Stereoselective Acetalization for the Synthesis of Liquid-Crystal Compounds Possessing a trans-2,5-Disubstituted 1,3-Dioxane Ring with Saturated Aqueous Solutions of Inorganic Salts

Article abstract of DOI:10.1021/acs.oprd.8b00408

Stereoselective process for the synthesis of trans-2,5-disubstituted 1,3-dioxane derivatives, which are important liquid-crystal compounds, was developed. The acetalization reaction between aldehydes and 2-substituted 1,3-propanediols in the presence of acids gave the corresponding 2,5-disubstituted 1,3-dioxane derivatives with high trans selectivity (trans/cis = >96:<4), when the reaction was performed with saturated aqueous solutions of inorganic salts having high water solubility, such as CaCl₂, LiCl, and ZnCl₂.

Full text of DOI:10.1021/acs.oprd.8b00408

Article
pubs.acs.org/OPRD
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Stereoselective Acetalization for the Synthesis of Liquid-Crystal
Compounds Possessing a trans-2,5-Disubstituted 1,3-Dioxane Ring
with Saturated Aqueous Solutions of Inorganic Salts
Haruki Maebayashi,† Tsugumichi Fuchigami,‡ Yasuyuki Gotoh,§ and Munenori Inoue*,†
†Sagami Chemical Research Institute, 2743-1 Hayakawa, Ayase, Kanagawa 252-1193, Japan
‡JNC Corporation, 1-1 Noguchi-Cho, Minamata, Kumamoto 867-8501, Japan
§JNC Corporation, Shin-Otemachi Bldg. 2-1 Otemachi 2-Chome Chiyoda-ku, Tokyo 100-8105, Japan
S
* Supporting Information
ABSTRACT: Stereoselective process for the synthesis of trans-2,5-disubstituted 1,3-dioxane derivatives, which are important
liquid-crystal compounds, was developed. The acetalization reaction between aldehydes and 2-substituted 1,3-propanediols in
the presence of acids gave the corresponding 2,5-disubstituted 1,3-dioxane derivatives with high trans selectivity (trans/cis =
>96:<4), when the reaction was performed with saturated aqueous solutions of inorganic salts having high water solubility, such
as CaCl2, LiCl, and ZnCl2.
KEYWORDS: liquid-crystal compound, acetalization, 1,3-dioxane ring, saturated aqueous solution of inorganic salts,
stereoselective synthesis
INTRODUCTION
■
Since the 1990s, liquid-crystal displays (LCDs) have been
playing a central role in flat panel for televisions (TVs),
personal computer (PC) monitors, smartphones, and tablet
computers, because active-matrix (AM) technology,1 in which
each pixel is separately controlled by thin-film transistor,
Figure 1. Structures of LC compounds 1 and 2.
progressed rapidly. With this advancement, a wide variety of
liquid-crystal (LC) compounds with appropriate physical
properties, including wide nematic range, large dielectric
anisotropy (Δε), high birefringence, small absorption loss,
and low viscosity, have been developed for AM-LCDs to meet
demands such as high contrast, wide-angle views, rapid
switching times, and low power consumption.2 Both twisted
nematic (TN) display3 and in-plane switching (IPS) display4
require LC compounds showing positive dielectric anisotropy
(Δε) values; therefore, considerable attention has been
devoted to the development of positive Δε-type LC
compounds. Several efforts were made to increase the value
of positive Δε by augmenting the molecular dipole moment
parallel to the long molecular axis direction. For that, the
following structural modifications of LC compounds were
applied: (i) introduction of a polar functional group such as
fluorine atom, trifluoromethyl group, trifluoromethoxy group,
and pentafluorosulfanyl group into the para and/or meta
positions of the terminal phenyl or cyclohexane rings,2 (ii)
introduction of a difluorooxymethylene bridge within the
mesogenic core,5 and (iii) replacement of a cyclohexane ring
by a 1,3-dioxane ring.6,7
the 1,3-dioxane ring in 1 is regarded to be an essential
mesogenic subunit to enhance Δε.
The 1,3-dioxane ring is an important functional group found
in biological active compounds,10 supramolecules,11 and
fragrances12 as well as LC compounds, and this moiety also
serves as a temporary protecting group for 1,3-diols, aldehydes,
and ketones in chemical synthesis.13 In general, the 1,3-dioxane
is formed by acetalization of the corresponding carbonyl
compounds and 1,3-propanediols in the presence of an acid
catalyst such as p-toluenesulfonic acid (TsOH).14 As the
acetalization reaction is an equilibrium reaction, the reaction is
executed in organic solvents with removing the resultant water
from the reaction media by azeotropic distillation (using
benzene, toluene, etc.) or using molecular sieves to prevent
reverse hydrolysis. LC compounds incorporating the 2,5-
disubstituted 1,3-dioxane ring were also prepared by the
TsOH-catalyzed acetalization of aldehydes with 2-substituted-
1,3-propanediols in refluxing toluene,6−8 where two possible
diastereomers with respect to the formed disubstituted 1,3-
dioxane ring were usually obtained with unsatisfactory
selectivity (trans/cis = ca. 60−80:40−20). As the trans isomer
After intensive investigations in the pursuit of large positive
Δε-type LC compounds, the Chisso (now JNC) group found a
new LC compound 1, trans-5-propyl-2-(trans-4-(3,4,5-
trifluorophenyl)cyclohexyl)-1,3-dioxane (Figure 1), in 1996,8
which showed a high Δε value (23.7). Considering that its
structurally related compound 2 possessed a Δε value of 8.3,9
Special Issue: Japanese Society for Process Chemistry
Received: November 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.8b00408
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Table 1. Synthesis of LC Compound 1 in Various Solvents
entry
solvent
toluene
temperature
trans-1/cis-1
1
−18 °C
56:44
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
toluene
toluene
hexane
cyclohexane
chloroform
THF
DME
CPME
acetone
DMSO
DMF
DMI
DMPU
NMP
H2O
[Bmim]BF4
[Bmim]PF6
rt
reflux
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
83:17
76:24
82.1:17.9
80.3:19.7
81.1:18.9
78.6:21.4
77.9:22.1
79.9:20.1
77.5:22.5
60.2:39.8
62.0:38.0
58.9:41.1
58.1:41.9
58.1:41.9
60.2:39.8
98.5:1.5
98.2:1.8
Table 2. Acetalization with Saturated Aqueous Solution of Several Inorganic Salts
a
entry
satd MXn in aq. acidic solution
solubility of MXn (g/100 g of H2O)
trans-1/cis-1
1
2
3
4
5
6
7
8
1 M HCl
58.5:41.5
97.3:2.7
68.6:31.4
59.5:40.5
90.0:10.0
97.8:2.2
satd LiCl in 0.1 M HCl
satd NaCl in 1 M HCl
satd KCl in 1 M HCl
satd MgCl2 in 1 M HCl
satd CaCl2 in 1 M HCl
satd BaCl2 in 1 M HCl
satd ZnCl2 in H2O
83.5
35.9
34.2
54.6
74.5
35.8
395
59.9:40.1
98.8:1.2
9
satd AlCl3 in H2O
1 M H2SO4
satd Na2SO4 in 0.5 M H2SO4
satd MgSO4 in 0.5 M H2SO4
45.8
53.5:46.5
58.5:41.5
58.0:42.0
59.0:41.0
10
11
12
19.5
33.7
a
Solubility at 20 °C (ref 22).
is responsible for exhibiting liquid crystal properties, 1,3-
dioxane 1, obtained as a trans-cis mixture from aldehyde 3 and
1,3-propanediol 5, was required to be subject to repeated
recrystallization to obtain pure trans-1.8
acetalization reaction of 2-substituted 1,3-propanediols and
aldehydes in the presence of saturated aqueous solutions of
inorganic salts.
Since the current process toward trans-1 lacks stereo-
selectivity and involves the substrate-waste repeated recrystal-
lization steps, thereby resulting in decreasing the yield of trans-
1, it was desired to develop an improved method to synthesize
1 with trans selective manner. Furthermore, in terms of green
chemistry it is highly recommended to use environmentally
friendly solvents (e.g., ionic liquids15 and H2O16) for the
synthetic process from chemical industry. Herein, we report a
stereoselective synthesis of trans-2,5-disubstituted 1,3-dioxane
derivatives, such as LC compound 1, through an acid-catalyzed
RESULTS AND DISCUSSION
■
Acetalization in Various Solvents. In the beginning, to
evaluate solvent effect for the synthesis of 1 we examined the
transacetalization reaction17 in various solvents as shown in
Table 1. All reactions were performed by treatment of
aldehyde 38 with acetonide 4 in the presence of a catalytic
amount (1 mol%) of TsOH for 24 h, producing an almost
quantitative yield of the desired 1,3-dioxane 1 in the indicated
trans-cis ratio. We regarded that the acetalization progressed
kinetically at low temperature (entry 1) and the equilibrium
B
DOI: 10.1021/acs.oprd.8b00408
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Scheme 1. Synthesis of 1 with Saturated Aqueous CaCl2 and ZnCl2 Solution
Table 3. Acetalization with Several Concentrations of Aqueous CaCl2Solution
a
entry
concentration of CaCl2 (wt%) in 1 M HCl (0.2 mL)
trans-1/cis-1
1
2
3
4
5
6
7
0
58.5:41.5
60.5:39.5
64.3:35.7
71.2:28.9
78.6:21.3
84.5:15.5
97.8:2.2
22.6 (36.8)
32.7 (61.3)
36.9 (73.6)
38.8 (79.8)
40.5 (85.9)
44.2 (100)
a
Parentheses indicate degree of saturation of CaCl2 solution in 1 M HCl.
occurred over room temperature to produce an ∼8:2 mixture
of 1 (entries 2−3). Less polar solvents (toluene, hexane,
cyclohexane, chloroform, tetrahydrofuran (THF), dimethoxy-
ethane (DME), cyclopentyl methyl ether (CPME), and
acetone) are effective to show moderate trans selectivity
(entries 2−10), while polar solvents (dimethyl sulfoxide
(DMSO), N,N-dimethylformamide (DMF), 1,3-dimethyl-2-
imidazolidinone (DMI), N,N'-dimethylpropyleneurea
(DMPU), and N-methylpyrrolidone (NMP)) decreased the
selectivity (entries 11−15). Interestingly, the acetalization with
water18 also took place to give 1 with a high conversion but
incomplete selectivity (entry 16). Fortunately, when the
reaction was performed in the presence of ionic liquids19
such as 1-butyl-3-methylimidazolium tetrafluoroborate
([Bmim]BF4) and 1-butyl-3-methylimidazolium hexafluoro-
phosphate ([Bmim]PF6) (entries 17−18), we found that
dioxane 1 was afforded with an almost complete trans
selectivity (trans/cis = >98:<2).
Acetalization with Saturated Aqueous Solution of
Several Inorganic Salts. Ionic liquids are environmentally
benign solvents due to low volatility, nonflammable nature,
and ease of recycling;15 however, their cost is still high for
industrial-scale process compared with that of organic
solvents.20 After considering the alternative solvent system in
place of ionic liquids, we came up with the idea to use
saturated aqueous solutions of inorganic salts21 for the
acetalization (Table 2). Initially, we attempted the reaction
of aldehyde 3 and 2-propyl-1,3-propanediol (5) by using 1 M
HCl, giving 1 as a kinetic product (entry 1, trans/cis = 58.5/
41.5) with an almost quantitative conversion. In this reaction,
the desired product 1 was precipitated out with progressing
reaction, and this precipitation from the reaction media
probably assisted in preventing reverse hydrolysis. Next,
several saturated aqueous solutions of inorganic salts (LiCl,
NaCl, KCl, MgCl2, CaCl2, BaCl2, ZnCl2, AlCl3, Na2SO4, and
MgSO4) with acids (HCl or H2SO4) were investigated. In the
presence of saturated (satd) LiCl solution in 0.1 M HCl, the
selectivity dramatically changed, giving rise to a 97.3/2.7
mixture of 1 (entry 2). Although some inorganic salts (NaCl,
KCl, BaCl2, AlCl3, Na2SO4, and MgSO4) were fruitless under
the same condition, we fortunately found that aqueous
saturated solutions of MgCl2, CaCl2, and ZnCl2 are also
effective to obtain 1 with high trans-selectivity (trans/cis =
>90/<10). The common property of these effective inorganic
salts is high solubility in water (>50 g in 100 g of H2O at 20
°C)22 as shown in Table 2.
Synthesis of 1 with Saturated Aqueous CaCl2 and
ZnCl2 Solution. Two representative solvent systems showing
high trans selectivity were then used for the synthesis and
isolation of 1 as shown in Scheme 1. Aldehyde 3 was subjected
to reaction with 1.1 equiv of 1,3-propanediol 5 with satd CaCl2
solution in 1 M HCl or satd ZnCl2 solution in H2O at 30 °C
for 24 h. The resulting products were purified by passing
through a silica gel column, giving rise to the targeted
compound 1 in 96% isolated yield (trans/cis = 96.1/3.9) and in
85% isolated yield (trans/cis = 98.1/1.3), respectively.
Acetalization with Several Concentrations of Aque-
ous CaCl2 Solution. Having obtained a good solvent system
for the stereoselective acetalization to 1, we next investigated
the effect of concentration of CaCl2 solution in 1 M HCl. The
acetalization reaction of 3 (0.2 mmol) and 5 was performed in
the presence of several concentrations of CaCl2 solution in 1
M HCl (0.2 mL, 0%∼100% satd CaCl2 solution) as shown in
Table 3. All reactions proceeded to give 1,3-dioxane 1 with the
indicated trans-cis ratio. These results pointed out that the
reaction with higher saturated solution of CaCl2 gave 1 with
higher trans selectivity and using satd CaCl2 solution was
mandatory to obtain trans-1 with satisfactory stereoselectivity.
Time-Dependent Change of the trans-cis Ratio in
Acetalization. To confirm the reaction pathway, we also
observed the time-dependent change of the ratio of trans-cis
isomers of 1. As shown in Table 4, we ran three to five
C
DOI: 10.1021/acs.oprd.8b00408
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Organic Process Research & Development
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Table 4. Time-Dependent Change of the trans-cis Ratio in Acetalization
reaction time (h)
reaction at 30 °C trans-1/cis-1
reaction at 50 °C trans-1/cis-1
1
3
9
24
72
58.3:41.7
65.2:34.9
91.1:8.9
97.9:2.1
98.4:1.6
67.7:32.3
92.2:7.8
98.7:1.3
experiments with satd CaCl2 solution in 1 M HCl at 30 and 50
°C and checked the trans-cis ratio of 1 after the indicated
reaction time. The acetalization at 30 °C was completed within
1 h to give 1 as a kinetically favored product (trans/cis =
58.3:41.7), which was gradually isomerized to the desired trans
isomer 1(trans/cis = >97:<3) after 24 h. At 50 °C the
equilibrium reaction was fast, giving rise to trans-1 for 9 h.
Consideration of the High Stereoselectivity. We
concluded that the optimized condition for the synthesis of
1 with high trans selectivity (trans/cis >96:4) was heating of
aldehyde 3 and 1,3-propanediol 5 at 50 °C with satd CaCl2
solution in 1 M HCl. The possible reason for this high
stereoselectivity is considered to be as follows. At the
beginning of the reaction, a mixture of substrates and satd
CaCl2 solution formed two liquid phases (organic phase (3
and 5) and aqueous phase), and as the reaction proceeded the
organic liquid phase disappeared. On the one hand, the trans-
cis mixture of acetal 1 precipitated out of water. On the other
hand, when the reaction was performed at 70 °C the initial
two-liquid-phase system was maintained, and the precipitation
was not observed due to the melting of the product, affording 1
in a moderate ratio (trans/cis = 83:17). Furthermore, hexane
was used as a cosolvent, and the reaction was conducted at 30
°C with keeping two-liquid-phase system (hexane and satd
CaCl2 solution in 1 M HCl) to produce 1 with a moderate
selectivity (trans/cis = 76:24). Therefore, the key to obtain
trans-1 with high selectivity is the precipitation of 1 during the
reaction and using saturated aqueous solution of inorganic salts
having high water solubility. On the basis of the fact that a
59:41 mixture of trans-1 and cis-1 is liquid and a 99:1 mixture
is solid (see experimental), cis-1 may be liquid or solidify
slowly during the reaction. Then, satd CaCl2 solution in 1 M
HCl would assist the isomerization of liquid cis-1 to solid trans-
1, resulting in the formation of trans-1 with stereoselective
manner.23 The role of saturated aqueous solution is currently
under investigation.
Scheme 2. Synthesis of Other LC Compounds
the acetalizations of diols (625 and 826) with aldehydes (3 and
10) smoothly progressed to give each compound in good
yields with high trans selectivity.
CONCLUSION
■
100 g Scale Synthesis of 1. We then applied the
developed method to a 100 g scale synthesis of LC compound
1. At 50 °C under Ar, 77.7 g of aldehyde 3 was allowed to react
with 39.8 g of 1,3-propanediol 5 with satd CaCl2 solution in 1
M HCl (320 mL), and the reaction was completed for 30 h,
generating 105 g of the targeted compound 1 (95% isolated
yield) with a high trans/cis ratio (trans/cis = 99.0:1.0) without
any difficulties.
Application of the Developed Method to Synthesis
of Other LC Compounds. Finally, other three LC
compounds (7, 9, and 1124) incorporating a 2-substituted
1,3-dioxane ring were synthesized by applying the developed
method as shown in Scheme 2. Under the optimized condition,
In conclusion, we developed a stereoselective method to
synthesize trans-2,5-disubstituted 1,3-dioxane derivatives,
which are important liquid crystal compounds. The acetaliza-
tion reaction of aldehydes and 2-substituted 1,3-propanediols
in the presence of acids with saturated aqueous solutions of
inorganic salts having high water solubility, such as CaCl2,
LiCl, and ZnCl2, proceeded to give the corresponding 2,5-
disubstituted 1,3-dioxane derivatives with high trans selectivity
(trans/cis > 96/4).
EXPERIMENTAL
General. All reactions involving air- and moisture-sensitive
reagents were performed using oven-dried glassware and
■
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DOI: 10.1021/acs.oprd.8b00408
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1
standard syringe-septum cap techniques. Routine monitoring
of reaction was performed using glass-supported Merck silica
gel 60 F254 thin-layer chromatography (TLC) plates. Flash
column chromatography was performed on Kanto chemical
Silica Gel 60 N (spherical, neutral 40−50 μm). All solvents
and reagents were obtained from commercial supplier and
were used without further purification. Infrared (IR) spectral
measurements were performed with a HORIBA FT-720
1442, 1348, 1226, 1153, 1034, 945, 849, 783, 700 cm−1; H
NMR for trans isomer (400 MHz, CDCl3) δ: 6.81−6.76 (2H,
m, Ar-H), 4.21 (1H, d, J = 5.1 Hz, C2-H), 4.08 (2H, dd, J = 4.6
Hz, 11.7 Hz, C4-Heq, C6-Heq), 3.29 (2H, t, J = 11.4 Hz, C4-Hax,
C6-Hax), 2.40 (1H, tt, J = 3.2 Hz, 11.8 Hz, Cbenzyl-H), 2.01−
1.88 (5H, m, C5-H), 1.57 (1H, m, overlap with H2O), 1.38−
1.18 (6H, m), 1.04−0.98 (2H, m), 0.90 (3H, t, J = 7.3 Hz,
Me); 13C NMR for trans isomer (101 MHz, CDCl3) δ: 151.1
(2C, ddd, J = 4.1 Hz, 9.7 Hz, 244.4 Hz), 143.8 (1C, dt, J = 4.5
Hz, 6.5 Hz), 137.6 (1C, td, J = 15.4 Hz, 248.6 Hz), 110.6 (2C,
dd, J = 5.3 Hz, 15.4 Hz), 104.8, 72.3 (2C), 43.6, 41.8, 34.3,
33.4 (2C), 30.4, 27.3 (2C), 19.6, 14.2; 19F{1H} NMR for trans
isomer (377 MHz, CDCl3) δ: −135.9 (2F, d, J = 20.4 Hz),
−165.2 (1F, t, J = 20.4 Hz); Anal. Calcd for C19H25F3O2: C,
66.65; H, 7.36; F, 16.65; O, 9.35. Found: C, 66.53; H, 7.32%.
The GC retention times are 13.2 min for cis-1 and 13.4 min for
trans-1. GCMS-EI: m/z 342 [M]+ (0.9), 341 [M-H]+ (1.2),
129 [M-C12H12F3]+ (100).
Synthesis of trans-5-Propyl-2-(trans-4-(3,4,5-
trifluorophenyl)cyclohexyl)-1,3-dioxane (1) with Satu-
rated Aqueous ZnCl2 Solution. 2-Propyl-1,3-propanediol
(5) (260 mg, 2.2 mmol) and trans-4-(3,4,5-trifluorophenyl)-
cyclohexanecarbaldehyde (3) (485 mg, 2.0 mmol) were placed
in a 20 mL glass centrifuge tube equipped with a Teflon-coated
stir bar. To this mixture, saturated aqueous ZnCl2 solution (2.0
mL) was added, and the resulting mixture was stirred at 30 °C
for 24 h under Ar. The reaction mixture was cooled to room
temperature and extracted with toluene. The organic phase was
dried over anhydrous K2CO3 and concentrated in vacuo. The
residue was filtered through silica gel pad (eluent: hexane) to
obtain 1 as a white powder (583 mg, 85%, trans/cis = 98.7:1.3,
GC purity >99.5%).
Large-Scale Synthesis of trans-5-Propyl-2-(trans-4-
(3,4,5-trifluorophenyl)cyclohexyl)-1,3-dioxane (1).
trans-4-(3,4,5-Trifluorophenyl)cyclohexanecarbaldehyde (5)
(77.7 g, 0.32 mol) and 2-propyl-1,3-propanediol (3) (39.8 g,
0.34 mol) were placed in a 500 mL glass recovery flask
equipped with a Teflon-coated stir bar and an air-cooled
condenser. To this mixture, saturated CaCl2 solution in 1 M
HCl (320 mL) was added, and the resulting mixture was
stirred at 50 °C for 18 h under Ar. To the reaction mixture,
concentrated HCl (1.00 mL) and CaCl2 (50.0 g) were added,
and the resulting suspension was stirred, until the ratio of cis-1
decreased to less than 2.5% (monitored by GC-MS) (12 h).
The reaction mixture was cooled to room temperature, and the
resulting suspension was filtered. The solid was thoroughly
washed with water and dried to obtain 1 as a white crystal (105
g, 95%, trans/cis = 99.0:1.0, GC purity >99.5%).
1
spectrometer. H, 13C, and 19F NMR spectra were measured
with a Bruker Ascend 400 spectrometer. Chemical shifts are
expressed in parts per million (ppm) using tetramethylsilane (δ
= 0, 1H NMR and 13C NMR) and trichlorofluoromethane (δ =
0, 19F NMR) as standard substances. Multiplicities are
indicated by s (singlet), d (doublet), t (triplet), dd (doublet
of doublet), dt (doublet of triplet), ddd (doublet of doublet of
doublet), td (triplet of doublet), tt (triplet of triplet), and m
(multiplet). Melting points were taken on Mettler Toledo
MP70 melting point system and uncorrected. Gas chromatog-
raphy−mass spectrometry (GC-MS) analysis was performed
on a Shimadzu GCMS-QP2010 equipped with a fused silica
capillary DB-5MS column (30 m × 0.25 mm, and 0.25 μm film
thickness, Agilent Technologies). The analytes were ionized
using EI (electron ionization) method. The inlet temperature
was maintained at 280 °C. The oven temperature was initially
held at 80 °C for 3 min and was then programmed to 300 °C
at 20 °C/min, where it was held constant for 8 min. Helium
was used as carrier gas.
Synthesis of a Mixture of trans/cis-5-Propyl-2-(trans-
4-(3,4,5-trifluorophenyl)cyclohexyl)-1,3-dioxane (1)
with TsOH. 2-Propyl-1,3-propanediol (5) (1.00 g, 8.5
mmol) and trans-4-(3,4,5-trifluorophenyl)cyclohexane-
carbaldehyde (3) (1.86 g, 7.7 mmol) were placed in a 20
mL glass centrifuge tube equipped with a Teflon-coated stir
bar. To this mixture, DMF (8.0 mL) and p-toluenesulfonic
acid monohydrate (15.0 mg, 0.079 mmol) were added, and the
resulting mixture was stirred at room temperature for 24 h
under Ar. The reaction mixture was diluted with water and
extracted with hexane. The organic phase was dried over
anhydrous K2CO3 and concentrated in vacuo to obtain a trans/
cis mixture of 1 as a colorless liquid (2.19 g, 83%, trans/cis =
1
58.7:41.3, GC purity 94.3%): H NMR for cis isomer (400
MHz, CDCl3) δ: 6.83−6.74 (2H, m, overlap with trans
isomer), 4.31 (1H, d, J = 5.0 Hz), 3.95−3.85 (4H, m), 2.40
(1H, m, overlap with trans isomer), 2.04−1.86 (5H, m, overlap
with trans isomer), 1.57 (1H, m, overlap with H2O and trans
isomer), 1.73−1.66 (2H, m), 1.44−1.17 (6H, m, overlap with
trans isomer), 0.94 (3H, t, J = 7.3 Hz). The GC retention time
is 13.2 min.
Synthesis of trans-5-Propyl-2-(trans-4-(3,4,5-
trifluorophenyl)cyclohexyl)-1,3-dioxane (1) with Satu-
rated CaCl2 Solution in 1 M HCl. 2-Propyl-1,3-propanediol
(5) (650 mg, 5.5 mmol) and trans-4-(3,4,5-trifluorophenyl)-
cyclohexanecarbaldehyde (3) (1.21 g, 5.0 mmol) were placed
in a 25 mL glass test tube equipped with a Teflon-coated stir
bar. To this mixture, saturated CaCl2 solution in 1 M HCl (5.0
mL) was added, and the resulting mixture was stirred at 30 °C
for 24 h under Ar. The reaction mixture was cooled to room
temperature, diluted with water, and extracted with toluene.
The organic phase was dried over anhydrous K2CO3 and
concentrated in vacuo. The residue was filtered through silica
gel pad (eluent: hexane) to obtain 1 as a white powder (1.65 g,
96%, trans/cis = 96.1:3.9, GC purity >99.5%); mp 92.2−93.2
°C; IR νmax (neat) 2958, 2920, 2852, 2359, 2333, 1612, 1531,
Synthesis of trans-5-(2-(trans-4-Propylcyclohexyl)-
ethyl)-2-(trans-4-(3,4,5-trifluorophenyl)cyclohexyl)-1,3-
dioxane (7). 2-(2-(trans-4-Propylcyclohexyl)ethyl)-1,3-pro-
panediol (6) (91.4 mg, 0.40 mmol) and trans-4-(3,4,5-
trifluorophenyl)cyclohexanecarbaldehyde (3) (96.9 mg, 0.40
mmol) were placed in a 10 mL glass test tube equipped with a
Teflon-coated stir bar. To this mixture, saturated CaCl2
solution in 1 M HCl (800 μL) was added, and the resulting
mixture was stirred at 50 °C for 9 h under Ar. The reaction
mixture was cooled to room temperature, diluted with water,
and extracted with toluene. The organic phase was dried over
anhydrous K2CO3 and concentrated in vacuo to obtain 7 as a
white powder (154.2 mg, 85%, trans/cis = 98.0:2.0, GC purity
98.8%); mp 100.0−106.4 °C; IR νmax (neat) 2910, 2850, 2359,
2339, 1533, 1442, 1344, 1227, 1153, 1136, 1041, 947, 852, 700
E
DOI: 10.1021/acs.oprd.8b00408
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
cm−1; 1H NMR (400 MHz, CDCl3) δ: 6.82−6.75 (2H, m, Ar-
H), 4.20 (1H, d, J = 5.1 Hz, C2-H), 4.08 (2H, dd, J = 4.6 Hz,
11.6 Hz, C4-Heq, C6-Heq), 3.28 (2H, t, J = 11.4 Hz, C4-Hax, C6-
Hax), 2.40 (1H, tt, J = 3.2 Hz, 11.8 Hz, Cbenzyl-H), 1.97−1.87
(5H, m), 1.72−1.68 (4H, m), 1.57 (1H, m, overlap with H2O),
1.37−1.08 (12H, m), 1.06−1.00 (2H, m), 0.88−0.82 (7H, m);
13C NMR (101 MHz, CDCl3) δ: 151.1 (2C, ddd, J = 4.0 Hz,
9.7 Hz, 245 Hz), 143.7 (1C, dt, J = 4.5 Hz, 6.5 Hz), 137.9 (1C,
td, J = 15.4 Hz, 248.6 Hz), 110.6 (2C, dd, J = 5.3 Hz, 15.4 Hz),
104.8, 72.3 (2C), 43.6, 41.8, 39.8, 37.9, 37.5, 34.7, 33.9, 33.4
(2C), 33.2 (2C), 33.2 (2C), 27.3 (2C), 25.6, 20.0, 14.4;
19F{1H} NMR (377 MHz, CDCl3) δ: −135.9 (2F, d, J = 20.6
Hz), −165.2 (1F, t, J = 20.5 Hz); Anal. Calcd for C27H39F3O2:
C, 71.65; H, 8.69; F, 12.59; O, 7.07. Found: C, 71.45; H,
8.72%. The GC retention times are 19.1 min for cis-7 and 20.3
min for trans-7. GCMS-EI: m/z 452 [M]+ (0.8), 451 [M-H]+
(0.5), 239 [M-C12H12F3]+ (26.6), 55 [C4H7]+ (100).
1518, 1429, 1389, 1281, 1153, 1130, 1115, 1032, 891, 806,
1
771, 683 cm−1; H NMR (400 MHz, CDCl3) δ: 7.32 (1H,
ddd, J = 2.1 Hz, 8.0 Hz, 10.6 Hz, Ar6-H), 7.20 (1H, m, Ar2-H),
7.13 (1H, m, Ar5-H), 5.32 (1H, s, C2-H), 4.30 (2H, dd, J = 4.6
Hz, 11.7 Hz, C4-Heq, C6eq-Heq), 3.62 (2H, t, J = 11.5 Hz, C4-
Hax, C6-Hax), 1.89 (1H, m, C5-H), 1.78−1.68 (4H, m), 1.30−
1.21 (4H, m), 1.20−1.12 (3H, m), 1.09−0.95 (3H, m), 0.92−
0.78 (5H, m); 13C NMR (101 MHz, CDCl3) δ: 150.6 (1C, dd,
J = 14.8 Hz, 250.9 Hz), 149.1 (1C, dd, J = 14.5 Hz, 249.5 Hz),
135.7 (1C, m), 122.3 (1C, dd, J = 3.8 Hz, 6.4 Hz), 116.9 (1C,
dd, J = 1.1 Hz, 16.2 Hz), 115.5 (1C, dd, J = 2.7 Hz, 16.7 Hz),
99.8, 71.2 (2C), 39.2, 37.5, 37.3, 37.0, 33.0 (2C), 29.9 (2C),
29.1, 23.0, 14.1; 19F{1H} NMR (377 MHz, CDCl3) δ: −138.4
(1F, d, J = 20.6 Hz), −138.5 (1F, d, J = 20.6 Hz); Anal. Calcd
for C20H28F2O2: C, 70.98; H, 8.34; F, 11.23; O, 9.45. Found:
C, 70.95; H, 8.19%. The GC retention times are 13.8 min for
cis-11 and 14.3 min for trans-11. GCMS-EI: m/z 338 [M]+
(12.2), 337 [M-H]+ (24.6), 319 [M-F]+ (0.8), 225 [M-
C6H3F3]+ (1.5), 113 [C6H3F3]+ (55.4), 67 [C5H7]+ (100).
Synthesis of trans-5-(trans-4-Butylcyclohexyl)-2-
(trans-4-(3,4,5-trifluorophenyl)cyclohexyl)-1,3-dioxane
(9). 2-(trans-4-Butylcyclohexyl)-1,3-propanediol (8) (85.8 mg,
0.40 mmol) and trans-4-(3,4,5-trifluorophenyl)cyclohexane-
carbaldehyde (3) (96.9 mg, 0.40 mmol) were placed in a 10
mL glass test tube equipped with a Teflon-coated stir bar. To
this mixture, saturated CaCl2 solution in 1 M HCl (800 μL)
was added, and the resulting mixture was stirred at 50 °C for 9
h under Ar. The reaction mixture was cooled to room
temperature, diluted with water, and extracted with toluene.
The organic phase was dried over anhydrous K2CO3 and
concentrated in vacuo to obtain 9 as a white powder (165.5
mg, 94%, trans/cis = 98.7:1.3, GC purity 98.9%); mp 115.2−
122.0 °C; IR νmax (neat) 2918, 2843, 2362, 2330, 1531, 1444,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.8b00408.
■
S
Optimization experiments and H, 13C, and 19F NMR
1
spectra of all synthetic compounds (1, 7, 9, and 11)
(PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: inoue@sagami.or.jp
■
1
1348, 1228, 1155, 1138, 1032, 847, 704 cm−1; H NMR (400
ORCID
MHz, CDCl3) δ: 6.82−6.75 (2H, m, Ar-H), 4.18 (1H, d, J =
5.0 Hz, C2-H), 4.16 (2H, dd, J = 4.6 Hz, 11.8 Hz, C4-Heq, C6-
Heq), 3.40 (2H, t, J = 11.4 Hz, C4-Hax, C6-Hax), 2.40 (1H, tt, J
= 3.0 Hz, 11.8 Hz, Cbenzyl-H), 1.97−1.88 (4H, m), 1.76−1.73
(3H, m), 1.67−1.63 (2H, m), 1.56 (1H, m, overlap with H2O),
1.38−1.12 (11H, m), 1.00−0.93 (3H, m), 0.89−0.78 (5H, m);
13C NMR (101 MHz, CDCl3) δ: 151.1 (2C, ddd, J = 4.0 Hz,
9.7 Hz, 244.5 Hz), 143.7 (1C, dt, J = 4.5 Hz, 6.5 Hz), 137.9
(1C, td, J = 15.4 Hz, 248.6 Hz), 110.6 (2C, dd, J = 5.2 Hz, 15.4
Hz), 104.6, 70.8 (2C), 43.6, 41.8, 39.6, 37.5, 37.4, 37.1, 33.4
(2C), 33.0 (2C), 29.9 (2C), 29.1, 27.3 (2C), 23.0, 14.1; 19F
NMR (377 MHz, CDCl3) δ: −135.9 (2F, d, J = 20.5 Hz),
−165.2 (1F, t, J = 20.6 Hz); Anal. Calcd for C26H37F3O2: C,
71.20; H, 8.50; F, 13.00; O, 7.30. Found: C, 71.05; H, 8.51%.
The GC retention times are 18.5 min for cis-9 and 19.2 min for
trans-9. GCMS-EI: m/z 438 [M]+ (0.6), 437 [M-H]+ (1.3),
225 [M-C12H12F3]+ (70.4), 55 [C4H7]+ (100).
Synthesis of trans-5-(trans-4-Butylcyclohexyl)-2-(3,4-
difluorophenyl)-1,3-dioxane (11). 2-(trans-4-Butylcyclo-
hexyl)-1,3-propanediol (8) (85.8 mg, 0.40 mmol) and 3,4-
difluorobenzaldehyde (10) (56.8 mg, 0.40 mmol) were placed
in a 10 mL glass test tube equipped with a Teflon-coated stir
bar. To this mixture, saturated CaCl2 solution in 1 M HCl
(800 μL) was added, and the resulting mixture was stirred at
50 °C for 9 h under Ar. The reaction mixture was cooled to
room temperature, diluted with water, and extracted with
toluene. The organic phase was dried over anhydrous K2CO3
and concentrated in vacuo to obtain 11 as a white powder
(133.7 mg, 99%, trans/cis = >99.5:<0.5, GC purity >99.5%);
mp 86.9−87.6 °C; IR νmax (neat) 2922, 2843, 2359, 2333,
Munenori Inoue: 0000-0002-1154-5781
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.oprd.8b00408
Org. Process Res. Dev. XXXX, XXX, XXX−XXX