Synthesis of optically active 4,4,4-trifluoro-3-{4-(4-methoxyphenyl)phenyl}butanoic acid and its application to chiral dopant for nematic liquid crystals

Article abstract of DOI:10.1016/j.jfluchem.2005.11.005

We synthesized an optically active 4,4,4-trifluoro-3-{4-(4-methoxyphenyl)phenyl}butanoic acid (5^*). New chiral dopants for nematic liquid crystals were derived from (R)-(-)-5^*, and their helical twisting power (HTP) values were measured. Their HTP values were largely influenced by the linkage between the asymmetric frame and the core moiety. The chiral dopant, (R)-(+)-4,4,4-trifluoro-1-(4-hexyloxyphenyl)-3-{4-(4-methoxyphenyl)phenyl}-1-butanone ((R)-(+)-7^*) showed the largest HTP value (-21.7 μm^-1).

Full text of DOI:10.1016/j.jfluchem.2005.11.005

Journal of Fluorine Chemistry 127 (2006) 620–626
www.elsevier.com/locate/fluor
Synthesis of optically active 4,4,4-trifluoro-3-{4-(4-methoxyphenyl)
phenyl}butanoic acid and its application to chiral dopant for
nematic liquid crystals
*
Kenta Tojo, Yoshio Aoki , Mikio Yasutake, Takuji Hirose
Department of Applied Chemistry, Faculty of Engineering, Saitama University, 255 Shimo-ohkubo,
Sakura-ku, Saitama 338-8570, Japan
Received 21 November 2005
Available online 7 February 2006
Abstract
We synthesized an optically active 4,4,4-trifluoro-3-{4-(4-methoxyphenyl)phenyl}butanoic acid (5*). New chiral dopants for nematic liquid
crystals were derived from (R)-(ꢀ)-5*, and their helical twisting power (HTP) values were measured. Their HTP values were largely influenced by
the linkage between the asymmetric frame and the core moiety. The chiral dopant, (R)-(+)-4,4,4-trifluoro-1-(4-hexyloxyphenyl)-3-{4-(4-
methoxyphenyl)phenyl}-1-butanone ((R)-(+)-7*) showed the largest HTP value (ꢀ21.7 mmꢀ1).
# 2005 Elsevier B.V. All rights reserved.
Keywords: Trifluoromethyl asymmetric frame; Chiral dopant; Helical twisting power; Nematic liquid crystals
1. Introduction
dopants [5a,b]. Recently, Hamakubo et al. reported a chiral
dopant with a helical chirality [6].
Chirality is one of the most interesting subjects in the field of
liquid crystals. Chiral nematic liquid crystals having macro
helical structure are currently used in liquid crystal display
(LCD) devices. Generally the chiral nematic materials consist
of achiral host mixtures of nematic liquid crystals, and a chiral
dopant with a large helical twisting power (HTP) [1]. The
helical structure of the chiral nematic liquid crystals is induced
by the interaction between the host liquid crystalline molecules
and the chiral dopants. Therefore, many optically active
compounds for application in nematic mixtures have been
synthesized. We have reported the HTP values of optically
active 3-phenylpropanoic acid derivatives [2]. On the other
hand, a noble compound derived from optically active tartaric
acid was reported as a chiral dopant, and its HTP value did not
have a temperature dependence [3]. Ferrarini et al. reported a
correlation between the molecular structure and helicity of
chiral atropisomers [4], and some optically active biphenyl or
binaphthyl derivatives were reported as atropisomeric chiral
A tilted smectic phase such as smectic C phase, made up of
optically active compounds shows ferroelectric properties, and
the liquid crystals are called ferroelectric liquid crystals (FLCs)
[7]. The microsecond response speeds of FLCs are very fast
compared with that of nematic liquid crystals. On the other
hand, noble liquid crystals showing antiferroelectric chiral
smectic phases have been reported [8]. Antiferroelectric liquid
crystal (AFLC) materials are expected to be applicable to high
speed display devices.
Fluorinated liquid crystal materials are very effective for
improving the physical properties of liquid crystals. Nematic
liquid crystalline materials with a fluoro or trifluoromethyloxy
group at the aromatic ring show low rotational viscosity and
appropriate dielectric anisotropy. In FLC materials, ortho
difluorophenyl structure is useful for generating the smectic C
phase [9]. In addition, the liquid crystalline materials with a
fluorine atom at the chiral center are useful for increasing the
spontaneous polarization of liquid crystals [10]. A trifluoro-
methyl asymmetric frame is effective for showing AFLC phase
[8,11]. We have reported the physical properties of optically
active 4,4,4-trifluoro-3-(4-methoxyphenyl)butanoic acid deriva-
tives,whichshowedinterestingmesophasessuchasAFLCphases
and the twist grain boundary (TGB) phase [12a–c].
* Corresponding author. Tel.: +81 48 858 9548; fax: +81 48 858 9548.
E-mail address: aoki@apc.saitama-u.ac.jp (Y. Aoki).
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.11.005

K. Tojo et al. / Journal of Fluorine Chemistry 127 (2006) 620–626
621
Fig. 2. Structure of new chiral dopants.
Fig. 1. Structure of TFPBA derivatives (12*–15*).
(R)-(ꢀ)-5* (Scheme 2), and did not show any mesophases.
Therefore, only their HTP values for nematic liquid crystals
were determined.
On the other hand, we have been investigating the
relationship between the existence of a polar group at the
chiral center and their HTP values for nematic liquid crystals.
We have reported the HTP values of optically active 4,4,4-
trifluoro-3-phenylbutanoic acid (TFPBA) derivatives (12*, 13*,
14*, 15*, Fig. 1) [13]. As a consequence, a trifluoromethyl
asymmetric frame was found to effectively increase the HTP
value of the chiral dopant. A trifluoromethyl group is a strong
polar group, so the electronic effect of a trifluoromethyl group
is probably effective for generating a large HTP value.
In the present paper, we report the synthesis and the HTP
evaluation of the new chiral dopants for nematic liquid crystals,
having a trifluoromethyl asymmetric frame and a biphenyl
structure at the chiral center, 4,4,4-trifluoro-3-{4-(4-methox-
yphenyl)phenyl}butanoic acid (5*) derivatives (6*, 7*, 10*, 11*,
Fig. 2).
The chiral nematic liquid crystalline mixtures were prepared
by adding chiral dopant (1 wt.%) to the host nematic liquid
crystal (ZLI-1132, Merck) [15]. The helical pitches in the chiral
nematic phases were measured using Cano wedge cells [16].
The HTP can be calculated by Eq. (1), where p is the pitch of the
chiral nematic phase in mm and c is the mass fraction of the
chiral dopant. In order to describe the HTP per molecule, we
have suggested the molar helical twisting power (MHTP), as
defined in Eq. (2), where Md is the molecular weight of the
chiral dopant [2]. In the present paper, we discuss the MHTP
values of the chiral dopants
HTP ðmmꢀ1Þ ¼ ð pcÞꢀ1
(1)
(2)
MHTP ðmmꢀ1 molꢀ1 kgÞ ¼ HTP Md ꢁ 10ꢀ3
2. Results and discussion
The helical senses of the chiral nematic phases were determined
by the contact method using the reference mixture prepared
from the host liquid crystal and cholesteryl nonanoate, which
has a helix with a minus sense (left-handed). The HTP, MHTP
values and helical senses of the new chiral dopants are sum-
marized in Table 1.
An optically active key intermediate 4,4,4-trifluoro-3-{4-(4-
methoxyphenyl)phenyl}butanoic acid (5*) was synthesized in
the usual manner (Scheme 1) [5]. An absolute configuration of
5* was decided through X-ray analysis of the diastereomeric
salt of (ꢀ)-5* and (1S, 2R)-(ꢀ)-2-(benzylaminocyclohexane)
methanol, and it was clarified that (ꢀ)-5* has (R)-configuration
[14]. All new chiral dopants (6*, 7*, 10*, 11*) were derived from
The order of absolute MHTP values in these chiral dopants
was 7* > 10* > 6* > 11*. In the case of the chiral dopants
Scheme 1. Synthesis of optically active 4,4,4-trifluoro-3-{4-(4-methoxyphenyl)phenyl}butanoic acid (5*): (a) CH3I, K2CO3, THF, CH3CN, 60 8C. (b) 1: Mg, dry
THF. 2: CF3COONa, 0 8C. (c) 1: NaH, dry THF. 2: 2, 60 8C. (d) H2, cat. Pt, EtOH, THF. (e) 1: KOHaq, 2: 1 M HClaq. (f) Optical resolution, (1R, 2S)-(ꢀ)-(2-
benzylaminocyclohexane) methanol.

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K. Tojo et al. / Journal of Fluorine Chemistry 127 (2006) 620–626
Scheme 2. Synthesis of new chiral dopants, 6*, 7*, 10*, 11*: (g) 4-hexyloxyphenol, DCC, DMAP, dry CHCl3. (h) 1: SOCl2, reflux. 2: hexyloxybenzene, AlCl3, dry
CS2, ꢀ20 8C. (i) LiAlH4, dry THF, reflux. (j) TsCl, DABCO, dry CH3CN. (k) 4-hexyloxyphenol, K2CO3, CH3CN, THF, 60 8C. (l) Et3SiH, CF3COOH.
derived from an optically active TFPBA, the order of the MHTP
values was the same as that of the 5* derivatives. On the other
hand, the PM3 calculations of (R)-6* and (R)-12* showed that
the conformation of (R)-6* was similar to that of (R)-12*
(Fig. 3). Therefore these results suggest that the conformations
of 5* derivatives and TFPBA derivatives are similar to each
other, and the order of MHTP values of 5* derivatives was the
same as that of the TFPBA derivatives.
Table 1
HTP and MHTP values of new chiral dopants, 6*, 7*, 10*, 11*
Linkage
HTPa
(mmꢀ1
MHTPb
(mmꢀ1 molꢀ1 kg)
)
6*
–COO–
–CO–
+8.3
ꢀ21.7
+14.3
+3.2
+4.2
ꢀ10.5
+6.9
7*
10*
11*
–CH2O–
–CH2–
+1.5
a
HTP (mmꢀ1) = ( pc)ꢀ1; p: helical pitch (mm), c: weight ratio of the chiral
dopant (c: 0.01).
b
MHTP (mmꢀ1 molꢀ1 kg) = HTP Mw ꢁ 10ꢀ3; Mw: molecular weight of the
chiral dopant, host L.C.: ZLI-1132 (Merck).
Fig. 3. PM3 models of (a) (R)-12* and (b) (R)-6*.

K. Tojo et al. / Journal of Fluorine Chemistry 127 (2006) 620–626
623
All of the new chiral dopants were derived from (R)-(ꢀ)-5*,
3.1.2. 1,1,1-Trifluoro-4-(4-methoxyphenyl)acetophenone
(2)
Under nitrogen, a dry THF solution of 4-(methoxyphenyl)-
and 6*, 10*, 11* induced a right-handed helical sense of the
chiral nematic phase. However, 7* induced the opposite helical
sense. Interestingly, only 7* showed plus optical rotation, while
other chiral dopants showed minus optical rotations.
The corresponding MHTP values of the new chiral dopants
(6*: +4.2 mmꢀ1 molꢀ1 kg, 7*: ꢀ10.5 mmꢀ1 molꢀ1 kg, 10*:
+6.9 mmꢀ1 molꢀ1 kg) were 20–45% larger than those of the
TFPBA derivatives (12*: 2.9 mmꢀ1 molꢀ1 kg, 13*: 7.9 mmꢀ1
molꢀ1 kg, 14*: 5.8 mmꢀ1 molꢀ1 kg). On the other hand, the
MHTP value of 11* (+1.5 mmꢀ1 molꢀ1 kg) was 29% smaller
than that of 15* (2.1 mmꢀ1 molꢀ1 kg). In most cases, a biphenyl
structure at the chiral center was found to increase the MHTP
value.
bromobenzene (22.0 g, 83.7 mmol) was slowly added to a
mixture of magnesium powder (2.13 g, 87.5 mmol) and dry
THF, and the reaction mixture was stirred for 4 h at 60 8C.
Under nitrogen, the mixture was slowly added to the dry THF
solution of 60% NaH (3.68 g, 92.1 mmol) and trifluoroacetic
acid at 0 8C. The mixture was then stirred for 36 h. Thereafter,
6 M hydrochloric acid was added. After evaporating the THF,
chloroform was added, and the phases were separated. The
aqueous phase was shaken with chloroform, and the combined
organic phases were washed with saturated aqueous sodium
hydrogen carbonate and brine. The organic phases were dried
over sodium sulphate. Removal of the solvent and purification
by reduced-pressure distillation yielded 7.41 g (26.5 mmol,
31.6%) of 2 as a light yellow solid; mp 107.2–108.0 8C; IR
(KBr): 2345, 1710, 1654, 1598, 1561, 1542, 1526, 1498, 1178,
1089, 1063; 1H NMR (200 MHz, CDCl3): d = 8.12 (d,
J = 8.8 Hz, 2H, aromatic), 7.72 (d, J = 8.8 Hz, 2H, aromatic),
7.60 (d, J = 8,8 Hz, 2H, aromatic), 7.20 (d, J = 8.8 Hz, 2H,
aromatic), 3.87 (s, 3H, OCH3); MS (EI): m/z = 278 [M+].
We synthesized new chiral dopants having a trifluoromethyl
group and a biphenyl group at the chiral center. New chiral
dopants showed relatively large HTP values. It is suggested that
a trifluoromethyl and a biphenyl asymmetric frame is useful for
increasing HTP value for nematic liquid crystals.
3. Experimental
3.1. General
3.1.3. Ethyl 4,4,4-trifluoro-3-{4-(4-
methoxyphenyl)phenyl}but-2-enoate (3)
All compounds were characterized by 1H NMR (Bruker AC-
300P or AC-200), IR (JASCO FT/IR-460), and MS (JEOL DX-
303). Their specific rotations, i.e. [a]D values were determined
using a JASCO DIP-370. The purities of the products were
measured by gas chromatography or high performance liquid
chromatography (HPLC). Optical purities were also deter-
mined by an HPLC system equipped with a chiral column
(Dicel AD-H). The X-ray crystal structure analysis was
performed using a Bruker SMART APEX diffractmeter.
Under nitrogen, a dry THF solution of ethyl diethylpho-
sphonoacetate (13.0 g, 58.0 mmol) was slowly added to a dry
THF solution of 60% NaH (2.32 g, 58.0 mmol) at 0 8C, and the
mixture was stirred for 3 h at room temperature. A dry THF
solution of 1,1,1-trifluoro-4-(4-methoxyphenyl)acetophenone
(14.8 g, 52.7 mmol) was added, and the mixture was stirred for
15 h at 60 8C. The mother liquor was decanted from the
precipitate. The precipitate was washed well by mixing it at
60 8C with several 25 ml portions of THF and decanting at
room temperature. After evaporating the solvent, 6 M hydro-
chloric acid and toluene were added and stirred for few minutes.
The phases were separated, and the aqueous phase was shaken
with toluene. The combined organic phases were washed with
saturated aqueous sodium hydrogen carbonate and brine. The
organic phase was dried over sodium sulphate. Removal of the
solvent and purification by reduced-pressure distillation yielded
18.0 g (51.4 mmol, 97.5%) of 3 as a light yellow liquid; IR
(neat): 2986, 2838, 1730, 1659, 1608, 1580, 1525, 1499, 1465,
3.1.1. 4-(4-Methoxyphenyl)bromobenzene (1)
Potassium carbonate (41.4 g, 150 mmol) was added to a
solution of 4-(4-hydroxyphenyl)bromobenzene (25 g,
100 mmol), THF (80 ml) and acetonitrile (20 ml), and the
reaction mixture was stirred for 20 min at room temperature.
Then iodomethane (21.3 g, 150 mmol) was added to the
reaction mixture, and the mixture was stirred for 3 days at
60 8C. After evaporating the THF and acetonitrile, chloroform
was added, and potassium carbonate was filtrated off.
Hydrochloric acid (6 M) was added to the solution, and the
phases were separated. The aqueous phase was shaken with
chloroform, and the combined organic phases were washed
with saturated aqueous sodium hydrogen carbonate and brine.
The organic phases were dried over sodium sulphate. Removal
of the solvent and purification by recrystallization from
toluene (100 ml) and hexane (100 ml) yielded 22.0 g
(83.7 mmol, 83.7%) of 1 as a colorless needles: mp 143.5–
143.8 8C; IR (KBr): 1604, 1523, 1482, 1289, 1255, 1199, 1179,
1079, 1037, 1010, 811; 1H NMR (200 MHz, CDCl3): d = 7.54
(d, J = 8.8 Hz, 2H, aromatic), 7.49 (d, J = 8.8 Hz, 2H,
aromatic), 7.40 (d, J = 8.3 Hz, 2H, aromatic), 6.98 (d,
J = 8.8 Hz, 2H, aromatic), 3.85 (s, 3H, OCH3); MS (EI): m/
z = 262 [M+].
1
1374, 1285, 1255, 1180, 1133, 1025, 824, 757, 664; H NMR
(200 MHz, CDCl3): 7.58 (d, J = 6.3 Hz, 2H, aromatic), 7.55 (d,
J = 6.3 Hz, 2H, aromatic), 7.34 (d, J = 8.3 Hz, 2H, aromatic),
6.98 (d, J = 8.3 Hz, aromatic), 6.62 (d, J = 1.5 Hz, C CH), 4.08
(q, J = 7.3 Hz, 2H, OCH2), 3.86 (s, 3H, OCH3), 1.09 (t,
J = 7.3 Hz, 3H, CH3); MS (EI): m/z = 350 [M+].
3.1.4. Ethyl 4,4,4-trifluoro-3-{4-(4-
methoxyphenyl)phenyl}butanoate (4)
Under hydrogen, ethyl 4,4,4-trifluoro-3-{4-(4-methoxyphe-
nyl)phenyl}but-2-enoate (19.5 g, 55.6 mmol), platinum black
(1.45 g), 16 ml of 95% ethanol, and 25 ml of THF were stirred
for 18 h at room temperature. The platinum black was filtered
off, followed by removal of the solvent, which yielded 19.1 g

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K. Tojo et al. / Journal of Fluorine Chemistry 127 (2006) 620–626
(54.3 mmol, 97.7%) of 4 as a white solid; mp 103.1–103.6 8C;
IR (KBr): 2694, 1730, 1606, 1501, 1383, 1333, 1272, 1205,
toluene, and the combined organic phases were washed with
sodium hydrogen carbonate and brine, and dried over sodium
sulphate. Removal of the solvent and purification by
preparative thin-layer chromatography (TLC) yielded (+)-4*
quantitatively.
The optical purity of (+)-4* was determined using HPLC with
a chiral column, ‘CHIRALCEL AD-H’ (4.6 mm ꢁ 250 mm,
carrier solvent hexane: 2-propanol = 15:85); the optical purity of
(+)-4* was 99% ee.
1
1159, 1112, 1037, 829, 807; H NMR (300 MHz, CDCl3):
d = 7.54 (d, J = 5.9 Hz, 2H, aromatic), 7.51 (d, J = 6.6 Hz, 2H,
aromatic), 7.37 (d, J = 8.1 Hz, 2H, aromatic), 6.97 (d,
J = 8.8 Hz, 2H, aromatic), 4.14–4.01 (m, 2H, OCH2), 3.99–
3.89 (m, 1H, C*H), 3.85 (s, 3H, OCH3), 3.08–3.01 (m, 1H,
C*CH2), 2.95–2.87 (m, 1H, C*CH2), 1.15 (t, J = 7.2 Hz, 3H,
CH3); MS (EI): m/z = 352 [M+].
3.1.5. 4,4,4-Trifluoro-3-{4-(4-
methoxyphenyl)phenyl}butanoic acid (5)
3.1.8. (R)-(ꢀ)-4-Hexyloxyphenyl 4,4,4-trifluoro-3-4-{4-(4-
methoxyphenyl)phenyl}butanoate (6*)
An aqueous solution of 85% potassium hydroxide (10.8 g,
162 mmol) was poured into a mixture of ethyl 4,4,4-trifluoro-3-
{4-(4-methoxyphenyl)phenyl}butanoate (19.0 g, 54.3 mmol),
20 ml of 95% ethanol, and 100 ml of THF. This mixture was
stirred for 2 h at room temperature. After evaporating the
ethanol, ether and 6 M hydrochloric acid were added, and the
phases were separated. The aqueous phase was shaken with
ether, and the combined organic phases were dried over sodium
sulphate. Removal of the solvent yielded 17.3 g (53.3 mmol,
98.3%) of 5 as a white solid; mp 178.2–179.1 8C; IR (KBr):
Under nitrogen, 4-N,N-dimethylaminopyridine (34 mg,
0.28 mmol) was added to the mixture of (R)-(ꢀ)-4,4,4-
trifluoro-3-{4-(4-methoxyphenyl)phenyl}butanoic acid (36
mg, 0.19 mmol) and 4-hexyloxyphenol (60 mg, 0.19 mmol)
and dry chloroform (3 ml), and the mixture was stirred for
10 min at room temperature. A dry chloroform solution (1 ml)
of N,N0-dicyclohexylcarbodiimide (38 mg, 0.19 mmol) was
added, and the reaction mixture was stirred for 10 h at room
temperature. After toluene was added the resulting mixture
was filtered. Hydrochloric acid (1 M) was then added to the
filtrate, and the phases were separated. The organic phase was
washed with saturated sodium hydrogen carbonate and brine
and dried over sodium sulphate. Removal of the solvent and
purification by preparative TLC yielded 75 mg (0.15 mmol,
81.1%) of (R)-(ꢀ)-6* as a white solid; mp 89.1–89.4 8C; IR
(KBr): 2938, 1748, 1610, 1507, 1379, 1275, 1249, 1189, 1152,
1
2960, 2367, 1716, 1500, 1429, 1254, 1170, 1112; H NMR
(300 MHz, DMSO-d6): d = 7.63 (d, J = 1.8 Hz, 2H, aromatic),
7.60 (d, J = 2.2 Hz, 2H, aromatic), 7.49 (d, J = 8.1 Hz, 2H,
aromatic), 7.03 (d, J = 8.8 Hz, 2H, aromatic), 4.13–3.97 (m,
1H, C*H), 3.79 (s, 3H, OCH3), 3.39 (br, 1H, OH), 3.07–2.96 (m,
2H, CH2); MS (EI): m/z = 324 [M+]; anal. calcd for
C17H15F3O3: C, 63.96; H, 4.66. Found: C, 62.89; H, 4.52.
1
1112, 1034, 1028, 965, 822; H NMR (300 MHz, CDCl3):
d = 7.56 (d, J = 8.5 Hz, 2H, aromatic), 7.52 (d, J = 8.5 Hz, 2H,
aromatic), 7.41 (d, J = 8.1 Hz, 2H, aromatic), 6.97 (d,
J = 8.5 Hz, 2H, aromatic), 6.79 (d, J = 9.6 Hz, 2H, aromatic),
6.74 (d, J = 9.2 Hz, 2H, aromatic), 3.99–4.0 (m, 1H, C*H),
3.86 (t, J = 6.6 Hz, 2H, OCH2), 3.81 (s, 3H, OCH3), 3.30–3.08
(m, 2H, C*CH2), 1.72 (quin, J = 6.6 Hz, 2H, OCCH2), 1.38–
1.41 (m, 2H, CH2), 1.32–1.27 (m, 4H, CH2), 0.88 (t,
J = 6.6 Hz, 3H, CH3); MS (EI): m/z = 500 [M+];
[a]D ꢀ 1048 (C 0.924, CHCl3); anal. calcd for C29H31F3O4:
C, 69.59; H, 6.24. Found: C, 69.29; H, 6.21.
3.1.6. Optically active 4,4,4-trifluoro-3-{4-(4-
methoxyphenyl)phenyl}butanoic acid (5*)
Racemic 4,4,4-trifluoro-3-{4-(4-methoxyphenyl)phenyl}-
butanoic acid (3.00 g, 9.26 mmol) and (1R, 2S)-(+)-2-
benzylaminocyclohexane methanol (2.03 g, 9.26 mmol) were
dissolved in 95% ethanol (100 ml) with heating. After cooling
to room temperature, the resulting, insoluble diastereomeric
salt was filtered off and recrystallized three times. Optically
active (+)-5* was liberated by adding 1 M hydrochloric acid.
After (+)-5* was extracted into ether, and the aqueous phase
was shaken with ether, and the combined organic phases were
dried over sodium sulphate. Removal of the solvent yielded
574 mg (1.77 mmol) of (+)-5* as a white solid; mp 182.1–
182.2 8C; [a]D + 48.28 (C 1.01, 95% EtOH). The (ꢀ)-5* was
obtained in a similar manner by using (1S, 2R)-(ꢀ)-2-
benzylaminocyclohexane methanol; mp 182.2–183.0 8C,
[a]D ꢀ 48.78 (95% EtOH, C 1.00).
3.1.9. (R)-(+)-4,4,4-Trifluoro-1-(4-hexyloxyphenyl)-3-{4-
(4-methoxyphenyl)phenyl}-1-butanone (7*)
Under nitrogen, thionyl chloride (4 ml) was added to (R)-(ꢀ)-
4,4,4-trifluoro-3-{4-(4-methoxyphenyl)phenyl} butanoic acid
(134 mg, 0.413 mmol), and heated under reflux for 3 h. After
the removal of thionyl chloride, dry carbon disulfide (1 ml) was
poured into the residue, and the dry carbon disulfide (1 ml)
solution of hexyloxybenzene (219 mg, 1.24 mmol) was added to
the mixture. Aluminum chloride (220 mg, 1.64 mmol) was then
added to the mixture at ꢀ20 8C, and stirred for 4 h at room
temperature. Then, 6 M hydrochloric acid and ether were added
to the reaction mixture, and the phases were separated. The
organic phase was washed with brine and dried over sodium
sulphate. Removal of the solvent and purification by preparative
TLC yielded 69 mg (0.14 mmol, 34.5%) of (R)-(+)-7* as a white
solid;mp 84.8–85.5 8C; IR (KBr):2935, 1677, 1602, 1501, 1307,
3.1.7. Ethyl 4,4,4-trifluoro-3-{4-(4-
methoxyphenyl)phenyl}butanoate (4*)
In order to determine the optical purity of (+)-5*, their ethyl
esters (4*) were prepared from (+)-5*.
Under nitrogen, (+)-5* (24 mg, 0.074 mmol) and phosphoryl
chloride (34 mg, 0.22 mmol) were dissolved in 99% ethanol
(2 ml), and the mixture was boiled for 2 h. After cooling to
room temperature, water and toluene were added, and the
phases were separated. The aqueous phase was washed with
1
1249, 1164, 1104, 838, 814; H NMR (300 MHz, CDCl3):

K. Tojo et al. / Journal of Fluorine Chemistry 127 (2006) 620–626
625
d = 7.90 (d, J = 9.2 Hz, 2H, aromatic), 7.51–7.41 (m, 6H,
3.1.12. (R)-(ꢀ)-[4-{3-(4-Hexyloxyphenyloxy)-1-
aromatic), 6.94 (d, J = 8.8 Hz, 2H, aromatic), 6.90 (d, J = 9.2 Hz,
2H, aromatic), 4.31–4.23 (m, 1H, C*H), 3.99 (t, J = 6.6 Hz, 2H,
OCH2), 3.81 (s, 3H, OCH3), 3.74–3.50 (m, 2H, C*CH2), 1.78
(quin, J = 6.6 Hz, 2H, OCCH2), 1.48–1.32 (m, 6H, CH2), 0.90 (t,
J = 7.0 Hz, 3H, CH3); MS (EI): m/z = 484 [M+]; [a]D + 828 (C
0.55, CHCl3); anal. calcd for C29H31F3O3: C, 71.88; H, 6.45.
Found: C, 71.1; H, 6.34.
trifluoromthylpropyl}phenyl]-4-methoxybenzene (10*)
Under nitrogen, potassium carbonate (330 mg, 2.39 mmol)
was added to a mixture of 4-hexyloxyphenol, acetonitrile (2 ml)
and THF (2 ml) and was then stirred for 5 min at room
temperature. The THF (2 ml) solution of (R)-(ꢀ)-4,4,4-
trifluoro-3-{4-(4-methoxyphenyl)phenyl}buthyl tosylate (113
mg, 0.244 mmol) was poured into the reaction mixture and was
stirred for 2 days at 60 8C. After cooling to room temperature,
toluene and 1 M hydrochloric acid were added, and the phases
were separated. The aqueous phase was shaken with ether, and
the combined organic phases were washed with saturated
sodium hydrogen carbonate and brine and dried over sodium
sulphate. Removal of the solvent and purification by
preparative TLC yielded 93 mg (0.191 mmol, 78.2%) of (R)-
(ꢀ)-10* as a light yellow solid; mp 58.3–59.1 8C; IR (KBr):
2925, 2855, 1603, 1509, 1477, 1232, 1159, 1114, 1066, 1039,
821; 1H NMR (300 MHz, CDCl3): d = 7.53 (d, J = 3.3 Hz, 2H,
aromatic), 7.50 (d, J = 3.7 Hz, 2H, aromatic), 7.34 (d, J = 8.07,
2H, aromatic), 6.97 (d, J = 8.8 Hz, 2H, aromatic), 6.77 (d,
J = 7.0 Hz, 4H, aromatic), 3.92–3.87 (m, 2H, OCH2), 3.84 (s,
3H, OCH3), 3.76–3.64 (m, 3H, C*H, OCH2), 2.60–2.50 (m, 1H,
C*CH2), 2.28–2.16 (m, 1H, C*CH2), 1.74 (quin, J = 7.0 Hz, 2H,
OCCH2), 1.46–1.31 (m, 6H, CH2), 0.89 (t, J = 5.3 Hz, CH3);
MS (EI): m/z = 486 [M+]; [a]D ꢀ 1278 (C 1.00, CHCl3); anal.
calcd for C29H33F3O3: C, 71.59; H, 6.84. Found: C, 71.28; H,
6.97.
3.1.10. (R)-(ꢀ)-4,4,4-Trifluoro-3-{4-(4-
methoxyphenyl)phenyl}butanol (8*)
Under nitrogen, (R)-(ꢀ)-4,4,4-trifluoro-3-{4-(4-methoxy-
phenyl)phenyl}butanoic acid (130 mg, 0.40 mmol) dissolved
in dry THF (1 ml) was added to the mixture of lithium
aluminum hydride (30 mg, 0.80 mmol) and dry THF (2 ml),
and was heated under reflux for 12 h. After cooling to room
temperature, 1 M hydrochloric acid and ether were added, and
the phases were separated. The aqueous phase was shaken with
ether, and combined organic phases were washed with saturated
sodium hydrogen carbonate and brine and dried over sodium
sulphate. Removal of the solvent and purification by
preparative TLC yielded 100 mg (0.32 mmol, 80.6%) of (R)-
(ꢀ)-8* as a white solid; mp 119.0–119.5 8C; IR (KBr): 3400,
2956, 1606, 1500, 1321, 1275, 1255, 1117, 1037, 812; 1H NMR
(300 MHz, CDCl3): d = 7.54 (d, J = 6.2 Hz, 2H, aromatic), 7.52
(d, J = 7.0 Hz, 2H, aromatic), 7.34 (d, J = 8.1 Hz, 2H,
aromatic), 6.98 (d, J = 8.8 Hz, 2H, aromatic), 3.85 (s, 3H,
OCH3), 3.77–3.55 (m, 2H, CH2O), 3.42–3.51 (m, 1H, C*H),
2.03–2.37 (m, 2H, C*CH2), 1.30 (br, 1H, OH); MS (EI): m/
z = 310 [M+]; [a]D ꢀ 52.78 (C 1.02, CHCl3).
3.1.13. (R)-(ꢀ)-1,1,1,-Trifluoro-2-{4-(4-
methoxyphenyl)phenyl}-4-(4-hexyloxyphenyl)butane (11*)
Under nitrogen, a trifluoroacetic acid (1 ml) solution of
triethylsilane (22 mg, 0.19 mmol) was poured into a mixture of
(R)-(+)-4,4,4-trifluoro-1-(4-hexyloxyphenyl)-3-{4-(4-methox-
yphenyl)phenyl}-1-butanone (30 mg, 0.062 mol) and trifluor-
oacetic acid (1 ml) and was stirred for 5 h at room temperature.
After adjusting the pH to approximately 11 through the addition
of 1 M sodium hydroxide, ether was added to the mixture, and
the phases were separated. The aqueous phase was shaken with
ether, and the combined organic phases were washed with brine
and dried over sodium sulphate. Removal of the solvent and
purification by preparative TLC yielded 28 mg (0.060 mmol,
96.1%) of (R)-(ꢀ)-11* as a colorless liquid; IR (KBr): 2933,
3.1.11. (R)-(ꢀ)-4,4,4-Trifluoro-3-{4-(4-
methoxyphenyl)phenyl}buthyl tosylate (9*)
Under nitrogen, 1,4-diazabicyclo[2.2.2]octane (106 mg,
0.948 mmol) dissolved in dry acetonitrile (2 ml) was poured
into a mixture of (R)-(ꢀ)-4,4,4-trifluoro-3-{4-(4-methoxyphe-
nyl)phenyl}butanol (98 mg, 0.32 mmol) and dry acetonitrile
(1 ml) at room temperature, and a dry acetonitrile solution
(2 ml) of tosyl chloride (89 mg, 0.47 mmol) was then added to
the reaction mixture, followed by stirring for 12 h. Ether and
1 M hydrochloric acid were added, and the phases were
separated. The aqueous phase was shaken with ether, and the
combined organic phases were washed with saturated sodium
hydrogen carbonate and brine and dried over sodium sulphate.
Removal of the solvent and purification by preparative TLC
yielded 113 mg (0.244 mmol, 77.2%) of (R)-(ꢀ)-9* as a white
solid; mp 134.4–135.1 8C; IR (KBr): 2962, 2366, 2345, 1604,
1500, 1361, 1253, 1175, 1110, 976, 815, 557; 1H NMR
(300 MHz, CDCl3): d = 7.67 (d, J = 8.1 Hz, 2H, aromatic), 7.48
(d, J = 8.8 Hz, 2H, aromatic), 7.45 (d, J = 8.1 Hz, 2H,
aromatic), 7.25 (d, J = 8.5 Hz, 2H, aromatic), 7.18 (d,
J = 8.1 Hz, 2H aromatic), 6.97 (d, J = 8.5 Hz, 2H, aromatic),
4.08 (dt, J1 = 9.5 Hz, J2 = 4.8 Hz, 1H, C*H), 3.82 (s, 3H,
OCH3), 3.78–3.69 (m, 1H, CH2O), 3.99–3.50 (m, 1H, CH2O),
2.48–2.37 (m, 1H, C*CH2), 2.34 (s, 3H, Ar–CH3), 2.17–2.05
(m, 1H, C*CH2); MS (EI): m/z = 464 [M+]; [a]D ꢀ 49.48 (C
1.00, CHCl3).
1
1611, 1512, 1463, 1248, 1177, 1154, 1111, 820; H NMR
(300 MHz, CDCl3): d = 7.57–7.52 (m, 4H, aromatic), 7.32 (d,
J = 8.1 Hz, 2H, aromatic), 7.01–6.96 (m, 4H, aromatic), 6.81
(d, J = 8.5 Hz, 2H, aromatic), 3.92 (t, J = 6.6 Hz, 2H, OCH2),
3.85 (s, 3H, OCH3), 3.30–3.15 (m, 1H, C*H), 2.61–2.17 (m, 4H,
C*CH2, C*CCH2), 1.77 (quin, J = 7.0 Hz, 2H, OCCH2), 1.45–
1.30 (m, 6H, CH2), 0.90 (t, J = 5.1 Hz, 3H, CH3); MS (EI): m/
z = 470 [M+]; [a]D ꢀ 508 (C 0.29, CHCl3); anal. calcd for
C29H33F3O2: C, 74.02; H, 7.07. Found: C, 73.97; H, 7.15.
Acknowledgements
The present study was supported in part by a Grant-in-Aid
for Scientific Research (No. 16750154) from the Ministry of
Education, Culture, Sports, Science and Technology.

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K. Tojo et al. / Journal of Fluorine Chemistry 127 (2006) 620–626
[10] Y. Nagashima, T. Ichihashi, K. Noguchi, M. Iwamoto, Y. Aoki, H. Nohira,
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