Catalytic enantioselective alkenylation and phenylation of trifluoromethyl ketones

Article abstract of DOI:10.1016/j.tetlet.2006.09.048

Catalytic enantioselective alkenylation and phenylation of trifluoromethyl ketones are described. High enantioselectivity (up to 84% ee) was produced in an alkenylation of aryl trifluoromethyl ketones using a CuF-DTBM-SEGPHOS complex as the catalyst (5-10

Full text of DOI:10.1016/j.tetlet.2006.09.048

Tetrahedron Letters 47 (2006) 8083–8086
Catalytic enantioselective alkenylation and phenylation
of trifluoromethyl ketones
Rie Motoki, Daisuke Tomita, Motomu Kanai* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
Received 1 August 2006; revised 11 September 2006; accepted 12 September 2006
Available online 28 September 2006
Abstract—Catalytic enantioselective alkenylation and phenylation of trifluoromethyl ketones are described. High enantioselectivity
(up to 84% ee) was produced in an alkenylation of aryl trifluoromethyl ketones using a CuF–DTBM-SEGPHOS complex as the
catalyst (5–10 mol %) and alkenylsilanes as the nucleophile. This is the first example of catalytic enantioselective alkenylation of
trifluoromethyl ketones. The products are versatile chiral building blocks, which contain a trifluoromethyl-substituted tertiary alco-
hol moiety.
Ó 2006 Elsevier Ltd. All rights reserved.
Due to their unique properties, fluorinated compounds
are attracting growing interest in medicinal chemistry
and material sciences.1 Catalytic asymmetric synthesis
of fluorine-containing molecules, however, has only re-
cently begun to be explored.2–4 In this letter, we describe
a Cu(I)-catalyzed enantioselective alkenylation and
phenylation of trifluoromethyl ketones that produces
enantiomerically enriched tertiary alcohols containing a
trifluoromethyl substituent (Scheme 1). To access this
potentially important class of compounds, asymmetric
trifluoromethylation of ketones is an alternative strategy.
Although there are many racemic catalytic trifluorome-
thylation methods,5 only two asymmetric versions of this
reaction type have been reported.6 Those reactions,
however, produced only moderate enantioselectivity
(6–64% ee), except for one special substrate. Further-
more, catalytic enantioselective addition of organozinc
reagents—one of the most intensively studied catalytic
enantioselective reactions7—has not been applied to
trifluoromethyl ketones as a substrate.8 Therefore, there
are no reports of synthetically useful catalytic carbon–
carbon bond-forming reaction to access enantiomerically
enriched trifluoromethyl-substituted tertiary alcohols to
date, except that substrates are highly activated trifluoro-
pyruvate derivatives.9 In this letter, we report the first
example of catalytic enantioselective alkenylation of
simple trifluoromethyl ketones. The same conditions are
also applicable to phenylation and alkynylation.
OH
1) CuF–(
R)-DTBM-SEGPHOS
(MeO)2RSi
+
R2
R2
O
(5–10 mol %)
R1
F3C
R1
CF3
2) TBAF
tBu
OMe
O
O
O
2
2
P
P
tBu
tBu
(R)-DTBM-SEGPHOS =
O
OMe
tBu
Scheme 1.
*
Corresponding authors. Fax: +81 3 5684 5206 (M.S.); e-mail: mshibasa@mol.f.u-tokyo.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.048

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R. Motoki et al. / Tetrahedron Letters 47 (2006) 8083–8086
We recently reported an enantioselective alkenylation
and arylation using CuF-chiral bisphosphine
aromatic trifluoromethyl ketones using 5 or 10 mol %
of catalyst (entries 1–4). A nucleophile containing a
longer alkenyl chain (2d), which was readily prepared
from 2a and the corresponding alkene via Grubbs
cross-metathesis,12 afforded the products with high
enantioselectivity (entries 5 and 6). Although the enantio-
selectivity was more moderate, the same reaction condi-
tions were applicable to catalytic phenylation reactions
using dimethoxydiphenylsilane (2e), which produced
enantiomerically enriched trifluoromethyl-substituted
diaryl methanols (4: entries 7 and 8).13,14
a
(DTBM-SEGPHOS as the optimized chiral ligand)
complex as the catalyst, and alkenylsilanes, alkenylbor-
onates, phenylsilane, and arylboronates as the nucleo-
philes.10 Enantiomerically enriched secondary allylic
alcohols and diarylmethanols can be synthesized from
a range of aldehydes using air- and moisture-stable
silicon- or boron-based sp2-hybridized carbon nucleo-
philes. Mechanistically, the reaction proceeds through
an organocopper species generated via transmetalation
from silicon or boron to copper. Although the reaction
did not proceed at all when simple ketones were used as
the substrate, activated ketones such as a-ketoesters
afforded the products in high enantioselectivity. We
expected that trifluoromethyl ketones would be reactive
under the catalytic enantioselective alkenylation reac-
tion conditions due to the strong electron-withdrawing
characteristic of the trifluoromethyl group.
Tertiary alcohols produced in the current study in an
enantiomerically enriched form are themselves interest-
ing chiral building blocks for pharmaceuticals and agro-
chemicals. Additionally, these compounds are versatile
because many variations of olefin transformation are
possible. For example, trifluoromethyl-substituted
hydroxy carboxylic acid 5, an important component of
Mosher’s acid,15 was synthesized from 3a via ozonolysis
and perchlorite oxidation in 87% yield (Scheme 2, Eq.
1). Tertiary allylic alcohol 3a is also a precursor of b-hy-
droxy carboxylic acid derivative 6, which is a representa-
tive aldol product between trifluoromethyl ketones and
an acetate-derived enolate, via Rh-catalyzed hydrobora-
tion16 followed by oxidation (Scheme 2, Eq. 2). Com-
pound 6 was previously synthesized through diastereo-
selective reaction using a chiral enolate, but the dia-
stereoselectivity was not satisfactory.17
When previously optimized reaction conditions were
applied to trifluoromethyl ketone 1d using 10 mol %
of chiral CuF catalyst (generated reductively in situ
from 10 mol % of CuF2Æ2H2O and 20 mol % of
DTBM-SEGPHOS) and vinyltrimethoxysilane (2a) as
a nucleophile in toluene solvent, the vinylation product
3d was obtained in only 12% yield (18 h, 76% ee: Table
1, entry 1). Over 80% of the starting ketone was recov-
ered unchanged. To improve the product yield, we used
vinyldimethoxymethylsilane (2b) as a nucleophile. Due
to the difference in electronic character, 2b should be
more active in generating vinylcopper through trans-
metalation than 2a when the corresponding silicates
are generated.11 Using 2b as the nucleophile, the
desired product was produced in quantitative yield with
83% ee (entry 2). A reaction using vinylboronate
(2c) produced less satisfactory yield, even in the pres-
ence of tetrabutylammonium difluorotriphenylsilicate
(TBAT: 15 mol %) as an additive (entry 3).10b In this
case, however, enantioselectivity was comparable to
the reaction using 2b.
As a preliminary extension, we found that this catalysis
can be applied to a catalytic enantioselective alkynyl-
ation of trifluoromethyl ketones (Scheme 3).18 As far
as we notice, this is the first example of catalytic enantio-
selective alkynylation of trifluoromethyl ketones.
In conclusion, we developed a catalytic enantioselective
alkenylation, phenylation, and alkynylation of trifluo-
romethyl ketones using a CuF–DTBM-SEGPHOS
complex. Air-stable alkenylsilanes, phenylsilane, and
alkynylsilane can be used as nucleophiles. The method
allowed for an entry to the catalytic enantioselective
synthesis of chiral trifluoromethyl-substituted tertiary
alcohols. Further improvement of the enantioselectivity
and substrate scope is ongoing.19
The optimized conditions were then applied to various
trifluoromethyl ketones and nucleophiles (Table 2).
High enantioselectivity was consistently produced from
Table 1. Nucleophile screening in catalytic enantioselective vinylation of trifluoroacetophenone (1d)
1) CuF–
(R)-DTBM-SEGPHOS
OH
(10 mol %), 70 oC, 18 h
O
M
p-Tol
+
F3C
p-Tol
CF3
2) TBAF
1d
2: 2 equiv
3d
Entry
1
2
3d
12%, 76% ee
(MeO)3Si
2a
2
(MeO)2MeSi
100%, 83% ee
26%, 82% ee
2b
3a
O
2c
B
O
a The reaction was conducted in the presence of TBAT (15 mol %).

R. Motoki et al. / Tetrahedron Letters 47 (2006) 8083–8086
8085
Table 2. Scope and limitations of Cu-catalyzed enantioselective alkenylation and phenylation of trifluoromethyl ketones
1) CuF–(
(5–10 mol %)
70 oC, toluene
R)-DTBM-SEGPHOS
O
R
HO
R1
(MeO)2R2Si
R
+
R1
CF3
2) TBAF
CF3
2b: R = CH=CH2, R2 = Me
2d: R = (
)-CH=CH(CH2)3CH3, R2 = MeO
2e: R = R2 = Ph
1
3 or 4
E
Entry
Substrate
Catalyst (mol %)
Nucleophile
Product
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
1a: X = H
1b: X = Cl
1c: X = Br
1d: X = Me
5
10
10
10
2b
2b
2b
2b
3a
3b
3c
3d
39
43
41
18
100
77
92
84c
84
82
83
O
CF3
100
X
5
6
7
1a
1d
1d
10
10
10
2d
2d
2e
3e
3f
17
45
10
75
75
80
80
80
67
4a
O
8
10
2e
4b
37
91
49
CF3 1e
a Isolated yield.
b Determined by chiral HPLC or GC.
c Absolute configuration was determined as shown.
1) O3, MeOH; Me2S
were added at room temperature. The reaction was per-
formed at 70 °C for 39 h. TBAF (1 M in THF, 0.25 mL)
was added after cooling to room temperature. H2O was
added, and products were extracted with AcOEt. The
combined organic layers were washed with brine, and
dried over Na2SO4. Filtration, evaporation of the
solvent, and purification through SiO2 (AcOEt/hex-
ane = 1/15) afforded 3a in quantitative yield. Enantio-
meric excess of 3a was determined by chiral HPLC
(DAICEL CHIRALPAK AS-H, iPrOH/hexane =
1/50, tR = 8.4 min (minor) and 9.1 min (major)). 1H
NMR (500 MHz, CDCl3): d = 2.74 (s, 1H), 5.56 (d,
J = 10.7 Hz, 1H), 5.62 (d, J = 16.8 Hz, 1H), 6.44 (dd,
J = 10.7 Hz, 16.8 Hz, 1H), 7.4 (m, 3H), 7.6 (m, 2H);
19F NMR (470 MHz, CDCl3): d = À79.7 (s); 13C
NMR (125 MHz, CDCl3): 77.2 (q, J = 29 Hz), 118.4,
124.6 (q, J = 286.1 Hz), 126.6, 128.3, 128.7, 135.6, 137.0.
2) NaClO2, isoprene, tBuOH-H2O
HO
Ph
CO2H
CF3
(eq 1)
3a
87% (2 steps)
5
1) Rh(PPh3)3Cl (5 mol %)
pinacolborane, THF;
NaOH, H2O2, 86%
O
HO CF3
Ph
2) Dess-Martin [O], CH2Cl2, 93%
(eq 2)
3a
OH
3) NaClO2, NaH2PO4, isoprene
tBuOH-H2O, 85%
6
Scheme 2. Conversion to synthetically useful trifluoromethyl-substi-
tuted tertiary alcohols.
1) CuF–(
R
)-DTBM-SEGPHOS
(10 mol %)
(2 equiv)
(EtO)3Si Ph
HO CF3
Ph
Acknowledgement
toluene, 70 oC, 19 h
1a
Ph
2) TBAF
Financial support was provided by a Grant-in-Aid for
Specially Promoted Research of MEXT.
7
>99%, 46% ee
Scheme 3. Catalytic enantioselective alkynylation of trifluoromethyl
ketone.
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