Solid-phase synthesis of liquid crystalline isoxazole library

Article abstract of DOI:10.1016/j.tetlet.2004.01.116

Combinatorial library of isoxazoles was prepared by 1,3-dipolar cycloaddition on solid support. p-Cyano derivatives showed nematic and/or smectic A phases. A bilayer smectic phase for 2h is proposed by the combination of molecular mechanics calculation and X-ray diffraction experiment.

Full text of DOI:10.1016/j.tetlet.2004.01.116

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2277–2279
Solid-phase synthesis of liquid crystalline isoxazole library
Takeharu Haino,a Masahiro Tanaka,a Keiko Ideta,b Kanji Kubo,b Akira Morib
and Yoshimasa Fukazawaa,*
aDepartment of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama,
Higashi-Hiroshima 739-8526, Japan
bInstitute for Materials Chemistry and Engineering, Kyushu University Kasuga, Fukuoka 816-8580, Japan
Received 5 January 2004; revised 20 January 2004; accepted 26 January 2004
Abstract—Combinatorial library of isoxazoles was prepared by 1,3-dipolar cycloaddition on solid support. p-Cyano derivatives
showed nematic and/or smectic A phases. A bilayer smectic phase for 2h is proposed by the combination of molecular mechanics
calculation and X-ray diffraction experiment.
Ó 2004 Elsevier Ltd. All rights reserved.
Liquid crystalline materials have received great atten-
tion for a wide variety of applications. Numerous liquid
crystalline compounds have been synthesized so far.
Some of them represent rod-like shapes, which are a
well-known class of typical liquid crystalline com-
pounds, showing smectic and nematic mesophases de-
rived from the self-organization of their anisometric
units.1 3,5-Disubstituted isoxazole liquid crystalline
compounds2 are in the class of rod-shaped molecules,
which exhibit classical nematic and smectic mesophases
even though the molecules have a bent core rather than
a rod-like core. Structure–property relationships in is-
oxazole liquid crystals still remain fairly uncharted.
Unsymmetrical diphenyl isoxazoles bearing an alkoxy
chain at one end of the molecules and a polar group at
the other are interesting mesogens because a polar group
affects their mesomorphic behaviors. However, 3,5-di-
phenyl isoxazoles having a polar group are not well
investigated.3 We set out to study the mesomorphic
behaviors of anisometric isoxazole-based compounds 1
and 2 having a cyano group as a polar functionality.
remains a time-consuming task to find the desired
compound. Combinatorial chemistry is one of the most
promising approaches to accelerate the discovery
process of desired functional molecules.4 In particular,
solid-phase combinatorial chemistry has gained a
momentum in the field of not only chemistry but also
material science, and has become a major tool for
searching desired functional compounds. Recently,
liquid crystalline libraries of troponoid5 and benzenoid6
amides were prepared on solid support. In this paper, we
report the solid-phase synthesis of the liquid crystalline
isoxazole library and its mesomorphic properties.
Our strategy for the synthesis of the isoxazole liquid
crystals on solid support is outlined in Figure 1. Phenyl
acetylene unit is immobilized on a polymer support by
the amide linkage, which can be easily cleaved by acid
catalysis and converted to the cyano group.7;8 1,3-
Dipolar cycloadditions of nitrile oxides are well docu-
mented and provide efficient entries to the synthesis of
isoxazoles. The cycloaddition on solid support8 with
nitrile oxides having a variety of alkoxy substituents
provides the isoxazole library, which can allow us to carry
out the systematic evaluation for the liquid crystallinity.
Intermolecular interaction of the flexible hydrophobic
chains on the benzene ring is a key factor to stabilize the
liquid crystalline phase. A variety of the alkyl chain has
to be examined until liquid crystalline phase appears. It
Parallel synthesis of the isoxazole library on solid sup-
port was carried out by using parallel synthesizer
MiniBlock.9 Rink resin 3 was selected as a solid support.
Free amine 4, prepared from 3 by removal of the Fmoc
group, was subjected to a condensation reaction of
ethynylbenzoic acid 5 or 6 with N,N0-diisopropyl-
carbodiimide and 1-hydroxybenzotriazole to afford
Keywords: Combinatorial chemistry; Liquid crystal; Isoxazole; 1,3-
Dipolar cycloaddition; Solid-phase synthesis.
* Corresponding author. Tel.: +81-824-24-7427; fax: +81-824-24-0724;
e-mail: fukazawa@sci.hiroshima-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.116

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T. Haino et al. / Tetrahedron Letters 45 (2004) 2277–2279
O
N
-
+
O
N
R
3
R
R
3
1
O
R
2
NH
1: R =H, R =CN, R =H or alkoxy
1
2
3
2: R =CN, R =H, R =H or alkoxy
Polymer support
1
2
3
Figure 1. Synthetic strategy of isoxazole liquid crystal on solid support.
condensate 7. The corresponding nitrile oxides were
generated in situ from hydroximinoyl chlorides 8 with
triethylamine, which were quickly reacted with the triple
bond of resin 7 to produce solid-attached diphenyl
isoxazole 9. Tf2O worked nicely to cleave the linkage to
liberate desired isoxazoles 1 or 2 into the solution.7 After
quick purification of the crude products by column
chromatography on SiO2, the isoxazoles were furnished
in good yield. Yields of all compounds are listed in
Table 1. All of the compounds were characterized by 1H
NMR spectroscopy and high-resolution mass spec-
trometry. Purities of all the products were confirmed by
1H NMR (>95%) (Scheme 1).
Thermal behavior of compounds 1a–2k was investigated
by differential scanning calorimetry (DSC) and polar-
ized optical microscopy. Transition temperatures are
shown in Table 1. Mesomorphic behaviors were found
in compounds 2b–k whereas compounds 1a–k and 2a
were not mesomorphic.
This should be due to the larger molecular dipole of
compounds 2 produced by the presence of the cyano
group at para-position. The CN group of compounds 1
made molecular breadth wider to decrease the thermal
stability of mesophases. The presence of the alkoxy
groups is substantial for the formation of liquid crys-
Table 1. Yields and transition temperatures of compounds 1 and 2
R3
Yield (%) Transition temperature
(°C)a
R3
Yield (%)
Transition temperature (°C)a
1a
1b
1c
1d
1e
1f
H
OCH3
98
72
85
49
64
77
61
88
62
71
65
Crꢀ172ꢀIso
Crꢀ159ꢀIso
Crꢀ157ꢀIso
Crꢀ138ꢀIso
Crꢀ131ꢀIso
Crꢀ116ꢀIso
Crꢀ112ꢀIso
Crꢀ109ꢀIso
Crꢀ110ꢀIso
Crꢀ114ꢀIso
Crꢀ112ꢀIso
2a
2b
2c
2d
2e
2f
H
OCH3
67
90
83
82
66
83
69
67
58
74
68
Crꢀ195ꢀIso
Crꢀ144ꢀNꢀ213ꢀIso
OC2H5
OC3H7
OC4H9
OC5H11
OC6H13
OC7H15
OC8H17
OC9H19
OC10H21
OC2H5
OC3H7
OC4H9
OC5H11
OC6H13
OC7H15
OC8H17
OC9H19
OC10H21
Crꢀ128ꢀNꢀ199ꢀIso
Crꢀ138ꢀ(SmAꢀ120ꢀ)Nꢀ191ꢀIso
Crꢀ126ꢀNꢀ185ꢀIso
Crꢀ115ꢀNꢀ180ꢀIso
1g
1h
1i
2g
2h
2i
Crꢀ112ꢀNꢀ178ꢀIso
Crꢀ114ꢀSmAꢀ160ꢀNꢀ180ꢀIso
Crꢀ113ꢀSmAꢀ168ꢀNꢀ176ꢀIso
Crꢀ92ꢀSmAꢀ176ꢀIso
Crꢀ93ꢀSmAꢀ173ꢀIso
1j
1k
2j
2kb
a Cr, crystal; N, a nematic phase; SmA, a smectic A phase; Iso, isotropic liquid. The transition temperatures were recorded by DSC during the first
heating process.
b A mixture of compound 2k and its regioisomer was reported.3
HO
O
O
O
O
O
5:3-ethynyl
6:4-ethynyl
NH-Fmoc
NH
NH
2
20% piperidine
DMF 1 hr.
MeO
MeO
MeO
DIC, HOBt, DMF 24 hr.
4
7
3
OMe
OMe
OMe
O
N
HO N
Cl
TEA, CH2Cl2 24 hr.
R
8
3
O
O
Tf2O, pyridine
CH2Cl2
1a~2k
R
3
NH
MeO
9
OMe
Scheme 1.

T. Haino et al. / Tetrahedron Letters 45 (2004) 2277–2279
2279
ꢀ
talline phases. There are two mesomorphic phases ob-
served in a series of compounds 2. Shorter chained
compounds 2b–g displayed a nematic phase whereas a
smectic phase was observed in longer chained com-
pounds 2j and 2k. Mesomorphic behaviors are thus
dependent on the chain length of R3.1 Extension of the
alkyl chain of 2 gave rise to a smectic A phase in which
the molecules are more ordered than in a nematic phase.
In order to investigate the structure of the molecular
array in the smectic A phase for 2h, X-ray diffraction
measurement at 140 °C was carried out. A sharp peak at
2h (2.87°), characteristic of the interlayer periodicity,
layer spacing, about 27–30 A. A plausible bilayer
smectic A phase is shown in Figure 3. The calculated
value is consistent with the layer space d given by the
X-ray diffraction.
In conclusion, we constructed the liquid crystalline
isoxazole library based on 1,3-dipolar cycloaddition.
The systematic investigation of the liquid crystalline
isoxazoles reveals that the alkyl side chains of the isox-
azole and the position of the polar cyano group plays an
important role for the production of the liquid crystal-
line phases.
ꢀ
gave the layer spacing d value of 30.8 A, which is obvi-
ꢀ
ously larger than the calculated molecular length (20 A)
of 2h.
References and notes
Fortunately, a single crystal of 2h was obtained. The
X-ray crystallography10 disclosed the antiparallel ori-
entation of two rigid cores due to the strong dipole–di-
pole interaction between the cyano groups (Fig. 2). This
gave us an important insight into the molecular array of
the liquid crystalline phase. The antiparallel orientation
allows us to propose a bilayer smectic A mesophase,
typically found in many mesogens incorporating strong
polar terminal groups.
1. Tschierske, C. J. Mater. Chem. 2001, 11, 2647–2671;
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Goodby, J. W.; Mehl, G. H.; Saez, I. M.; Tuffin, R. P.;
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Mackenzie, G.; Auzely-Velty, R.; Benvegnu, T.; Plusquel-
lec, D. Chem. Commun. 1998, 2057–2070.
2. Brown, D. H.; Styring, P. Liq. Cryst. 2003, 30, 23–30;
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37–46; Gallardo, H.; Zucco, C.; Da Silva, L. Mol. Cryst.
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Gallardo, H.; Muller, J.; Taylor, T. R. Mol. Cryst. Liq.
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Molecular modeling based on the crystal structure with
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€
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1997, 22, 265–273.
4. Combinatorial Chemistry, Synthesis and Application; Wil-
son, S. R., Czarnik, A. W., Eds.; John Wiley & Sons: New
York, 1997.
5. Hashimoto, M.; Mori, A.; Inoue, H.; Nagamiya, H.; Doi,
T.; Takahashi, T. Tetrahedron Lett. 2003, 44, 1251–1254.
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Figure 2. Crystal structure of compound 2h.
8. Fuchi, N.; Doi, T.; Cao, B.; Kahn, M.; Takahashi, T.
Synlett 2002, 285–289; Bose, D. S.; Jayalakshmi, B.
Synthesis 1999, 64–65; Campagna, F.; Carotti, A.; Casini,
G. Tetrahedron Lett. 1997, 1813–1816.
9. Personal synthesizer MiniBlock is supplied by Mettler
Toledo Co. Ltd.
10. Crystallographic data for 2h: C23H24N2O2, FW ¼ 360.45,
ꢂ
ꢀ
ꢀ
triclinic, space group P1, a ¼ 5:7310ð2Þ A, b ¼
ꢀ
9:7650ð5Þ A, c ¼ 18:387ð1Þ A, a ¼ 100:235ð2Þ°, b ¼
O
3
ꢀ
93:032ð2Þ°, c ¼ 97:182ð4Þ°, V ¼ 1001:70ð9Þ A , T ¼
293 K, and Z ¼ 2; of 4094 total unique reflections, 2955
were considered observed at the level of jF0j > 3:0rjF0j.
The structure was solved by the direct method (Sir 92).
Full-matrix least squares refinements converged to a
conventional R factor of 0.057, wR ¼ 0:254, GOF ¼ 1.30.
Supplementary crystallographic data have been deposited
with the Cambridge Crystallographic Data Centre, UK as
supplementary publication number CCDC No. 226886.
11. Mohamadi, F.; Richards, N. G. J.; Guida, W. C.;
Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.;
Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11,
440–467.
N
O
C
N
Figure 3. Proposed bilayer structure of 2h in a smectic A phase.