1,3-Dipolar cycloaddition reaction applied to synthesis of new unsymmetric liquid crystal compounds-based isoxazole

Article abstract of DOI:10.1016/j.tetlet.2008.12.021

In this study, a regioselective, simple and versatile copper(I)-catalyzed procedure for preparation of a series of liquid crystals based on unsymmetrical 3,5-disubstituted isoxazole was developed. Using different substituted chloro oximes and phenyl acety

Full text of DOI:10.1016/j.tetlet.2008.12.021

Tetrahedron Letters 50 (2009) 905–908
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
1,3-Dipolar cycloaddition reaction applied to synthesis of new unsymmetric
liquid crystal compounds-based isoxazole
*
André A. Vieira, Fernando R. Bryk, Gilmar Conte, Adailton J. Bortoluzzi, Hugo Gallardo
Departamento de Química, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, SC, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, a regioselective, simple and versatile copper(I)-catalyzed procedure for preparation of a ser-
ies of liquid crystals based on unsymmetrical 3,5-disubstituted isoxazole was developed. Using different
substituted chloro oximes and phenyl acetylenes, 1,3-dipolar cycloaddition reaction was carried out. A
second series containing the isoxazole ring and a triple bond in the rigid core was also synthesized. From
the 3-(4-bromophenyl)-5-(4-(decyloxy)phenyl)isoxazole, new liquid-crystalline compounds were pre-
pared by Sonogashira cross-coupling. All of the derivates of the isoxazole ring compounds exhibited mes-
omorphism. Smectic C, smectic A, and nematic phases were observed by optical microscopy and DSC
analysis. The yield of these reactions varied from moderate to excellent (47–93%). The structure of the
rigid core was investigated by single crystal X-ray diffraction, which confirmed the regioselectivity of
the [3+2] dipolar cycloaddition reaction.
Received 20 October 2008
Revised 1 December 2008
Accepted 5 December 2008
Available online 10 December 2008
Keywords:
Liquid crystal
Isoxazole
1,3-Cycloaddition
Sonogashira reaction
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Several methods have been adopted for the synthesis of unsym-
metrical 3,5-disubstituted isoxazoles, including approaches based
Liquid crystal compounds have found application in widespread
scientific and technological areas, especially as flat-panel displays,1
light emitting diodes (OLEDs),2 anisotropic networks,3 photocon-
ductors, and semiconductor materials.4 Numerous liquid-crystal-
line compounds have been synthesized with a wide variety of
shapes, the most popular being the rod-like shape, also called cal-
amitic.5 The calamitic liquid crystals are a well-known class that
shows typical smectic and nematic mesophases derived from the
self-organization of their anisometric units. During the past dec-
ades, a large number of liquid-crystalline compounds containing
heterocyclic units have been synthesized.5 This research field has
grown even more in the recent years because of improvements
in synthetic methodologies. The interest in such compounds arises
from the fact that the incorporation of heteroatoms can result in
large changes in the corresponding liquid-crystalline phases and/
or in the physical properties of the observed phases because most
of the usual heteroatoms (S, O, and N) introduced are chemically
classified as more polarizable than carbon.6 Unsymmetrical 3,5-
disubstituted isoxazole liquid-crystalline compounds can be intro-
duced into the class of calamitc molecules. However, to the best of
our knowledge, little detailed research on the relationships be-
tween structure and mesomorphic properties of unsymmetrical
3,5-disubstituted isoxazole derivative has been reported.
on condensation of 1,3-dicarbonyl compounds with hydroxyl-
amine7 (which have been isolated as equal mixtures of two regioi-
somers), anchoring a nitrile oxide precursor onto the solid phase,8
condensations,9 and intramolecular cyclization of amino acids.10
These procedures have often exhibited quite low yields, side reac-
tions result in impurities, and both regioisomers are often
obtained.
In particular, nitrile oxides which undergo efficient [3+2] cyclo-
addition with terminal alkynes can be a convenient protocol to the
synthesis of isoxazoles. However, a survey of the literature showed
that 1,3-dipolar cycloadditions reaction between dipolarophiles
derived from activated alkynes and nitrile oxides generally re-
sulted in moderate yields and low regioselectivity. Further, the
use of catalysts in 1,3-dipolar cycloaddition of nitrile oxides and al-
kynes permitted significant improvements, especially concerning
yields and regioselectivity, that in general are quite low in uncata-
lyzed processes.11,12 Thus, within this topic, a very important reac-
* Corresponding author. Tel.: +55 48 37219544; fax: +55 48 37216850.
E-mail addresses: hugo.gallardo@pq.cnpq.br, hugo@qmc.ufsc.br (H. Gallardo).
Scheme 1. Reagents: (a) NH2OHÁHCl, KOH, CH3CH2OH/H2O; (b) DMF, NCS; (c) CuI,
KHCO3, t-butanol/THF.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.021

906
A. A. Vieira et al. / Tetrahedron Letters 50 (2009) 905–908
Table 1
Yields for 1,3-cycloaddition reaction of 3–7 and their mesomorphic behavior
Entry
3
X
Aryla
Yield
84
Transition temperatures (°C)b
Br
Cr 99 SmC 114 SmA184 I
R
4
5
6
OC10H21
OC10H21
OC10H21
74
62
72
Cr 105 N 186 I
R
R
Cr 117 SmA 136 N 238 I
Cr 93 N 134 I
R
O
O
O
O
7
OC10H21
50
Cr 130 SmA 244 I
R
a
R = OC10H21.
b
Cr = crystal phase; SmA = smectic A; SmC = smectic C; N = nematic phase; I = isotropic.
Using the same rigid core system, (3) was reacted again with
the terminal alkynes via Sonogashira coupling to give a second
series.
2. Results and discussion
Scheme 2. Reagents: (a) PdCl2(PPh3)2, CuI, PPh3, THF/TEA.
The strategy for the synthesis of the final compounds is outlined
in Scheme 1.
The first step was the synthesis of the oxime intermediates from
4-(decyloxy)benzaldehyde or 4-(bromo) benzaldehyde using
hydroxylamine chloride and potassium hydroxide in an ethanol/
water mixture at room temperature. The respective aldoximes
were transformed to the corresponding N-hydroxybenzimidoyl
chlorides (1 and 2) with N-chlorosuccinimide in dimethylformam-
ide. Several terminal aryl acetylenes with distinct electronic-sys-
tems were also prepared. The alkynes were prepared according
to the literature13 from different aryl bromides by palladium cata-
lyzed with 2-methyl-3-butyn-2-ol (Sonogashira coupling reaction)
followed by protective group elimination. The 3,5-disubstituted
isoxazoles were obtained by 1,3-dipolar cycloaddition reaction be-
tween an appropriately substituted chloro oxime and an aryl acet-
ylene. Starting from the freshly prepared 4-bromo-N-
hydroxybenzimidoyl chloride (1), the nitrile oxide was best ob-
tained in situ (from the corresponding aldoximes by oxidative
halogenation/dehydrohalogenation) and reacted with the 1-(decyl-
oxy)-4-ethynylbenzene with a catalytic amount of copper (I) io-
dine (5 mol %) and potassium bicarbonate in an ethanol/water
mixture,14 affording compound 3. The general procedure was ap-
plied to obtain the final compounds 4–7, but by using 4-(decyl-
oxy)-N-hydroxybenzimidoyl chloride (2) and the respective aryl
acetylene. All of the cycloaddition reactions were carried out at
room temperature. Compounds 3–7 showed liquid-crystalline
properties, compound 3 being the precursor for compounds 8–
12. The reaction yields for the 1,3-cycloaddition reactions are
shown in Table 1.
Table 2
Yields for Sonogashira cross-coupling of 8–12 and their mesomorphic behavior
Entry
Aryl’a
Yield%
Transition temperaturesb (°C)
8
66
Cr 125 SmC 220 N 240 I
R
9
93
Cr 135 SmA 234 N 274 I
Cr 173 N 310 I
R
10
11
74c
47c
75c
R
O
O
O
Cr 130 SmC 266 N 316 I
Cr 136 SmC 300 I
R
R
12
O
a
R = OC10H21.
b
Cr = crystal phase; SmA = smectic A; SmC = smectic C; N = nematic phase;
I = Isotropic.
c
Yields obtained using pyridine as solvent.
tion is the 1,3-dipolar cycloaddition mediated by Cu(I). This meth-
odology enables the preparation of unsymmetrical 3,5-disubsti-
tuted isoxazoles with specific regioselectivity.
The target compounds 8–12 were synthesized from 3 as out-
lined in Scheme 2.
Bromide 3 was used as the building block for construction of the
carbon–carbon triple bond. The reactions were carried out through
Sonogashira cross-coupling with different aryl acetylenes15 (see
Table 2). These reactions employed 10% dichlorobis(triphenylphos-
phine)palladium as the catalyst, 5 mol % of the co-catalyst cop-
In this Letter, we report a convenient procedure for the regiose-
lective synthesis of unsymmetrical 3,5-disubstituted isoxazoles
from alkynes and imidoyl chloride catalyzed by Cu(I). Several aryl
acetylenes were reacted with imidoyl chloride to give new liquid
crystal derivates from isoxazoles.

A. A. Vieira et al. / Tetrahedron Letters 50 (2009) 905–908
907
Figure 1. Molecular structure of compound 14. Torsion angle values for planes A and B = 25.2(1)°; B and C 25.3(1)°; and C and D 4.6(2)°.
The structure of compound 14 clearly shows the regioselectivity
of the 1,3-dipolar cycloaddition reaction mediated by Cu(I). The
molecular geometry of the molecule under discussion is not planar
but consists of structural fragments (benzene and isoxazole rings)
with more or less perfect planarity (Fig. 1). The overall molecular
conformation results from the dihedral angles between these frag-
ments observed from the crystallographic data on the structures
(see Supplementary data).
The structures of all of the synthesized compounds were fully
characterized by IR, 1H and 13C NMR, and CHN mass analyses.
A brief study of the mesomorphism of the final molecules 3–7
and 8–12 was performed using polarizing optical microscopy
(POM) and the results are shown in Tables 1 and 2. All of the com-
pounds prepared exhibited mesophases characteristic of calamitic
liquid crystal, that is, smectic C (SmC) and nematic (N) phases, with
Schlieren textures, and smectic A (SmA) with the focal-conic fan-
shaped texture. Compounds 8, 9, and 11 showed dimorphism of
SmC and N phases, and compound 3 of SmA and N phases. The
characteristic textures of the calamitic liquid crystal are shown
in Figure 2. Compounds 4, 6, 7, 10, and 12 presented only nematic
or smectic phase.
Figure 2. Photomicrographs (33Â) of compound 9 showing: (a) Schlieren texture of
N phase at 235 °C; and (b) focal-conic fan-shaped texture of SmA phase at 140 °C
upon cooling. Samples were sandwiched between untreated glass slides and viewed
through crossed polarizers.
per(I) iodine, and triphenylphosphine as an additive in a triethyl-
amine/tetrahydrofuran mixture (1:3) under reflux. As expected,
these compounds also showed mesomorphic behavior. The reac-
tion yields for the Sonogashira reaction products 8–12 are pre-
sented in Table 2.
3. Conclusions
In conclusion, a regioselective, simple and convenient cop-
per(I)-catalyzed procedure for preparation of liquid crystals based
on unsymmetrical 3,5-disubstituted isoxazole was developed.
Using different substituted chloro oximes and aryl acetylenes,
which were obtained by 1,3-dipolar cycloaddition reaction, a series
of liquid crystals based on isoxazole was reported. A second series
containing the isoxazole ring and triple bond in the rigid core was
also synthesized by Sonogashira cross-coupling. The final materials
4–7 and 8–12 were obtained in moderate to good yields (47–93%).
These compounds showed liquid-crystalline behavior with a varied
polymorphic SmC, SmA, and N phases.
However, using the same procedure for compounds 10, 11, and
12 only traces of the desired compounds were obtained with a
considerable amount of homo-coupling product. This finding had
been previously reported by our group in the synthesis of similar
molecules,16 and thus in the synthetic route of these final com-
pounds the functionalities need to be reversed. In this reaction,
the Sonogashira coupling of the aryl acetylenes was used to built
the triple bond terminal in compound 3, and the intermediary 5-
(4-(decyloxy)phenyl)-3-(4-ethynylphenyl) isoxazole (13) was ob-
tained with 76% global yield. Finally, the target compounds 10,
11, and 12 were obtained by reaction of aryl acetylene 13 with
the respective aryl bromide via Sonogashira coupling. The yields
of these reactions were low (17–30%). The reaction was therefore
repeated using pyridine as the solvent17, and the yields increased
to 74%, 47%, and 75%, respectively.
In order to analyze the rigid core and, particularly, the regiose-
lectivity of these 1,3-cycloaddition reactions catalyzed by Cu(I), we
tried to obtain a single crystal of the final compounds synthesized.
Due to the difficulty in obtaining good single crystals, a 3,5-disub-
stituted isoxazole derivative without terminal chains, 5-phenyl-3-
[4-(phenylethynyl) phenyl]isoxazole (14), was also prepared
(Fig. 1). This compound was synthesized from 3-(4-bromophe-
nyl)-5-phenylisoxazole, prepared from compound 1 with phenyl-
acetylene by 1,3-dipolar cycloaddition reaction, and subsequent
Sonogashira reaction with the same acetylene, in 56% yield. Yellow
single crystals of 14 suitable for X-ray analysis were obtained by
recrystallization from chloroform.18
Acknowledgments
The authors thank Conselho Nacional de Desenvolvimento
Científico e Tecnológico (PRONEX CNPq,, FAPESC), Brazil. We also
thank Dr. Rodrigo Cristiano for the helpful discussions and Dr. Gus-
tavo A. Micke for the MS spectra.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.12.021.
References and notes
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14. General procedure to [3+2] dipolar cycloadditions: To a 50 mL round-bottomed
flask
1-(decyloxy)-4-ethynylbenzene
(1.0 g,
5.5 mmol),
4-bromo-N-
hydroxybenzimidoyl chloride (1.33 g, 5.6 mmol), were suspended in 20.0 mL
of a 3:1 t-butanol/THF. Catalytic portion of CuI (76 mg, 0.4 mmol) was added,
and the solution stirred for 10 min. After that KHCO3 (0.565 g, 5.6 mmol) was
added, and the reaction mixture was stirred at room temperature for 24 h. TLC
analysis indicated complete consumption of starting materials. The yellow
product was filtered off, and recrystallized from n-heptane. Gallardo, H.; Ely, F.;
Bortoluzzi, A. J.; Conte, G. Liq. Cryst. 2005, 32, 667.
15. General procedure for Sonogashira’s coupling reactions:
bromophenyl)-5-(4-(decyloxy)phenyl) isoxazole (0.5 g;
PdCl2(PPh3)2 (70 mg, 0.1 mmol), CuI (9.5 mg, 0.05 mmol)
A
mixture of 3-(4-
1.09 mmol),
and
triphenylphosphine (26.2 mg, 0.1 mmol) in THF/triethylamine 2:1 (30 mL)
was stirred under reflux for 45 min. Then, respective terminal arylacetylene
(1.1 mmol) dissolved in 10 mL of THF was added dropwise. The reaction
mixture was refluxed for a further 4–6 h, TLC analysis indicated the end of the
reaction. Cooling at room temperature, the product was almost entirely
precipitated, filtered, and was washed with triethylamine (20 mL). The product
was purified by recrystallization on n-heptane to give the respective final
compound. (a) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46. (b) Rajendra,
M. S.; Neves Filho, R. A. W.; Schneider, R.; Vieira, A. A.; Gallardo, H. Liq. Cryst.
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Hidalgo, P.; Carrasco, E.; Barbera, J.; Silvino, L. Liq. Cryst. 2006, 33, 875.
17. Melissars, A. P.; Litt, M. H. J. Org. Chem. 1992, 57, 6998.
18. Crystal data of compound 14: Formula C23H15NO, FW 321.36, monoclinic, space
group P21/c, cell parameters: a = 7.403(1) Å, b = 5.770(1) Å, c = 39.119(5) Å,
b = 93.78(1)°, V = 1667.3(4) Å3, Z = 4,
q l ,
calc = 1.280 Mg/m3, = 0.078 mmÀ1
T = 293 K, F(000) = 672, 2942 measured reflections, 2894 unique
11. (a) Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel, A.; Voit, B.; Pyun,
J.; Frechet, J. M. J.; Sharpless, K. B.; Fokin, V. V. Angew. Chem. 2004, 116, 4018;
(b) Demko, Z. P.; Sharpless, K. B. Angew. Chem. 2002, 114, 2214; (c) Chassaing,
S.; Sido, A. S. S.; Alix, A.; Kumarraja, M.; Pale, P.; Sommer, J. Chem. Eur. J. 2008,
14, 6713.
(Rint = 0.0490), parameters 226, GOOF (F2) = 1.034, R1 [I > 2
r(I)] = 0.0596, wR2
(all data) = 0.1931. Crystallographic data (excluding structure factors) for the
structure in this letter have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication numbers CCDC
703235. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 (0)1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk).
12. Himo, F.; Lovell, T.; Hildgraf, R.; Rostovtesv, V. V.; Noodleman, L.; Sharpless, K.
B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210.