Nonenzymatic kinetic resolution of racemic 2,2,2-trifluoro-1-aryl ethanol via enantioselective acylation

Article abstract of DOI:10.1016/j.tet.2009.01.058

Kinetic resolution of a series of 2,2,2-trifluoro-1-aryl ethanol with (R)-benzotetramisole as the catalyst has been investigated. The result showed that when the aryl group in the substrate was a phenyl (or a phenyl substituted by an electron-donating group) or a naphthyl (an extended phenyl) group, the system could give an s value higher than 20. Preparative KR examples demonstrated the applicability of this method in the preparation of some of enantiomerically pure 2,2,2-trifluoro-1-aryl ethanol or 2,2,2-trifluoro-1-aryl-ethyl iso-butyrate.

Full text of DOI:10.1016/j.tet.2009.01.058

Tetrahedron 65 (2009) 2232–2238
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Nonenzymatic kinetic resolution of racemic 2,2,2-trifluoro-1-aryl ethanol
via enantioselective acylation
*
Qing Xu, Hui Zhou, Xiaohong Geng, Peiran Chen
Laboratory of Organic Fluorine Chemistry, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Kinetic resolution of a series of 2,2,2-trifluoro-1-aryl ethanol with (R)-benzotetramisole as the catalyst
has been investigated. The result showed that when the aryl group in the substrate was a phenyl (or
a phenyl substituted by an electron-donating group) or a naphthyl (an extended phenyl) group, the
system could give an s value higher than 20. Preparative KR examples demonstrated the applicability of
this method in the preparation of some of enantiomerically pure 2,2,2-trifluoro-1-aryl ethanol or 2,2,2-
trifluoro-1-aryl-ethyl iso-butyrate.
Received 30 September 2008
Received in revised form 3 January 2009
Accepted 13 January 2009
Available online 20 January 2009
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Nonenzymatic kinetic resolution
2,2,2-Trifluoro-1-aryl ethanol
Enantioselective acylation
Benzotetramisole
1. Introduction
2. Results and discussion
Organic fluorine chemistry is a rapid growing field of organic
chemistry.1 Chiral fluoroorganic compounds are important in the
synthesis of biologically active molecules. The methodology of
asymmetric fluorination, trifluoromethylation, and perfluoro-
alkylation has recently been reviewed.2 Among the huge number of
fluoroorganic compounds, chiral 1-substituted 2,2,2-trifluoro-eth-
anols are of great importance and being used as intermediates for
the transformation of introducing a chiral CF3 group into molecules.
For stereoselective preparation of enantiopure 2,2,2-trifluoro-1-
alkyl(or aryl)-ethanol, methods have been reported, which include
(1) asymmetric reduction of trifluoromethyl ketones;3 (2) enantio-
selective trifluoromethylation of aldehydes;4 and (3) lipase-cata-
lyzed kinetic resolution of racemic 2,2,2-trifluoro-1-aryl ethanols.5
Recently, nonenzymatic kinetic resolution of racemic non-fluo-
rinated secondary alcohols has been an active research topic. Small
molecules of organocatalysts have been designed and synthesized
for this purpose, some of which showed high efficiency.6 We ex-
tended the application of organocatalyst to fluorinated secondary
alcohols and reported the kinetic resolution of 2,2-difluoro-3-hy-
droxy-3-aryl-propionates.7 Here we report our kinetic resolution
results of 2,2,2-trifluoro-1-aryl ethanols.
2.1. Optimization of reaction conditions
2.1.1. Variation of catalyst
Among a number of the reported organocatalysts in the
literatures,6 we chose 6-trifluoromethyl-2,3-dihydroimidazo[1,2-
a]pyridine (CF3-PIP) (I), benzotetramisole (BTM) (II), and 5,6-
dibromo-2,3-dihydroimidazo[1,2-a]pyridine (5,6-Br2-PIP) (III),
which were developed by Birman and co-workers,6j,k due to their
high efficiencyin thekineticresolutionofnon-fluorinatedsecondary
alcohols and good accessibility. Screening using 2,2,2-trifluoro-1-
phenyl ethanol as a model compound showed that BTM (II) was the
best one of the three. Table 1 summarizes the results.
2.1.2. Variation of acylating reagent
Different anhydrides were tested and isobutylic anhydride gave
the best s value (Table 2). The low s value given by benzoic anhy-
dride could probably be attributed to the competitive interaction of
the benzene ring in benzoic anhydride molecule with the aryl
group in BTM molecule.
2.1.3. Variation of solvent
As shown in Table 3, diisopropyl ether gave the best s value
(entries 8–11). The reason could be its proper polarity. Increasing
catalyst load did not give better selectivity (entries 1 vs 3). Higher
reactant concentration did not make significant improvement
(entries 1 vs 2). The results showed that slow addition of the
* Corresponding author. Tel.: þ86 21 67792612.
E-mail address: prchen@dhu.edu.cn (P. Chen).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.058

Q. Xu et al. / Tetrahedron 65 (2009) 2232–2238
2233
Table 1
Table 3
Variation of catalyst
Variation of solvent
O
Entry
Solvent
Reaction time (h)
% eeE
% eeA
% CHPLC
s
OH
O
R
1
CHCl3
CHCl3
CHCl3
CH2Cl2
Et2O
Toluene
CCl4
i-Pr2O
i-Pr2O
i-Pr2O
1.5
3.5
4
10
24
5
60.9
52.2
55.1
19.1
78.6
78.1
63.9
84.0
86.1
76.2
64.7
76.2
72
54
62
61
6
35
15
50
45
41
51
60
44
9
8
9
2
13
9
OH
CF3
2a
3b
4
84.5
85.0
1.2
42.3
13.2
63
67.7
59.9
77.8
96.6
59.6
CF3
CF3
(RCO)2O
+
5
6
7
Br
CF3
Br
2
9
8c,e
9d,e
10
11e
12
2.5
4.5
2
1.5
9
23
25
17
18
13
S
N
N
N
N
N
N
Ph
Ph
Ph
i-Pr2O
Ethylene glycol
Dimethyl ether
CF3-PIP
I
5, 6-Br2-PIP
III
BTM
II
Reaction conditions: 0.3 mmol substrate, 4 mol % (R)-BTM as catalyst, 100 mol %
(i-PrCO)2O, 1 ml solvent, 28 ꢁC.
Entry
Catalyst
Reaction time (h)
% eeE
% eeA
% CHPLC
s
a
5 ml of solvent.
b
1
2
3
I
II
III
1
1
1
64.7
66.6
36
37.1
73.1
3.8
37
52
10
7
20 mol % of catalyst.
c
11
2
0 ꢁC.
d
ꢀ40 ꢁC.
e
By slow addition of (i-PrCO)2O over a period of 0.5 h.
Reaction conditions: 0.3 mmol substrate, 20 mol % catalyst, 100 mol % (i-PrCO)2O,
1 ml CHCl3, 14 ꢁC. eeE and eeA were established by CSP-HPLC. Enantioselectivity
factor (s) is defined as s¼ln[(1ꢀCHPLC)(1ꢀeeA)]/ln[(1ꢀCHPLC)(1þeeA)], where
CHPLC¼100ꢂeeA/(eeEþeeA) (Ref. 8).
substitution (entry 5) led to the decrease of s value probably be-
cause the larger steric hindrance of MeS– than that of MeO– and
Me– made the s value of entry 5 lower than that of entries 2, 3, and
4. Meanwhile, in the case of electron-withdrawing substituent,
with the increasing electronegativity of the substituent (–Cl, 3.0;
–CN, 3.208; –NO2, 3.421; and –F, 4.09), the s values dropped down
gradually (20, 16, 13, and 13, entries 9, 12, 11, and 8). Both of 1-
naphthyl and 2-naphthyl (entries 13 and 14) were enlarged aro-
matic system of the phenyl and produced stronger interaction with
the catalyst, therefore, gave much higher s values.
Table 2
Variation of acylating reagent
Entry
Anhydride
Reaction time (h)
% eeE
% eeA
% CHPLC
s
1
2
3
(EtCO)2O
(i-PrCO)2O
Bz2O
4
1.5
2
75.3
66.6
25.7
30.9
73.1
3
29
52
9
10
11
2
Reaction conditions: 0.3 mmol substrate, 20 mol % (R)-BTM as catalyst, 75 mol %
anhydride, 1 ml CHCl3, 28 ꢁC.
2.3. Configuration of the fast reacting enantiomer
and the slow reacting enantiomer
anhydride to the reaction could give a little higher enantiose-
lectivity and reaction rate (entries 10 vs 11). At lower reaction
temperature (ꢀ40 ꢁC), the selectivity factor (s) was almost the same
as that at 0 ꢁC, but the reaction time was much longer (entries 8 vs
9). By comparison of entry 8 with entry 10, 0 ꢁC appeared to be the
most proper reaction temperature.
In summary, through the above-mentioned optimization, we
could establish our reaction conditions: racemic substrate
(0.3 mmol), BTM (4 mol %) as the catalyst, isopropyl ether (1 ml) as
the solvent, isobutylic anhydride (0.3 mmol) as the acylating re-
agent, and 0 ꢁC as the reaction temperature.
According to the transition state model proposed by Birman6j
(Fig. 1), the (S)-enantiomer was favorable to interact with the cat-
alyst leading to the acylated product. Therefore, the (S)-enantiomer
was the fast reacting enantiomer, which was isolated from the re-
action mixture as the acylated product, while the (R)-enantiomer
was the slow reacting one, remaining in the reaction system as the
unacylated alcohol. Configuration of some of the acylated products
and the unreacted alcohols (3a,4c 3b,3a 3c,4c 3d,4c 3h,4c 3i,4c 3m,3a
3n4c) is further proved by comparison of the observed optical ro-
tations of the obtained products with those reported in the litera-
tures. However, in the case of thienyl compound 1o (entry 16), the
slow reacting enantiomer was assigned to (S)-configuration by
comparison of the observed optical rotation with the reported
literature,3b while the fast reacting one to (R)-configuration due to
the Cahn–Ingold–Prolog rule.
2.2. Kinetic resolution of 2,2,2-trifluoro-1-aryl ethanol
Under the above optimized reaction conditions, sixteen racemic
substrates were subjected to the kinetic resolution. Results are
summarized in Table 4.
According to the transition state model proposed by Birman,6j
2.4. KR examples in preparative scale
the enantioselectivity depended on how strong the
p–p and the
cation– interactions were between the aromatic ring of the sub-
p
We have chosen 2,2,2-trifluoro-1-(1-naphthyl)ethanol (1m) and
2,2,2-trifluoro-1-(2-naphthyl)ethanol (1n) to carry out the pre-
parative kinetic resolution to demonstrate the applicability of this
method. In the case of 1m, we obtained the (S)-acylated product
(2m) with 86.2% ee (266.6 mg, 30% yield) and the (R)-unreacted
alcohol (3m) with 92% ee (257.8 mg, 38% yield); while in the case of
(1n), the (S)-acylated product (2n) with 77% ee (222.2 mg, 25%
yield) and the (R)-unreacted alcohol (3n) with >99% ee (284.9 mg,
42% yield) were obtained. The results showed that by adjusting the
reaction time (i.e., the % conversion), this method could be used to
obtain each of the enantiomers for some of the ethyl 2,2,2-trifluoro-
1-aryl ethanol with high ee in reasonable yield.
strate and the aromatic system of the catalyst (Fig. 1). These in-
teractions were a sum of electronic and steric ones in nature.
Electron-donating substituent (entries 2–5) favored the in-
teractions electronically, while such favorable effect might, to some
extent, be compromised by their bulky volume. In the case of
electron-withdrawing substituent (entries 6–12), the interactions
were diminished both electronically and sterically.
Specifically, in the case of the electron-donating substituent
(entries 2–5), 2-Me, 4-Me, 4-MeO–, and 4-MeS– groups on the
phenyl ring gave higher s values due to their electron-donating and
conjugate effects to the aromatic system. However, 4-MeS–

2234
Q. Xu et al. / Tetrahedron 65 (2009) 2232–2238
Table 4
Table 4 (continued)
Kinetic resolution of 2,2,2-trifluoro-1-aryl ethanol
Reaction
time (h)
Entry
R
% eeE
% eeA
% CHPLC
s
O
OH
OH
CF3
O
0 °C
R-BTM,
(i-PrCO)2O
R
CF3
R
i-Pr2O
R
CF3
14
0.5
89.7 (2n)
95.7 (3n)
52
71
rac 1(a-p)
2(a-p)
3(a-p)
1n
Entry
R
Reaction
% eeE
% eeA
% CHPLC
s
time (h)
15
16
1.5
0.5
45.1 (2o)
69.5 (2p)
56.5 (3o)
70.8 (3p)
56
50
5
1o
S
1
2
3
4
2.5
2.0
1.0
2.5
83.5 (2a)
87.1 (2b)
87.4 (2c)
89.0 (2d)
68.1 (3a)
65.1 (3b)
70.3 (3c)
68.5 (3d)
45
43
45
43
23
28
31
35
12
1a
1p
CH3
1b
CF3
H
X
(S)
X
(R)
H
CF3
OH
OH
H3C
O
O
i-Pr
i-Pr
S
N
S
N
1c
N
N
Ph
Ph
disfavored
H3CO
favored
1d
Figure 1. A schematic presentation of the proposed transition state model, adapted
from Birman et al.6j
5
1.0
81.9 (2e)
82.2 (3e)
50
25
H3CS
3. Conclusion
1e
In this work, we have investigated the kinetic resolution of
a series of 2,2,2-trifluoro-1-aryl ethanol with (R)-benzotetramisole
as the catalyst. The result showed that when the aryl group in the
substrate was a phenyl (or a phenyl substituted by an electron-
donating group) or a naphthyl (an extended phenyl) group, the
system could give an s value higher than 20. Preparative KR ex-
amples demonstrated the applicability of this method in the
preparation of some of enantiomerically pure 2,2,2-trifluoro-1-aryl
ethanol or 2,2,2-trifluoro-1-aryl-ethyl iso-butyrate.
6
7
2.0
1.0
61.3 (2f)
45.5 (2g)
85.4 (3f)
47.3 (3g)
58
51
11
4
F
1f
F
F
1g
1h
1i
8
9
6.0
0.5
71.2 (2h)
76 (2i)
72.5 (3h)
86.2 (3i)
50
53
13
20
4. Experimental section
4.1. Methods and materials
Cl
1H NMR spectra were recorded on a Bruker AV-400 (400 MHz)
spectrometer with Me4Si as an internal standard. 19F NMR spectra
were obtained on a Bruker AM-300 (282 MHz) spectrometer using
CFCl3 as an external standard; downfield shifts being designated as
O2N
10
11
12
1.0
0.5
0.5
69.0 (2j)
49.6 (2k)
73.1 (2l)
91.1 (3j)
98.3 (3k)
83 (3l)
57
66
53
17
13
16
positive, all chemical shifts (d) were expressed inparts permillionand
1j
1k
1l
coupling constants (J) are in hertz. Mass spectra were recorded on
a Finnigan MAT 8430 instrument using EI ionization at 70 eV. IR
spectrawere recorded on a Nicolet 380 spectrometer. High resolution
mass spectral analyses were performed on a Finnigan MAT 8430
spectrometer. Optical rotations were measured by WZZ-2 polarime-
ter. Melting points were measured on a WRS-2A melting point ap-
paratus. Enantiomericexcess(ee)valuesweredeterminedbyaBreeze
LC system (Waters Corporation) on a Chiralcel OJ-H or OD-H column
using iso-propanol/hexanes as mobile phase. All solvents used in the
reaction were purified by re-distillation. Anhydrides were purified by
re-distillation over P2O5. Other reagents were used aspurchased from
commercial suppliers without further purification.
O2N
NC
13
2.0
86.2 (2m)
92 (3m)
52
44
Catalysts 6-trifluoromethyl-2,3-dihydroimidazo-[1,2-a]pyridine
(CF3-PIP) (I), (R)-benzotetramisole (BTM) (II), and 5,6-dibromo-2,
1m

Q. Xu et al. / Tetrahedron 65 (2009) 2232–2238
2235
3-dihydroimidazo[1,2-a]pyridine (5,6-Br2-PIP) (III) were synthe-
4.2.5. (S)-2,2,2-Trifluoro-1-(4-methyl-phenyl)ethyl
iso-butyrate (2c)
sized according to known procedures6j,k and confirmed by com-
parison of the melting point, mass and 1H NMR spectra, and specific
optical rotation with the reported data. Racemic 2,2,2-trifluoro-1-
aryl ethanols were prepared from various aldehydes and (tri-
fluoromethyl)trimethylsilane and the acylated derivatives were
prepared according to known methods,4g except racemic 2,2,2-
trifluoro-1-phenyl ethanol was purchased from Aldrich Company
and purified as necessary.
1H NMR (400 MHz, CDCl3): 7.27 (d, J¼8.04 Hz, 2H), 7.13 (d,
J¼7.96 Hz, 2H), 6.02 (dd, J¼6.96, 13.92 Hz, 1H), 2.61–2.63 (m, 1H),
2.28 (s, 3H), 1.18–1.11 (m, 6H); 19F NMR (376 MHz, CDCl3): ꢀ76.15
(d, J¼6.76 Hz, 3F); MS (EI, 70 eV) m/z: 260 (Mþ, 13), 71 (100), 43
(75), 240 (41), 173 (36), 123 (17), 43 (98), 41 (7), 170 (7); HR-EI calcd
for C13H15O2F3: 260.1024, found: 260.1030; IR (film, cmꢀ1):
2925, 2851, 1756, 1617, 1519, 1462, 1266, 1176, 1135, 913, 804, 744;
25.6
ee¼66.5%, [
a]
29.12 (c 1.87, EtOH); HPLC (Chiralcel OJ-H,
D
4.2. General kinetic resolution experiment
hexane/i-PrOH¼90:10, 1.0 ml/min, 220 nm) tmajor(S)¼4.78 min,
tminor(R)¼5.71 min.
A 5 ml vial charged with catalyst (4 mol %) was flushed with
nitrogen for several times. To the vial was added racemic 2,2,2-
trifluoro-1-aryl ethanol (0.3 mmol) in i-Pr2O (0.5 ml) and to the
solution isobutylic anhydride (0.3 mmol) in i-Pr2O (0.5 ml) was
added in a period of 0.5 h (at which point timing was started). The
content was stirred at 0 ꢁC and monitored by HPLC (C18 column,
MeOH/H2O¼80:20, 254 nm). The reaction was stopped when the
conversion reached ca. 50% and purified by HPTLC to separate the
ester and the unreacted alcohol. Enantiomeric excess was de-
termined for the obtained acylated products and the unreacted
alcohols, respectively, on a Chiralcel OJ-H or OD-H column moni-
tored at 220 nm or 254 nm using hexanes/i-propyl alcohol as the
mobile phase. The absolute configuration of the resolution com-
pounds was obtained by comparison of the observed optical rota-
tion with the literature data.
4.2.6. (R)-2,2,2-Trifluoro-1-(4-methyl-phenyl)ethanol (3c)
1H NMR (400 MHz, CDCl3): 7.26 (d, J¼8.00 Hz, 2H), 7.12 (d,
J¼8.00 Hz, 2H), 4.86 (dd, J¼6.70, 13.42 Hz, 1H), 2.63 (s, 1H), 2.28 (s,
3H); 19F NMR (376 MHz, CDCl3): ꢀ78.34 (d, J¼6.39 Hz, 3F); MS (EI,
70 eV) m/z: 190 (Mþ,19),173 (8),121 (100), 91 (45), 77 (29), 69 (36); IR
(film, cmꢀ1): 3406, 3031, 2921, 2868, 1617, 1519, 1417, 1270, 1170, 1128,
26.4
20
806, 775, 722, 694; ee¼75.7%, [
a
]
ꢀ9.8 (c 0.08, CH2Cl2) {lit.4c
[a]
D
D
ꢀ18.4 (c 0.43, CH2Cl2)}; HPLC (Chiralcel OJ-H, hexane/i-PrOH¼70:30,
0.8 ml/min, 220 nm) tmajor(R)¼6.71 min, tminor(S)¼7.69 min.
4.2.7. (S)-2,2,2-Trifluoro-1-(4-methoxy-phenyl)ethyl
iso-butyrate (2d)
1H NMR (400 MHz, CDCl3): 7.31 (d, J¼8.71 Hz, 2H), 6.86–6.82 (m,
2H), 6.01 (dd, J¼6.95, 13.90 Hz, 1H), 3.74 (s, 3H), 2.61–2.63 (m, 1H),
1.16–1.11 (q, J¼6.98 Hz, 6H); 19F NMR (376 MHz, CDCl3): ꢀ76.25 (d,
J¼6.77 Hz, 3F); MS (EI, 70 eV) m/z: 276 (Mþ, 48), 137 (61), 139 (22),
189 (75), 186 (31), 71 (100), 43 (98), 41 (10); HR-EI calcd for
C13H15O3F3: 276.0973, found: 276.0985; IR (film, cmꢀ1): 2977, 2938,
4.2.1. (S)-2,2,2-Trifluoro-1-phenylethyl iso-butyrate (2a)
1H NMR (400 MHz, CDCl3): 7.47–7.39 (m, 5H), 6.14 (dd, J¼6.8,
13.8 Hz, 1H), 2.62–2.68 (m, 1H), 1.23 (q, J¼7.2 Hz, 6H); 19F NMR
(376 MHz, CDCl3): ꢀ76.07 (d, J¼6.8 Hz, 3F); MS (EI, 70 eV) m/z: 246
(Mþ, 2), 226 (32),159 (20),109 (19),107 (4), 71 (100), 72 (6), 43 (74);
HR-EI calcd for C12H13O2F3: 246.0868, found: 246.0862; IR (film,
2843, 1755, 1615, 1516, 1466, 1355, 1253, 1181, 1136, 1036,
24.6
933, 835, 689, 583; ee¼89%, [
a
]
D
41.7 (c 1.49, CH2Cl2); HPLC:
(Chiralcel OJ-H, hexane/i-PrOH¼90:10, 1.0 ml/min, 220 nm)
tmajor(S)¼6.54 min, tminor(R)¼8.18 min.
cmꢀ1): 3070, 3039, 2979, 2939, 2880, 1757, 1498, 1470, 1267, 1181,
25.5
1132, 1025, 933, 758, 702, 635; ee¼83.5%, [
a
]
ꢀ17.7 (c 0.71,
D
CHCl3); HPLC (Chiralcel OJ-H, hexane/i-PrOH¼95:05, 0.4 ml/min,
4.2.8. (R)-2,2,2-Trifluoro-1-(4-methoxy-phenyl)ethanol (3d)
254 nm) tmajor(S)¼14.04 min, tminor(R)¼15.97 min.
1H NMR (400 MHz, CDCl3): 7.32 (d, J¼8.70 Hz, 2H), 6.87–6.83
(m, 2H), 4.89 (q, 1H), 3.74 (s, 3H), 2.47 (s, 1H); 19F NMR (376 MHz,
CDCl3): ꢀ78.50 (d, J¼6.77 Hz, 3F); MS (EI, 70 eV) m/z: 206 (Mþ, 8),
121 (100), 137 (34), 109 (12), 189 (3), 93 (39), 77 (23), 91 (22), 69
4.2.2. (R)-2,2,2-Trifluoro-1-phenyl ethanol (3a)
25.2
20
ee¼96.6%, [
a
]
D
ꢀ20.41 (c 0.48, CHCl3) {lit.4e 56% ee, [
a
]
ꢀ12.5
D
(c 0.4, CH2Cl2) for the (R)-enantiomer}; HPLC (Chiralcel OJ-H,
hexane/i-PrOH¼95:05, 1.0 ml/min, 254 nm) tmajor(R)¼21.02 min,
tminor(S)¼29.04 min.
(13); IR (film, cmꢀ1): 3443, 2920, 2845, 1614, 1517, 1463, 1252, 1172,
24.6
1126, 818, 695; ee¼68.5%, [
a
]
D
ꢀ12.55 (c 0.4, CH2Cl2) {lit.4c 41% ee,
20
[a
]
ꢀ8.9 (c 1.0, CH2Cl2)}; HPLC (Chiralcel OJ-H, hexane/
D
i-PrOH¼90:10, 1.0 ml/min, 254 nm) tmajor(R)¼26.09 min, tminor(S)
¼
4.2.3. (S)-2,2,2-Trifluoro-1-(20-methyl-phenyl)ethyl
28.65 min.
iso-butyrate (2b)
Colorless oil; 1H NMR (400 MHz, CDCl3):
d
7.49 (d, J¼7.6 Hz, 1H),
4.2.9. (S)-2,2,2-Trifluoro-1-(4-methylsulfanyl-phenyl)ethyl
iso-butyrate (2e)
7.30–7.19 (m, 3H), 6.42 (dd, J¼6.8, 13.6 Hz, 1H), 2.69 (m, 1H), 2.48 (s,
3H), 1.24–1.18 (m, 6H); 19F NMR (376 MHz, CDCl3): ꢀ75.75 (d,
J¼6.77 Hz, 3F); MS (EI, 70 eV) m/z: 260 (M, 5),172 (100),173 (19),171
1H NMR (400 MHz, CDCl3): 7.36 (d, J¼8.00 Hz, 2H), 7.27–7.25 (m,
2H), 6.08 (dd, J¼6.87, 13.76 Hz, 1H), 2.74–2.64 (m, 1H), 2.48 (s, 3H),
1.22–1.25 (m, 6H); 19F NMR (376 MHz, CDCl3): ꢀ76.11 (d, J¼6.77 Hz,
3F); MS (EI, 70 eV) m/z: 292 (Mþ, 98), 205 (100), 43 (92), 71 (78),
153 (31), 293 (24), 155 (21), 202 (16); HR-EI calcd for C13H15O2F3S:
(14), 91 (12), 71 (22), 59 (20), 43 (50), 41 (16); IR (film, cmꢀ1): 3033,
25
2981, 2881, 1756, 1467, 1273, 1183, 1140, 913, 693; ee¼87.1%, [
a]
D
29.6 (c 1.0, CHCl3); HPLC (Chiralcel OJ-H, hexane/i-PrOH¼100:0,
1.0 ml/min, 220 nm) tmajor¼4.81 min, tminor¼5.66 min.
292.0743, found: 292.0745; IR (film, cmꢀ1): 2978, 2926, 1755, 1602,
24.2
1496, 1470, 1353, 1277, 1181, 1135, 829, 804; ee¼73.9%, [
a
]
25.0
D
4.2.4. (R)-2,2,2-Trifluoro-1-(20-methyl-phenyl)ethanol (3b)
(c 1.78, acetone); HPLC (Chiralcel OJ-H, hexane/i-PrOH¼95:05,
1.0 ml/min, 254 nm) tmajor(S)¼7.63 min, tminor(R)¼11.89 min.
Colorless oil; 1H NMR (400 MHz, CDCl3): 7.58 (d, J¼8.00 Hz, 1H),
7.30–7.24 (m, 2H), 7.21–7.18 (m, 1H), 5.30 (dd, J¼6.56, 13.16 Hz, 1H),
2.37 (s, 3H).19F NMR (376 MHz, CDCl3): ꢀ77.68 (d, J¼5.26 Hz, 3F); MS
(EI, 70 eV) m/z: 190 (Mþ, 37), 172 (28), 121 (100), 91 (92), 93 (82), 77
(51), 69 (14); IR (film, cmꢀ1): 3394, 3032, 2961,1607,1492,1463,1266,
1171, 1133, 760, 728, 1270, 1170, 1128, 806, 775, 722, 694; ee¼65.0%,
4.2.10. (R)-2,2,2-Trifluoro-1-(4-methylsulfanyl-phenyl)ethanol (3e)
1H NMR (400 MHz, CDCl3): 7.38 (d, J¼8.32 Hz, 2H), 7.27 (d,
J¼8.6 Hz, 2H), 4.97 (dd, J¼6.68, 13.36 Hz, 1H), 2.48 (s, 3H); 19F NMR
(376 MHz, CDCl3): ꢀ78.38 (d, J¼6.76 Hz, 3F); MS (EI, 70 eV) m/z:
222 (Mþ, 44), 153 (100), 109 (50), 77 (18), 78 (13), 69 (12); IR (film,
16
25
[a]
ꢀ28.2 (c 1.0, CHCl3) {lit.3a 74.0% ee, [
a]
ꢀ26.0 (c 0.66, CHCl3) for
D
D
the (R)-enantiomer}; HPLC (Chiralcel OJ-H, hexane/i-PrOH¼95:05,
1.0 ml/min, 220 nm) tmajor¼15.94 min, tminor¼12.53 min.
cmꢀ1): 3423, 2986, 2925, 1601, 1497, 1437, 1407, 1267, 1170, 1128,
24.3
1093, 913, 807, 742, 677; ee¼96.4%, [
a
]
ꢀ20.3 (c 0.22, acetone);
D

2236
Q. Xu et al. / Tetrahedron 65 (2009) 2232–2238
24.6
HPLC (Chiralcel OJ-H, hexane/i-PrOH¼90:10, 1.0 ml/min, 220 nm)
tmajor(R)¼23.34 min, tminor(S)¼25.43 min.
1173, 1129, 913, 743, 575; ee¼72.5%, [
a]
ꢀ16.3 (c 0.246, CH2Cl2)
D
20
{lit.4c 57% ee, [
a
]
ꢀ20 (c 0.02, CH2Cl2)}; HPLC (Chiralcel OJ-H,
D
hexane/i-PrOH¼70:30, 1.0 ml/min, 220 nm) tmajor(R)¼5.38 min,
tminor(S)¼5.77 min.
4.2.11. (S)-2,2,2-Trifluoro-1-(2-fluoro-phenyl)ethyl
iso-butyrate (2f)
1H NMR (400 MHz, CDCl3): 7.50 (t, J¼7.20 Hz, 1H), 7.38–7.42 (m,
1H), 7.22–7.18 (m, 1H), 7.11 (td, J¼0.80, 9.52 Hz, 1H), 6.52 (dd,
J¼6.80, 13.60 Hz, 1H), 2.70 (m, 1H), 1.25–1.19 (m, 6H); 19F NMR
(376 MHz, CDCl3): ꢀ76.36 (m, 3F), ꢀ116.48 (m, 1F); MS m/z: 264
(Mþ, 1), 57 (100), 43 (76), 71 (72), 73 (69), 60 (57), 85 (45), 55 (40),
41 (38); HR-EI calcd for C12H12O2F4: 264.0773, found: 264.0775; IR
(film, cmꢀ1): 2963, 2928, 2856, 1762, 1620, 1592, 1494, 1464, 1358,
4.2.17. (S)-2,2,2-Trifluoro-1-(4-chloro-phenyl)ethyl
iso-butyrate (2i)
1H NMR (400 MHz, CDCl3): 7.42–7.37 (m, 4H), 6.10 (q, J¼6.84 Hz,
1H), 2.75–2.65 (m, 1H), 1.25–1.20 (m, 6H); 19F NMR (376 MHz,
CDCl3): ꢀ76.12 (d, J¼6.77 Hz, 3F); MS (EI, 70 eV) m/z: 279 (Mþ, 2),
43 (100), 71 (80), 41 (46), 57 (87), 97 (42), 55 (56), 69 (52); HR-EI
calcd for C12H12O2F3Cl: 280.0478, found: 280.0479; IR (film, cmꢀ1):
1263, 1187, 1096, 801, 756, 691; ee¼61.3%, [
a
]
23.2 19.1 (c 1.03, ace-
3094, 2980, 1760, 1601, 1494, 1471, 1389, 1354, 1270, 1183, 1016,
D
26.1
tone); HPLC (Chiralcel OJ-H, hexane/i-PrOH¼100:0, 1.0 ml/min,
931, 873, 833, 730, 682; ee¼76%; [
a
]
51.6 (c 3.61, EtOH);
D
254 nm) tmajor(S)¼5.59 min, tminor(R)¼6.11 min.
HPLC (Chiralcel OJ-H, hexane/i-PrOH¼90:10, 1.0 ml/min, 220 nm)
tmajor(S)¼4.81 min, tminor(R)¼5.19 min.
4.2.12. (R)-2,2,2-Trifluoro-1-(2-fluoro-phenyl)ethanol (3f)
1H NMR (400 MHz, CDCl3): 7.60 (t, J¼7.2 Hz, 1H), 7.42–7.36 (m,
1H), 7.22 (td, J¼1.2, 7.6 Hz, 1H), 7.12–7.07 (m, 1H), 5.41 (dd, J¼6.52,
13.04 Hz, 1H), 2.62 (s, 1H); 19F NMR (376 MHz, CDCl3): ꢀ78.59 (m,
3F), ꢀ117.92 (m, 1F); MS (EI, 70 eV) m/z: 194 (Mþ, 16), 177 (6), 125
4.2.18. (R)-2,2,2-Trifluoro-1-(4-chloro-phenyl)ethanol (3i)
1H NMR (400 MHz, CDCl3): 2.94 (s, 1H), 5.02 (q, J¼6.6 Hz, 1H),
7.44–7.37 (m, 4H); 19F NMR (376 MHz): ꢀ78.47 (d, J¼6.77 Hz, 3F);
MS (EI, 70 eV) m/z: 210 (Mþ, 23), 141 (100), 77 (83), 143 (39), 113
(100), 97 (48), 77 (33), 69 (11); IR (film, cmꢀ1): 3435, 2922, 2851,
(23),139 (14), 111 (12); IR (film, cmꢀ1): 3398, 2924, 1600, 1496, 1411,
26.4
26.1
1638, 1462, 1127, 1090, 913, 744; ee¼85.4%, [
a
]
ꢀ30.74 (c 0.43,
1268, 1173, 1129, 1091, 811, 731, 529; ee¼86.2%, [
a
]
ꢀ71.2 (c 0.43,
D
D
20
CHCl3); HPLC (Chiralcel OJ-H, hexane/i-PrOH¼98:2, 1.0 ml/min,
254 nm) tminor(S)¼23.83 min, tmajor(R)¼27.60 min.
EtOH) {lit.4c 45% ee, [
a]
ꢀ1.1.4 (c 0.1, CH2Cl2) for the (R)-enantio-
D
mer}; HPLC (Chiralcel OJ-H, hexane/i-PrOH¼90:10, 1.0 ml/min,
220 nm) tmajor(R)¼9.47 min, tminor(S)¼11.31 min.
4.2.13. (S)-2,2,2-Trifluoro-1-(3-fluoro-phenyl)ethyl
iso-butyrate (2g)
4.2.19. (S)-2,2,2-Trifluoro-1-(3-nitro-phenyl)ethyl iso-butyrate (2j)
1H NMR (400 MHz, CDCl3): 8.35–8.28 (m, 2H), 7.79 (d, J¼7.72 Hz,
1H), 7.62 (t, J¼8.04 Hz, 1H), 6.22 (dd, J¼6.88, 13.52 Hz, 1H), 2.70–
2.80 (m,1H),1.25 (q, J¼7.00 Hz, 6H); 19F NMR (376 MHz): ꢀ75.91 (d,
J¼6.77 Hz, 3F); MS m/z: 292 (Mþ, 4), 71 (100), 43 (94), 204 (13), 203
(11), 154 (4), 158 (4), 72 (5), 41 (11); HR-EI calcd for C12H12NO4F3:
1H NMR (400 MHz, CDCl3): 7.40–7.35 (m, 1H), 7.25–7.09 (m, 3H),
6.12 (dd, J¼6.78,13.54 Hz,1H), 2.71–2.78 (m,1H),1.25–1.20 (m, 6H);
19F NMR (376 MHz, CDCl3): ꢀ76.04 (d, J¼7.52 Hz, 3F), ꢀ111.79 to
ꢀ111.85 (m,1F); MS m/z: 264 (Mþ, 2), 43 (100), 71 (93),177 (20),127
(17), 41 (11), 244 (8), 72 (4), 44 (3); HR-EI calcd for C12H12O2F4:
264.0773, found: 264.0779; IR (film, cmꢀ1): 2979, 2931, 1759, 1596,
291.0718, found: 291.0716; IR (film, cmꢀ1): 3094, 2980, 1760, 1537,
23.8
24.8
1492, 1354, 1271, 1187, 1137, 927, 781, 711; ee¼45.5%, [
a]
42.5
1471, 1353, 1267, 1187, 1139, 880, 712, 688; ee¼69%, [
a
]
24.14
D
D
(c 1.76, acetone); HPLC (Chiralcel OD-H, hexane/i-PrOH¼100:0,
1.0 ml/min, 254 nm) tmajor(S)¼5.27 min, tminor(R)¼5.68 min.
(c 2.42, EtOH); HPLC (Chiralcel OJ-H, hexane/i-PrOH¼100:0, 1.0 ml/
min, 220 nm) tminor(R)¼23.56 min, tmajor(S)¼26.20 min.
4.2.14. (R)-2,2,2-Trifluoro-1-(3-fluoro-phenyl)ethanol (3g)
4.2.20. (R)-2,2,2-Trifluoro-1-(3-nitro-phenyl)ethanol (3j)
1H NMR (400 MHz, CDCl3): 7.40–7.35 (m, 1H), 7.25–7.21 (m, 2H),
7.12–7.07 (m, 1H), 5.03 (dd, J¼6.56, 13.12 Hz, 1H), 2.89 (s, 1H); 19F
NMR (376 MHz, CDCl3): ꢀ78.34 (d, J¼3.76 Hz, 3F), ꢀ112.23 (t,
J¼7.52 Hz, 1F); MS (EI, 70 eV) m/z: 193 (Mþ, 49), 177 (15), 157 (6),
Mp 50.6–52.2 ꢁC; 1H NMR (400 MHz, CDCl3): 3.27 (s, 1H), 5.12–
5.22 (m, 1H), 7.61 (t, J¼8.00 Hz, 1H), 7.85 (d, J¼8.00 Hz, 1H), 8.26–
8.28 (m, 1H), 8.39 (s, 1H); 19F NMR (376 MHz): ꢀ81.60 (d,
J¼8.00 Hz, 3F); MS (EI, 70 eV) m/z: 221 (Mþ, 7), 152 (100), 105
(22), 77 (22), 78 (14), 106 (11), 153 (9); IR (KBr): 3479, 3092, 2917,
123 (100), 95 (30), 69 (28); IR (film, cmꢀ1): 3418, 2923, 2851, 1617,
26.6
1596, 1490, 1258, 1178, 1128, 841, 788, 711; ee¼47.3%, [
a
]
ꢀ18.6
2843, 1619, 1586, 1537, 1474, 1357, 1266, 1178, 1131, 807, 713, 684;
D
25.4
(c 0.5, CHCl3); HPLC (Chiralcel OJ-H, hexane/i-PrOH¼95:05, 1.0 ml/
min, 254 nm) tminor(S)¼15.5 min, tmajor(R)¼16.79 min.
ee¼91.1%, [
a
]
ꢀ14.8 (c 0.58, EtOH); HPLC (Chiralcel OJ-H,
D
hexane/i-PrOH¼90:10, 1.0 ml/min, 220 nm) tmajor(R)¼17.36 min,
tminor(S)¼20.47 min.
4.2.15. (S)-2,2,2-Trifluoro-1-(4-fluoro-phenyl)ethyl
iso-butyrate (2h)
4.2.21. (S)-2,2,2-Trifluoro-1-(4-nitro-phenyl)ethyl iso-butyrate (2k)
1H NMR (400 MHz, CDCl3): 8.30–8.27 (dt, J¼2.36, 4.32 Hz, 2H),
7.66 (d, J¼8.75 Hz, 2H), 6.22 (q, J¼6.66 Hz, 1H), 2.78–2.71 (m, 1H),
1.26–1.23 (m, 6H); 19F NMR (376 MHz): ꢀ75.68 (d, J¼6.77 Hz, 3F);
MS (EI, 70 eV) m/z: 291 (Mþ, 2), 292 (3), 71 (100), 43 (73), 204 (4),
41 (12), 72 (5), 158 (6), 157 (8); HR-EI calcd for C12H12NO4F3:
291.0718, found: 291.0728; IR (film, cmꢀ1): 3084, 2978, 1759, 1605,
1H NMR (400 MHz, CDCl3): 7.46–7.43 (m, 2H), 7.12–7.07 (m, 2H),
6.11 (dd, J¼6.15, 13.00 Hz, 1H), 2.62–2.68 (m, 1H), 1.22–1.24 (m, 6H);
19F NMR (376 MHz, CDCl3): ꢀ76.24 (d, J¼3.87 Hz, 3F), ꢀ110.97 to
ꢀ111.05 (m,1F); MS m/z: 264 (Mþ, 3), 71 (100), 43 (85), 244 (26),177
(26), 127 (18), 41 (9), 240 (8), 173 (5); HR-EI calcd for C12H12O2F4:
264.0773, found: 264.0768; IR (film, cmꢀ1): 2979, 2931, 1759, 1596,
1492, 1354, 1271, 1187, 1137, 927, 781, 711; ee¼71.2%, [
a]
24.3 11.7 (c
1530, 1351, 1267, 1187, 1139, 849, 712; ee¼49.6%, [
a]
D
25.7 22.8 (c 6.75,
D
1.31, CH2Cl2); HPLC (Chiralcel OJ-H, hexane/i-PrOH¼95:05, 1.0 ml/
CHCl3); HPLC (Chiralcel OJ-H, hexane/i-PrOH¼98:02, 1.0 ml/min,
254 nm) tminor(R)¼11.98 min, tmajor(S)¼17.16 min.
min, 220 nm) tmajor(S)¼5.09 min, tminor(R)¼5.59 min.
4.2.16. (R)-2,2,2-Trifluoro-1-(4-fluoro-phenyl)ethanol (3h)
4.2.22. (R)-2,2,2-Trifluoro-1-(4-nitro-phenyl)ethanol (3k)
1H NMR (400 MHz, CDCl3): 7.38–7.42 (m, 2H), 7.03 (t, J¼8.80 Hz,
2H), 4.95 (dd, J¼6.57, 13.24 Hz, 1H), 2.72 (s, 1H); 19F NMR (376 MHz,
CDCl3): ꢀ78.60 (d, J¼3.76 Hz, 3F), ꢀ111.81 (m, 1F); MS (EI, 70 eV)
m/z: 194 (Mþ, 23), 125 (100), 97 (63), 77 (27), 95 (21), 75 (10), 126
(10), 69 (8); IR (film, cmꢀ1): 3420, 2922, 2852, 1608, 1514, 1232,
Mp 129–131 ꢁC; 1H NMR (400 MHz, CDCl3): 3.08 (s, 1H), 5.19 (q,
J¼6.0 Hz, 1H), 7.70 (d, J¼8.4 Hz, 2H), 8.26–8.30 (m, 2H); 19F NMR
(376 MHz): ꢀ78.14 (d, J¼6.77 Hz, 3F); MS (EI, 70 eV) m/z: 221 (Mþ, 9),
152 (100), 77 (17), 122 (9), 105 (13), 106 (10), 153 (9); IR (KBr): 3413,
2972, 1607, 1531, 1347, 1262, 1160, 1129, 820, 712; ee¼98.3%, [
26.0
a]
D

Q. Xu et al. / Tetrahedron 65 (2009) 2232–2238
2237
ꢀ11.2 (c 1.9, CHCl3); HPLC (Chiralcel OJ-H, hexane/i-PrOH¼90:10,
1.0 ml/min, 254 nm) tmajor(R)¼19.61 min, tminor(S)¼22.35 min.
(R)-enantiomer}; HPLC (Chiralcel OJ-H, hexane/i-PrOH¼70:30,
1.0 ml/min, 254 nm) tmajor(R)¼8.66 min, tminor(S)¼11.80 min.
4.2.23. (S)-2,2,2-Trifluoro-1-(4-cyano-phenyl)ethyl
4.2.29. (E)-(S)-1,1,1-Trifluoro-4-phenyl-3-buten-2-yl
iso-butyrate (2l)
iso-butyrate (2o)
1H NMR (400 MHz, CDCl3): 7.74–7.71 (dt, J¼8.4, 1.6 Hz, 2H), 7.58
(d, J¼8.8 Hz, 2H), 6.16 (q, J¼6.69 Hz, 1H), 2.77–2.70 (m, 1H), 1.26–
1.23 (m, 6H); 19F NMR (376 MHz): ꢀ75.76 (d, J¼6.77 Hz, 3F); MS (EI,
70 eV) m/z: 271 (Mþ, 2), 71 (100), 43 (78), 41 (20), 134 (20), 67 (18),
57 (17), 55 (16), 69 (14); HR-EI calcd for C13H12NO2F3: 271.0830,
found: 271.0820; IR (film, cmꢀ1): 2977, 2919, 2232, 1758, 1537, 1467,
1H NMR (400 MHz, CDCl3): 7.43–7.29 (m, 5H), 6.85 (d,
J¼15.92 Hz, 1H), 6.12 (dd, J¼7.68, 15.92 Hz, 1H), 5.86–5.79 (m, 1H),
2.62–2.68 (m, 1H), 1.23–1.26 (m, 6H); 19F NMR (376 MHz): ꢀ76.50
(d, J¼6.76 Hz, 3F); MS m/z: 272 (Mþ, 6), 71 (100), 43 (80), 57 (39), 85
(17), 41 (12), 252 (11), 55 (10), 73 (8); HR-EI calcd for C14H15O2F3:
272.1024, found: 272.1016; IR (film, cmꢀ1): 3030, 2978, 2936, 1754,
25
1354, 1265, 1187, 1137, 932, 841, 688; ee¼73.1%, [
a]
25.7 38.2 (c 3.01,
1652, 1470, 1388, 1268, 1185, 1136, 968, 750, 689; ee¼45.1%, [
a]
D
D
CHCl3); HPLC (Chiralcel OJ-H, hexane/i-PrOH¼98:02, 1.0 m/min,
220 nm) tminor(R)¼12.25 min, tmajor(S)¼13.03 min.
35.7 (c 1.6 CHCl3); HPLC (Chiralcel OJ-H, hexane/i-PrOH¼95:05,
0.2 ml/min, 254 nm) tmajor(S)¼25.71 min, tminor(R)¼28.04 min.
4.2.24. (R)-2,2,2-Trifluoro-1-(4-cyano-phenyl)ethanol (3l)
4.2.30. (E)-(R)-1,1,1-Trifluoro-4-phenyl-3-buten-2-ol (3o)
Mp 88.5–89.5 ꢁC; 1H NMR (400 MHz, CDCl3): 3.15 (d, J¼4.46 Hz,
1H), 5.10–5.14 (m, 1H), 7.63 (d, J¼8.00 Hz, 2H), 7.71 (d, J¼8.00 Hz,
2H); 19F NMR (376 MHz): ꢀ78.17 (d, J¼6.77 Hz, 3F); MS (EI, 70 eV)
m/z: 201 (Mþ, 18), 132 (100), 104 (51), 77 (26), 102 (10), 133 (10), 134
1H NMR (400 MHz, CDCl3): 7.36–7.18 (m, 5H), 6.79 (d, J¼15.89 Hz,
1H), 6.13 (dd, J¼6.50, 15.96 Hz, 1H), 4.60–4.64 (m, 1H), 2.33 (s, 1H);
19F NMR (376 MHz): ꢀ79.04 (d, J¼6.76 Hz, 3F); MS (EI, 70 eV) m/z:
202 (Mþ, 55), 133 (100), 115 (36), 77 (23), 91 (20), 103 (17); IR (film,
cmꢀ1): 3435, 2920, 2843, 1635, 1127, 1090, 913, 744; ee¼67.6%, [
a]
D
25
(7), 69 (6); IR (KBr): 3388, 3064, 2974, 2918, 2240, 1611, 1505, 1411,
25.8
1350, 1265, 1162, 1128, 816, 690; ee¼83%, [
a
]
ꢀ12.4 (c 1.4,
ꢀ20.3 (c 0.17, CH3OH); HPLC (Chiralcel OJ-H, hexane/i-PrOH¼95:05,
1.0 ml/min, 220 nm) tmajor(R)¼20.21 min, tminor(S)¼24.48 min.
D
CHCl3); HPLC (Chiralcel OJ-H, hexane/i-PrOH¼90:10, 1.0 ml/min,
220 nm) tmajor(R)¼19.06 min, tminor(S)¼22.73 min.
4.2.31. (R)-2,2,2-Trifluoro-1-(2-thienyl)ethyl iso-butyrate (2p)
1H NMR (400 MHz, CDCl3): 7.33–6.95 (m, 3H), 6.38 (dd, J¼6.68,
13.32 Hz, 1H), 2.60–2.64 (m, 1H), 1.14 (q, J¼7.00 Hz, 6H); 19F NMR
(376 MHz): ꢀ76.37 (d, J¼5.64 Hz, 3F); MS m/z: 252 (Mþ, 1), 71
(100), 43 (95), 165 (11), 57 (10), 41 (9), 115 (9), 45 (6), 69 (3); HR-EI
4.2.25. (S)-2,2,2-Trifluoro-1-(1-naphthyl)ethyl iso-butyrate (2m)
1H NMR (400 MHz, CDCl3): 8.16 (d, J¼8.56 Hz, 1H), 7.92–7.88 (m,
2H), 7.74 (d, J¼7.24 Hz, 1H), 7.62–7.49 (m, 3H), 7.02 (dd, J¼6.80,
13.32 Hz, 1H), 2.71–2.75 (m, 1H), 1.21–1.25 (m, 6H); 19F NMR
(376 MHz): ꢀ75.01 (d, J¼6.77 Hz, 3F); MS m/z: 296 (Mþ, 48), 71
(100), 43 (87), 41 (9), 290 (28), 157 (13), 189 (11), 159 (9); HR-EI
calcd for C16H15O2F3: 296.1024, found: 296.1026; IR (film, cmꢀ1):
calcd for C10H11O2F3S: 252.0432, found: 252.0428; IR (film, cmꢀ1):
20
3011, 2969, 1738, 1365, 1216, 1091, 1019, 798, 530; ee¼80%, [
a]
D
67.6 (c 0.54, CH3OH); HPLC (Chiralcel OJ-H, hexane/i-PrOH¼100:0,
1.0 ml/min, 220 nm) tmajor(R)¼7.94 min, tminor(S)¼8.55 min.
3056, 2979, 1755, 1470, 1270, 1184, 1135, 799, 777, 698; ee¼79.5%,
26.5
[
a]
ꢀ29.1 (c 0.5, CHCl3); HPLC (Chiralcel OJ-H, hexane/i-
D
PrOH¼95:05,
0.2 ml/min,
254 nm)
tminor(R)¼33.55 min,
4.2.32. (S)-2,2,2-Trifluoro-1-(2-thienyl) ethanol (3p)
tmajor(S)¼36.24 min.
1HNMR(400 MHz,CDCl3):7.28(dd,J¼1.00,5.08 Hz,1H),7.13–7.08
(m, 1H), 6.93 (dd, J¼3.64, 5.04 Hz,1H), 5.16 (q, J¼6.16 Hz,1H), 2.63 (s,
1H); 19F NMR (376 MHz): ꢀ78.67 (d, J¼4.88 Hz, 3F); MS (EI, 70 eV) m/
z: 182(Mþ, 41),113 (100),111 (78), 85(68),149 (28),165(8), 69(22); IR
4.2.26. (R)-2,2,2-Trifluoro-1-(1-naphthyl)ethanol (3m)
1H NMR (400 MHz, CDCl3): 7.99 (d, J¼8.00 Hz, 1H), 7.87–7.77 (m,
3H), 7.54–7.46 (m, 3H), 5.81 (q, J¼8.00 Hz,1H), 2.84 (s,1H); 19F NMR
(376 MHz): ꢀ76.76 (d, J¼7.52 Hz); MS (EI, 70 eV) m/z: 226 (Mþ, 86),
157 (100), 129 (88), 128 (52), 127 (31), 158 (13), 227 (12), 77 (6); IR
(film, cmꢀ1): 3423, 3047, 2921,1593,1515,1264,1167,1125, 800, 781,
(film, cmꢀ1): 3435, 2921, 2847, 1640, 1128, 1089, 706, 592; ee¼41%,
20
[a]
ꢀ7.28 (c 0.88, CH3OH) {lit.3b 99% ee, [
a]
D
25 27.6 (c 0.88, CH3OH) for
D
the (R)-enantiomer}; HPLC (Chiralcel OJ-H, hexane/i-PrOH¼70:30,
1.0 ml/min, 220 nm) tmajor(S)¼6.16 min, tminor(R)¼7.95 min.
25.7
24
698, 632; ee¼96.4%, [
a
]
ꢀ12.4 (c 0.56, EtOH) {lit.3a 97% ee, [
a]
D
D
ꢀ21.1 (c 1.0, EtOH) for the (R)-enantiomer}; HPLC (Chiralcel OJ-H,
hexane/i-PrOH¼70:30, 1.0 ml/min, 220 nm) tmajor(R)¼8.41 min,
tminor(S)¼9.46 min.
4.3. Examples of preparative kinetic resolution for 2,2,2-
trifluoro-1-(1-naphthyl)ethanol (1m) and 2,2,2-trifluoro-
1-(2-naphthyl)ethanol (1n)
4.2.27. (S)-2,2,2-Trifluoro-1-(2-naphthyl)ethyl iso-butyrate (2n)
1H NMR (400 MHz, CDCl3): 7.94–7.86 (m, 4H), 7.56–7.51 (m, 3H),
6.30 (dd, J¼7.2, 13.96 Hz, 1H), 2.72–2.74 (m, 1H), 1.22–1.26 (m, 6H);
19F NMR (376 MHz): ꢀ75.70 (d, J¼6.77 Hz); MS m/z: 296 (Mþ, 24),
71 (100), 43 (72), 209 (12), 226 (8.6), 159 (7), 206 (6), 129 (5); HR-EI
calcd for C16H15O2F3: 296.1024, found: 296.1031; IR (film, cmꢀ1):
A 25 ml toasted flask was flushed with N2 for several times, then
charged with 30 mg (0.12 mmol) of (R)-BTM and 678.6 mg
(3 mmol) of the racemic substrate (1m or 1n) in 5 ml of diisopropyl
ether. A solution of 474.6 mg (3 mmol) of isobutyric anhydride in
5 ml diisopropyl ether was added slowly with stirring over a period
of 0.5 h. The content was stirred at 0 ꢁC under N2 atmosphere and
monitored by HPLC (C18 column, MeOH/H2O¼80:20, 254 nm).
When the reaction reached about 50% conversion, the reaction was
quenched with MeOH (5 ml) and evaporated in vacuo. The residue
was dissolved in chloroform and washed with brine and water, and
then chromatographed on silica gel (petroleum ether/ethyl
acetate¼20:1–10:1) to separate the acylated (S)-enantiomer and
the unreacted (R)-enantiomer. The outcomes are as follows.
3062, 2982, 2941, 1753, 1600, 1468, 1352, 1269, 1188, 1134, 932,
25.3
823, 745, 700; ee¼89.7%, [
a]
25.2 (c 5.12, CHCl3); HPLC
D
(Chiralcel OJ-H, hexane/i-PrOH¼70:30, 1.0 ml/min, 220 nm)
tmajor(S)¼5.26 min, tminor(R)¼6.61 min.
4.2.28. (R)-2,2,2-Trifluoro-1-(2-naphthyl)ethanol (3n)
Mp 84.2–84.4 ꢁC; 1H NMR (400 MHz, CDCl3): 8.0–7.8 (m, 4H),
7.6–7.5 (m, 3H), 5.21 (q, J¼8.00 Hz, 1H), 2.62 (s, 1H); 19F NMR
(376 MHz): ꢀ77.99 (d, J¼6.77 Hz); MS (EI, 70 eV) m/z: 226 (Mþ, 73),
(S)-2,2,2-Trifluoro-1-(1-naphthyl)ethyl
iso-butyrate
(2m):
227 (10), 157 (85), 128 (59), 129 (100), 127 (36), 158 (11), 77 (9); IR
266.6 mg (30% yield), 86.2% ee, colorless oil.
(R)-2,2,2-Trifluoro-1-(1-naphthyl)ethanol (3m): 257.8 mg (38%
yield), 92% ee, colorless oil.
26.3
(KBr, cmꢀ1): 3344, 2920, 2851, 1238, 1125, 817; ee¼95.7%, [
a
]
D
20
ꢀ27 (c 0.44, CHCl3) {lit.4c 71% ee, [
a]
ꢀ23.7 (c 0.16, CH2Cl2) for the
D

2238
Q. Xu et al. / Tetrahedron 65 (2009) 2232–2238
4. (a) Kuroki, Y.; Iseki, K. Tetrahedron Lett. 1999, 40, 8231–8234; (b) Chang, Y.; Cai, C.
(S)-2,2,2-Trifluoro-1-(2-naphthyl)ethyl
222.2 mg (25% yield), 77% ee, colorless oil.
iso-butyrate
(2n):
Tetrahedron Lett. 2005, 46, 3161–3164; (c) Song, J. J.; Tan, Z.; Reeves, J. T.; Gallou,
F.; Yee, N. K.; Senanayake, C. H. Org. Lett. 2005, 7, 2193–2196; (d) Mizuta, S.;
Shibata, N.; Akiti, S.; Fujimoto, H.; Nakamura, S.; Toru, T. Org. Lett. 2007, 9, 3707–
3710; (e) Zhao, H.; Qin, B.; Liu, X.; Feng, X. Tetrahedron 2007, 63, 6822–6826; (f)
Mizuta, S.; Shibata, N.; Hibino, M.; Nagano, S.; Nakamura, S.; Toru, T. Tetrahedron
2007, 63, 8521–8528; (g) Zhu, S.-F.; Pang, W.; Xing, C.-H.; Zhu, S.-Z. Chin. J. Chem.
2007, 25, 233–236.
(R)-2,2,2-Trifluoro-1-(2-naphthyl)ethanol (3n): 284.9 mg (42%
yield), >99% ee, white solid, mp 84.2–84.4 ꢁC (lit.5c mp 83–83.3 ꢁC).
Acknowledgements
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We are grateful to The National Natural Science Foundation of
China for financial support (Grant No. 20602007).
Supplementary data
Supplementary data includes synthetic procedures of the cata-
lyst, the racemic substrates, 1H MNR, 19F NMR spectra, and chiral
HPLC chromatograms. Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2009.01.058.
References and notes
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