Cyclocondensation of Hydroxylamine with 1,3-Bis(het)arylmonothio 1,3-Diketones and 1,3-Bis(het)aryl-3-(methylthio)-2-propenones: Synthesis of 3,5-Bis(het)arylisoxazoles with Complementary Regioselectivity

Article abstract of DOI:10.1002/ejoc.201301667

Efficient routes for the regioselective synthesis of 3,5-bis(het)arylisoxazoles with complementary regioselectivity have been developed. The methods involve the cyclocondensation of hydroxylamine hydrochloride with either 1,3-bis(het)aryl-monothio-substituted 1,3-diketones 1 or with 3-methylthio-1,3-bis(het)aryl-2-propenones 2 under various reaction conditions. In the first protocol, diketones 1 were treated with hydroxylamine hydrochloride in the presence of sodium acetate/acetic acid (pH 2.2) in refluxing ethanol/benzene to give 3,5-bis(het)arylisoxazoles 5, in which the het(aryl) moiety attached to thiocarbonyl group of the monothio-substituted 1,3-diketones is installed at the 3-position. On the other hand, the reaction of hydroxylamine hydrochloride with 3-(methylthio)-1,3-bis(het)aryl-2-propenones 2 in the presence of barium hydroxide in refluxing ethanol gave 3,5-bis(het)arylisoxazoles 6 with complementary regioselectivity in high yields. A probable mechanism for the formation of regioisomeric isoxazoles 5 and 6 from precursors 1 and 2 has been suggested.

Full text of DOI:10.1002/ejoc.201301667

FULL PAPER
DOI: 10.1002/ejoc.201301667
Cyclocondensation of Hydroxylamine with 1,3-Bis(het)arylmonothio
1,3-Diketones and 1,3-Bis(het)aryl-3-(methylthio)-2-propenones: Synthesis of
3,5-Bis(het)arylisoxazoles with Complementary Regioselectivity
Byregowda Raghava,[a] Gangajji Parameshwarappa,[b] Anand Acharya,[b]
Toreshettahally R. Swaroop,[a] Kanchugarakoppal S. Rangappa,*[a] and
Hiriyakkanavar Ila*[b]
Keywords: Synthetic methods / Nitrogen heterocycles / Oxygen heterocycles / Regioselectivity / Cyclization
Efficient routes for the regioselective synthesis of 3,5-bis-
(het)arylisoxazoles with complementary regioselectivity have
been developed. The methods involve the cyclocondensation
of hydroxylamine hydrochloride with either 1,3-bis(het)aryl-
monothio-substituted 1,3-diketones 1 or with 3-methylthio-
1,3-bis(het)aryl-2-propenones 2 under various reaction con-
ditions. In the first protocol, diketones 1 were treated with
hydroxylamine hydrochloride in the presence of sodium acet-
ate/acetic acid (pH 2.2) in refluxing ethanol/benzene to give
3,5-bis(het)arylisoxazoles 5, in which the het(aryl) moiety at-
tached to thiocarbonyl group of the monothio-substituted
1,3-diketones is installed at the 3-position. On the other
hand, the reaction of hydroxylamine hydrochloride with 3-
(methylthio)-1,3-bis(het)aryl-2-propenones 2 in the presence
of barium hydroxide in refluxing ethanol gave 3,5-bis-
(het)arylisoxazoles 6 with complementary regioselectivity in
high yields. A probable mechanism for the formation of re-
gioisomeric isoxazoles 5 and 6 from precursors 1 and 2 has
been suggested.
urated oximes.[1,1g,4] Therefore the development of new
methods for the synthesis of these heterocycles is an area
of considerable interest.
Introduction
Isoxazole and its derivatives constitute an important
class of five membered heterocycles[1] because this struc-
tural motif is present in numerous biologically active natu-
ral products (ibotenic acid, muscimol, isoxazole-4-carbox-
ylic acid), pharmaceuticals (such as bextra, valdecoxib, le-
flunomide, and cloxacillin),[1–3] and functional materi-
als.[3c,3g] Substituted isoxazoles are potent and selective ago-
nists of human cloned dopamine D4 receptors, and they
show a broad range of biological activities[3a–3f,3h] such as
GABA antagonist, analgesic, antiviral, antimicrobial, hypo-
glycemic, ulcerogenic, and anticancer activities, and also, as
agrochemicals, herbicidal[3e] and antifungal[3e,3i,3j] activities.
Isoxazole derivatives also serve as versatile building
blocks[4] in organic synthesis,[3c] as they can be converted
into several useful functionalities, such as β-hydroxy
ketones, β-hydroxynitriles, γ-amino alcohols, and α,β-unsat-
Numerous synthetic approaches for the construction of
the isoxazole framework have been reported,[1,2] and among
them, the two most prevalent methods are: (i) [3+2] dipolar
cycloadditions between alkynes (or alkenes) and nitrile ox-
ides;[1,2b,3,4g,5] and (ii) cyclocondensation of hydroxylamine
with 1,3-dicarbonyl compounds[1,3i,6b] or other three-
carbon 1,3-electrophilic variants[6a–6c] (i.e., α,β-unsaturated
ketones,[4e,6c,6d]
enamino
ketones,[6e]
β-chlorovinyl
ketones,[6f] β-alkylthioenones,[6g,6h] and ynones[6i,6j]). Al-
though the [3+2] cycloaddition method is highly convergent
and versatile, it suffers from several limitations, such as low
yields of products, side-reactions due to competing dimer-
ization of nitrile oxide,[1b,1f,5a,5b] and, frequently, poor re-
gioselectivity.[1b,7] Similarly, the classical reaction of unsym-
metrically substituted 1,3-dicarbonyl compounds with hy-
droxylamine usually results in the formation of regioisom-
eric mixtures of isoxazoles.[1] Therefore, several useful and
elegant methods for regioselective synthesis of isoxazoles
have been developed in recent years. Fokin’s group has re-
ported routes to 3,5-/3,4-disubstituted and 3,4,5-trisubsti-
tuted isoxazoles based on the copper-[8a,8b] or ruthe-
nium-[8c]catalysed [3+2] cycloaddition of various nitrile ox-
ides with terminal/internal alkynes. Similarly, Larock[9a,9b]
has described iodine-catalysed electrophilic cyclization of
O-methyloximes of acetylenic ketones to give 3,5-substi-
[a] Department of Studies in Chemistry, University of Mysore,
Manasagangotri, Mysore 570008, India
E-mail: rangappaks@yahoo.com
http://uni-mysore.ac.in
[b] New Chemistry Unit, Jawahar Lal Nehru Centre for Advanced
Scientific Research,
Bangalore 560064, India
E-mail: hila@jncasr.ac.in
http://jncasr.ac.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301667.
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Regioselective Synthesis of 3,5-Bis(het)arylisoxazoles
tuted-4-iodooxazoles, which can be transformed further
As part of our ongoing research programme directed
into 3,4,5-substituted isoxazoles by palladium-catalysed towards the design and development of new methods for
cross-coupling.[9b,9c] In parallel strategies, Miyata and co- the synthesis of substituted and condensed five- and six-
workers have developed a practical synthesis of 3,5-disubsti- membered heterocycles using polarized ketene dithioacetals
tuted isoxazoles by silver-catalysed cyclization of O-benzyl- and other organosulfur compoundsa as versatile three-car-
alkynyloxime ethers,[10a] along with a gold-catalysed dom- bon 1,3-bielectrophilic building blocks,[19] we have pre-
ino reaction of O-allylalkynyloxime ethers involving cycliza- viously reported the highly regioselective synthesis of 5-(or
tion and subsequent Claisen-type rearrangement to give tri- 3-)methylthio-3-(or 5-)-substituted pyrazoles[20a] and 5-(or
substituted isoxazoles in a highly regioselective manner.[10b] 3-)methylthio-3-(or 5-)arylisoxazoles[17b] by cyclocondensa-
Other recently published methods include the iodocycliz- tion of α-oxoketene dithioacetals (or β-oxadithioesters)
ation of N-alkoxycarbonyl-O-propargylic hydroxyl- with arylhydrazines and hydroxylamine, respectively, under
amines;[11a] a sequential iron- and palladium-catalysed different conditions. In a continuation of these studies, we
transformation of propargyl alcohols into N-protected pro- became interested in 1,3-substituted-monothio 1,3-diket-
pargylhydroxylamines, and their subsequent cyclization and ones of the general structure 1,[21,22] and the corresponding
coupling with various aryl iodides to give trisubstituted 1,3-bis(het)aryl-3-(methylthio)-2-propenones 2, a new class
isoxazoles in a multistep one-pot reaction;[11b] base-cata- of potentially useful three-carbon 1,3-bielectrophile build-
lysed cyclocondensation of activated nitromethylene com- ing blocks that are virtually unexplored.[22e–22g] Based on
pounds with dipolarophiles;[3c,12a–12c] zinc-triflate-catalysed these intermediates, we have recently reported efficient re-
aerobic cross-dehydrogenative coupling (CDC) of alkynes gioselective synthesis of unsymmetrically substituted 1-aryl-
with nitrones;[13a] hypervalent-iodine-induced cycloaddition 3,5-bis(het)aryl pyrazoles 3 and 4 with complementary re-
of nitrile oxides to alkynes;[13b–13d] N-heterocyclic-carbene- gioselectivity by cyclocondensation of either 1 or 2 with ar-
catalysed 1,3-dipolar cycloaddition of nitrile oxides and ylhydrazines under different conditions (Scheme 1).[23a] En-
alkynes;[5f] and dipolar cycloaddition of acetylenic couraged by these results, and by our ongoing interest in
boronates[4g,14] and silaacetylenes[5j] with nitrile oxides. A these newly developed organosulfur building blocks (1 and
completely regioselective synthesis of unsymmetrically 3,5- 2),[23b,23c] we became interested in exploring the reaction of
disubstituted isoxazoles by the reaction of the 1,4-dianions hydroxylamine with β-thioxo ketones 1 and the correspond-
of oximes derived from α-alkyl ketones with various ing β-(methylthio)-2-propenones 2, with a view to de-
amides/esters has also been described by Olofson[15a,15b] veloping regioselective syntheses of unsymmetrically substi-
and others.[15c] Efforts have also been made to improve the tuted 3,5-bis(het)arylisoxazoles 5 and 6 based on these in-
regioselectivity of the reaction of hydroxylamine with three- termediates (Tables 1 and 2). We have achieved this goal,
carbon components by altering the electrophilicity of the and our results are reported in this paper.
terminal carbons in these intermediates,[16] or by controlling
the reaction conditions by changing the pH of the me-
dium,[17] or by the introduction of a leaving group (such as
a bromo or benzotriazolyl moiety) at the α-position of α,β-
Results and Discussion
unsaturated ketones, which would allow the in situ transfor-
Monothio β-diketones 1a–1l were prepared in good
mation of the initially formed oxazolines into aromatic yields, by modification of an earlier reported pro-
isoxazoles.[18] Nevertheless, new methods for the efficient cedure,[22a–22d] by condensation of aryl/heteroaryl methyl
and regioselective synthesis of substituted isoxazoles from ketones with various aryl/heteroaryl dithioesters in the pres-
readily accessible precursors are highly desirable.
ence of sodium hydride as base (Scheme 1).[23a] These 1,3-
Scheme 1. Synthesis of 1,3-bis(het)arylpyrazoles 3 and 4 with complementary regioselectivity from precursors 1 and 2.
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Table 1. Regioselective synthesis of 3,5-bis(het)arylisoxazoles 5a–5l from 1,3-monothio β-diketones 1a–1l.
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Regioselective Synthesis of 3,5-Bis(het)arylisoxazoles
substituted monothio diketones were directly converted into 1a–1l and β-alkylthioenones 2a–2l were characterized
the corresponding β-methylthio-β-het(aryl)enones (i.e., with the help of spectral and analytical data, which showed
2a–2l) by in situ alkylation of thiolate salts with methyl iod- that monothio β-diketones 1a–1l exist in enol form
ide under similar conditions.[23a] Monothio 1,3-diketones 1A.[23a]
Table 2. Regioselective synthesis of 3,5-bis-(het)arylisoxazoles 6a–6l from 3-(methyl)thiopropenones 2a–2l.
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FULL PAPER
The reaction of unsymmetrically substituted monothio regiochemistry, starting from the same 1,3-monothio 1,3-
1,3-diketone 1a with hydroxylamine hydrochloride was first diketone precursors 1a–1l, by treating them with hydroxyl-
examined under various conditions with a view to ob- amine under various reaction conditions. However, all our
taining either of the unsymmetrically substituted isoxazoles attempts to achieve this goal were unsuccessful, and only
5a or 6a in a regiocontrolled fashion. The use of bases such intractable mixtures of products were formed. We therefore
as sodium carbonate, sodium hydrogen carbonate, or so- turned our attention to β-(methylthio)-β-(het)arylenones
dium ethoxide in refluxing ethanol led only to the forma- 2a–2l,[23a] which are easily accessible from various active-
tion of intractable mixtures of products, along with unre- methylene ketones in a one-pot reaction involving base-in-
acted starting material 1a (with Na2CO3 or NaHCO3). Un- duced thioacylation with dithioesters followed by alkylation
der neutral conditions, 1a was recovered unchanged with (Scheme 1).
no trace of any product. However, when 1a was treated with
As a model experiment, enone 2a was subjected to cycli-
hydroxylamine hydrochloride in the presence of sodium zation with hydroxylamine hydrochloride under different
acetate in a mixture of acetic acid, benzene, ethanol, and conditions, varying the solvent, the base, and the tempera-
water (1:1:0.5:0.1; pH = 2.2) at reflux, a single product was ture. After a few unsuccessful attempts, we did indeed ob-
isolated after work-up of the reaction, which was charac- tain the regioisomeric 3-phenyl-5-(4-methoxyphenyl)isox-
terized as 3-(4-methoxyphenyl)-5-phenylisoxazole (5a; azole (6a) exclusively in 80% yield, by treatment of 1,3-
Table 1, entry 1), on the basis of its spectral and analytical diarylenone 2a with hydroxylamine hydrochloride in the
data and by comparison of its melting point with that re- presence of barium hydroxide in refluxing ethanol (Table 2,
ported in the literature.[24] Similarly, the corresponding 1- entry 1). The structure of isoxazole 6a was confirmed with
(4-methoxyphenyl)-3-(3-bromophenyl)monothio 1,3-diket- the help of spectral and analytical data, and by comparison
one (1b), with two different substituents on two aryl groups, of its melting point with that reported in the literature.[25]
also gave the corresponding 3-(4-methoxyphenyl)-5-(3- These reaction conditions were found to be generally appli-
bromophenyl)isoxazole (5b) in good yield, in a highly re- cable for the synthesis of other regioisomeric 3,5-diaryl-
gioselective manner (Table 1, entry 2). The regiochemistry isoxazoles (6b and 6c), 3,5-aryl/heteroaryl-isoxazoles (6d–
of 5b was further confirmed from its X-ray diffraction data 6h), and 3,5-bis(heteroaryl)isoxazoles 6i–6k, along with
(Figure S1). Isoxazoles 5a and 5b are apparently formed by methyl arylisoxazole 6l, in excellent yields (Table 2, en-
attack of the amino functionality of hydroxylamine onto tries 2–12). In every case, the formation of only one re-
the thiocarbonyl group of 1a to form the Ar–C=N bond of gioisomer 6 was observed, and no trace of the other
isoxazoles. 1-Phenyl-3-(2-naphthyl)-monothio-1,3-diketone isomer (5a–5l) was isolated. The structures of newly
1
(1c) also reacted in a similar manner with hydroxylamine synthesized isoxazoles 6a–6l were confirmed from their H
under these conditions to give exclusively 3-phenyl-5-(2- NMR, 13C NMR, and HRMS spectra, along with
naphthyl)-isoxazole (5c) in 80% yield (Table 1, entry 3). X-ray diffraction data for isoxazoles 6b and 6e (Figures
Similarly, 3,5-(het)arylisoxazoles 5d–5h bearing one aryl S39–S42).
and one heteroaryl group could also be prepared in high
The probable mechanism for the formation of regioisom-
yields as single regioisomers under the same conditions, eric isoxazoles 5 and 6 from the corresponding 1,3-mono-
starting from the corresponding aryl/heteroaryl 1,3-mono-
thio diketones (i.e., 1d–1h; Table 1, entries 4–8). Further di-
versity was added by the regioselective introduction
of two different heteroaryl groups at the 3- and 5-positions
of the isoxazole framework by subjecting 1,3-bis(het)-
aryl monothio diketone precursors 1i–1k to the same reac-
tion conditions. This led to the formation of 3,5-bis(het)-
arylisoxazoles 5i–5k in high overall yields (Table 1, en-
tries 9–12).
As an example of the extension of this methodology for
the synthesis of alkyl-substituted isoxazoles, 3-methyl-5-(4-
methoxyphenyl)isoxazole (5l) was also obtained in good
yield from the corresponding methyl-substituted monothio
1,3-diketone (i.e., 1l) under similar conditions (Table 1, en-
try 12). The structures and regiochemistry of these newly
synthesized isoxazoles were confirmed with the help of
spectral and analytical data, and also by the X-ray diffrac-
tion data of isoxazoles 5b and 5e (Figure S2).
Having developed a completely regioselective synthesis
of 3,5-bis(het)arylisoxazoles 5a–5l from 1,3-substituted
monothio diketones 1a–1l, we became interested in de-
veloping appropriate reaction conditions for the synthesis
Scheme 2. Probable mechanism for the formation of regioisomeric
of 1,3-disubstituted isoxazoles 6a–6l with complementary isoxazoles 5 and 6 from 1 and 2.
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Regioselective Synthesis of 3,5-Bis(het)arylisoxazoles
General Procedure for the Preparation of 1,3-Bis(het)arylmonothio
β-Diketones 1a–1l: 1,3-Bis(het)arylmonothio β-diketones were pre-
pared following our earlier reported procedure[23a] by reaction of
the corresponding (hetero)aryl methyl ketone (3.0 mmol) with the
appropriate (hetero)aryl dithioesters (3.0 mmol) using sodium hy-
dride (0.25 g, 6.3 mmol) in DMF (10 mL), and subsequent work-
up. Known 1,3-bis(het)aryl-3-(methylthio)-2-propenones 1b, 1e, 1f,
1j, and 1l were characterized by comparison of their spectral and
analytical data with literature data.[23a] The spectral and analytical
data of unknown 1,3-monothio diketones 1a, 1c, 1d, 1g–1i, and 1k
thio ketone and 3-(methylthio)propenone precursors 1 and
2 upon reaction with hydroxylamine under different condi-
tions is shown in Scheme 2. Thus, at lower pH, under acidic
conditions, monothio diketone 1 is present mainly in the
enolic form, which means that the thiocarbonyl group is the
only possibility for the point of initial nucleophilic attack
by hydroxylamine. Intramolecular heterocyclization via in-
termediates 7–8 then gives isoxazoles 5 exclusively, in which
the het(aryl) group attached to the thiocarbonyl group in 1
is installed at the 3-position. On the other hand, under basic are given below.
conditions (pH 5–9), 3-(methylthio)propenones 2 undergo
3-(4-Methoxyphenyl)-1-phenyl-3-thioxopropan-1-one (1a): Red so-
intial nucleophilic attack by hydroxylamine at the carbonyl
group to give only the regioisomeric isoxazoles (i.e., 6) after
subsequent intramolecular cyclization via intermediates 9–
11 (Scheme 2).[17,18,26,27]
lid, m.p. 61–63 °C. R = 0.59 (1:9 EtOAc/hexane). IR (KBr): ν =
˜
f
2926, 1599, 1550, 1174, 773 cm–1. H NMR (400 MHz, CDCl3): δ
1
= 15.98 (s, 1 H), 8.00 (d, J = 7.2 Hz, 2 H), 7.90 (d, J = 8.8 Hz, 2
H), 7.55–7.49 (m, 3 H), 7.44 (s, 1 H), 6.94 (d, J = 8.8 Hz, 2 H),
3.87 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 206.5, 178.1,
162.8, 138.5, 135.7, 132.5, 129.0, 128.9, 127.2, 113.9, 108.8,
55.6 ppm. HRMS (ESI): calcd. for C16H14O2S [M + H]+ 271.0793;
found 271.0787.
Conclusions
In summary, we have demonstrated that 1,3-bis(het)aryl-
monothio 1,3-diketones 1 are versatile three-carbon 1,3-
electrophilic components for the highly regioselective syn-
thesis of 3,5-diaryl/(het)aryl isoxazoles 5, by cyclocondensa-
tion with hydroxylamine under controlled reaction condi-
tions. Furthermore, it was also possible to achieve the syn-
thesis of 3,5-diaryl/(het)aryl isoxazoles 6 with complimen-
tary regiochemistry, by using β-(methylthio)-β-aryl/(het)-
arylenones 2 as three-carbon components, and treating
them with hydroxylamine in the presence of barium hydrox-
ide. Both monothio 1,3-diketones and β-(methylthio)pro-
penone precursors 1 and 2 are readily accessible from a
large variety of active methylene ketones in high yields, and
so there is great scope for the incorporation of diverse aryl/
1-(Naphthalen-3-yl)-3-phenyl-3-thioxopropan-1-one (1c): Red solid,
m.p. 100–102 °C. R = 0.59 (1.5:8.5 EtOAc/hexane). IR (KBr): ν =
˜
f
3047, 1545, 1447 cm–1. H NMR (400 MHz, CDCl3): δ = 15.36 (s,
1
1 H), 8.58 (d, J = 1.4 Hz, 1 H), 8.03 (dd, J = 8.4, 1.4 Hz, 1 H),
7.98 (d, J = 8.0 Hz, 1 H), 7.94 (s, 1 H), 7.91 (d, J = 8.0 Hz, 1 H),
7.88–7.85 (m, 2 H), 7.63–7.44 (m, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 203.9, 179.7, 145.8, 135.5, 133.1, 133.0, 131.3, 129.6,
128.8, 128.75, 128.70, 128.6, 128.0, 127.1, 127.0, 123.3, 111.1 ppm.
HRMS (ESI): calcd. for C19H14OS [M + H]+ 291.0844; found
291.0838.
1-(Thiophen-2-yl)-3-thioxo-3-p-tolylpropan-1-one (1d): Red solid,
m.p. 96–98 °C. R = 0.6 (1:9 EtOAc/hexane). IR (KBr): ν = 2918,
˜
f
1557, 1410, 1240 cm–1. H NMR (400 MHz, CDCl3): δ = 13.67 (s,
1
1 H), 7.84 (dd, J = 3.8, 1.0 Hz, 1 H), 7.68 (d, J = 8.2 Hz, 2 H),
(het)aryl motifs into the product isoxazoles in a highly re- 7.64 (dd, J = 4.8, 1.0 Hz, 1 H), 7.29 (s, 1 H), 7.24 (d, J = 8.2 Hz,
2 H), 7.16 (dd, J = 4.8, 3.8 Hz, 1 H), 2.40 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 191.2, 176.1, 142.5, 141.8, 141.4, 132.8,
gioselective fashion and in excellent yield. Further work to
investigate the mechanism of these regioselective processes,
130.5, 129.4, 128.6, 126.9, 110.6, 21.5 ppm. HRMS (ESI): calcd.
and also to use them for the synthesis of pharmaceutically
for C14H12OS2 [M + H]+ 261.0408; found 261.0399.
important targets is currently underway.
1-Phenyl-3-(pyridin-3-yl)-3-thioxopropan-1-one (1g): Red solid, m.p.
90–92 °C. R = 0.43 (3:7 EtOAc/hexane). IR (KBr): ν = 2927, 1631,
˜
f
1585, 1534 cm–1. H NMR (400 MHz, CDCl3): δ = 14.52 (s, 1 H),
1
Experimental Section
9.21 (dd, J = 2.0, 0.4 Hz, 1 H), 8.77 (dd, J = 4.8, 1.6 Hz, 1 H), 8.30
(ddd, J = 8.0, 2.0, 1.6 Hz, 1 H), 7.81–7.79 (m, 2 H), 7.54–7.49 (m,
1 H), 7.47–7.43 (m, 3 H), 7.42 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 201.9, 178.1, 153.0, 148.6, 145.0, 134.7, 132.0, 131.6,
128.8, 127.0, 123.8, 110.8 ppm. HRMS (ESI): calcd. for
C14H11NOS [M + H]+ 242.064; found 242.0639.
General Information: All chemicals were bought from commercial
suppliers, and were used without further purification. Solvents were
dried according to standard procedures. All reactions were moni-
tored by thin-layer chromatography using Merck TLC Silica gel
plates, which were visualized with UV light. Column chromatog-
raphy was carried out using Merck silica gel (100–200 mesh). Nu-
clear magnetic resonance spectra were recorded using a 400 MHz
Fourier transform NMR spectrometer with CDCl3 as solvent.
Chemical shifts are reported in ppm on the δ scale, using residual
solvent protons as internal standard (δ = 7.26 for CDCl3 in 1H
NMR spectra; δ = 77.16 for CDCl3 in 13C NMR spectra). Coupling
constants are reported as J values in Hertz (Hz). Splitting patterns
are designated as s (singlet), d (doublet), t (triplet), q (quartet), dd
(doublet of doublets), dt (doublet of triplets), ddd (doublet of
doublet of doublets), m (multiplet), and br (broad). Infrared spec-
tra were recorded using an FTIR instrument, and HRMS spectra
were recorded with a Q-TOF mass spectrometer. Melting points
were recorded using an electrothermal capillary melting-point ap-
paratus.
1-[4-(Dimethylamino)phenyl]-3-(pyridin-3-yl)-3-thioxopropan-1-one
(1h): Red solid, m.p. 118–120 °C. Rf = 0.41 (3:7 EtOAc/hexane).
IR (KBr): ν = 2923, 1583, 1549, 1482, 1246, 1087, 840 cm–1. 1H
˜
NMR (400 MHz, CDCl3): δ = 16.29 (s, 1 H), 9.16 (s, 1 H), 8.71 (d,
J = 5.2 Hz, 1 H), 8.23–8.21 (m, 1 H), 7.98 (d, J = 6.0 Hz, 2 H),
7.43–7.39 (m, 1 H), 7.36 (d, J = 3.2 Hz, 1 H), 6.64 (d, J = 6.0 Hz,
2 H), 3.07 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 208.3,
172.3, 153.5, 152.1, 148.0, 134.2, 133.1, 132.1, 129.6, 123.7, 111.0,
106.3, 40.2 ppm. HRMS (ESI): calcd. for C16H16N2OS [M + H]+
285.1062; found 285.1060.
1-(1-Methyl-1H-indol-3-yl)-3-(thiophen-2-yl)-3-thioxopropan-1-one
(1i): Red solid, m.p. 122–124 °C. Rf = 0.51 (2:8 EtOAc/hexane). IR
(KBr): ν = 2926, 1558, 1507, 1449 cm–1
.
1H NMR (400 MHz,
˜
Eur. J. Org. Chem. 2014, 1882–1892
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org 1887

K. S. Rangappa, H. Ila et al.
FULL PAPER
CDCl3): δ = 15.87 (s, 1 H), 8.43–8.41 (m, 1 H), 7.92 (s, 1 H), 7.81
(dd, J = 3.8, 1.2 Hz, 1 H), 7.58 (dd, J = 5.2, 1.2 Hz, 1 H), 7.39 (s,
1 H), 7.36–7.32 (m, 3 H), 7.16 (dd, J = 5.2, 3.8 Hz, 1 H), 3.85 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 198.3, 170.2, 141.0,
138.4, 133.8, 130.9, 129.2, 128.6, 125.5, 124.6, 123.5, 122.9, 122.1,
110.4, 106.7, 33.7 ppm. HRMS (ESI): calcd. for C16H13NOS2 [M
+ H]+ 300.0517; found 300.0499.
(E/Z)-3-(Methylthio)-1-phenyl-3-(pyridin-3-yl)prop-2-en-1-one (2g):
E/Z = 73:27. Yellow solid, m.p. 64–66 °C. Rf = 0.40 (2:8 EtOAc/
hexane). IR (KBr): ν = 2922, 1631, 1579, 1534 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 9.15 (d, J = 1.6 Hz, 0.73 H), 9.0 (d, J =
1.6 Hz, 0.27 H), 8.72 (dd, J = 4.8, 1.6 Hz, 0.73 H), 8.62 (dd, J =
4.8, 1.6 Hz, 0.27 H), 8.26 (ddd, J = 8.0, 2.0, 1.6 Hz, 0.73 H), 8.02
(ddd, J = 8.0, 2.0, 1.6 Hz, 0.27 H), 7.46–7.38 (m, 2.92 H), 7.33–
7.29 (m, 3.08 H), 7.06 (s, 0.73 H), 6.53 (s, 0.26 H), 2.47 (s, 0.81 H),
1.97 (s, 2.18 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 187.4,
186.7, 167.2, 163.3, 152.7, 152.6, 149.9, 149.5, 138.5, 137.5, 135.9,
135.6, 134.5, 134.0, 129.6, 129.2, 128.9, 128.5, 128.4, 128.0, 123.7,
123.4, 118.4, 115.4, 16.8, 16.6 ppm. HRMS (ESI): calcd. for
C15H13NOS [M + H]+ 356.0796; found 356.0791.
1-(Furan-2-yl)-3-(1-methyl-1H-pyrrol-2-yl)-3-thioxopropan-1-one
(1k): Red solid, m.p. 48–50 °C. Rf = 0.46 (2:8 EtOAc/hexane). IR
(KBr): ν = 2938, 1614, 1539, 1390 cm–1 1H NMR (400 MHz,
.
˜
CDCl3): δ = 15.55 (s, 1 H), 7.58 (s, 1 H), 7.21 (s, 1 H), 7.14 (d, J
= 3.8 Hz, 1 H), 6.95 (dd, J = 8.0, 3.8 Hz, 1 H), 6.91 (s, 1 H), 6.57
(t, J = 1.6 Hz, 1 H), 6.18 (t, J = 3.6 Hz, 1 H), 4.08 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 197.0, 164.0, 150.1, 145.7, 140.3,
133.7, 115.5, 114.7, 112.9, 108.7, 106.3, 38.9 ppm. HRMS (ESI):
calcd. for C12H11NO2S [M + H]+ 234.0589; found 234.0580.
(E/Z)-1-[4-(Dimethylamino)phenyl]-3-(methylthio)-3-(pyridin-3-yl)-
prop-2-en-1-one (2h): E/Z = 80:20. Yellow solid, m.p. 98–100 °C. Rf
= 0.42 (2:8 EtOAc/hexane). IR (KBr): ν = 2926, 1608, 1507 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 9.17 (dd, J = 2.0, 0.6 Hz, 0.8 H),
8.97 (dd, J = 2.2, 0.8 Hz, 0.2 H), 8.71 (dd, J = 4.4, 1.6 Hz, 0.8 H),
8.57 (dd, J = 4.8, 1.6 Hz, 0.2 H), 8.26 (dt, J = 8.0, 2.0 Hz, 0.8 H),
8.0 (dt, J = 8.0, 2.2 Hz, 0.2 H), 7.39 (ddd, J = 8.0, 4.4, 0.6 Hz, 0.8
H), 7.29–7.21 (m, 2.2 H), 7.04 (s, 0.8 H), 6.74 (d, J = 8.8 Hz, 1.6
H), 6.53 (d, J = 8.8 Hz, 0.4 H), 6.39 (s, 0.2 H), 3.02 (s, 4.8 H), 2.93
(s, 1.2 H), 2.46 (s, 0.6 H), 2.10 (s, 2.4 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 188.3, 186.5, 169.9, 164.4, 152.4, 152.0, 151.7, 151.2,
149.9, 149.4, 135.9, 135.6, 135.0, 134.5, 130.5, 129.6, 126.0, 124.2,
124.6, 123.2, 117.7, 114.1, 111.8, 111.3, 40.5, 40.2, 17.4,16.8 ppm.
HRMS (ESI): calcd. for C17H18N2OS [M + H]+ 299.1218; found
299.1218.
General Procedure for the Preparation of 1,3-Bis(het)aryl-3-(meth-
ylthio)-2-propenones 2a–2l: The 1,3-bis(het)aryl-3-(methylthio)-2-
propenones were prepared following our earlier reported pro-
cedure[23a] by reaction of the corresponding (hetero)aryl methyl
ketones (3.0 mmol) with the appropriate (hetero)aryl dithioesters
(3.0 mmol) using sodium hydride (0.25 g, 6.3 mmol) in DMF
(10 mL), followed by treatment with methyl iodide (0.28 mL,
4.5 mmol) and subsequent work-up. Known 1,3-bis(het)aryl-3-
(methylthio)-2-propenones 2b, 2e, 2f, 2j, and 2l were characterized
by comparison of their spectral and analytical data with literature
data.[23a] The spectral and analytical data of unknown 1,3-bis-
(het)aryl-3-(methylthio)-2-propenones 2a, 2c, 2d, 2g–2i, and 2k are
given below.
(E/Z)-1-(1-Methyl-1H-indol-3-yl)-3-(methylthio)-3-(thiophen-2-yl)-
prop-2-en-1-one (2i): E/Z = 76:24. Yellow solid, m.p. 51–53 °C. Rf
(E/Z)-3-(4-Methoxyphenyl)-3-(methylthio)-1-phenylprop-2-en-1-
one (2a): E/Z = 77:23. Pale yellow semi-solid. Rf = 0.45 (2:8 EtOAc/
= 0.53 (2:8 EtOAc/hexane). IR (KBr): ν = 2918, 1608, 1524,
˜
1
1407 cm–1. H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.0 Hz,
hexane). IR (KBr): ν = 2925, 1608, 1499, 1248, 1015, 773 cm–1. 1H
˜
0.76 H), 7.70 (dd, J = 4.0, 1.6 Hz, 0.24 H), 7.68 (dd, J = 3.6, 1.2,
0.76 Hz), 7.55 (dd, J = 5.2, 1.2, 0.76 Hz), 7.52–7.51 (m, 0.72 H),
7.37 (d, J = 8.0 Hz, 0.76 H), 7.33–7.27 (m, 0.96 H), 7.25 (d, J =
1.2 Hz, 0.76 H), 7.23–7.21 (m, 0.72 H), 7.12 (s, 0.76 H), 7.10–7.06
(m, 1 H), 3.85 (s, 2.3 H), 3.78 (s, 0.7 H), 2.50 (s, 0.7 H), 2.16 (s, 2.3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 181.0, 179.5, 157.8,
154.6, 147.2, 146.9, 137.2, 132.3, 132.2, 131.8, 130.5, 130.1, 129.1,
128.1, 127.9, 126.5, 126.0, 122.9, 122.5, 121.4, 121.1, 120.7, 120.3,
118.2, 114.4, 112.9, 112.7, 110.0, 109.8, 33.3, 17.4, 16.9 ppm.
HRMS (ESI): calcd. for C17H15NOS2 [M + H]+ 314.0670; found
314.0658.
NMR (400 MHz, CDCl3): δ = 7.98–7.96 (m, 1.54 H), 7.85–7.83 (m,
0.46 H), 7.52–7.34 (m, 3 H), 7.28 (d, J = 8.8 Hz, 2 H), 7.08 (s, 0.77
H), 6.95 (d, J = 8.8 Hz, 1.54 H), 6.81 (d, J = 8.8 Hz, 0.46 H), 6.56
(s, 0.23 H), 3.84 (s, 2.31 H), 3.76 (s, 0.69 H), 2.43 (s, 0.69 H), 1.99
(s, 2.31 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 188.9, 188.5,
164.6, 161.1, 160.5, 160.2, 139.2, 138.8, 132.2, 131.2, 131.1, 130.1,
129.9, 129.6, 128.6, 128.5, 128.3, 128.1, 119.2, 115.6, 114.1, 113.7,
55.5, 55.3, 16.9, 16.5 ppm. HRMS (ESI): calcd. for C17H16O2S [M
+ H]+ 285.0949; found 285.0942.
(E/Z)-3-(Methylthio)-1-(naphthalen-3-yl)-3-phenylprop-2-en-1-one
(2c): E/Z = 87:13. Yellow solid, m.p. 134–136 °C. Rf = 0.4 (1:9
EtOAc/hexane). IR (KBr): ν = 2926, 1630, 1532, 1482 cm–1. 1H
(E/Z)-1-(Furan-2-yl)-3-(1-methyl-1H-pyrrol-2-yl)-3-(methylthio)-
prop-2-en-1-one (2k): E/Z = 70:30. Yellow solid, m.p. 65–67 °C. Rf
˜
NMR (400 MHz, CDCl3): δ = 8.4.5 (br. s, 0.87 H), 8.37 (br. s, 0.13
H), 8.09 (dd, J = 8.6, 1.6 Hz, 0.87 H), 7.93–7.79 (m, 2.87 H), 7.58–
7.42 (m, 3.87 H), 7.38–7.36 (m, 1.39 H), 2.49 (s, 0.4 H), 1.97 (s, 2.6
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 188.6, 188.3, 164.8,
160.9, 138.9, 137.9, 136.4, 136.1, 135.3, 132.7, 132.5, 129.9, 129.5,
129.4, 129.2, 129.1, 128.9, 128.7, 128.5, 128.4, 128.3, 128.2, 128.1,
127.8, 127.7, 126.7, 124.6, 124.4, 119.3, 116.2, 16.7, 16.5 ppm.
HRMS (ESI): calcd. for C20H16OS [M + H]+ 305.1000; found
305.0995.
= 0.56 (2:8 EtOAc/hexane). IR (KBr): ν = 2916, 1574, 1505,
˜
1
1471 cm–1. H NMR (400 MHz, CDCl3): δ = 7.48–7.45 (m, 1 H),
7.11 (dd, J = 3.6, 0.8 Hz, 0.7 H), 7.05 (dd, J = 3.4, 0.4 Hz, 0.3 H),
6.98 (s, 0.7 H), 6.71–6.69 (m, 0.6 H), 6.66 (dd, J = 2.4, 2.0 Hz, 0.7
H), 6.46 (dd, J = 3.6, 2.0 Hz, 0.7 H), 6.44 (dd, J = 3.4, 2.0 Hz, 0.3
H), 6.29 (dd, J = 3.8, 2.0 Hz, 0.3 H), 6.13 (dd, J = 3.6, 2.0 Hz, 0.7
H), 6.10–6.09 (m, 1.0 H), 3.55 (s, 2.1 H), 3.41 (s, 0.9 H), 2.39 (s,
0.9 H), 1.85 (s, 2.1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
77.4, 174.5, 155.4, 154.5, 154.2, 153.4, 145.7, 145.4, 130.1, 128.9,
125.9, 124.4, 120.0, 116.1, 113.9, 112.5, 112.4, 112.2, 110.8, 108.2,
108.1, 34.3, 34.2, 16.9, 15.8 ppm. HRMS (ESI): calcd. for
C13H13NO2S [M + H]+ 248.0745; found 248.0740.
(E)-3-(Methylthio)-1-(thiophen-2-yl)-3-p-tolylprop-2-en-1-one (2d):
Yellow solid, m.p. 86–88 °C. Rf = 0.40 (2:8 EtOAc/hexane). IR
(KBr): ν = 2920, 1616, 1541, 1410 cm–1. 1H NMR (400 MHz, [D ]-
˜
6
DMSO): δ = 7.98 (dd, J = 3.8, 1.0 Hz, 1 H), 7.93 (dd, J = 4.4,
1.0 Hz), 7.29 (d, J = 8.2 Hz, 2 H), 7.26 (d, J = 8.2 Hz, 2 H), 7.19 General Procedure for the Synthesis of 3-Methyl/(het)aryl-5-(het)-
(dd, J = 4.4, 3.8 Hz, 1 H), 2.36 (s, 3 H), 1.89 (s, 3 H) ppm. 13C arylisoxazoles 5a–5l from Monothio 1,3-Diketones 1a–1l: A solution
NMR (100 MHz, CDCl3): δ = 181.1, 164.8, 146.3, 139.1, 135.8,
132.8, 130.5, 129.4, 128.1, 128.0, 119.0, 21.4, 16.9 ppm. HRMS chloride (0.1 g, 12 mmol) in water (10 mL) was added to a stirred
(ESI): calcd. for C15H14OS2 [M + H]+ 275.0564; found275.0557.
solution of 1-aryl/heteroaryl-3-thioxo-3-alkyl/aryl/heteroaryl prop-
of sodium acetate (0.06 g, 9 mmol) and hydroxylamine hydro-
1888
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1882–1892

Regioselective Synthesis of 3,5-Bis(het)arylisoxazoles
an-1-one 1 (3 mmol) in benzene (100 mL) and AcOH (100 mL).
The reaction mixture was made homogeneous by the addition of
EtOH (55 mL), and then it was heated at reflux for 3–4 h (moni-
tored by TLC). The mixture was then concentrated to dryness un-
der reduced pressure, and the residue was extracted with CH2Cl2
(2 ϫ 50 mL). The organic phase was washed with water (2 ϫ
100 mL) and brine (1 ϫ 100 mL), and dried using anhydrous
Na2SO4. The solvent was evaporated under reduced pressure to
give crude isoxazoles 5, which were purified by column chromatog-
raphy on silica gel using hexane/EtOAc as eluent.
127.0, 126.8, 125.9, 97.3 ppm. HRMS (ESI): calcd. for C14H10N2O
[M + H]+ 223.0871; found 223.0872.
3-(5-Phenylisoxazol-3-yl)pyridine (5g): Off-white solid, m.p. 107–
108 °C. R = 0.55 (3:7 EtOAc/hexane). IR (KBr): ν = 2946, 1571,
˜
f
1449, 765 cm–1. 1H NMR (400 MHz, CDCl3): δ = 9.08 (d, J =
1.2 Hz, 1 H), 8.71 (d, J = 1.2 Hz, 1 H), 8.21 (d, J = 8.0 Hz, 1 H),
7.88–7.84 (m, 2 H), 7.62–7.46 (m, 3 H), 7.44 (dd, J = 8.0, 4.8 Hz,
1 H), 6.87 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.2,
160.6, 151.2, 148.1, 134.2, 130.7, 129.2, 127.3, 126.1, 125.5, 123.9,
97.3 ppm. HRMS (ESI): calcd. for C14H10N2O [M + H]+ 223.0871;
found 223.0871.
3-(4-Methoxyphenyl)-5-phenylisoxazole (5a): White solid, m.p. 120–
122 °C (ref.[28a] 120 °C). Rf = 0.52 (1:9 EtOAc/hexane). IR (KBr):
N,N-Dimethyl-4-[3-(pyridine-3-yl)isoxazole-5-yl]benzenamine (5h):
Pale yellow solid, m.p. 157–159 °C. Rf = 0.59 (2:8 EtOAc/hexane).
ν = 2935, 1609, 11457, 1257, 756 cm–1 1H NMR (300 MHz,
.
˜
CDCl3): δ = 7.84–7.79 (m, 4 H), 7.50–7.42 (m, 3 H), 7.0 (d, J =
8.8 Hz, 2 H), 6.77 (s, 1 H), 3.86 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.3, 162.7, 161.2, 130.3, 129.1, 128.3, 127.7, 126.0,
121.8, 114.5, 97.4, 55.5 ppm. HRMS (ESI): calcd. for C16H13NO2
[M + H]+ 252.1025; found 252.1015.
IR (KBr): ν = 2960, 1608, 1465, 1248, 790 cm–1 1H NMR
.
˜
(400 MHz, CDCl3): δ = 9.06 (br. s, 1 H), 8.66 (br. d, J = 3.2 Hz, 1
H), 8.12 (dt, J = 8.0, 2.0 Hz, 1 H), 7.73 (d, J = 8.8 Hz, 2 H), 7.42
(dd, J = 8.0, 4.8 Hz, 1 H), 6.84 (s, 1 H), 6.76 (d, J = 8.8 Hz, 2 H),
3.02 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.9, 163.2,
151.8, 150.8, 147.1, 133.0, 128.0, 124.2, 123.9, 116.2, 112.2, 98.3,
40.4 ppm. HRMS (ESI): calcd. for C16H15N3O [M + H]+ 266.1293;
found 266.1286.
5-(3-Bromophenyl)-3-(4-methoxyphenyl)isoxazole (5b): White solid,
m.p. 116–118 °C. R = 0.48 (2:8 EtOAc/hexane). IR (KBr): ν =
˜
f
2926, 1611, 1522, 1436, 1200 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 7.96 (s, 1 H), 7.78 (d, J = 8.8 Hz, 2 H), 7.75 (d, J = 8.4 Hz, 1
H), 7.56 (d, J = 8.4 Hz, 1 H), 7.34 (t, J = 8.0 Hz, 1 H), 7.00 (d, J
= 8.8 Hz, 2 H), 6.77 (s, 1 H), 3.86 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 168.5, 162.7, 161.1, 133.0, 130.5, 129.4,
128.8, 128.2, 124.3, 123.1, 121.4, 114.4, 98.1, 55.4 ppm. HRMS
(ESI): calcd. for C16H12BrNO2 [M + Na]+ 351.9949; found
351.9949.
1-Methyl-2-[3-(thiophen-2-yl)isoxazole-5-yl]-1H-indole (5i): Yellow
crystalline solid, m.p. 115–117 °C. Rf = 0.73 (2:8 EtOAc/hexane).
IR (KBr): ν = 2916, 1620, 1453, 751 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 8.0 (d, J = 8.0 Hz, 1 H), 7.64 (s, 1 H), 7.55 (d, J =
2.8 Hz, 1 H), 7.44–7.40 (m, 2 H), 7.37–7.29 (m, 2 H), 7.14 (dd, J
= 4.8, 3.6 Hz, 1 H), 6.64 (s, 1 H), 3.87 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 167.0, 157.8, 137.2, 131.4, 128.8, 127.6,
127.2, 127.1, 124.8, 122.9, 121.3, 120.1, 110.0, 103.8, 95.2,
33.3 ppm. HRMS (ESI): calcd. for C16H12N2OS [M + Na]+
303.0568; found 303.0568.
5-(Naphthalene-2-yl)-3-phenylisoxazole (5c): Off-white solid, m.p.
129–130 °C. R = 0.79 (2:8 EtOAc/hexane). IR (KBr): ν = 3049,
˜
f
2922, 1615, 1566 cm–1. H NMR (300 MHz, CDCl3): δ = 8.37 (s,
1
1 H), 7.95 (d, J = 8.8 Hz, 2 H), 7.92–7.87 (m, 4 H), 7.56 (dd, J =
6.4, 3.2 Hz, 2 H), 7.52 (d, J = 8.8 Hz, 3 H), 6.95 (s, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 169.5, 162.1, 133.0, 132.1, 129.0,
128.2, 127.94, 127.88, 127.7, 126.9, 126.3, 126.0, 125.9, 124.6,
123.7, 121.9, 96.9 ppm. HRMS (ESI): calcd. for C19H13NO [M +
Na]+ 294.0895; found 294.0897.
2-[5-(Furan-2-yl)isoxazol-3-yl]-1-methyl-1H-indole (5j): Off-white
solid, m.p. 108–110 °C. R = 0.28 (2:8 EtOAc/hexane). IR (KBr): ν
˜
f
= 2922, 1643, 1573, 741 cm–1. 1H NMR (400 MHz, CDCl3): δ =
8.22 (dd, J = 7.2, 1.0 Hz, 1 H), 7.56 (dd, J = 1.6, 1.0 Hz, 1 H), 7.51
(s, 1 H), 7.38–7.26 (m, 3 H), 6.94 (d, J = 3.2 Hz, 1 H), 6.72 (s, 1
H), 6.56 (dd, J = 3.2, 1.6 Hz, 1 H), 3.84 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 160.9, 158.5, 144.0, 143.8, 137.5, 129.3,
125.7, 122.9, 121.8, 121.1, 112.0, 110.3, 109.7, 104.6, 97.4,
33.3 ppm. HRMS (ESI): calcd. for C16H12N2O2 [M + Na]+
287.0796; found 287.0796.
5-(Thiophen-2-yl)-3-p-tolyisoxazole (5d): White solid, m.p. 68–
70 °C. R = 0.62 (2:8 EtOAc/hexane). IR (KBr): ν = 3101, 2915,
˜
f
1599, 1423 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.73 (d, J =
8.0 Hz, 2 H), 7.55 (d, J = 2.4 Hz, 1 H), 7.45 (d, J = 4.4 Hz, 1 H),
7.27 (d, J = 8.0 Hz, 2 H), 7.14 (d, J = 4.0 Hz, 1 H), 6.67 (s, 1 H),
2.41 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.2, 162.9,
140.2, 129.6, 129.4, 128.0, 127.9, 126.9, 126.7, 126.1, 97.2,
21.4 ppm. HRMS (ESI): calcd. for C14H11NOS [M + Na]+
264.0459; found 264.0459.
5-(Furan-2-yl)-3-(1-methyl-1H-pyrrol-2-yl)isoxazole (5k): Brown
viscous liquid. R = 0.50 (2:8 EtOAc/hexane). IR (KBr): ν = 2946,
˜
f
1643, 1569, 1458, 735 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.55
(s, 1 H), 6.91 (d, J = 3.2 Hz, 1 H), 6.77 (s, 1 H), 6.60 (s, 2 H), 6.54
(t, J = 1.2 Hz, 1 H), 6.20 (s, 1 H), 3.98 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 160.4, 156.7, 144.0, 143.3, 126.7, 122.0,
112.6, 111.9, 110.3, 108.3, 98.1, 37.1 ppm. HRMS (ESI): calcd. for
C12H10N2O2 [M + H]+ 215.0821; found 215.0820.
5-(3-Methylthiophen-2-yl)-3-(3,4,5-trimethoxyphenyl)isoxazole (5e):
Brown solid, m.p. 63–65 °C. Rf = 0.70 (3:7 EtOAc/hexane). IR
1
(KBr): ν = 2930, 1589, 1235 cm–1. H NMR (400 MHz, CDCl ): δ
˜
3
= 7.36 (d, J = 5.2 Hz, 1 H), 7.07 (s, 2 H), 6.96 (d, J = 5.2 Hz, 1
H), 6.57 (s, 1 H), 3.95 (s, 6 H), 3.90 (s, 3 H), 2.54 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 165.9, 162.6, 153.6, 139.8, 138.3,
131.5, 126.8, 124.4, 123.6, 104.2, 98.0, 60.9, 56.3, 15.7 ppm. HRMS
(ESI): calcd. for C17H17NO4S [M + Na]+ 354.0776; found
354.0778.
5-(4-Methoxyphenyl)-3-methylisoxazole (5l): Off-white solid, m.p.
90–92 °C (ref.[28b] 92–93 °C). Rf = 0.83 (3:7 EtOAc/hexane). IR
1
(KBr): ν = 2932, 1608, 1432, 1254,787 cm–1. H NMR (400 MHz,
˜
CDCl3): δ = 7.70 (d, J = 8.0 Hz, 2 H), 6.97 (d, J = 8.0 Hz, 2 H),
6.22 (s, 1 H), 3.80 (s, 3 H), 2.33 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 172.0, 164.5, 163.0, 129.7, 124.4, 116.5, 101.2, 57.9,
13.9 ppm. HRMS (ESI): calcd. for C11H11NO2 [M + H]+ 190.0868;
found 190.0870.
4-(3-Phenylisoxazol-5-yl)pyridine (5f): Dark yellow solid, m.p. 121–
123 °C. R = 0.32 (3:7 EtOAc/hexane). IR (KBr): ν = 2922, 1580,
˜
f
1403, 696 cm–1. H NMR (400 MHz, CDCl3): δ = 8.78–8.69 (m, 2
General Procedure for the Synthesis of Regioisomeric 3-(Het)aryl-5-
1
H), 7.88–7.84 (m, 2 H), 7.75 (d, J = 5.2 Hz, 1 H), 7.71 (d, J = methyl/(het)arylisoxazoles 6a–6l from 3-(Methylthio)-1,3-substituted
5.2 Hz, 1 H), 7.50–7.45 (m, 3 H), 7.02 (s, 1 H) ppm. 13C NMR 2-Propenones 2a–2l: Hydroxylamine hydrochloride (0.1 g, 12 mmol)
(100 MHz, CDCl3): δ = 167.7, 163.2, 134.2, 130.4, 129.0, 128.5, was added to a stirred suspension of Ba(OH)2 (0.15 g, 9 mmol) in
Eur. J. Org. Chem. 2014, 1882–1892
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1889

K. S. Rangappa, H. Ila et al.
FULL PAPER
EtOH (95%; 30 mL), and then a solution of 3-methylthio-1-aryl/
heteroaryl-3-alkyl/aryl/heteroaryl propenone (3 mmol) in ethanol
(10 mL) was added. The reaction mixture was heated at reflux with
stirring for 8–10 h (monitored by TLC). The mixture was then con-
centrated to dryness under reduced pressure, and the residue was
extracted with CH2Cl2 (2ϫ 50 mL). The organic phase was washed
with water (2ϫ 100 mL) and brine (1ϫ 100 mL), dried (Na2SO4),
and concentrated under reduced pressure to give crude isoxazoles
6, which were purified by column chromatography on silica gel
using hexane/EtOAc as eluent.
3-(3-Phenylisoxazol-5-yl)pyridine (6g): Off-white solid, m.p. 140–
142 °C (ref.[28c] 143–144 °C). Rf = 0.58 (3:7 EtOAc/hexane). IR
1
(KBr): ν = 2922, 1609, 1404 cm–1. H NMR (400 MHz, CDCl ): δ
˜
3
= 9.09 (br. s, 1 H), 8.70 (d, J = 4.8 Hz, 1 H), 8.15 (d, J = 8.0 Hz,
1 H), 7.89–7.87 (m, 2 H), 7.50–7.49 (m, 3 H), 7.45 (dd, J = 8.0,
4.8 Hz, 1 H), 6.93 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 167.6, 163.1, 151.0, 147.1, 132.9, 130.3, 129.0, 128.7, 126.9, 123.8,
123.7, 98.5 ppm. HRMS (ESI): calcd. for C14H10N2O [M + H]+
223.0871; found 223.0873.
N,N-Dimethyl-4-[5-(pyridin-3-yl)isoxazol-3-yl]benzenamine (6h):
White solid, m.p. 143–145 °C. Rf = 0.52 (2:8 EtOAc/hexane). IR
5-(4-Methoxyphenyl)-3-phenylisoxazole (6a): White solid, m.p. 124–
126 °C (ref.[28c] 126–127 °C). Rf = 0.51 (1.5:8.5 EtOAc/hexane). IR
(KBr): ν = 2895, 1616, 1524, 791 cm–1 1H NMR (400 MHz,
.
˜
(KBr): ν = 2940, 1609, 1449, 1265, 773 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 9.06 (d, J = 1.2 Hz, 1 H), 8.68 (dd, J = 4.4, 1.2 Hz, 1
H), 8.19 (dt, J = 8.0, 2.0 Hz, 1 H), 7.70 (d, J = 8.8 Hz, 2 H), 7.41
(ddd, J = 8.0, 3.2, 0.4 Hz, 1 H), 6.75 (d, J = 8.8 Hz, 2 H), 6.64 (s,
1 H), 3.04 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.0,
160.4, 151.7, 150.9, 148.1, 134.2, 127.3, 125.9, 123.9, 115.0, 111.9,
94.3, 40.3 ppm. HRMS (ESI): calcd. for C16H15N3O [M + H]+
266.1293; found 266.1288.
CDCl3): δ = 7.85–7.80 (m, 4 H), 7.51–7.43 (m, 3 H), 7.0 (d, J =
8.8 Hz, 2 H), 6.77 (s, 1 H), 3.87 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.0, 162.4, 160.8, 129.9, 128.8, 128.0, 127.4, 125.6,
121.5, 114.2, 97.1, 55.2 ppm. HRMS (ESI): calcd. for C16H12NO2
[M + Na]+ 351.9949; found 351.9948.
3-(3-Bromophenyl)-5-(4-methoxyphenyl)isoxazole (6b): White solid,
m.p. 112–114 °C. R = 0.51 (2:8 EtOAc/hexane). IR (KBr): ν =
˜
f
2968, 1616, 1451, 1257, 781 cm–1. H NMR (400 MHz, CDCl3): δ
1
1-Methyl-2-[5-(thiophen-2-yl)isoxazol-3-yl]-1H-indole (6i): Pale yel-
= 8.0 (t, J = 1.6 Hz, 1 H), 7.80–7.75 (m, 3 H), 7.59–7.56 (m, 1 H),
7.34 (t, J = 8.0 Hz, 1 H), 7.00 (d, J = 9.2 Hz, 2 H), 6.68 (s, 1 H),
3.87 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.9, 161.9,
161.4, 133.0, 131.5, 130.6, 130.0, 127.6, 125.5, 123.1, 120.2, 114.6,
96.1, 55.6 ppm. HRMS (ESI): calcd. for C16H13NO2 [M + H]+
252.1025; found 252.1019.
low solid, m.p. 98–100 °C. Rf = 0.76 (3:7 EtOAc/hexane). IR (KBr):
1
ν = 3103, 2919, 1620, 1387 cm–1. H NMR (400 MHz, CDCl ): δ
˜
3
= 8.0 (d, J = 7.8 Hz, 1 H), 7.43 (d, J = 7.8 Hz, 1 H), 7.35–7.09 (m,
6 H), 6.52 (s, 1 H), 3.83 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 151.3, 141.3, 138.7, 137.3, 132.9, 126.7, 125.9, 122.4,
120.3, 120.0, 119.5, 115.9, 111.3,110.0, 109.6, 104.6, 32.9 ppm.
HRMS (ESI): calcd. for C16H12N2OS [M + Na]+ 303.0568; found
303.0569.
3-(Naphthalen-2-yl)-5-phenylisoxazole (6c): Yellow solid, m.p. 128–
129 °C. R = 0.80 (2:8 EtOAc/hexane). IR (KBr): ν = 3118, 1566,
˜
f
1449, 823, 739 cm–1. H NMR (400 MHz, CDCl3): δ = 8.31 (br. s,
1
1 H), 8.03 (dd, J = 8.4, 1.6 Hz, 1 H), 7.95–7.92 (m, 2 H), 7.89–7.87
2-[3-(Furan-2-yl)isoxazol-5-yl]-1-methyl-1H-indole (6j): Off-white
(m, 3 H), 7.55–7.48 (m, 5 H), 6.97 (s, 1 H) ppm. 13C NMR solid, m.p. 122–124 °C. R = 0.31 (2:8 EtOAc/hexane). IR (KBr): ν
˜
f
1
(100 MHz, CDCl3): δ = 170.6, 163.1, 134.2, 133.4, 130.4, 129.2, = 3114, 2925, 1630, 1562 cm–1. H NMR (400 MHz, CDCl3): δ =
128.9, 128.6, 128.0, 127.6, 127.1, 126.8, 126.7, 126.6, 126.0, 124.1,
7.98 (d, J = 8.0 Hz, 1 H), 7.65 (s, 1 H), 7.58 (s, 1 H), 7.41–7.28 (m,
97.7 ppm. HRMS (ESI): calcd. for C19H13NO [M + Na]+ 294.0895; 3 H), 6.95 (d, J = 6.8 Hz, 1 H), 6.68 (s, 1 H), 6.55 (d, J = 2.0 Hz,
found 294.0898.
1 H), 3.88 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.9,
158.5, 144.0, 143.8, 137.5, 129.3, 125.7, 122.8, 121.8, 121.1, 112.0,
110.3, 109.7, 104.6, 97.4, 33.3 ppm. HRMS (ESI): calcd. for
C16H12N2O2 [M + Na]+ 287.0796; found 287.0792.
3-(Thiophen-2-yl)-5-p-tolylisoxazole (6d): White solid, m.p. 66–
68 °C. R = 0.65 (2:8 EtOAc/hexane). IR (KBr): ν = 2918, 1599,
˜
f
1432, 797 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.69 (d, J =
8.0 Hz, 2 H), 7.50 (dd, J = 3.6, 1.2 Hz, 1 H), 7.42 (dd, J = 5.2,
1.2 Hz, 1 H), 7.27 (d, J = 8.0 Hz, 2 H), 7.12 (dd, J = 5.2, 3.6 Hz,
1 H), 6.68 (s, 1 H), 2.39 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.7, 158.2, 140.8, 131.1, 129.8, 127.8, 127.6, 127.4,
125.9, 124.6, 97.0, 21.6 ppm. HRMS (ESI): calcd. for C14H11NOS
[M + Na]+ 264.0460; found 264.0460.
3-(Furan-2-yl)-5-(1-methyl-1H-pyrrol-2-yl)isoxazole (6k): White so-
lid, m.p. 76–78 °C. R = 0.71 (2:8 EtOAc/hexane). IR (KBr): ν =
˜
f
3127, 2933, 1612, 1457 cm–1. 1H NMR (400 MHz, CDCl3): δ =
7.56 (br. s, 1 H), 6.93 (d, J = 3.6 Hz, 1 H), 6.77 (br. s, 1 H), 6.7 (d,
J = 3.2 Hz, 1 H), 6.54 (d, J = 1.2 Hz, 1 H), 6.50 (s, 1 H), 6.20 (t,
J = 3.2 Hz, 1 H), 3.90 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 164.3, 155.1, 144.5, 143.9, 127.0, 121.3, 112.7, 111.9, 110.2,
108.9, 96.1, 36.5 ppm. HRMS (ESI): calcd. for C12H10N2O2 [M +
H]+ 215.0821; found 215.0822.
3-(3-Methylthiophen-2-yl)-5-(3,4,5-trimethoxyphenyl)isoxazole (6e):
Yellow solid, m.p. 77–79 °C. Rf = 0.73 (3:7 EtOAc/hexane). IR
1
(KBr): ν = 2933, 1620, 1450 cm–1. H NMR (400 MHz, CDCl ): δ
˜
3
= 7.32 (d, J = 4.8 Hz, 1 H), 7.05 (s, 2 H), 6.97 (d, J = 4.8 Hz, 1
H), 6.64 (s, 1 H), 3.94 (s, 6 H), 3.89 (s, 3 H), 2.54 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 169.7, 158.4, 153.7, 140.0, 138.2,
131.6, 125.9, 124.7, 122.6, 103.3, 98.5, 61.0, 56.3, 15.8 ppm. HRMS
(ESI): calcd. for C17H17NO4S [M + Na]+ 354.0776; found
354.0778.
3-(4-Methoxyphenyl)-5-methylisoxazole (6l): Off-white solid, m.p.
112–114 °C (ref.[28d] 111–112 °C). Rf = 0.77 (2:8 EtOAc/hexane).
1
IR (KBr): ν = 3070, 2926, 1662, 1452 cm–1. H NMR (400 MHz,
˜
CDCl3): δ = 7.71 (d, J = 8.2 Hz, 2 H), 6.96 (d, J = 8.2 Hz, 2 H),
6.23 (s, 1 H), 3.85 (s, 3 H), 2.45 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 172.0, 164.6, 163.3, 130.5, 124.3, 116.6, 101.9, 57.7,
14.7 ppm. HRMS (ESI): calcd. for C11H11NO2 [M + H]+ 190.0868;
found 190.0867.
4-(5-Phenylisoxazol-3-yl)pyridine (6f): Pale yellow solid, m.p. 125–
127 °C. R = 0.31 (2:8 EtOAc/hexane). IR (KBr): ν = 3110, 2935,
˜
f
1555, 1441, 756, 697 cm–1. H NMR (400 MHz, CDCl3): δ = 8.76
1
(d, J = 4.8 Hz, 2 H), 7.85 (d, J = 8.0 Hz, 2 H), 7.75 (d, J = 4.8 Hz,
2 H), 7.50 (d, J = 8.0 Hz, 3 H), 6.88 (s, 1 H) ppm. 13C NMR Supporting Information (see footnote on the first page of this arti-
(100 MHz, CDCl3): δ = 171.4, 161.1, 136.6, 130.4, 129.1, 129.0, cle): Scanned copies of 1H and 13C NMR spectra of compounds
127.0, 126.8, 125.9, 97.2 ppm. HRMS (ESI): calcd. for C14H10N2O 1a, 1c, 1d, 1g–1i, 1k, 2a, 2c, 2d, 2g–2i, 2k, 5a–5l, and 6a–6l and
[M + H]+ 223.0871; found 223.0870.
also ORTEP diagrams of crystal structure of 5b, 6b, 5e, and 6e.
1890
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1882–1892

Regioselective Synthesis of 3,5-Bis(het)arylisoxazoles
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Acknowledgments
The authors thank Prof. C. N. R. Rao (FRS) for his encourage-
ment, the Council of Scientific and Industrial Research (CSIR),
New Delhi for SRF grants (to B. R., A. A., and T. R. S.), Jawahar-
lal Nehru Center for Advanced Scientific Research (JNCASR),
Bangalore for an RA grant (to G. P.) and financial support, and
the Indian National Science Academy, New Delhi for an INSA
Senior Scientist position (to H. I.).
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Received: November 6, 2013
Published Online: January 23, 2014
1892
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