Remote asymmetric trifluoromethylation induced by chiral sulfinyl group: Synthesis of enantiomerically pure 1-(2-naphthyl)-2,2,2-trifluoroethanol

Article abstract of DOI:10.1016/j.tetlet.2005.12.061

The reaction of 1-[(2,4,6-triisopropylphenyl)sulfinyl]-2-naphthaldehyde with (trifluoromethyl)trimethylsilane using tetramethylammonium fluoride gave trifluoromethylated compounds in high yield with high diastereoselectivity. Desilylation and subsequent r

Full text of DOI:10.1016/j.tetlet.2005.12.061

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1337–1340
Remote asymmetric trifluoromethylation induced by chiral
sulfinyl group: synthesis of enantiomerically pure
1-(2-naphthyl)-2,2,2-trifluoroethanol
Hideki Sugimoto, Shuichi Nakamura, Yoshihiro Shibata,
Norio Shibata and Takeshi Toru*
Department of Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku,
Nagoya 466-8555, Japan
Received 14 October 2005; revised 5 December 2005; accepted 9 December 2005
Available online 9 January 2006
Abstract—The reaction of 1-[(2,4,6-triisopropylphenyl)sulfinyl]-2-naphthaldehyde with (trifluoromethyl)trimethylsilane using tetra-
methylammonium fluoride gave trifluoromethylated compounds in high yield with high diastereoselectivity. Desilylation and
subsequent recrystallization yielded the enantiomerically and diastereomerically pure trifluoroethanol, which afforded chiral 1-(2-
naphthyl)-2,2,2-trifluoroethanol after removal of the sulfinyl group.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
addition reactions of TMSCF3 to aldehydes1b and
imines.10 Recently, we have reported diastereoselective
reactions of 1-[(2,4,6-triisopropylphenyl)sulfinyl]-2-
naphthaldehyde with several nucleophiles by the use of
the rotational barrier around the C–S bond axis.11 We
report herein the first remote asymmetric induction in
the trifluoromethylation with TMSCF3 caused by a
rotational barrier around the C–S bond axis of 1-sulfin-
yl-2-naphthaldehydes.
The synthesis of trifluoromethylated compounds entails
a problem to be solved, which involves an interesting
aspect of the reaction mechanism and pharmaceutical
chemistry.1 However, there are only a few reports for
the preparation of chiral 1-substituted 2,2,2-trifluoroeth-
anols, which include, for example, enzymatic resolu-
tion,2 asymmetric hydrogenation,3 and reduction.4 The
nucleophilic addition of a trifluoromethyl group using
(trifluoromethyl)trimethylsilane (TMSCF3) is another
efficient method for the trifluoromethylation.5 Enantio-
selective trifluoromethylation with TMSCF3 has so far
been reported to be unsuccessful probably because of
a reactive trifluoromethylating intermediate formed dur-
ing the reaction; for example, the moderately enantio-
selective trifluoromethylation6,7 of aldehydes and ketones
with TMSCF3 on treatment with chiral quaternary
ammonium fluoride derived from cinchonine and highly
enantioselective trifluoromethylation of a specific aceto-
phenone derivative.8 On the other hand, no nucleophilic
trifluoromethylation through the 1,4-asymmetric induc-
tion has been reported9 among the diastereoselective
2. Results and discussion
First of all, the reaction of 1-(arylsulfinyl)-2-naphthalde-
hydes 1a–c with TMSCF3 was examined using a cataly-
tic amount (0.2 equiv) of tetramethylammonium
fluoride (Me4NF). The reaction of 1-(p-tolylsulfinyl)-2-
naphthaldehyde 1a with TMSCF3 in CH2Cl2 afforded
the trimethylsilylated alcohols 2a with low diastereo-
selectivity (Scheme 1 and Table 1, entry 1). On the other
hand, the reaction of 1-[(2,4,6-trimethylphenyl)sulfinyl]-
and 1-[(2,4,6-triisopropylphenyl)sulfinyl]-2-naphthalde-
hydes 1b and 1c showed high diastereoselectivity (entries
2 and 3). When the reaction of 1c was performed in tolu-
ene, THF, or acetonitrile, the trifluoromethylated
product was not formed. The reaction using a catalytic
amount of tetrabutylammonium fluoride (Bu4NF)
afforded the product 2a with high diastereoselectivity
Keywords: Trifluoromethylation; 1,4-Asymmetric induction; Chiral
alcohol; Sulfinyl group.
*
Corresponding author. Tel./fax: +81 52 735 5217; e-mail: toru@
nitech.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.061

1338
H. Sugimoto et al. / Tetrahedron Letters 47 (2006) 1337–1340
O
O
O
Ar
Ar
Ar
S
X
TMSCF3
Ammonium Fluoride
S
OSiMe3
CF3
S
OSiMe3
CF3
R
CH2Cl2, temp
(RS∗,R∗)-2a-f
(RS∗,S∗)-2a-f
1a: Ar = p-Tol, X = O,
1b: Ar = Mes, X = O,
1c: Ar = Tip, X = O,
1d: Ar = Tip, X = O,
1e: Ar = Tip, X = O,
R = H
R = H
R = H
R = Me
R = Ph
1f : Ar = Tip, X = N-Ph, R = H
Scheme 1.
Table 1. Nucleophilic trifluoromethylation of 1-(arylsulfinyl)-2-naphthaldehydes 1a–c
Entry
Substrate
X
R
Ammonium fluoride
(equiv)
TMSCF3
(equiv)
Temp
(°C)
Product
Yield
(%)
Diastereomer ratioa
ðRꢁS; RꢁÞ : ðRSꢁ; SꢁÞ
1
2
3
4
5
6
7
8
9c
10c
11c
12c
1a
1b
1c
1c
1c
1c
1c
1c
1c
1d
1e
1f
O
O
O
O
O
O
O
O
O
O
O
N-Ph
H
H
H
H
H
H
H
H
H
Me
Ph
H
Me4NF (0.2)
Me4NF (0.2)
Me4NF (0.2)
Bu4NF (0.2)
Me4NF (0.2)
Me4NF (1.5)
Me4NF (3)
Me4NF (3)
Me4NF (3)
Me4NF (3)
Me4NF (3)
Me4NF (3)
1.5
1.5
1.5
1.5
1.5
1.5
3
3
3
3
3
ꢀ78
2a
2b
2c
2c
2c
2c
2c
2c
2c
2d
2e
2f
85
79
92
31b
17
89
97
97
96
—
—
—
55:45
79:21
85:15
92:8
92:8
88:12
88:12
90:10
91:9
—
ꢀ78
ꢀ78
ꢀ78
ꢀ94
ꢀ78
ꢀ78
ꢀ94
ꢀ94
ꢀ78!rt
ꢀ78!rt
ꢀ78!rt
—
—
3
a Determined by 19F NMR.
b The desilylated alcohol was also obtained in 32% yield in a diastereomer ratio of 79:21.
c
˚
Molecular sieves 4 A was added.
together with the desilylated alcohol with moderate dia-
stereoselectivity (entry 4). The reaction of 1c using
TMSCF3 and a catalytic amount of Me4NF at ꢀ94 °C
gave the product 2c with higher diastereoselectivity than
the reaction performed at ꢀ78 °C, but the yield was low-
ered (entry 5). When the reaction was carried out using
an excess amount of TMSCF3 at ꢀ78 °C, 2c was
obtained in high yield with high diastereoselectivity
(entries 6 and 7). The yield and stereoselectivity were
even better in the reaction at ꢀ94 °C (entry 8). All these
reactions afforded the ðRꢁS; RꢁÞ-isomer predominantly.
On the other hand, ketones 1d, 1e and the imine 1f did
not afford the trifluoromethylated products on treat-
ment with TMSCF3 in the presence of Me4NF even at
room temperature (entries 10–12).
O
O
Tip
Tip
S
1c
1c
O
S
OSiMe3
CF2SePh
TMSCF2SePh (3 equiv)
Me4NF (3 equiv), MS 4A
H
*
CH2Cl2, -94 oC
3: 91%, dr = 98 : 2
O
Tip
S
OPO(OEt)2
CF2H
TMSCF2PO(OEt)2 (3 equiv)
Me4NF (3 equiv), MS 4A
*
CH2Cl2, -78 oC rt
4: 57%, dr = >98 : 2
Scheme 2.
Difluoromethylation of 1c with TMSCF2SePh12 at
ꢀ94 °C also succeeded in forming product 3 in high
yield with high diastereoselectivity. Completion of the
13
reaction of 1c with TMSCF2PO(OEt)2 needed higher
temperature, giving the product 4 that resulted from
intramolecular rearrangement (Scheme 2).14
The relative stereochemistry of the major diastereomer
of 2c was determined to be ðRꢁS; RꢁÞ by the X-ray crystal-
lographic analysis (Fig. 1). In order to prepare an opti-
cally active chiral trifluoroethanol derivative, the
enantiomerically pure sulfoxide (R)-1c was prepared as
previously reported.11a The reaction of (R)-1c with
TMSCF3 and Me4NF afforded 2c in high diastereoselec-
Figure 1. The Chem 3D structure derived from X-ray crystallography
of ðRꢁS; RꢁÞ-2c.

H. Sugimoto et al. / Tetrahedron Letters 47 (2006) 1337–1340
1339
O
O
O
Tip
Tip
Tip
S
O
S
OSiMe3
CF3
S
OH
CF3
a
b
H
(R)-1c
95% ee
2c: 85%
(RS,R) : (RS,S) = 88 : 12
5: 95%
(RS,R) : (RS,S) = 88 : 12
recrystallization
(RS,R) : (RS,S) = >99 : <1
OH
CF3
c
(R)-6: 55 %, 99% ee
˚
Scheme 3. Reagents and conditions: (a) TMSCF3, Me4NF, MS 4 A, CH2Cl2, ꢀ94 °C; (b) Bu4NF, CH2Cl2, 0 °C; (c) n-BuLi, HMPA, THF,
ꢀ78!ꢀ30 °C.
O
Tip
7
* S
H
CF3
Me3SiCF3
F-
Me
Me
Me3SiCF3
O
Si Me
O
CF3
O
O
O
Tip
1c
S
Tip
CF3
S
Me
Si Me
F
CF3
Me
8
7
Me3SiF
O
Tip
*S
H
O
Tip
SiMe3
CF3
S
O
O
(RS,R)-2c
Figure 2. Preferred conformation of 1c and the assumed reaction mechanism.
tivity (Scheme 3).15 After the removal of the trimethylsil-
yl group from 2c with Bu4NF, recrystallization of 5
from hexane/CH2Cl2 afforded the enantiomerically as
well as diastereomerically pure trifluoroethanol (RS,R)-
5. Subsequent cleavage of the sulfinyl group with n-BuLi
gave 2-naphthyltrifluoroethanol (R)-6 with 99% ee.16
O
O
Tip
Tip
S
O
S
OH
a
∗
H
CF3
9
10
65%, 33% de
We previously reported a highly stereoselective reac-
tion of 1-[(2,4,6-triisopropylphenyl)sulfinyl]-2-naphth-
aldehyde 1c with Grignard reagents controlled by
restriction of the rotation around the C–S bond axis.11
The X-ray crystallographic analysis, 1H and 13C
NMR, and MO calculation of 1c clearly showed that
the sulfinyl oxygen is arranged away from the peri-H8
proton in the naphthalene ring and the carbonyl oxygen
away from the sulfinyl group (Fig. 2). In this structure,
one of the faces of the aldehyde is highly shielded
by the bulky 2,4,6-triisopropylphenyl group. Thus,
the hypervalent silicate intermediates 7 and 8 assumed
as trifluoromethylating agents5,17 approach the less
hindered face of the naphthaldehyde to form the
(RS,R)-isomer. In fact, the nucleophilic trifluoromethyla-
tion of 2-[(2,4,6-triisopropylphenyl)sulfinyl]benzalde-
Scheme 4. Reagents and conditions: (a) (1) TMSCF3 (3 equiv),
Me4NF (3 equiv), MS 4 A, CH2Cl2, ꢀ94 °C, (2) 6 N HCl.
˚
hyde 918 afforded the product 10 in high yield but with
low diastereoselectivity because of the low rotational
barrier about the Cph–S bond (Scheme 4). These results
suggest that the stereochemical outcome in the reaction
of 1c is strongly related to the rotational barrier about
the Cnaph–S bond.
3. Conclusion
In summary, we have disclosed the first remote asym-
metric induction in the nucleophilic trifluoromethylation
by the sulfinyl group as a chiral auxiliary.

1340
H. Sugimoto et al. / Tetrahedron Letters 47 (2006) 1337–1340
imines has been reported. (a) Prakash, G. K. S.; Mandal,
Acknowledgments
M.; Olah, G. A. Angew. Chem., Int. Ed. 2001, 40, 589–590;
(b) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Org. Lett.
2001, 3, 2847–2850.
We thank Dr. Shinya Kusuda, Ono Pharmaceutical Co.,
Ltd., for the X-ray crystallographic analyses and TO-
SOH F-TECH INC. for a gift of Me3SiCF3. This work
was partly supported by a Grant-in Aid for Scientific
Research (No. 11650890) from the Ministry of Educa-
tion, Science, Sports and Culture of Japan.
11. (a) Nakamura, S.; Yasuda, H.; Watanabe, Y.; Toru, T. J.
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References and notes
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15. Typical procedure: TMSCF3 (0.07 mL, 0.50 mmol) and
Me4NF (46.6 mg, 0.14 mmol) were successively added to a
ꢀ94 °C solution of (R)-1c (67.8 mg, 0.167 mmol) in
CH2Cl2, and the mixture was stirred for 30 min at the
same temperature. The reaction was quenched with water
and the mixture was extracted with CH2Cl2. The com-
bined extracts were washed with brine, dried over Na2SO4,
and concentrated under reduced pressure to leave a
residue, which was purified by column chromatography
(silica gel 10 g, hexane/ethyl acetate = 95/5) to give 2c
(77.5 mg, 85%).
16. To a solution of (RS,R)-3 (25.0 mg, 0.053 mmol) and
HMPA (0.037 mL, 0.21 mmol) in THF (2 mL) was added
n-BuLi (0.194 mL, 1.35 mol Lꢀ1 in hexane, 0.262 mmol) at
ꢀ78 °C. The mixture was then allowed to warm to ꢀ30 °C
and stirred for 2 h. After water was added, the mixture
was extracted with CH2Cl2. The combined extracts were
washed with brine, dried over Na2SO4, and concentrated
under reduced pressure to leave a residue, which was
purified by column chromatography (silica gel 10 g,
benzene ) to give (R)-4 (6.5 mg, 55%). The enantiomer
excess was determined to be 99% ee by the HPLC analysis:
Daicel Chiralcel OJ-H, hexane/iPrOH = 80/20, flow rate
1.5 mL/min; tR, 12.1 (R), 17.2 (S) min.
9. For electrophilic 1,4-asymmetric trifluoromethylations,
see: (a) Iseki, K.; Nagai, T.; Kobayashi, Y. Tetrahedron
Lett. 1993, 34, 2169–2170; (b) Kitazume, T.; Ishikawa, N.
J. Am. Chem. Soc. 1985, 107, 5186–5192.
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Yagupolskii, Y. L. Angew. Chem., Int. Ed. 1999, 38, 2252–
2253.
10. The preparation of optically active amines by the diaste-
reoselective addition of TMSCF3 to N-tert-butylsulfinyl-
18. Nakamura, S.; Oda, M.; Yasuda, H.; Toru, T. Tetra-
hedron 2001, 57, 8469–8480.