A first high enantiocontrol of an asymmetric tertiary carbon center attached with a fluoroalkyl group via Rh(I)-catalyzed conjugate addition reaction

Article abstract of DOI:10.1016/j.tetlet.2008.01.122

Treatment of fluoroalkylated electron-deficient olefins with various boronic acids in the presence of a catalytic amount of Rh(I) coordinated with (S)-BINAP in toluene/H₂O at the reflux temperature for 3 h gave the corresponding conjugate addit

Full text of DOI:10.1016/j.tetlet.2008.01.122

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2106–2110
A first high enantiocontrol of an asymmetric tertiary carbon
center attached with a fluoroalkyl group via Rh(I)-catalyzed
conjugate addition reaction
Tsutomu Konno *, Tomoo Tanaka, Tomotsugu Miyabe, Atsunori Morigaki, Takashi Ishihara
Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
Received 14 January 2008; accepted 29 January 2008
Available online 1 February 2008
Abstract
Treatment of fluoroalkylated electron-deficient olefins with various boronic acids in the presence of a catalytic amount of Rh(I) coor-
dinated with (S)-BINAP in toluene/H2O at the reflux temperature for 3 h gave the corresponding conjugate addition products with high
enantioselectivity in high yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Fluorine-containing compounds; Asymmetric tertiary carbon; Enantioselective synthesis; Rhodium; Conjugate addition
Rf
H
Introduction of a fluoroalkyl group into an asymmetric
carbon center constitutes a major interest in organofluorine
chemistry owing to the recent outstanding applications of
optically active fluoroalkylated compounds in the medici-
nal, pharmaceutical, and agricultural fields.1 Out of such
compounds, molecules having an asymmetric tertiary car-
bon center without any heteroatom substituent (1, Fig. 1)
to date have been one of the most challenging synthetic tar-
gets due to their synthetic difficulty as well as their unique
biological activities.2
There have been some reports on various diastereoselec-
tive synthetic methods for the preparation of optically
active 1 thus far, for example, asymmetric Michael
addition3 or aldol reaction4 by using chiral oxazolidinone
derivatives, asymmetric 2,3-Wittig5 or Ireland–Claisen6
rearrangements, SN20 reaction7 by utilizing the chirality
transfer system, the synthesis of 1 by using various sugars
as a chiral template;8 etc.9 However, little attention has
been paid to an enantioselective synthesis of 1 by using chi-
ral transition-metal catalyst.10 Herein, we wish to describe
Rf = CHF , CF , etc.
R , R ˚ heteroatom substituent
2
3
1
2
1
2
R
R
1
Fig. 1. Chiral fluoroalkylated compounds.
a first highly enantioselective synthetic approach to an
asymmetric tertiary carbon framework 1 having a fluoro-
alkyl group via Rh(I)-catalyzed conjugate addition reac-
tion of various fluoroalkylated electron-deficient olefins 2
with boronic acids (Scheme 1).
Our initial studies were performed using b-trifluoro-
methylated-a,b-unsaturated ketone 2a, prepared readily
according to the reported procedure,11 and phenylboronic
Rh(I)
Rf
H
1
EWG
+
R B(OH)
2
Rf
1
2
R
R
1
2
Rf = CHF , CF , etc.
EWG = an electron-
withdrawing group
2
3
1
2
R , R = Aryl, alkyl
*
Scheme 1. The conjugate addition of fluoroalkylated electron-deficient
olefins.
Corresponding author. Tel.: +81 75 724 7517; fax: +81 75 724 7580.
E-mail address: konno@chem.kit.ac.jp (T. Konno).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.122

T. Konno et al. / Tetrahedron Letters 49 (2008) 2106–2110
2107
Table 1
EtO2C) on the benzene ring could participate nicely in the
conjugate addition to give the corresponding adducts 4b–d,
4g–i in excellent yields (84–96% yield) with high enantio-
selectivity (90–94% ee). However, the use of ortho-substi-
tuted arylboronic acid, such as o-chlorophenyl- (3f) or
1-naphthylboronic acid (3k), resulted in a significant
decrease of the reaction efficacy (3% or 51% yield in entry
6 or 11), while meta-substitution of the benzene ring of
RB(OH)2 did not influence on the reaction at all (entry
5). 2-Thienylboronic acid (3j) was also found to be a good
Michael donor in the reaction (entry 10), though the yield
decreased slightly. On the other hand, alkenylboronic acids
3l, 3m led to a significant decrease of the enantioselectivity
or the chemical yield (entries 12 and 13).
We also examined the conjugate addition reaction using
various types of fluorine-containing electron-deficient ole-
fins. As shown in entries 14–16, the reaction of various elec-
tron-deficient olefins, such as a,b-unsaturated ester 2b or
amide 2c, nitroalkene 2d, proceeded smoothly to give the
corresponding adducts 4l–n in good yields. Especially, the
high enantioselectivity (92% ee) was observed in the case
of the amide (entry 15). Unfortunately, the vinyl sulfone
2e and the vinylphosphonate 2f did not give the satisfac-
tory results, the product being afforded in very low yields
as well as in a very low enantioselective manner (entries
17 and 18). Changing the fluoroalkyl group from a CF3
group to a CHF2 group also caused a slight decrease of
the enantiomeric excess. The use of (Z)-substrate 2h affor-
ded the Michael adduct 4a with the same absolute confi-
guration as in the reaction of (E)-substrate 2a (entry 1 vs
entry 20).
In order to reveal why the same product, (R)-stereo-
isomer 4a, was obtained preferentially in both (E)- and
(Z)-substrates, we first treated (Z)-2a only with 5 mol %
of [Rh(C8H12)2]BF4 in the absence of arylboronic acid in
toluene/H2O (v/v = 4/1) at the reflux temperature for 3 h
(Scheme 2). In this case, ca. 30% of (E)-2a was obtained
together with ca. 70% of the starting material. On the other
hand, treatment of (Z)-2a only with 6 mol % of (S)-BINAP
gave (E)-2a in only ca. 3% yield. Very interestingly, the use
of [Rh(C8H12)2]BF4 and (S)-BINAP without arylboronic
acid led to complete consumption of (Z)-2a, (E)-2a being
obtained quantitatively. These experimental results indi-
cate that rhodium catalyst coordinated with (S)-BINAP
as a ligand catalyzes the isomerization much more rapidly
than the conjugate addition reaction.
To evaluate the influence of a fluoroalkyl group upon
the reaction, we also examined the reaction of nonfluori-
nated counterparts 2i–o (Table 2, entries 21–27). As shown
in entries 21–23, increasing the bulkiness of an Rf group
caused a decrease of the yield as well as the enantiomeric
excess. It should be emphasized that the substrate 2j having
an isopropyl group at b position, which is believed to be
similar to a CF3 group in bulkiness,12 gave the Michael
adduct 4r with only 77% ee (entry 22). As shown in entries
24–27, introduction of an electron-withdrawing group on
the benzene ring in Rf resulted in an increase of an
Investigation of the reaction conditions
PhB(OH)2 (3a) (X equiv.)
[Rh(C8H12)2]BF4 (Y mol %)
)-BINAP (1.2 equiv. of Rh catalyst)
O
CF
O
3
(
S
F C
Ph
Ph
Ph
3
Solvent/H2O (v/v=4/1), reflux, 3 h
2a
4a
Entry
X
Y
Solvent
Yielda of Enantiomeric
(equiv)
(mol %)
4a/%
excessb (% ee)
1
2
3
4
5
1.2
2.4
2.4
2.4
1.2
0.5
0.5
1.0
5.0
5.0
Toluene
Toluene
Toluene
Toluene
Toluene
60
91
95
96
55
72
74
85
90
96 (90)
6
7
8c
9
1.2
1.2
1.2
1.2
1.2
1.2
5.0
5.0
5.0
5.0
5.0
5.0
Hexane
THF
DMF
CH3OH
1,4-Dioxane 78
CH3NO2 22
0
—
34
2
4
23
36
23
32
9
10
11
a
Determined by 19F NMR. Value in parentheses is of isolated yield.
Determined by HPLC (Chiralpac AD).
Carried out at 100 °C.
b
c
acid (3a) as shown in Table 1. Thus, treatment of 1.0 equiv
of 2a with 1.2 equiv of 3a in the presence of 0.5 mol % of
[Rh(C8H12)2]BF4 and 0.6 mol % of (S)-BINAP in toluene/
H2O (v/v = 4/1) at the reflux temperature for 3 h gave the
corresponding conjugate addition product 4a with 55%
enantiomeric excess in 60% yield (entry 1). In this case,
the product with R absolute configuration was afforded
preferentially (vide infra). When 2.4 equiv of 3a was used,
the chemical yield and the enantiomeric excess were both
increased (entry 2). Although the employment of 1 mol %
of rhodium catalyst did not cause any influence of the reac-
tion (entry 3), 5 mol % of the catalyst led to a significant
improvement of the optical purity, the desired adduct with
85% enantiomeric excess being obtained in 96% yield (entry
4). Eventually, the best yield was obtained when the reac-
tion was carried out by using 1.2 equiv of phenylboronic
acid in the presence of 5 mol % of [Rh(C8H12)2]BF4 and
6 mol % of (S)-BINAP (entry 5). In this case, the product
with 90% enantiomeric excess was obtained in 96% yield.
As shown in entries 6–11, we also examined the solvent
effect on the conjugate addition. As a result, hexane, THF,
DMF, CH3OH, and CH3NO2 were not the solvent of
choice, the corresponding adducts being obtained in very
low yields (0–32%). Quite interestingly, 1,4-dioxane, which
is generally used in the Rh(I)-catalyzed conjugate addition
of nonfluorinated electron-deficient olefins, resulted in the
significant decrease of the optical purity of 4a (23% ee),
though the yield was high (entry 10).
With the optimum reaction conditions (Table 1, entry
5), we next investigated the conjugate addition of various
boronic acids. The results are summarized in Table 2.
As shown in entries 2–4 and 7–9, various types of aryl-
boronic acids 3b–d, 3g–i having an electron-donating (CH3,
CH3O) or an electron-withdrawing group (Cl, F, CH3CO,

2108
T. Konno et al. / Tetrahedron Letters 49 (2008) 2106–2110
Table 2
Rhodium-catalyzed conjugate addition reactions of various arylboronic acids into various electron-deficient olefins
Rf
RB(OH)2 (3) (1.2 equiv.), [Rh(C8H12)2]BF4 (5 mol %), (
S
)-BINAP (6 mol %)
1
1
R
R
R
Rf
R1
Toluene/H2O (4/1), reflux, 3 h
2
(R)-4
Entry
Rf
Product
R
Product
Yielda/% of 4
Enantiomeric excessb (%)
1
2
3
4
5
6
7
8
9
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
COPh
COPh
COPh
COPh
COPh
COPh
COPh
COPh
COPh
2a
2a
2a
2a
2a
2a
2a
2a
2a
Ph(a)
4a
4b
4c
4d
4e
—
4f
96 (90)
95 (91)
96 (89)
95 (94)
89 (81)
3
84 (80)
96 (95)
95 (80)
90
92
92
94
p-CH3C6H4 (b)
p-CH3OC6H4 (c)
p-ClC6H4 (d)
m-ClC6H4 (e)
o-ClC6H4 (f)
p-FC6H4 (g)
p-CH3(O)CC6H4 (h)
p-EtO2CC6H4 (i)
91
N.D.c
90
4g
4h
93
92
(j)
10
11
CF3
CF3
COPh
COPh
2a
2a
4i
4j
79 (64)
51
90
70
S
(k)
(l)
12
13
CF3
CF3
COPh
COPh
2a
2a
4k
78 (70)
11
40
Ph
—
N.D.c
(m)
n-Bu
14
15
16
17
18
19
20d
CF3
CF3
CF3
CF3
CF3
CHF2
CF3
CO2Et
CONMe2
NO2
SO2Ph
P(O)(OEt)2
COPh
2b
2c
2d
2e
2f
Ph(a)
Ph(a)
Ph(a)
Ph(a)
Ph(a)
Ph(a)
Ph(a)
4l
60
53 (46)
60
30 (27)
13
96 (92)
91
N.D.c
92
4m
4n
4o
—
4p
4a
N.D.c
9
N.D.c
74
2g
2h
COPh
90
21
22
23
24
25
26
27
a
CH3
i-Pr
t-Bu
p-CH3C6H4
p-CH3OC6H4
p-CF3C6H4
p-NCC6H4
COPh
COPh
COPh
COPh
COPh
COPh
COPh
2i
Ph(a)
Ph(a)
Ph(a)
Ph(a)
Ph(a)
Ph(a)
Ph(a)
4q
4r
—
4s
4t
75e
57e
Trace
30e
68e
84
92
77
—
67
65
75
89
2j
2k
2l
2m
2n
2o
4u
4v
40e
Determined by 19F NMR. Values in parentheses are of isolated yields.
Determined by HPLC (Chiralpac AD-H).
Not determined.
(Z)-Substrate was used instead of (E)-substrate.
Determined by 1H NMR.
b
c
d
e
enantiomeric excess, while aromatic substituents having an
electron-donating group on the benzene ring in Rf led to a
decrease of an enantiomeric excess. These results indicate
that high enantioselectivity in 2a,c in spite of the bulkiness
of a CF3 group may be ascribed in part to a strongly
electron-withdrawing effect of a CF3 group.
The stereochemical assignment of 4 was made as follows
(Scheme 3). Thus, treatment of 4a with 2.0 equiv of LiAlH4
in THF at 0 °C for 1 h gave a 1:1 diastereomeric mixture of
the corresponding alcohol 5a in 81% yield, which were sub-
jected to 2.0 equiv of CuSO4–SiO2 in hexane at the reflux
temperature for 2 h,13 giving the known compound 6a.
The comparison of the observed optical rotation of 6a with
its literature value made it possible to determine the abso-
lute configuration of 4a as R.9b Additionally, the stereo-
chemical determination of the major stereoisomer of 4a,
b, h, u was made on the basis of the single-crystal X-ray
analysis, and it was found that all compounds had R abso-
lute configuration.
The proposed mechanism for the present reaction is out-
lined in Scheme 4.14 Thus, (E)-substrate (or which pro-
duced via isomerization of Z-isomer) may come close to
arylrhodium species coordinated with (S)-BINAP (Int-A),
avoiding the phenyl group on phosphorus atom. Then, si

T. Konno et al. / Tetrahedron Letters 49 (2008) 2106–2110
2109
Without RB(OH)2
Michael adduct, and the rhodium species coordinated with
(S)-BINAP may be regenerated.
[Rh(C8H12)2]BF4 (5 mol %)
Toluene/H2O (v/v=4/1)
reflux, 3 h
ca. 30% yield
In summary, we have demonstrated the rhodium-cata-
lyzed conjugate addition reaction of various arylboronic
acids into various fluorine-containing electron-deficient
olefins. As a result, the reaction of b-fluoroalkylated-a,b-
unsaturated ketones and amide with various arylboronic
acids led to a first example of the highly enantioselective
construction of an asymmetric tertiary carbon center
attached with a fluoroalkyl group. Further studies on the
rhodium-catalyzed conjugate addition reactions are now
under way in our laboratory.
Without RB(OH)2
O
CF
O
3
(S)-BINAP (6 mol %)
F C
Ph
Ph
)-2a
Toluene/H2O (v/v=4/1)
reflux, 3 h
3
(
Z
(E)-2a
ca. 3% yield
Without RB(OH)2
(S)-BINAP (6 mol %)
[Rh(C8H12)2]BF4 (5 mol %)
Toluene/H2O (v/v=4/1)
reflux, 3 h
quant.
Acknowledgement
Scheme 2. The reaction of Z-isomer in the absence of arylboronic acid.
We greatly acknowledge TOSOH F-TECH, INC. for
supplying trifluoroacetaldehyde ethyl hemiacetal for the
preparation of 2a and ethyl 4,4,4-trifluorocrotonate.
CF OH
CF
O
3
3
LiAlH4 (2.0 equiv.)
THF, 0 ˚C, 1 h
Ph
Ph
Ph
Ph
References and notes
4a (84% ee)
5a
81% (d.r. = 1 : 1)
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