Enantioselective carbon-carbon bond forming reactions using fluorous chiral catalysts

Article abstract of DOI:10.1016/S0022-1139(02)00320-2

Fluorous chiral BINOLs and BINAP were prepared and used as the ligands for an asymmetric addition of Et₂Zn to aromatic aldehydes and an asymmetric Heck reaction, respectively. The enantioselectivities were similar in homogeneous system to those of the original non-fluorous reactions. Consecutive reactions were examined by utilizing fluorous-organic biphase and fluorous solid phase extraction techniques. Enantioselectivities in consecutive reactions were close to that attained in the non-fluorous system. The solid phase extraction method also enabled us to perform a simultaneous screening procedure.

Full text of DOI:10.1016/S0022-1139(02)00320-2

Journal of Fluorine Chemistry 120 (2003) 121–129
Enantioselective carbon–carbon bond forming reactions
using fluorous chiral catalysts
*
Yutaka Nakamura , Seiji Takeuchi, Yoshiaki Ohgo
Niigata University of Pharmacy and Applied Life Sciences, 5-13-2 Kamishin’ei cho, Niigata 950-2081, Japan
Received 1 August 2002; received in revised form 7 October 2002; accepted 11 October 2002
Abstract
Fluorous chiral BINOLs and BINAP were prepared and used as the ligands for an asymmetric addition of Et Zn to aromatic aldehydes and
2
an asymmetric Heck reaction, respectively. The enantioselectivities were similar in homogeneous system to those of the original non-fluorous
reactions. Consecutive reactions were examined by utilizing fluorous–organic biphase and fluorous solid phase extraction techniques.
Enantioselectivities in consecutive reactions were close to that attained in the non-fluorous system. The solid phase extraction method also
enabled us to perform a simultaneous screening procedure.
#
2002 Elsevier Science B.V. All rights reserved.
Keywords: Addition reactions; Heck reactions; Asymmetric reactions; Fluorine and compounds; Perfluoroalkyl compounds
1
. Introduction
The fluorous phase can be separated and recycled. Fluorous
biphasic catalytic methods have advanced rapidly, and a
large number of fluorous catalysts have been reported (see
recent examples for fluorous biphase catalysis in [3]).
Fluorous compounds can be separated from non-fluorous
compounds by simple workup techniques of liquid–liquid
extraction or solid phase extraction. For example, the liquid–
liquid separation technique has demonstrated that fluorous
tin hydrides have similar reactivity to the original tributyltin
hydride but higher efficiency than the original one. The
fluorous tin compounds are readily separable from organic
compounds at the end of a reaction by the fluorous–organic
biphase extraction with an organic solvent and FC-72 (a
mixture of perfluorohexanes). The recovered tin compounds
from FC-72 phase are recyclable without purification [4].
Fluorous solid phase extraction was introduced by Curran
[1a]. The fluorous solid phase extraction is a very useful
method to separate organic products from a fluorous catalyst
or ligand, especially in cases where the fluorine content is
not high enough to carry out the catalytic reaction in
fluorous–organic biphase system successfully. Fluorous
reverse phase (FRP) silica gel is polyfluoroalkylsilyl-bonded
silica gel, which is easily prepared but now commercially
available [5]. A crude reaction mixture is charged on the
FRP silica gel and the silica gel is eluted first with a
Fluorous techniques are novel separation and immobili-
zation techniques that are attracting great current interest in
organic synthesis (see reviews in [1]). Fluorinated or highly
fluorinated solvents such as perfluoroalkanes are called
‘
fluorous solvents’. They are immiscible with typical
organic solvents and water at ambient temperature. How-
ever, these organic and fluorous two phases are miscible
when the temperature is elevated. Compounds that have
highly fluorinated carbon chains or perfluoroalkyl chains are
dissolved in fluorous solvents. Fluorous techniques are
based on these natures.
One of the techniques is called ‘fluorous biphase cata-
lysis’. Horv a´ th and Rav a´ i [2] introduced this innovative
approach to catalysis in 1994. A metal complex bearing
one or more highly fluorinated ligands is dissolved in a
fluorous solvent, and this is mixed with substrates in an
organic solvent. The catalytic reaction is then effected under
biphasic conditions. In a significant variant, warming ren-
ders the organic and fluorous phases miscible and the
reaction occurs under homogeneous conditions. In either
case, the organic phase contains the pure products, and the
fluorous phase contains the catalyst at room temperature.
‘‘fluorophobic’’ solvent such as acetonitrile to remove the
*
organic compounds. Elution with a ‘‘fluorophilic’’ solvent
such as FC-72 provides fluorous compounds.
Corresponding author. Tel.: þ81-25-269-3170; fax: þ81-25-268-1230.
E-mail address: nakamura@niigata-pharm.ac.jp (Y. Nakamura).
0022-1139/02/$ – see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 3 2 0 - 2

122
Y. Nakamura et al. / Journal of Fluorine Chemistry 120 (2003) 121–129
Scheme 1.
These fluorous techniques are very attractive techniques
same procedures described above. The approximate parti-
tion coefficients of FBINOLs were determined by the simple
method described in the footnote of Table 1, and the results
are summarized in the table.
for researchers who are seeking practical and environmen-
tally friendly catalytic systems of asymmetric reactions.
Chiral ligands for metal catalysts are usually laborious to
prepare and expensive. Therefore, fluorous chiral ligands
that are reusable have a potential to afford catalytic systems
that fit the needs of the researchers [6].
The data in Table 1 show that (R)-F BINOL and (R)-
1
3
F BINOL are highly fluorous and efficiently extracted to
17
FC-72 phase.
We have focused our attention on preparation of effective
and recyclable fluorous chiral ligands and their application
to catalytic asymmetric reactions [7]. Chiral BINOL and
BINAP are among the most useful and popular ligands for
catalytic asymmetric reactions [8]. If the molecules have
enough fluorine content in the fluorous tag, the fluorous
molecules are recyclable in an organic–fluorous biphasic
system and can be recovered easily by fluorous separation
techniques for reuse. We report here the usefulness of these
techniques for creating practical and environmentally
benign catalytic asymmetric reaction systems.
We chose the asymmetric addition of diethylzinc to
aromatic aldehydes catalyzed by a BINOL-Ti complex to
examine usefulness of the FBINOLs. The reaction has been
reported by Nakai and Chan independently [11]. It was
selected for testing the FBINOLs by utilizing the fluor-
ous–organic biphase and solid phase extraction techniques
because the reaction occurs in high enantiomeric excess and
yield by a simple procedure and with the use of commer-
cially available reagents.
At the outset, a standard reaction was carried out under the
same reaction conditions as those reported except that the
FBINOLs and benzotrifluoride (BTF) were used as the chiral
ligand and the solvent. The products and FBINOLs were
simply and cleanly separated with 1H,1H,2H,2H-perfluoro-
octyldimethylsilyl-bonded silica gel (FRP silica gel) by
washing successively with acetonitrile and FC-72 and the
results for several aromatic aldehydes are summarized in
Table 2.
2
. Results and discussion
2.1. Asymmetric addition of diethylzinc to aromatic
aldehydes catalyzed by fluorous BINOL-Ti complexes
Fluorous chiral BINOLs, (R)-F BINOL and (R)-F -
17
The chemical yields and the enantioselectivities are simi-
lar to those reported by Nakai (97 and 85% e.e. for ben-
zaldehyde, respectively) [11a] and the recoveries of the
FBINOLs were quantitative. 1-Naphthylaldehyde afforded
higher enantioselectivity (91% e.e.) than that of 2-naphthy-
1
3
BINOL, were prepared by the following route shown in
Scheme 1. The readily available tris(polyfluoroalkyl)silyl
0
group were introduced to the 6 and 6 positions as a fluorous
0
tag of methoxymethyl (MOM) protected 6,6 -dibromo
BINOL (I) [9]. The polyfluoroalkylsilylated BINOL deriva-
0
tive (II) was obtained in 91% yield via lithiation at the 6 and 6
positions of I and then reaction with (C F CH CH ) SiBr
6
13
2
2 3
Table 1
according to Curran’s method [10]. The MOM group of II
was deprotected with hydrochloric acid in THF under reflux
Partition coefficients of (R)-FBINOLs in organic solvent and FC-72
FBINOL
Rfh
F (%)
Organic
solvent
Organic
solvent/FC-72
0
and vigorous stirring. (R)-6,6 -bis[tris(1H,1H,2H,2H-Perfluor-
0
0
ooctyl)silyl]-1,1 -binaphth-2,2 -diol (III; (R)-F BINOL) was
isolated in 97% yield. The enantiomeric excess (e.e.) of the
R)-F BINOL was determined to be higher than 99% by
13
(
(
R)-F13BINOL
R)-F17BINOL
C
C
6
F
F
13CH
2
2
CH
2
2
–
–
61.16
64.10
CHCl
Toluene
3
5/95
2/98
(
13
8
17CH
CH
CH Cl
Toluene
2
2
1/99
1/99
HPLC using a chiral column and the (S)-enentiomer of III as a
standard. This was prepared by the same procedures as those
of (R)-F BINOL from (S)-starting material.
A mixture of 100 mg of (R)-FBINOLs in FC-72 (2 ml) and organic solvent
2 ml) was stirred at room temperature for 10 min. Then the two phases
13
(
0
(
binaphth-2,2 -diol (IV; (R)-F BINOL) was also synthesized
R)-bis[tris(1H,1H,2H,2H-Perfluorodecyl)silyl]-1,1 -
0
were separated and the solvents were evaporated in vacuo. The contents of
the fluorous compound in each phase were determined by weighing the
residue.
1
7
from I and (C F CH CH ) SiBr in 76% overall yield by the
17
8
2
2 3

Y. Nakamura et al. / Journal of Fluorine Chemistry 120 (2003) 121–129
123
Table 2
Catalytic asymmetric addition of diethylzinc (1 M in hexane) to several aromatic aldehydes using FBINOL-Ti complexes
a
b
c
d
Entry
Solvent
FBINOL
Ar
Yield (%)
e.e. (%)
Recovered FBINOL (%)
1
2
3
4
5
6
7
8
9
BTF/hexane (1:1, v/v)
BTF/hexane (1:1, v/v)
BTF/hexane (1:1, v/v)
BTF/hexane (1:1, v/v)
BTF/hexane (1:1, v/v)
BTF/hexane (1:1, v/v)
BTF/hexane (1:1, v/v)
BTF/hexane (1:1, v/v)
BTF/hexane (1:1, v/v)
BTF/hexane (1:1, v/v)
F
F
F
F
F
F
F
F
F
F
13BINOL
17BINOL
13BINOL
13BINOL
13BINOL
13BINOL
13BINOL
13BINOL
13BINOL
13BINOL
Ph
Ph
92
86
93
95
97
91
98
93
93
93
84
83
78
85
80
99
100
98
2-MeO–C
3-MeO–C
4-MeO–C
6
6
6
H
H
H
4
4
4
–
–
–
100
96
e
4-Me–C
6
H
4
–
81
100
98
1-Naphthyl
2-Naphthyl
91
78
98
e
4-Cl–C
4-Br–C
6
H
4
–
82
e
100
100
1
0
6
H
4
–
86
a
b
c
d
e
Substrate/FBINOL/Ti(O-iPr)
4
/Et2Zn ¼ 1:0.2:1.2:3 (molar ratio).
Isolated yield.
Determined by HPLC analysis using DAICEL CHIRALCEL OD or OD-H. The (R)-configuration of the product in each case.
Separated from the organic compounds by solid phase extraction with FRP silica gel.
TM
Determined by capillary GC analysis using SUPELCO b-DEX 120
.
laldehyde (78% e.e.), which may be caused by the difference
in steric hindrance around their aldehyde carbon atoms.
Subsequently, we examined a consecutive reaction by
using the (R)-F BINOL recovered by the fluorous silica
to aldehydes (see some examples of multisubstrate screening
in asymmetric catalysis in [12a]). They used polymer-bound
chiral ligand for the catalyst and gas chromatography with a
chiral column for the analysis. The report and the successful
results of consecutive reaction shown in Table 2 prompted us
to apply Liscamp’s methodology to our reaction system of
fluorous solid extraction method. Thus, we carried out the
reaction by using five different aldehydes as substrates. The
product mixture was first separated on FRP silica gel, and
then analyzed by gas chromatography with a SUPELCO b-
13
gel separation. The reaction was carried out in BTF at 0 8C
for 1 h and the (R)-F BINOL was separated from the product
with FRP silica gel. The recovered (R)-F BINOL was reused
13
13
for the next reaction without further purification. The results of
four consecutive reactions are summarized in Table 3.
As seen in Table 3, the enantioselectivities were the same
as those reported by Nakai [10] and the recoveries of (R)-
F BINOL were quantitative.
TM
DEX 120 chiral capillary column. The enantiomer pairs
of the corresponding products were well separated under the
GC conditions and the results are summarized in Table 4
together with the data obtained by the separately performed
experiments for each substrate.
1
3
Liscamp and coworkers have reported a simultaneous
substrate screening procedure for the ability to enantiose-
lectively catalyze the Ti(O-iPr) -mediated addition of Et Zn
4
2
Table 3
Catalytic asymmetric addition of diethylzinc (1 M in hexane) to benzaldehyde reusing the same (R)-F13BINOL
a
b
c
d
Run
Solvent
FBINOL
Yield (%)
e.e. (%)
Recovered (R)-F13BINOL (%)
1
2
3
4
BTF/hexane (1:1, v/v)
BTF/hexane (1:1, v/v)
BTF/hexane (1:1, v/v)
BTF/hexane (1:1, v/v)
F13BINOL
F13BINOL
F13BINOL
F13BINOL
92
93
96
89
84
85
84
83
99
97
99
99
a
Substrate/F13BINOL/Ti(O-iPr)
4
/Et2Zn ¼ 1:0.2:1.2:3 (molar ratio).
b
c
d
Isolated yield.
Determined by HPLC analysis using DAICEL CHIRALCEL OD. The (R)-configuration of the product in each case.
Separated from the organic compounds by solid phase extraction with FRP silica gel.

124
Y. Nakamura et al. / Journal of Fluorine Chemistry 120 (2003) 121–129
Table 4
Simultaneous catalytic asymmetric addition of diethylzinc (1 M in hexane) to various aromatic aldehydes
a
Entry
Ar
(R)-F13BINOL
(R)-F17BINOL
b,c
b,c
e.e. (%)
b,c
b,c
e.e. (%)
Yield (%)
Yield (%)
d
1
2
3
4
5
Ph
97 (92)
85 (93)
94 (91)
94 (93)
96 (93)
82 (84 )
83 (81)
91 (86)
81
83 (83)
83
6 4
4-Me–C H –
d
76 (78 )
2-MeO–C
4-Cl–C
4-Br–C
6
H
4
–
73
79
6
H
4
–
83 (82)
84 (86)
87
84
6
H
4
–
83
85
a
Substrate/FBINOL/Ti(O-iPr)
4
/Et2Zn ¼ 1:0.2:1.2:3 (molar ratio).
b
c
d
Numbers in parentheses are the data obtained by the separately performed experiments for each substrate.
TM
Determined by capillary GC analysis using SUPELCO b-DEX 120
Determined by HPLC analysis using DAICEL CHIRALCEL OD-H.
.
As seen in Table 4, the chemical yields and the enantios-
electivities were very similar to those obtained by the
reaction of each substrate.
mixture was stirred vigorously at 0 8C for 2 h, and then the
organic phase was withdrawn with a syringe and was
quenched with 1N hydrochloric acid to ensure removal of
any residual (R)-F BINOL and to liberate the product
The successful results in the uniphase reaction encour-
aged us to examine a toluene and FC-72 biphase system.
Thus, the reaction was carried out repeatedly by using
benzaldehyde and (R)-F BINOL as shown in Fig. 1.
1
3
alcohol from the Ti complex. The products and residual
(R)-F BINOL were separated with FRP silica gel by wash-
1
3
ing successively with acetonitrile and FC-72. The product
alcohol was obtained from the acetonitrile eluate. Fresh
Ti(O-iPr) , the Et Zn and benzaldehyde solution were added
1
3
When Ti(O-iPr)4 was added to the solution of (R)-
F BINOL in FC-72, the reaction mixture first became a
1
3
4
2
light red and homogeneous and then a colorless oily material
separated out on the surface of the FC-72 solution. A 1 M
solution of Et Zn in hexane was then added. After cooling to
to the fluorous phase, and the reaction was carried out in the
same way. The reaction was repeated five times and the
results are summarized in Table 5.
2
0
8C, a benzaldehyde solution in toluene was added. The
As seen in Table 5, the enantioselectivity remained at 80%
or above throughout five runs. However, about 10% of (R)-
F BINOL was recovered from the organic phase in every
organic phase (toluene and hexane) became pale yellow-
brown and the FC-72 phase remained light red. The reaction
1
3
Fig. 1. Method for catalytic asymmetric addition of diethylzinc to benzaldehyde using a (R)-F13BINOL-Ti complex in FC-72-organic solvent biphase
system.

Y. Nakamura et al. / Journal of Fluorine Chemistry 120 (2003) 121–129
125
Table 5
Catalytic asymmetric addition of diethylzinc (1 M in hexane) to benzaldehyde using a (R)-F13BINOL-Ti complex in FC-72-organic solvent biphase system
a
b
c
Run
Solvent
FBINOL
Yield (%)
e.e. (%)
Recovered (R)-F13BINOL (%)
1
2
3
4
5
Toluene/hexane/FC-72 (3:3:5, v/v/v)
Toluene/hexane/FC-72 (3:3:5, v/v/v)
Toluene/hexane/FC-72 (3:3:5, v/v/v)
Toluene/hexane/FC-72 (3:3:5, v/v/v)
Toluene/hexane/FC-72 (3:3:5, v/v/v)
F13BINOL
F13BINOL
F13BINOL
F13BINOL
F13BINOL
81
89
87
87
87
83
82
82
81
80
10
12
12
11
10
a
Isolated yield.
b
c
Determined by HPLC analysis using DAICEL CHIRALCEL OD.
Separated from the organic compounds by solid phase extraction with FRP silica gel.
experiment. Therefore, it seems likely that a significant
amount of the chiral catalyst was in the organic phase
and the asymmetric reaction took place only in that phase.
That the organic phase had a pale brown color also supports
this conclusion. To test this postulate, we carried out the
reaction separately in the organic phase and in a toluene–FC-
get the enantioselectivity higher than 83% e.e. in the biphase
system and that hexane plays an important role to bring
about the high enantiomeric excess.
When the reaction was carried out consecutively by using
(R)-F BINOL and Et Zn solution in hexane as in Table 5,
leaching of (R)-F BINOL into the organic phase was only
1
7
2
1
7
7
2 biphase system. The procedure was the same until the
about 1% in each experiment, while the enantioselectivities
were consistently 78–79% e.e. as shown in Table 7.
reaction mixture was cooled at 0 8C after the addition of
Et Zn solution. Toluene was added to the reaction mixture
Judging from all these results, it is concluded that a certain
amount of FBINOLs are necessary to exist in the organic
phase for getting enantioselectivity as high as 83% e.e. in the
organic and FC-72 biphase system. However, it is also clear
that the enantioselectivity was slightly improved and the
immobilization of the F BINOL in FC-72 phase was much
2
and the two phases were separated. The benzaldehyde
solution was added to the organic phase and the reaction
was carried out as described above. The Et Zn solution and
2
the benzaldehyde solution were added to the FC-72 phase
and the reaction was carried out in the same way. From the
organic phase the product was obtained in 73% e.e. (88%
yield) and 10% of (R)-F BINOL was recovered. From the
1
7
improved compared to the results of F BINOL in toluene–
1
3
FC-72 and in organic (toluene and hexane)–FC-72 biphase
systems, respectively, as a result of the increased fluorous
content of the ligand.
1
3
toluene–FC-72 biphase system the product was obtained in
7% e.e. (81% yield) and 88% of (R)-F BINOL was
7
1
3
recovered. Therefore, it is clear that some of the chiral
complex was actually in the organic phase but that the
amount of the complex was too little to give the expected
2.2. Preparation of a fluorous chiral BINAP and
application to an asymmetric Heck reaction
8
toluene–FC-72 biphase system was somewhat higher in
3% e.e. On the other hand, the enantioselectivity in the
The important chiral ligand BINAP is usually prepared
0
spite of the lack of excess amount of Ti(O-iPr) . The
4
from the corresponding O,O -bistriflate derivative of BINOL
[13]. Very recently, Stuart and coworkers [6d] reported the
presence of excess amount of Ti(O-iPr) was reported to
4
be indispensable for the reaction to result in high enantios-
electivity and yield [12a].
When a consecutive reaction was carried out by using
Table 6
Catalytic asymmetric addition of diethylzinc (1.1 M in toluene) to
benzaldehyde using a (R)-F13BINOL-Ti complex in FC-72–organic
Et Zn solution in toluene (1.1 M) instead of hexane solution
2
a
in order to clarify a role of hexane in the biphase system, the
enantioselectivities were lowered to 77–78% e.e., but the
solvent biphase system
Run Solvent
FBINOL
Yield
b
(%)
e.e.
(%)
Recovered
c
amount of (R)-F BINOL that leached into the toluene phase
1
3
(R)-F13BINOL
d
(%)
decreased to less than 1%, as shown in Table 6.
This reaction was also carried out in the toluene phase and
in the toluene–FC-72 biphase system separately in the same
way as described above. The enantioselectivity in the
biphase system, 78% e.e. (85% yield), was similar to the
values in Table 6. However, the enantioselectivity in the
separated toluene phase was dramatically reduced to 30%
e.e. (49% yield) and the recovery of (R)-F BINOL from
1
2
3
Toluene/FC-72
3:5, v/v)
F
13BINOL 85
78
78
77
<1
<1
<1
(
Toluene/FC-72 F13BINOL 85
(3:5, v/v)
Toluene/FC-72
3:5, v/v)
F13BINOL 80
(
a
b
c
Substrate/F13BINOL/Ti(O-iPr)
4
/Et2Zn ¼ 1:0.2:1.2:3 (molar ratio).
1
3
Isolated yield.
Determined by HPLC analysis using DAICEL CHIRALCEL OD.
the phase was negligible. Results (e.e., recovery of (R)-
F BINOL from organic phase) seem to suggest that
1
3
The (R)-configuration of the product in each case.
d
Separated from the organic compounds by solid phase extraction with
hexane dissolves the catalyst much better than toluene.
Therefore, it is deduced that both phases are necessary to
FRP silica gel.

126
Y. Nakamura et al. / Journal of Fluorine Chemistry 120 (2003) 121–129
Table 7
Catalytic asymmetric addition of diethylzinc (1 M in hexane) to benzaldehyde using a (R)-F17BINOL-Ti complex in FC-72–organic solvent biphase system
a
b
c
d
Run
Solvent
FBINOL
Yield (%)
e.e. (%)
Recovered (R)-F17BINOL (%)
1
2
3
Toluene/hexane/FC-72 (1:1:2, v/v/v)
Toluene/hexane/FC-72 (1:1:2, v/v/v)
Toluene/hexane/FC-72 (1:1:2, v/v/v)
F
F
F
17BINOL
17BINOL
17BINOL
82
82
77
79
78
78
1
1
1
a
Substrate/F17BINOL/Ti(O-iPr)
Isolated yield.
4
/Et2Zn ¼ 1:0.2:1.2:3 (molar ratio).
b
c
d
TM
Determined by capillary GC analysis using SIPELCO b-DEX 120 . The (R)-configuration of the product in each case.
Separated from the organic compounds by solid phase extraction with FRP silica gel.
0
preparation of (R)-6,6 -bis(1H,1H,2H,2H-perfluorooctyl)-
0
the crude product was oxidized with H O , and the oxidized
2 2
0
2
,2 -bis(diphenylphosphino)-1,1 -binaphthyl and its applica-
product was easily purified by flash chromatography and
recrystallization (87% yield based on V). That (R)-F BINAP
is very sensitive to oxygen in the air and is easily oxidized to
tion to asymmetric hydrogenation. The ligand was prepared
by the conventional procedure from the corresponding
BINOL bistriflate precursor in good yield (85%). The
derived ruthenium complex catalyzed the asymmetric
hydrogenation of dimethyl itaconate in excellent enantios-
electivity (95.7% e.e.), which is similar to that obtained in
the original Ru-BINAP complex reaction (95.4% e.e.). We
have recently prepared a more heavily fluorinated chiral
BINAP (F BINAP) and we report herein the synthesis of
1
3
(R)-F BINAPO apparently stems from its fluorous charac-
1
3
teristics. It is well known that a long fluorous chain has strong
affinity for oxygen [2]. Next, we examined reduction of (R)-
F BINAPO by the silane reduction method [14] which has
1
3
been used as the standard reduction method of a chiral
phosphine oxide such as BINAP oxide. However, (R)-
F13BINAP was not obtained by the reaction despite close
scrutiny of the reaction conditions. We also attempted to carry
1
3
the reagent and its use in a Heck reaction (Scheme 2).
When the bistriflate of (R)-F BINOL (V) was phosphi-
out the reduction by using SmI -HMPA in the THF system
2
1
3
nated with Ph PH by using NiCl (dppe) in BTF at 100 8C for
[15], but the yield was not high and it was practically
impossible to separate (R)-F BINAP from the non-polar
2
2
3
by TLC analysis in good yield. However, (R)-F BINAP IV
days under argon, the desired product (VI) was actually seen
1
3
by-products. Fortunately, we succeeded in getting high yield
of (R)-F BINAP by employing Imamoto’s method for reduc-
1
3
and the starting material, bistriflate V, had very close rf values
on TLC and it was very hard to separate them by flash column
chromatography. During the workup and repeated attempts to
purify the product with flash column chromatography, a
significant amount of the desired product was oxidized to
the corresponding dioxide (VII; (R)-F BINAPO). Therefore,
1
3
tion of chiral phosphine oxides [16]. The reaction was carried
out as follows: (R)-F BINAPO was dissolved in 1,2-
1
3
dimethoxyethane (DME) and then methyl triflate (MeOTf)
was added to the solution. The reaction mixture was stirred
for 2 h at room temperature under argon. After cooling to
1
3
Scheme 2.

Y. Nakamura et al. / Journal of Fluorine Chemistry 120 (2003) 121–129
127
Table 8
tively. The enantiomeric purity of (R)- and (S)-F BINAPO
13
Partition coefficients of (R)-F13BINAPO and (R)-F13BINAP in organic
was analyzed by HPLC by using DAICEL CHIRALCEL OD-
H column to be higher than 99% e.e. Partition coefficients of
(R)-F BINAPO and (R)-F BINAP are shown in Table 8.
solvent and FC-72
F (%)
Method
Organic
solvent
FC-72/organic
solvent
13
13
In order to get preliminary information about (R)-
F BINAP, we examined an asymmetric Heck reaction.
(
(
R)-F13BINAPO
R)-F13BINAP
53.09
53.70
A
A
CH
Cl
2 2
76/24
90/10
1
3
Benzene
Hayashi and coworkers [17] have reported that Pd(OAc)2-
R)-BINAP catalyzes the reaction between 2,3-dihydrofuran
(
A
B
B
B
Benzene
Benzene
79/21
74/26
98/2
and 4-chlorophenyl triflate at 40 8C for 22 h to give 2-(4-
chlorophenyl)-2,3-dihydrofuran (1) in 91% e.e. We carried
out reactions under the same reaction conditions except that
BTF and (R)-F BINAP were used as the solvent and the
CH
3
CN
DMF
98/2
Method A: a mixture of 100 mg of (R)-F13BINAPO or (R)-F13BINAP in
FC-72 (2 ml) and organic solvent (2 ml) was stirred at room temperature
for 10 min. Then the two phases were separated and the solvents were
evaporated in vacuo. The contents of the fluorous compound in each phase
were determined by weighing the residue. Method B: a mixture of 20 mg
of (R)-F13BINAP in purified FC-72 (1 ml) and organic solvent (1 ml) was
stirred at room temperature for 10 min under argon. The contents of the
fluorous compound in each phase were determined by HPLC analysis.
1
3
chiral ligand, and the results are summarized in Table 9
entries 1–3). As seen in Table 9, the reaction rate is lower in
the case of (R)-F BINAP than in that of (R)-BINAP. BTF is
(
1
3
a good solvent for (R)-F BINAP (entry 2, 90% e.e.) but not
13
for (R)-BINAP (entry 1, 76% e.e.). Benzene was also a good
solvent for (R)-F BINAP (entry 3, 92% e.e.), although the
1
3
chemical yield of 2-(4-chlorophenyl)-2,5-dihydrofuran (2)
increased. The enantiomeric excess of the product 1 was
TM
0
8C, LiAlH was added to the solution and then the reaction
determined by GC analysis using SUPELCO b-DEX 120
4
mixture was stirred at room temperature for 2 h. The color of
the reaction mixture changed from light yellow to dark red
and then to yellow. The reaction was quenched by a small
amount of saturated Na SO solution and then the reaction
chiral capillary column. (R)-F BINAP was recovered by
1
3
using fluorous reverse phase silica gel in about 70% yield.
However, this percentage of recovery was not precise
because the recovered material was a mixture of (R)-
F BINAP and (R)-F BINAPO (mostly (R)-F BINAPO).
2
4
mixture was directly loaded on a short silica gel column and
eluted by a degassed solvent (hexane/Et2O ¼ 20:1) under
argon. Careful workup, purification and solvent removal
followed by flash column chromatography under argon
afforded an oily residue which gradually transformed to white
crystals (68%).
1
3
13
13
Finally, we carried out the Heck reaction in a benzene–
FC-72 biphasic system (entries 4 and 5 in Table 9). The
enantioselectivity was marginally higher (93% e.e.),
although the chemical yield was much lower (39%) than
in the original reaction (entry 4). After the first reaction, the
benzene layer was changed for a fresh substrate benzene
solution to test for recycling of the catalyst. However, the
31
The
P NMR spectra of (R)-F BINAP and (R)-
13
F BINAPO showed singlets at ꢀ14.1 and 28.7 ppm, respec-
13
Table 9
Asymmetric Heck reaction of 2,3-dihydrofuran with 4-chlorophenyl triflate
a
b
c
e.e. (%) (configuration)
d
Entry
Ligand
Solvent
Reaction
time (h)
Yield (%)
1
2
1/2
1
2
e
e
e
e
e
1
2
3
4
(R)-BINAP
BTF
24
77
62
62
50
67
59
6
8
92/8
76 (R)
90 (R)
92 (R)
93 (B)
93 (R)
ND
ND
ND
ND
ND
(R)-F13BINAP
(R)-F13BINAP
(R)-F13BINAP
(R)-F13BINAP
BTF
Benzene
88/12
72/28
69/31
62/38
f
f
f
59
22
18
Benzene/FC-72 (1:1, v/v)
Benzene/FC-72 (1:1, v/v)
39
g
f
f
f
5
2
<1
a
4
-Cl-C
6
H
4
Otf/2,3-dihydrofuran/i-Pr
2
Net/Pd(OAc)
2
/Ligand ¼ 1:0:5.0:3.0:0.03:0.06 (molar ratio).
b
c
d
e
f
Isolated yield.
TM
.
Determined by capillary GC analysis using SUPELCO b-DEX 120
Assigned by the sign of the optical rotation.
Not determined.
TM
Determined by capillary GC analysis with SUPELCO b-DEX 120 by using mesitylene as an internal standard.
The fluorous phase in Entry 4 was reused as the catalyst solution.
g

128
Y. Nakamura et al. / Journal of Fluorine Chemistry 120 (2003) 121–129
[
[
2] I.T. Horv a´ th, J. R a´ vai, Science 266 (1994) 72–75.
reaction did not proceed at all, probably because of inactiva-
tion of the catalyst by ligand oxidation (entry 5). (R)-
F BINAP was demonstrated to have been oxidized in the
3] (a) E. de Wolf, A.L. Spek, B.W.M. Kuipers, A.P. Philipse, J.D.
Meeldijk, P.H.H. Bomans, P.M. Frederik, B.-J. Deelman, G. van
Koten, Tetrahedron 58 (2002) 3911–3922;
1
3
FC-72 phase by monitoring with TLC. The color change of
the FC-72 phase from wine-red to brown midway in the first
reaction suggested the inactivation of the catalyst as well.
In conclusion, we have prepared highly fluorinated chiral
BINOLs, (R)-F BINOL and (R)-F BINOL, and BINAP,
(
b) D.F. Foster, D. Gudmunsen, D.J. Adams, A.M. Stuart, E.G.
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5
(
1
3
17
(
(
R)-F BINAP, and applied them to catalytic asymmetric
13
(e) D. Sinou, D. Maillard, G. Pozzi, Eur. J. Org. Chem. (2002) 269–
275.
C–C bond forming reactions. The FBINOLs were examined
in the consecutive reactions by using fluorous–organic
biphase and fluorous solid phase extraction techniques. In
the biphase system, we obtained an enantioselectivity near
maximum value that was attained in non-fluorous uniphase
system and a good immobilization of the catalyst in the
fluorous phase by tuning the fluorine atom content of the
ligands. The FBINOLs were easily recovered by the solid
phase extraction with FRP silica gel and reusable without
further purification to give almost the same chemical yield
and enantioselectivity as the first use. The solid phase extrac-
tion technique was applied successfully to a simultaneous
screening procedure. On the other hand, (R)-F BINAP was
[
4] D.P. Curran, S. Hadida, J. Am. Chem. Soc. 118 (1996) 2531–2532.
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[
1
425–1427;
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715;
(c) FluoroFlash
(
6
TM
FRP silica gel cartridges and columns are
commercially available from Fluorous Technologies Inc.
[
6] (a) D. Maillard, G. Pozzi, S. Quici, D. Sinou, Tetrahedron 58 (2002)
3
971–3976;
b) Y. Tian, Q. Chuan, T.C.W. Mak, K.S. Chan, Tetrahedron 58
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(
(
3
(
1
3
examined to an asymmetric Heck reaction. The preliminary
results revealed that (R)-F BINAP had good solubility in
(
1
3
Chem. (2001) 4639–4649;
(f) D. Bonafoux, Z. Hua, B. Wang, I. Ojima, J. Fluorine Chem. 112
fluorinated solvents and provided similar enantioselectivity in
the BTF homogeneous system to that of the original reaction
and higher enantiomeric excess in the benzene–FC-72 bipha-
sic system than that of the original one. However, (R)-
(
2001) 101–108;
(
g) F. Fache, O. Piva, Tetrahedron Lett. 42 (2001) 5655–5657;
(h) B. Hungerhoff, H. Sonnenschein, F. Theil, Angew. Chem. Int.
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F BINAP is easily oxidized by a trace amount of oxygen
1
3
(i) M. Cavazzini, G. Pozzi, S. Quici D. Maillard, D. Sinou, Chem.
Commun. (2001) 1220–1221;
in the fluorous phase during the reaction, probably because of
the strong affinity of the fluorous solvent and the tags of (R)-
F BINAP for oxygen. Therefore, preventing (R)-F BINAP
(
j) Y. Tian, K.S. Chan, Tetrahedron Lett. 41 (2000) 8813–8816;
k) M. Cavazzini, A. Manfredi, F. Montanari, S. Quici, G. Pozzi,
(
1
3
13
Chem. Commun. (2000) 2171–2172;
l) G. Pozzi, M. Cavazzini, F. Cinato, F. Montanari, S. Quici, Eur. J.
Org. Chem. (1999) 1947–1955;
m) H. Kleijn, E. Rijnberg, J.T.B.H. Jastrzebski, G. van Koten, Org.
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from oxidation throughout the reaction is the main problem to
be solved to achieve more successful use of it.
(
(
(
Acknowledgements
(
[
[
7] (a) I. Ojima (Ed.), Catalytic Asymmetric Synthesis, second ed.,
Wiley-VCH, New York, 2000;
The author would like to thank Professor Dennis P.
Curran, University of Pittsburgh, for his helpful suggestions.
This work was partially supported by Grant-in-Aid for
Scientific Research from the Ministry of Education, Science,
Sports and Culture, Japan.
(b) R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley,
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8] (a) Y. Nakamura, S. Takeuchi, S. Zhang, K. Okumura, Y. Ohgo,
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(
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