Stereoselective synthesis and physicochemical properties of liquid-crystal compounds possessing a trans-2,5-disubstituted tetrahydropyran ring with negative dielectric anisotropy

Article abstract of DOI:10.1002/chem.201405495

Three stereoselective syntheses and the physicochemical properties of trans,trans-5-(4-ethoxy-2,3-difluoro-phenyl)-2-(4-propylcyclohexyl)tetrahydropyran, which is an important liquid-crystal compound with a large negative dielectric anisotropy (Δε = -7.3), are described. The key step in the construction of the trans-2,5-disubstituted tetrahydropyran ring in the first approach involved a benzylic cation mediated intramolecular olefin cyclization of a 2-allyloxy-1-arylethanol derivative. The second method included the Et₂Zn-induced 1,2-aryl shift of a bromohydrin obtained from a hetero-Diels-Alder reaction, followed by stereoselective bromination. The third approach utilized the hetero-Diels-Alder reaction of trans-4-propylcyclohexanecarboxaldehyde and a 2-aryl-3-(trimethylsilyl)oxy-1,3-butadiene, followed by stereoselective protonation. From results obtained by using a quantum chemical calculation method, the reason why the target compound shows a large negative Δε value is discussed.

Full text of DOI:10.1002/chem.201405495

DOI: 10.1002/chem.201405495
Full Paper
&
Synthesis Design
Stereoselective Synthesis and Physicochemical Properties of
Liquid-Crystal Compounds Possessing a trans-2,5-Disubstituted
Tetrahydropyran Ring with Negative Dielectric Anisotropy
Keisuke Araki,[a] Tetsuya Yamamoto,[a] Ryoji Tanaka,[a] Saori Tanaka,[a] Makoto Ushioda,[b]
Yasuyuki Gotoh,*[c] Tetsu Yamakawa,*[a] and Munenori Inoue*[a]
Abstract: Three stereoselective syntheses and the physico-
chemical properties of trans,trans-5-(4-ethoxy-2,3-difluoro-
phenyl)-2-(4-propylcyclohexyl)tetrahydropyran, which is an
important liquid-crystal compound with a large negative
dielectric anisotropy (De=ꢀ7.3), are described. The key step
in the construction of the trans-2,5-disubstituted tetrahydro-
pyran ring in the first approach involved a benzylic cation
mediated intramolecular olefin cyclization of a 2-allyloxy-1-
arylethanol derivative. The second method included the
Et2Zn-induced 1,2-aryl shift of a bromohydrin obtained from
a hetero-Diels–Alder reaction, followed by stereoselective
bromination. The third approach utilized the hetero-Diels–
Alder reaction of trans-4-propylcyclohexanecarboxaldehyde
and a 2-aryl-3-(trimethylsilyl)oxy-1,3-butadiene, followed by
stereoselective protonation. From results obtained by using
a quantum chemical calculation method, the reason why the
target compound shows a large negative De value is
discussed.
Introduction
MVA modes require LC compounds with negative De values,
efforts have been focused on the development of negative De-
type LC compounds through the introduction of electron-
withdrawing groups, especially fluorine atoms, at the lateral
position on the core structure, such as phenyl, naphthyl, and
cyclohexyl rings.[4] After intensive investigations in the pursuit
of further large negative De-type LC compounds, Goto et al.
recently reported the first examples of negative De-type LC
compounds with a tetrahydropyran ring, such as trans,trans-5-
(4-ethoxy-2,3-difluorophenyl)-2-(4-propylcyclohexyl)tetrahydro-
pyran (1).[5] Compared with its structurally related compounds,
1-aryl-4-cyclohexylcyclohexane derivative 2 (De=ꢀ5.4) and
In the last two decades, liquid-crystal displays (LCDs) have re-
placed cathode ray tube monitors and have been playing
a central role in flat panels for TVs, PC monitors, cell phones,
and tablet computers. This dramatic advancement is due to
the development of active matrix technology, in which each
pixel is separately controlled by a thin-film transistor. With this
advancement, in-plane switching (IPS)[1] and multidomain verti-
cally aligned (MVA)[2] modes for LCDs have been developed to
meet demands such as wide-angle views, fast switching times,
and low power consumption. In these modes, fluorinated
liquid-crystal (LC) compounds possessing broad nematic
ranges, large dielectric anisotropy values (De), and low ion sol-
vation abilities have been widely used.[3] Because both IPS and
2-aryl-5-cyclohexyltetrahydropyran derivative
3
(De=ꢀ3.8),
compound 1 exhibited a large negative dielectric anisotropy
value (De=ꢀ7.3). This result indicated that the 5-aryl-2-cyclo-
hexyltetrahydropyran structure in 1 was essential for a large
negative De value, and was considered to be due to almost
parallel dipole moments of its tetrahydropyran and benzene
rings calculated for the most stable conformation.
[a] Dr. K. Araki,+ Dr. T. Yamamoto,+ Dr. R. Tanaka, S. Tanaka,++
Dr. T. Yamakawa, Dr. M. Inoue
Sagami Chemical Research Institute (SCRI), 2743-1 Hayakawa
Ayase, Kanagawa 252-1193 (Japan)
E-mail: t_yamakawa@sagami.or.jp
inoue@sagami.or.jp
[b] M. Ushioda
JNC Petrochemical Corporation, 5-1, Goi Kaigan
Ichihara, Chiba 290-8551 (Japan)
[c] Dr. Y. Gotoh
JNC Corporation, Shin-Otemachi Bldg.
2-1 Otemachi 2-Chome Chiyoda-ku, Tokyo 100-8105 (Japan)
E-mail: y.gotoh@jnc-corp.co.jp
[+] These authors contributed equally to this work.
Previously, the synthesis of 1 was achieved through the ring
opening of oxetane 4 with lithium enolate, which was derived
from ester 5 with lithium diisopropylamide (LDA), followed by
[
++] Undergraduate student from Department of Chemistry, Kitasato University.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405495.
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Scheme 1. Previous synthesis of 1 by Goto et al. DIBAL=diisobutylaluminum
hydride.
acid-induced lactonization and reduction of the resulting lac-
tone 6 in two steps, as shown in Scheme 1.[5] The drawback of
this method is the difficulty in controlling the stereochemistry
of the 2,5-disubstitued tetrahydropyran ring of 1. The low total
yield (10% in 4 steps) is due to the formation of an undesired
cis isomer, which must be removed by repeated recrystalliz-
ation.
Scheme 2. Synthetic strategies I and II for the preparation of 1.
TMS=trimethylsilyl.
Many natural products that incorporate tetrahydropyran
rings have been isolated and synthesized in a stereoselective
manner[6] and most of them are 2,6-disubstituted tetrahydro-
pyrans. In terms of the stereoselective synthesis of 2,5-disubsti-
tuted tetrahydropyran derivatives, several methods of using
cationic cyclization, C-glycosylation, and silane reduction of
acetals have been disclosed so far,[7,8] but their stereoselectivity
was not as high. Therefore, to facilitate access to the important
LC compound 1, and develop a method for the stereoselective
construction of trans-2,5-disubstituted pyrans, we initiated
a project toward the stereoselective synthesis of 1. In addition,
we attempted to clarify the influence of the position of oxygen
in the tetrahydropyran ring on its physicochemical properties
by using quantum chemical calculations. Herein, we would
disclose three different stereoselective approaches toward the
synthesis of 1 and its unique physical features as a LC
compound.
by bromination of the resulting cycloadduct 12 from the
kinetically favorable b face, would stereoselectively produce
tetrahydropyrone 11. After installing the aryl substituent
in an inversion manner, target compound
1 would be
produced by removing the carbonyl group in ketone 10 by
Wolff–Kishner reduction.
To realize synthetic strategy I, we initially focused on Prins
cyclization. Our synthesis commenced from 1,3-butadiene
monoxide (14), which was subjected to epoxide ring opening
with Grignard reagent 4-ethoxy-2,3-difluorophenylmagenesium
bromide (15) to produce the desired homoallyl alcohol 7 in
22% yield (Scheme 3).[13] To evaluate the key Prins reaction, we
next pursued cyclization between 7 and commercially available
cyclohexanecarboxaldehyde 8 by following a literature proce-
dure.[14] Unfortunately, exposure of 7 and 8 to a mixture of
[Fe(acac)3] and TMSCl did not give desired tetrahydropyran 18,
but instead a mixture of unexpected tetrahydrofuran deriva-
tives 16 and 17 in a total yield of 90% were obtained; the
stereochemistry was not elucidated. These compounds were
probably produced through 2-oxonia Cope rearrangement of
intermediate I (Scheme 2) followed by 5-exo-trig cyclization of
the resulting oxonium cation or Wagner–Meerwein ring con-
traction of the tetrahydropyran ring after Prins cyclization of
I.[15] Further investigation into the Prins reaction with other
Lewis acids was carried out in vain.
Results and Discussion
Synthesis
Because the key structural feature of target compound 1 is
a trans-2,5-disubstituted tetrahydropyran ring, our major task
was to elaborate the tetrahydropyran ring with the correct
stereochemistry. To achieve this task, we initially envisaged two
different synthetic strategies (Scheme 2): 1) a carbocation-
mediated cyclization strategy (strategy I), and 2) a hetero-
Diels–Alder/arylation strategy (strategy II). In strategy I, we
regarded Prins cyclization[8,9] and benzylic cation cyclization[10]
as promising synthetic routes to form the tetrahydropyran ring
in a stereocontrolled manner because the expected cationic
cyclizations would proceed through rigid chair-form
transition states by placing two substituents at the equatorial
positions, resulting in the formation of the desired trans
isomer. In strategy II, we envisioned that a hetero-Diels–Alder
reaction between aldehyde 8 and siloxydiene 13,[11,12] followed
Because of the inefficiency of the preparation of alcohol 7
and poor results of the key Prins reaction, we reconsidered
synthetic strategy I and decided to carry out the benzylic
cation mediated cyclization. First, we initiated the preparation
of benzyl alcohol 9, which was the precursor of the key benzyl-
ic cation cyclization, from aldehyde 8 (Scheme 4). To this end,
aldehyde 8 was allowed to react with vinylmagnesium chloride
to give allyl alcohol 19 in 92% yield, which was then etherified
with bromoacetaldehyde diethyl acetal in the presence of NaH
as a base in dioxane at 1008C to produce diethylacetal 20 in
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(Table 1, entries 7–10). Each reaction produced tetrahydropyr-
ans 22 in good yield and the best result was given by the
treatment of 9 with MeSO3H in CH2Cl2 at ꢀ788C to RT for 21 h;
this gave the desired tetrahydropyran 22 f in 90% yield. All
cyclizations proceeded with high stereoselectivity. The relative
configuration of each product (22a–22h) was determined by
1H NMR spectroscopy and the whole structure of 22 f was fully
confirmed by single-crystal X-ray structural analysis (see the
Supporting Information). As expected, cyclization proceeded
via transition-state II (Scheme 2), in which two substituents
were located at the equatorial positions, and the resulting car-
bocation was trapped by the corresponding counteranion of
the acid to produce the desired trans isomer.
Scheme 3. Attempted Prins cyclization of homoallyl alcohol 7 and aldehyde
8. (acac=acetylacetonate)
Finally, mesylate 22 f was reduced with NaBH4 in 1,3-
dimethyl-2-imidazolidinone (DMI; Scheme 5) to give rise to the
desired product 1 in 75% yield (6 steps, 40% total yield from
8). All spectral data (1H, 13C, and 19F NMR spectroscopy, IR
spectroscopy; and MS) of 1 were identified with those of the
authentic sample.
According to the second synthetic plan (strategy II,
Scheme 2), another method to synthesize 1 began with the
hetero-Diels–Alder reaction of cyclohexanecarboxaldehyde 8
and siloxydiene 13.[11] As shown in Scheme 6, a mixture of 8
and 13 in toluene was treated with Me2AlCl at ꢀ788C to
produce dihydropyran 12, which was then treated in situ with
NBS to provide bromide 11 in 80% yield almost entirely as the
Scheme 4. Synthesis of alcohol 9.
89% yield. Although we attempted a one-pot vinylation–ether-
ification procedure (aldehyde 8, vinylmagnesium chloride in
THF; BrCH2CH(OEt)2), unfortunately this sequence resulted in
a low yield. Next, exposure of the resulting diethylacetal 20 to
1m HCl led to the formation of aldehyde 21 (92%), which was
treated with Grignard reagent 15 to produce the desired
alcohol 9 in 79% yield.
Scheme 5. Completion of the synthesis of 1.
Having obtained the desired
alcohol 9, we turned our
attention to constructing the tet-
Table 1. Benzylic cation mediated cyclization of 9 with several acids.
rahydropyran ring through the
key benzylic cation mediated
cyclization of 9.[10] We employed
several Lewis and Brønsted acids
for the cyclization and the re-
sults are shown in Table 1. Al-
though initial attempts with
TiCl4, ZnBr2, and MgBr2 did not
give the desired product 22
(Table 1, entries 1–3), fortunately
with other Lewis acids, such as
AlCl3, BiBr3, and BF3·Et2O–AcOH,
the desired cyclization proceed-
ed to give tetrahydropyran 22 in
48–87% yield (Table 1, entries 4–
6). Next, some Brønsted acids
(CF3CO2H, MeSO3H, p-TsOH, and
PhSO3H) were also examined
Entry
Conditions
Yield of 22 [%]
1
2
3
4
5
6
TiCl4 (5 equiv), CH2Cl2, ꢀ788C to RT, 15 h
ZnBr2 (5 equiv), CH2Cl2, 08C to RT, 20 h
MgBr2 (5 equiv), CH2Cl2, 08C to RT, 25 h
complex mixture
no reaction
no reaction
AlCl3 (1 equiv), CH2Cl2, ꢀ788C to ꢀ408C, 6 h
48 (22a: X=Cl)
67 (22b: X=Br)
73 (22c: X=OAc)
14 (22d: X=F)
76 (22e: X=OCOCF3)
90 (22 f: X=OMs)
74 (22g: X=OTs)
50 (22h: X=OSO2Ph)
BiBr3 (1.5 equiv), CH2Cl2, 08C to RT, 7.5 h
BF3·Et2O (10 equiv), AcOH (5 equiv), CH2Cl2, ꢀ788C to RT, 19 h
7
8
9
10
CF3CO2H (5.2 equiv), CH2Cl2, RT, 10.5 h
MsOH[a] (2 equiv), CH2Cl2, ꢀ788C to RT, 21 h
p-TsOH[b] (2 equiv), CH2Cl2, ꢀ788C to RT, 5 h
PhSO3H (2 equiv), CH2Cl2, ꢀ788C to RT, 15 h
[a] MsOH=methanesulfonic acid. [b] p-TsOH=para-toluenesulfonic acid.
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cis isomer (cis/trans=15:1 by 1H NMR spectroscopy), the
Although we succeeded in the realization of strategy II, we
felt there was still room for improvement in the hetero-Diels–
Alder strategy. Because bromination of cycloadduct 12 took
place with high selectivity, we envisioned that cycloadduct 24,
which should be obtained from arylsiloxybutadiene 25
through a hetero-Diels–Alder reaction with 8, would also be
protonated from the desired b face to produce tetrahydropyr-
an-3-one 10 as a synthetic precursor for target compound
1 (Scheme 8).
1
relative stereochemistry of which was determined by H NMR
spectroscopy.[16,17] The stereoselectivity of bromination was ex-
plained by transition-state III, in which the bromonium cation
was accessed from the b face of the silylenol ether, leading to
the formation of the favorable chair-like conformation. Because
cycloadduct 11 was prone to isomerize into the trans form
during the chromatography on silica gel, cycloadduct 11 was
immediately treated with aryl Grignard reagent 15 to produce
bromohydrin 23 in 60% yield. The structure of 23 was
confirmed by single-crystal X-ray structural analysis (see the
Supporting Information).
Scheme 8. Improved synthetic strategy II for 1.
Our improved synthesis for 1 commenced with the prepara-
tion of methyl vinyl ketone 28, which is a precursor for arylsi-
loxybutadiene 25, from 2,3-butanedione (26; Scheme 9). Dione
26 was treated with aryl Grignard reagent 15 to produce alco-
hol 27 in 75% yield; this was followed by dehydration of the
resulting hydroxyl group in 27 with p-TsOH in toluene at reflux
to produce 28 in 73% yield. We then tried the key hetero-
Diels–Alder reaction between aldehyde 8 and arylsiloxybuta-
diene 25, which was generated from 28 with LDA and
TMSCl.[20] Thus, treatment of a mixture of 8 and 25 with
Me2AlCl in CH2Cl2 gave tetrahydropyran 24,[11] which was ste-
reoselectively protonated with AcOH from the expected b face
to provide ketone 10 in 75% yield.[21] This compound was the
same as 10 synthesized by the route shown in Scheme 7.
Under the conditions mentioned previously (Scheme 7), tetra-
hydropyran 10 was converted into the desired product
1 (5 steps, 30% total yield from 26).
Scheme 6. Synthesis of 23. NBS=N-bromosuccinimide.
Because the aryl substituent in bromohydrin 23 was located
anti to the bromine atom, we envisaged that the 1,2-aryl mi-
gration of 23 would give the desired product 10. Fortunately,
exposure of 23 to Et2Zn in CH2Cl2 under reflux gave ketone 10
in 81% yield (Scheme 7).[18] The relative configuration of 10
1
was determined by H NMR spectroscopy and the whole struc-
ture of 10 was characterized by single-crystal X-ray structural
analysis (see the Supporting Information). This result indicated
that 1,2-aryl migration proceeded with inversion of the config-
uration at the C-5 position. Finally, the carbonyl group of the
resulting ketone 10 was removed by Wolff–Kischner reduction
(TsNHNH2, followed by ZnCl2 and NaBH3CN)[19] to produce de-
sired product 1 in 72% yield (4 steps, 28% total yield from 8).
Scheme 7. Synthesis of 1.
Scheme 9. Improved synthesis of 1.
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Physicochemical properties
enough to discuss the De value of a compound that had
negative De containing plural permanent dipoles.
Goto et al. reported the physicochemical properties of 1 and
comparable compound 3 (Table 2 and Table 3).[5] Table 2 pro-
vides the transition temperatures and transition enthalpies of
1 and 3. Table 3 provides the values of TNI (nematic–isotropic
transition temperature), De, Dn (optical anisotropy), and h (vis-
cosity) for compounds 1 and 3; these values were extrapolated
from the measured values of LC mixtures obtained by dissolv-
ing the compound in a nematic LC mixture (host mixture)
comprising of several kinds of phenyl cyclohexylcarboxylates
29. Compound 1 exhibits a large De value relative to 3, al-
though there is less difference in the other values of properties
of 1 and 3.
Recently, one of us reported that ꢀm2(1ꢀ3cos2b), calculated
by the DFT method for biphenylyltetrahydropyran derivatives
with negative De values, was the physical quantity proportion-
al to De and could be used as an index of De.[22] Here, b is de-
fined as an angle, which is comprised of the moment of inertia
of a molecule and its dipole moment. Each value of m and
b was calculated for 8 stable conformers with a high existence
probability among the 144 conformers of the biphenylyltetra-
hydropyran. The average value of ꢀm2(1ꢀ3cos2b) of the eight
conformers showed a relatively favorable correlation with the
measured value of De. This result revealed that the Maier–
Meier theory[23] could be applicable to estimate the De value
of LC compounds with negative
De values through this method.
Table 2. Transition temperatures and transition enthalpies of 1 and 3.[5]
Herein, we expanded upon
considerations from the previous
paper;[22] thus, for each of the
Compound
Transition
temperatures[a] [8C]
Transition
enthalpies[a] [kJmolꢀ1
]
144 conformers of compounds
1 and 3, which were obtained by
rotating dihedral angles q1 and q2
from 0 to 3608 at intervals of 308
(Figure 1), individual partial struc-
tures optimized through calcula-
tions at the B3LYP/6-31G (d)[24]
level were sought. Subsequently,
individual values of dipole mo-
ments m and b were also calculat-
ed at the same level to estimate
C 66.7 N 139.9 I
C 28.6 N 0.77 I
C 107.7 (SmB 94.6) N 164.0 I
C 33.7 (SmB 4.14) N 0.74 I
[a] C=crystalline, SmB=smectic B, N=nematic, I=isotropic.
ꢀm2(1ꢀ3cos2b). Furthermore, the probability of the existence
of each of the 144 conformers was obtained by using the
Boltzmann distribution based on the relative energy calculated
by the DFT method. Finally, we obtained the weighted-average
efficiency of m, b, and ꢀm2(1ꢀ3cos2b) by considering the prob-
ability of the existence of each of the 144 conformers (Table 4)
and the measured values of De.[25]
Table 3. Extrapolated values of several physicochemical properties of
1 and 3.[5]
Compound
TNI [8C]
De
Dn
h [mPas]
1[a]
121.3
138.6
74.6
ꢀ7.30
ꢀ3.80
ꢀ1.3
0.107
0.112
0.087
68.4
66.2
74.6
3[a]
host mixture[b]
[a] Extrapolated data from mixtures consisting of 15% of the compound
and 85% of nematic host mixture. [b] Host mixture was comprised of five
compounds (27.6% of 29a, 17.2% of 29b, 20.7% of 29c, 20.7% of 29d,
and 13.8% of 29e).
Previously, it was reported that the reason why compound
1 exhibited a large dielectric anisotropy, De, relative to 3, was
the imparity in the direction of the dipole of the most stable
conformer, which was obtained from the relative energy of 12
conformers generated by rotating the difluorobenzene ring.[5]
The calculation was performed by means of a semiempirical
quantum chemistry method (MOPAC/AM1). However, in that
case, consideration was only given to the dipole moment, m,
and direction of its single-conformer molecules as representa-
tive values of the compound. We decided that it was not
Figure 1. Two rotated dihedral angles (q1 and q2) in compounds 1 and 3.
The distributions of the calculated dipole moments m and
b of each of the 144 conformers generated by rotating dihe-
dral angles q1 and q2 for individual structures of compounds
1 and 3 and the distributions of ꢀm2(1ꢀ3cos2b) and the proba-
bility of the existence of each of these 144 conformers are
shown in Figures S2 and S3 in the Supporting Information,
respectively.
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Table 4. Calculated values of m, b, and ꢀm2(1ꢀ3cos2b) for 1 and 3.[a]
Table 6. Results of preservation tests at ꢀ208C.[a]
m [debye]
b [8]
ꢀm2(1ꢀ3cos2b)/De
ꢀ7.76
ꢀ4.18
De
Concentration (wt% in host mixture)[b]
10
15
20
1
3
3.6630
2.8470
68.3
66.3
ꢀ7.30
ꢀ3.80
1
2
3
N
N
N
N
N
C
N
C
C
[a] Obtained by taking into account existence probabilities and measured
values of De.
[a] Each solution of compounds 1, 2, and 3 in the host mixture was left
at ꢀ208C for 30 days. N indicates that a nematic phase was maintained;
C indicates that crystals were deposited. [b] Details of the composition of
the host mixture are given in Table 3.
The values of ꢀm2(1ꢀ3cos2b) were ꢀ7.76 for 1 and ꢀ4.18
for 3, and the difference was the same as the difference in
measured De between 1 (De=ꢀ7.30) and 3 (De=ꢀ3.80). Be-
cause there was little difference in the values of b for 1 and 3,
that is, b was approximately 678 for both compounds, we
speculated that the large difference in De was mainly due to
the difference in the dipole moment, m.
Conclusion
We developed three different stereoselective syntheses of 1,
which was a LC compound with a large negative dielectric an-
isotropy. The key feature of the first approach included the
benzylic cation mediated intramolecular olefin cyclization of 9
to give the desired trans-2,5-disubstituted tetrahydropyran 22
with high stereoselectivity. The second approach utilized
a hetero-Diels–Alder reaction of 8 and siloxydiene 13. After ste-
reoselective bromination of cycloadduct 12 and 1,2-aryl migra-
tion of 23, target compound 1 was obtained. In the third
method, siloxydiene 25 was used for a hetero-Diels–Alder reac-
tion and stereoselective protonation of the resulting cycload-
duct 24 gave ketone 10, which was reduced to produce 1. We
clarified why compound 1 exhibited a large De, relative to
compound 3, by using quantum chemical calculations.
Furthermore, the introduction of ꢀm2(1ꢀ3cos2b), obtained by
calculations that considered the probability of the existence of
individual conformers, was particularly useful to estimate De;
a parameter that could be a guideline in designing new
compounds. From this study, LC mixtures containing the LC
compound with a tetrahydropyran ring exhibited favorable
properties as LC mixtures for VA-LCD.
To ascertain the usefulness of compound 1 synthesized by
using the newly devised synthetic method as structural
components of LC mixtures for vertically aligned (VA) LCDs, we
prepared a model mixture (mixture A) by dissolving 15 wt% of
1 in the nematic LC mixture used to obtain the values in
Table 3, and a model mixture containing 15 wt% compound
2[5] (mixture B). Their physicochemical properties were
compared, as shown in Table 5. The results revealed that LC
mixtures with a low voltage driving, without loss of the
other properties, could be adjusted by adopting compound 1.
Table 5. Physicochemical properties of model mixtures A and B.
TNI [8C]
h [mPas]
Dn
De
Vth [V]
mixture A[a]
mixture B[b]
81.3
87.4
27.0
23.3
0.089
0.091
ꢀ2.39
ꢀ2.10
2.64
2.95
[a] Mixture A was composed of 15% of 1 and 85% of the nematic host
mixture. Details of the composition of the host mixture are given in
Table 3. [b] Mixture B was composed of 15% of the compound 2 and
85% of the nematic host mixture.
Experimental Section
Because recent LCDs are required to avoid the problem of
image defects at low temperatures, LC mixtures must have
low-temperature phase stability (LTS). Thus, it is important
that, at low temperatures, no specific structural component is
crystallized, and that no smectic phase is observed. To test the
LTS of 1, 2, and 3, each of the three compounds was dissolved
in the LC mixture for vertical alignment (host mixture in
Table 3), which exhibits a nematic phase at ꢀ208C. By varying
the concentration of these compounds (10, 15, and 20%), nine
new mixtures were prepared. These mixtures were stored in
sample glass tubes at ꢀ208C for 30 days. After the 30 day
period, we visually checked the condition of the mixtures. The
results of these preservation tests are given in Table 6.
Compared with compounds 2 and 3, all mixtures of compound
1 remained nematic at ꢀ208C, and thus, showed superior LTS
performance in a low-temperature environment.
General
All reactions involving air- and moisture-sensitive reagents were
carried out by using oven-dried glassware and standard syringe–
septum cap techniques. Routine monitoring of the reaction was
carried out by using glass-supported Merck silica gel 60 F254 TLC
plates. Flash column chromatography was performed on Kanto
Chemical Silica Gel 60 N (spherical, neutral 40–50 mm). All solvents
and reagents were obtained from commercial suppliers and were
used without further purification. Melting points were taken on
a Mettler Toledo MP70 melting point system. IR spectra were re-
corded on a HORIBA FT-720 spectrometer. 1H, 13C, and 19F NMR
spectra were measured with a Bruker AVANCE III spectrometer.
Chemical shifts are expressed in ppm by using tetramethylsilane
(d=0 ppm; 1H and 13C NMR spectroscopy) and CFCl3 (d=0 ppm;
19F NMR spectroscopy) as standards. 19F NMR spectra were record-
ed with 1H decoupling. Multiplicities are indicated by s (singlet),
brs (broad singlet), d (doublet), brd (broad doublet), t (triplet), brt
(broad triplet), q (quartet), dd (doublet of doublets), brdd (broad
doublet of doublets), ddd (doublet of doublets of doublets), dddd
(doublet of doublets of doublets of doublets), and m (multiplet).
Chem. Eur. J. 2015, 21, 2458 – 2466
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HRMS spectra were measured on a JEOL MStation JMS-700 mass
spectrometer.
90%) as a white solid. M.p. 110.5–111.58C; 1H NMR (400 MHz,
CDCl3): d=6.82 (ddd, J=9.0, 7.6, 1.8 Hz, 1H), 6.68 (ddd, J=9.0, 7.6,
1.8 Hz, 1H), 4.72 (ddd, J=10.5, 9.8, 5.0 Hz, 1H), 4.10 (q, J=7.0 Hz,
2H), 3.96 (ddd, J=10.8, 4.3, 2.0 Hz, 1H), 3.34 (dd, J=11.0, 10.8 Hz,
1H), 3.26–3.17 (m, 2H), 3.03 (s, 3H), 2.56 (brd, J=12.3 Hz, 1H), 2.04
(ddd, J=12.3, 12.3, 10.5 Hz, 1H), 1.86–1.47 (m, 6H), 1.44 (t, J=
7.0 Hz, 3H), 1.36–1.11 (m, 6H), 1.00–0.79 (m, 2H), 0.87 ppm (t, J=
7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=149.7 (dd, J(C,F)=247,
11 Hz, 1C), 147.3 (dd, J(C,F)=8.1, 3.4 Hz, 1C), 141.5 (dd, J(C,F)=
248, 15 Hz, 1C), 121.2 (dd, J(C,F)=5.2, 5.1 Hz, 1C), 119.9 (d, J(C,F)=
13 Hz, 1C), 109.5 (d, J(C,F)=2.2 Hz, 1C), 82.7 (s, 1C), 75.4 (s, 1C),
71.6 (brs, 1C), 65.3 (s, 1C), 39.5 (s, 1C), 38.9 (s, 1C), 37.6 (s, 1C),
37.1 (s, 1C), 36.6 (s, 1C), 35.9 (s, 1C), 33.2 (s, 1C), 32.9 (s, 1C), 29.9
(s, 1C), 24.8 (s, 1C), 19.9 (s, 1C), 14.6 (s, 1C), 14.3 ppm (s, 1C);
19F NMR (376 MHz, CDCl3): d=ꢀ141.7 (d, J(F,F)=19 Hz, 1F),
ꢀ158.9 ppm (d, J(F,F)=19 Hz, 1F); IR (neat): n˜ =2979, 2939, 2922,
2885, 2860, 1643, 1516, 1473, 1448, 1415, 1396, 1360, 1346, 1331,
1315, 1290, 1244, 1221, 1194, 1169, 1136, 1113, 1078, 1055, 991,
976, 955, 939, 930, 912, 883, 869, 839, 829, 802, 789, 771, 735, 727,
701, 619 cmꢀ1; elemental analysis calcd (%) for C23H34F2O5S: C
59.98, H 7.44; found: C 59.79, H 7.41.
Compound 9
Iodine (15 mg, 0.059 mmol) was added to a stirred suspension of
magnesium turnings (275 mg, 11.3 mmol) in THF (7.5 mL), and
then a solution of 1-bromo-4-ethoxy-2,3-difluorobenzene (1.01 g,
2.12 mmol) in THF (1.0 mL) was added. The resulting mixture was
heated at reflux until the color from iodine disappeared. A solution
of 1-bromo-4-ethoxy-2,3-difluorobenzene (2.02 g, 8.48 mmol) in
THF (4.0 mL) was added dropwise over 30 min to the resulting so-
lution at room temperature. The reaction mixture was stirred at
room temperature for 1 h to give a 0.65m solution of 15 in THF. A
solution of 21 (754 mg, 3.37 mmol) in THF (3.5 mL) at 08C under
argon was added dropwise to the stirred solution of 15 in THF
(0.65m, 8.0 mL, 5.23 mmol) and the resulting solution was stirred
at 08C for 1 h. The reaction was stopped by adding a 1m aqueous
solution of HCl (5.3 mL) and the resulting mixture was stirred at
room temperature for 5 min. The reaction mixture was extracted
with diethyl ether (3ꢁ5 mL). The extract was washed with water
(5 mL) and brine (5 mL), then dried over MgSO4. Concentration of
the solution in vacuo afforded a residue that was purified by
column chromatography on silica gel (hexane/ethyl acetate) to
give 9 (1.02 g, 79%) as a white solid as a mixture of two diastereo-
mers. M.p. 75.4–79.18C; 1H NMR (400 MHz, CDCl3): d=7.17 (ddd,
J=9.3, 8.1, 2.3 Hz, 1H), 6.73 (ddd, J=9.0, 8.1, 1.9 Hz, 1H), 5.66 (m,
1H), 5.22 (brd, J=10.6 Hz, 1H), 5.13 (brd, J=17.1 Hz, 1H), 5.11 (m,
1H), 4.11 (q, J=7.3 Hz, 2H), 3.69 (brdd, J=9.6, 3.2 Hz, 0.5H), 3.51–
3.35 (m, 2H), 3.20 (dd, J=9.4, 9.3 Hz, 0.5H), 2.85 (d, J=2.5 Hz,
0.5H), 2.80 (d, J=2.6 Hz, 0.5H), 1.92 (m, 1H), 1.82–1.64 (m, 3H),
1.44 (t, J=7.3 Hz, 3H), 1.51–1.10 (m, 7H), 1.06–0.79 (m, 3H),
0.87 ppm (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=148.7
(dd, J(C,F)=247, 2.9 Hz, 0.5C), 148.6 (dd, J(C,F)=247, 2.9 Hz, 0.5C),
147.7 (dd, J(C,F)=8.1, 2.1 Hz, 0.5C), 147.6 (ddd, J(C,F)=8.1, 2.3,
2.3 Hz, 0.5C), 141.1 (dd, J(C,F)=247, 2.9 Hz, 0.5C), 141.0 (dd,
J(C,F)=247, 2.9 Hz, 0.5C), 137.3 (s, 0.5C), 137.1 (s, 0.5C), 121.25 (d,
J(C,F)=11 Hz, 0.5C), 121.21 (d, J(C,F)=11 Hz, 0.5C), 121.0 (dd,
J(C,F)=5.2, 5.1 Hz, 1C), 118.2 (s, 0.5C), 118.0 (s, 0.5C), 109.4 (d, J=
2.8 Hz, 1C), 87.3 (s, 0.5C), 86.4 (s, 0.5C), 73.0 (s, 1C), 72.3 (s, 0.5C),
67.0 (s, 0.5C), 66.3 (s, 0.5C), 65.3 (s, 0.5C), 42.5 (s, 0.5C), 42.4 (s,
0.5C), 39.7 (s, 1C), 37.5 (s, 1C), 32.84 (s, 0.5C), 32.82 (s, 0.5C), 32.79
(s, 1C), 28.94 (s, 0.5C), 28.91 (s, 0.5C), 28.7 (s, 1C), 20.0 (s, 1C), 14.7
(s, 1C), 14.3 ppm (s, 1C); 19F NMR (376 MHz, CDCl3): d=ꢀ143.5 (d,
J(F,F)=20 Hz, 0.5F), ꢀ143.8 (d, J(F,F)=20 Hz, 0.5F), ꢀ160.37 (d,
J(F,F)=20 Hz, 0.5F), ꢀ160.43 ppm (d, J(F,F)=20 Hz, 0.5F); IR (neat):
n˜ =3456 (brs), 2978, 2952, 2920, 2846, 1514, 1477, 1294, 1105,
1076, 1057, 991, 955, 939, 928, 810, 800, 789, 729 cmꢀ1; elemental
analysis calcd (%) for C22H32F2O3: C 69.08, H 8.43; found: C 68.99, H
8.21.
Compound 1
Sodium borohydride (18.9 mg, 0.50 mmol) was added to a stirred
solution of 22 f (46.0 mg, 0.10 mmol) in 1,3-dimethylimidazolidine
(1.0 mL) at room temperature and the resulting mixture was stirred
at 1008C for 20 h. The reaction was stopped by adding a 16%
aqueous solution NH4Cl (4 mL) and chloroform (2 mL) was added,
then the resulting mixture was stirred at room temperature for
5 min. The reaction mixture was extracted with ethyl acetate (3ꢁ
3 mL). The extract was washed with water (3 mL) and brine (3 mL),
then dried over MgSO4. Concentration of the solution in vacuo af-
forded a residue that was purified by column chromatography
(hexane/ethyl acetate) on silica gel to give 1 (27.3 mg, 75%) as
1
a white solid. M.p. 63.9–65.28C; H NMR (400 MHz, CDCl3): d=6.80
(ddd, J=9.1, 7.5, 2.0 Hz, 1H), 6.67 (ddd, J=9.1, 7.5, 1.9 Hz, 1H),
4.09 (q, J=7.0 Hz, 2H), 4.00 (ddd, J=11.2, 4.0, 2.2 Hz, 1H), 3.37 (dd,
J=11.2, 11.1 Hz, 1H), 3.10–3.00 (m, 2H), 1.97 (m, 2H), 1.83–1.66 (m,
5H), 1.53–1.24 (m, 5H), 1.43 (t, J=7.0 Hz, 3H), 1.24–0.79 (m, 6H),
0.87 ppm (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=149.8
(dd, J(C,F)=246, 10 Hz, 1C), 146.8 (dd, J(C,F)=8.1, 3.7 Hz, 1C),
141.6 (dd, J(C,F)=247, 15 Hz, 1C), 123.1 (d, J(C,F)=13 Hz, 1C),
121.1 (dd, J(C,F)=5.9, 5.1 Hz, 1C), 109.4 (d, J(C,F)=3.0 Hz, 1C), 82.2
(s, 1C), 72.4 (s, 1C), 65.3 (s, 1C), 43.2 (s, 1C), 39.7 (s, 1C), 37.4 (s,
1C), 36.1 (s, 1C), 33.02 (s, 1C), 32.94 (s, 1C), 29.7 (s, 1C), 29.1 (s,
1C), 28.61 (s, 1C), 28.59 (s, 1C), 20.0 (s, 1C), 14.7 (s, 1C), 14.4 ppm
(s, 1C); 19F NMR (376 MHz, CDCl3): d=ꢀ142.4 (d, J(F,F)=20 Hz, 1F),
ꢀ159.6 ppm (d, J(F,F)=20 Hz, 1F); IR (neat): n˜ =2925, 2908, 2844,
1518, 1475, 1396, 1303, 1284, 1271, 1182, 1113, 1080, 1041, 966,
885, 796, 775, 727 cmꢀ1
; elemental analysis calcd (%) for
C22H32F2O2: C 72.10, H 8.80; found: C 72.08, H 8.83.
Compound 22 f
A solution of 9 (382 mg, 1.0 mmol) in CH2Cl2 (2.0 mL) at ꢀ788C
was added dropwise to a stirred solution of MsOH (0.13 mL,
2.0 mmol) in CH2Cl2 (2.0 mL), and the resulting solution was stirred
at ꢀ408C for 6 h, then slowly warmed to room temperature over
15 h. The reaction was stopped by adding a saturated aqueous so-
lution of NaHCO3 (2.0 mL) and the resulting mixture was stirred at
room temperature for 10 min. The reaction mixture was extracted
with chloroform (3ꢁ3 mL). The extract was washed with water
(2 mL) and dried over MgSO4. Concentration of the solution in
vacuo afforded a residue that was purified by column chromatog-
raphy on silica gel (hexane/ethyl acetate) to give 22 f (415 mg,
Compound 23
A solution of chlorodimethylaluminum in hexane (1.0m, 0.77 mL,
0.77 mmol) at ꢀ408C under argon was added dropwise to a stirred
solution of 8 (0.79 g, 5.1 mmol) in toluene (26 mL) and the result-
ing mixture was stirred for 30 min. Then 13 (0.82 g, 5.8 mmol) was
added and stirred for 3 h. DMF (12 mL) was added to the resulting
mixture, followed by NBS (1.78 g, 10.0 mmol) at ꢀ408C. The result-
ing mixture was allowed to warm to 58C over 40 min and stirred
at 58C for an additional 5 min. The reaction was stopped by
adding a saturated aqueous solution of NaHCO3 (20 mL) and the
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aqueous phase was extracted with ethyl acetate (2ꢁ50 mL). The
extract was washed with brine (100 mL) ad dried over Na2SO4. Con-
centration of the solution in vacuo afforded crude 11 (1.6 g) as
centration of the solution in vacuo afforded a residue that was pu-
rified by recrystallization (hexane/diethyl ether 4/1) to give 10
1
(0.46 g, 81% yield). M.p. 138.8–140.98C; H NMR (400 MHz, CDCl3):
1
a colorless oil. Based on H NMR spectroscopy results, the stereose-
d=6.78–6.68 (m, 2H), 4.28 (dd, J=11.2, 6.8 Hz, 1H), 4.11 (q, J=
7.0 Hz, 2H), 3.92 (dd, J=11.2, 6.8 Hz, 1H), 3.76 (ddd, J=11.2,
11.2 Hz, 1H), 3.52 (ddd, J=11.5, 6.2, 2.6 Hz, 1H), 2.58 (dd, J=14.3,
2.6 Hz, 1H), 2.48 (dd, J=14.2, 11.5 Hz, 1H), 2.00–1.95 (m, 1H), 1.81
(d, J=12.9 Hz, 2H), 1.74–1.69 (m, 1H), 1.55–1.47 (m, 1H), 1.44 (t,
J=7.0 Hz, 3H), 1.32 (td, J=14.3, 7.2 Hz, 2H), 1.24–0.96 (m, 5H),
0.94–0.86 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=204.7 (1C),
149.9 (dd, J(C,F)=245.4, 10.9 Hz, 1C), 147.9 (dd, J(C,F)=8.0, 3.4 Hz,
1C), 141.6 (dd, J(C,F)=246.0, 14.6 Hz, 1C), 123.9 (dd, J(C,F)=5.1,
5.1 Hz, 1C), 115.3 (d, J(C,F)=12.6 Hz, 1C), 109.5 (d, J(C,F)=2.7 Hz,
1C), 83.1 (1C), 71.1 (d, J(C,F)=1.1 Hz, 1C), 65.4 (1C), 51.7 (d,
J(C,F)=0.9 Hz, 1C), 45.3 (1C), 43.2 (1C), 39.6 (1C), 37.3 (1C), 32.8
(1C), 32.7 (1C), 28.5 (1C), 28.2 (1C), 20.0 (1C), 14.7 (1C), 14.4 ppm
(1C); 19F NMR (376 MHz, CDCl3): d=ꢀ139.3 (d, J(F,F)=20.2 Hz, 1F),
ꢀ159.0 ppm (d, J(F,F)=20.2 Hz, 1F); IR (neat): n˜ =2987, 2952, 2931,
2870, 2854, 1714, 1631, 1514, 1477, 1454, 1398, 1329, 1292, 1240,
1227, 1213, 1178, 1155, 1134, 1109, 1038, 1009, 993, 955, 889, 814,
806, 739, 717, 696, 631 cmꢀ1; HRMS (EI): m/z calcd for C22H30F2O3
[M]+: 380.2163; found: 380.2160.
lectivity was approximately trans/cis=1:15. Purification of 11 by
column chromatography on silica gel was difficult because 11 iso-
merized to form the corresponding cis isomer. Therefore, com-
pound 11 was used for the next reaction without further purifica-
1
tion. M.p. 116.2–117.78C; H NMR (400 MHz, CDCl3): d=4.59 (ddd,
J=11.3, 7.0, 1.1 Hz, 1H), 4.44 (dd, J=11.3, 7.0 Hz, 1H), 3.63 (dd, J=
11.3, 11.3 Hz, 1H), 3.41 (ddd, J=11.5, 6.2, 2.3 Hz, 1H), 2.75 (dd, J=
14.0, 2.3 Hz, 1H), 2.53 (ddd, J=14.0, 11.5, 1.1 Hz, 1H), 1.92 (dddd,
J=9.1, 9.1, 3.3, 3.3 Hz, 1H), 1.80 (d, J=13.4 Hz, 2H), 1.66 (dddd, J=
9.1, 9.1, 3.2, 3.2 Hz, 1H), 1.51–1.42 (m, 1H), 1.31 (ddd, J=14.4, 14.4,
7.2 Hz, 2H), 1.23–1.12 (m, 3H), 1.11–0.96 (m, 2H), 0.94–0.80 ppm
(m, 5H); 13C NMR (100 MHz, CDCl3): d=198.3 (s, 1C), 83.4 (s, 1C),
73.1 (s, 1C), 52.5 (s, 1C), 46.2 (s, 1C), 42.9 (s, 1C), 39.5 (s, 1C), 37.2
(s, 1C), 32.6 (s, 1C), 32.6 (s, 1C), 28.4 (s, 1C), 28.2 (s, 1C), 19.9 (s,
1C), 14.3 ppm (s, 1C); IR (neat): n˜ =2952, 2919, 2852, 1720, 1466,
1448, 1342, 1294, 1244, 1155, 1130, 1070, 955, 822, 717, 696 cmꢀ1
;
HRMS (FAB): m/z calcd for C14H23BrO2 [M+H]+: 303.0960; found:
303.0966.
A stirred solution of 1-bromo-4-ethoxy-2,3-difluorobenzene (2.37 g,
10.0 mmol) in THF (10 mL) was added dropwise to a solution of
iPrMgCl·LiCl in THF (1.3m, 7.8 mL, 10 mmol) at 08C under argon.
The resulting mixture was warmed to room temperature and
stirred for 3 h. A solution of 11 (1.6 g) in THF (10 mL) at 08C was
added to the resulting solution by means of a cannula. The mix-
ture was stirred at room temperature for 2 h. The reaction was
stopped by adding a 1.0m aqueous solution of HCl (5 mL). The re-
action mixture was extracted with ethyl acetate (2ꢁ80 mL). The ex-
tract was washed with brine (30 mL) and dried over Na2SO4. Con-
centration of the solution in vacuo afforded a residue that was pu-
rified by recrystallization (hexane) to give 23 (1.27 g, 54% yield
from 8) as a white solid. M.p. 99.5–101.08C; 1H NMR (400 MHz,
CDCl3): d=7.16 (ddd, J=8.9, 8.9, 2.3 Hz, 1H), 6.73 (ddd, J=8.9, 7.2,
1.8 Hz, 1H), 5.04 (dd, J=8.5, 4.0 Hz, 1H), 4.12 (q, J=7.0 Hz, 2H),
4.04 (ddd, J=12.0, 8.5, 1.6 Hz, 1H), 3.72 (dd, J=12.0, 4.0 Hz, 1H),
3.43 (ddd, J=9.4, 4.7, 4.7 Hz, 1H), 2.63 (d, J=1.6 Hz, 1H), 2.41
(ddd, J=14.6, 4.7, 1.6 Hz, 1H), 2.22 (dd, J=14.6, 4.7 Hz, 1H), 2.09–
2.04 (m, 2H), 1.80–1.77 (m, 3H), 1.46 (t, J=7.0 Hz, 3H), 1.32 (ddd,
J=14.4, 14.4, 7.2 Hz, 2H), 1.18–1.15 (m, 3H), 0.98–0.84 ppm (m,
7H); 13C NMR (100 MHz, CDCl3): d=148.9 (dd, J(C,F)=246.4,
11.6 Hz, 1C), 148.2 (dd, J(C,F)=8.2, 3.2 Hz, 1C), 141.8 (dd, J(C,F)=
246.4, 15.6 Hz, 1C), 124.3 (d, J(C,F)=8.3 Hz, 1C), 121.3 (dd, J(C,F)=
4.5, 4.5 Hz, 1C), 108.8 (d, J(C,F)=2.1 Hz, 1C), 78.6 (1C), 72.7 (dd,
J(C,F)=4.3, 1.5 Hz, 1C), 65.3 (1C), 64.4 (1C), 58.6 (d, J(C,F)=7.2 Hz,
1C), 39.7 (1C), 38.8 (1C), 37.3 (1C), 56.4 (d, J(C,F)=1.7 Hz, 1C), 32.8
(1C), 32.6 (1C), 29.8 (1C), 29.4 (1C), 20.0 (1C), 14.7 (1C), 14.4 ppm
(1C); 19F NMR (376 MHz, CDCl3): d=ꢀ137.4 (brs, 1F), ꢀ158.7 ppm
(d, J(F,F)=19.2 Hz, 1F); IR (neat): n˜ =2952, 2922, 2844, 1628, 1510,
1466, 1308, 1288, 1186, 1113, 1080, 1065, 1026, 866, 796, 773, 737,
669, 660, 625 cmꢀ1; HRMS (EI): m/z calcd for C22H31BrF2O3 [M]+:
460.1425; found: 460.1419.
Compound 1
A mixture of 10 (0.191 g, 0.50 mmol) and p-toluenesulfonylhydra-
zide (0.114 g, 0.61 mmol) in ethanol (4 mL) was heated at 608C for
1 h. After ethanol was removed in vacuo, zinc chloride (0.177 g,
1.3 mmol) and sodium cyanoborohydride (0.157 g, 2.5 mmol) were
added to a solution of the obtained crude residue in methanol
(2.5 mL) and ethanol (2.5 mL) and the resulting mixture was stirred
at 608C for 3 h. The reaction was stopped by adding a saturated
aqueous solution of Na2CO3 (10 mL) and the reaction mixture was
extracted with ethyl acetate (3ꢁ40 mL). The extract was washed
with brine (50 mL) and dried over Na2SO4. Concentration of the so-
lution in vacuo afforded a residue that was purified by column
chromatography (hexane/ethyl acetate 19/1) on silica gel to give
1 (0.133 g, 72% yield).
Compound 10
A solution of LDA in THF (1.0m, 7.5 mL, 7.5 mmol) at ꢀ308C under
argon was added dropwise over 15 min to a stirred solution of 28
(1.70 g, 7.5 mmol) and chlorotrimethylsilane (0.98 g, 9.0 mmol) in
THF (25 mL) and the resulting mixture was stirred at ꢀ308C for
0.5 h. The reaction mixture was concentrated in vacuo at 08C and
the reaction was stopped by adding an ice-cooled 0.5m aqueous
solution of HCl (40 mL). The reaction mixture was extracted with
hexane (70 mL) and the extract was washed with ice-cooled water
(30 mL), a saturated aqueous solution of Na2CO3 (30 mL), and brine
(30 mL), and then dried over Na2SO4. Concentration of the solution
in vacuo afforded crude 25 (1.93 g) as a colorless liquid, which was
used for the next reaction without further purification.
A solution of chlorodimethylaluminum in hexane (1.0m, 1.2 mL,
1.2 mmol) at ꢀ208C under argon was added to a stirred solution
of 8 (0.632 g, 4.1 mmol) in CH2Cl2 (6 mL) and the mixture was
stirred for 15 min. Then crude 25 (1.19 g) was added dropwise
over 0.5 h to the resulting mixture and stirred for 0.5 h. The reac-
tion was stopped by adding a concentrated aqueous solution of
HCl (10 mL) at ꢀ208C and the mixture was stirred at room temper-
ature for 0.5 h. The reaction mixture was extracted with CH2Cl2/
ethyl acetate (1:3, 2ꢁ30 mL) and the extract was washed with
brine (50 mL), then dried over Na2SO4. Concentration of the solu-
Compound 10
A solution of Et2Zn in hexane (1.0m, 0.90 mL, 0.90 mmol) at 08C
under argon was added to a stirred solution of 23 (692 mg,
1.50 mmol) in dichloromethane (9 mL) and the resulting mixture
was heated under reflux for 2 h. The reaction was stopped by
adding a saturated aqueous solution of NH4Cl (20 mL) and the re-
action mixture was extracted with ethyl acetate (2ꢁ30 mL). The ex-
tract was washed with brine (30 mL) and dried over Na2SO4. Con-
Chem. Eur. J. 2015, 21, 2458 – 2466
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2006; c) L. Lietzau, M. Czanta, A. Manabe, PCT Int. Appl.
WO2008019746, 2008.
tion in vacuo afforded a residue that was purified by recrystalliza-
tion (hexane/ethyl acetate 6/1) to give 10 (1.14 g, 75% yield).
[9] For the latest review on the Prins cyclization, see: a) E. Arundale, L. A.
Mikeska, Chem. Rev. 1952, 51, 505–555; b) D. R. Adams, S. P. Bhatnagar,
Synthesis 1977, 661–672; c) B. B. Snider, in The Prins Reaction and Car-
bonyl Ene Reactions, Vol. 2 (Eds.: B. M. Trost, I. Fleming, C. H. Heathcock),
Pergamon, New York, 1991, pp. 527–561; d) L. E. Overman, L. D. Pen-
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Acknowledgements
We thank A. Sato at A Rabbit Science Japan Co., Ltd. for
elemental analysis.
Keywords: cyclization · density functional calculations · liquid
crystals · structure–activity relationships · synthesis design
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Published online on December 12, 2014
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