CBS reductions with a fluorous prolinol immobilized in a hydrofluoroether solvent

Article abstract of DOI:10.1021/ol702778v

A fluorous prolinol precatalyst bearing only 34 fluorine atoms has been immobilized in the hydrofluoroether solvent HFE-7500. The CBS reduction of acetophenone proceeded rapidly, in high yield and in high ee in the absence of any organic solvent. The organic product was stripped from the HFE-7500 phase with a polar solvent, and the HFE-7500 phase was reused as is with satisfactory results through eight runs. This process is an attractive prototype for the large-scale use, recovery, and reuse of fluorous organocatalysts.

Full text of DOI:10.1021/ol702778v

ORGANIC
LETTERS
2008
Vol. 10, No. 5
749-752
CBS Reductions with a Fluorous
Prolinol Immobilized in a
Hydrofluoroether Solvent
Qianli Chu,†,‡ Marvin S. Yu,*,† and Dennis P. Curran*,‡
Fluorous Technologies, Inc., UPARC, 970 William Pitt Way, Pittsburgh,
PennsylVania 15238, and Department of Chemistry, UniVersity of Pittsburgh,
Pittsburgh, PennsylVania 15260
curran@pitt.edu
Received November 19, 2007
ABSTRACT
A fluorous prolinol precatalyst bearing only 34 fluorine atoms has been immobilized in the hydrofluoroether solvent HFE-7500. The CBS
reduction of acetophenone proceeded rapidly, in high yield and in high ee in the absence of any organic solvent. The organic product was
stripped from the HFE-7500 phase with a polar solvent, and the HFE-7500 phase was reused “as is” with satisfactory results through eight
runs. This process is an attractive prototype for the large-scale use, recovery, and reuse of fluorous organocatalysts.
As the field of organocatalysis expands,1-3 the efficient
separation of such catalysts from reaction products becomes
an increasingly important aim.4 The high loading levels
typically used with organocatalysts (often 10-20 mol %)
make them inherently less atom economical than many
transition metal catalysts, but this potential disadvantage can
be offset to a degree on large scale by efficient protocols
for recovery and reuse.5 Consequently, a variety of recyclable
analogues of organocatalysts have been synthesized and
studied. Most of these catalysts have phase tags6 (polymer,7
ionic liquid,8 other9), but it can be difficult to identify tagged
catalysts whose reactivity and selectivity levels match those
of their parents.
Light fluorous reagents and reactants often show similar
selectivities to their non-fluorous analogues,10 and indeed
several promising light fluorous organocatalysts have recently
† Fluorous Technologies, Inc.
‡ University of Pittsburgh.
(1) (a) Berkessel, A., Gro¨ger, H., Eds. Asymmetric Organocatalysis:
From Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley-
VCH: Weinheim, 2005. (b) Christmann, M., Bra¨se, S., Eds. Asymmetric
Synthesis: the Essentials; Wiley-VCH: Weinheim, 2007, 161-221. (c)
Dalko, P. I., Ed. EnantioselectiVe Organocatalysis: Reactions and Experi-
mental Procedures; Wiley-VCH: Weinheim, 2007.
(2) For selected reviews on organocatalysis: (a) Dalko, P.; Moisan, L.
Angew. Chem., Int. Ed. 2004, 43, 5138-5175. (b) Houk, K. N.; List, B.
Acc. Chem. Res. 2004, 37, 487-631. (c) Lelais, G.; MacMillan, D. W. C.
Aldrichimica Acta 2006, 39, 79-87. (d) Kocˇovsky´, P.; Malkov, A.
Tetrahedron 2006, 62, 255-502.
(3) For a series of focused reviews on organocatalysis, see: List, B.
Chem. ReV. 2007, 107, 5413-5415 and subsequent articles in the Special
Issue.
(5) Blaser, H. U., Schmidt, E., Eds. Asymmetric Catalysis on Industrial
Scale; Wiley-VCH: Weinheim, 2004.
(6) (a) Curran, D. P. Angew. Chem., Int. Ed. 1998, 37, 1175-1196. (b)
Yoshida, J.; Itami, K. Chem. ReV. 2002, 102, 3693-3716.
(7) (a) Alza, E.; Cambeiro, X. C.; Jimeno, C.; Perica`s, M. A. Org. Lett.
2007, 9, 3717-3720. (b) Selka¨la¨, S. A.; Tois, J.; Pihko, P. M.; Koskinen,
A. M. P. AdV. Synth. Catal. 2002, 344, 941-945. (c) Benaglia, M.;
Celentano, G.; Cinquini, M.; Puglisi, A.; Cozzi, F. AdV. Synth. Catal. 2002,
344, 149-152.
(8) Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J. Angew. Chem.,
Int. Ed. 2006, 45, 3093-3097.
(9) Zhang, Y.; Zhao, L.; Lee, S. S.; Ying, J. Y. AdV. Synth. Catal. 2006,
348, 2027-2032.
(4) (a) De Vos, D. E., Vankelecom, I. F. J., Jacobs, P. A., Eds. Chiral
Catalyst Immobilization and Recycling; Wiley-VCH: Weinheim, 2000. (b)
Corma, A.; Garcia, H. AdV. Synth. Catal. 2006, 348, 1391-1412.
(10) (a) Curran, D. P. In The Handbook of Fluorous Chemistry; Gladysz,
J. A., Curran, D. P., Horvath, I. T., Eds.; Wiley-VCH: Weinheim, 2004;
pp 128-156. (b) Curran, D. P. Aldrichimica Acta 2006, 39, 3-9.
10.1021/ol702778v CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/13/2008

been introduced by us and others.11 Representative structures
are shown in Figure 1. These catalysts are typically recovered
study of mutual solubilities of HFEs with organic solvents16
suggested that solvents like HFE-7500 (C3F7CF(OC2H5)CF-
(CF3)2, Figure 2) might be able to immobilize organocatalysts
Figure 2. Structure and selected properties of HFE-7500.
with only two fluorous tags. HFE-7500 is commercially
available17 and has many attractive features for industrial
use.18
Enantioselective borane reductions of ketones in the
presence of chiral proline-derived oxazaborolides (Corey-
Bakshi-Shibata or CBS catalysts) are commonly used to
make chiral secondary alcohols.19 Beyond CBS catalysts,
there are now many organocatalysts that feature a proline
derivative as a central element.1,2 On the heels of the
introduction of fluorous prolinols by Bolm,11a Soo´s and co-
workers used 1 (Figure 1) as a catalyst in CBS reductions.11b
Like reactions of other light fluorous catalysts, these reactions
were conducted in an organic solvent (THF), and the
precatalyst was recovered by a workup process that included
fluorous solid-phase extraction. Yields and selectivities were
comparable to the non-fluorous precatalyst. With this back-
drop, we set out to develop conditions for reaction and
recovery of 1 that involved only liquid-liquid separations.
Fluorous prolinol 1 was prepared according to the reported
five-step procedure and was obtained in gram quantities in
35% overall yield.11a,b,20 With 34 fluorine atoms and 56%
fluorine by molecular weight, the prolinol is not expected
to be applicable to traditional biphasic processes that use
perfluorocarbons as the fluorous phase. Indeed, 1 is soluble
in typical organic solvents (THF, Et2O, CH2Cl2) and is not
expected to have high partition coefficients into FC-72.11a
As a prelude to biphasic reactions, we first conducted a
standard reduction with 1 in THF, followed by extractive
workup with HFE-7500 (Scheme 1, Procedure A). According
to the usual procedure, BH3 (1 equiv) in THF was added to
prolinol 1 (0.1 equiv) in THF at room temperature. After 1
Figure 1. Selected organocatalysts with fluorous tags.
by fluorous solid-phase extraction,12 a process that is well
suited for small-scale reactions, but less so for large-scale
ones.
Liquid-liquid biphasic separations (fluorous biphasic
reactions) are convenient for large-scale chemical processes,
but very large fluorous phase tags are usually used.13 These
tags bear at least 50 fluorines, often many more, so the
catalysts have high molecular weights and can be complex
and costly to make. This may not be a problem for
organometallic catalysts, provided that the catalyst levels are
low. However, it is a problem for organocatalysts, which
are commonly used in high-loading levels. Also, perfluoro-
alkane solvents are usually used for fluorous biphasic
reactions, but the environmental persistence of these solvents
detracts from their use on large scale.
Several groups have recently shown that hydrofluoroethers
(HFEs, RfOR) have favorable reaction and separation
properties, and can often be used to replace traditional
perfluoroalkane solvents with considerable advantage in
fluorous/organic liquid-liquid processes.14,15 A systematic
(11) Fluorous prolinols: (a) Park, J. K.; Lee, H. G.; Bolm, C.; Kim, B.
M. Chem. Eur. J. 2005, 11, 945-950. (b) Dalicsek, Z.; Pollreisz, F.;
Gomory, A.; Soo´s, T. Org. Lett. 2005, 7, 3243-3246. (c) Zu, L.; Li, H.;
Wang, J.; Yu, X.; Wang, W. Tetrahedron Lett. 2006, 47, 5131-5134. (d)
Goushi, S.; Funabiki, K.; Ohta, M.; Hatano, K.; Matsui, M. Tetrahedron
2007, 63, 4061-4066. (e) Cui, H.; Li, Y.; Zheng, C.; Zhao, G.; Zhu, S. J.
Fluorine Chem. 2008, 129, 45-50. Other fluorous organocatalysts: (f) Zu,
L. S.; Wang, J.; Li, H.; Wang, W. Org. Lett. 2006, 8, 3077-3079. (g)
Chu, Q. L.; Zhang, W.; Curran, D. P. Tetrahedron Lett. 2006, 47, 9287-
9290.
(12) (a) Curran, D. P. In The Handbook of Fluorous Chemistry; Gladysz,
J. A., Curran, D. P., Horvath, I. T., Eds.; Wiley-VCH: Weinheim, 2004;
pp 101-127. (b) Zhang, W.; Curran, D. P. Tetrahedron 2006, 62, 11837-
11865.
(15) Ryu, I.; Matsubara, H.; Emnet, C.; Gladysz, J. A.; Takeuchi, S.;
Nakamura, Y.; Curran, D. P. In Green Reaction Media in Organic Synthesis;
Blackwell: Ames, IO, 2005; pp 59-124.
(16) Chu, Q.; Yu, M. S.; Curran, D. P. Tetrahedron 2007, 63, 9890-
9895.
(17) HFE-7500 is a product of the 3M Novotec line of engineering
fluids: http://products3.3m.com/catalog/. Current list prices for HFE fluids
range from $50 to $90/L.
(13) Gladysz, J. A.; Emnet, C.; Rabai, J. In The Handbook of Fluorous
Chemistry; Gladysz, J. A., Curran, D. P., Horvath, I. T., Eds.; Wiley-VCH:
Weinheim, 2004; pp 56-100.
(14) (a) Fukuyama, T.; Arai, M.; Matsubara, H.; Ryu, I. J. Org. Chem.
2004, 69, 8105-8107. (b) Matsubara, H.; Maeda, L.; Ryu, I. Chem. Lett.
2005, 34, 1548-1549. (c) Mizuno, M.; Goto, K.; Miura, T.; Inazu, T. QSAR
Comb. Sci. 2006, 25, 742-752. (d) Yu, M. S.; Curran, D. P.; Nagashima,
T. Org. Lett. 2005, 7, 3677-3680. (e) Curran, D. P.; Bajpai, R.; Sanger, E.
AdV. Synth. Catal. 2006, 348, 1621-1624.
(18) According to the 3M Product Information Sheet, HFE-7500 is not
flammable, does not cause ozone depletion, has much lower global warming
potential than perfluorocarbons or perfluoroethers, and is not expected to
be classified as a volatile organic chemical (VOC) by the U.S. EPA.
(19) (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986-
2012. (b). Burkhardt, E.; Matos, K. Chem. ReV. 2006, 106, 2617-2650.
(20) (a) Intermediates for this synthesis are commercially available from
Fluorous Technologies, Inc. (b) D.P.C. owns an equity interest in this
company.
750
Org. Lett., Vol. 10, No. 5, 2008

Scheme 1. Fluorous CBS Reductions of Acetophenones,
Procedures A-C, 0.5 mmol scale
Table 1. Fluorous CBS Reduction of Acetophenone in
HFE-7500/THF with Different Precatalyst Loadings, Procedure
B
entry
precatalyst (equiv)
conversiona (%)
eeb (%)
1
2
3
4
0.1
>99
>99
>99
42
93
84
83
54
0.05
0.025
0.005
a Determined by GC analysis on a Hewlett-Packard 5890 instrument with
split mode (column: 30 m x 0.32 mm x 0.25 mm HP-1 methyl siloxane).
b Determined by HPLC analysis on a Chiracel OD column (hexane/
isopropanol, 98:2; flow, 1 mL/min; λ ) 210 nm).
a Removes the product from the HFE-7500 phase prior to recycle.
bWash solvent for the HFE-7500 phase prior to recycle.
eroded to 84%, while at 0.5 mol % (0.005 equiv), it was
only 54%. These results suggest that any recycle process
starting with 10% precatalyst will begin to suffer decreased
selectivity when half of the precatalyst has decomposed or
leached, if not before.21 Further, because high precatalyst
loading is essential, recovery and reuse is especially impor-
tant.
To test the recycling possibilities for Procedure B, we
began by repeating the experiment with 10% precatalyst
loading and obtained comparable results (compare entries 1
in Tables 1 and 2). Now, the HFE-7500 phase was not
h, acetophenone (0.5 mmol, 1 equiv) in THF was added.
Reaction progress was followed by GC, and after 1 h, the
reaction was quenched with methanol, and the solvents were
evaporated.
The residue was partitioned between acetonitrile and HFE-
7500, and the two phases were separated and analyzed by
GC. The acetonitrile phase contained 98% of the (+)-2-
phenylethanol product and no detectable prolinol 1. Evapora-
tion of the acetonitrile provided 2-phenylethanol in 96%
yield, 97% GC purity, and 92% ee. The HFE-7500 phase
contained the remaining 2% of the 2-phenylethanol along
with all of the fluorous prolinol 1. Evaporation of this phase
and vacuum drying (removes the residual 2-phenylethanol)
provided 1 in 99% yield in comparable purity (GC, 1H NMR)
to that of the starting sample.
Encouraged by the results with traditional liquid-liquid
extraction, we next explored a procedure where HFE-7500
was used as the primary reaction solvent in place of THF
(Scheme 1, Procedure B). Borane‚THF (1 M in THF, 0.6
equiv) was added to a solution of fluorous prolinol 1 (54.5
mg, 0.1 equiv) in HFE-7500 (2 mL). The resulting solvent
blend is about 90% HFE-7500/10% THF. After 1 h, neat
acetophenone (0.5 mmol) was added. Two hours later, the
reaction was quenched with MeOH (0.1 mL). The HFE-7500
phase was extracted with acetonitrile to strip away the
product, then washed with water, dried, and evaporated.
The acetonitrile layer contained 87% of the (+)-2-
phenylethanol product in 93% ee and was free of fluorous
prolinol 1 (Table 1, entry 1). The remaining 13% of
2-phenylethanol was in the HFE-7500 phase along with the
prolinol 1. The decreased partitioning of 2-phenylethanol in
this experiment compared to that in the previous one is
presumably due to the presence of THF (the reaction solvent
is evaporated in Procedure A but not in Procedure B). In
principle, the presence of small amounts of the product in
the catalyst phase is not a problem, and this phase can be
reused without further processing.
Table 2. Fluorous CBS Reduction of Acetophenone in
HFE-7500/THF with Acetonitrile Extraction, Procedure B
run
borane (equiv)
conversiona (%)
eeb (%)
1
2
3
4
5
6
0.6
1.2
1.2
1.2
1.2
1.2
>99
>99
>99
>99
>99
>99
92
92
89
76
63
45
a Determined by GC analysis on a Hewlett-Packard 5890 instrument with
split mode (column: 30 m x 0.32 mm x 0.25 mm HP-1 methyl siloxane).
b Determined by HPLC analysis on a Chiracel OD column (hexane/
isopropanol, 98:2; flow, 1 mL/min; λ ) 210 nm).
evaporated, but simply dried over molecular sieves and
reused. The same process was repeated five more times, each
time adding the HFE-7500 phase from the prior reaction
cycle to the next reaction cycle along with fresh BH3‚THF
(now 1.2 equiv) and acetophenone. The conversions for all
six reactions were >99% (Table 1), but the high ee was only
maintained through the first three runs. After the sixth run,
the final HFE-7500 phase was concentrated, and the fluorous
prolinol 1 was recovered in 46% yield and about 90% purity.
This corresponds to an average recovery of 88% per run.
To improve this process, we next decided to remove the
THF entirely by using BH3‚DMS (DMS is dimethylsulfide)
(21) These experiments to test for breakdown in ee are important because
the recyclability of catalysts in multiple run experiments can be made to
look artificially high simply by overloading the initial charge. See: Gladysz,
J. A. Pure Appl. Chem. 2001, 73, 1319-1324.
Similar experiments were then conducted at lower pre-
catalyst loadings, as summarized in Table 1, entries 2-4.
When the loading was reduced to 5% (0.05 equiv), the ee
Org. Lett., Vol. 10, No. 5, 2008
751

in place of BH3‚THF, and to replace the acetonitrile
extraction solvent with the more fluorophobic DMSO
(Scheme 1, Procedure C). These changes should favor the
partitioning of both organic and fluorous components into
their respective phases. To simplify the recycling, we also
omitted the water wash and drying of the HFE-7500 phase.
Thus, after stripping the product into DMSO, the HFE-7500
phase was used directly in the next run.
Pretreatment of 1 with B(OMe)3 is not needed. The ethylene-
spacer fluorous prolinol could be recovered by low-temper-
ature precipitation, but its reuse provided a product with low
ee.
More generally, the convenient procedures in this work
differ from most other fluorous biphasic processes in that
there is no thermomorphic component (heating or cooling).22
The reaction and separation processes both take place at
ambient temperatures.
A cycle of nine runs was conducted by Procedure C, and
the results are shown in Table 3. Even though the reaction
Further, Procedure C is a rare example of fluorous catalysis
without organic solvents,23 a type of process that has high
potential in sustainable chemistry applications. Gladysz and
co-workers have described a hydroboration reaction catalyzed
by a fluorous rhodium complex immobilized in perfluoro-
methylcyclohexane.24 This catalyst has 117 fluorine atoms
compared to the 34 fluorine atoms of 1. Ryu and co-workers
immobilized a palladium species bearing 21 fluorines in
F-626 (a high-boiling perfluoroalkyl alkyl ether).14a
Ryu’s results and those herein show the potential perfor-
mance advantage of the hydrofluoroether solvents over
perfluorocarbons in fluorous catalysis; they are more polar
and hence better reactions solvents, and they allow the use
of catalysts with lower fluorine content. Accordingly, while
Procedure C uses an organic solvent (DMSO) to strip the
product from the catalyst phase, we propose that it will be
possible to develop other processesswith either organic or
organometallic catalystssin which the precursor is added
directly to the HFE phase and later the product is harvested
by simple phase separation. Such processes are attractive
because they have no organic solvent at either the reaction
or separation.
In summary, a fluorous prolinol precatalyst bearing only
two fluorous chains has been effectively immobilized in the
hydrofluoroether solvent HFE-7500. The CBS reduction of
acetophenone proceeded rapidly and in high yield in this
medium, in the absence of any organic solvent. The organic
product was readily recovered by stripping it from the HFE-
7500 phase with a polar solvent. The catalyst phase was
directly reused with satisfactory results through eight runs.
This process is an attractive prototype for the large-scale use,
recovery, and reuse of fluorous organocatalysts.
Table 3. Fluorous CBS Reduction of Acetophenone in Neat
HFE-7500 with DMSO Extraction, Procedure C
run
borane (equiv)
conversiona (%)
eeb (%)
1
2
3
4
5
6
7
8
9
0.6
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
>99
>99
99
>99
98
>99
>99
98
94
95
94
93
93
90
91
88
74
>99
a Determined by GC analysis on a Hewlett-Packard 5890 instrument with
split mode (column: 30 m x 0.32 mm x 0.25 mm HP-1 methyl siloxane).
b Determined by HPLC analysis on a Chiracel OD column (hexane/
isopropanol, 98:2; flow, 1 mL/min; λ ) 210 nm).
solvent is now only HFE-7500 (there is no THF cosolvent),
the reaction was still complete in 2 h, and the ee of the
product was even marginally increased to 94%. This time,
the ee was much more satisfactory on recycle, remaining
essentially constant through the first five runs, then slowly
dropping down to 88% by the eighth run.
In run 9, the first large decrease in ee was observed (74%),
and the process was terminated. The HFE-7500 phase was
concentrated, and fluorous prolinol 1 was recovered in 54%
yield (average 94% yield per cycle) and about 90% purity.
The recovered catalyst was purified by flash chromatography
and later reused for other experiments. The nine DMSO
phases were combined and diluted with brine, and this phase
was extracted with ether. After concentration and flash
chromatography, (+)-2-phenylethanol was isolated in 84%
combined yield with 99% CG purity. In total, 0.05 mmol of
prolinol 1 (54.5 mg) was used to completely reduce 4.5 mmol
of acetophenone, providing 3.9 mmol (474 mg) of (+)-2-
phenylethanol in >90% ee.
Acknowledgment. F.T.I. thanks the National Science
Foundation (SBIR) and D.P.C. thanks the National Institutes
of Health for funding of this work.
Supporting Information Available: Complete experi-
mental procedures. This material is available free of charge
via the Internet at www.pubs.acs.org.
It is interesting to compare and contrast these new
processes with related fluorous reactions and separations.
Funabiki and co-workers very recently described CBS
reductions with a fluorous prolinol related to 1, but with
ethylene spacers to insulate the C6F13 groups.11d Reactions
in toluene with BH3 gave moderate ees, but high ees were
obtained if the initial CBS reagent was made with B(OMe)3.
OL702778V
(22) Biffis, A.; Braga, M.; Basato, M. AdV. Synth. Catal. 2004, 346, 451-
458.
(23) Gladysz, J. A.; Correa de Costa, R. In The Handbook of Fluorous
Chemistry; Gladysz, J. A., Curran, D. P., Horvath, I. T., Eds.; Wiley-VCH:
Weinheim, 2004; pp 24-40.
(24) Juliette, J. J. J.; Rutherford, D.; Horvath, I. T.; Gladysz, J. A. J.
Am. Chem. Soc. 1999, 121, 2696-2704.
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Org. Lett., Vol. 10, No. 5, 2008