U.S. patent application number 12/047717 was filed with the patent office on 2008-08-14 for separation of fluorous compounds.
Invention is credited to DENNIS P. CURRAN, MASATO MATSUGI, MARVIN S. YU.
Application Number | 20080194887 12/047717 |
Document ID | / |
Family ID | 35481553 |
Filed Date | 2008-08-14 |
United States Patent
Application |
20080194887 |
Kind Code |
A1 |
CURRAN; DENNIS P. ; et
al. |
August 14, 2008 |
SEPARATION OF FLUOROUS COMPOUNDS
Abstract
A method of separating at least a first non-fluorous compound
from a mixture of compounds including at least the first
non-fluorous compound and a second fluorous compound includes:
charging the of compounds to a non-fluorous solid (stationary)
phase and eluting with a fluorous eluting fluid (mobile phase). In
one embodiment, the non-fluorous solid phase is polar in nature.
The method can further include a second phase elution with a
suitable organic solvent. A method conducting a chemical reaction,
includes: mixing at least a first fluorous compound and a second
compound, the first fluorous compound differing in fluorous nature
from the second compound; exposing the first mixture to conditions
to convert at least one of the first fluorous compound and the
second compound to give a second mixture containing at least a
third compound, charging the second mixture to a non-fluorous solid
phase; and eluting with a fluorous fluid
Inventors: |
CURRAN; DENNIS P.;
(PITTSBURGH, PA) ; MATSUGI; MASATO; (NAGOYA,
JP) ; YU; MARVIN S.; (PITTSBURGH, PA) |
Correspondence
Address: |
BARTONY & HARE, LLP
1806 FRICK BUILDING, 437 GRANT STREET
PITTSBURGH
PA
15219-6101
US
|
Family ID: |
35481553 |
Appl. No.: |
12/047717 |
Filed: |
March 13, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10870514 |
Jun 17, 2004 |
7364908 |
|
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12047717 |
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Current U.S.
Class: |
570/136 |
Current CPC
Class: |
C07B 39/00 20130101;
C07C 22/08 20130101; Y10T 436/13 20150115; C07C 17/263 20130101;
C07C 17/38 20130101; C07C 21/18 20130101; C07C 69/63 20130101; C07C
17/263 20130101; C07C 67/56 20130101; C07C 22/08 20130101; Y10T
436/19 20150115; C07C 67/56 20130101; C07C 17/263 20130101; C07C
21/18 20130101 |
Class at
Publication: |
570/136 |
International
Class: |
C07C 17/013 20060101
C07C017/013 |
Goverment Interests
GOVERNMENTAL RIGHTS
[0002] This invention was made with government support under grant
RO1 GM033372 awarded by the National Institutes of Health. The
government has certain rights in this invention.
Claims
1. A method of conducting a chemical reaction, comprising: mixing
at least a first fluorous compound and a second compound, the first
fluorous compound differing in fluorous nature from the second
compound; exposing the first mixture to conditions to convert at
least one of the first fluorous compound and the second compound to
give a second mixture containing at least a third compound,
charging the second mixture to a non-fluorous solid phase; and
eluting with a fluorous fluid.
2. The method of claim 1 further comprising the step of eluting
with an organic fluid after eluting with a fluorous fluid.
3. A method of separating a first organic compound from a mixture
comprising at least a second organic compound, the method
comprising the steps of: selectively reacting the first organic
compound with a fluorous reaction component to attach a fluorous
moiety to the first organic compound to result in a fluorous
compound; separating the fluorous compound from the second organic
compound by charging the mixture to a non-fluorous solid phase and
eluting with a fluorous fluid.
4. A method of synthesizing an organic target product comprising
the steps of: reacting a first organic compound with a first
fluorous reaction component to attach a fluorous moiety to the
first organic compound to result in a second fluorous reaction
component; reacting the second fluorous reaction component in a
reaction scheme including at least one reaction with at least a
second organic compound to produce a fluorous target product in a
reaction mixture; and separating the fluorous target product from
any excess second organic compound and any organic byproduct by
charging the reaction mixture to a non-fluorous solid phase and
eluting with a fluorous fluid.
5. The method of claim 4 further comprising the step of reacting
the fluorous target product to cleave the fluorous moiety and
generate the organic target product.
6-9. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] The present application is a divisional of U.S. application
Ser. No. 10/870,514, filed Jun. 17, 2004, the disclosure of which
is incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0003] The present invention relates generally to separation of
compounds and, particularly, to separation of compounds based upon
differences in the fluorous nature of the compounds.
[0004] References set forth herein may facilitate understanding of
the present invention or the background of the present invention.
Inclusion of a reference herein, however, is not intended to and
does not constitute an admission that the reference is available as
prior art with respect to the present invention.
[0005] The separation of fluorous compounds from non-fluorous,
organic compounds and/or from other fluorous compounds having a
different fluorous nature is increasingly popular. Various fluorous
separation techniques or methods are used to separate mixtures
containing, for example, organic molecules and one or more fluorous
molecules (organic molecules bearing fluorous domains or tags) from
each other based predominantly on the fluorous nature of molecules
(for example, the absence of a fluorous domain, the size of a
fluorous domain and/or structure of a fluorous domain or molecule).
In general, differences in the fluorous nature of molecules affect
the interaction of the molecules with a "fluorophilic" or fluorous
phase in the fluorous separation method. Early fluorous separation
methods based on liquid-liquid separations have been augmented by
solid-liquid separations like fluorous solid phase extraction
(FSPE) and fluorous chromatography. See, for example, Zhang, W.
Tetrahedron 2003, 59, 4475-4489; Curran, D. P. In Stimulating
Concepts in Chemistry; Vogtle, F., Stoddardt, J. F., Shibasaki, M.,
Eds.; Wiley-VCH: New York, 2000; Dobbs, A. P.; Kimberley, M. R. J.
Fluorine Chem. 2002, 118, 3-17; Barthel-Rosa, L. P.; Gladysz, J. A.
Coord. Chem. Rev. 1999, 192, 587-605; Curran, D. P. Synlett 2001,
1488-1496; and U.S. Pat. Nos. 6,734,318, 6,727,390. 6,156,896,
5,859,247, and 5,777,121. 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.
[0006] Since their introduction in 1997, standard fluorous solid
phase extractions have proven broadly useful for separating light
fluorous molecules from organic molecules. See, for example,
Curran, D. P.; Hadida, S.; He, M. J. Org. Chem. 1997, 62,
6714-6715; Zhang, Q.; Luo, Z.; Curran, D. P. J. Org. Chem. 2000,
65, 8866-8873. As illustrated in FIG. 1A, in a standard fluorous
solid phase extraction to separate organic and fluorous compounds,
a mixture of organic and fluorous compounds is loaded onto a
"fluorophilic" (fluorous) silica gel followed by first pass elution
with a "fluorophobic" (non-fluorous) solvent. Polar organic
solvents (for example, 80-100% aqueous methanol or acetonitrile)
are the most common 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
Et.sub.2O or THF) then washes the fluorous fraction from the
column.
[0007] Fluorous solvents or fluorous eluting fluids also have been
used in connection with non-fluorous stationary phases in
chromatographic separations of organic, non-fluorous compounds.
See, for example, U.S. Pat. Nos. 5,824,225 and 5,968,368, J. A.
Attaway, Journal of Chromatography 1967, 31, 231-3; M. Z. Kagan,
Journal of Chromatography, A 2001, 918, 293-302; and J. A.
Blackwell, L. E. Schallinger, Journal of Microcolumn Separations
1994, 6, 551-6. U.S. Pat. No. 5,824,225 indicates, for example,
that use of using low boiling point (hydro)fluorocarbons and
(hydro)fluorocarbon ethers as eluting fluids can facilitate removal
of such solvents from the compounds which they elute.
[0008] Fluorinated eluting fluids have also been used to separate
highly fluorinated macromolecules including hydroxyl end groups in
silica gel columns. In that regard, European Patent Nos. 538827 and
538828 disclose the chromatographic separation of macromolecular
mixtures of perfluoro polyoxyalkylenes in columns containing a
stationary phase bearing polar groups able to bond with the
hydroxyl end groups of the polymers (for example, a silica gel)
using nonpolar fluorinated solvents (for example,
1,1,2,-trichloro-1,2,2-trifluoroethane) as elution agents.
[0009] Matsuzawa and Mikami have shown that cyclodextrins form
inclusion complexes with fluorous compounds and separated a
fluorinated ester (C.sub.6H.sub.5CO.sub.2CH.sub.2Rf) tagged with
different perfluoroalkyl tags Rf (that is, --CF.sub.3,
--C.sub.2F.sub.5, --C.sub.3F.sub.7, --C.sub.7F.sub.15 or
--C.sub.9F.sub.19) using HPLC columns packed with .beta.- or
.gamma.-cyclodextrins. H. Matsuzawa, K. Mikami, Synlett 2002,
1607-12. In general, the separation tagged compounds synthesized by
tagging a single organic compound with tags of differing nature can
be effected by many separation techniques and is of little
interest. The inclusion complexes formed between cyclodextrins and
fluorous compound may result in an HPLC column packed with
cyclodextrins bound to silica gel operating similarly to a column
packed with fluorous silica gel as the cyclodextrins complex with
fluorous solvents used in a separation.
[0010] Given the increasing utility and popularity of separations
of a wide variety of mixtures of organic compounds based upon
differences in fluorous nature, it is desirable to develop
additional fluorous separation methods through which different
organic compounds can be separated based upon differences in a
fluorous nature thereof.
SUMMARY OF THE INVENTION
[0011] In one aspect, the present invention provides a method or
separating at least a first non-fluorous compound from a mixture of
compounds including at least the first non-fluorous compound and a
second fluorous compound. The method includes charging the of
compounds to a non-fluorous solid (stationary) phase and eluting
with a fluorous eluting fluid (mobile phase). In one embodiment,
the non-fluorous solid phase is polar in nature. The method can
further include a second phase elution with a suitable organic
solvent.
[0012] No complexing agent such as cyclodextrin is required in the
stationary phase to form a complex with the fluorous compound(s) in
the mixture.
[0013] In another aspect, the present invention provides a method
of conducting a chemical reaction, including: mixing at least a
first fluorous compound and a second compound, the first fluorous
compound differing in fluorous nature from the second compound;
exposing the first mixture conditions to convert at least one of
the first fluorous compound and the second compound to give a
second mixture containing at least a third compound, charging the
second mixture to a non-fluorous solid phase; and eluting with a
fluorous fluid.
[0014] In another aspect, the present invention provides a method
of separating a first organic compound from a mixture comprising at
least a second organic compound. The method includes the steps of:
selectively reacting the first organic compound with a fluorous
reaction component to attach a fluorous moiety to the first organic
compound to result in a fluorous compound; and separating the
fluorous compound from the second organic compound by charging the
mixture to a non-fluorous solid phase and eluting with a fluorous
fluid.
[0015] In a further aspect, the present invention provides a method
of synthesizing an organic target product including the steps of:
reacting a first organic compound with a first fluorous reaction
component to attach a fluorous moiety to the first organic compound
to result in a second fluorous reaction component; reacting the
second fluorous reaction component in a reaction scheme including
at least one reaction with at least a second organic compound to
produce a fluorous target product in a reaction mixture; and
separating the fluorous target product from any excess second
organic compound and any organic byproduct by charging the reaction
mixture to a non-fluorous solid phase and eluting with a fluorous
fluid. The method can further include the step of reacting the
fluorous target product to cleave the fluorous moiety and generate
the organic target product.
[0016] In another aspect, the present invention provides a method
of separating compounds including the steps of: tagging at least a
first organic compound with a first fluorous tagging moiety to
result in a first fluorous tagged compound; tagging at least a
second organic compound with a second fluorous tagging moiety
different from the first tagging moiety to result in a second
fluorous tagged compound; and separating the first fluorous tagged
compound from a mixture including the second fluorous tagged
compound by charging the mixture to a non-fluorous solid phase and
eluting with a fluorous fluid.
[0017] In another aspect, the present invention provides a method
of physically separating compounds including the steps of: tagging
at least a first organic compound with a first fluorous tagging
moiety to result in a first fluorous tagged compound; tagging at
least a second organic compound with a second fluorous tagging
moiety different from the first fluorous tagging moiety to result
in a second fluorous tagged compound; and physically separating the
first tagged compound from a mixture including the second fluorous
tagged compound by charging the mixture to a non-fluorous solid
phase and eluting with a fluorous fluid.
[0018] In a further aspect, the present invention provides a method
of physically separating compounds including the steps of: tagging
a plurality of organic compounds with a plurality of fluorous
tagging moieties to result in a plurality of fluorous tagged
compounds, each of the fluorous tagging moieties being different;
and physically separating at least one of the plurality of fluorous
tagged compounds from other fluorous tagged compounds with a
different tag by charging a mixture of the fluorous tagged
compounds to a non-fluorous solid phase and eluting with a fluorous
fluid.
[0019] In still a further aspect, the present invention provides a
method for carrying out a chemical reaction including the steps of:
tagging a plurality of compounds with different fluorous tagging
moieties to create fluorous tagged compounds, conducting at least
one chemical reaction on the fluorous tagged compounds to produce a
mixture of fluorous tagged products, and separating at least one of
the fluorous tagged products from the mixture of fluorous tagged
products by charging the mixture to a non-fluorous solid phase and
eluting with a fluorous fluid.
[0020] The fluorous eluting fluid of the present invention can, for
example, be an individual fluorous fluid or a mixture of fluorous
fluids. Many fluorous solvents are commercially available and
include perfluoroalkanes (for example, perfluorohexane,
perfluoromethylcyclohexane), perfluoroethers (for example,
perfluorobutyltetrahydrofuran), perfluoroamines (for example,
perfluorotributyl amine). Many fluorous solvents and fluids are
performance fluid mixtures sold under trade names like
FLUORINERT.RTM. (for example, FC-72, FC-75, etc.) available from
Minnesota Mining and Manufacturing Company of Saint Paul, Minn.,
FLUTEC.TM. available from F2 Chemicals Ltd. of Lancashire, United
Kingdom, and GALDEN.RTM. available from Ausimont S. P. A. of Milan,
Italy. Examples and descriptions of representative fluorous
solvents can be found in L. P. Barthel-Rosa, J. A. Gladysz, Coord.
Chem. Rev. 1999, 192, 587-605, the disclosure of which is
incorporated herein by reference. Also useful are highly
fluorinated hydrocarbons, ethers (for example, perfluorobutyl ethyl
ether), amines, halides (for example, perfluorooctyl bromide,
referred to as "Oxygent"). Individual fluorous fluids or mixtures
of fluorous fluids are preferentially more than 50% fluorine by
molecular weight (as determined by a weighted average of the
individual components of the fluid), and more preferentially are
more than 60% percent fluorine by molecular weight.
[0021] The fluorous eluting fluid can also be an individual
fluorous fluid or a mixture of fluorous fluids along with a
cosolvent or a mixture of cosolvents. The cosolvents are selected
from highly polar fluorous solvents (acids, alcohols), hybrid
solvents, or organic solvents. The purpose of the cosolvent is to
modify the Rf of one of more of the components being separated
without substantially changing the fluorous nature of the
separation. Generally, fluorous solvents are very non-polar, so one
of the functions of the cosolvent is to increase the Rf of one or
more components of the mixture on the non-fluorous solid phase.
Therefore, the cosolvents are typically more polar than the
fluorous solvent. Polar fluorinated alcohols (for example,
2,2,2-trifluoroethanol and 1,1,1,3,3,3-hexafluoroisopropanol),
acids (for example trifluoroacetic acid and pentafluoropriopionic
acid) and related fluorinated polar molecules are useful
cosolvents. Also useful are other so-called "hybrid" (sometimes
called "amphiphilc") solvents like benzotrifluoride and
1,1,2-trichloro-1,2,2,-trifluoroethane. Liquid or supercritical
carbon dioxide can also be used as cosolvents. Also useful are
conventional organic solvents. Preferred organic solvents include
non-polar or moderately polar solvents like ethers (for example,
diethyl ether, tetrahydrofuran), hydrocarbons (for example, hexane,
toluene), and chlorocarbons (for example, dichloromethane). The
preferred amount of cosolvent(s) is less than 50 volume % relative
to the fluorous solvent(s), and the more preferred amount is less
than 40 volume %. The fluorous eluting fluid should generally be a
single fluid phase, and in many cases, the amount of organic
solvent is limited by its miscibity in the fluorous fluid. Polar
organic solvents (for example, DMF, methanol, acetonitrile, DMSO)
are less preferred because they cause large increases in Rf of many
compounds on polar non-fluorous stationary phases and because they
have low solubilities in many fluorous fluids. However, they can be
used in small amounts for some separations (typically, less than 5
volume %). Water can also be used in small amounts on occasion
(typically less than 5 volume %). For example, cosolvents are
generally used from commercial sources and special precautions for
drying are not needed.
[0022] Preferred non-fluorous solid phases of the current invention
are polar and are selected from an array of common chromatographic
stationary phases. Many porous or mesoporous inorganic oxides or
polymers, or bonded phases thereof, are useful. Examples of typical
non-fluorous solid phases include silica gel (sold in many forms
under many names), alumina (sometimes called aluminum oxide),
titania, or zirconia. Polar bonded phases of silica gel and related
media are also useful. Such bonded phases include a plethora of
polar groups including, for example, hydroxy groups, amino groups,
ammonium groups, sulfonate groups, carboxylate groups and nitrile
groups. Common chiral stationary phases such as Whelk-O and like
phases available from Regis Technologies, Inc. of Morton Grove,
Ill. and the CHIRALCEL phases available from Daicel Chemical
Industries, Ltd. of Osaka, Japan, are also useful. Less preferred,
but occasionally useful, stationary phases include non-polar bonded
phases of silica gel such as reverse phase silica gel with a
hydrocarbon bonded phase. Stationary phases with fluorous nature
(for example, fluorous silica gel) are generally not desirable for
use in the present invention.
[0023] As used herein, the term "fluorous", when used in connection
with an organic (carbon-containing) molecule, moiety or group,
refers generally to an organic molecule, moiety or group having a
domain or a portion thereof rich in carbon-fluorine bonds (for
example, fluorocarbons, fluorohydrocarbons, fluorinated ethers and
fluorinated amines). As used herein, the term "perfluorocarbons"
refers generally to organic compounds in which all hydrogen atoms
bonded to carbon atoms have been replaced by fluorine atoms. The
terms "fluorohydrocarbons" and "hydrofluorocarbons" include organic
compounds in which at least one hydrogen atom bonded to a carbon
atom has been replaced by a fluorine atom. Preferred
fluorohydrocarbons and fluorohydrocarbon groups for use in the
present invention have approximately two or more fluorines for
every hydrogen. The attachment of fluorous moieties to organic
compounds is discussed in U.S. Pat. Nos. 6,734,318, 6,727,390.
6,156,896, 5,859,247, and 5,777,121, the disclosures of which are
incorporated herein by reference.
[0024] As used herein, the term "fluorous tagging" refers generally
to attaching a fluorous moiety or group (referred to as a "fluorous
tagging moiety" or "fluorous tagging group") to a compound to
create a "fluorous tagged compound". Preferably, the fluorous
tagging moiety is attached via covalent bond. However, other strong
attachments such as ionic bonding or chelation can also be used.
Fluorous tagging moieties used in certain embodiments of the
reverse fluorous solid phase extraction separations of the present
invention can be fluorous moieties that differ in fluorous nature
(for example, fluorine content, size of the fluorous domain and/or
structure of the fluorous domain). In certain cases, the fluorous
tagging moieties are protecting groups.
[0025] As used herein, the term "solid phase extraction" (spe)
refers generally to a liquid-solid separation technique in which a
mixture of compounds is charged to a solid stationary phase. The
charged mixture is then eluted with a fluid (for example, a solvent
or mixture of solvents). One or several components of the mixture
are eluted from the solid phase while another component or
components is/are retained.
[0026] Further elutions with different liquids are sometimes
conducted to elute additional components. While the reverse
fluorous technique of the present invention is described generally
in a solid phase extraction setting, it is clear to those skilled
in the art that it is equally applicable to substantially any type
of liquid-solid chromatography that uses a non-fluorous stationary
phase. Examples include, but are not limited to, column
chromatography, flash chromatography, paper chromatography, thin
layer chromatography, medium pressure liquid chromatograhy (mplc),
and high performance/pressure liquid chromatography (hplc). These
and other common techniques are described, for example, in Chemical
Separations by C. Meloan (Wiley-Interscence, 1999) and The Essence
of Chromatograpy by C. F. Poole (Elsevier, 2003), the disclosures
of which are incorporated herein by reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] The present invention, along with the attributes and
attendant advantages thereof, will best be appreciated and
understood in view of the following detailed description taken in
conjunction with the accompanying drawings.
[0028] FIG. 1A illustrates a currently practiced or standard
fluorous solid phase extraction.
[0029] FIG. 1B illustrates an embodiment of a reverse fluorous
solid phase extraction of the present invention.
[0030] FIG. 2 illustrates a thin layer chromatographic separation
of fluorous esters using a reverse fluorous solid phase extraction
of the present invention.
[0031] FIG. 3 illustrates a comparison between results of a thin
layer chromatographic separation using reverse fluorous conditions
of the present invention and standard conditions.
[0032] FIG. 4 illustrates result of preparation of
3-(perfluoroalkyl)prop-1-enes by reverse fluorous solid phase
extraction.
[0033] FIG. 5 illustrates the use of reverse fluorous solid phase
extraction in connection with the multi-step sequence of allylation
and nitrile oxide cycloaddition.
[0034] FIG. 6 illustrates the removal of triphenylphosphine and its
derived oxide from perfluoroalkyl butyrates via by reverse fluorous
solid phase extraction.
[0035] FIG. 7 illustrates isolation of F-Boc amides via reverse
fluorous solid phase extraction.
DETAILED DESCRIPTION OF THE INVENTION
[0036] In the fluorous separation techniques of the present
invention, the solid, stationary phase has fluorophobic
(non-fluorous) characteristics, while the liquid, mobile phase has
fluorophilic (fluorous) characteristics. In one embodiment as
illustrated in FIG. 1B, reverse fluorous solid phase extraction
involves charging of a mixture of, for example, organic and
fluorous compounds (for example, fluorous-tagged compounds) to a
non-fluorous, polar solid phase. First pass elution with a fluorous
liquid phase elutes the fluorous fraction from the column while
leaving the organic fraction behind. If desired, second phase
elution with a suitable organic solvent can elute the organic
fraction.
[0037] Since fluorous solvents have been used only in a limited
fashion in chromatographic processes, we first performed simple
thin layer chromatographic (TLC) experiments with fluorous esters
1a-d to evaluate solvent and solid phase pairings. Several
combinations of TLC plates and various fluorous solvents were
studied. TLC plates studied included regular silica gel (Silica Gel
60 F.sub.254 available from MERCK), base-coated silica gel
(NH-DM1020 available from Fuji Silysia Chemical Co. Ltd.),
C18-silica gel (C18-Silica Gel 60 F.sub.254 available from MERCK),
aluminum oxide (Aluminum oxide 150 F.sub.254 available from MERCK),
and .alpha.-cellulose (AVICEL F Microcrystalline Cellulose
available from ANALTECH). Fluorous solvents studied included FC-72
(a mixture of perfluorohexanes, c-C.sub.6F.sub.11CF.sub.3,
C.sub.4F.sub.9OMe, benzotrifluoride (BTF; C.sub.6H.sub.5CF.sub.3)
and hexafluoroisopropanol. We found, for example, that a
combination of a regular silica gel with mixtures of
FC-72/Et.sub.2O or FC-72/hexafluoroisopropanol provided both good
separations and convenient Rf values, and these combinations were
used in subsequent studies. Rf is the chromatographic retention
factor. In that regard, the retention factor Rf of a compound in
TLC is defined as the distance traveled by the compound divided by
the distance traveled by the solvent front. The retention factor Rf
should not be confused with the chemical substituent designation
Rf, discussed below, which represents a fluorous moiety or group (a
perfluoroalkyl group in the studies of the present invention).
[0038] FIG. 2 shows the Rf's of fluorinated benzoate esters (1a-d)
on a regular silica gel TLC plate eluted with 2/1 FC-72/Et.sub.2O.
As expected, the Rf's 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's than the non-fluorous methyl ester
1d.
[0039] Control TLC experiments with standard organic solvents
revealed the unique features of using the fluorous solvent mixture
with standard silica gel (see FIG. 3). For example, elution of a
mixture of fluorous ester 1a and triphenylphosphine on standard
silica gel with 100% hexane showed that triphenylphosphine was the
less polar of the two compounds (Rf's: PPh.sub.3, 0.30; 1a, 0.24).
Rf's in 100% hexane were variable, possibly as a result of the
water content of the silica gel. However, the relative polarities
were not variable. When the same mixture was eluted with 2/1
FC-72/Et.sub.2O on a silica TLC plate, the Rf of 1a increased to
0.68 while the Rf of PPh.sub.3 decreased dramatically to 0.03. This
decrease reflects the "fluorophobicity" of triphenylphosphine,
which has little or no solubility in FC-72. The separation provided
by the fluorous solvents is unique and cannot be reproduced with
the common organic solvents used in silica TLC and chromatography
experiments.
[0040] We also studied preparative separations of mixtures of
fluorous and organic compounds by reverse fluorous solid phase
extraction. Ryu and coworkers described allylation of
perfluoroalkyl iodides (RfI) with allyl stannanes to provide allyl
perfluoroalkanes. Ryu, I.; Kreimerman, S.; Niguma, T.; Minakata,
S.; Komatsu, M.; Luo, Z.; Curran, D. P. Tetrahedron Lett. 2001, 42,
947-950, the disclosures of which are incorporated herein by
reference. In that work, the target allylated products (fluorous)
were separated from the tin residues (organic) by standard fluorous
solid phase extraction. We conducted a similar set of reactions
with purification by reverse fluorous solid phase extraction. The
results of twelve experiments are summarized in FIG. 4.
[0041] In a typical procedure for reverse fluorous solid phase
extraction in the studies of FIG. 4, a perfluoroalkyl iodide such
as perfluorodecyl iodide (RfI, 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 solid phase extraction. A short column was packed with
regular silica gel (6.0 g) using FC-72/Et.sub.2O (2/1) as the
solvent. The crude reaction mixture was then loaded onto this
column and eluted with 20 ml of FC-72/Et.sub.2O (2/1) to give
3-(perfluorodecyl)prop-1-ene in 97% yield (271 mg). After similar
reactions and separations, the allylated products 2a-d, 3a-d and
4a-d were isolated in yields ranging from 69-93%. The nuclear
magnetic resonance (NMR) spectra of these products were clean, and
gas chromatography (GC) or high pressure liquid chromatography
(HPLC) purities exceeded 90% in all cases. The purity of the
products was determined by GC in the case of R=H or R=Me and HPLC
(Nova Pak.RTM. Silica, UV detection at 254 nm) in the case of
R=Ph.
[0042] To show that reverse spe can be used to clean up multi-step
sequences, we conducted the sequence of allylation and nitrile
oxide cycloaddition shown in FIG. 5. Five iodides were allylated as
above and the crude products were directly subjected to nitrile
oxide cycloaddition under oxidative conditions with excess
benzaldehyde oxime. See Naji, N.; Soufiaoui, M.; Moreau, P. J.
Fluorine Chem. 1996, 79, 179-183, the disclosure of which is
incorporated herein by reference. TLC analysis of the crude
products using standard organic solvents showed multiple spots and
were suggestive of difficult chromatographic purifications. In
contrast, TLC experiments with 2/1 FC-72/ether showed only a single
spot (Rf .about.0.2) above the origin attributed to the target
products. Reverse fluorous spe provided clean isoxazolines 5a-e in
48-68% yield.
[0043] The TLC experiments in FIG. 3 suggest that reverse fluorous
spe should be useful for removing triphenylphosphine 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, triphenylphosphine, and
Aldrichthiol.TM.-2 (2,2-dipyridyl disulfide). See Mukaiyama, T.;
Matsueda, R.; Suzuki, M. Tetrahedron Lett. 1970, 22, 1901-1904, the
disclosure of which is incorporate herein by reference. Reaction
for 24 h in refluxing benzene, followed by cooling and reverse
fluorous solid phase extraction provided the products 7a-7d in
62-85% yield, free from reagents and reagent-derived byproducts
(see FIG. 6).
[0044] We also applied the reverse fluorous solid phase extraction
procedure to a standard amide coupling reaction of isonipecotic
acid protected on nitrogen with three different fluorous Boc groups
as illustrated in FIG. 7. Such reactions are described in Luo, Z.;
Williams, J.; Read, R. W.; Curran, D. P. J. Org. Chem. 2001, 66,
4261-4266 and Tabuchi, S.; Itani, H.; Sakata, Y.; Oohashi, H.;
Satoh, Y. Bio. & Med. Chem. Lett. 2002, 12, 1171-1175, the
disclosures of which are incorporated herein by reference.
Couplings of 8a-c (0.06 mmol) with excess tetrahydroisoquinoline
(0.24 mol) were effected under standard conditions with EDCI, HOBt
and Et.sub.3N in CHCl.sub.3 (1 mL). The mixtures were partially
concentrated and charged to 1 g of silica gel. Elution with 5 mL
FC-72/hexyluoroisopropanol (5/1) provided products 9a-c in 72-81%
yield with hplc purities of 93-96%. The purity of the products was
determined by HPLC (Nova Pak.RTM. Silica) with UV detection at 254
nm. Unreacted or spent reagent and reactant byproducts were not
evident in the .sup.1H NMR spectra of any of these products. The
satisfactory result with the substrate 8a bearing the small
C.sub.4F.sub.9 fluorous tag is especially noteworthy because these
tags are normally considered too small for reliable separations by
standard fluorous solid phase extraction. The relative polarities
of the reagents and reactants may contribute to the success with
9a.
[0045] The reverse fluorous solid phase extraction methods of the
present invention can readily use inexpensive silica gel along with
fluorous solvents that are routinely recovered and recycled.
Several useful solvent conditions are identified above, and these
and others can readily be evaluated by simple thin layer
chromatography (TLC) experiments. Because fluorous products elute
first, the method is especially useful when the fluorous products
are the target product of a given reaction. Fluorous products are
the target products, for example, in fluorous tagging methods (such
as illustrated, for example, in FIG. 7) and in the synthesis of
highly fluorinated molecules (such as illustrated, for example, in
FIG. 4). The reverse fluorous solid phase extraction can be aided
by choosing organic components that are polar, since these are
naturally better retained on silica gel. Extensions to flash
chromatographic and HPLC separations are readily accomplished.
EXPERIMENTAL EXAMPLES
[0046] General: All melting points are uncorrected. Reagents were
used as they were received from Aldrich. .sup.1H and .sup.19F NMR
spectra were measured in CDCl.sub.3 with TMS or CHCl.sub.3 as the
internal standard. 2-Methylallyltributyltin and
2-phenylallyltributyltin were prepared by known procedure. See
Keck, G. E.; Enholm, E. J.; Yates, J. B.; Wiley, M. R. Tetrahedron,
1985, 41, 4079-4094 and Tanaka, H.; Hai, A. K. M. A.; Ogawa, H.;
Torii, S. Synlett, 1993, 835-836, the disclosures of which are
incorporated herein by reference. Fluorous benzoates 1a-c were
prepared by condensation of the corresponding fluoroalcohols and
benzoyl chloride. Fluorous alkenes 2a-b, 2d, 3a-b, 3d, 4a, fluorous
ester 7c and fluorous amides 9c were known compounds. See
Matsuzawa, H.; Mikami, K. Synlett, 2002, 1607-1612; Ryu, I.;
Kreimerman, S.; Niguma, T.; Minakata, S.; Komatsu, M.; Luo, Z.;
Curran, D. P. Tetrahedron Lett. 2001, 42, 947-950; Umemoto, T.;
Kuriu, Y.; Nakayama, S. Tetrahedron Lett. 1982, 23, 1169-1172;
Kondou, H.; Kawana, T.; Yatagai, H. Pat. Specif (Aust.) (1989), 56
pp. CAN 112:170785; and Luo, Z.; Williams, J.; Read, R. W.; Curran,
D. P. J. Org. Chem. 2001, 66, 4261-4266, the disclosures of which
is incorporated herein by reference. The purities of 2a-d and 3a-d
were determined by GC. The purities of 4a-d were determined by
HPLC.
Benzoic acid
2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-nonadecafluorodecyl ester
1a
[0047] Colorless solid; mp 52.5-53.0.degree. C.; .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 4.84 (t, 2H, J=13.3 Hz), 7.50 (t, 2H,
J=7.9 Hz), 7.64 (t, 1H, J=7.9 Hz), 8.08 (d, 2H, J=7.2 Hz); .sup.19F
NMR (272 MHz, CDCl.sub.3)-124.9 (2F), -121.9 (2F), -121.5 (2F),
-120.6 (8F), -118.0 (2F), -79.5 (3F).
Benzoic acid 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctyl
ester 1b
[0048] Colorless oil; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
4.84 (t, 2H, J=13.3 Hz), 7.50 (t, 2H, J=7.6 Hz), 7.64 (t, 1H, J=7.6
Hz), 8.08 (d, 2H, J=7.3 Hz); .sup.19F NMR (272 MHz, CDCl.sub.3)
.delta.-124.9 (2F), -121.9 (2F), -121.5 (2F), -120.7 (4F), -118.0
(2F), -79.6 (3F).
Benzoic acid 2,2,3,3,4,4,4-heptafluorobutyl ester 1c
[0049] Colorless oil; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
4.82 (t, 2H, J=13.2 Hz), 7.49 (t, 2H, J=7.5 Hz), 7.63 (t, 1H, J=7.5
Hz), 8.08 (d, 2H, J=7.4 Hz); .sup.19F NMR (272 MHz, CDCl.sub.3)
.delta.-126.3 (2F), -119.1 (2F), -79.6 (3F).
Example 1
Typical Procedure for a Preparation of
3-(Perfluoroalkyl)Prop-1-Enes by Reverse Fluorous Solid Phase
Extraction
[0050] Under Argon atmosphere, perfluorooctyl iodide (272 mg, 0.5
mmol), tributylallylstannane (330 mg, 1.0 mmol) and AIBN (9 mg, 10
mol %) were dissolved in 5 mL of hexane. After stirring at
80.degree. C. for 5 h, 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 FC-72/diethylether
(2/1), and the solvent was evaporated to provide the 2a (189 mg,
82%) as a colorless oil.
4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-Heptadecafluoroundec-1-ene
2a
[0051] Colorless oil (82% yield, 95.1% GC purity); .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 2.86 (dt, 2H, J=18.2, 6.7 Hz), 5.35 (m,
2H), 5.80 (m, 2H); .sup.19F NMR (272 MHz, CDCl.sub.3) .delta.-125.2
(2F), -122.4 (2F), -121.9 (2F), -120.7 (6F), -112.1 (2F), -79.4
(3F).
4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,13,13,13-Heneicosafluorotridec-1-
-ene 2b
[0052] Colorless oil (97% yield, 97.0% purity); .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 2.86 (dt, 2H, J=18.2, 6.7 Hz), 5.36 (m,
2H), 5.81 (m, 2H); .sup.19F NMR (272 MHz, CDCl.sub.3) .delta.-124.8
(2F), -121.9 (2F), -121.6 (2F), -120.6 (10F), -112.1 (2F), -79.5
(3F).
4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,13,13,14,14,15,15,15-Pentacosafl-
uoropentadec-1-ene 2c
[0053] Colorless solid (89% yield, 94.5% purity); mp
74.5-75.0.degree. C.; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
2.86 (dt, 2H, J=18.3, 6.9 Hz), 5.35 (m, 2H), 5.81 (m, 2H); .sup.19F
NMR (272 MHz, CDCl.sub.3) .delta.-124.9 (2F), -121.9 (2F), -121.5
(2F), -120.5 (14F), -112.0 (2F), -79.5 (3F); HRMS (EI) Calcd for
C.sub.15H.sub.5F.sub.25 (M.sup.+): 659.9992. Found: 659.9996.
4,4,5,5,6,6,7,7,8,8,9,9,10,11,11,11-Hexadecafluoro-10-trifluoromethylundec-
-1-ene 2d
[0054] Colorless oil (86% yield, 92.2% purity); .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 2.86 (dt, 2H, J=18.3, 6.9 Hz), 5.36 (m,
2H), 5.81 (m, 2H); .sup.19F NMR (272 MHz, CDCl.sub.3) .delta.-184.8
(1F), -121.9 (2F), -120.3 (4F), -119.6 (2F), -113.8 (2F), -112.1
(2F), -70.8 (6F).
4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-Heptadecafluoro-2-methylundec-1-ene
3a
[0055] Colorless oil (69% yield, purity); .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 1.96 (s, 3H), 2.94 (t, 2H, J=19.1 Hz), 5.06 (s,
1H), 5.19 (s, 1H); .sup.19F NMR (272 MHz, CDCl.sub.3) .delta.-125.1
(2F), -122.2 (2F), -121.5 (2F), -120.7 (6F), -111.5 (2F), -79.5
(3F).
4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,13,13,13-Heneicosafluoro-2-meth-
yltridec-1-ene 3b
[0056] Colorless solid (89% yield, 92.0% purity); mp
49.5-51.5.degree. C.; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
1.88 (s, 3H), 2.79 (t, 2H, J=19.4 Hz), 4.98 (s, 1H), 5.11 (s, 1H);
.sup.19F NMR (272 MHz, CDCl.sub.3) .delta.-124.9 (2F), -122.0 (2F),
-121.7 (2F), -120.6 (10F), -111.7 (2F), -79.5 (3F).
4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,13,13,14,14,15,15,15-Pentacosafl-
uoro-2-methylpentadec-1-ene 3c
[0057] Colorless amorphous (75% yield, 91.3% purity); .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 1.88 (s, 3H), 2.79 (t, 2H, J=19.1
Hz), 4.98 (s, 1H), 5.11 (s, 1H); .sup.19F NMR (272 MHz, CDCl.sub.3)
.delta.-124.8 (2F), -122.0 (2F), -121.5 (2F), -120.5 (14F), -111.5
(2F), -79.5 (3F).
4,4,5,5,6,6,7,7,8,8,9,9,10,11,11,11-Hexadecafluoro-2-methyl-10-trifluorome-
thylundec-1-ene 3d
[0058] Colorless amorphous (84% yield, 92.0% purity); .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 1.88 (s, 3H), 2.79 (t, 2H, J=19.3
Hz), 4.97 (s, 1H), 5.11 (s, 1H); .sup.19F NMR (272 MHz, CDCl.sub.3)
.delta.-185.0 (1F), -122.4 (2F), -120.5 (4F), -119.6 (2F), -113.9
(2F), -111.8 (2F), -70.8 (6F).
[1-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-Heptadecafluorononyl)vinyl]benzene
4a
[0059] Colorless amorphous (93% yield, 97.5% purity); .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 3.29 (t, 2H, J=18.6 Hz), 5.39 (s,
1H), 5.65 (s, 1H), 7.29-7.42 (m, 5H); .sup.19F NMR (272 MHz,
CDCl.sub.3) .delta.-124.9 (2F), -122.1 (2F), -121.5 (2F), -120.7
(4F), -120.4 (2F), -111.2 (2F), -79.5 (3F); HRMS (EI) Calcd for
C.sub.17H.sub.9F.sub.17 (M.sup.+): 536.0432. Found: 536.0408.
[1-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-Heneicosafluoroundecyl)-
vinyl]benzene 4b
[0060] Colorless solid (93% yield, 97.5% purity); mp
57.0-58.0.degree. C.; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
3.30 (t, 2H, J=18.6 Hz), 5.39 (s, 1H), 5.65 (s, 1H), 7.27-7.43 (m,
5H); .sup.19F NMR (272 MHz, CDCl.sub.3) .delta.-125.3 (2F), -122.1
(2F), -121.5 (2F), -120.6 (10F), -111.2 (2F), -79.5 (3F); HRMS (EI)
Calcd for C.sub.19H.sub.9F.sub.21 (M.sup.+): 636.0369. Found:
636.0344.
[1-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,13,13,13-Pentacosafl-
uorotridecyl)vinyl]benzene 4c
[0061] Colorless solid (90% yield, 90.8% purity); mp
81.5-82.5.degree. C.; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
3.30 (t, 2H, J=18.7 Hz), 5.39 (s, 1H), 5.65 (s, 1H), 7.31-7.42 (m,
5H); .sup.19F NMR (272 MHz, CDCl.sub.3) .delta.-124.9 (2F), -122.4
(2F), -121.8 (2F), -120.5 (14F), -111.2 (2F), -79.5 (3F); HRMS (EI)
Calcd for C.sub.21H.sub.9F.sub.25 (M.sup.+): 736.0305. Found:
736.0342.
[1-(2,2,3,3,4,4,5,5,6,6,7,7,8,9,9,9-Hexadecafluoro-8-trifluoromethylnonyl)-
vinyl]benzene 4d
[0062] Colorless amorphous (86% yield, 99.4% purity); .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 3.29 (t, 2H, J=18.5 Hz), 5.39 (s,
1H), 5.65 (s, 1H), 7.29-7.43 (m, 5H); .sup.19F NMR (272 MHz,
CDCl.sub.3) .delta.-184.9 (1F), -122.3 (2F), -120.3 (4F), -119.6
(2F), -113.8 (2F), -111.2 (2F), -70.7 (6F); HRMS (EI) Calcd for
C.sub.18H.sub.9F.sub.19 (M.sup.+): 586.0401. Found: 586.0401.
Example 2
Typical Procedure for a Preparation of 5 by Reverse Fluorous Solid
Phase Extraction
[0063] Under argon atmosphere, perfluorooctyl iodide (272 mg, 0.5
mmol), tributylallylstannane (330 mg, 1.0 mmol) and AIBN (9 mg, 10
mol %) were dissolved in 5 mL of hexane. After stirring at
80.degree. C. for 5 h, the reaction mixture was cooled,
concentrated and added diethylether (10 ml). To the reaction
mixture, benzaldehide oxime (363 mg, 3.0 mmol) and sodium
hypochlorite solution (10 ml, available chlorine 10-13%) were added
at -10.degree. C. and stirred vigorously at 23.degree. C. for 24 h.
After the organic layer was separated and concentrated in vacuo,
the residue was charged to a column containing 8 g of standard
silica gel. The column was eluted with 70 mL FC-72/diethylether
(3/1), and the solvent was evaporated to provide the 5b (197 mg,
68%) as a colorless solid.
5-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-Pentadecafluorooctyl)-3-phenyl-4,5-dihydr-
o-isoxazole 5a
[0064] Colorless solid (62% yield); mp 91.0-92.0.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.45 (m, 1H), 2.76 (m,
1H), 3.19 (m, 1H), 3.62 (m, 1H), 5.14 (m, 1H), 7.43 (m, 3H), 7.69
(dd, 2H, J=7.5, 1.9 Hz); .sup.19F NMR (272 MHz, CDCl.sub.3)
.delta.-125.0 (2F), -122.3 (2F), -121.5 (2F), -120.9 (2F), -120.4
(2F), -111.4 (2F), -79.6 (3F); HRMS (EI) Calcd for
C.sub.17H.sub.10F.sub.15NO (M.sup.+): 529.0520. Found:
529.0523.
5-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-Heptadecafluorononyl)-3-phenyl-4,5-di-
hydroisoxazole 5b
[0065] Colorless solid (68% yield); mp 100.5-101.0.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.45 (m, 1H), 2.78 (m,
1H), 3.22 (m, 1H), 3.60 (m, 1H), 5.11 (m, 1H), 7.44 (m, 3H), 7.69
(d, 2H, J=7.5 Hz); .sup.19F NMR (272 MHz, CDCl.sub.3) .delta.-124.9
(2F), -122.2 (2F), -121.5 (2F), -120.7 (4F), -120.4 (2F), -111.3
(2F), -79.5 (3F); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 36.3,
41.0, 74.2, 105-120 (m, C.sub.8F.sub.17), 126.8, 129.0, 130.6,
156.8.
5-(2,2,3,3,4,4,5,5,6,6,7,7,8,9,9,9-Hexadecafluoro-8-trifluoromethylnonyl)--
3-phenyl-4,5-dihydroisoxazole 5c
[0066] Colorless solid (63% yield); mp 89.0-90.0.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.46 (m, 1H), 2.80 (m,
1H), 3.20 (m, 1H), 3.65 (m, 1H), 5.11 (m, 1H), 7.45 (m, 3H), 7.69
(m, 2H); .sup.19F NMR (272 MHz, CDCl.sub.3) .delta.-184.9 (1F),
-122.2 (2F), -120.3 (4F), -119.5 (2F), -113.8 (2F), -111.4 (2F),
-70.6 (6F); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 36.2, 41.0,
74.2, 105-120 (m, C.sub.8F.sub.17), 126.8, 128.9, 130.6, 156.8;
HRMS (EI) Calcd for C.sub.19H.sub.10F.sub.19NO (M.sup.+): 629.0486.
Found: 629.0459.
5-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-Heneicosafluoroundecyl)--
3-phenyl-4,5-dihydroisoxazole 5d
[0067] Colorless solid (55% yield); mp 120.0-121.0.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.46 (m, 1H), 2.80 (m,
1H), 3.20 (m, 1H), 3.60 (m, 1H), 5.10 (m, 1H), 7.44 (m, 3H), 7.68
(m, 2H); .sup.19F NMR (272 MHz, CDCl.sub.3) .delta.-124.9 (2F),
-122.2 (2F), -121.5 (2F), -120.5 (10F), -111.4 (2F), -79.5 (3F);
HRMS (EI) Calcd for C.sub.20H.sub.10F.sub.21NO (M.sup.+): 679.0452.
Found: 679.0427.
5-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,13,13,13-Pentacosaflu-
orotridecyl)-3-phenyl-4,5-dihydroisoxazole 5e
[0068] Colorless solid (55% yield); mp 144.0-144.5.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.45 (m, 1H), 2.79 (m,
1H), 3.20 (m, 1H), 3.61 (m, 1H), 5.11 (m, 1H), 7.44 (m, 3H), 7.69
(m, 2H); .sup.19F NMR (272 MHz, CDCl.sub.3) .delta.-124.9 (2F),
-122.2 (2F), -121.5 (2F), -120.5 (14F), -111.3 (2F), -79.5 (3F);
HRMS (EI) Calcd for C.sub.22H.sub.10F.sub.25NO (M.sup.+): 779.0359.
Found: 779.0363.
Example 3
Typical Procedure for a Preparation of 7 by Reverse Fluorous Solid
Phase Extraction
[0069] Under argon atmosphere,
3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluorooctan-1-ol 6a (182 mg, 0.5
mmol), butyric acid (66 mg, 0.75 mmol), triphenylphospine (197 mg,
0.75 mmol) and Aldrithiol.TM.-2 (165 mg, 0.75 mmol) were dissolved
in 5 mL of benzene. After stirring at 80.degree. C. for 24 h, 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 FC-72/diethylether (2/1), and the solvent was evaporated to
provide the 7a (185 mg, 85%) as a colorless oil.
Butyric acid 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl ester
7a
[0070] Colorless oil (85% yield); .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 0.96 (t, 3H, J=7.4 Hz), 1.66 (m, 2H), 2.32 (t, 2H, J=7.4
Hz), 2.50 (m, 2H), 4.39 (t, 2H, J=6.5 Hz); .sup.19F NMR (272 MHz,
CDCl.sub.3) .delta.-125.0 (2F), -122.4 (2F), -121.7 (2F), -120.7
(2F), -112.5 (2F), -79.5 (3F); HRMS (EI) Calcd for
C.sub.12H.sub.11F.sub.13O.sub.2 (M.sup.+): 434.0541. Found:
434.0551.
Butyric acid 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctyl
ester 7b
[0071] Colorless oil (62% yield); .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 0.98 (t, 3H, J=7.4 Hz), 1.67 (m, 2H), 2.41 (t, 2H, J=7.4
Hz), 4.60 (t, 2H, J=13.6 Hz); .sup.19F NMR (272 MHz, CDCl.sub.3)
.delta.-124.9 (2F), -122.1 (2F), -121.5 (2F), -120.8 (4F), -118.3
(2F), -79.5 (3F); HRMS (EI) Calcd for
C.sub.12H.sub.9F.sub.15O.sub.2 (M.sup.+): 470.0383. Found:
470.0363.
Butyric acid
2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-nonadecafluorodecyl ester
7c
[0072] Colorless oil (63% yield); .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 0.98 (t, 3H, J=7.4 Hz), 1.67 (m, 2H), 2.41 (t, 2H, J=7.4
Hz), 4.60 (t, 2H, J=13.6 Hz); .sup.19F NMR (272 MHz,
CDCl.sub.3)-124.9 (2F), -122.1 (2F), -121.5 (2F), -120.7 (8F),
-118.3 (2F), -79.5 (3F).
Butyric acid
2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11-eicosafluoroundecyl
ester 7d
[0073] Colorless solid (66% yield); mp 32.0-33.0.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.98 (t, 3H, J=7.4 Hz),
1.70 (m, 2H), 4.60 (t, 2H, J=13.7 Hz), 6.07 (m, 1H); .sup.19F NMR
(272 MHz, CDCl.sub.3) .delta.-135.8 (2F), -128.0 (2F), -122.1 (4F),
-120.6 (10F), -118.3 (2F); HRMS (EI) Calcd for
C.sub.15H.sub.10F.sub.20O.sub.2 (M.sup.+): 602.0369. Found:
602.0361.
Example 4
Typical Procedure for a Preparation of 9 by Reverse Fluorous Solid
Phase Extraction
[0074] Under argon atmosphere, piperidine-1,4-dicarboxylic acid
mono(4,4,5,5,6,6,7,7,7-nonafluoro-1,1-dimethylheptyl) ester 8a
(27.7 mg, 0.06 mmol), EDCI (17.3 mg, 0.09 mmol), HOBT (12.2 mg,
0.09 mmol) and triethylamine (12.5 .mu.l, 0.09 mmol) were dissolved
in 1 mL of chloroform. After stirring at 23.degree. C. for 16 h,
the reaction mixture was concentrated and charged to a column
containing 1 g of standard silica gel. The column was eluted with 5
mL FC-72/hexafluoroisopropanol (5/1), and the solvent was
evaporated to provide the 9a (27.0 mg, 81%) as a colorless
solid.
4-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)piperidine-1-carboxylic
acid 4,4,5,5,6,6,7,7,7-nonafluoro-1,1-dimethylheptyl ester 9a
[0075] Colorless solid (81% yield, 96.0% purity); mp
83.5-84.0.degree. C.; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
1.55 (s, 6H), 1.74 (bs, 4H), 2.05-2.18 (m, 4H), 2.78-3.00 (m, 5H),
3.74 (t, 1H, J=5.9 Hz), 3.84 (bs, 1H), 4.15 (m, 2H), 4.69 (s, 1H),
4.71 (s, 1H), 7.15-7.27 (m, 4H); .sup.19F NMR (272 MHz, CDCl.sub.3)
.delta.-124.8 (2F), -123.0 (2F), -113.3 (2F), -79.8 (3F).
4-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)piperidine-1-carboxylic
acid 4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluoro-1,1-dimethylnonyl
ester 9b
[0076] Colorless solid (74% yield, 96.2% purity); mp
97.0-97.5.degree. C.; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
1.51 (s, 6H), 1.74 (bs, 4H), 2.06-2.18 (m, 4H), 2.84-2.95 (m, 5H),
3.74 (t, 1H, J=5.9 Hz), 3.85 (bs, 1H), 4.16 (m, 2H), 4.69 (s, 1H),
4.71 (s, 1H), 7.17-7.27 (m, 4H); .sup.19F NMR (272 MHz, CDCl.sub.3)
.delta.-124.9 (2F), -122.0 (2F), -121.6 (2F), -120.7 (2F), -113.1
(2F), -79.6 (3F).
4-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)piperidine-1-carboxylic
acid
4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoro-1,1-dimethyl-undec-
yl ester 9c
[0077] Colorless solid (72% yield, 93.0% purity); mp
111.5-112.0.degree. C.; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
1.54 (s, 6H), 1.76 (bs, 4H), 2.19-2.25 (m, 4H), 2.80-3.00 (m, 5H),
3.74 (t, 1H, J=6.0 Hz), 3.85 (bs, 1H), 4.15 (m, 2H), 4.71 (s, 1H),
4.75 (s, 1H), 7.18-7.30 (m, 4H).
[0078] The foregoing description and accompanying drawings set
forth the preferred embodiments of the invention at the present
time. Various modifications, additions and alternative designs
will, of course, become apparent to those skilled in the art in
light of the foregoing teachings without departing from the scope
of the invention. The scope of the invention is indicated by the
following claims rather than by the foregoing description. All
changes and variations that fall within the meaning and range of
equivalency of the claims are to be embraced within their
scope.
* * * * *