Reverse fluorous solid-phase extraction: A new technique for rapid separation of fluorous compounds

Article abstract of DOI:10.1021/ol049040o

Fluorous-tagged compounds can rapidly be separated from organic (non-tagged) compounds by the new separation technique of reverse fluorous solid-phase extraction (r-fspe). In a reversal of the roles of solid and liquid phases in standard fluorous spe, a mixture is charged to a polar solid phase (standard silica gel) and then eluted with a fluorous solvent or solvent mixture. The organic components of the mixture are retained, while the fluorous components pass.

Full text of DOI:10.1021/ol049040o

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2717-2720
Reverse Fluorous Solid-Phase
Extraction: A New Technique for Rapid
Separation of Fluorous Compounds
Masato Matsugi and Dennis P. Curran*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
curran@pitt.edu
Received May 24, 2004
ABSTRACT
Fluorous-tagged compounds can rapidly be separated from organic (non-tagged) compounds by the new separation technique of reverse
fluorous solid-phase extraction (r-fspe). In a reversal of the roles of solid and liquid phases in standard fluorous spe, a mixture is charged to
a polar solid phase (standard silica gel) and then eluted with a fluorous solvent or solvent mixture. The organic components of the mixture
are retained, while the fluorous components pass.
The separation of fluorous-tagged compounds from organic
compounds has become increasingly popular,1 and early
methods based on liquid-liquid separations2 have been
augmented by solid-liquid separations such as fluorous
solid-phase extraction (fspe) and fluorous chromatography.3
Most of these types of separations rely on a fluorous silica
solid-phase (silica gel with a fluorocarbon bonded phase)
coupled with an organic solvent. We describe herein a new,
complementary separation technique called reverse fluorous
solid-phase extraction. As the name implies, the usual roles
of the liquid and solid phases are reversed in this technique.
Since their introduction in 1997,4 standard fluorous solid-
phase extractions have proven to be broadly useful for
separating light fluorous molecules5 from organic molecules.
As illustrated in Figure 1 (left), a mixture of organic and
fluorous-tagged compounds is loaded onto fluorous silica
gel followed by first-pass elution with a “fluorophobic”
solvent. Polar organic solvents (for example, 80-100%
aqueous methanol or acetonitrile) are the most common
(1) (a) Zhang, W. Tetrahedron 2003, 59, 4475-4489. (b) Curran, D. P.
In Stimulating Concepts in Chemistry; Vo¨gtle, F., Stoddardt, J. F., Shibasaki,
M., Eds.; Wiley-VCH: New York, 2000.
(2) (a) Dobbs, A. P.; Kimberley, M. R. J. Fluorine Chem. 2002, 118,
3-17. (b) Barthel-Rosa, L. P.; Gladysz, J. A. Coord. Chem. ReV. 1999,
192, 587-605.
(3) (a) Curran, D. P. Synlett 2001, 1488-1496. (b) Curran, D. P.
Separations with Fluorous Silica Gel and Related Materials. In The
Handbook of Fluorous Chemistry; Gladysz, J., Horva´th, I., Curran, D. P.;
Wiley-VCH: Weinheim, 2004; pp 101-127.
(4) Curran, D. P.; Hadida, S.; He, M. J. Org. Chem. 1997, 62, 6714-
6715.
(5) (a) Zhang, Q.; Luo, Z.; Curran, D. P. J. Org. Chem. 2000, 65, 8866-
8873. (b) Curran, D. P. A User’s Guide to Light Fluorous Chemistry. In
The Handbook of Fluorous Chemistry; Gladysz, J., Horva´th, I., Curran, D.
P.; Wiley-VCH Weinheim, 2004; pp 128-155.
10.1021/ol049040o CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/16/2004

Figure 2. TLC of 1a-d using reverse fluorous spe conditions.
separations and convenient Rf9 values. Figure 2 shows the
Rf values of benzoate esters (1a-d) on a regular silica gel
TLC plate eluted with 2/1 FC-72/Et2O.
As expected, the Rf values of the esters increased with
their fluorine content. This is the reverse of their behavior
on fluorous silica gel eluting with polar organic solvents.
The fluorous esters 1a-c had significantly higher Rf values
than the ethyl ester 1d.
Control TLC experiments with standard organic solvents
revealed the unique features of using the fluorous solvent
mixture with standard silica gel (Figure 3). For example,
Figure 1. Fluorous solid-phase extractions. Left: a standard
fluorous solid-phase extraction; Right: a new reverse fluorous solid-
phase extraction.
fluorophobic solvents. During this first elution, the non-
tagged organic compound is rapidly washed from the column,
while the fluorous-tagged compound is retained. A second-
pass elution (not shown) with a “fluorophilic” solvent (often
Et2O or THF) then washes the fluorous fraction from the
column.
We hypothesized that the whole process could be
“reversed” by exchanging the characteristics of the fluoro-
philic solid phase with the fluorophobic liquid phase. As
shown in Figure 1 (right), reverse fluorous solid-phase
extraction involves charging of a mixture of organic and
fluorous-tagged compounds to a polar solid phase. First-pass
elution with a fluorous liquid phase should elute the fluorous-
tagged fraction from the column while leaving the organic
fraction behind. If desired, second-phase elution with a
suitable organic solvent should elute the organic fraction.
Since fluorous solvents have only rarely been used in
chromatographic processes,6 we began with simple TLC
experiments with fluorous esters 1a-c and control 1d to
identify useful solvent and solid-phase pairings. By testing
assorted combinations of TLC plates7 (regular silica gel, base-
coated silica gel, C18-silica gel, aluminum oxide, R-cellulose)
and various fluorous solvents8 (FC-72, c-C6F11CF3, C4F9-
OMe, BTF, hexafluoro-2-propanol), we discovered that a
combination of a regular silica gel with mixtures of FC-72/
Et2O or FC-72/hexafluoro-2-propanol provided both good
Figure 3. Comparison of TLC between reverse fluorous spe
conditions and normal conditions.
elution of a mixture of fluorous ester 1a and triphenylphos-
phine on standard silica gel with 100% hexane showed that
triphenylphosphine was the less polar of the two compounds
(Rf values: PPh3, 0.30; 1a, 0.24).10 When the same mixture
was eluted with 2/1 FC-72/Et2O on a silica TLC plate, the
Rf of 1a increased to 0.68, while the Rf of PPh3 decreased
dramatically to 0.03. This decrease reflects the “fluoropho-
bicity” of triphenylphosphine, which has little or no solubility
in FC-72. We conclude that the excellent separation provided
by the fluorous solvents is unique and cannot be reproduced
with the common organic solvents used in silica TLC and
chromatography experiments.
Armed with these results, we next studied preparative
separations of mixtures of fluorous and organic compounds
by reverse fluorous spe. Ryu and co-workers described
allylation of perfluoroalkyl iodides (RfI) with allyl stannanes
to provide allyl perfluoroalkanes.11 In this work, the target
(6) (a) Attaway, J. A.; Barabas, J.; Wolford, R. W. Anal. Chem. 1965,
37, 1289-1295. (b) Attaway, J. A. J. Chromatog. 1967, 31, 231-233. (c)
Blackwell, J. A.; Schallinger, L. A. J. Microcolumn Sep. 1994, 6, 551-
556. (d) Kagan, M. Z. J. Chromatogr. A 2001, 918, 293-302. (e)
Matsuzawa, H.; Mikami, K. Synlett 2002, 1607-1612.
(7) TLC plates used in this study were as follows: regular silica gel,
Silica Gel 60 F254 (MERCK); base-coated silica gel, NH-DM1020 (Fuji
Silysia Chemical Co., Ltd.); C18-silica gel, C18-Silica Gel 60 F254
(MERCK); aluminum oxide, Aluminum oxide 150 F254 (MERCK); and
R-cellulose, AVICEL F Microcrystalline Cellulose (ANALTECH).
(8) FC-72 is a mixture of perfluorohexanes. BTF is benzotrifluoride:
C6H5CF3.
(9) Rf is the chromatographic retention factor, and Rf is a perfluoroalkyl
group.
(10) Rf values in 100% hexane were variable, possibly due to the water
content of the silica gel. However, the relative polarities were not variable.
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Org. Lett., Vol. 6, No. 16, 2004

Table 1. Preparation of 3-(Perfluoroalkyl)prop-1-enes by Reverse Fluorous Solid Phase Extraction
allylated products (fluorous) were separated from the tin
residues (organic) by standard fluorous spe. We conducted
a similar set of reactions with purification by reverse fluorous
spe, and the results of 12 experiments are summarized in
Table 1. A mixture of a perfluoroalkyl iodide (RfI, 0.5
mmol), excess allylstannane (1.0 mmol), and AIBN (10 mol
%) in hexane was heated at reflux for 5 h.12 The reaction
mixture was cooled, concentrated, and charged to a column
containing 6 g of standard silica gel. The column was eluted
with 20 mL of 2/1 FC-72/ether, and the solvent was
evaporated to provide the allylated products 2a-d, 3a-d,
and 4a-d in yields ranging from 69 to 97%. The NMR
spectra of these products were clean, and GC or HPLC
purities exceeded 90% in all cases.13
were allylated as above, and the crude products were directly
subjected to nitrile oxide cycloaddition under oxidative
conditions14 with excess benzaldehyde oxime. TLC of the
crude products using standard organic solvents showed
multiple spots and was suggestive of difficult chromato-
graphic purifications. In contrast, TLC experiments with 2/1
FC-72/ether showed only a single spot (Rf ∼ 0.2) above the
origin. Reverse fluorous spe provided clean isoxazolines
5a-e in 48-68% yield.
The TLC experiments in Figure 3 suggest that reverse
fluorous spe should be useful for removing triphenylphos-
phine and its derived oxide from fluorous compounds. To
show this, we reacted limiting amounts of four fluorous
alcohols 6a-d (0. 5 mmol) with excess (0.75 mmol) butyric
acid, triphenyl phosphine, and aldrichthiol-2 (2,2-dipyridyl
disulfide).15 Reaction for 24 h in refluxing benzene, followed
by cooling and reverse fluorous spe, provided the products
To show that reverse fspe can be used to clean up multistep
sequences, we conducted the sequence of allylation and
nitrile oxide cycloaddition shown in Figure 4. Five iodides
(11) Ryu, I.; Kreimerman, S.; Niguma, T.; Minakata, S.; Komatsu, M.;
Luo, Z.; Curran, D. P. Tetrahedron Lett. 2001, 42, 947-950.
(12) Typical Procedure for Reverse Fluorous Spe in Table 1.
Perfluorodecyl iodide (323 mg, 0.5 mmol), allyltributyltin (330 mg, 1 mmol),
AIBN (9 mg, 0.05 mmol), and hexane (5 mL) were placed in a flask under
an argon atmosphere, and the mixture was refluxed for 5 h. After removal
of the volatile components by evaporation, the mixture was submitted to
separation by reverse fluorous spe. A short column was packed with regular
silica gel (6.0 g) using FC-72/Et2O (2/1) as the solvent. The crude reaction
mixture was then loaded onto this column and eluted with 20 mL of FC-
72/Et2O (2/1) to give 3-(perfluorodecyl)prop-1-ene in 97% yield (271 mg).
(13) Purity of the products was determined by GC in the case of R ) H
or R ) Me and HPLC (Nova Pak Silica, UV detection at 254 nm) in the
case of R ) Ph.
(14) Naji, N.; Soufiaoui, M.; Moreau, P. J. Fluorine Chem. 1996, 79,
179-183.
Figure 4. Two-step reaction with reverse fluorous spe purification.
Org. Lett., Vol. 6, No. 16, 2004
(15) Mukaiyama, T.; Matsueda, R.; Suzuki, M. Tetrahedron Lett. 1970,
22, 1901-1904.
2719

Figure 5. Separation of fluorous esters from triphenylphosphine,
triphenylphosphine oxide, and other coupling products.
7a-d in 62-85% yield, free from reagents and reagent-
derived byproducts (Figure 5).
Finally, we applied the reverse fluorous spe procedure to
a standard amide coupling reaction of isonipecotic acid
protected on nitrogen with three different fluorous Boc
groups.16,17 Couplings of 8a-c (0.06 mmol) with excess
tetrahydroisoquinoline (0.24 mmol) were effected under
standard conditions with EDCI, HOBt, and Et3N in CHCl3
(1 mL). The mixtures were partially concentrated and charged
to 1 g of silica gel. Elution with 5 mL of FC-72/hexafluoro-
2-propanol (5/1) provided products 9a-c in 72-81% yield
with HPLC purities of 93-96%.18 Unreacted or spent reagent
Figure 6. Isolation of F-Boc amides by using reverse fluorous
spe.
can readily be evaluated by simple TLC experiments.
Because the fluorous products elute first, the method is
especially useful when the fluorous products are the target
of a given reaction. This is the case in fluorous tagging
methods (such as in Figure 6) and in the synthesis of highly
fluorinated molecules (such as in Table 1). The separation
in the reverse fluorous solid-phase extraction can be aug-
mented by choosing organic components that are polar, since
these are naturally better retained on silica gel, and by
choosing fluorous compounds that are nonpolar. Extensions
to flash chromatographic and HPLC separations are readily
envisioned.
1
and reactant byproducts were not evident in the H NMR
spectra of any of these products. The satisfactory result with
the substrate 8a bearing the small C4F9 fluorous tag is
especially noteworthy because these tags are normally
considered to be too small for reliable separations by standard
fluorous spe. The relative polarities of the reagents and
reactants likely contribute to the success of this separation.
In summary, we have introduced the new technique of
reverse fluorous solid-phase extraction for separating fluo-
rous-tagged molecules from organic molecules. The tech-
nique uses inexpensive silica gel along with fluorous solvents
that are routinely recovered and recycled.19 Several useful
solvent conditions have been identified, and these and others
Acknowledgment. The idea for reverse fluorous solid-
phase extractions emerged from a conversation with Dr.
Marvin Yu of Fluorous Technologies, Inc. We thank the
National Institutes of Health for funding this work. We also
thank Asahi Glass Co., Ltd. (hexafluoro-2-propanol), 3M
(C4F9OEt), and Fuji Silisia Co. (base-coated TLC plates) for
important samples.
(16) Luo, Z.; Williams, J.; Read, R. W.; Curran, D. P. J. Org. Chem.
2001, 66, 4261-4266.
Supporting Information Available: Procedures for reac-
tions and spe purifications along with spectroscopic data for
products and copies of NMR spectra of typical products after
spe. This material is available free of charge via the Internet
at http://pubs.acs.org.
(17) Tabuchi, S.; Itani, H.; Sakata, Y.; Oohashi, H.; Satoh, Y. Biol. Med.
Chem. Lett. 2002, 12, 1171-1175.
(18) Purity of the products was determined by HPLC (Nova Pak Silica)
with UV detection at 254 nm.
(19) Other readily available fluorous solvents can be used in place of
FC-72; see ref 2c. FC-72 can be recovered from FC-72/ether mixtures by
simple distillation; the fraction boiling at 54-57 °C was collected and
reused.
OL049040O
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Org. Lett., Vol. 6, No. 16, 2004