Synthesis of 3,5-disubstituted 1,2,4-oxadiazoles and their behavior of liquid crystallines

Article abstract of DOI:10.1016/j.tetlet.2014.01.066

The synthesis of 3,5-disubstituted 1,2,4-oxadiazoles by the cyclocondensation of amidoximes with trifluoroacetic anhydride or benzoic acid derivatives in moderate to high yields is described. The study on the phase transition behavior has disclosed that s

Full text of DOI:10.1016/j.tetlet.2014.01.066

Tetrahedron Letters 55 (2014) 1557–1560
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 3,5-disubstituted 1,2,4-oxadiazoles and their behavior
of liquid crystallines
a
a
Jian Guo a, Ruimao Hua a,b, , Yan Sui , Jianhua Cao
⇑
a Hebei Engineering & Technology Center for FPD Materials, Shijiazhuang 050091, China
b Department of Chemistry, Tsinghua University, Beijing 100084, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 3,5-disubstituted 1,2,4-oxadiazoles by the cyclocondensation of amidoximes with
trifluoroacetic anhydride or benzoic acid derivatives in moderate to high yields is described. The study
on the phase transition behavior has disclosed that some of the synthesized oxadiazoles show smectic
or nematic phases depending on their structures, which have the high potential application as liquid
crystalline monomers.
Received 21 October 2013
Revised 8 January 2014
Accepted 16 January 2014
Available online 23 January 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
3,5-Disubstituted 1,2,4-oxadiazoles
Liquid crystal
Nematic phase
Phase transition
Smectic phase
3,5-Disubstituted 1,2,4-oxadiazoles are important five-
membered heterocyclic compounds not only occurring in natural
and artificial products showing interesting biological and physio-
logical activities,1 but also being applied as the functionalized
organic materials, particularly as liquid crystalline monomers.1a It
has been found that the high polarization of the electronic system
in heterocyclic moieties can easily adjust the phase transition tem-
perature and change the types of liquid crystal phase by controlling
the polarity and configuration of molecules,2 also may result in the
increase of molecular dipole and dielectric anisotropy.3 Therefore,
as one of the typical five-membered heterocycles, recently a variety
of 3,5-diaryl-1,2,4-oxadiazole derivatives have been synthesized,
and applied as the bent-core liquid crystals with intriguing
properties.4
There is no doubt that the development of the excellent liquid
crystal displays (LCDs) with the advantages of fast response, high
contrast ratio, and low driving voltage greatly depends on the de-
sign and synthesis of new types of liquid crystalline monomers and
liquid crystal mixtures. It can be expected that heterocyclic com-
pounds having the strong electron withdrawing group of trifluoro-
methyl as a substituent should lead to the further increase of
molecular dipole and dielectric anisotropy, this Letter therefore
describes the synthesis of 3-aryl-5-trifluoromethyl (2a–i) and
3,5-diaryl 1,2,4-oxadiazole derivatives (2j–k), as well as the inves-
tigation on their phase transition behavior.
There have been many synthetic routes for the formation of
3,5-disubstituted 1,2,4-oxadiazoles,5 but one of the most efficient
methods is the cyclization of O-acylamidoximes, which can be
formed from the acylation of amidoximes with acid anhydride or
carboxylic acid derivatives.6 Therefore the reaction of easily
available amidoximes with trifluoroacetic anhydride (TFAA) under
the modified reaction conditions (without the use of base) was
employed for the synthesis of 3-aryl-5-trifluoromethyl-1,2,4-
oxadiazoles, and the obtained results are included in Table 1. The
choice of the structural species of the R group (aryl group) in the
present study such as fluorinated aryl, cyclohexyl aryl, is based
on the known knowledge on their application as the fundamental
structural moieties in liquid crystallines. As shown in Table 1, a
variety of 5-trifluoromethyl-1,2,4-oxadiazoles bearing different
aryl groups at 3-position could be synthesized in good yields in
toluene under refluxing conditions for 4 h, and the structures of
all the target products were confirmed by their 1H NMR, 13C
NMR, 19F NMR, and elemental analyses or HRMS.7
The proposed mechanism for the formation of 3-aryl-5-trifluo-
romethyl-1,2,4-oxadiazoles is shown in Scheme 1, which involves
the formation of O-trifluoroacetyl amidoxime as the crucial inter-
mediate, and followed by cyclization reaction via nucleophilic
addition and dehydration.
In addition, the synthesis of 3,5-diaryl-1,2,4-oxadiazole deriva-
tives was also studied by the first direct cyclocondensation of
amidoxime with benzoic acid derivatives via the formation of
the corresponding amides as the intermediates with the use
of N-ethyl-N0-dimethylaminopropylcarbodiimide hydrochloride
⇑
Corresponding author. Tel.: +86 10 62792596; fax: +86 10 62771149.
E-mail address: ruimao@mail.tsinghua.edu.cn (R. Hua).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2014.01.066

1558
J. Guo et al. / Tetrahedron Letters 55 (2014) 1557–1560
Table 1
N
OH
Synthesis of 5-trifluoromethyl 1,2,4-oxadiazolesa
R
1
N
N
NH2
+
.
EDCI HCl (1.5 equiv)
O
F
N
OH
N
R
O
.
HOBt H2O (1.5 equiv)
toluene
reflux for 4h
R
R
F
+
(CF3CO)2O
1.2 equiv
F
F
Et3N (3.0 equiv)
NH2
N
DMF, 90 oC, 4 h
CF3
1
2
n-C3H7
n-C3H7
COOH
1.5 equiv
F
F
F
N
O
N
HO
O
R =
MeO
2k 45%
R =
MeO
N
CF3
n-Pr
N
CF3
F
2j 52%
2a 87%
2b 88%
F
Scheme 2. Synthesis of 3,5-diaryl-1,2,4-oxadiazoles from the condensation of
amidoximes with benzoic acid derivatives.
N
N
N
O
O
n-BuO
n-Pr
n-BuO
N
CF3
CF3
2c 82%
2d 81%
2f 94%
Table 2
Melting points (°C) or phase transition temperatures (ptt, °C) of 3,5-disubstituted
1,2,4-oxadiazoles by DSC
F
F
O
N
N
CF3
O
N
Oxadiazole
mp
ptt
Oxadiazole
mp
ptt
N
CF3
n-Pr
2a
74.4–75.2
2h
Cr 114.7
S 184.4
N 258.1 I
141.6 N
173.2 I
2e 90%
O
2c
2f
Cr 48.5
S 85.2 I
Cr 83.4
S 96.8 I
2i
69.8–69.9
89.8–90.4
F
F
N
CF3
N
2j
Cr 71.7
N 153.5 I
2g 82%
2h 85%
O
2g
41.6–42.2
2k
O
N
N
CF3
CF3
N
nematic phases with a wide nematic temperature range from
184.4 to 253.1 °C, 141.6 to 173.2 °C, and 71.7 to 153.5 °C, respec-
tively. It should be noted that 2h–j possess a common structural
moiety of n-propyl–cyclohexyl–phenyl at 3-position of the oxadi-
azole ring, which is a possible crucial structure to show the nema-
tic phase. Since 2h–j have the wide nematic temperature range,
they have highly potential application in the preparation of practi-
cal liquid crystal mixture for LCDs as the liquid crystalline mono-
mers. The typical schlieren textures of 2c, 2f, 2h, 2i, and 2j are
shown in Figure 1.
O
n-Pr
n-Pr
N
2i 92%
F
a
The reactions were carried out with 2.0 mmol of 1 and 2.4 mmol of trifluoro-
acetic anhydride in 30.0 mL of toluene under reflux for 4 h.
In addition, as shown in Table 1 2h and 2i have the same core
structure, but they show considerable different phase transition
temperature and nematic temperature range. On the basis of the
DFT calculations (Fig. 2), it has been found that both 2h and 2i have
the similar configurations with the 3-aryl group (2h), or 3-fluoro-
aryl group (2i) and the oxadiazole ring being in the same plane.
These results indicate that the introduction of ortho-fluorines in
the aryl group of 3-position of the oxadiazole ring cannot affect
the configuration of the substituted oxadiazole ring, but is the cru-
cial factor to greatly change the phase transition behavior. Further-
more, as shown in Figure 2, the configuration of 3,5-diary groups
and oxadiazole ring in 2j is also in the same plane. All these ob-
served results are very interesting and important to provide a hint
to elucidate the relationship of structure or configuration with
phase transition behavior.
In conclusion, we have synthesized a number of 3-aryl-5-tri-
fluoromethyl- and 3,5-diaryl-1,2,4-oxadiazole derivatives in mod-
erate to high yields by the cyclocondensation of amidoximes
with either trifluoroacetic anhydride or benzoic acids. It is the first
Letter on the formation of 3,5-diaryl-1,2,4-oxadiazoles by direct
cyclocondensation of amidoxime with benzoic acids in the
presence of EDCIꢀHCl and HOBtꢀH2O as the condensing agents,
providing a new and alternative route for the construction of the
1,2,4-oxadiazole ring. The investigation on the phase transition
behavior of the synthesized 1,2,4-oxadiazole disclosed that the
molecular and electronic structures greatly affect their thermal
properties of mp and cp, 2c and 2f show smectic phases, and
2h–j show nematic phases with a wide nematic temperature.
F3C
N
OH
O
O
Ar
O
NH2
CF3COOH
+
F3C
N
N
N
O
N
O
O
CF3
OH
H2O
Ar
Ar
CF3
Ar
N
H
NH2
CF3
O
Scheme 1. Plausible mechanism for the formation of 1,2,4-oxadiazoles.
(EDCIꢀHCl) and 1-hydroxybenzotriazole hydrate (HOBtꢀH2O) as the
condensing agents. As shown in Scheme 2, 2j and 2k could be syn-
thesized in 52% and 45% yields, respectively. The obtained results
indicate that EDCIꢀHCl and HOBt H2O are the efficient condensing
agents for the selective condensation of amidoxime with acids to
give amides,8 which was further transferred to the desired 3,5-dia-
ryl-1,2,4-oxadiazoles under the same conditions. Therefore, the
presented procedure has developed a new and alternative route
for the construction of the 1,2,4-oxadiazole ring.
The phase transition behavior of the solid products was investi-
gated by differential scanning calorimetry (DSC) and polarizing
optical microscopy (POM) to study their thermal properties of
the melting points (mp) and/or phase transition temperatures
(Table 2), as well as textures of phase (Fig. 1). It was found that
the mp and phase transition temperature greatly depend upon
the molecular and electronic structures of oxadiazoles. As shown
in Table 2, 2c and 2f show smectic phases, 2h, 2i, and 2j show

J. Guo et al. / Tetrahedron Letters 55 (2014) 1557–1560
1559
Figure 1. (a) Smectic texture of 2c at 50.2 °C during cooling. (b) Smectic texture of 2f at 85.1 °C during cooling. (c) Schlieren texture of the nematic phase of 2h at 235.4 °C
during cooling. (d) Schlieren texture of the nematic phase of 2i at 150 °C during cooling. (e) Schlieren texture near the I–N transition of 2j at 153.4 °C during cooling.
F
F
N
N
O
O
2h
2i
F
F
F
N
F
N
F
F
N
N
F
O
F
2j
Figure 2. The configuration of 2h, 2i, and 2j by DFT calculations using Gaussian 09. (Hydrogen atoms are omitted for clarity.)

1560
J. Guo et al. / Tetrahedron Letters 55 (2014) 1557–1560
Work is in progress to apply 2h–j as the liquid crystalline mono-
mers in the making practical liquid crystal mixture for LCDs.
The general experimental procedure for the synthesis of
3-aryl-5-trifluoromethyl 1,2,4-oxadiaozles (2a–i): a mixture of
amidoximes (2.0 mmol) and trifluoroacetic anhydride (504.0 mg,
2.4 mmol) in dried toluene (30 mL) was refluxed for 4 h. After
removal of the volatiles, the residue was treated with brine
(30 mL), and then extracted with EtOAc (3 ꢁ 20 mL). The combined
organic layers were then dried over Na2SO4 and evaporated. 2a–i
was purified by chromatography (petroleum ether).
Supplementary data
Supplementary data (general method, characterization data and
charts of 1H, 13C, and 19F NMR for all products are concluded) asso-
ciated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.01.066.
References and notes
1. Selected reports, see: (a) Pace, A.; Pierro, P. Org. Biomol. Chem. 2009, 7, 4337; (b)
Boström, J.; Hogner, A.; Llinàs, A.; Wellner, E.; Plowright, A. T. J. Med. Chem. 2012,
55, 1817; (c) Khatik, G. L.; Kaur, J.; Kumar, V.; Tikoo, K.; Nair, V. A. Bioorg. Med.
Chem. Lett. 2012, 22, 1912.
2. (a) Pantalone, K.; Seed, A. J. Liq. Cryst. 2002, 29, 945; (b) Parra, M. L.; Saavedra, C.
G.; Hidalgo, P. I. Liq. Cryst. 2008, 35, 55.
The general experimental procedure for the synthesis of 3,5-diaryl-
1,2,4-oxadiazole derivatives (2j–k):
A mixture of amidoximes
(4.0 mmol), 2,3-difluoro-4-n-propylbenzoic acid (1.2 g, 6.0 mmol),
EDCIꢀHCl (1.2 g, 6.2 mmol), HOBtꢀH2O (811.0 mg, 6.0 mmol), and
triethylamine (1.7 mL, 12.0 mmol) in dried DMF was heated to
90 °C for 4 h with stirring. The mixture was then extracted with
EtOAc (3 ꢁ 20 mL), and the combined layers were washed with
saturated NaHCO3 and brine, dried over MgSO4, and concentrated
to a yellow residue. 2j–k was purified by chromatography (petro-
leum ether).
3. Dingemans, T. J.; Murthy, N. S.; Samuski, E. T. J. Phys. Chem. B 2001, 105, 8845.
4. (a) Francescangeli, O.; Stanic, V.; Torgova, S. I.; Strigazzi, A.; Scaramuzza, N.;
Ferrero, C.; Dolbnya, I. P.; Weiss, T. M.; Berardi, R.; Muccioli, L.; Orlandi, S.;
Zannoni, C. Adv. Funct. Mater. 2009, 19, 2592; (b) Shanker, G.; Tschierske, C.
Tetrahedron 2011, 67, 8635; (c) Shanker, G.; Nagaraj, M.; Kocot, A.; Vij, J. K.;
Prehm, M.; Tschierske, C. Adv. Funct. Mater. 2012, 22, 1671.
ˇ
5. Jakopin, Z.; Dolenc, M. S. Curr. Org. Chem. 2008, 12, 850.
6. Poulain, R. F.; Tartar, A. L.; Déprez, B. P. Tetrahedron Lett. 2001, 42, 1495.
7. The detailed characterization data and copies of NMR charts of all the products
are reported in Supplementary data.
Acknowledgment
8. Selected report on the use of EDCIꢀHCl and HOBtꢀH2O as condensing agents of
acid and amine giving amide, see: Suzuki, N.; Suzuki, T.; Ota, Y.; Nakano, T.;
Kurihara, M.; Okuda, H.; Yamori, T.; Tsumoto, H.; Nakagawa, H.; Miyata, N. J.
Med. Chem. 2009, 52, 2909.
This project was supported by the National Natural Science
Foundation of China (21032004).