylboronic acid (3). Divinylated
compound 4, with a conveniently modified BINOL scaffold,
was then copolymerized with styrene and divinylbenzene to
generate resin 5,17 which was in turn phosphorylated to
generate PS-TRIP.
The synthesis proved to be very reproducible, leading in all
cases to functionalization levels (determined by elemental
analysis of P) of 0.20−0.23 mmol g−1. Remarkably, the whole
sequence involves only three more steps than the route for the
homogeneous TRIP and both the bromination and the Suzuki
coupling are very high yielding.
After optimizing the synthesis, we set our sights in finding a
benchmark reaction to put the new catalytic resin PS-TRIP to
the test. We envisaged that the asymmetric allylboration of
aldehydes reported by Antilla et al.18 might be an interesting
choice, given the versatility of chiral homoallylic alcohols as
building blocks in synthesis and the simplicity of the reaction
protocol. To our delight, working with 10 mol % PS-TRIP in
toluene at 0 °C, the reaction between benzaldehyde and
allylboronic pinacol ester gave 8a in excellent yield and
enantioselectivity (Table 1, entry 1). Lowering the catalyst
loading to 5 mol % allowed us to reach similar results (entry 2),
whereas changing the solvent resulted in lower ee’s (entries 3−
5). If the reaction was cooled to −30 °C, the result with
benzaldehyde was affected minimally (entry 6), but more
electrophilic aldehydes gave better ee’s. We attribute this to a
noncatalyzed background reaction, and thus, in order to
minimize this unwanted process, we decided to carry out the
rest of the scope at −30 °C. Lastly, when concentration was
increased to 0.1 M, the reaction turned out to be much faster
while maintaining yield and ee (entry 7).
Once the reaction parameters had been fine-tuned (5 mol %
PS-TRIP, 0.1 M in toluene, −30 °C, 6 h), we decided to study
the scope of the reaction. Thus, a wide range of aldehydes was

entry

solvent

T (°C)

t (h)

yield (%)

ee (%)

1b
2
3
4
5
6
7c

toluene
toluene
THF
CH2Cl2
EtOAc
toluene
toluene

0
0
0
0
0
−30
−30

16
16
48
16
48
16
6

89
92
traces
90
67
97
96

96
94
n.d.
88
52
95
95

a

Reactions carried out at a concentration of 0.06 M with 5 mol % PSTRIP and 1.2 equiv of 7a. bWith 10 mol % PS-TRIP. cConcentration:
0.1 M.

submitted to these conditions (18 examples), the results being
summarized in Scheme 2. PS-TRIP proved to be excellent in
the catalytic preparation of highly enantioenriched homoallylic
alcohols. Electron-poor and electron-rich aromatic aldehydes
(products 8a−o) are generally well-tolerated, giving rise to
outstanding yields and enantioselectivities (up to 96% ee).
ortho-Halogenated derivatives seem to be the exception, giving
rise to only moderate ee’s (products 8e,j). In contrast, a
toluidine with the same substitution pattern (product 8o)
reached up to 95% ee, indicating that the results with ohalobenzaldehydes likely arise from a combination of steric and
electronic factors. Heteroaromatic substituents like 3-furyl
(product 8l) gave very good results, whereas use of a 3pyridine resulted in a completely racemic product (8k); this is
probably due to the basicity of this heteroaromatic moiety,
which might interact with the phosphoric acid in 1. Other
interesting substrates include an α,β-unsaturated aldehyde
(product 8p), a linear one (product 8q), and isophthalaldehyde, which gave rise to the C2-symmetric product 8r through
double allylation.
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ACS Catalysis
Scheme 2. Aldehyde Scopea

Scheme 3. Scope of the Allylating Partner

sake of simplicity. To this end, the three-pump system outlined
in Figure 2 was assembled. As depicted, a packed bed reactor
containing PS-TRIP was fed with two solutions containing the
aldehyde and the allylboronic ester. Downstream of the
column, an aqueous solution of NaHSO3 was used to scavenge
any unreacted aldehyde. Preliminary attempts to run the flow
experiment without this last step resulted in good enantioselectivities in aliquots taken from the outstream but somewhat
diminished ee’s on the collected product. We attribute this
observation to a background reaction taking place in the
collecting flask between the excess allylboronic ester and the
small amounts of aldehyde remaining in the outstream.
Under these conditions, the flow experiment was kept
running for 28 h, after which 4.60 g of 8a were isolated (92%
yield, 91% ee). These numbers amount to a total TON of 282
and a productivity of 2.22 mmol h−1 gresin−1. Remarkably, no
detectable decrease in the catalytic activity of the resin took
place in the 28 h experiment. This fact, together with the easy
reactivation of PS-TRIP allows visualizing the small cartridge
containing only 0.5 g of catalyst as a micropilot plant, suitable
for the production of decimol amounts of enantiopure
homoallylic alcohol in short periods of time (ca. 90 h) with
highly reduced energy costs (no cooling required) and material
costs (in a flow process with a nondeactivating catalyst, the
TON increases linearly with time). Even more interestingly,
catalyst cartridges involving 5 to 50 g of PS-TRIP (amounts
within reach of the procedure reported herein) could be used
for kilogram production under very favorable cost and safety
conditions.

a

All reactions were carried out with the same sample of PS-TRIP
(recycled after each run).

However, perhaps the most remarkable feature of the catalyst
is that all the scope shown in Scheme 2 (18 examples) has been
run with the same sample of PS-TRIP, which has been reused
extensively showing no decay in activity.
Indeed, at the end of the scope, benzaldehyde was allylated
again, completely replicating the results obtained at the
beginning. This shows the outstanding robustness of PSTRIP, which can be quantified in an accumulated TON of 321.
Even more interestingly, during this process, the catalyst did
lose activity a couple of times (e.g., after running the test with
3-pyridinecarboxaldehyde), but simply washing the resin with a
solution of HCl in EtOAc led to a complete recovery of the
catalytic activity. The allylating partner scope was also briefly
studied, giving excellent results in the trans-crotylation and
dimethylallylation of benzaldehyde (products 8s and 8u,
Scheme 3). The cis-crotylboronic derivative gave a slower
reaction, thus providing somewhat decreased enantioselectivity,
perhaps due to a competitive background reaction. However, 8t
was still isolated in 83% ee.
Encouraged by the excellent results displayed by 1, we
decided to study the related flow process.19 A preliminary batch
test showed that 8a gave similar results at RT and at −30 °C, so
we decided to carry out this flow experiment at 25 °C for the

3. CONCLUSIONS
In summary, we have prepared a polystyrene-supported TRIP
catalyst that has proven to be very active and enantioselective in
the allylation of aldehydes. The synthetic route, which involves
the copolymerization of a vinylated analogue of the TRIP diol,
requires only three more steps than that of the homogeneous
counterpart and is amenable to multigram production. The
slightly longer synthesis is exceedingly compensated by the high
recyclability of PS-TRIP, which has given accumulated TONs
in batch as high as 321 (the catalyst was still active after 18
runs). The catalytic resin has also been put to the test by means
of a flow experiment spanning 28 h, in which 4.60 g of allylated
product were obtained (TON of 282, productivity of 2.22
mmol h−1 gresin−1) without a decrease in activity. Thus, we
believe that the recyclability and robustness of PS-TRIP make
it an interesting alternative to the already successful
homogeneous version.
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Letter

ACS Catalysis

Figure 2. Experimental setup for the continuous flow catalytic enantioselective allylation.

■

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ASSOCIATED CONTENT

S
* Supporting Information

The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.6b02621.
Synthetic procedures, characterization data, copies of
NMR spectra, and HPLC chromatograms (PDF)

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: crodriguez@iciq.es.
*E-mail: mapericas@iciq.es.
Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS
This work was funded by the Institute of Chemical Research of
Catalonia (ICIQ) Foundation, MINECO (Grant CTQ201569136-R and FPI predoctoral grant to L. C.-A) and DEC
Generalitat de Catalunya (Grant 2014SGR827). We also thank
MINECO for a Severo Ochoa Excellence Accreditation 2014−
2018 (SEV-2013-0319).

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