Efficient separation of a trifluoromethyl substituted organocatalyst: Just add water

Article abstract of DOI:10.1039/b908967e

A practical, cost-saving tagging approach is developed which takes advantage of the hydrophobicity of trifluoromethyl groups, exemplified by the application and recovery of a CBS precatalyst using tuned aqueous-organic media with minimum 50% water content

Full text of DOI:10.1039/b908967e

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Efficient separation of a trifluoromethyl substituted organocatalyst:
just add waterw
´ ´
Zoltan Dalicsek, Ferenc Pollreisz and Tibor Soos*
Received (in Cambridge, UK) 6th May 2009, Accepted 28th May 2009
First published as an Advance Article on the web 17th June 2009
DOI: 10.1039/b908967e
A practical, cost-saving tagging approach is developed which
takes advantage of the hydrophobicity of trifluoromethyl groups,
exemplified by the application and recovery of a CBS precatalyst
using tuned aqueous–organic media with minimum 50% water
content.
Furthermore, there is growing environmental concern about
long-chain perfluoroalkyl compounds with uncertainty regarding
their bioaccumulation and potential toxicity to populations
over long term exposure.8 These challenges provide an impetus
for the development of tagging approaches which utilize
alternative motifs,9 and in our case the trifluoromethyl
group,10 the smallest perfluorinated tag, is
a chemical
Organocatalyst development in asymmetric synthesis is a
frontier activity in modern organic chemistry.1 This field has
witnessed recent and rapid innovations which have extended
the scope and repertoire in asymmetric synthesis. Although
these catalysts are chemically more stable than metal based
catalysts, the catalytic activity (TOF) displayed by organo-
catalysts remains poorer in general. In order to attain high
turnover numbers for these valuable catalysts, their recovery
and reuse is a current research focus of intense interest.2
Various approaches have been explored, including soluble
and insoluble supports, fluorous and ionic liquid tagging.3
Despite promising results, the relatively high cost of the tagged
catalysts and their often tedious synthesis limit their wide-
spread utility. Herein, we report a practical, low-cost tagging
and separation approach which takes advantage of trifluoro-
methyl groups as a hydrophobic tag. The method is applied to
the well-known organocatalyst 44 which as a result can be
easily separated if tuned aqueous media are used.
functionality already used widely in pharmaceuticals and
agrochemicals. Also there is no doubt that it is particularly
attractive to achieve alternative extraction protocols without
having to resort to any fluorous solid or liquid media.
To assess the possibility of trifluoromethyl tag based
catalyst recovery in CBS methodology, we have synthesized
three different prolinols 2–4 with an increasing number of
trifluoromethyl groups (n = 0, 2, 4, Fig. 1).
Eluting these prolinols 2–4 on C-18 reversed phase TLCw
using MeOH as a mobile phase, however, there was no
separation. Nevertheless, by gradually increasing the water
content11 a point was reached (MeOH–H2O, 1 : 1 vol. ratio)
where prolinol 4 was retained but non-tagged prolinol 2
(representing also a ‘‘general organic molecule’’) eluted
efficiently.12 This observation clearly demonstrates the influence
that the small ‘‘superhydrophobic’’ CF3 group can exert on the
chromatographic characteristics of appropriately tagged
molecules, when combined with a tuned organic solvent
system with relatively high water content.
Our laboratory has recently reported the development of an
operationally straightforward and recoverable fluorous CBS
methodology.5 The fluorous tagging6 enabled the organo-
catalyst 1 (Fig. 1) to function in homogeneous conditions
and promoted the chiral secondary alcohol formation with
high enantioselectivity. Moreover, the precatalyst 1 could be
easily and efficiently recovered using fluorous solid-phase
extraction. A further development of this protocol was
recently reported by Curran et al., who employed the hydro-
fluoroether HFE-7500 as a solvent.7 The fluorous catalyst was
secured in the hydrofluoroether by fluorous affinity but the
organic product could be separated by washing HFE-7500
phase with a polar solvent.
After identification of the minimally decorated fluorous
prolinol 4 as a recoverable catalyst precursor it was explored
as a precatalyst in asymmetric CBS reductions (Table 1).
Accordingly, acetophenone (5a) was tested as a substrate for
reduction in THF at room temperature. The protocol involved
Although perfluorohexyl and perfluorooctyl affinity tags
have gained widespread use in fluorous catalyst immobiliza-
tion, these tags retain drawbacks. Besides the elaborate nature
of many of Rf6 and Rf8 tagged catalysts (e.g. catalyst 1), their
costs are high particularly for process development prospects.
Chemical Research Center of Hungarian Academy of Sciences,
P. O. Box 17, Budapest, H-1525, Hungary.
E-mail: tibor.soos@chemres.hu; Fax: +36 1438-1145;
Tel: +36 1438-1110
w Electronic supplementary information (ESI) available: Experimental
procedures, spectroscopic data, reversed phase HPLC experiments
and description of U-tube extractor. See DOI: 10.1039/b908967e
Fig. 1 Synthesized 1–4 diphenyl prolinols.
Chem. Commun., 2009, 4587–4589 | 4587
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Table 1 Asymmetric reduction of 5a–d using phase tagged prolinol
precatalyst 4
Table 2 Leaching of prolinol 4 into products after SPE extractions
Entry
Support/SPE cartridge
6ab
6bb
6cc
6db
1a
2a
3a
4a
g-Al2O3/FSPE
14.2
3.8
3.1
5.4
—
—
1.5
2.6
—
—
—
—
g-Al2O3/C-18 SPE
a-Al2O3/C-18 SPE
a-Al2O3/a-Al2O3
o0.01
o0.01
0.2
2.7
a
Entry Substrate Additive Reducing agent Yielda (%) eeb (%)
Given in percentage, 100% was the original catalyst load.
c
MeOH–water 1 : 1 (vol. ratio) was used. DMF–water 1 : 1
b
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5a
5b
5b
5c
5c
5d
5d
5d
5d
—
—
—
BH3 THF
BH3 THF
BH3 THF
82c
83d
85e
85f
89g
87f
90g
81e
82f
76f
96h
96i
96i
16
76
90
94
94
95
95
87
94
98
98
98
98
(vol. ratio) proved to be a better solvent for highly apolar compounds.
B(OMe)3 BH3 DMS
B(OMe)3 BH3 DMS
B(OMe)3 BH3 DMS
B(OMe)3 BH3 DMS
gel was explored. In the event, C-18 SPE cartridges efficiently
(Table 2, entry 2) separated the minimally decorated 4 from
non-tagged product 6a using the same aqueous solvent
systemw. Interestingly, this non-fluorous protocol proved to
be a better alternative for extraction in binary separation, even
with the relatively high fluorine content (43%) of 4. However,
in both cases a technical problem arose from the wettability of
the solid supports: the large proportion of water in the eluent
increased the resistance of the loaded cartridges which resulted
in a slow filtration. To reduce this effect, the less wettable
corundum (a-Al2O3) was evaluated as a mechanical support.
This modification did facilitate the filtration and it also
improved the separation efficiency (Table 2, entry 3). This
new separation method was then applied to work-up of CBS
reductions and it proved relatively easy and efficient to
separate the chemically robust catalyst precursor 4 from both
apolar alcohols 6b, 6c and the more polar 6d. Although it was
anticipated that the alumina would function only as a mechanical
support, these outcomes indicate that corundum can also
enhance separation. Interestingly, the replacement of C-18
SPE with corundum resulted in only slightly higher leaching
of 4 into the products (Table 2, entry 4). These observations
suggest a future role for a-Al2O3 in work-up procedures.
Encouraged by the above results, the separation methodology
was now extended to liquid–liquid extraction, which is more
amenable to scale up. It was again an objective to avoid
fluorous solvents.13 Due to the unrivaled fluorophobicity of
water, the partitioning of tagged 4 between a biphasic
hexanes–MeOH or acetonitrile (ACN) can now be modulated
by the addition of water. For example, partitioning of the
quenched reaction mixture of 6d into hexanes–aqueous ACN
(4 : 1) resulted in the complete separation of two functionally
similar aminols (with no requirement for pH dependent separa-
tion), 4 and 6d after only one extraction (Table 1, entry 11).
The pyridinol 6d remained in the water–ACN phase, while the
tagged precatalyst 4 was recovered (499.5%, efficiency) from
the hexane phase. Furthermore, the phase tagged
precatalyst 4 proved to be sufficiently robust to withstand
several reaction cycles, and it could be recycled without any
deleterious effect on the yield and the enantioselectivity
(Table 1, entries 12 and 13).
—
BH3 THF
9
B(OMe)3 BH3 DMS
B(OMe)3 BH3 DMS
B(OMe)3 BH3 DMS
B(OMe)3 BH3 DMS
B(OMe)3 BH3 DMS
10
11
12
13
a
b
Isolated yields. Determined by chiral HPLC (Chiralcel OD or OJ).
d
The substrate was added in one portion. The reducing agent
c
e
was added dropwise within 1 h. The substrate was added dropwise
f
within 1 h. In situ generation of oxazaborolidine using 10 mol%
additive and 2.0 mmol of 5a–d was added dropwise within 1 h followed
g
by solid-phase extractive work-up. Performed in 25 mmol scale
h
and isolated with U-tube method. Performed in 25 mmol scale and
i
isolated with liquid–liquid extraction. Recycling experiments in
25 mmol scale with liquid–liquid extractive work-up.
the in situ generation of the catalyst, to circumvent the
independent synthesis of the catalytically active oxazaborolidine,
and thus efficient recycling of precatalyst 4 became the
objective rather than the hydrolytically sensitive catalyst.
Optimization of the experimental parameters revealed that
both the reducing agent and the mode of addition had a
pronounced effect on the resultant enantioselectivities
(Table 1, entries 1–4). After optimization of reaction conditions
(entry 4), a range of polar and apolar aromatic substrates were
explored (entries 6, 9 and 10). The enantioselectivities were
high in all cases and they were not further optimized.
Then we sought to examine the feasibility of binary separation
of the tagged precatalyst 4 from the reaction products 6a–d
using solid-phase extraction (SPE) and/or liquid–liquid
extractions. Since prolinol 4 can be viewed as a refinement
of fluorous prolinol 1, in the first instance fluorous silica gel
was explored for solid-phase extraction (FSPE). On consump-
tion of the acetophenone (5a), the reaction mixture was
quenched, evaporated onto Brockman II type neutral alumina
(g-Al2O3) and loaded onto the FSPE cartridge. This overcame
a technical difficulty of manipulating the small scale reaction
and allowed reliable and reproducible data. As expected from
the preceding solvent tuning experiments, minimally tagged 4
could be separated from the reaction products using
water–MeOH (1 : 1) as the eluent. The reaction product 6a
eluted well after washing the loaded cartridge with the aqueous
solvent, but the eluent contained 14.9% of the precatalyst 4
(Table 2, entry 1). A second-pass elution with THF then
removed the retained precatalyst 4 having no detectable
product contamination. In order to investigate a completely
non-fluorous extraction protocol, C-18 reversed phase silica
Although the less polar reaction products 6a and b were also
separated by the above method, repetitive extraction of the
hexane phase was necessary to obtain a full separation. For
large-scale reactions this could clearly generate aqueous waste
volume, which should be avoided. With this limitation in mind
we have designed an apparatus to minimize the quantity of
aqueous–organic blended phases for these extraction
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This journal is The Royal Society of Chemistry 2009
4588 | Chem. Commun., 2009, 4587–4589

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tagged prolinol 4). Moreover, the developed separation
protocols rely on cheap traditional solvents13 and inorganic
adsorbent. Therefore, the main attractive feature of our
separation methodology is its extraordinary technical and
synthetic simplicity and low cost. The extension of this
minimal decoration approach toward other relevant reactions
(e.g. Wittig, Suzuki, Mitsunobu and Appel reactions) was
successful and will be reported shortly.
We thank MOTIM Ltd. for
a generous donation of
corundum. A grant OTKA K-69086 is gratefully acknowledged.
Notes and references
Fig. 2 Novel continuous U-tube extractor. (a) Feeding hexanes
solution containing crude reaction mixture: precatalyst 4 and the
products 6a or 6b. (b) Aqueous methanol (1 : 1 vol. ratio) liquid
membrane. (c) Receiver hexanes solution. (d) Inner tube with a porous
glass ‘‘frit’’ at the bottom. (e) Syphon. (f) Distillating pot containing
hexanes.
¨
1 (a) A. Berkessel and H. Groger, Asymmetric Organocatalysis,
Wiley-VCH, Weinheim, 2005; (b) Enantioselective Organocatalysis,
ed. P. I. Dalko, Wiley-VCH, Weinheim, 2007.
2 Recent reviews: (a) F. Cozzi, Adv. Synth. Catal., 2006, 348, 1367;
(b) M. Benaglia, New J. Chem., 2006, 30, 1525;
(c) M. Gruttadauria, F. Giacalone and R. Noto, Chem. Soc.
Rev., 2008, 37, 1666.
protocols (Fig. 2).w This apparatus is a straightforward
combination of a U-tube and a continuous extractor and it
generates a sustainable chemical gradient of the extracted
materials between the feeding and receiver arm of the U-tube.
Additionally, the applied aqueous–methanol phase functions
as a liquid membrane, allowing a selective passive transport of
the non-tagged organic products 6a and b but retains the
precatalyst 4 in the feeding hexanes solution. Thus, the
continuously distilled hexanes extract the reaction products
6a and b from the aqueous methanol until no more product is
left in the feeding arm (precatalyst 4 was recovered with
499% efficiency). Finally, the products 6a and b were
obtained after concentration of the distillation reservoir
(Table 1, entries 5 and 7). This straightforward liquid
membrane methodology offers distinct advantages over
conventional liquid–liquid separation techniques. It uses less
solvent and organic waste residues are substantially reduced.
In summary, CF3 groups are shown to be a sufficient and
practical design element for catalyst immobilization in combi-
nation with an optimized aqueous extraction solvent system.14
Importantly, this approach offers an efficient alternative to the
widely explored practice of appending long perfluoroalkylated
C4, C6, C8 segment(s) or other soluble polymers for the
homogeneous recovery of organocatalysts. Also, this minimal
CF3 tagging approach results in a relatively low molecular
weight immobilized catalyst which is clearly beneficial when
relatively high catalyst loading is required (e.g. 10 mol%) as is
the case currently in the field of organocatalysis.1,2a There are
limitations and clearly the larger the organic motif in a given
situation, the more CF3 groups will be required for efficient
performance. Solvent tuning is a critical and important
aspect, although there is a lot of latitude and up to 50%
water–co-solvent mixtures are able to dissolve organic
molecules positioned across a broad polarity range (even the
apolar naphthyl derivate 6c can be separated effectively from
3 Selected recent papers: (a) S. H. Youk, S. H. Oh, H. S. Rho,
J. E. Lee, J. W. Lee and C. E. Song, Chem. Commun., 2009, 2220;
(b) B. Ni, Q. Zhang, K. Dhungana and A. D. Headleyv, Org. Lett.,
2009, 11, 1037; (c) S. Luo, J. Li, L. Zhang, H. Xu and J.-P. Cheng,
Chem.–Eur. J., 2008, 14, 1273; (d) F. O. Seidel and J. A. Gladysz,
Adv. Synth. Catal., 2008, 350, 2443; (e) P. Yu, J. He and C. Guo,
Chem. Commun., 2008, 2355; (f) V. Polshettiwar, B. Baruwati and
R. S. Varma, Chem. Commun., 2009, 1837.
4 Selected paper and review: (a) Y. Hayashi, T. Itoh, S. Aratake and
H. Ishikawa, Angew. Chem., Int. Ed., 2008, 47, 2082;
(b) A. Lattanzi, Chem. Commun., 2009, 1452.
´
5 Z. Dalicsek, F. Pollreisz, A. Gomory and T. Soo
´
s, Org. Lett., 2005,
¨
¨
7, 3243.
6 (a) Handbook of Fluorous Chemistry, ed. J. A. Gladysz,
I. T. Horvath, D. P. Curran, Wiley-VCH, NewYork, 2004.
´
7 Q. Chu, M. S. Yu and D. P. Curran, Org. Lett., 2008, 10, 749.
8 Selected papers: (a) M. A. J. Dinglasan, Y. Ye, E. A. Edwards and
S. A. Mabury, Environ. Sci. Technol., 2004, 38, 2857; (b) C. Lau,
K. Anitole, C. Hodes, D. Lai, A. Pfahles-Hutchens and J. Seed,
Toxicol. Sci., 2007, 99, 366.
9 Recent efforts to use shorter Rf4 fluorous tag: (a) D. Szabo
´
,
J. Mohl, A.-M. Balint, A. Bodor and J. Rabai, J. Fluorine Chem.,
´
´
2006, 127, 1496; (b) Q. Chu, C. Henry and D. P. Curran, Org.
Lett., 2008, 10, 2453.
10 Recent paper reports the smooth biodegradation of C6H5CF3:
N. Iwai, R. Sakai, S. Tsuchida, M. Kitazume and T. Kitazume,
J. Fluorine Chem., 2009, 130, 434.
11 The advantageous effect of water on the separation and partition
coefficient in fluorous chemistry: (a) V. Montanari and K. Kumar,
J. Am. Chem. Soc., 2004, 126, 9528; (b) M. S. Yu, D. P. Curran and
T. Nagashima, Org. Lett., 2005, 10, 3677.
12 In a similar experience, gradual addition of water to the ACN
mobile phase resulted in significant and non-linear differences in
the retention times of protected prolinols IIa–c in RP-HPLC
experiments. Based on these experiments, we conclude that the
observed retention of 4 was the result of its high affinity to the TLC
stationary phase and not the low solubility in the applied eluent
(22 mg mLÀ1). See ESIw.
13 Insight into the solvent selection in industry: H.-U. Blaser and
M. Studer, Green Chem., 2003, 5, 112.
14 Selected examples for related polar–apolar separation:
(a) D. E. Bergbreiter, P. L. Osburn, T. Smith, C. Li and
J. D. Freis, J. Am. Chem. Soc., 2003, 125, 6254; (b) M. Heiden
and H. Plenio, Chem.–Eur. J., 2004, 10, 1789.
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