Critical assessment of two classical synthetic methods for preparation of thiophene-substituted isoxazoles

Article abstract of DOI:10.1007/s11164-013-1101-8

Formation of thiophene-substituted isoxazoles by reaction of chalcone dibromides and 1,3-diketones with hydroxylamine hydrochloride has been examined under different conditions. Use of KOH as base in the reaction of dibromide chalcone analogs with hydroxy

Full text of DOI:10.1007/s11164-013-1101-8

Res Chem Intermed
DOI 10.1007/s11164-013-1101-8
Critical assessment of two classical synthetic methods
for preparation of thiophene-substituted isoxazoles
Gheorghe Roman
Received: 10 December 2012 / Accepted: 4 February 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract Formation of thiophene-substituted isoxazoles by reaction of chalcone
dibromides and 1,3-diketones with hydroxylamine hydrochloride has been examined
under different conditions. Use of KOH as base in the reaction of dibromide chalcone
analogs with hydroxylamine hydrochloride yields mixtures of isomeric isoxazoles in
modest yields. Replacement of KOH with pyridine affords negligible amounts of
isoxazoles only, the intermediate 2-bromoprop-2-en-1-one being isolated from the
reaction as the major product. Substitution of the b-bromine atom from a chalcone
dibromides with a methoxy group by solvolysis occurred when no base was used.
Mixtures of isomeric isoxazoles in which the isoxazole that had a 2-thienyl group at
position 5 were always major components, were obtained in good yields from
reaction of thiophene-containing 1,3-diketones with hydroxylamine hydrochloride,
irrespective of reaction pH. At low pH, regioselectivity was poorer than that
observed for reaction of chalcone dibromides with hydroxylamine hydrochloride, but
yields were substantially better. At high pH, yields were comparable with those at
low pH and regioselectivity for 3-aryl-5-(2-thiophenyl)isoxazole was slightly
enhanced, but the dioxime corresponding to the initial 1,3-diketone was also pro-
duced in low yields as a mixture of stereoisomers.
Keywords Chalcone analogs ꢀ Chalcone dibromides ꢀ 1,3-Diketone ꢀ Isoxazole ꢀ
Ring closure
Electronic supplementary material The online version of this article (doi:
10.1007/s11164-013-1101-8) contains supplementary material, which is available to authorized users.
G. Roman (&)
Petru Poni Institute of Macromolecular Chemistry, 41A Aleea Gr. Ghica Voda,
˘
700487 Ias¸i, Romania
e-mail: gheorghe.roman@icmpp.ro
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G. Roman
Introduction
Isoxazoles are an important class of heterocyclic compounds because of their use as
intermediates in organic synthesis and their numerous applications. In addition to
their intrinsic value as structural units, isoxazoles are used in organic synthesis
because of their versatility as synthons, primarily because they combine a
potentially unlimited range of structural modification of their substituents with
facile cleavage of the weak N–O bond [1, 2]. Isoxazoles also have a variety of
technical applications in the production of dye-sensitized solar cells [3], fluorescent
chemosensors for the fluoride anion [4], herbicides [5], and liquid crystals [6, 7]. In
addition, isoxazole is a structure widely encountered in drug design, especially in
the development of inhibitors of c-aminobutyric acid (GABA) uptake [8], GABAA
antagonists [9], or GABA agonists [10], but also in the structures of antibiotics [11],
antithrombotic agents [12, 13], HIV infection inhibitors [14], antiviral candidates
[15, 16], antifungals [17, 18], anticancer compounds [19–21], and antitubercular
drugs [22–24].
A literature survey shows that 1,3-dipolar cycloaddition of nitrile oxides and
alkynes and reaction of hydroxylamine with 1,3-dicarbonyl compounds are the most
widely used synthetic methods for closure of the isoxazole ring [1, 25]. The
shortcoming of both methods is the generation of a mixture of regioisomeric
isoxazoles when asymmetrically substituted starting materials are used. Despite
recent progress in the control of regioselectivity in cycloadditions of nitrile oxides
and alkynes by use of copper(I) catalysts [26, 27], this approach remains
unattractive for large-scale synthesis of 3,5-diarylisoxazoles, first because of the
limited number and prohibitive cost of commercially available arylacetylenes, and,
second, the difficult preparation of these alkynes by multi-step procedures that use
expensive starting materials. In contrast, the latter strategy for construction of the
isoxazole ring uses 1,3-dicarbonyl compounds or their synthetic equivalents which
are readily accessible from inexpensive commercially available starting materials
by two or three-step simple synthetic procedures. However, methods using this
strategy usually yield a mixture of positional isomers in ratios that vary from one
method to another. For example, synthesis of isoxazoles from a,b-dihalocarbonyl
compounds (chalcone dibromides) as synthetic equivalents to 1,3-dicarbonyl
compounds is usually regarded as highly selective, because only the isoxazole
regioisomer derived from attack of hydroxylamine on the carbonyl function is
usually formed. In contrast, oximation of unsymmetrical 1,3-diketones leads to both
regioisomeric isoxazoles in the form of a mixture whose composition depends on
the reaction conditions (solvent, temperature, pH) and on the nature of the aryl
groups which, in turn, as a result of the steric and electronic properties, affects the
equilibrium between the two possible tautomeric enol forms of the unsymmetrical
1,3-diketone [1].
Easy access to large amounts of thiophene-substituted 3,5-diarylisoxazoles was
required for a project in our laboratory. In an attempt to identify the best
synthetic method for large-scale preparation of these compounds, we conducted
a thorough investigation of the reaction of hydroxylamine with dibromides of
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Preparation of thiophene-substituted isoxazoles
thienyl-containing chalcone analogs and the corresponding thienyl-containing 1,3-
diketones. Our conclusions from this study are reported below.
Results and discussion
The four thienyl-containing chalcone analogs 1–4 required for this study were
synthesized either by Claisen condensation of thiophene-2-carboxaldehyde with
either 40-chloroacetophenone or 40-bromoacetophenone or by condensation of
2-acetylthiophene with either 4-chlorobenzaldehyde or 4-bromobenzaldehyde
(Scheme 1). Compounds 1–4 were then transformed into the corresponding
thienyl-containing chalcone dibromides 5–8 by treatment with bromine at room
temperature [28]. On the basis of the value of the coupling constant (approximately
11 ppm) between the protons on the chiral carbon atoms, dibromides 5–8 exist in
the erythro form in solution [29]. By diluting the reaction mixture with petroleum
ether, compounds 5–8 were recovered in good yields and excellent purity, and were
used as such in the subsequent step. Ring closure of these intermediates to
thiophene-substituted isoxazoles 11–14 was initially performed by use of a reported
procedure [30, 31] which entails slow addition of aqueous KOH to a suspension of
the chalcone dibromide in hot ethanol containing hydroxylamine hydrochloride
(Method A in the Experimental section). The solid isolated after work-up of the
reaction mixture was subjected to 1H NMR analysis, and the important signal of the
proton at C4 in the isoxazole ring was monitored in the 6.5–7.0 ppm region. Despite
previous reports which mention formation of only one of the two possible
regioisomers, this reaction afforded both isomeric isoxazoles, as shown by the two
singlets in the aforementioned region, which were always observed. Thus,
dibromides 5 and 6 afforded isoxazoles 9 and 10, respectively, as the major
components in the mixture (94 %) whereas isoxazoles 11 and 12 amounted to
approximately 6 % of the sample in each case. Isoxazoles 11 and 12 were obtained
as the major components in the mixture (97 %) from dibromides 7 and 8,
respectively, whereas isoxazoles 9 and 10, respectively, accounted for the remainder
of the sample (3 %). As noted previously [32], repeated recrystallization from
ethanol of mixtures of regioisomers 9 and 11 resulted in no variation in their ratio,
as proved by NMR. The same behavior was noticed for mixtures of regioisomeric
isoxazoles 10 and 12. Use of different combinations of solvents in TLC analysis of
the mixture on silica gel did not enable discrimination between the two regioisomers
of each pair, making their separation by column chromatography virtually
impossible. Nevertheless, the purity of isoxazoles 9–12 obtained by this method
is acceptable for most intents and purposes. Unfortunately, yields of this synthetic
method are low [31], and isoxazoles 9–12 have been obtained after one
recrystallization in yields ranging from 38 to 24 %. Although yields can be
improved slightly if the base is added very slowly to the reaction mixture, yields
remain modest, rendering this method unattractive for large-scale synthesis.
The identity of isoxazoles 9–12 could not be established solely by study of NMR
data. Although reaction of chalcone dibromides with hydroxylamine is believed to
be highly selective, because, usually, only the regioisomer formed by attack of the
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G. Roman
Scheme 1 Synthesis of thiophene-substituted isoxazoles from thienyl-containing chalcone dibromides.
Reaction conditions: (a) 40-chloroacetophenone or 40-bromoacetophenone, ethanol, 40 % NaOH, rt,
overnight; (b) 4-chlorobenzaldehyde or 4-bromobenzaldehyde, ethanol, 40 % NaOH, rt, overnight;
(c) bromine, chloroform, rt, 2 h; (d) hydroxylamine hydrochloride, KOH, ethanol–water, 70–75 °C,
5–10 min
nitrogen atom of hydroxylamine on the carbonyl group of the chalcone dibromide is
obtained, the method still is not entirely unequivocal [1]. Despite the wealth of
information about assignment of the structures of isoxazoles resulting from reaction
of chalcone dibromides with hydroxylamine, which supports the aforementioned
conclusion, the structures of isoxazoles 9–12 ought to be proved beyond any doubt.
Confirmation of their structure was finally achieved by corroborating the results
from two different experiments, which led to the same conclusion. The first
experiment was an attempt to synthesize one of the regioisomers of a pair via a
different synthetic path that would indubitably lead to an isoxazole with a well-
defined structure as the sole reaction product. To unambiguously obtain one
regioisomer as the sole reaction product, the location of the aryl groups at C3 and
C5 of the isoxazole ring in the starting material must be known precisely, and
subsequent transformation of the starting material into the isoxazole should not
affect the positions of these substituents. Brief examination of literature revealed
that oxidation of isoxazolines to isoxazoles is a reaction that meets the latter
criterium. The required starting material, isoxazoline 13, was obtained first by
oximation of chalcone analog 3, by use of a literature method [33]; the by-product
hydroxylamino oxime 14 was also isolated and characterized as a mixture of
stereoisomers A and B in the relative ratio 1.4 to 1 (Scheme 2). A synthetic method
[34], very similar to that described by Lesiak and Nielek, has recently been used to
1
obtain isoxazoline 13, but the appearance, melting point, and H NMR spectrum
reported by Ramiz et al. for the compound allegedly having the structure of 13 differ
substantially from those of isoxazoline 13 obtained by us. Isoxazoline 13 has now
been fully characterized, and correlation spectroscopy has been used to confirm the
position of the 4-chlorophenyl and 2-thienyl substituents on the isoxazole ring. The
2D HMBC spectrum of compound 13 reveals strong correlation between C5 in the
isoxazoline ring (82.1 ppm) and the protons of the 4-chlorophenyl moiety
(7.30–7.37 ppm), and the proton at C5 in the isoxazoline ring (5.71 ppm) correlates
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Preparation of thiophene-substituted isoxazoles
with the carbon atoms in the chlorophenyl substituent (127.4 ppm). Also, C3 in the
isoxazoline ring (152.0 ppm) correlates strongly with one proton in the thiophene
ring (7.19 ppm). Next, because the complex of 1,4-diazabicyclo[2.2.2]octane
(DABCO) with bromine has recently been reported to cleanly and effectively
oxidize isoxazolines to the corresponding isoxazoles [35], the experiment described
by Azarifar et al. was repeated. However, in our hands, the reaction took a different
course, and isoxazoline 15, resulting from bromination of the thiophene ring of
isoxazoline 13, was obtained as the sole reaction product (Scheme 2). This is not
surprising, because isoxazolines are known to resist oxidation to isoxazole by
bromine [1]. The crude reaction mixture still contained approximately 20 %
unreacted starting material, but no trace of either regioisomeric isoxazole 9 or 11
could be detected by NMR. Repeated recrystallization of the solid isolated from the
reaction mixture yielded the pure isoxazoline 15 which melted sharply at
100–101 °C. Azarifar et al. reported a melting point of 191–193 °C for the
compound they isolated from an identical experiment. In addition, the melting point
of the product reported by Azarifar et al. is also different from the melting point of
isoxazoles 9 or 11 reported in this paper; together this raises serious questions about
the diligence of these authors. Next, oxidation of isoxazoline 13 was attempted by
another method. Although chromium(VI) oxide in acetic acid has long been known
as an oxidizing system able to dehydrogenate isoxazolines to isoxazoles [36], use of
this method resulted in detection of only minute traces of isoxazole 11, both in the
solid isolated after work-up and in the chloroform extract of an aliquot of the filtrate
obtained after isolation of the aforementioned solid. The isolated solid consisted
mostly of unreacted isoxazoline 13, whereas the residue obtained from the
chloroform extract was a complex mixture of by-products most likely formed as a
result of destructive oxidation of the isoxazoline ring. As this experiment was
deemed inconclusive, we decided to use 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ) as dehydrogenating agent. The residue obtained after processing the reaction
mixture consisted of a mixture of unreacted starting material 13 and the expected
isoxazole 11 in an approximate ratio of 9:11, according to NMR analysis. Isoxazole
11 was identified in the mixture on the basis of the presence of a singlet at 6.75 ppm
in the 1H NMR spectrum, assigned to the proton at C4 in the isoxazole ring, but no
separation of a pure sample from the reaction mixture was attempted. Despite the
fact that isoxazoline 13 was not completely converted to the corresponding
isoxazole under these conditions, this experiment confirms that initial assignment of
the structure of isoxazole 11 was correct. Taking into account that replacement of
chlorine in 11 by bromine in 12 does not induce a significant change in the chemical
1
shift of the proton at C4 in the isoxazole ring, and that the H NMR spectrum of
isoxazole 12 also contains a singlet at 6.75 ppm, isoxazole 12 must also be the
regioisomer having the 2-thienyl substituent attached to C3 whereas the 4-bromo-
phenyl moiety substitutes C5 of the isoxazole ring. The 1H NMR spectra of
isoxazoles 9 and 10 both contain a signal at 6.66 ppm for the proton at C4 in the
isoxazole ring; they must, therefore, both have a 2-thienyl substituent at C5 and
either a 4-chlorophenyl moiety or a 4-bromophenyl, respectively, at C3.
Additional confirmation of the structures of isoxazoles 9–12 was obtained by use
of mass spectroscopy. Isomer determination by mass spectroscopy relies on the
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G. Roman
Scheme 2 Synthesis and reaction of 5-(4-chlorophenyl)-3-(thiophen-2-yl)-4,5-dihydroisoxazole 13 with
different oxidizing agents. Reactions and conditions: (a) hydroxylamine hydrochloride, KOH, ethanol–
water, reflux, 5 h; (b) DABCO–Br2 complex, glacial acetic acid, rt, 5 h; (c) CrO3, glacial acetic acid,
75–80 °C, 45 min; (d) DDQ, anhydrous dioxane, reflux, 6 h
unique fragmentation pattern of 3,5-diarylisoxazoles, which very often gives as the
base peak an acylium ion derived from the aromatic substituent at position 5 of the
parent isoxazole, with other species [1]. The most intense peak in the MS–MS
spectrum of isoxazole 9 was m/z 110.99, which is consistent with the m/z value for
an acylium ion derived from thiophene, whereas the MS–MS analysis of the
molecular ion of compound 11 resulted in a base peak at m/z 138.95 corresponding
to the acylium ion derived from a chlorophenyl moiety. Therefore, the thienyl
substituent is located at C5 in isoxazole 9 whereas the 4-chlorophenyl residue is
located at C5 in regioisomer 11.
It has been reported [37] that reaction of hydroxylamine hydrochloride with 2,3-
dibromo-1-(5-chloro-2-hydroxyphenyl)-3-(2-furyl)propan-1-one in pyridine at
reflux temperature yields the expected 3-(5-chloro-2-hydroxyphenyl)-5-(2-furyl)is-
oxazole whereas the same reactants produce the isomeric 5-(5-chloro-2-hydroxy-
phenyl)-3-(2-furyl)isoxazole in methanol at reflux temperature. Therefore, reaction
of hydroxylamine hydrochloride with dibromide 5 was examined under these
conditions also. Heating dibromide 5 with hydroxylamine hydrochloride in pyridine
at reflux temperature for 3 h (Method B in the Experimental section) furnished a
1
brown oil after work-up. H NMR analysis showed that this oil contained both
isoxazole 9 and isoxazole 11 in an approximate ratio of 2 to 1. These results suggest,
at least for dibromide 5, that this method is even less selective than that with KOH
as base. Moreover, the isoxazoles seem to be minor components in the reaction
mixture. Further work-up of the residue enabled isolation of modest amount of a
solid, which was analyzed by NMR and shown to be a mixture of the Z and
E isomers of 2-bromo-1-(4-chlorophenyl)-3-(2-thienyl)prop-2-en-1-one 16. The
approximate ratio of the Z and E isomers of compound 16 was determined to be
approximately 4 to 1 on the basis of the ratio of the signals of the ethylenic proton
for each stereoisomer (peaks with d 7.75 and 7.99 ppm in Fig. 1S in the
Supplementary Material). Isolation from the reaction mixture of the unsaturated
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Preparation of thiophene-substituted isoxazoles
bromo ketone 16 (Scheme 3), an intermediate in the synthesis of isoxazole 9 from
dibromide 5, suggests that pyridine is not a strong enough base to promote
conversion of 16 into acetylenic ketone 17. This is in agreement with previous
results showing that dehydrohalogenation of dibromides similar to 5 in the presence
of triethylamine affords a-bromo ketones in excellent yields [38], but further loss of
hydrogen bromide from unsaturated bromo ketones to yield acetylenic ketones
requires use of a stronger base, such as KOH [39].
Reaction of dibromide 5 with hydroxylamine hydrochloride in the absence of a
base (Method C in the Experimental section) afforded no isoxazole (shown by NMR
analysis of the crude reaction mixture). The product of the reaction is, instead,
2-bromo-1-(4-chlorophenyl)-3-methoxy-3-(2-thienyl)propan-1-one 18, which arises
from nucleophilic substitution of the reactive bromine in the position b to the
carbonyl function with a methoxy group by solvolysis (Scheme 3). Similar behavior
has been reported [40] for dibromides of analogs of chalcone derived from
4-methoxybenzaldehyde, which exchange the bromine in the position b to the
carbonyl with an alkoxy group when heated with alcohols for a short time. The
structure of compound 18 was established on the basis of several NMR experiments
including 2D homonuclear and heteronuclear correlation spectroscopy (Figs. 2S,
3S, 4S, 5S in the Supplementary Material). These experiments confirm that the
methoxy group is located on the carbon atom adjacent to the thiophene ring.
Reaction of hydroxylamine hydrochloride with thiophene-containing 1,3-dike-
tones was also investigated (Scheme 4). The intermediate dicarbonyl compounds 19
and 20 were obtained in excellent yield by reaction of dibromides 5 and 7,
respectively, with sodium methoxide in methanol and subsequent hydrolysis [41].
The equilibrium between the diketo and keto–enol forms of these compounds is
strongly shifted toward the latter in deuterated chloroform (98 % keto–enol form for
Scheme 3 Reaction of dibromide 5 with hydroxylamine hydrochloride at high and low pH. Reaction
conditions: (a) hydroxylamine hydrochloride, pyridine, reflux, 3 h; (b) hydroxylamine hydrochloride,
methanol, reflux, 5 h
123

G. Roman
compound 19; 95 % keto–enol form for compound 20), as determined by NMR. On
the basis of information available in the literature, this type of compound enolizes at
the carbonyl neighboring the thiophene moiety [42]. Oximation of unsymmetrical
1,3-diketones 19 and 20 was conducted in alcoholic solvents at reflux at either low pH
(hydroxylamine hydrochloride only) or high pH (in the presence of pyridine). At low
pH (Method D in the Experimental section), oximation of 19 led to a mixture of
isoxazole 9 (86 %), isoxazole 11 (10 %), and unreacted starting material (4 %). A
first recrystallization from ethanol removed the unreacted diketone 19, and yielded a
mixture of isoxazoles 9 (89 %) and 11 (11 %); the ratio of these isomers remained the
same after a second recrystallization from ethanol. Reaction of 20 with hydroxyl-
amine hydrochloride under the same conditions afforded a mixture of isoxazole 10
(80 %), isoxazole 12 (9 %), and unreacted starting material (11 %). Because of the
large amount of unreacted diketone 20 in the crude reaction mixture, its complete
removal required three recrystallizations from ethanol, and the final ratio of isoxazole
10 to isoxazole 12 was 9:1. Conversion of 19 and 20 into the corresponding isoxazoles
was, in both cases, 60–70 % after purification, which makes this synthetic approach
more efficient than reaction of dibromides 5–8 with hydroxylamine. However, the
regioselectivity of the reaction was, in each case, slightly poorer than that obtained
from reaction of the dibromides 5–8 with hydroxylamine hydrochloride in the
presence of KOH, so the purity of isoxazoles 9 and 10 obtained by use of this method
qualifies them as technical grade materials only. Furthermore, this method leads
predominantly to isoxazoles with a 2-thienyl substituent at position 5, presumably
because of the direction of enolization of the substrate. Similar results have previously
been reported for 1-phenyl-3-(2-thienyl)propane-1,3-dione [43].
Scheme 4 Synthesis and reaction of 1,3-diketones 16 and 17 with hydroxylamine hydrochloride at low
and high pH. Reaction conditions: (a) MeONa, methanol, reflux, 1 h, then 36 % HCl, reflux, 5 min;
(b) hydroxylamine hydrochloride, methanol, reflux, 7 h; (c) hydroxylamine hydrochloride, pyridine,
ethanol, reflux, 5 h
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Preparation of thiophene-substituted isoxazoles
At high pH (Method E in the Experimental section), transformation of 1,3-diketone
19 by reaction with hydroxylamine was complete, also affording a mixture of
isoxazoles 9 and 11 and a by-product which was easily separated from the isomeric
isoxazoles on the basis of its limited solubility in chloroform (Scheme 4). The mixture
of isomeric isoxazoles recovered from the chloroform extract was indicative of 65 %
conversion of starting material 19, and contained 93 % isoxazole 9 and 7 % isoxazole
11; its composition remained unchanged after one recrystallization from ethanol. 1,3-
Diketone 20 behaved similarly under the same reaction conditions, and an isolation
procedure identical with that used for processing the crude reaction mixture obtained
from diketone 19 afforded a mixture of isoxazoles 10 (93.5 %) and 12 (6.5 %) whose
composition was not altered by recrystallization from ethanol. The purity of
isoxazoles 9 and 10 obtained by use of this approach is comparable with that of the
same isoxazoles obtained from dibromides using KOH as base, but the yields were
significantly better. Again, one should note that only isoxazoles having a 2-thienyl
substituent at position 5 are available by use of this approach.
NMR analysis of the fraction insoluble in chloroform from reaction of 1,3-
diketone 19 with hydroxylamine hydrochloride in the presence of pyridine showed
that, apart from the signals in the aromatic region (Fig. 6S in the Supplementary
Material), the proton spectrum of the by-product contained one pair of singlets in the
aliphatic region and two distinct pairs of singlets in the off-set (Fig. 7S in the
Supplementary Material). Integration of these peaks clearly showed that one signal
of each of these pairs is associated with one compound, and that a different
compound is responsible for the other signal in each of these pairs. The close
chemical shift values of the signals in each pair suggest that the structures of these
two compounds are very similar. The ratio of the signal in the aliphatic region to the
corresponding signals in the pairs in the off-set is 2:1:1. Taking into consideration
other possible interactions between the starting materials in addition to that leading
to isoxazoles, the two compounds in the by-product from oximation of 1,3-diketone
19 are most likely stereoisomers of 1-(4-chlorophenyl)-3-(thiophen-2-yl)propane-
1,3-dione dioxime 21. Of the four possible stereoisomers of this dioxime, the (1E,3Z)
and (1Z,3E) isomers A and B (Scheme 4) are the most plausible candidates for the
two components of the by-product, because both isomers are stabilized by an
intramolecular hydrogen bond. Because the ratio of these two stereoisomers is
approximately 1:7, the signals in the proton spectrum of their mixture can be
tentatively assigned. Inspection of the 13C NMR spectrum confirmed the presence of
the aliphatic carbon atom of the methylene group, and the absence of any carbonyl
functions in the structure of the compounds in the fraction insoluble in chloroform.
The molecular formula for the compound in this fraction was also supported by
results obtained from mass spectrometry (Fig. 8S in the Supplementary Material).
The ESI–MS spectrum of the fraction insoluble in chloroform was recorded in
methanol, and the peak for the most abundant singly charged species at m/z 293.0855
can be assigned to the deprotonated compound [M – H]-. Results from elemental
analysis were also consistent with the values calculated for dioxime 21. The fraction
insoluble in chloroform obtained from processing the crude reaction mixture
resulting from reaction of diketone 20 was also investigated, and the presence of a
mixture of stereoisomeric dioximes 22 was corroborated by results from NMR
123

G. Roman
analysis, mass spectrometry, and elemental analysis. The ratio of the two
stereoisomers of dioxime 22 is approximately 1:1.3. As a consequence, accurate
assignment of the peaks in the proton spectrum of their mixture is more difficult, and
the 13C NMR spectrum of 22 is reported as the sum of peaks for both stereoisomers.
Conclusions
Reaction of two pairs of thienyl-containing chalcone dibromides with hydroxyl-
amine hydrochloride in the presence of KOH was investigated, and shown to lead to
modest yields of mixtures of isomeric isoxazoles in which the isomer resulting from
oximation of the carbonyl function in the starting chalcone dibromide is the major
component. No pure product could be obtained by repeated recrystallization of these
mixtures. In the presence of pyridine, an intermediate in the synthesis of isoxazoles,
the unsaturated bromoketone resulting from dehydrobromination of the starting
chalcone dibromide, was isolated. In the absence of the base, replacement of the
bromine atom at the position b to the carbonyl function with a methoxy group from
the solvent occurred. Good yields of 3-aryl-5-(2-thienyl)isoxazoles (also as mixtures
with their regioisomers) were obtained from the reaction of thienyl-containing 1,3-
diketones with hydroxylamine hydrochloride, irrespective of the pH of the reaction
mixture. The regioselectivity of the reaction improved slightly at high pH, but yields
of isoxazoles decreased to some extent because of formation of the dioximes of the
starting 1,3-diketones as by-products.
Experimental
All chemicals were purchased from commercial suppliers and used without further
purification. Melting points were taken on a Mel-Temp II apparatus and are
uncorrected. Elemental analysis was conducted in-house, on a PerkinElmer 2400
Series II CHNS/O system. Analytical TLC was performed on pre-coated plates
1
(Merck silica gel 60, F254); spots were visualized by UV illumination. H and 13C
NMR spectra were recorded on a Bruker Avance 400-MHz spectrometer. The
signals from residual protons in the deuterated solvents were used as internal
1
standards for the H NMR spectra. The chemical shifts for carbon atoms are given
relative to CDCl3 (d = 77.16 ppm) or d6-DMSO (d = 39.52 ppm). Mass spec-
trometry data were obtained on an Agilent 6520 Series Accurate-Mass Quadrupole
Time-of-Flight (Q-TOF) LC–MS using electrospray ionization (negative-ion mode
for the analysis of compound 21, and positive-ion mode for compounds 9 and 11).
For isoxazoles 9 and 11, fragmentation of the molecular ion (m/z 262) was
performed in MS–MS mode at a collision energy of 40 eV.
General procedure for synthesis of chalcones 1–4
A solution of the required ketone (20 mmol) and aldehyde (20 mmol) in ethanol
(20 mL) was treated at room temperature with efficient stirring with 40 % NaOH
123

Preparation of thiophene-substituted isoxazoles
(5–7 drops). The mixture was kept at room temperature overnight, then the solid
was isolated by filtration, washed thoroughly with small volumes of cold
2-propanol, air-dried, and recrystallized from methanol.
1-(4-Chlorophenyl)-3-(thiophen-2-yl)prop-2-en-1-one (1)
Yellowish crystals, yield 82 %, mp 121–122 °C (lit. mp 118–120 °C [44]; lit. mp
121–122 °C [45]).
1-(4-Bromophenyl)-3-(thiophen-2-yl)prop-2-en-1-one (2)
Yellow crystals, yield 84 %, mp 130–131 °C (lit. mp 133–135 °C [44]).
3-(4-Chlorophenyl)-1-(thiophen-2-yl)prop-2-en-1-one (3)
Light yellow crystals, yield 79 %, mp 132–133 °C (lit. mp 133 °C [46]; lit. mp
132–133 °C [47]).
3-(4-Bromophenyl)-1-(thiophen-2-yl)prop-2-en-1-one (4)
Yellow crystals, yield 66 %, mp 136–137 °C (lit. mp 131–133 °C [48]).
General procedure for synthesis of thienyl-containing chalcone dibromides 5–8
A solution of bromine (1.6 g, 10 mmol) in chloroform (5 mL) was added dropwise
to a solution of chalcone analog 1–4 (10 mmol) in the smallest volume of
chloroform (10–15 mL) at room temperature. The reaction mixture was stirred at
room temperature for 2 h then diluted with petroleum ether (bp 40–60 °C, 50 mL)
and refrigerated for 3 h. The solid was isolated by filtration, washed with petroleum
ether, and air-dried.
2,3-Dibromo-1-(4-chlorophenyl)-3-(thiophen-2-yl)propan-1-one (5)
1
Colorless solid, yield 75 %, mp 144–145 °C; lit. mp 144–145 °C [28]; H NMR
(CDCl3, 400 MHz): d 5.72 (d, J = 10.8 Hz, 1H), 5.97 (d, J = 10.8 Hz, 1H), 7.01
(dd, J = 3.6 and 5.2 Hz, 1H), 7.27 (dd, J = 0.8 and 3.6 Hz, 1H), 7.45 (d,
J = 5.2 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H); 13C NMR
(CDCl3, 100 MHz): d 44.7, 48.3, 127.0, 127.6, 128.7, 129.6, 130.5, 132.7, 141.1,
142.1, 189.9.
2,3-Dibromo-1-(4-bromophenyl)-3-(thiophen-2-yl)propan-1-one (6)
1
Colorless solid, yield 73 %, mp 138–139 °C (dec); lit. mp 131–134 °C [28]; H
NMR (CDCl3, 400 MHz): d 5.71 (d, J = 11.2 Hz, 1H), 5.97 (d, J = 11.2 Hz, 1H),
7.01 (dd, J = 3.6 and 5.2 Hz, 1H), 7.27 (dd, J = 0.8 and 3.6 Hz, 1H), 7.45 d,
J = 5.2 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H); 13C NMR
123

G. Roman
(CDCl3, 100 MHz): d 44.7, 48.2, 127.0, 127.7, 128.7, 129.9, 130.5, 132.6, 133.1,
142.1, 190.1.
2,3-Dibromo-3-(4-chlorophenyl)-1-(thiophen-2-yl)propan-1-one (7)
Colorless solid, yield 78 %, mp 188–189 °C; lit. mp 189–198 °C [28]; 1H NMR (d6-
DMSO, 400 MHz): d 5.78 (d, J = 11.2 Hz, 1H), 6.56 (d, J = 11.2 Hz, 1H), 7.40
(dd, J = 4.0 and 4.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H),
8.23 (dd, J = 0.8 and 4.8 Hz, 1H), 8.55 (dd, J = 0.8 and 4.0 Hz, 1H); 13C NMR
(d6-DMSO, 100 MHz): d 47.0, 49.4, 128.7, 129.3, 130.7, 133.7, 135.8, 137.6, 138.1,
140.8, 184.8.
2,3-Dibromo-3-(4-bromophenyl)-1-(thiophen-2-yl)propan-1-one (8)
Colorless solid, yield 86 %, mp 191–192 °C (dec); 1H NMR (d6-DMSO, 400 MHz):
d 5.77 (d, J = 11.2 Hz, 1H), 6.56 (d, J = 11.2 Hz, 1H), 7.40 (dd, J = 4.0 and
4.8 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 8.23 (dd, J = 0.8
and 4.8 Hz, 1H), 8.55 (dd, J = 0.8 and 4.0 Hz, 1H); 13C NMR (d6-DMSO,
100 MHz): d 47.0, 49.4, 122.4, 129.3, 130.9, 131.6, 135.9, 138.0, 138.1, 140.8,
184.8.
Oximation of chalcone 3
A mixture of 3-(4-chlorophenyl)-1-(thiophen-2-yl)prop-2-en-1-one 3 (1.245 g,
5 mmol) and hydroxylamine hydrochloride (1.38 g, 20 mmol) in methanol
(20 mL) was treated with a solution of KOH (1.98 g, 30 mmol, purity 85 %) in
water (7 mL). The mixture was heated at reflux temperature for 5 h, then the solvent
was removed under reduced pressure. The residue was stirred with water (100 mL)
for 30 min, then the solid was isolated by filtration and washed with water
(2 9 15 mL). The dry solid (1 g) was suspended in chloroform (15 mL), and the
suspension was filtered to remove a small amount of insoluble material. The residue
obtained after removal of the chloroform under reduced pressure was recrystalli-
zation from ethanol to afford the analytical sample (315 mg) of isoxazoline 13. The
aqueous filtrate from isolation of the crude isoxazoline was treated, with efficient
stirring, with 10 % HCl until pH 5–6. The solid was then isolated by filtration, air-
dried, and recrystallized from 2-propanol to give the analytical sample of
hydroxylamino oxime 14.
5-(4-Chlorophenyl)-3-(thiophen-2-yl)-4,5-dihydroisoxazole (13)
Colorless solid, yield 24 %, mp 88–89 °C; 1H NMR (CDCl3, 400 MHz): d 3.30 (dd,
J = 8.0 and 16.4 Hz, 1H), 3.79 (dd, J = 11.2 and 16.4 Hz, 1H), 5.71 (dd, J = 8.0
and 11.2 Hz, 1H), 7.06 (dd, J = 4.0 and 5.0 Hz, 1H), 7.19 (dd, J = 0.4 and 3.6 Hz,
1H), 7.30–7.37 (m, 4H), 7.41 (dd, J = 0.4 and 5.0 Hz, 1H); 13C NMR (CDCl3,
100 MHz): d 44.1, 82.1, 127.4, 127.5, 128.6, 128.7, 129.1, 131.8, 134.3, 139.3,
152.0.
123

Preparation of thiophene-substituted isoxazoles
3-(4-Chlorophenyl)-3-(hydroxyamino)-1-(thiophen-2-yl)propan-1-one oxime (14),
mixture of stereoisomers A and B
Off-white solid, yield 10 %, mp 171–172 °C (softening at 148 °C); 1H NMR
(d6-DMSO, 400 MHz): d 2.77 (dd, J = 8.4 and 14.4 Hz, 1H, stereoisomer A), 2.93
(dd, J = 8.4 and 12.8 Hz, 1H, stereoisomer B), 3.07 (dd, J = 6.8 and 13.2 Hz, 1H,
stereoisomer B), 3.21 (dd, J = 5.6 and 14.4 Hz, 1H stereoisomer A), 4.23 (d,
J = 5.2 Hz, 1H, stereoisomers A and B), 5.95 (s, 1H, stereoisomer B, exchangeable
with D), 6.00 (s, 1H, stereoisomer A, exchangeable with D), 7.00 (dd, J = 4.0 and
5.2 Hz, 1H, stereoisomer B), 7.16 (dd, J = 4.0 and 5.2 Hz, 1H, stereoisomer A),
7.21 (d, J = 4.0 Hz, 1H, stereoisomer B), 7.25–7.37 (m, 5H, stereoisomers A and B,
1H exchangeable with D), 7.40 (d, J = 5.2 Hz, 1H, stereoisomer B), 7.62 (d,
J = 4.0 Hz, 1H, stereoisomer A), 7.73 (d, J = 5.2 Hz, 1H, stereoisomer A), 11.17
(s, 1H, stereoisomer B, exchangeable with D), 11.68 (s, 1H, stereoisomer A,
exchangeable with D).
Attempted oxidation of isoxazoline 13 with DABCO–Br2 complex
5-(4-Chlorophenyl)-3-(thiophen-2-yl)-4,5-dihydroisoxazole 13 (422 mg, 1.6 mmol)
was added in one portion to a suspension of DABCO–Br2 complex (503 mg,
3.2 mmol) in glacial acetic acid (5 mL), and the mixture was stirred at room
temperature for 6 h. The mixture was treated with aqueous 20 % Na2CO3 until the
pH reached 8, and the solid was then isolated by filtration, air-dried, and
recrystallized repeatedly from ethanol.
3-(5-Bromothiophen-2-yl)-5-(4-chlorophenyl)-4,5-dihydroisoxazole (15)
Colorless crystals, yield 45 %, mp 100–101 °C; 1H NMR (CDCl3, 400 MHz):
d 3.24 (dd, J = 8.4 and 16.4 Hz, 1H), 3.73 (dd, J = 10.8 and 16.4 Hz, 1H), 5.70
(dd, J = 8.4 and 10.8 Hz, 1H), 6.90 (d, J = 4.0 Hz, 1H), 7.01 (d, J = 4.0 Hz, 1H),
7.30 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz):
d 43.4, 82.3, 116.4, 127.4, 128.8, 129.2, 130.3, 133.4, 134.4, 139.0, 151.4.
Attempted oxidation of isoxazoline 13 with CrO3
A
solution of 5-(4-chlorophenyl)-3-(thiophen-2-yl)-4,5-dihydroisoxazole 13
(711 mg, 2.7 mmol) and CrO3 (540 mg, 5.4 mmol) in glacial acetic acid (20 mL)
was heated in an oil bath at 90 °C for 45 min. The mixture was poured into water
(300 mL), and left at room temperature for 24 h. The solid (203 mg) was isolated
by filtration, air-dried, and analyzed by NMR. An aliquot of the filtrate (100 mL)
was extracted with chloroform (2 mL 9 25 mL), and the combined extracts were
washed with water (2 9 15 mL), and dried over anhydrous Na2SO4. The residue
obtained after removal of chloroform under reduced pressure was analyzed by
NMR.
123

G. Roman
Oxidation of isoxazoline 13 with DDQ
mixture of 5-(4-chlorophenyl)-3-(thiophen-2-yl)-4,5-dihydroisoxazole 13
A
(527 mg, 2 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (908 mg,
4 mmol) in anhydrous 1,4-dioxane (10 mL) was heated at reflux temperature for
6 h. The mixture was left at room temperature overnight. It was then filtered, the
1
solvent was removed under reduced pressure, and the residue was analyzed by H
NMR.
General procedure for synthesis of 1,3-diketones 19 and 20
A solution of sodium methoxide (prepared from sodium (575 mg, 25 at-gr) and
15 mL methanol) was added dropwise to a suspension of either dibromide 5 or
dibromide 7 (10 mmol) in methanol (15 mL) at room temperature. The reaction
mixture was then heated at reflux temperature for 1 h, left to cool to 40–50 °C,
treated dropwise with 36 % HCl (2.5 mL), then heated again at reflux temperature
for 5 min. The reaction mixture was then diluted with water (60 mL), and stirred for
1 h at room temperature. The solid was isolated by filtration, air-dried, and
recrystallized from ethanol.
1-(4-Chlorophenyl)-3-hydroxy-3-(thiophen-2-yl)prop-2-en-1-one (19)
1
Yellow crystals, yields 86 %, mp 128–129 °C (lit. mp 130–131 °C [49]); H NMR
(CDCl3, 400 MHz): d 6.64 (s, 1H), 7.17 (dd, J = 4.0 and 4.8 Hz, 1H), 7.45 (d,
J = 8.4 Hz, 2H), 7.65 (dd, J = 0.8 and 4.8 Hz, 1H), 7.81 (dd, J = 0.8 and 4.0 Hz,
1H), 7.88 (d, J = 8.4 Hz, 2H), 16.29 (s, 1H); 13C NMR (CDCl3, 100 MHz): d 93.2,
128.3, 128.5, 129.1, 130.7, 133.0, 133.1, 138.6, 142.1, 179.7, 183.1.
1-(4-Bromophenyl)-3-hydroxy-3-(thiophen-2-yl)prop-2-ene-1-dione (20)
Yellow crystals, yield 87 %, mp 142–143 °C; 1H NMR (CDCl3, 400 MHz): d 6.64
(s, 1H), 7.17 (dd, J = 4.0 and 4.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.65 (dd,
J = 0.8 and 4.8 Hz), 7.77–7.83 (m, 3H), 16.26 (br s, 1H); 13C NMR (CDCl3,
100 MHz): d 93.2, 127.2, 128.4, 128.5, 130.7, 132.1, 133.0, 133.5, 142.1, 179.7,
183.2.
General procedures for synthesis of isoxazoles 9–12
Method A (from chalcone dibromides 5–8 in the presence of KOH)
A suspension of dibromide 5–8 (3 mmol) in ethanol (30 mL) was heated to a gentle
boiling then a solution of hydroxylamine hydrochloride (417 mg, 6 mmol) in water
(1.5 mL) was added. The mixture was treated dropwise with a solution of KOH
(990 mg, 85 % purity, 15 mmol) in water (2 mL), and, after heating to near boiling
point for 5–10 min, the mixture was cooled to room temperature, gradually diluted
123

Preparation of thiophene-substituted isoxazoles
with water (70 mL), and kept overnight at room temperature. The solid was isolated
by filtration, washed thoroughly with water and recrystallized from ethanol.
3-(4-Chlorophenyl)-5-(thiophen-2-yl)isoxazole (9)
Off-white crystals, yield 32 %, mp 129–131 °C (lit. mp 127–128 °C [50]); 1H NMR
(CDCl3, 400 MHz): d 6.66 (s, 1H), 7.15 (dd, J = 3.6 and 4.8 Hz, 1H), 7.42–7.50
(m, 3H), 7.56 (dd, J = 0.8 and 3.6 H, 1H), 7.78 (d, J = 8.8 Hz, 2H); 13C NMR
(CDCl3, 100 MHz): d 97.2, 127.3, 127.5, 128.2, 128.3, 128.4, 129.2, 129.4, 136.3,
162.1, 165.8.
3-(4-Bromophenyl)-5-(thiophen-2-yl)isoxazole (10)
Off-white crystals, yield 24 %, mp 141–143 °C; 1H NMR (CDCl3, 400 MHz):
d 6.66 (s, 1H), 7.15 (dd, J = 4.0 and 5.2 Hz, 1H), 7.47 (dd, J = 1.2 and 5.2 Hz,
1H), 7.56 (dd, J = 1.2 and 4.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.71 (d,
J = 8.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz): d 97.2, 124.6, 127.4, 128.0, 128.3,
128.4, 128.5, 129.2, 132.3, 162.2, 165.8.
5-(4-Chlorophenyl)-3-(thiophen-2-yl)isoxazole (11)
Off-white crystals, yield 38 %, mp 160–162 °C (lit. mp 191–193 °C [35]); 1H NMR
(CDCl3, 400 MHz): d 6.74 (s, 1H), 7.14 (dd, J = 3.6 and 4.8 Hz, 1H), 7.42–7.49
(m, 3H), 7.51 (d, J = 3.6 Hz, 1H), 7.75 (d, J = 8.8 Hz, 2H); 13C NMR (CDCl3,
100 MHz): d 98.0, 125.8, 127.3, 127.6, 127.8, 127.9, 129.5, 130.8, 136.6, 158.4,
169.4.
5-(4-Bromophenyl)-3-(thiophen-2-yl)isoxazole (12)
Off-white crystals, yield 32 %, mp 164–165 °C; 1H NMR (CDCl3, 400 MHz):
d 6.75 (s, 1H), 7.14 (dd, J = 3.6 and 5.2 Hz, 1H), 7.44 (dd, J = 1.2 and 5.2 Hz,
1H), 7.51 (d, J = 1.2 and 3.6 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.68 (d,
J = 8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz): d 98.0, 124.9, 126.2, 127.5, 127.6,
127.8, 127.9, 130.7, 132.5, 158.4, 169.4.
Method B (from chalcone dibromide 5 in the presence of pyridine)
A mixture of dibromide 5 (2 mmol) and hydroxylamine hydrochloride (167 mg,
2.4 mmol) in pyridine (5 mL) was heated at reflux temperature for 3 h. The reaction
mixture was diluted with water (15 mL), and treated, with efficient stirring, with
dilute HCl (36.5 % HCl–water 1:4 v/v) until pH 4. The supernatant was decanted,
and the reddish oil was then dissolved in ethyl acetate (20 mL). The organic phase
was washed thoroughly with water, and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure, and the residue was triturated with 2-propanol
(10 mL). The solid was filtered and recrystallized from 2-propanol.
123

G. Roman
(2-Bromo-1-(4-chlorophenyl)-3-(2-thienyl)prop-2-en-1-one (16) (mixture
of Z and E isomers)
1
Tan crystals, yield 19 %, mp 119–120 °C (lit. mp 120–121 °C [50]); H NMR
(CDCl3, 400 MHz): d 7.14–7.21 (m, 1H), 7.44–7.53 (m, 2H), 7.65–7.74 (m, 2H),
7.75 (s, 0.2H), 7.99 (s, 0.8H).
Method C (from chalcone dibromide 5 at low pH)
A mixture of dibromide 5 (2 mmol) and hydroxylamine hydrochloride (167 mg,
2.4 mmol) in methanol (10 mL) was heated at reflux temperature for 5 h. The
solvent was removed under reduced pressure, and the residue was dissolved in warm
2-propanol (5 mL), diluted with petroleum ether (bp 40–60 °C, 25 mL), and
refrigerated overnight at -20 °C, when a solid separated. The solid was isolated by
filtration to give compound 18.
2-Bromo-1-(4-chlorophenyl)-3-methoxy-3-(2-thienyl)propan-1-one (18)
1
Tan crystals, yield 52 %, mp 49–50 °C (2-propanol–petroleum ether); H NMR
(CDCl3, 400 MHz): d 3.27 (s, 3H), 5.09 (d, J = 9.6 Hz, 1H), 5.13 (d, J = 10.0 Hz,
1H), 7.05 (dd, J = 3.6 and 4.8 Hz, 1H), 7.20 (d, J = 3.6 Hz, 1H), 7.40 (d,
J = 4.8 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H); 13C NMR
(CDCl3, 100 MHz): d 47.8, 58.0, 79.4, 126.5, 126.8, 128.6, 129.3, 130.4, 133.5,
140.5, 141.6, 191.7.
Method D (from 1,3-diketones 19 and 20 at low pH)
A mixture of 1,3-diketone (3 mmol) and hydroxylamine hydrochloride (417 mg,
6 mmol) was heated at reflux temperature in a mixture of methanol (15 mL) and
water (1 mL) for 7 h. The mixture was left to cool to room temperature, then the
solid formed on dilution with water (35 mL) was isolated by filtration and analyzed
1
by H NMR spectroscopy. Repeated recrystallization of the crude reaction mixture
from ethanol afforded a mixture of isoxazoles, as evidenced by NMR.
3-(4-Chlorophenyl)-5-(thiophen-2-yl)isoxazole (9) and 5-(4-chlorophenyl)-3-
(thiophen-2-yl)isoxazole (11)
Yield 76 %, ratio between 9 and 11 approximately 8 to 1, mp 128–133 °C.
3-(4-Bromophenyl)-5-(thiophen-2-yl)isoxazole (10) and 5-(4-bromophenyl)-3-
(thiophen-2-yl)isoxazole (12)
Yield 61 %, ratio between 10 and 12 approximately 9 to 1, mp 137–141 °C.
123

Preparation of thiophene-substituted isoxazoles
Method E (from 1,3-diketones 19 and 20 at high pH)
A mixture of 1,3-diketone (3 mmol), hydroxylamine hydrochloride (313 mg,
4.5 mmol), and pyridine (3 mL) in ethanol (10 mL) was heated at reflux
temperature for 5 h. After being kept at room temperature for 24 h, the mixture
was poured on to water (75 mL), and the resulting solid was isolated by filtration
and air-dried. The solid was extracted with chloroform (2 9 25 mL), then the
solvent was removed from the extract under reduced pressure to afford a mixture of
isomeric isoxazoles. The fraction insoluble in chloroform was collected by filtration
to give the dioximes 21 or 22.
3-(4-Chlorophenyl)-5-(thiophen-2-yl)isoxazole (9) and 5-(4-chlorophenyl)-3-
(thiophen-2-yl)isoxazole (11)
Yield 61 %, ratio between 9 and 11 approximately 12 to 1, mp 130–132 °C.
1-(4-Chlorophenyl)-3-(thiophen-2-yl)propane-1,3-dione dioxime (21), mixture
of stereoisomers A and B
Colorless solid, yield 10 %, mp 178–179 °C; 1H NMR (d6-DMSO, 400 MHz):
d 4.23 (s, 2H), 7.00 (dd, J = 4.0 and 4.8 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H),
7.32–7.43 (m, 3H), 7.58 (d, J = 8.4 Hz, 2H), 11.60 (s, 1H), 11.79 (s, 1H) (for the
major stereoisomer); 4.19 (s, 2H), 7.15 (dd, J = 4.0 and 4.8 Hz, 1H), 7.32–7.43 (m,
2H), 7.64 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 4.0 Hz, 1H), 7.74 (d, J = 4.8 Hz, 1H),
11.62 (s, 1H), 11.84 (s, 1H) (for the minor stereoisomer); 13C NMR (d6-DMSO,
100 MHz): d 22.5, 125.9, 126.8, 127.2, 127.7, 128.2, 133.5, 134.3, 139.4, 148.7,
152.2 (for the major stereoisomer); Anal. Calcd. for C13H11ClN2O2S: C, 52.97; H,
3.76; N, 9.50. Found: C, 52.61; H, 3.95; N, 9.22.
3-(4-Bromophenyl)-5-(thiophen-2-yl)isoxazole (10) and 5-(4-bromophenyl)-3-
(thiophen-2-yl)isoxazole (12)
Yield 59 %, ratio between 10 and 12 approximately 14 to 1, mp 142–144 °C.
1-(4-Bromophenyl)-3-(thiophen-2-yl)propane-1,3-dione dioxime (22), mixture
of stereoisomers A and B
Colorless solid, yield 13 %, mp 184–185 °C; 1H NMR (d6-DMSO, 400 MHz):
d 4.23 (s, 2H), 6.97–7.03 (m, 1H), 7.31 (d, J = 3.6 Hz, 1H), 7.39 (d, J = 5.2 Hz,
1H), 7.47–7.61 (m, 4H), 11.61 (s, 1H), 11.82 (s, 1H) (for the major stereoisomer);
4.18 (s, 2H), 7.12–7.18 (m, 1H), 7.47–7.61 (m, 4H), 7.68 (d, J = 3.6 Hz, 1H), 7.74
(d, J = 5.2 Hz, 1H), 11.65 (s, 1H), 11.85 (s, 1H) (for the minor stereoisomer); 13C
NMR (d6-DMSO, 100 MHz): d 22.5, 28.9, 121.9, 122.2, 124.0, 125.7, 125.9, 126.8,
127.3, 128.0, 128.1, 128.6, 130.9, 131.1, 134.7, 135.4, 139.4, 144.4, 148.8, 149.6,
152.3, 152.4 (for both stereoisomers). Anal. Calcd. for C13H11BrN2O2S: C, 46.03;
H, 3.27; N, 8.26. Found: C, 45.74; H, 3.51; N, 8.03.
123

G. Roman
Acknowledgments The research leading to these results has received funding from the European
Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 264115—
˘
STREAM. The assistance of Miss Mihaela Balan with the 2D NMR experiments is gratefully
acknowledged. The author thanks Dr Mihaela Silion for her valuable help with the mass spectrometry
experiments.
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