3,5-diarylisoxazoles: A New Entry to Soft Crystal Phase

Article abstract of DOI:10.1080/15421406.2015.1030975

This work describes the synthesis and characterization of a new liquid-crystalline compounds based on isoxazoles. Classical synthetic methodologies were employed in the preparation of this compounds, and the [3+2] 1,3-dipolar cycloaddition was the key ste

Full text of DOI:10.1080/15421406.2015.1030975

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3,5-diarylisoxazoles: A New Entry to Soft
Crystal Phase
Rafaela R. da Rosaa, Irwing S. Brosea, Guilherme D. Vilelaa & Aloir A.
Merloa
a Chemistry Institute, Universidade Federal do Rio Grande do Sul,
Porto Alegre, Brazil
Published online: 06 Jul 2015.
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To cite this article: Rafaela R. da Rosa, Irwing S. Brose, Guilherme D. Vilela & Aloir A. Merlo (2015)
3,5-diarylisoxazoles: A New Entry to Soft Crystal Phase, Molecular Crystals and Liquid Crystals, 612:1,
158-168, DOI: 10.1080/15421406.2015.1030975
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Mol. Cryst. Liq. Cryst., Vol. 612: pp. 158–168, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 1542-1406 print/1563-5287 online
DOI: 10.1080/15421406.2015.1030975
3,5-diarylisoxazoles: A New Entry to Soft Crystal
Phase
RAFAELA R. DA ROSA, IRWING S. BROSE,
GUILHERME D. VILELA, AND ALOIR A. MERLO∗
Chemistry Institute, Universidade Federal do Rio Grande do Sul, Porto Alegre,
Brazil
This work describes the synthesis and characterization of a new liquid-crystalline
compounds based on isoxazoles. Classical synthetic methodologies were employed in
the preparation of this compounds, and the [3+2] 1,3-dipolar cycloaddition was the
key step to prepare isoxazolines as precursors to isoxazoles. The structural and thermal
1
characterization was performed using H and 13C NMR techniques, polarized-light
optical microscopy and differential scanning calorimetry. Compounds 7a-e displayed
the SmA mesophase. Soft crystal phase (CrE) was observed for compounds 7a and 7b
containing chlorine and bromine atoms. For 7e containing a nitro group crystal phases
below SmA mesophase were also observed.
Keywords [3+2] 1; 3-dipolar cycloaddition; MnO2 oxidation; soft crystal phase; CrE;
liquid crystals
Introduction
The design and synthesis of new molecules with unique liquid crystals (LC) properties
is a permanent challenge to the chemists. Many progresses have been done in this field,
especially in the preparation of molecules with unusual molecular architecture beyond the
classical calamitic- or discotic-shaped [1]. Among them, bent-core liquid crystals can be
classified as unusual liquid crystals and they emerge as interesting class of LC with amazing
behavior [2]. Usually bent-core mesogens have 1,3-phenylene unit connected by aromatics
rings providing a 120◦ bent in the middle of the aromatic core [3].
Bent-shaped molecules are also founded in 5-membered heterocyclic if the bending
angle varies between about 135◦ and 160◦. In this sense molecules with this bending angle
are more elongated in comparison to the 1,3-phenylene derivatives where the bending
angle is 120◦ caused by the meta-substitution [4]. Typical mesophase formed by calamitic
molecules, e.g N, SmA and SmC are observed when the bending angle increase to about
140◦ or more. So, the precise adjust of the molecular bent is crucial to reach the bent-
core mesophases. Unfortunately, most of 5-membered heterocyclic used in the synthesis of
new LC render calamitic mesophases [5] in despite of several synthetic efforts to change
∗Address correspondence to Aloir A. Merlo, Chemistry Institute, Universidade Federal do Rio
Grande do Sul, Porto Alegre, Brazil. E-mail: aloir.merlo@ufrgs.br
Color versions of one or more of the figures in the article can be found online at
www.tandfonline.com/gmcl.
[624]/158

Isoxazoles: A New Entry to Soft Crystal Phase
[625]/159
the topology - size, nature and shape - of the aromatic rings connected to the pentagonal
heterocyclic.
However, we have to mention that when the bending angle approach to the 120◦
the possibility to reach optimal curvature of 1,3-phenylene core is greater. Thus, 2,5-
disubstituted 1,3,4-oxadiazoles with a bending angle of ca 134◦ is one of the 5-membered
heterocyclic ring that have gained attention of LC community because they are at the
borderline between classical rod-like LCs and the bent-core mesogens [3]. Even the non-
symmetric 3,5-disubstituted 1,2,4-oxadiazoles with a molecular bend of 140◦ have received
attention due to their ferroelectric and biaxility behavior [6]. In this sense a number of new
five-membered heterocyclic have been synthesized and the structural properties analyzed
[7].
Less bent than 2,5-disubstituted 1,3,4-oxadiazoles or non-symmetric 3,5-disubstituted
1,2,4-oxadiazoles ring 3,5-disubstituted isoxazoles are real candidates to access highly
ordered liquid crystals phase [8a] with potential applications in optical-electronic devices
[8b-c]. Soft crystal mesophases are of great interest in electronic devices application since
its organized structure next to a crystalline arrangement favors the intermolecular charge
transport [8d].
Among the know strategy to prepare isoxazoles, [3+2] cycloaddition of 1,3-dipole to
alkynes or indirectly to alkene followed by oxidation and condensation reaction of hydrox-
ylamine with carbonyl compounds are the most important [9]. The interest in cycloaddition
reaction of alkenes to 1,3-dipole has improved due to pharmacological properties of cy-
cloadduct isoxazolines [10]. Isoxazolines are versatile precursors that readily undergoes
further transformation e.g., alkylation [11], reductive cleavage [12] oxidation reaction to
isoxazoles [13].
Our previous synthesis work related with design of new molecular architecture has
shown that isoxazolines and isoxazoles serve as platform for new liquid-crystalline materials
[14]. In this work we are extending our approach of new liquid crystals compounds by
describing the synthesis and characterization of a series of new LC compounds based on
the 3,5-disubstituted isoxazoles 7a-e.
Results and Discussion
Synthesis
The sequential synthetic methodologies were employed in the preparation of isoxazoles
core in this study. The Scheme I outlined the linear synthesis of isoxazoles 6a-e in four
steps. The [3+2] 1,3-dipolar cycloaddition of arylnitrile oxide with 4-tert-butoxystyrene
as the key step in our synthetic plan to prepare the intermediate isoxazolines 4a-e followed
by MnO2 oxidation to afford the protected phenol isoxazoles 5a-e [13]. Benzaldehydes
1a-e were chosen as starting materials to be transformed into oximes 2a-e in high yields.
Oximes are precursors for arylnitrile oxide, a reactive intermediate 1,3-dipoles for [3+2]
cycloaddition. Solution of oximes were exposed to N-chlorosuccinimide (NCS) oxidant
and the dipolarophile 4-tert-butoxystyrene (3), a masked phenol, to give the isoxazolines
4a-e in moderate to good yields.
The one-pot reactions were carried out in the sequence (i) chlorination reaction of
2a-e using N-clorosuccinimide and hydrochloride acid [15], in dichoromethane solution to
yield the arylhydroximoyl chloride derivatives [16], (ii) addition of the dipholarofile, and

160/[626]
R. R. Da Rosa et al.
Scheme 1. Sequential synthetic route to obtain the phenol isoxazoles 6a-e.
(iii) dehydrohalogenation reaction by addition of triethylamine for in situ generation of the
reactive arylnitrile oxide.
The next step was the oxidation of isoxazolines to isoxazoles which was performed in
toluene solution using activated MnO2. Thus, the protected-isoxazoles 5a-e were obtained
in high yields by simple filtration of toluene solution over celite. After accomplished the
transformation of isoxazolines into isoxazoles we proceed the remotion of t-butyl group
from ether 5a-e under acid condition - HBr/HOAc to give the phenols 6a-e in quantitative
yields [17].
The free phenols 6a-e opens to us a new avenue to be explored in the liquid crystals field.
Preliminary results in this sense has been done toward the preparation of polymethacrylate
liquid-crystalline carrying the phenol 6a where the liquid crystals behavior has been am-
plified and preserved by the polymerization reaction of the corresponding monomer [18].
Scheme 2. Alkylation reaction to afford the final liquid-crystalline compounds 7a-e.

Isoxazoles: A New Entry to Soft Crystal Phase
[627]/161
Table 1. Transition temperatures (◦C) and enthalpies (kJ.mol−1) on heating of the isoxazoles
7a-e
Entry
X
Cr
Cr1
Cr2
CrE
SmA
N
I
7a [13] Br
•
•
99
96 (-)
•
•
119
100
•
•
191
190 (6.7) •
•
7b
Cl
(16.4)∗
97 (40.9)
90 (35.8)
7c
7d
F
CH3
•
•
•
•
154 (5.9) •
124 • 141 (1.0) •
(0.9)
7e
NO2
•
79
(7.8)
•
101
(13.5)
•
130
(13.4)
•
206 (4.7) •
∗enthalpy value is the sum of the enthalpies of transitions Cr→CrE and CrE→SmA. The enthalpies
are presented in brackets. Cr: crystal phase; CrE: soft crystal E; SmA: smectic A; N: nematic
mesophase.
According to the Scheme II phenols 6a-e were alkylated with 1-bromooctane with the
formation of liquid-crystalline final compounds 7a-e.
Liquid Crystal Properties
Transitional data are tabulated in Table 1 for all isoxazoles 7a-e. Transition temperatures and
enthalpy values were obtained by differential scanning calorimetry (DSC) and polarized-
light optical microscopy (POM).
From Table 1 we can see that all LC isoxazoles synthesized displayed an enantiotropic
behavior. DSC thermograms of 7b-e are described in Figure 1 and all samples display a
sharp and well-defined peaks associated with transitions temperatures for isoxazoles 7b-e.
The transition temperatures and enthalpy values were collected from second heating scans.
The texture of the mesophase [19] was identified by microscopy studies. When the sample
is cooled from its isotropic phase, the smectic A phase appears, which exhibited focal-conic
texture. The stable enantiotropic smectic A phase was found in all the samples 7a-e. For
example, on heating the sample 7c enters into the smectic A phase at 97◦C and finally
melts to an isotropic liquid at 154◦C. The mesophase range for 7c is 57◦C. The two peaks
observed at 97◦C and 154◦C were associated with Cr → SmA and SmA → I transitions,
respectively, during the microscopy studies.
Similar behavior was observed to the last member containing the nitro group 7e. As
expected for more planar and anisotropic group, nitro substituent induce a large mesophase
range (ꢀT = 76◦C) and more stable mesophase behavior by comparison of clearing tem-
perature between 7c and 7e. In fact, 7e is the most stable LC in this study. Additionally,
the compound 7e showed two crystalline phase transitions probably due the intermolecular
interactions of the nitro polar group [20].
For the 7a and 7b, along with SmA mesophase, on cooling, accompany another
mesophase below transition from isotropic to SmA mesophase, with persistent continuous
bands across the backs of the fans (Figure 2) for a long time. These changes are an indicative
of a smectic A mesophase to a soft crystal phase E transition [19]. To these compounds 7a
and 7b compounds the arced focal conic fan texture was assigned as crystal E phase (CrE).
Our previous results showed that the 3,5-disubstituted isoxazoles are a good candidate to
promotes the formation of a variety of soft LC phase which are under investigation and will
be published soon [8a].

162/[628]
R. R. Da Rosa et al.
Figure 1. DSC curves of isoxazoles a) 7b, b) 7c, c) 7d and d) 7e.
LC 7c with fluorine atom displayed only one orthogonal mesophase SmA and absence
of any soft crystal phase or crystal to crystal transition. This particular behavior is related
to the extreme electronegativity, size and lone pair of fluorine atom which result in both
low atomic polarizability and small size [21].
Nematic mesophase was observed only for 7d with mesophase range of the 14◦C.
In this series it can be seen that the less and small polar group favors the appearance
Figure 2. Textures observed by POM on cooling for compound 7b.

Isoxazoles: A New Entry to Soft Crystal Phase
[629]/163
nematic mesophase probably due to weak intermolecular interactions in the mesophase
with predominance of Van der Waals attraction. All compounds in the series 7a-e dis-
played the SmA mesophase, but only compounds containing chlorine and bromine atoms
have a soft crystal E phase. Thus, this result is a good indication that there is a stronger
correlation on the mesomorphic behavior concerning polar or steric effects of the sub-
stituent, since the compound containing fluorine atom 7c neither with methyl group 7d
did not exhibit this mesophase. Results here are showing that a steric and polar effect that
comes from large and polar group [22] are important parameters to be considered in the
design of new liquid-crystal materials. The incorporation of larger and high polarizabil-
ity atoms induce the formation of smectic phase and the appearance of CrE mesophases
(soft crystal) [19], and they have a great impact on the size and shape of isoxazoles
mesogens.
Conclusion
A series of 3,5-diarylisoxazoles liquid crystal 7a-e were synthesized and mesomorphic
properties were presented and discussed. [3+2] 1,3-dipolar cycloaddition and MnO2-
oxidation were used to prepare the hard core 3,5-disubstituted phenylisoxazoles 6a-e.
Alkylation reaction with linear alky bromides yielded the 3,5-diarylisoxazoles liquid crystal
7a-e. Enantiotropic behavior was observed for all LC isoxazoles. For 7a and 7b containing
terminal bromine and chlorine atoms displayed SmA phase and soft crystal phase (CrE).
For 7c having a terminal fluorine atom showed only SmA mesophase. LC isoxazole 7d
with a terminal methyl group presented a nematic mesophase along SmA mesophase. And
finally, 7e with a nitro group displayed only SmA mesophase. Additionally, upon heating,
7e showed three crystal phase transition below SmA mesophase. Previous reported and this
has showed that isoxazoles are key hard core to access a collection of new CL compounds
with soft crystal phases.
Experimental Section
General
1H NMR and 13C NMR spectra in CDCl3 were obtained using Varian Inova 300, Varian
VNMRs 300 and Bruker Avance 400 spectrometers (Chemistry Institute – UFRGS). The
coupling constants (J) are expressed by Hz and chemical shifts (δ) are given in parts per
million (ppm) relative to tetramethylsilane (TMS) used as internal standard. The thermal
transitions and the textures were determined using an Olympus BX43 polarizing micro-
scope in conjunction with a Mettler FP90 controller and HT84 heating stage and TA
Instruments Q20 Serie Differential Scanning Calorimeter using ultra-pure N2 gas at a flow
rate of 50 mL.min−1 and the rate of heating or cooling was 10◦C.min−1 without isotherms
(LAMAT-UFRGS).
The reagents hydroxylamine hydrochloridrate, 4-bromobenzaldehyde, 4-
chlorobenzaldehyde, 4-fluorobenzaldehyde, 4-methylbenzaldehyde, 4-nitrobenzaldehyde,
4-tert-butoxystyrene, N-chlorosuccinimide (NCS), 1-bromooctane, were used as received
from Aldrich Co. Analytical. Thin Layer Chromatography (TLC) was conducted on Merck
aluminium plates with 0.2mm of silica gel 60F-254. Anhydrous sodium sulfate was used
to dry all organic extracts. All other solvents and reagents were used without previous
purification.

164/[630]
R. R. Da Rosa et al.
Procedures
Synthesis of aldoximes 2a-e. Representative procedure for compound 2a. In a round bottom
flask to a solution of 4-chlorobenzaldehyde (5.00 g, 35.57 mmol) in ethanol (135 mL) was
added hydroxylamine hydrochloride (6.92 g, 99.60 mmol) and a solution of sodium acetate
(11.67 g, 142.28 mmol) in water (70 mL). The mixture was stirred under reflux for 40
minutes, ethanol was removed by heat and vacuum. The concentrate was crystallized on
freezer overnight to give the pure product.
Data for 4-bromobenzaldehyde oxime (2a): white crystalline solid; yield: 96%; m.p.
109–111◦C; 1H NMR (300 MHz, CDCl3) δ 8.16 (s, 1H), 8.12 (s, 1H), 7.51 (m, 4H); 13C
NMR (75.5 MHz, CDCl3) δ 149.7, 132.3, 131.0, 128.7, 124.6.
Data for 4-chlorobenzaldehyde oxime (2b): white crystalline solid; yield: 97%; m.p.
101–103◦C; 1H NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 7.52 (m, 2H), 7.36 (m, 2H).
Data for 4-fluorobenzaldehyde oxime (2c): white crystalline solid; yield: 92%; m.p.
84–86◦C; 1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 8.17 (s, 1H), 7.59 (m, 2H), 7.11 (m,
2H). 13C NMR (75.5 MHz, CDCl3) δ 163.8 (d, 1JC-F = 250.5 Hz), 149.5, 129.0 (d, 3JC-F
=
8.4 Hz), 128.0 (d, 4JC-F = 3.4 Hz), 116.0 (d, 2JC-F = 22.1 Hz).
Data for 4-methylbenzaldehyde oxime (2d): pink pale solid; yield: 90%; m.p. 68–70◦C;
1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.38 (m, 2H), 7.09 (m, 2H), 2.27 (s, 3H); 13
NMR (75.5 MHz, CDCl3) δ 150.3, 140.3, 129.5, 129.0, 127.0, 21.4.
C
Data for 4-nitrobenzaldehyde oxime (2e): Yellow solid; yield: 99%; m.p. 127–129◦C;
1H NMR (300 MHz, CDCl3) δ 8.25 (m, 2H), 8.21 (s, 1H), 8.11 (s, 1H), 7.76 (m, 2H); 13
NMR (75.5 MHz, CDCl3/DMSO d6) δ 147.7, 146.8, 139.0, 127.1, 123.6.
C
Synthesis of isoxazolines 4a-e (Cycloaddition [3+2] 1,3-Dipolar). Representative proce-
dure for compound 4d. In a round bottom flask, were added 4-methylbenzaldehyde oxime
(2d) (2.03 g, 15.00 mmol), N-chlorossuccinimide (2.20 g, 16.50 mmol), dichloromethane
(45 mL) and a drop of HClconc, the mixture was stirred for 4 hours to form the oximoyl
chloride. After the formation of the intermediate the mixture was cooled in ice bath, and
to the solution were added 4-tert-butoxystyrene (3a) (2.82 mL, 15.00 mmol) and triethy-
lamine (6.27 mL, 45.00 mmol) dropwise, then the mixture was stirred at room temperature
for 24 hours. After the reaction time the mixture was washed with 1M HCl (2 × 20 mL)
and brine (2 × 20 mL), the organic layer was dried over Na2SO4 and the solvent was
removed under reduced pressure giving the crude material. The product was purified by
recrystallization in ethanol.
Data for 3-(4-bromophenyl)-5-(4-(tert-butoxy)phenyl)isoxazoline (4a): white crys-
1
talline solid; yield: 59%; m.p. 121–123◦C; H NMR (300 MHz, CDCl3) δ 7.55 (m, 4H),
7.28 (m, 2H), 6.99 (m, 2H), 5.70 (dd, 1H, 3Jcis = 11.1 Hz, 3Jtrans = 8.7 Hz), 3.71 (dd, 1H,
2Jgem = 16.8 Hz, 3Jcis = 11.1 Hz), 3.31 (dd, 1H, 2Jgem = 16.8 Hz, 3Jtrans = 8.7 Hz), 1.34
(s, 9H); 13C NMR (75.5 MHz, CDCl3) δ 155.5, 155.4, 135.12, 131.9, 128.5, 128.1, 126.7,
126.6, 124.3, 82.7, 78.7, 42.7, 28.8.
Data for 5-(4-(tert-butoxy)phenyl)-3-(4-chlorophenyl)isoxazoline (4b): white crys-
1
talline solid; yield: 53%; m.p. 135–136◦C; H NMR (300 MHz, CDCl3) δ 7.63 (m, 2H),
7.38 (m, 2H), 7.28 (m, 2H), 6.99 (m, 2H), 5.71 (dd, 1H, 3Jcis = 10.9 Hz, 3Jtrans = 8.8 Hz),
3.71 (dd, 1H, 2Jgem = 16.8 Hz, 3Jcis = 11.1 Hz), 3.32 (dd, 1H, 2Jgem = 16.8 Hz, 3Jtrans
=
8.7 Hz), 1.35 (s, 9H); 13C NMR (75.5 MHz, CDCl3) δ = 155.7, 155.5, 136.1, 135.3, 129.1,
128.2, 128.1, 126.8, 124.5, 82.9, 78.9, 42.9, 29.0.
Data for 5-(4-(tert-butoxy)phenyl)-3-(4-fluorophenyl)isoxazoline (4c): white crys-
1
talline solid; yield: 55%; m.p. 139–140◦C; H NMR (300 MHz, CDCl3) δ 7.68 (m, 2H),

Isoxazoles: A New Entry to Soft Crystal Phase
[631]/165
7.29 (m, 2H), 7.09 (m, 2H), 6.99 (m, 2H), 5.70 (dd, 1H, 3Jcis = 10.9 Hz, 3Jtrans = 8.6 Hz),
3.72 (dd, 1H, 2Jgem = 16.7 Hz, 3Jcis = 10.9 Hz), 3.33 (dd, 1H, 2Jgem = 16.7 Hz, 3Jtrans
=
8.6 Hz), 1.34 (s, 9H); 13C NMR (75.5 MHz, CDCl3) δ 163.7 (d, 1JC-F = 250.7 Hz), 155.5,
155.3, 135.3, 128.6 (d, 3JC-F = 8.3 Hz), 126.7, 125.8 (d, 4JC-F = 3.1 Hz), 124.3, 115.8 (d,
2JC-F = 21.8 Hz), 82.6, 78.7, 43.0, 28.8.
Data for 5-(4-(tert-butoxy)phenyl)-3-(4-methylphenyl)isoxazoline (4d): White solid;
yield: 56%; m.p. 106–108◦C; 1H NMR (300 MHz, CDCl3) δ = 7.59 (m, 2H), 7.29 (m, 2H),
7.21 (m, 2H), 6.98 (m, 2H), 5.65 (dd, 1H, 3Jcis = 11.0 Hz, 3Jtrans = 8.6 Hz), 3.72 (dd, 1H,
2Jgem = 16.7 Hz, 3Jcis = 11.0 Hz), 3.33 (dd, 1H, 2Jgem = 16.7 Hz, 3Jtrans = 8.6 Hz), 2.37
(s, 3H), 1.34 (s, 9H); 13C NMR (75.5 MHz, CDCl3) δ = 156.3, 155.4, 140.5, 135.7, 129.6,
126.9, 126.8, 124.5, 82.4, 78.8, 43.2, 29.0, 21.6.
Data for 5-(4-(tert-butoxy)phenyl)-3-(4-nitrophenyl)isoxazoline (4e): Light yellow
1
solid; yield: 40%; m.p. 143◦C; H NMR (300 MHz, CDCl3) δ 8.26 (m, 2H), 7.86 (m,
2H), 7.28 (m, 2H), 7.50 (m, 2H), 5.79 (dd, 1H, 3Jcis = 11.1 Hz, 3Jtrans = 8.7 Hz), 3.77 (dd,
1H, 2Jgem = 16.8 Hz, 3Jcis = 11.1 Hz), 3.38 (dd, 1H, 2Jgem = 16.8 Hz, 3Jtrans = 8.7 Hz), 1.34
(s, 9H); 13C NMR (75.5 MHz, CDCl3) δ 155.8, 154.7, 148.4, 135.6, 134.5, 127.3, 126.6
124.3, 124.0, 83.6, 78.8, 42.2, 28.8.
Synthesis of isoxazoles 5a-e (Oxidation Reaction). Representative procedure for 5a. In a
round bottom flask were added isoxazoline 4a (0.50 g, 1.34 mmol), toluene (25 mL) and
MnO2 (1.75 g, 20.13 mmol), the reaction was carried under azeotropic reflux overnight.
After consumption of starting material the mixture was cooled down and filtered over a
plug of celite and washed with CH2Cl2. The solvent was removed under reduced pressure
giving the product.
Data for 3-(4-bromophenyl)-5-(4-(tert-butoxy)phenyl)isoxazole (5a): white crystalline
solid; yield: 99%; m.p. 157–158◦C; 1H NMR (300 MHz, CDCl3) δ 7.72 (m, 4H), 7.59 (m,
2H), 7.08 (m, 2H), 6.69 (s, 1H), 1.40 (s, 9H); 13C NMR (75.5 MHz, CDCl3) δ 170.6, 161.9,
157.6, 132.1, 128.2, 126.8, 124.2, 126.7, 123.9, 122.0, 96.3, 79.4, 28.8.
Data for 5-(4-(tert-butoxy)phenyl)-3-(4-chlorophenyl)isoxazole (5b): white crystalline
solid; yield: 97%; m.p. 151–152◦C; 1H NMR (300 MHz, CDCl3) δ 7.76 (m, 2H), 7.71 (m,
2H), 7.41 (m, 2H), 7.08 (m, 2H), 6.68 (s, 1H), 1.39 (s, 9H); 13C NMR (75.5 MHz, CDCl3)
δ 170.5, 161.8, 157.6, 135.8, 129.1, 128.0, 127.6, 126.7, 123.8, 122.0, 96.4, 79.4, 28.8.
Data for 5-(4-(tert-butoxy)phenyl)-3-(4-fluorophenyl)isoxazole (5c): white crystalline
solid; yield: 96%; m.p. 146–147◦C; 1H NMR (300 MHz, CDCl3) δ 7.85 (m, 2H), 7.74 (m,
2H), 7.16 (m, 2H), 7.09 (m, 2H), 6.70 (s, 1H), 1.41 (s, 9H); 13C NMR (75.5 MHz, CDCl3)
δ 170.5, 163.7 (d, 1JC-F = 249.7 Hz), 162.0, 157.6, 128.7 (d, 3JC-F = 8.6 Hz), 126.8, 125.4
(d, 4JC-F = 3.1 Hz), 124.0, 122.2, 116.0 (d, 2JC-F = 21.8 Hz), 96.4, 79.5, 28.9.
Data for 5-(4-(tert-butoxy)phenyl)-3-(4-methylphenyl)isoxazole (5d): white solid;
1
yield: 80%; m.p. 111–112◦C; H NMR (300 MHz, CDCl3) δ 7.71 (m, 4H), 7.21 (m,
2H), 7.05 (m, 2H), 6.67 (s, 1H), 2.35 (s, 3H), 1.37 (s, 9H); 13C NMR (75.5 MHz, CDCl3) δ
169.9, 162.7, 157.3, 139.8, 129.4, 126.5, 126.21, 123.7, 122.2, 96.5, 96.4, 79.1, 28.7, 21.3.
Data for 5-(4-(tert-butoxy)phenyl)-3-(4-nitrophenyl)isoxazole (5e): yellow crystalline
solid, yield: 95%; m.p. 180–182◦C; 1H NMR (300 MHz, CDCl3) δ 8.34 (m, 2H), 8.04 (m,
2H), 7.75 (m, 2H), 7.36 (benzene), 7.11 (m, 2H), 6.79 (s, 1H), 1.42 (s, 9H); 13C NMR
(75.5 MHz, CDCl3) δ 171.4, 164.7, 158.0, 148.7, 135.4, 127.6, 126.9, 124.2, 123.9, 121.7,
96.5, 79.5, 28.9.
Synthesis of Phenols 6a-e. (Hydrolysis). Representative procedure for 6c. A solution of
isoxazole 5c (0.75 g, 2.41 mmol), methanol (54 mL), glacial acetic acid (1.79 mL,

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R. R. Da Rosa et al.
31.33 mmol), HBrconc (3.55 mL, 31.33 mmol) was stirred under reflux for 4–6 hours.
After the consumption of starting material (followed by TLC) the mixture was cooled to
room temperature and neutralized to pH∼6 with saturated solution of NaHCO3, the product
was precipitated and filtered off, giving a pure product.
Data for 3-(4-bromophenyl)-5-(4-hydroxyphenyl)isoxazole (6a): beige solid; yield:
99%; m.p. 204–206◦C; 1H NMR (300 MHz, CDCl3, 3 drops of DMSO d6) δ 9.48 (s, 1H),
7.73 (m, 2H), 7.67 (m, 2H), 7.60 (m, 2H), 6.95 (m, 2H), 6.68 (s, 1H), 2.83 (water); 13C
NMR (75.5 MHz, CDCl3, 3 drops of DMSO d6) δ 170.7, 164.4, 161.5, 159.2, 131.7, 127.9,
127.1, 123.6, 118.2, 115.8, 95.0.
Data for 3-(4-chlorophenyl)-5-(4-hydroxyphenyl)isoxazole (6b) : white solid; yield:
1
99%; m.p. 201–203◦C; H NMR (300 MHz, acetone d6) δ 7.94 (m, 2H), 7.77 (m, 2H),
7.55 (m, 2H), 7.18 (s, 1H), 7.01 (m, 2H); 13C NMR (75.5 MHz, acetone d6) δ 171.9, 162.7,
160.6, 136.2, 130.1, 129.3, 129.2, 128.4, 120.0, 116.9, 96.8.
Data for 3-(4-fluorophenyl)-5-(4-hydroxyphenyl)isoxazole (6c) : white solid; yield:
1
99%; m.p. 209–210◦C; H NMR (300 MHz, acetone d6) δ 7.99 (m, 2H), 7.78 (m, 2H),
7.29 (m, 2H), 7.16 (s, 1H), 7.02 (m, 2H); 13C NMR (75.5 MHz, acetone d6) δ 171.7, 164.5
1
3
4
(d, JC-F = 247.7 Hz), 162.7, 160.6, 129.7 (d, JC-F = 8.5 Hz), 128.3, 126.8 (d, JC-F
=
3.1 Hz), 119.8, 116.9, 116.7 (d, 2JC-F = 22.0 Hz), 96.7.
Data for 5-(4-hydroxyphenyl)-3-(4-methylphenyl)isoxazole (6d): pink pale solid;
yield: 99%; m.p. 179–181◦C; 1H NMR (300 MHz, acetone d6) δ 7.80 (m, 4H), 7.33 (d, 2H,
J = 8.4 Hz), 7.12 (s, 1H), 7.00 (d, 2H, J = 8.7 Hz), 2.39 (s, 3H); 13C NMR (75.5 MHz,
acetone d6) δ 171.4, 163.6, 160.4, 140.9, 130.5, 128.4, 127.7, 127.5, 120.2, 116.9, 96.7,
21.4.
Data for 5-(4-hydroxyphenyl)-3-(4-nitrophenyl)isoxazole (6e): yellow solid; yield:
1
90%; m.p. 240–242◦C; H NMR (300 MHz, acetone d6) δ 8.40 (m, 2H), 8.22 (m, 2H),
7.80 (m, 2H), 7.32 (s, 1H), 7.03 (m, 2H); 13C NMR (75.5 MHz, acetone d6) δ 172.5, 162.1,
160.9, 149.7, 136.5, 128.6, 128.4, 125.0, 119.5, 117.0, 97.1.
Synthesis of isoxazoles 7a-e (Alkylation Reaction). Representative procedure for compound
7e. In a round bottom two-necked flask fitted with reflux condenser, were added phenol
6e (0.40 g, 1.42 mmol), acetonitrile (6 mL) and potassium hydroxide (0.09 g, 1.56 mmol).
The mixture was heated at 90◦C until homogeneous. After that 1-bromooctane (0.28 mL,
1.56 mmol) was added dropwise and the reaction mixture was stirred under reflux for
4–6 hours (followed by TLC). At the end of the reaction the solvent was evaporated, added
CH2Cl2 (10 mL) and the mixture was washed with H2O (2 × 5 mL), NaHCO3 (2 × 5 mL)
and NaClsat (2 × 5 mL). The organic phase was dried with Na2SO4 and, after filtration, the
solvent was evaporated. The crude material was recrystallized in ethanol.
Data for 3-(4-bromophenyl)-5-(4-(octyloxy)phenyl)isoxazole (7a): white solid; yield:
1
84%; Transition temperatures: Cr 99◦C CrE 119◦C SmA 191◦C I; H NMR (300 MHz,
CDCl3) δ 7.73 (m, 4H), 7.60 (d, 2H, J = 8.4 Hz), 6.97 (d, 2H, J = 8.6 Hz), 6.66 (s, 1H),
4.00 (t, 2H), 1.81 (m, 2H), 1.55–1.10 (m, 14H), 0.88 (t, 3H); 13C NMR (75.5 MHz, CDCl3)
δ 210.3, 170.8, 161.9, 160.8, 132.1, 128.3, 128.2, 127.4, 124.1, 119.8, 114.9, 95.7, 68.2,
31.9, 29.6, 29.4, 29.3, 29.1, 26.0, 22.7, 14.1.
Data for 3-(4-chlorophenyl)-5-(4-(octyloxy)phenyl)isoxazole (7b): white solid; yield:
1
70%; Transition temperatures: Cr 96◦C CrE 100◦C SmA 190◦C I; H NMR (400 MHz,
CDCl3) δ 7.80–7.74 (m, 4H), 7.45 (d, 2H, J = 8.4 Hz), 6.98 (d, 2H, J = 8.8 Hz), 6.66
(s, 1H), 4.01 (t, 2H, J = 6.4 Hz), 1.84–1.77 (m, 2H), 1.50–1.23 (m, 10H), 0.89 (t, 3H,
J = 6.4 Hz); 13C NMR (100 MHz, CDCl3) δ 170.8, 161.9, 160.9, 135.9, 129.2, 128.1,

Isoxazoles: A New Entry to Soft Crystal Phase
[633]/167
127.8, 127.4, 119.8, 114.9, 95.8, 68.2, 31.8, 29.4, 29.3, 29.2, 26.0, 22.7, 14.1; EA, calc. for
C23H26ClNO2, 383.91 g/mol:, C 71.96, H 6.83, N 3.65, found: C 72.59, H 6.90, N 3.66.
Data for 3-(4-fluorophenyl)-5-(4-(octyloxy)phenyl)isoxazole (7c): white solid; yield:
77%; Transition temperatures: Cr 97◦C SmA 154◦C I; 1H NMR (300 MHz, CDCl3) δ 7.77
(m, 2H), 7.67 (m, 2H), 7.09 (m, 2H), 6.91 (m, 2H), 6.58 (s, 1H), 3.93 (t, 2H, J = 6.6 Hz),
1.73 (m, 2H), 1.46–1.12 (m, 10H), 0.82 (t, 3H, J = 6.8 Hz); 13C NMR (75.5 MHz, CDCl3)
δ 170.6, 163.7 (d, 1JC-F = 249.7 Hz), 161.9, 160.8, 128.6 (d, 3JC-F = 8.5 Hz), 127.4, 125.6
(d, 4JC-F = 3.3 Hz), 119.8, 115.9 (d, 2JC-F = 21.9 Hz), 114.9, 95.8, 68.2, 31.8, 29.3, 29.2,
29.1, 26.0, 22.6, 14.1; EA, calc. for C23H26FNO2, 367.46 g/mol:, C 75.18, H 7.13, N 3.81,
found: C 75.13, H 7.21, N 3.80.
Data for 3-(4-methylphenyl)-5-(4-(octyloxy)phenyl)isoxazole (7d): white solid; yield:
1
77%; Transition temperatures: Cr 90◦C SmA 124◦C N 141◦C I; H NMR (400 MHz,
CDCl3) δ 7.76 (m, 4H), 7.27 (d, 2H, J = 8.0 Hz), 6.97 (d, 2H, J = 8.8 Hz), 6.67 (s, 1H),
4.00 (t, 2H, J = 6.4 Hz), 2.41 (s, 1H), 1.84–1.77 (m, 2H), 1.50–1.23 (m, 10H), 0.89 (t,
3H, J = 6.8 Hz); 13C NMR (75.5 MHz, CDCl3) δ 170.3, 162.8, 160.7, 140.0, 129.5, 127.3,
126.7, 126.4, 120.1, 114.9, 95.9, 68.2, 31.8, 29.3, 29.2, 29.1, 26.0, 22.7, 21.4, 14.1; EA,
calc. for C24H29NO2, 363.49 g/mol:, C 79.30, H 8.04, N 3.85, found: C 79.00, H 8.05, N
3.88.
Data for 3-(4-nitrophenyl)-5-(4-(octyloxy)phenyl)isoxazole (7e): light yellow solid;
1
yield: 74%; Transition temperatures: Cr 79◦C Cr1 101◦C Cr2 130◦C SmA 206◦C I; H
NMR (300 MHz, CDCl3) δ 8.33 (m, 2H), 8.03 (m, 2H), 7.76 (m, 2H), 6.99 (m, 2H), 6.75 (s,
1H), 4.01 (t, 2H, J = 6.6 Hz), 1.81 (m, 2H), 1.54–1.19 (m, 10H), 0.89 (t, 3H, J = 6.8 Hz);
13C NMR (75.5 MHz, CDCl3) δ 171.6, 161.2, 161.1, 148.7, 135.5, 127.7, 127.6, 124.3,
119.5, 115.1, 96.0, 68.4, 31.9, 29.5, 29.4, 29.3, 26.1, 22.8, 14.2; EA, calc. for C23H26N2O4,
394.46 g/mol:, C 70.03, H 6.64, N 7.10, found: C 70.52, H 6.72, N 7.14..
Acknowledgments
The authors gratefully acknowledge the INCT-Cata´lise, Fapergs-Edital PqG 2012 and Edital
01/12-PPG-Qu´ımica-UFRGS. Rafaela R. da Rosa thanks CNPq agency for her fellowship.
Irwing S. Brose is an undergraduate student and thanks PIBIC-CNPq for his fellowship.
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