Asymmetric trifluoromethylation of ketones with (trifluoromethyl) trimethylsilane catalyzed by chiral quaternary ammonium phenoxides

Article abstract of DOI:10.1246/cl.2007.666

Asymmetric trifluoromethylation of ketones with (trifluoromethyl) trimethylsilane catalyzed by cinchonidine-derived quaternary ammonium phenoxides proceeded smoothly to afford the trifluoromethylated compounds in high yields with moderate to high enantios

Full text of DOI:10.1246/cl.2007.666

6
66
Chemistry Letters Vol.36, No.5 (2007)
Asymmetric Trifluoromethylation of Ketones
with (Trifluoromethyl)trimethylsilane
Catalyzed by Chiral Quaternary Ammonium Phenoxides
1
1
ꢀ1;2
Hitoshi Nagao, Yoshinobu Yamane, and Teruaki Mukaiyama
Center for Basic Research, The Kitasato Institute, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003
Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
1
2
(Received March 6, 2007; CL-070243; E-mail: mukaiyam@abeam.ocn.ne.jp)
Asymmetric trifluoromethylation of ketones with (trifluoro-
ammonium phenoxides were then applied to the Lewis base-
5
methyl)trimethylsilane catalyzed by cinchonidine-derived qua-
ternary ammonium phenoxides proceeded smoothly to afford
the trifluoromethylated compounds in high yields with moderate
to high enantioselectivities.
catalyzed trifluoromethylation. In this communication, we
would like to report on enantioselective trifluoromethylation of
ketones with (trifluoromethyl)trimethylsilane in the presence
of a catalytic amount of cinchonidine-derived quaternary ammo-
nium phenoxide.
In the first place, a reaction of 3-nitroacetophenone (2a) with
(trifluoromethyl)trimethylsilane in the presence of 10 mol % of
various cinchonidine-derived quaternary ammonium phenoxides
In recent years, trifluoromethylated compounds have attract-
ed considerable interests in the fields of pharmacy and agro-
1
6
ꢂ
chemistry. The introduction of a strong electron-withdrawing
trifluoromethyl group has brought notable changes in physical,
chemical, and biological properties of the compounds. Also, de-
1a–1i in CH Cl at ꢁ78 C for 1 h was tried (Table 1). When
2
2
the catalyst 1a having a simple phenyl group was used, tri-
fluoromethylation proceeded smoothly to afford (2S)-[1,1,1-tri-
fluoro-2-(3-nitrophenyl)propan-2-yloxy]trimethylsilane (3a) in
93% yield with poor enantioselectivity (13% ee) (Entry 1). How-
ever, these enantioselectivities turned to increase up when sub-
stituents such as 2-naphthyl (1d), 3,5-bis(trifluoromethyl) phenyl
(1f), and 3,5-diphenylphenyl (1g) groups were introduced
(Entries 4, 6, and 7). It was shown next that the enantiomeric
excess of 3a increased up to 60% ee when catalysts having
bulky substituents on the nitrogen atom of cinchonidine
such as 1h (Ar = 3,5-bis(3,5-di-tert-butylphenyl)phenyl or 1i
(Ar = 3,5-bis[3,5-bis(trifluoromethyl)phenyl]phenyl) were used
(Entries 8 and 9).
2
velopment of some useful medicines that have trifluoromethyl
moiety at the asymmetric center further emphasized the impor-
tance of the synthesis of chiral trifluoromethylated compounds.
Although a few methods have been reported on the asymmetric
3
introduction of a trifluoromethyl group into ketones, the scope
of these methods remained modest in enantiomeric excess or
substrate specificity. Recently, it was reported from our labora-
tory that the novel types of cinchonidine-derived quaternary
ammonium phenoxides were useful substances as new asymmet-
4
ric catalysts. In order to establish an efficient method for the
preparation of chiral trifluoromethylated-alcohols, this chiral
Next, the effect of solvents was examined (Table 2). When
ꢂ
Table 1. Effect of catalysts
the catalyst 1i was used in toluene at ꢁ78 C, trifluoromethyla-
tion did not proceed because the catalyst scarcely dissolved in
toluene (Entry 1). While the use of polar solvents such as THF
or EtCN gave 3a with low enantioselectivity (19% ee or 58%
ee, Entries 3 and 4), the use of less-polar solvent as toluene in-
creased the enantiomeric excess of 3a up to 79% ee (Entry 2).
In order to carry out the reaction at lower temperature
N
HO
H
Ar
OPh
O
F3C OSiMe3
N
1
O N
O2N
2
(
10 mol %)
Me SiCF
3
+
3
CH Cl , −78 °C, 1h
2
2
Table 2. Effect of solvents
2
a
3a
O
F3C OSiMe3
catalyst 1i
a
O N
O2N
Entry
Catalyst
Yield /% % eeb,c
2
(10 mol %)
Me SiCF
+
3
3
1
2
3
4
5
6
7
8
9
1a: Ar = Ph
93
98
99
97
96
95
95
99
99
13
8
Solv., 1h
1b: Ar = 2,6-F2C6H3
1c: Ar = 1-Naphthyl
1d: Ar = 2-Naphthyl
2
a
3a
11
26
17
34
50
61
62
ꢂ
a
b,c
Entry
Solv.
Temp/ C Yield /% % ee
1e: Ar = 3,5-(t-Bu)2C6H3
1f: Ar = 3,5-(CF3)2C6H3
1g: Ar = 3,5-(Ph)2C6H3
1
2
3
4
5
Toluene
Toluene
EtCN
ꢁ78
ꢁ20
ꢁ20
ꢁ78
ꢁ78
N.R.
99
—
79
19
58
87
65
92
1h: Ar = 3,5-[3,5-(t-Bu)2C6H3]2C6H3
1i: Ar = 3,5-[3,5-(CF3)2C6H3]2C6H3
THF
Toluene/CH2Cl2 = 7/3
98
aIsolated yield. bEnantiomeric excess was determined by HPLC
analysis using a chiral column (DAICEL Chiralcel OD-H) with hex-
ane/2-propanol (volume ratio = 20:1) as a solvent. Enantiomeric
excess was measured after desilylation of 3a.
a
b
Isolated yield. Enantiomeric excess was determined by HPLC
analysis using a chiral column (DAICEL Chiralcel OD-H) with
hexane/2-propanol (volume ratio = 20:1) as solvent.
Enantiomeric excess was measured after desilylation of 3a.
c
a
c
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.5 (2007)
667
Table 3. Enantioselective synthesis of trifluoromethylated silyl
ethers by using catalyst 1i
This study was supported in part by the Grant of the 21st
Century COE Program from Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan. The authors
wish to thank Mr. Masahiko Bando (Otsuka Pharmaceutical
Co., Ltd.) for his support in X-ray crystallographic analysis.
catalyst 1i
O
F3C OSiMe3
R1 R2
(
10 mol %)
R1
R2
+ Me3SiCF3
toluene−CH Cl (7:3 v/v)
2
2
−
78 °C, 1h
3
2
References and Notes
Entry
R1
R2
Product Yield/%a % eeb
1
For a review on trifluoromethylation, see: a) R. P. Singh,
J. M. Shreeve, Tetrahedron 2000, 56, 7613. b) G. K. S.
Prakash, M. Mandal, J. Fluorine Chem. 2001, 112, 123.
c) J.-A. Ma, D. Cahard, Chem. Rev. 2004, 104, 6119.
a) J. Wouters, F. Moureau, G. Evrard, J.-J. Koening, S.
Jegham, P. George, F. Durant, Bioorg. Med. Chem. 1999,
c
1
2
3
4
5
6
7
8
9
2-(NO2)C6H4
4-(NO2)C6H4
3-(CN)C6H4
3-BrC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
3b
3c
3d
3e
3f
93
97
96
97
90
91
95
90
93
99
71
73
71
61
59
51
77
46
60
64
c
c
c
c
c
c
2
3-(MeO)C6H4
1-Naphthyl
2-Naphthyl
3-Pyridyl
3g
3h
3i
7
, 1683. b) J. Ren, J. Milton, K. L. Weaver, S. A. Short,
D. I. Stuart, D. K. Stammers, Structure 2000, 8, 1089.
a) K. Iseki, T. Nagai, Y. Kobayashi, Tetrahedron Lett. 1994,
3
4
4-Pyridyl
3-(NO2)C6H4
b
3j
3k
5, 3137. b) S. Caron, N. M. Do, P. Arpin, A. Lariv e´ e,
Synthesis 2003, 1693.
3
c
10
a
Isolated yield. Enantiomeric excess was determined by HPLC
analysis using a chiral column (DAICEL Chiralcel OD-H or
Chiralpak AD-H) with hexane/2-propanol (volume ratio =
a) T. Tozawa, H. Nagao, Y. Yamane, T. Mukaiyama, Chem.
Asian J. 2007, 2, 123. b) T. Mukaiyama, H. Nagao, Y.
Yamane, Chem. Lett. 2006, 35, 916. c) H. Nagao, Y.
Yamane, T. Mukaiyama, Chem. Lett. 2006, 35, 1398.
d) H. Nagao, Y. Yamane, T. Mukaiyama, Chem. Lett.
2
0:1) as a solvent. cEnantiomeric excess was measured after
desilylation of 3.
2
007, 36, 8.
F3C OSiMe3 1)
TBAF
3) 4-Bromobenzoyl chloride
Et N, CH Cl , rt, 1 h
5
6
Y. Kawano, N. Kaneko, T. Mukaiyama, Bull. Chem. Soc.
Jpn. 2006, 79, 1133.
O N
2
THF, rt, 0.5 h
3
2
2
*
2)
H2
4) Recrystallization
For the preparation and X-ray crystallographic analysis of
quaternary ammonium p-nitrophenoxide, see: E. J. Corey,
F. Xu, M. C. Noe, J. Am. Chem. Soc. 1997, 119, 12414.
Typical experimental procedure for the preparation of 3
is shown in the following (Table 2, Entry 5): To a stirred
solution of 1i (27 mg, 0.015 mmol) in toluene–CH2Cl2
cat. Pd/C
EtOH−EtOAc
rt, 2 h
from Et O−Hexane
2
3
a
(
87% ee)
7
Br
H
N
F3C OH
(S)
(
7:3, 0.6 mL) were successively added a solution of 3-nitro-
acetophenone (49.5 mg, 0.3 mmol) in toluene–CH2Cl2 (7:3,
.8 mL) and a solution of (trifluoromethyl)trimethylsilane
O
4
74% (96% ee)
ORTEP drawing of compound 4
0
(
ꢁ
59.7 mg, 0.42 mmol) in toluene–CH2Cl2 (7:3, 0.8 mL) at
78 C. After the mixture was stirred for 1 h at the same
Scheme 1. Conversion of 3a to carboxamide 4 and determina-
tion of their absolute configurations.
ꢂ
temperature, it was quenched with sat. NH4Cl (aq) and
the mixture was extracted with EtOAc. The organic layer
was washed with brine, dried over anhydrous Na2SO4, and
evaporated. The crude product was purified by preparative
TLC (hexane/EtOAc = 5/1) to give a (2S)-[1,1,1-tri-
fluoro-2-(3-nitrophenyl)propan-2-yloxy]trimethylsilane (3a)
ꢂ
(
ꢁ78 C), the use of a mixed-solvent was examined. Then, a 7:3
(
and gave the 3a in 98% yield with high enantioselectivity
v/v) mixture of toluene and CH2Cl2 was found most effective
(
87% ee, Entry 5).7
Next, reactions of (trifluoromethyl)trimethylsilane with var-
1
ious ketones were tried in the presence of cinchonidine-derived
quaternary ammonium phenoxide 1i in toluene–CH2Cl2 at
(90.3 mg, 98%, 87% ee) as a coloress oil. H NMR
(270 MHz, CDCl3) ꢀ 8.42 (s, 1H), 8.26-8.20 (m, 1H), 7.90
(dd, J ¼ 8:0 Hz, 0.9 Hz, 1H), 7.58 (t, J ¼ 8:0 Hz, 1H), 1.88
(s, 3H), 0.2 (s, 9H). The enantiomeric excess was measured
after desilylation of 3a and determined by HPLC analysis us-
ing DAICEL Chiralcel OD-H, hexane/2-propanol = 20/1,
ꢁ ¼ 254 nm, flow rate = 1.0 mL/min, retention time =
12.3 min (minor) and 15.2 min (major).
ꢂ
ꢁ
78 C for 1 h (Table 3). In most cases, the reactions proceeded
smoothly to provide the corresponding trifluoromethylated silyl
ethers in high yields with moderate to good enantioselectivities.
Absolute configuration of trifluoromethylated compound 3a
was determined to be S by X-ray crystallographic analysis after
the conversion to the corresponding carboxamide 4 as shown in
Scheme 1. Hydrogenation of the desilylated alcohol followed by
N-acylation with 4-bromobenzoyl chloride gave the benzamide
8
The product 4 was recrystallized from hexane/Et2O. Crystal
data: C16H13BrF3NO2 (FW 388.18), monoclinic, P21,
˚
˚
˚
4
the crystalline compound that was identified clearly by X-ray
crystallographic analysis.
Thus, successful asymmetric trifluoromethylation of various
ketones was achieved in high yield with high stereochemical
control in the presence of cinchonidine-derived chiral ammoni-
um phenoxide 1i as a Lewis base catalyst.
, which was then recrystallized from Et2O/hexane to afford
a ¼ 13:089ð5Þ A, b ¼ 6:456ð2Þ A, c ¼ 18:059ð5Þ A, ꢂ ¼
˚
˚ 3 ˚ 3
93:74ð3Þ A, V ¼ 1522:7ð9Þ A , V ¼ 2117ð1Þ A , Z ¼ 4:0,
8
ꢁ3
Dcalcd ¼ 1:693 g cm , T ¼ 295 K. X-ray intensities were
measured on a Rigaku AFC-5S diffractometer with graph-
˚
ite-monochromated Mo Kꢃ radiation (ꢁ ¼ 0:710690 A).
The final R factors was 0.043 (Rw ¼ 0:130 for all data) for
3441 reflections with I > 2ꢄðIÞ.
Published on the web (Advance View) April 14, 2007; doi:10.1246/cl.2007.666