Reaction of 1,3-Bis(het)arylmonothio-1,3-diketones with Sodium Azide: Regioselective Synthesis of 3,5-Bis(het)arylisoxazoles via Intramolecular N-O Bond Formation

Article abstract of DOI:10.1021/acs.joc.0c02216

An efficient new synthesis of 3,5-bis(het)arylisoxazoles, involving the reaction of 1,3-bis(het)arylmonothio-1,3-diketones with sodium azide in the presence of IBX catalyst, has been reported. The reaction proceeds at room temperature in high yields and is applicable to a broad range of substrates including the synthesis of 5-methyl-3-arylisoxazoles, a key subunit present in several β-lactamase-resistant antibiotics. A probable mechanism for the formation of isoxazoles has been suggested. A few of the 5-styryl/arylbutadienyl-3-(het)arylisoxazoles have also been synthesized by reacting the corresponding 1-(het)aryl-1-(methylthio)-4-(het)arylidene-but-1-en-3-ones with sodium azide at higher temperatures. The reaction of β-ketodithioesters with sodium azide is shown to furnish β-ketonitriles in good yields.

Full text of DOI:10.1021/acs.joc.0c02216

pubs.acs.org/joc
Article
Reaction of 1,3-Bis(het)arylmonothio-1,3-diketones with Sodium
Azide: Regioselective Synthesis of 3,5-Bis(het)arylisoxazoles via
Intramolecular N−O Bond Formation
Mary Antony P, Gantala L. Balaji, Pethaperumal Iniyavan, and Hiriyakkanavar Ila*
Cite This: https://dx.doi.org/10.1021/acs.joc.0c02216
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: An efficient new synthesis of 3,5-bis(het)arylisoxazoles,
involving the reaction of 1,3-bis(het)arylmonothio-1,3-diketones with sodium
azide in the presence of IBX catalyst, has been reported. The reaction
proceeds at room temperature in high yields and is applicable to a broad
range of substrates including the synthesis of 5-methyl-3-arylisoxazoles, a key
subunit present in several β-lactamase-resistant antibiotics. A probable
mechanism for the formation of isoxazoles has been suggested. A few of the
5-styryl/arylbutadienyl-3-(het)arylisoxazoles have also been synthesized by
reacting the corresponding 1-(het)aryl-1-(methylthio)-4-(het)arylidene-but-
1-en-3-ones with sodium azide at higher temperatures. The reaction of β-ketodithioesters with sodium azide is shown to furnish β-
ketonitriles in good yields.
these [3 + 2] cycloaddition reactions has been achieved using
copper7a−c or ruthenium catalysts.7d There also exist few
metal-free protocols for the synthesis of isoxazoles involving
the use of hypervalent iodine reagents for in situ generation of
nitrile oxides from oximes.8 Another typical general approach
for these heterocycles involves cyclocondensation of hydroxyl-
amine with β-diketones or their equivalents, three carbon 1,3-
electrophilic units3e,9 bearing sp or sp2 carbons such as
propargyl ketones, α,β-unsaturated ketones, enaminones, β-
chloro/alkylthioenones, α,β-unsaturated nitriles, or α-oxokete-
nedithioacetals, which also suffer from regioselectivity
problems, yielding sometimes regioisomeric mixtures of
isoxazoles. In recent years, halonium-ion-mediated or tran-
sition-metal-catalyzed, electrophilic cycloisomerization of
several acetylenic hydroxylamine derivatives such as 2-alkyn-
1-one-O-alkyloximes10 or O-propargylic-N-tosyl/alkylhydroxyl-
amine derivatives11 to substituted isoxazoles has also been
reported.
INTRODUCTION
■
The isoxazole motif is a privileged heterocyclic scaffold present
in a plethora of natural products (ibotenic acid, muscimol,
isoxazole-4-carboxylic acid) and synthetic compounds,1,2
displaying a broad range of biological and pharmacological
activities,3 thus emerging as a key structure in drug discovery,
agrochemicals, as well as in material science. The isoxazole
framework constitutes the core structure of many marketed
drugs such as valdecoxib/parecoxib (COX2 inhibitor, antiin-
flammatory), sulfamethoxazole (antibacterial), leflunomide
(antirheumatic), isocarboxazid (antidepressant), antibiotics
oxacillin, cloxacillin, flucoxacillin, and micafungin (antifungal)
(Figure 1).3,4 Isoxazole derivatives also serve as versatile
building blocks in organic synthesis,3e,5 as they can be
converted into several useful functionalities such as β-
hydroxyketones, β-hydroxynitriles, γ-aminoalcohols, and α,β-
unsaturated oximes. Therefore, given the relevance of these
class of compounds in organic and medicinal chemistry, the
development of new synthetic methods for substituted
isoxazoles from readily accessible, starting materials under
mild conditions is an important and useful endeavor.
Although numerous methods have been reported for the
synthesis of isoxazoles,1,2,3e [3 + 2] dipolar cycloaddition of
nitrile oxides with alkynes is probably the most direct route to
access these heterocycles.3c,6 However, the nitrile oxides
themselves are typically prepared, sometimes from unstable
hydroximinoyl chloride, oximes, or by dehydration of nitro-
alkanes under frequently harsh conditions.1a,b Besides, the
uncatalyzed thermal cycloaddition of nitrile oxides with alkynes
is neither chemo- nor regioselective, and as a consequence,
leads to the formation of multiple products. Regioselectivity in
However, all these useful synthesis of isoxazoles originate
from starting materials with a pre-existing N−O bond, such as
nitrile oxides, hydroxylamine, oximes, and their derivatives. On
the other hand, an alternative synthetic protocol involving
direct intramolecular construction of the N−O bond provides
an attractive approach for the synthesis of isoxazoles. There are
Received: September 15, 2020
https://dx.doi.org/10.1021/acs.joc.0c02216
© XXXX American Chemical Society
J. Org. Chem. XXXX, XXX, XXX−XXX
A

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
acrylamide in the presence of iodosobenzene, with only
limited examples.14c Recently, Reddy and co-workers have
reported the synthesis of 3,5-substituted isoxazoles via
denitrogenative cyclization of substituted alkynones with
trimethylsilyl azide in a specific solvent, that is, trichloro-
ethylene (Scheme 1c).15a Although the authors have shown a
broad substrate scope for this cyclization reaction, considering
the cost and hazardousness of trimethylsilyl azide, as well as
the use of carcinogenic solvent and not so easily accessible
alkynones, development of an alternative new method for
isoxazole synthesis via intramolecular N−O bond formation
employing cheaper reagents and readily available starting
materials will be much more attractive and desirable.15b,c
During the course of our ongoing research program directed
toward design and development of new synthetic routes for
five- and six-membered heterocycles from various organosulfur
building blocks, we have recently reported the synthesis and
application of unsymmetrically substituted 1,3-bis(het)-
arylmonothio-1,3-diketones of the general structure 2, a new
class of versatile organosulfur synthons, which are readily
available in good yields by base-mediated condensation of
active methylene ketones with (het)aryldithioesters 1 (Table
2).16a These 1,3-monothiodiketones 2 can be considered as
1,3-diketone surrogates, displaying significant different reac-
tivity and electronic properties of carbonyl and thiocarbonyl
groups. By employing these monothiodiketones, we have
previously developed efficient regioselective synthesis of 1-aryl-
3,5-bis(het)arylpyrazoles,16a substituted thiophenes/push−pull
thiophene acrylates,16b trisubstituted imidazoles,16c and
substituted benzo[b]thiophenes by transition-metal-catalyzed
coupling-cyclization with o-bromoiodoarenes.16d We had also
described previously a regioselective synthesis of 3,5-bis(het)-
arylisoxazoles by cyclocondensation of 1,3-monothiodiketones
as three carbon 1,3-biselectrophilic components with hydroxyl-
amine under controlled reaction conditions (Scheme 2a).3e In
continuation of these studies, we further envisaged to explore
synthetic applications and reactivity of these intermediates, and
we now report an alternate novel high-yield regioselective
synthesis of 3,5-disubstituted isoxazoles by reaction of 1,3-
monothiodiketones with sodium azide in the presence of a
catalytic amount of IBX (Scheme 2b). The key feature of this
new isoxazole synthesis is that it involves an intramolecular
ring closure via formation of the N−O bond and proceeds
under mild conditions at room temperature, employing easily
accessible reagents and starting materials.
Figure 1. Examples of bioactive isoxazoles.
few previous reports for the synthesis of 2,1-benzoisoxazoles
via intramolecular N−O bond formation involving either
hypervalent-iodine-mediated12a,b/transition-metal-catalyzed in-
tramolecular oxidative cyclization of o-aminocarbonyl com-
pounds12c or thermal decomposition of o-azidocarbonyl
compounds.12d However, examples of such approaches for
the construction of isoxazole ring are only few in the literature
and less explored (Scheme 1). Among them, photochemical or
thermal isomerization of 2H-acylazirines is an old example,13a,b
whereas recently these transformations have also been
achieved by some metal catalysts such as Grubb’s ruthe-
nium−carbene complex13c or rhodium acetate dimer
(Rh2(OAc)4) (Scheme 1a).13d Interestingly, these acylazirines
themselves have been obtained previously via photochemical
isomerization of appropriate isoxazoles in the presence of light
of particular wavelengths.13b Recently, Zhao and co-workers
have reported a one-pot procedure for substituted isoxazoles
involving PhI(OAc)2-mediated oxidation of enaminone to
acylazirines and their in situ isomerization to trisubstituted
isoxazoles mediated by Fe(II) chloride (Scheme 1b).13a On
the other hand, Auricchio and co-workers have demonstrated
previously the FeCl2 catalyzed isomerization of isoxazoles to
2H-azirines or enaminones (Scheme 1b) and have shown that,
in the presence of this catalyst, both the isoxazoles and azirines
exist in equilibrium.14a,b Therefore, these methods cannot be
considered useful for a general synthesis of substituted
isoxazoles via intramolecular N−O bond formation. A few of
the 5-anilino-4-acylisoxazoles have also been reported to be
formed by oxidative N−O bond formation of β-amino-
RESULTS AND DISCUSSION
■
The desired 1,3-bis(het)arylmonothio-1,3-diketones 2a−v
were synthesized in good yields according to our earlier
reported procedure16a by reacting the respective active
methylene ketones with appropriate (het)aryldithioesters 1 in
the presence of sodium hydride (Table 2). We selected 1,3-
monothiodiketone 2a as the model substrate for examining its
reaction with sodium azide (or trimethylsilyl azide) under a
variety of reaction conditions (Table 1). Thus, when 2a was
reacted with sodium azide (2 equiv) in DMF as solvent for 24
h at room temperature, no reaction was observed (entry 1).
However, when the reaction mixture was heated at 90 °C for
12 h, the work-up of the reaction mixture furnished a product
(58%) (entry 2), which was characterized as 3-(4-methox-
yphenyl)-5-phenylisoxazole 3a on the basis of comparison of
its spectral and analytical data with that of the reported one.3e
A dramatic improvement in the yield of 3a was observed when
B
https://dx.doi.org/10.1021/acs.joc.0c02216
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 1. Synthesis of Isoxazoles via Intramolecular N−O Bond Formation
2a was reacted with sodium azide in the presence of IBX (20
mol %) for 2 h at room temperature (entry 3). Reducing the
catalytic loading to 10 mol % did not affect the yield of 3a
(entry 4). Use of DMP (Dess−Martin periodinane) or CuI as
catalyst, instead of IBX, under identical conditions also
furnished isoxazole 3a however, in decreased yields (entries
5−7). Similarly, DMF was found to be the best solvent and
reduced yields of 3a were obtained in other solvents such as
THF, CH3CN, or DMSO (entries 8−10), or when 1 equiv of
sodium azide was employed (entry 11). Interestingly, 2a was
found to be completely inert toward trimethylsilyl azide even at
higher temperatures or in the presence of catalysts such as
Ag2CO3, AgNO3, IBX, and CuI, or in solvents such as DMF,
DMSO, or even trichloroethylene,15a yielding only the starting
material or an intractable reaction mixture (Table 1, entries
12−19). We therefore selected reaction of 2a with 2 equiv of
sodium azide in DMF in the presence of 10 mol % of IBX at
room temperature for 2 h as the standard reaction conditions
for our further studies (Table 1, entry 4).
Having established the optimized reaction conditions for the
conversion of 1,3-monothiodiketone 2a to isoxazole 3a (Table
1, entry 4), we next examined the substrate scope of this new
reaction for direct synthesis of isoxazoles from various 1,3-
monothiodiketones 2 bearing different substituents (Table 2).
Thus 1,3-monothiodiketones 2b−f bearing either electron-
donating or -withdrawing substituents on the phenyl rings
attached to thiocarbonyl or carbonyl moieties reacted
smoothly with sodium azide under identical conditions in
the presence of the IBX catalyst, affording the corresponding
isoxazoles 3b−f in excellent yields (Table 2, entries 2−6). The
presence of an ortho substituent on the aryl ring, attached to
either carbonyl (2f) or thiocarbonyl group (2g), also did not
affect the yields of product isoxazoles 3f−g (entries 6−7). The
isoxazole 3g bearing the (4-methoxybenzyloxyphenyl) group at
the 3-position could be transformed into 3-(2-hydroxyphenyl)-
isoxazole 3g′ on treatment with trifluoroacetic acid (Table 2,
entry 7).
Versatility of the reaction was further evident by synthesis of
various (het)aryl-substituted isoxazoles (entries 7−17). Thus,
C
https://dx.doi.org/10.1021/acs.joc.0c02216
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 2. Synthesis of Substituted Isoxazoles from 1,3-Monothio-β-diketones
by appropriate choice of (het)aryl groups in the starting 1,3-
monothiodiketones 2, it was possible to introduce various five-
or six-membered heterocyclic substituents such as 2-thienyl-
(entries 8−11), 2-furyl-(entry 11), 2-(N-methylpyrrolyl-)
(entry 12), (2-thiazolyl-) (entry 13), 3-(N-methylindolyl-)
(entries 14−15), and 3- or 4-pyridyl groups (entries 7, 15−17)
at either 3- or 5-positions of isoxazoles 3h−q in a highly
regioselective fashion in excellent yields (Table 2, entries 7−
17). Entry 10 shows the introduction of a sterically crowded t-
butyl group in the isoxazole ring. The structures and
regiochemistry of all these new isoxazoles 3b−q were
confirmed by their spectral and analytical data and also by
X-ray crystallographic data of isoxazole 3l (Supporting
Information, Figure S1).
We also synthesized few 5-methyl-3-(het)arylisoxazoles
(3r−t) (entries 18−20) as this outstanding subunit is present
in many marketed drugs, such as valdecoxib and parecoxib,
oxacillin, cloxacillin, and flucloxacillin, a group of β-lactamase-
resistant antibiotics, which are widely used clinically to treat
infections caused by penicillin-resistant Staphylococcus aureus
(Figure 1).4b Thus, the 5-methyl-3-(het)arylisoxazoles 3r−t
were synthesized in high yields from the respective 1-methyl-3-
(het)aryl monothiodiketones 2r−t under optimized reaction
conditions (Table 2, entries 18−20). We also reacted
thioketones 2u derived from butyrophenone and cyclic
thioketone 2v obtained from α-tetralone with sodium azide
under optimized reaction conditions with a view to synthesize
trisubstituted isoxazole 3u and bicyclic isoxazole 3v (Table 2,
entries 21−22). However, these reactions failed to furnish the
desired isoxazoles 3u−v, yielding either a starting material or a
complex reaction mixture even at higher temperature, which is
probably due to steric crowding in the starting monothio-1,3-
diketones 2u−v (Scheme 6). We also carried out gram-scale
synthesis by reacting 2a and sodium azide under optimized
conditions, affording isoxazole 3a in 85% yield (Scheme S1 in
the Supporting Information).
To further extend the scope of this novel isoxazole synthesis,
we undertook the preparation of 3-(het)aryl-5-enylisoxazoles
8a−d by employing a similar strategy (Scheme 4). However,
attempted synthesis of 1-(styryl)-3-(4-methoxyphenyl)-
monothio-1,3-diketone 5a by reacting benzylideneacetone 4
with dithioesters 2a in the presence of sodium hydride under
standard reaction conditions was not successful and only a
complex mixture of products was formed (Scheme 3).
We therefore intended to synthesize the desired isoxazoles 8
via an alternate route by the reaction of the corresponding 1-
(het)aryl-1-(methylthio)-4-(het)arylidene-but-1-en-3-ones 7
with sodium azide (Schemes 3 and 4).The desired β-
(methylthio) enones 7a−d were obtained in good yields by
Aldol condensation of various aldehydes with 1-(het)aryl-1-
(methylthio)-but-1-en-3-ones 6a−b (obtained by in situ S-
methylation of 1,3-monothiodiketones 1s or 1t with methyl
iodide) in the presence of sodium hydroxide (Scheme 3).
We next examined the reaction of 7a with sodium azide
under various reaction conditions, with a view to synthesizing
5-styrylisoxazole 8a (Table 3). Thus, 7a remained unchanged
when reacted with sodium azide in DMF at rt either in the
absence or in the presence of IBX (entries 1−2); however, at
D
https://dx.doi.org/10.1021/acs.joc.0c02216
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
The other substituted β-oxodithioesters 9b−e also furnished
the corresponding β-ketoacetonitriles 11b−e in high yields
(Scheme 5). It should be noted that Wang and co-workers
have recently reported the formation of β-ketonitriles during
reaction of β-ketodithioesters with hydroxylamine in EtOH at
room temperature in daylight.17
Table 1. Optimization of the Reaction Conditions for the
Reaction of 2a with Azides
a
Mechanism. A plausible mechanism for the formation of
isoxazoles 3 from 1,3-monothiodiketones 2 and sodium azide
is depicted in Scheme 6. Thus, nucleophilic attack of the
thiocarbonyl group on IBX results in the formation of
intermediate A, which undergoes conjugate addition−elimi-
nation with sodium azide furnishing β-azidoenone intermedi-
ate C. Subsequent intramolecular electrocyclization of
intermediate C, with concurrent N−O bond formation and
extrusion of nitrogen, provides isoxazoles 3 in high yields. An
alternative mechanism involving acylazirine intermediate E is
ruled out as acylazirines are reported to yield isoxazoles either
under drastic thermal or photolytic conditions or in the
presence various transition-metal catalysts.13,14 The failure of
sterically congested monothio-1,3-diketone 2u and cyclic
ketone 2v to furnish trisubstituted isoxazoles 3u−v (Table 2,
entries 21−22) suggests that N−O bond formation occurs
through a planar reactive intermediate such as C by
electrocyclization and the presence of substituents (R1) at
the 2-position in intermediate C′ causes a destabilizing
interaction during planarization (Scheme 6). The probable
mechanism for the regeneration of the IBX catalyst in the
absence of any oxidizing agent18 is not very clear; however, it
seems that the thiolated IBX intermediate D formed during the
reaction appears to lose thiolate anions, regenerating back the
IBX catalyst.
The probable mechanism for the formation of β-ketonitriles
11 from the reaction of sodium azide with β-ketodithioesters 9
is depicted in Scheme 7. Thus, nucleophilic addition of azide
anion on the thiocarbonyl group of a dithioester affords
intermediate D, which, on sequential extrusion of the
methylthio group and nitrogen via intermediates D−E, affords
thiazirine intermediate F, which, on subsequent extrusion of
sulfur, yields β-ketonitriles 11 in high yields. Unlike the
reaction of β-ketodithioesters with hydroxylamine in the
presence of daylight to give β-ketonitriles,17 the present
reaction proceeds even under the dark.
catalyst
temp
time
(h)
yield
b
entry
azide
(mol %)
solvent
(°C)
(%)
1
2
NaN3
NaN3
NaN3
NaN3
NaN3
NaN3
NaN3
NaN3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
CH3CN
DMSO
DMF
DMF
DMF
DMSO
DMSO
DMSO
C2HCl3
DMF
rt
90
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
100
100
rt
rt
rt
24
12
2
2
5
58
90
89
75
70
65
48
70
73
c
3
IBX
IBX
DMP
CuI
CuI
IBX
IBX
IBX
IBX
d
4
c
5
c
6
6
c
7
12
10
6
8
9
NaN3
NaN3
NaN3
10
11
12
13
14
15
16
17
18
19
6
10
24
12
12
12
12
12
12
24
60
f
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
g
g
f
Ag2CO3
AgNO3
f
f
f
IBX
CuI
rt
rt
f
DMF
a
Standard conditions: 2a (1.0 mmol), NaN3 or TMSN3 (2.0 equiv),
solvent (5 mL), catalyst (10 or 20 mol %). Isolated yield. 20 mol %
catalyst. 10 mol % catalyst. 1 equiv of NaN3. Starting material.
Intractable reaction mixture.
b
c
d
e
f
g
100 °C, 8a was obtained in improved yield under relatively
drastic conditions on prolonged heating (entry 3). The best
yield of 8a was obtained when the reaction was conducted at a
higher temperature in DMSO instead of DMF for 12 h (Table
3, entry 4), while the reaction in the presence of IBX afforded
only lower yields of 8a under identical conditions (entry 5).
Following these optimal conditions (entry 4), the other
substituted 3-(het)aryl-5-styryl (8b-c) and 5-(4-phenylbuta-
1,3-dien-1-yl)isoxazole 8d were obtained in good yields
(Scheme 4). The inertness of 1-(methylthio)-1-(het)aryl-4-
(het)arylidene-but-1-en-3-ones 7 toward conjugate addition
with sodium azide at room temperature requiring higher
temperature appears to be probably due the steric hindrance
created by the presence of two substituents at the 1-position of
the enone moiety in 7.
With the successful synthesis of 1,3-disubstituted isoxazoles
3 from 1,3-monothiodiketones 2, we further became interested
in exploring the reaction of other thiocarbonyl compounds
such as β-ketodithioesters 9 with sodium azide under various
reaction conditions (Scheme 5). Thus, when 9a was reacted
with sodium azide in DMF either at room temperature or at a
higher temperature (or in the presence of IBX), the expected
3-(methylthio)-5-(4-methoxyphenyl)isoxazole 10 could not be
isolated from the reaction mixture. The only product isolated
in varying yields was identified as (4-methoxybenzoyl)-
acetonitrile 11a (Scheme 5). The best yield of 11a (80%)
was obtained when 9a was reacted with 2 equiv of sodium
azide in DMF at 90 °C for 3 h (Scheme 5).
CONCLUSIONS
■
In summary, we have developed a highly efficient, novel
synthetic approach for substituted isoxazoles involving IBX-
catalyzed reaction of sodium azide with 1,3-bis(het)-
arylmonothiol-1,3-diketones under very mild conditions. The
methodology is applicable to a broad range of substrates and is
also appropriate for the synthesis of 5-methyl-3-arylisoxazoles,
a key subunit present in several β-lactamase-resistant anti-
biotics. Unlike previously known widely applicable synthetic
approaches for isoxazoles, the present synthesis provides a new
set of disconnection involving tandem intermolecular C−N
and intramolecular N−O bond formation. The examples of
such kind of synthetic sequences for isoxazole synthesis are
very few in literature (Scheme 1). The ready availability of
starting materials, namely, 1,3-monothiodiketones, mild
reaction conditions, operational simplicity, and good yields
of the product isoxazoles along with high regioselectivity, must
make the present methodology more useful and particularly
attractive in organic synthesis. We believe that this kind of
E
https://dx.doi.org/10.1021/acs.joc.0c02216
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Table 2. Substrate Scope of Isoxazole Synthesis
a
b
Yields of isolated products. Obtained by heating 3g with TFA at 60 °C for 2 h.
were dried according to the standard procedures. All the reactions
were monitored by thin layer chromatography (TLC) using standard
TLC silica gel plates and visualized with UV light. Column
chromatography was performed using Merck silica gel (100−200
mesh). Nuclear magnetic resonance spectra were recorded on Bruker
(400 MHz) ultra shield plus and Jeol (600 MHz) ECZ 600R FT-
NMR spectrometer with CDCl3, DMSO-d6 as solvent. Chemical shifts
approach could find application in future for designing
synthesis of other new heterocycles.
EXPERIMENTAL SECTION
■
General Information. All the reagents were purchased from
commercial suppliers and used without further purification. Solvents
F
https://dx.doi.org/10.1021/acs.joc.0c02216
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 3. Synthesis of 1-(Methylthio)-1-(het)aryl-4-(het)arylidene-but-1-en-3-ones 7a−d
Scheme 4. Synthesis of 3-(Het)aryl-5-styryl/
(Arylbutadienyl)isoxazoles 8a−d
Scheme 5. Synthesis of β-Ketonitriles by Reaction of β-
Oxodithioesters with NaN3
Table 3. Optimization of Reaction Conditions for the
Synthesis of 8a from 7a
were reported in δ (ppm) using residual solvent protons as the
internal standard (δ 7.26 for CDCl3 and δ 2.50 for DMSO-d6, in H
1
NMR, δ 77.16 for CDCl3, and δ 39.52 for DMSO-d6 in 13C NMR
spectra). Coupling constants were reported as J values in hertz (Hz).
Splitting patterns are designated as s (singlet), d (doublet), t (triplet),
q (quartet), dd (doublet of doublet), dt (doublet of triplet), td (triplet
of doublet), m (multiplet), and br (broad). Infrared spectra of neat
samples were recorded in attenuated total reflectance mode using an
FT-IR instrument (Agilent Technologies), and HRMS spectra on a
6538 UYHD accurate mass Q-TOF LC/MS spectrometer through
electro spray ionization (ESI) mode. Melting points were recorded
using an electro thermal capillary melting point apparatus and are
uncorrected.
All the 1,3-bis(het)arylmonothiodiketones 2a−v were prepared by
base-induced condensation of various active methylene ketones with
appropriate dithioesters 1 according to our earlier reported
procedure.16a The known 1,3-bis(het)arylmonothiodiketones 2a, 2r,
2v were characterized by comparison of their spectral and analytical
data with the reported one,16a,19 whereas the spectral and analytical
a
entry catalyst
solvent
temp (°C) time (h) product yield (%)
1
DMF
DMF
DMF
DMSO
DMSO
RT
RT
100
100
100
24
15
12
12
12
8a
8a
8a
8a
8a
b
2
3
4
5
IBX
60
80
68
b
IBX
a
b
Yield of isolated product. IBX (10 mol %).
G
https://dx.doi.org/10.1021/acs.joc.0c02216
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 6. Plausible Mechanism for the Formation of Isoxazole 3 from 2 and NaN3
122.9, 113.2, 106.6, 48.6, 25.4, 24.4; HRMS (ESI) m/z: calcd for
C20H21BrNOS [M + H]+, 402.0527 and [M + H + 2]+, 404.0527;
found, 402.0502 and 404.0484.
Scheme 7. Plausible Mechanism for the Formation of β-
Ketonitriles 11 from β-Oxodithioester 9
1-(3,4-Dimethoxyphenyl)-3-(4-fluorophenyl)-3-thioxopro-
pan-1-one (2d). Red solid (210 mg, 80%); mp 112−114 °C; Rf 0.46
(1:9 EtOAc/hexane); IR (neat, cm−1): 3555, 2927, 2309, 1703, 1257,
1
1020; H NMR (400 MHz, CDCl3): δ 15.48 (br, 1H), 7.82 (dd, J =
8.2, 5.4 Hz, 2H), 7.64 (dd, J = 8.4, 2.4 Hz, 1H), 7.55 (d, J = 2.0 Hz,
1H), 7.38 (s, 1H), 7.11 (t, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 1H),
3.99 (s, 6H); 13C{H} NMR (100 MHz, CDCl3): δ 199.9, 179.6,
165.8, 163.3, 153.3, 149.3, 141.8, 141.7, 129.0, 128.9, 128.1, 121.4,
115.6, 115.3, 110.8, 109.9, 109.8, 56.14, 56.11; HRMS (ESI) m/z:
calcd for C17H16FO3S [M + H]+, 319.0804; found, 319.0800.
3-Thioxo-1-(4-(trifluoromethyl)phenyl)-3-(3,4,5-
trimethoxyphenyl)propan-1-one (2e). Red solid (230 mg, 86%);
mp 109−111 °C; Rf 0.45 (1:9 EtOAc/hexane); IR (neat, cm−1):
3300, 3109, 2845, 1750, 1012, 1054; 1H NMR (400 MHz, CDCl3): δ
15.34 (br, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H),
7.37 (s, 1H), 7.07 (s, 2H), 3.95 (s, 6H), 3.93 (s, 3H); 13C{H} NMR
(100 MHz, CDCl3): δ 205.8, 176.9, 153.0, 141.6, 140.9, 139.1, 133.9,
133.6, 127.4, 125.93, 125.89, 125.86, 125.83, 124.9, 122.3, 110.1,
104.7, 61.0, 56.4; HRMS (ESI) m/z: calcd for C19H18F3O4S [M +
H]+, 399.0872; found, 399.0857.
data of unknown 1,3-monothiodiketones 2b−q and 2s−u are given
below. All the known β-ketodithioesters 9a−d and the unknown 9e
were prepared according to an earlier reported procedure.20 The
spectral and analytical data of 9e are given below.
3-(Benzo[d][1,3]dioxol-5-yl)-1-phenyl-3-thioxopropan-1-
one (2b). Red solid (237 mg, 79%); mp 65−67 °C; Rf 0.53 (1:9
EtOAc/hexane); IR (neat, cm−1): 3525, 3010, 2912, 1703, 1253,
1050; 1H NMR (400 MHz, CDCl3): δ 15.93 (br, 1H), 7.99 (d, J = 7.6
Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.51−7.46 (m, 3H), 7.43 (d, J = 2.0
Hz, 1H), 7.39 (s, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.04 (s, 2H); 13C{H}
NMR (100 MHz, CDCl3): δ 205.9, 178.1, 150.7, 148.1, 140.2, 135.5,
132.5, 128.8, 127.1, 121.9, 109.1, 107.9, 107.7, 101.9; HRMS (ESI)
m/z: calcd for C16H13O3S [M + H]+, 285.0585; found, 285.0589.
1-(3-Bromophenyl)-3-(4-(piperidin-1-yl)phenyl)-3-thioxo-
propan-1-one (2c). Red solid (220 mg, 76%); mp 102−104 °C; Rf
0.34 (1:9 EtOAc/hexane); IR (neat, cm−1): 3584, 3101, 2941, 1721,
1465, 685; 1H NMR (400 MHz, CDCl3): δ 16.23 (br, 1H), 8.09 (t, J
= 1.8 Hz 1H), 7.94 (d, J = 9.2 Hz, 2H), 7.88 (d, J = 7.6 Hz, 1H), 7.64
(d, J = 8.0 Hz, 1H), 7.36−7.32 (m, 2H), 6.84 (d, J = 9.2 Hz, 2H),
3.38 (s, 4H), 1.68 (s, 6H); 13C{H} NMR (100 MHz, CDCl3): δ
206.4, 175.8, 153.4, 138.2, 134.5, 134.3, 130.3, 129.7, 129.4, 125.3,
1-(2-Methoxyphenyl)-3-(4-methoxyphenyl)-3-thioxopro-
pan-1-one (2f). Red liquid (200 mg, 75%); Rf 0.52 (1:9 EtOAc/
1
hexane); IR (neat, cm−1): 3655, 2947, 2509, 1733, 1558, 1227; H
NMR (600 MHz, CDCl3): δ 16.02 (br, 1H), 7.93 (dd, J = 7.8, 1.8 Hz,
1H), 7.89 (dd, J = 6.9, 2.1 Hz, 2H), 7.75 (s, 1H), 7.47 (td, J = 8.7, 1.8
Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.92 (dd, J
= 6.6, 2.4 Hz, 2H), 3.93 (s, 3H), 3.85 (s, 3H); 13C{H} NMR (150
MHz, CDCl3): δ 204.9, 177.3, 162.6, 158.2, 138.5, 133.2, 130.5,
129.1, 125.1, 121.1, 114.3, 113.8, 112.0, 56.0, 55.6; HRMS (ESI) m/z:
calcd for C17H16KO3S [M + K]+, 339.0452; found, 339.0449.
3-(2-((4-Methoxybenzyl)oxy)phenyl)-1-(pyridin-4-yl)-3-thio-
xopropan-1-one (2g). Red solid (224 mg, 78%); mp 101−103 °C;
Rf 0.38 (3:7 EtOAc/hexane); IR (neat, cm−1): 3150, 3109, 2945,
H
https://dx.doi.org/10.1021/acs.joc.0c02216
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1
1740, 1675, 1213; H NMR (400 MHz, CDCl3): δ 13.92 (br, 1H),
Hz, 1H), 7.95 (dd, J = 7.8, 1.8 Hz, 2H), 7.84 (s, 1H), 7.54−7.45 (m,
3H), 7.37 (s, 1H), 7.35−7.28 (m, 3H), 3.75 (s, 3H); 13C{H} NMR
(100 MHz, CDCl3): δ 203.4, 173.9, 138.3, 135.8, 133.6, 131.7, 128.8,
126.6, 125.7, 125.3, 123.4, 122.9, 122.3, 110.3, 106.5, 33.6; HRMS
(ESI) m/z: calcd for C18H16NOS [M + H]+, 294.0947; found,
294.0935.
3-(1-Methyl-1H-indol-3-yl)-1-(pyridin-3-yl)-3-thioxopropan-
1-one (2o). Orange solid (238 mg, 79%); mp 124−126 °C; Rf 0.53
(3:7 EtOAc/hexane); IR (neat, cm−1): 3739, 3208, 2981, 1752, 1358,
1200; 1H NMR (400 MHz, CDCl3): δ 16.18 (br, 1H), 9.12 (d, J = 2.4
Hz, 1H), 8.71 (dd, J = 4.8, 1.6 Hz, 1H), 8.59 (dd, J = 7.2, 1.6 Hz,
1H), 8.15 (td, J = 8.0, 2.0 Hz, 1H), 7.85 (s, 1H), 7.39 (dd, J = 8.0 Hz,
4.8 Hz, 1H), 7.36−7.28 (m, 3H), 7.26 (s, 1H), 3.77 (s, 3H); 13C{H}
NMR (100 MHz, CDCl3): δ 203.9, 170.4, 151.8, 147.7, 138.3, 133.9,
133.6, 131.7, 125.8, 125.3, 123.6, 123.5, 123.2, 122.4, 110.3, 106.2,
33.6; HRMS (ESI) m/z: calcd for C17H15N2OS [M + H]+, 295.0900;
found, 295.0914.
8.63 (d, J = 6.0 Hz, 2H), 7.67 (dd, J = 7.8, 1.8 Hz, 1H), 7.51 (s, 1H),
7.45−7.40 (m, 3H), 7.32 (d, J = 8.8 Hz, 2H), 7.08−7.03 (m, 2H),
6.81 (d, J = 8.8 Hz, 2H), 5.06 (s, 2H), 3.76 (s, 3H); 13C{H} NMR
(100 MHz, CDCl3): δ 201.4, 176.1, 159.7, 154.1, 150.5, 143.4, 135.2,
132.2, 131.3, 129.5, 128.1, 121.3, 120.4, 114.6, 114.0, 113.1, 70.7,
55.3; HRMS (ESI) m/z: calcd for C22H20NO3S [M + H]+, 378.1158;
found, 378.1148.
1-(4-Chlorophenyl)-3-(thiophen-2-yl)-3-thioxopropan-1-
one (2h). Orange solid (215 mg, 69%); mp 112−114 °C; Rf 0.52
(1:9 EtOAc/hexane); IR (neat, cm−1): 3650, 3111, 2952, 1737, 1081,
704; 1H NMR (400 MHz, CDCl3): δ 16.02 (br, 1H), 7.89 (d, J = 6.4
Hz, 2H), 7.78 (d, J = 4.0 Hz, 1H), 7.65 (d, J = 5.2 Hz, 1H) 7.46 (d, J
= 8.8 Hz, 2H), 7.38 (s, 1H), 7.15 (t, J = 4.4, Hz, 1H); 13C{H} NMR
(100 MHz, CDCl3): δ 200.7, 174.6, 152.3, 138.7, 134.4, 133.4, 129.2,
128.8, 128.2, 127.7, 106.4; HRMS (ESI) m/z: calcd for C13H10ClOS2
[M + H]+, 280.9856; found, 280.9841.
1-(Pyren-1-yl)-3-(thiophen-2-yl)-3-thioxopropan-1-one (2i).
Yellow solid (234 mg, 78%); mp 98−99 °C; Rf 0.56 (2:8 EtOAc/
3-(4-(Dimethylamino)phenyl)-1-(pyridin-3-yl)-3-thioxopro-
pan-1-one (2p). Reddish brown solid (220 mg, 80%); 118−120 °C;
Rf 0.31 (2:8 EtOAc/hexane); IR (neat, cm−1): 3715, 2932, 2856,
1
hexane); IR (neat, cm−1): 3650, 3100, 2885, 1790, 1650, 1049; H
1
2323, 1050, 1018; H NMR (400 MHz, CDCl3): δ 16.30 (br, 1H),
NMR (600 MHz, CDCl3): δ 16.34 (br, 1H), 8.71 (d, J = 9.0 Hz, 1H),
8.28−8.16 (m, 6H), 8.09−8.05 (m, 2H), 7.76 (dd, J = 4.2, 1.2 Hz,
1H), 7.65 (dd, J = 5.4, 1.2 Hz, 1H), 7.42 (s, 1H), 7.14 (t, J = 5.4 Hz,
1H); 13C{H} NMR (150 MHz, CDCl3): δ 199.6, 179.5, 152.5, 134.6,
133.5, 131.3, 130.7, 130.6, 129.5, 129.1, 128.9, 127.9, 127.3, 127.2,
126.6, 126.4, 126.3, 126.2, 125.1, 124.8, 124.6, 124.5, 112.7; HRMS
(ESI) m/z: calcd for C23H15OS2 [M + H]+, 371.0564; found,
371.0534.
9.17 (d, J = 2.4 Hz, 1H), 8.78 (dd, J = 4.8, 1.6 Hz, 1H), 8.23 (d, J =
8.4 Hz, 1H), 7.99 (d, J = 9.2 Hz, 2H), 7.41 (dd, J = 8.0, 4.8 Hz, 1H),
7.37 (s, 1H), 6.65 (d, J = 8.4 Hz, 2H), 3.08 (s, 6H); 13C {H} NMR
(100 MHz, CDCl3): δ 208.3, 172.2, 153.4, 152.0, 147.9, 134.1, 133.0,
132.0, 129.1, 123.6, 110.9, 106.2, 40.1; HRMS (ESI) m/z: calcd for
C16H17N2OS [M + H]+, 285.1062; found, 285.1033.
1,3-Dsi(pyridin-3-yl)-3-thioxopropan-1-one (2q). Red solid
(217 mg, 78%); mp 99−100 °C; Rf 0.56 (4:6 EtOAc/hexane); IR
4,4-Dimethyl-1-(thiophen-2-yl)-1-thioxopentan-3-one (2j).
1
(neat, cm−1): 3705, 3081, 2869, 1708, 1089, 1665; H NMR (400
Yellow liquid (256 mg, 81%); Rf 0.46 (1:9 EtOAc/hexane); IR
1
(neat, cm−1): 3715, 3109, 2905, 1699, 1060, 1453; H NMR (400
MHz, CDCl3): δ 14.88 (br, 1H), 9.22 (s, 1H), 9.01 (s, 1H), 8.79 (s,
1H), 8.73 (s, 1H), 8.26 (d, J = 7.2 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H),
7.45 (dd, J = 7.8, 4.6 Hz, 1H), 7.41 (s, 2H); 13C{H} NMR (100
MHz, CDCl3): δ 200.9, 177.9, 153.2, 151.9, 148.4, 146.9, 140.5,
134.6, 134.4, 131.2, 123.8, 123.5, 110.6; HRMS (ESI) m/z: calcd for
C13H11N2OS [M + H]+, 243.0592; found, 243.0569.
MHz, CDCl3): δ 15.78 (br, 1H), 7.69 (dd, J = 4.0, 1.2 Hz, 1H), 7.59
(dd, J = 5.0, 1.4 Hz, 1H), 7.11 (dd, J = 5.0, 3.8 Hz, 1H), 6.93 (s, 1H),
1.29 (s, 9H); 13C{H} NMR (100 MHz, CDCl3): δ 199.1, 192.9,
152.0, 133.6, 128.5, 127.4, 105.8, 38.9, 27.7; HRMS (ESI) m/z: calcd
for C11H14OS2 [M + H]+, 227.0559; found, 227.0540.
4-(4-Methoxyphenyl)-4-thioxobutan-2-one (2s). Yellow solid
1-(Furan-2-yl)-3-(thiophen-2-yl)-3-thioxopropan-1-one (2k).
(205 mg, 82%); mp 80−82 °C; Rf 0.32 (1:9 EtOAc/hexane); IR
Red solid (243 mg, 80%); mp 97−98 °C; Rf 0.41 (1:9 EtOAc/
1
(neat, cm−1): 3525, 3201, 2869, 1745, 1225, 1068; H NMR (400
1
hexane); IR (neat, cm−1): 3720, 3201, 2885, 1730, 1200, 1050; H
MHz, CDCl3): δ 14.98 (br, 1H), 7.79 (d, J = 8.8 Hz, 2H), 6.89 (d, J =
8.8 Hz, 2H), 6.74 (s, 1H), 3.84 (s, 3H), 2.22 (s, 3H); 13C{H} NMR
(100 MHz, CDCl3): δ 200.8, 185.9, 162.6, 136.9, 128.8, 113.7, 111.9,
55.5, 25.9; HRMS (ESI) m/z: calcd for C11H13O2S [M + H]+,
209.0636; found, 209.0614.
NMR (400 MHz, CDCl3): δ 15.52 (br, 1H), 7.76 (dd, J = 4.0, 1.2 Hz,
1H), 7.64 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 5.2, 1.2 Hz, 1H), 7.38 (s,
1H), 7.25 (d, J = 3.6 Hz, 1H), 7.13 (dd, J = 5.0, 3.8 Hz, 1H), 6.61
(dd, J = 3.6, 1.6 Hz, 1H); 13C{H} NMR (100 MHz, CDCl3): δ 198.5,
165.9, 152.2, 149.6, 146.4, 134.2, 128.7, 127.5, 116.3, 113.2, 105.5;
HRMS (ESI) m/z: calcd for C11H9O2S2 [M + H]+, 237.0038; found,
237.0025.
4-(Thiophen-2-yl)-4-thioxobutan-2-one (2t). Red solid (260
mg, 64%); mp 84−86 °C; Rf 0.41 (1:9 EtOAc/hexane); IR (neat,
1
cm−1): 3400, 2900, 2895, 1704, 1205, 1075; H NMR (400 MHz,
3-(1-Methyl-1H-pyrrol-3-yl)-3-thioxo-1-(4-(trifluoromethyl)-
phenyl)propan-1-one (2l). Orange solid (231 mg, 76%); mp 52−
54 °C; Rf 0.34 (2:9 EtOAc/hexane); IR (neat, cm−1): 3729, 3078,
CDCl3): δ 15.55 (br, 1H), 7.68 (d, J = 4.0 Hz, 1H), 7.60 (d, J = 5.2
Hz, 1H), 7.12 (t, J = 4.4 Hz, 1H), 6.77 (s, 1H), 2.20 (s, 3H); 13C{H}
NMR (100 MHz, CDCl3): δ 199.1, 182.6, 151.5, 134.0, 128.6, 127.6,
109.6, 24.6; HRMS (ESI) m/z: calcd for C8H9OS2 [M + H]+,
185.0095; found, 185.0073.
1
2927, 1055, 1069, 1296; H NMR (400 MHz, CDCl3): δ 15.96 (br,
1H), 8.00 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.25 (s, 1H),
6.97 (d, J = 3.2 Hz, 2H), 6.22 (t, J = 3.4 Hz, 1H), 4.08 (s, 3H);
13C{H} NMR (100 MHz, CDCl3): δ 199.5, 170.9, 140.7, 139.2,
134.5, 133.3, 133.0, 132.7, 132.4, 127.9, 127.6, 126.8, 125.72, 125.69,
125.65, 125.61, 125.17, 122.5, 119.7, 115.5, 108.8, 107.4, 38.9; HRMS
(ESI) m/z: calcd for C15H13F3NOS [M + H]+, 312.0670; found,
312.0654.
3-(4-(Methylthio)phenyl)-1-(thiazol-2-yl)-3-thioxopropan-1-
one (2m). Red solid (208 mg, 78%); mp 89−90 °C; Rf 0.46 (1:9
EtOAc/hexane); IR (neat, cm−1): 3729, 3078, 2927, 1055, 1069,
1296; 1H NMR (400 MHz, CDCl3): δ 12.39 (br, 1H), 8.02 (d, J = 2.8
Hz, 1H), 7.91 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 2.8 Hz,
1H), 7.26 (d, J = 8.8 Hz, 2H), 1.87 (s, 3H); 13C{H} NMR (100
MHz, CDCl3): δ 189.5, 174.1, 166.9, 144.8, 144.2, 139.3, 127.4,
125.5, 125.2, 109.4, 15.0; HRMS (ESI) m/z: calcd for C13H12NOS3
[M + H]+, 294.0081; found, 294.0062.
3-(1-Methyl-1H-indol-3-yl)-1-phenyl-3-thioxopropan-1-one
(2n). Orange solid (256 mg, 85%); mp 121−123 °C; Rf 0.54 (2:8
EtOAc/hexane); IR (neat, cm−1): 3742, 3101, 2323, 1745, 1360,
1235; 1H NMR (400 MHz, CDCl3): δ 16.41 (s, 1H), 8.55 (d, J = 7.2
General Procedure for the Synthesis of 1-(Methylthio)-1-
(het)aryl-1-buten-3-one 6a−b. To a stirred suspension of NaH
(34 mg, 1.0 mmol, 100%) in DMF (10 mL) under an N2 atmosphere,
a solution of acetone (70 mg, 1.2 mmol) and (het)aryl dithioesters 1
(1.0 mmol) in DMF (5 mL) was added at 0 °C, and the reaction
mixture was further stirred at room temperature for 1 h. It was then
cooled (monitored by TLC), followed by dropwise addition of methyl
iodide (170 mg, 1.2 mmol) and stirring was further continued at room
temperature for 1 h (monitored by TLC). The reaction mixture was
then poured into water (50 mL) and extracted with EtOAc (3 × 50
mL). The combined organic extracts were washed with H2O (3 × 50
mL) and brine (1 × 50 mL), dried (Na2SO4), and evaporated under
reduced pressure to give crude products 6, which were purified by
column chromatography using EtOAc/hexane as eluent.
(E/Z)-1-(4-Methoxyphenyl)-1-(methylthio)but-1-en-3-one (6a).
E/Z = 67:33; yellow viscous liquid (204 mg, 74%); Rf 0.41 (1:9
1
EtOAc/hexane); IR (neat, cm−1): 3200, 2900, 2895, 1711, 1212; H
NMR (600 MHz, CDCl3): δ 7.13 (dd, J = 6.6, 1.8 Hz, 0.67H), 7.08
I
https://dx.doi.org/10.1021/acs.joc.0c02216
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(dd, J = 6.6, 1.8 Hz, 1.25H), 6.80 (dd, J = 6.6, 2.4 Hz, 1.33H), 6.78
(dd, J = 6.6, 1.8 Hz, 0.68H), 6.22 (s, 0.58H), 5.81 (s, 0.38H), 3.69 (s,
2.05H), 3.68 (s, 1.06H), 2.21 (s, 1.06H), 2.11 (s, 2H), 1.79 (s, 2H),
1.69 (s, 1.04H); 13C{H} NMR (150 MHz, CDCl3): δ 195.9, 195.8,
161.3, 160.7, 160.1, 159.6, 130.5, 129.9, 129.6, 129.4, 122.7, 120.9,
113.9, 113.8, 60.3, 55.3, 30.5, 30.1, 16.3, 14.2; HRMS (ESI) m/z:
calcd for C12H15O2S [M + H]+, 223.0793; found, 223.0778.
0.63H), 6.14 (d, J = 15.0 Hz, 0.34H), 6.04 (s, 0.40H), 3.81 (s,
1.88H), 3.76 (s, 1.25H), 2.37 (s, 1.24H), 1.94 (s, 1.87H); 13C{H}
NMR (150 MHz, CDCl3): δ 187.1, 186.6, 163.4, 161.0, 160.2, 140.8,
140.7, 134.3, 133.3, 131.2, 130.99, 130.95, 130.55, 130.15, 129.7,
129.6, 129.5, 128.3, 128.1, 128.0, 126.4, 125.7, 122.7, 120.8, 114.0,
55.5, 55.4, 16.9, 16.6; HRMS (ESI) m/z: calcd for C17H17O2S2 [M +
H]+, 317.0670; found, 317.0616.
(E/Z)-1-(Methylthio)-1-(thiophen-2-yl)but-1-en-3-one (6b). E/Z
= 67:33; brown viscous liquid (214 mg, 71%); Rf 0.41 (1:9 EtOAc/
(1Z,4E,6E)-1-(Methylthio)-7-phenyl-1-(thiophen-2-yl)hepta-
1,4,6-trien-3-one (7d). Trienone 7d was obtained following the above
general procedure for 7a−c using cinnamaldehyde (132 mg, 1.0
mmol) and 6b (198 mg, 1.0 mmol), E/Z = 66:34; yellow viscous
liquid (231 mg, 65%); Rf 0.52 (1:9 EtOAc/hexane); IR (neat, cm−1):
2952, 2808, 1703, 1620, 1050; 1H NMR (400 MHz, CDCl3): δ 7.47−
7.44 (m, 1.41H), 7.42−7.40 (m, 0.96H), 7.39−7.38 (m, 1.0H), 7.37−
7.36 (m, 0.64H), 7.34−7.32 (m, 1.43H), 7.29 (dd, J = 5.6, 1.6 Hz,
1.36H), 7.26 (dd, J = 3.4, 1.4 Hz, 0.68H), 7.16 (dd, J = 3.6, 1.2 Hz,
0.72H), 7.07 (dd, J = 5.2, 3.6 Hz, 0.71H), 7.01 (dd, J = 5.2, 3.6 Hz,
0.33H), 6.92 (s, 1.05H), 6.89 (s, 0.33H), 6.85 (d, J = 15.6 Hz,
0.36H), 6.73 (s, 0.71H), 6.43 (d, J = 15.2 Hz, 0.71H), 6.09 (d, J =
10.4 Hz, 0.67H), 2.41 (s, 0.98H), 2.18 (s, 2.12H); 13C{H} NMR
(100 MHz, CDCl3): δ 188.4, 187.1, 153.1, 149.8, 142.2, 141.8, 140.9,
140.6, 140.2, 136.3, 130.9, 130.1, 129.9, 129.0, 128.96, 128.82, 128.77,
128.18, 127.50, 127.41, 127.31, 127.20, 127.15, 127.07, 126.9, 123.8,
121.4, 17.4, 16.9; HRMS (ESI) m/z: calcd for C18H17OS2 [M + H]+,
313.0715; found, 313.0727.
General Procedure for the Synthesis of 3-(Het)aryl-5-
(het)aryl/alkylisoxazoles 3. To a stirred solution of 1,3-
monothiodiketone 2 (1.0 mmol) in DMF (3 mL), a solution of
IBX (50 mg, 10 mol %) in DMF (3 mL) was added dropwise at room
temperature under an N2 atmosphere, and after stirring for 5 min,
sodium azide (45 mg, 2.0 mmol) was added and stirring was
continued at room temperature for further 1−2 h (monitored by
TLC). The reaction mixture was then quenched with saturated
NH4Cl solution (25 mL) and extracted with EtOAc (3 × 25 mL), and
the combined organic layer was washed with water (3 × 25 mL) and
brine (25 mL), dried (Na2SO4), and evaporated under vacuum to give
crude isoxazoles 3, which were further purified by column
chromatography using hexane/ethyl acetate as eluent.
1
hexane); IR (neat, cm−1): 3200, 2900, 2895, 1711, 1212; H NMR
(600 MHz, CDCl3): δ 7.42 (d, J = 4.8 Hz, 0.34H), 7.34 (d, J = 4.8
Hz, 0.60H), 7.19 (d, J = 3.0 Hz, 0.37H), 7.10 (d, J = 3.6 Hz, 0.67H),
7.03 (dd, J = 5.1, 3.3 Hz, 0.67H), 7.01 (dd, J = 3.6, 1.8 Hz, 0.34H),
2.35 (s, 1.02H), 2.24 (s, 2.08H), 2.12 (s, 2.07H), 1.95 (s, 1.01H);
13C{H} NMR (150 MHz, CDCl3): δ 196.4, 195.8, 152.1, 150.7,
139.8, 137.7, 129.7, 128.9, 128.3, 127.6, 127.4, 124.2, 122.0, 30.9,
29.9, 17.2, 16.9; HRMS (ESI) m/z: calcd for C9H11OS2 [M + H]+,
199.0251; found, 199.0233.
General Procedure for the Synthesis of 1-(Methylthio)-1-
(het)aryl-4-(het)arylidene-but-1-en-3-one 7a−c. To a stirred
suspension of NaOH (40 mg, 1.0 mmol) in ethanol (3 mL), a
solution of 1-(methylthio)-1-(het)aryl-1-buten-3-one 6 (1.0 mmol) in
ethanol (3 mL) was added dropwise at room temperature, followed
by addition of a solution of (het)arylaldehyde (1.0 mmol) in ethanol
(3 mL). After further stirring for 1−2 h (monitored by TLC), the
reaction mixture was evaporated under reduced pressure, and the
residue was dissolved in EtOAc (10 mL), diluted with water (10 mL),
and further extracted with EtOAc (3 × 10 mL); the combined organic
layer was washed with water (3 × 25 mL) and brine (25 mL), dried
(Na2SO4), and evaporated under vacuum to give crude products 7,
which were further purified by column chromatography using EtOAc/
hexane as eluent.
(1Z,4E)-1-(4-Methoxyphenyl)-1-(methylthio)-5-phenylpenta-1,4-
dien-3-one (7a). E/Z = 67:33; brown viscous liquid (200 mg, 77%);
Rf 0.41 (1:9 EtOAc/hexane); IR (neat, cm−1): 3425, 2932, 2892,
1
1704, 1200, 1068; H NMR (600 MHz, CDCl3): δ 7.62 (d, J = 16.2
Hz, 0.66H), 7.55 (d, J = 7.2 Hz, 1.34 H), 7.42 (d, J = 15.6 Hz,
0.35H), 7.37−7.34 (m, 2.21H), 7.28−7.25 (m, 2.07H), 7.20 (d, J =
7.2 Hz, 1.04H), 6.94 (d, J = 9.0 Hz, 1.33H), 6.89 (d, J = 8.4 Hz,
1.09H), 6.86 (d, J = 16.2 Hz, 0.66H), 6.59 (s, 1.90H), 6.36 (d, J =
15.6 Hz, 1.70H), 6.10 (s, 0.69H), 3.81 (s, 2.25H), 3.75 (s, 1.28H),
2.37 (s, 1.31H), 1.95 (s, 2.04H); 13C{H} NMR (150 MHz, CDCl3):
δ 187.8, 187.3, 163.5, 161.0, 160.2, 160.1, 141.8, 140.8, 135.2, 131.1,
130.6, 130.1, 129.93, 129.90, 129.59, 129.54, 128.9, 128.8, 128.3,
128.1, 127.5, 126.6, 122.9, 122.5, 120.9, 113.9, 55.5, 16.9, 16.6;
HRMS (ESI) m/z: calcd for C19H19O2S [M + H]+, 311.1106; found,
311.1089.
(1Z,4E)-5-(4-Bromophenyl)-1-(4-methoxyphenyl)-1-(methylthio)-
penta-1,4-dien-3-one (7b). E/Z = 69:31; yellow solid (208 mg,
81%); mp 100−102 °C; Rf 0.45 (1:9 EtOAc/hexane); IR (neat,
cm−1): 2941, 2902, 1700, 1200, 1068; 1H NMR (600 MHz, CDCl3):
δ 7.48 (d, J = 16.2 Hz, 0.62H), 7.41 (d, J = 8.4 Hz, 1.37H), 7.33 (d, J
= 9.0 Hz, 2.05H), 7.28 (t, J = 8.1 Hz, 1.06H), 7.19 (d, J = 7.8 Hz,
1.38H), 6.99 (d, J = 8.4 Hz, 0.62H), 6.88 (d, J = 7.8 Hz, 1.39H), 6.83
(d, J = 8.4 Hz, 0.63H), 6.79 (d, J = 15.6 Hz, 0.62H), 6.52 (s, 0.69H),
6.28 (d, J = 15.6 Hz, 0.31H), 6.04 (s, 0.30H), 3.77 (s, 2.08H), 3.72 (s,
0.94H), 2.34 (s, 0.93H), 1.91 (s, 2.06H); 13C{H} NMR (150 MHz,
CDCl3): δ 187.3, 186.7, 164.0, 161.1, 160.6, 160.2, 140.2, 139.1,
134.2, 134.1, 132.1, 131.9, 130.8, 130.7, 129.8, 129.7, 129.6, 129.4,
127.9, 127.2, 124.2, 124.0, 122.5, 120.8, 114.0, 113.9, 55.5, 16.9, 16.7;
HRMS (ESI) m/z: calcd for C19H18BrO2S [M + H]+, 389.0211 and
[M + H + 2]+, 291.0211; found, 389.0231, 391.0213.
3-(4-Methoxyphenyl)-5-phenylisoxazole (3a). White solid (215
mg, 90%); mp 120−122 °C (reported 120 °C);13c Rf 0.52 (1:9
1
EtOAc/hexane); IR (neat, cm−1): 3018, 2879, 1764, 1501, 1018: H
NMR (400 MHz, CDCl3): δ 7.85−7.79 (m, 4H), 7.50−7.45 (m, 3H),
7.00 (d, J = 8.8 Hz, 2H), 6.78 (s, 1H), 3.87 (s, 3H); 13C{H} NMR
(100 MHz, CDCl3): δ 170.2, 162.6, 161.0, 130.1, 128.9, 128.2, 127.6,
125.8, 121.7, 114.3, 97.3, 55.4; HRMS (ESI): calcd for C16H14NO2
[M + H]+, 252.1025; found, 252.1015.
3-(Benzo[d][1,3]dioxol-5-yl)-5-phenylisoxazole (3b). Pale yellow
solid (200 mg, 75%); mp 92−94 °C; Rf 0.47 (1:9 EtOAc/hexane); IR
1
(neat, cm−1): 3010, 2912, 1690, 1550, 1000; H NMR (400 MHz,
CDCl3): δ 7.83 (dd, J = 7.8, 1.8 Hz, 2H), 7.51−7.45 (m, 3H), 7.38
(d, J = 2.0 Hz, 1H), 7.34 (dd, J = 8.0, 1.6 Hz, 1H), 6.91 (d, J = 8.0 Hz,
1H), 6.75 (s, 1H), 6.04 (s, 2H); 13C{H} NMR (100 MHz, CDCl3): δ
170.3, 162.6, 149.2, 148.3, 130.2, 128.9, 127.5, 125.8, 123.1, 121.2,
108.6, 107.0, 101.5, 97.3; HRMS (ESI) m/z: calcd for C16H12NO3 [M
+ H]+, 266.0817; found, 266.0803.
5-(3-Bromophenyl)-3-(4-(piperidin-1-yl)phenyl)isoxazole (3c).
White solid (218 mg, 85%) mp 103−105 °C; Rf 0.46 (1:9 EtOAc/
hexane); IR (neat, cm−1): 3101, 2941, 1665, 980, 685; 1H NMR (400
MHz, CDCl3): δ 7.97 (s, 1H), 7.77−7.71 (m, 3H), 7.56 (d, J = 8.0
Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.78 (s,
1H), 3.28 (t, J = 5.4 Hz, 4H), 1.71 (d, J = 5.6 Hz, 4H), 1.63 (d, J = 4.8
Hz, 2H); 13C{H} NMR (100 MHz, CDCl3): δ 168.2, 162.9, 153.0,
132.9, 130.5, 129.6, 128.8, 127.8, 124.3, 123.0, 118.4, 115.5, 98.0,
49.6, 25.5, 24.3; HRMS (ESI) m/z: calcd for C20H20BrN2O [M +
H]+, 383.0759 and [M + H + 2]+, 385.0759; found, 383.0691 and
385.0674.
(1Z,4E)-1-(4-Methoxyphenyl)-1-(methylthio)-5-(thiophen-2-yl)-
penta-1,4-dien-3-one (7c). E/Z = 60:40; yellow viscous liquid (230
mg, 69%); Rf 0.56 (1:9 EtOAc/hexane); IR (neat, cm−1): 2900, 2782,
1
1690, 1230, 699; H NMR (600 MHz, CDCl3): δ 7.72 (d, J = 15.6
Hz, 0.61H), 7.52 (d, J = 15.6 Hz, 0.33H), 7.31 (d, J = 7.8 Hz, 1.25H),
7.24−7.21 (m, 2.15H), 7.06 (d, J = 3.6 Hz, 0.42H), 7.01 (d, J = 4.2
Hz, 0.62H), 6.93 (d, J = 4.2 Hz, 0.43H), 6.91 (d, J = 8.4 Hz, 1.34H),
6.87 (d, J = 8.4 Hz, 0.85H), 6.64 (d, J = 15.0 Hz, 0.62H), 6.49 (s,
5-(3,4-Dimethoxyphenyl)-3-(4-fluorophenyl)isoxazole (3d).
White solid (250 mg, 90%); mp 98−99 °C; Rf 0.48 (1:9 EtOAc/
1
hexane); IR (neat, cm−1): 2927, 2309, 1557, 1205, 755; H NMR
(400 MHz, CDCl3): δ 7.85 (dd, J = 6.0, 3.6 Hz, 2H), 7.41 (dd, J =
J
https://dx.doi.org/10.1021/acs.joc.0c02216
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
5.6, 1.2 Hz, 1H), 7.34 (d, J = 1.6 Hz, 1H), 7.17 (t, J = 5.8 Hz, 2H),
6.96 (d, J = 5.6 Hz, 1H), 6.69 (s, 1H), 3.98 (s, 3H), 3.95 (s, 3H);
13C{H} NMR (100 MHz, CDCl3): δ 170.6, 164.7, 163.1, 162.2,
150.9, 149.4, 128.84, 128.79, 125.6, 125.5, 120.4, 119.3, 116.2, 116.0,
111.4, 108.8, 96.3, 56.2, 56.1; HRMS (ESI) m/z: calcd for
C17H15FNO3 [M + H]+, 300.1036; found, 300.1030.
5-(4-(Trifluoromethyl)phenyl)-3-(3,4,5-trimethoxyphenyl)-
isoxazole (3e). White solid (234 mg, 79%), mp 108−109 °C; Rf 0.42
(1:9 EtOAc/hexane); IR (neat, cm−1): 3109, 2845, 1512, 1450, 1054;
1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 8.4 Hz, 2H), 7.75 (d, J =
8.4 Hz, 2H), 7.09 (s, 2H), 6.90 (s, 1H), 3.95 (s, 6H), 3.92 (s, 3H);
13C{H} NMR (100 MHz, CDCl3): δ 168.8, 163.1, 153.7, 139.9,
132.1, 131.8, 130.5, 126.15, 126.10, 126.07, 126.04, 125.1, 124.1,
122.4, 104.2, 98.9, 60.9, 56.3; HRMS (ESI) m/z: calcd for
C19H17F3NO4 [M + H]+, 380.1110; found, 380.1017.
181.8, 157.3, 131.4, 127.5, 127.2, 126.9, 96.6, 32.8, 28.8; HRMS (ESI)
m/z: calcd for C11H14NOS [M + H]+, 208.0796; found, 208.0825.
5-(Furan-2-yl)-3-(thiophen-2-yl)isoxazole (3k). White solid (210
mg, 85%); mp 134−136 °C; Rf 0.52 (1:9 EtOAc/hexane); IR (neat,
1
cm−1): 3255, 3001, 1669, 1596, 1543, 755; H NMR (600 MHz,
CDCl3): δ 7.55 (s, 1H), 7.50 (d, J = 4.2 Hz, 1H), 7.43 (d, J = 5.4 Hz,
1H), 7.13 (d, J = 4.2 Hz, 1H), 6.94 (d, J = 3.6 Hz, 1H), 6.67 (s, 1H),
6.55 (d, J = 4.2 Hz, 1H); 13C{H} NMR (150 MHz, CDCl3): δ 157.9,
144.8, 144.3, 127.9, 127.8, 127.7, 112.1, 111.9, 110.9, 96.7; HRMS
(ESI) m/z: calcd for C11H8NO2S [M + H]+, 218.0276; found,
218.0233.
3-(1-Methyl-1H-pyrrol-2-yl)-5-(4-(trifluoromethyl)phenyl)-
isoxazole (3l). Off-white solid (247 mg, 80%); mp 112−114 °C; Rf
0.48 (1:9 EtOAc/hexane); IR (neat, cm−1): 3255, 3001, 1669, 1596,
1543, 755; 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 8.0 Hz, 2H),
7.74 (d, J = 8.0 Hz, 2H), 6.79 (t, J = 2.4 Hz, 1H), 6.78 (s, 1H), 6.62
(dd, J = 4.0, 1.6 Hz, 1H), 6.23 (dd, J = 3.8, 2.6 Hz, 1H), 4.00 (s, 3H);
13C{H} NMR (100 MHz, CDCl3): δ 167.0, 157.2, 132.3, 131.9,
5-(2-Methoxyphenyl)-3-(4-methoxyphenyl)isoxazole (3f). Yellow
liquid (270 mg, 77%); Rf 0.35 (1:9 EtOAc/hexane); IR (neat, cm−1):
1
2947, 2509, 1733, 1558, 980; H NMR (600 MHz, CDCl3): δ 8.01
131.7, 131.3, 130.5, 127.8, 126.95, 126.09, 126.05, 126.01, 125.9,
125.1, 122.4, 121.9, 119.7, 112.7, 108.4, 99.9, 37.2; HRMS (ESI) m/z:
calcd for C15H12F3N2O [M + H]+, 293.0902; found, 293.0872.
3-(4-(Methylthio)phenyl)-5-(thiazol-2-yl)isoxazole (3m). Yellow
liquid; (230 mg, 80%); Rf 0.48 (1:9 EtOAc/hexane); IR (neat, cm−1):
(d, J = 8.4 Hz, 1H), 7.83 (d, J = 7.8 Hz, 2H), 7.41 (t, J = 7.5 Hz. 1H),
7.08 (t, J = 7.5 Hz, 1H), 7.04 (s, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.99
(d, J = 7.8 Hz, 2H), 3.99 (s, 3H), 3.86 (s, 3H); 13C{H} NMR (150
MHz, CDCl3): δ 170.9, 161.8, 161.4, 132.9, 131.4, 130.5, 129.9,
127.6, 125.4, 123.1, 120.1, 114.6, 96.1, 56.4, 55.9; HRMS (ESI) m/z:
calcd for C17H16NO3 [M + H]+, 282.1130; found, 282.1106.
1
3255, 3001, 1669, 1596, 1543, 755; H NMR (400 MHz, CDCl3): δ
8.01 (d, J = 3.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 3.2 Hz,
1H), 7.34 (d, J = 8.4 Hz, 2H), 7.16 (s, 1H), 2.54 (s, 3H); 13C{H}
NMR (100 MHz, CDCl3); 164.5, 162.8, 154.4, 144.5, 141.9, 127.2,
126.3, 124.8, 121.4, 99.7, 15.3; HRMS (ESI) m/z: calcd for
C13H11N2OS2 [M + H]+, 275.0313; found, 275.0287.
3-(2-((4-Methoxybenzyl)oxy)phenyl)-5-(pyridin-4-yl)isoxazole
(3g). Yellow solid (230 mg, 84%); mp 130−131 °C; Rf 0.45 (2:8
1
EtOAc/hexane); IR (neat, cm−1): 3109, 2945, 1675, 1558, 1213; H
NMR (400 MHz, CDCl3): δ 8.71 (dd, J = 4.6, 1.8 Hz, 2H), 8.01 (dd,
J = 7.6, 1.6 Hz, 1H), 7.55 (dd, J = 4.6, 1.8 Hz, 2H), 7.43−7.41 (m,
1H), 7.39 (d, J = 8.8 Hz, 2H), 7.37 (s, 1H), 7.18−7.09 (m, 2H),
7.07−6.93 (m, 2H), 5.12 (s, 2H), 3.83 (s, 3H); 13C{H} NMR (100
MHz, CDCl3): δ 166.4, 160.7, 159.7, 156.5, 150.7, 134.5, 131.5,
129.3, 129.2, 128.5, 121.4, 119.4, 117.8, 114.1, 113.2, 103.9, 70.7,
55.3; HRMS (ESI) m/z: calcd for C22H19N2O3 [M + H]+, 359.1396;
found, 359.0688.
2-(5-(Pyridin-4-yl)isoxazol-3-yl)phenol (3g′). Orange solid (250
mg, 95%); mp 127−128 °C; Rf 0.62 (2:8 EtOAc/hexane); IR (neat,
cm−1): 3540, 3109, 2945, 1675, 1558; 1H NMR (400 MHz, CDCl3):
δ 10.33 (br s, 1H), 8.88 (s, 2H), 8.06 (d, J = 5.6 Hz, 2H), 7.76 (s,
1H), 7.78 (dd, J = 7.8, 6.2 Hz, 1H), 7.36 (td, J = 8.6, 1.8 Hz, 1H),
7.06 (d, J = 8.0 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H); 13C{H} NMR (100
MHz, CDCl3): δ 165.6, 161.1, 155.6, 149.1, 135.1, 131.6, 128.6,
120.2, 119.4, 116.6, 114.6, 104.9; HRMS (ESI) m/z: calcd for
C14H11N2O2 [M + H]+, 239.0821; found, 239.0795.
5-(1-Methyl-1H-indol-2-yl)-3-phenylisoxazole (3n). Yellow liquid
(220 mg, 82%); Rf 0.51 (1:9 EtOAc/hexane); IR (neat, cm−1): 3255,
1
3001, 1669, 1596, 1543, 755; H NMR (400 MHz, CDCl3): δ 8.24
(d, J = 7.2 Hz, 1H), 7.86 (dd, J = 8.2, 1.4 Hz, 2H), 7.52 (s, 1H),
7.51−7.44 (m, 3H), 7.39−7.27 (m, 3H), 6.79 (s, 1H), 3.85 (s, 3H);
13C{H} NMR (100 MHz, CDCl3): δ 168.9, 158.8, 137.4, 129.9,
128.9, 127.8, 125.8, 125.7, 122.7, 121.7, 120.9, 109.6, 104.9, 97.6,
33.1; HRMS (ESI) m/z: calcd for C18H15N2O [M + H]+, 275.1184;
found, 275.1187.
5-(1-Methyl-1H-indol-3-yl)-5-(pyridin-3-yl)isoxazole (3o). Yellow
liquid (245 mg, 84%); Rf 0.48 (1:9 EtOAc/hexane); IR (neat, cm−1):
1
3255, 3001, 1669, 1596, 1543, 755; H NMR (400 MHz, CDCl3): δ
9.08 (d, J = 2.0, 1H), 8.68 (d, J = 3.6 Hz, 1H), 8.22 (dd, J = 7.0, 1.4
Hz, 1H), 8.16 (dt, J = 7.6, 1.9 Hz, 1H), 7.55 (s, 1H), 7.46−7.28 (m,
4H), 6.89 (s, 1H), 3.87 (s, 3H); 13C{H} NMR (100 MHz, CDCl3): δ
166.1, 158.9, 150.7, 147.0, 137.5, 132.9, 129.2, 125.6, 124.0, 123.8,
122.9, 121.6, 121.1, 109.6, 104.5, 98.6, 33.2; HRMS (ESI) m/z: calcd
for C17H14N3O [M + H]+, 276.1136; found, 276.1138.
5-(4-Chlorophenyl)-3-(thiophen-2-yl)isoxazole (3h). Orange solid
(215 mg, 78%); mp 103−105 °C; Rf 0.48 (1:9 EtOAc/hexane); IR
1
(neat, cm−1): 3111, 2952, 1557, 1081, 755; H NMR (400 MHz,
CDCl3): δ 7.76 (d, J = 8.4 Hz, 2H), 7.52 (dd, J = 3.6, 1.2 Hz, 1H),
7.46 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 1.2 Hz, 1H), 7.14 (dd, J = 5.2,
3.6 Hz, 1H), 6.74 (s, 1H); 13C{H} NMR (100 MHz, CDCl3): δ
169.3, 158.3, 136.5, 130.6, 129.4, 127.74, 127.70, 127.5, 127.1, 125.7,
97.8; HRMS (ESI) m/z: calcd for C13H9ClNOS [M + H]+, and [M +
H + 2]+, 262.0093 and 264.0093; found, 262.0063.
5-(Pyren-1-yl)-3-(thiophen-2-yl)isoxazole (3i). Yellow solid (235
mg, 90%); mp 124−126 °C; Rf 0.52 (1:9 EtOAc/hexane); IR (neat,
cm−1): 3100, 2885, 1650, 1532, 956; 1H NMR (400 MHz, CDCl3): δ
8.61 (d, J = 9.2 Hz, 1H), 8.29 (d, J = 8.0 Hz, 1H), 8.24−8.15 (m,
4H), 8.13 (s, 1H), 8.08−8.05 (m, 2H), 7.62 (d, J = 2.4 Hz, 1H), 7.49
(d, J = 6.4 Hz, 1H), 7.19 (dd, J = 5.2, 3.6 Hz, 1H), 6.95 (s, 1H);
13C{H} NMR (100 MHz, CDCl3): δ 171.1, 158.1, 132.7, 131.2,
130.9, 130.6, 129.2, 128.9, 128.7, 127.74, 127.69, 127.5, 127.2, 126.65,
126.42, 126.13, 125.9, 124.9, 124.7, 124.4, 124.1, 121.5, 101.9; HRMS
(ESI) m/z: calcd for C23H14NOS [M + H]+, 352.0796; found,
352.0737.
N,N-Dimethyl-4-(5-(pyridin-3-yl)isoxazol-3-yl)aniline (3p). Yel-
low solid (254 mg, 88%); mp 121−123 °C; Rf 0.46 (2:8 EtOAc/
1
hexane); IR (neat, cm−1): 3255, 3001, 1669, 1596, 1543, 755; H
NMR (600 MHz, CDCl3): δ 9.06 (s, 1H), 8.69 (d, J = 3.6 Hz, 1H),
8.19 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 9.0 Hz, 2H), 7.41 (dd, J = 7.8,
4.8 Hz, 1H), 6.76 (d, J = 9.0 Hz, 2H), 6.65 (s, 1H), 3.05 (s, 6H);
13C{H} NMR (150 MHz, CDCl3): δ 171.9, 160.4, 151.7, 150.9,
148.1, 134.1, 127.3, 125.9, 123.8, 114.9, 111.9, 94.3, 40.3; HRMS
(ESI) m/z: calcd for C16H16N3O [M + H]+, 266.1293; found,
266.1276.
3,5-Di(pyridin-3-yl)isoxazole (3q). Yellow liquid (260 mg, 79%);
Rf 0.48 (1:9 EtOAc/hexane); IR (neat, cm−1): 3255, 3001, 1669,
1596, 1543, 755; 1H NMR (400 MHz, CDCl3): δ 9.09 (d, J = 3.6 Hz,
2H), 8.72 (d, J = 4.8 Hz, 2H), 8.22 (dt, J = 8.0, 2.0 Hz, 1H), 8.16 (dt,
J = 8.0, 2.0 Hz, 1H), 7.49−7.44 (m, 2H), 6.98 (s, 1H); 13C{H} NMR
(100 MHz, CDCl3): δ 168.3, 160.7, 151.3, 147.9, 147.1, 144.9, 134.1,
133.0, 123.9, 123.5, 98.2; HRMS (ESI) m/z: calcd for C13H10N3O [M
+ H]+, 224.0824; found, 224.0825.
5-(tert-Butyl)-3-(thiophen-2-yl)isoxazole (3j). Yellow liquid (245
mg, 92%); Rf 0.48 (1:9 EtOAc/hexane); IR (neat, cm−1): 3255, 3001,
5-Methyl-3-phenylisoxazole (3r).4b Yellow oil (215 mg, 86%); Rf
1
1
1669, 1596, 1543, 755; H NMR (400 MHz, CDCl3): δ 7.43 (d, J =
0.36 (1:9 EtOAc/hexane); H NMR (400 MHz, CDCl3): δ 7.72−
3.6 Hz, 1H), 7.39 (d, J = 5.2 Hz, 1H), 7.09 (dd, J = 4.8, 3.6 Hz, 1H),
7.69 (m, 2H), 7.37−7.35 (m, 3H), 6.21 (s, 1H), 2.47 (s, 3H); 13C{H}
NMR (100 MHz, CDCl3): δ 168.9, 161.5, 128.8, 128.3, 127.8, 125.7,
6.17 (s, 1H), 1.35 (s, 9H); 13C{H} NMR (100 MHz, CDCl3): δ
K
https://dx.doi.org/10.1021/acs.joc.0c02216
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
98.7, 11.3; HRMS (ESI) m/z: calcd for C10H10NO [M + H]+,
160.0762; found, 160.0747.
NMR (400 MHz, CDCl3): δ 15.2 (br, 1H), 7.83 (dd, J = 7.6, 2.0 Hz,
1H), 7.36 (td, J = 7.2, 2.0 Hz, 1H), 7.28 (s, 1H), 6.97 (td, J = 7.6, 1.8
Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 3.81 (s, 3H), 2.57 (s, 3H); 13C{H}
NMR (100 MHz, CDCl3): δ 214.7, 167.6, 157.9, 132.8, 130.2, 123.1,
120.9, 113.0, 111.8, 55.5, 17.2; HRMS (ESI) m/z: calcd for
C11H13O2S2 [M + H]+, 241.0357; found, 241.0367.
General Procedure for the Reaction of β-Oxodithioesters 9
with Sodium Azide: Synthesis of β-Oxoacetonitriles 11. To a
stirred suspension of NaN3 (130 mg, 1.0 mmol) in DMF (3 mL), a
solution of β-oxodithioester (1.0 mmol) in DMF (3 mL) was added
dropwise at room temperature under an N2 atmosphere, and the
reaction mixture was heated 90 °C in an oil bath for 2 h (monitored
by TLC) with continuous stirring. It was then quenched with
saturated NH4Cl solution (25 mL), extracted with EtOAc (3 × 25
mL), the combined organic layer was washed with water (3 × 25 mL)
and brine (25 mL), dried (Na2SO4), and evaporated under vacuum to
give products 11, which were further purified by column
chromatography using hexane/ethyl acetate as eluent.
3-(4-Methoxyphenyl)-5-methylisoxazole (3s).4b Pale yellow solid
1
(200 mg, 92%); mp 84−87 °C; Rf 0.34 (1:9 EtOAc/hexane); H
NMR (400 MHz, CDCl3): δ 7.69 (d, J = 8.8 Hz, 2H); 6.93 (d, J = 8.8
Hz, 2H), 6.19 (s, 1H), 3.82 (s, 3H), 2.45 (s, 3H); 13C{H} NMR (100
MHz, CDCl3): δ 169.6, 162.1, 160.4, 128.4, 121.5, 114.6, 101.6, 55.3,
12.2; HRMS (ESI) m/z: calcd for C11H12NO2 [M + H]+, 190.0868;
found, 190.0854.
5-Methyl-3-(thiophen-2-yl)isoxazole (3t).4b Yellow oil (230 mg,
1
79%); Rf 0.35 (1:9 EtOAc/hexane); H NMR (400 MHz, DMSO-
d6): δ 7.69 (dd, J = 5.2, 1.2 Hz, 1H), 7.63 (dd, J = 3.8, 1.4 Hz, 1H),
7.19 (dd, J = 5.2, 3.6 Hz, 1H), 6.71 (s, 1H), 2.45 (s, 3H); 13C{H}
NMR (100 MHz, DMSO-d6): δ 170.2, 157.4, 130.2, 128.4, 128.3,
127.9, 99.9, 11.8; HRMS (ESI) m/z: calcd for C8H8NOS [M + H]+,
166.0327; found, 166.0321.
General Procedure for the Synthesis of 3-(Het)aryl-5-styryl/
aryldienyl Isoxazoles 8. To a stirred solution of β-(methylthio)-β-
(het)aryl-3-styrl/aryldienyl-1-propen-3-ones 7 (1.0 mmol) in DMSO
(5 mL), sodium azide (130 mg, 2.0 mmol) was added and the
reaction mixture was heated at 100 °C in an oil bath for 10 h
(monitored by TLC). The reaction mixture was then cooled at rt,
quenched with saturated NH4Cl solution (25 mL), and extracted with
EtOAc (3 × 25 mL); the organic phase was washed with water (2 ×
25 mL) and brine (1 × 25 mL), dried (Na2SO4), and evaporated
under reduced pressure to give crude products 8, which were purified
by column chromatography on silica gel using hexane/ethyl acetate as
eluent.
3-(4-Methoxyphenyl)-3-oxopropanenitrile (11a). Pale yellow
solid (220 mg, 80%); mp 132−137 °C (mp 132−137 °C);17 Rf
0.32 (2:9 EtOAc/hexane); 1H NMR (600 MHz, CDCl3): δ 7.89 (d, J
= 9.0 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 4.02 (s, 2H), 3.89 (s, 3H);
13C{H} NMR (150 MHz, CDCl3): δ 185.5, 164.8, 130.5, 124.9,
114.4, 114.2, 55.8, 26.3; HRMS (ESI) m/z: calcd for C10H10NO2 [M
+ H]+, 176.0706; found, 176.0701.
3-Oxo-3-(4-(trifluoromethyl)phenyl)propanenitrile (11b). Yellow
solid (200 mg, 70%); mp 104−106 °C (mp 104−106 °C);17 Rf 0.35
(2:9 EtOAc/hexane); 1H NMR (600 MHz, CDCl3): δ 8.02 (d, J = 8.4
Hz, 2H), 7.79 (d, J = 7.8 Hz, 2H); 13C{H} NMR (150 MHz, CDCl3):
δ 186.5, 136.9, 136.4, 136.1, 135.7, 135.4, 128.9, 127.8, 127.3, 126.3,
126.2, 124.6, 121.9, 113.3, 29.7; HRMS (ESI) m/z: calcd for
C10H6F3NO [M]+, 213.0401; found, 213.0429.
3-(Naphthalen-2-yl)-3-oxopropanenitrile (11c). White solid (210
mg, 76%); mp 100−101 °C (mp 100−101 °C);17 Rf 0.31 (2:9
EtOAc/hexane); 1H NMR (400 MHz, CDCl3): δ 8.39 (s, 1H), 7.98−
7.89 (m, 4H), 7.66 (t, J = 7.6, Hz, 1H), 7.59 (t, J = 7.6, Hz, 1H), 4.21
(s, 2H); 13C{H} NMR (100 MHz, CDCl3): δ 185.6, 136.2, 132.3,
131.7, 130.7, 129.8, 129.5, 129.2, 127, 127.4, 123.4, 113.9, 29.9;
HRMS (ESI) m/z: calcd for C13H9NNaO [M + Na]+, 218.0576;
found, 218.0563.
(E)-3-(4-Methoxyphenyl)-5-styrylisoxazole (8a). Yellow viscous
liquid (234 mg, 80%); Rf 0.51 (1:9 EtOAc/hexane); IR (neat, cm−1):
1
3255, 3001, 1669, 1596, 1543, 755; H NMR (600 MHz, CDCl3): δ
7.77 (d, J = 9.0 Hz, 2H), 7.54 (d, J = 7.2 Hz, 2H), 7.41−7.39 (m,
3H), 7.37−7.33 (m, 1H), 7.02−6.98 (m, 3H), 6.53 (s, 1H), 3.87 (s,
3H); 13C{H} NMR (150 MHz, CDCl3): δ 168.4, 162.1, 154.9, 135.6,
134.9, 130.1, 128.9, 128.3, 127.2, 114.9, 114.4, 109.6, 99.4, 55.5;
HRMS (ESI) m/z: calcd for C18H16NO2 [M + H]+, 278.1181; found,
278.1161.
(E)-5-(4-Bromostyryl)-3-(4-methoxyphenyl)isoxazole (8b). White
solid (200 mg, 75%); mp 105−106 °C; Rf 0.41 (1:9 EtOAc/hexane);
1
IR (neat, cm−1): 3255, 3001, 1669, 1596, 1543, 755; H NMR (600
3-Oxo-3-(thiophen-2-yl)propanenitrile (11d). Off-white solid
(235 mg, 74%); mp 98−100 °C (mp 98−100 °C);17 Rf 0.33 (2:9
EtOAc/hexane); 1H NMR (600 MHz, CDCl3): δ 7.79 (m, 2H),
7.19−7.18 (m, 1H), 3.99 (s, 2H); 13C{H} NMR (150 MHz, CDCl3):
δ 179.5, 140.9, 136.2, 133.7, 128.7, 113.4, 29.5; HRMS (ESI) m/z:
calcd for C7H6NOS [M + H]+, 152.0170; found, 152.0182.
3-(2-Methoxyphenyl)-3-oxopropanenitrile (11e). White solid
(250 mg, 72%); mp 102−104 °C (mp 102−104 °C); Rf 0.32 (2:9
MHz, CDCl3): δ 7.79 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H),
7.59 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 16.2 Hz, 1H), 7.31 (d, J = 16.2
Hz, 1H), 7.09 (s, 1H), 7.04 (d, J = 8.4 Hz, 2H), 3.79 (s, 3H); 13C{H}
NMR (150 MHz, CDCl3): δ 168.9, 162.5, 161.3, 135.2, 133.7, 132.4,
129.8, 128.6, 122.9, 121.4, 115.1, 114.8, 100.7, 55.9; HRMS (ESI) m/
z: calcd for C18H15BrNO2 [M + H]+, 356.0286 and [M + H + 2]+,
358.0286; found, 356.0321, 358.0312.
(E)-3-(4-Methoxyphenyl)-5-(2-(thiophen-2-yl)vinyl)isoxazole
(8c). White solid (226 mg, 68%); mp 108−109 °C; Rf 0.41 (1:9
EtOAc/hexane); IR (neat, cm−1): 3255, 3001, 1669, 1596, 1543, 755;
1H NMR (600 MHz, CDCl3): δ 7.76 (d, J = 7.8 Hz, 2H), 7.48 (d, J =
15.6 Hz, 1H), 7.32 (d, J = 4.8 Hz, 1H), 7.19 (d, J = 4.2 Hz, 1H), 7.06
(d, J = 7.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 15.6 Hz,
1H), 6.48 (s, 1H), 3.86 (s, 3H); 13C{H} NMR (150 MHz, CDCl3): δ
168.3, 162.5, 161.1, 141.1, 129.3, 128.3, 127.7, 126.7, 121.6, 114.5,
114.3, 112.4, 99.3, 56.3; HRMS (ESI) m/z: calcd for C16H14NO2S [M
+ H]+, 284.0745; found, 284.0725.
1
EtOAc/hexane); H NMR (400 MHz, CDCl3): δ 7.86 (dd, J = 7.6,
1.6 Hz, 1H), 7.57 (td, 7.9, 1.7 Hz, 1H), 7.07−7.01 (m, 2H), 4.08 (s,
2H), 3.97 (s, 3H); 13C{H} NMR (100 MHz, CDCl3): δ 188.1, 159.2,
135.7, 131.4, 124.5, 121.2, 114.6, 111.8, 55.8, 34.1; HRMS (ESI) m/z:
calcd for C10H10NO2 [M + H]+, 176.0712; found, 176.0710.
ASSOCIATED CONTENT
■
sı
* Supporting Information
5-(1E,3E)-4-Phenylbuta-1,3-(dien-1-yl)-3-(thiophen-2-yl)-
isoxazole (8d). Yellow solid (212 mg, 67%); mp 107−108 °C; Rf 0.43
(1:9 EtOAc/hexane); IR (neat, cm−1): 3255, 3001, 1669, 1596, 1543,
755; 1H NMR (400 MHz, CDCl3): δ 7.47−7.41 (m, 3H), 7.38−7.34
(m, 2H), 7.29 (d, J = 6.4 Hz, 1H), 7.21−7.11 (m, 2H), 6.94 (d, J = 10
Hz, 1H), 6.90 (d, J = 5.12 Hz, 1H), 6.84 (d, J = 15.6 Hz, 1H), 6.54
(d, J = 15.2 Hz, 1H) 6.44 (s, 1H); 13C{H} NMR (100 MHz, CDCl3):
δ 168.9, 157.9, 137.4, 136.5, 135.6, 130.9, 128.8, 128.6, 127.6, 127.5,
127.4, 127.3, 126.9, 116.0, 99.2; HRMS (ESI) m/z: calcd for
C17H14NOS [M + H]+, 280.0796; found, 280.0803.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02216.
Copies of 1H NMR, 13C NMR, and spectra of
compounds 2b−2t, 6a−6b, 7a−7d, 3a−3t, 8a−8d, 9e,
and 11a−11e (PDF)
Accession Codes
CCDC 1983738 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
Methyl 3-(2-Methoxyphenyl)-3-oxopropanedithioate (9e).
Yellow solid (220 mg, 78%); mp 95−97 °C; Rf 0.34 (1:9 EtOAc/
1
hexane); IR (neat, cm−1): 3255, 3001, 1669, 1596, 1543, 755; H
L
https://dx.doi.org/10.1021/acs.joc.0c02216
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Sun, H.-p. The recent progress of isoxazole in medicinal chemistry.
Bioorg. Med. Chem. 2018, 26, 3065−3075. (c) Zhou, X.; Xu, X.; Shi,
Z.; Liu, K.; Gao, H.; Li, W. Enolate-mediated 1,3-dipolar cyclo-
addition reaction of β-functionalized ketones with nitrile oxides:
direct access to 3,4,5-trisubstituted isoxazoles. Org. Biomol. Chem.
2016, 14, 5246−5250. and references cited therein (d) Mohammed,
S.; Vishwakarma, R. A.; Bharate, S. B. Metal-free DBU promoted
regioselective synthesis of isoxazoles and isoxazolines. RSC Adv. 2015,
5, 3470−3473. and references cited therein (e) Raghava, B.;
Parameshwarappa, G.; Acharya, A.; Swaroop, T. R.; Rangappa, K. S.;
Ila, H. 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 Complemen-
tary Regioselectivity. Eur. J. Org. Chem. 2014, 1882−1892. and
references cited therein (f) Morita, T.; Fuse, S.; Nakamura, H.
Generation of an 4-Isoxazolyl Anion Species: Facile Access to
MultifunctionalizedIsoxazoles. Angew. Chem., Int. Ed. 2016, 55,
13580−13584. and references cited therein
(4) (a) Kadam, K. S.; Gandhi, T.; Gupte, A.; Gangopadhyay, A. K.;
Sharma, R. Alkyl Nitrites: Novel Reagents for One-Pot Synthesis of
3,5-Disubstituted Isoxazoles from Aldoximes and Alkynes. Synthesis
2016, 48, 3996−4008. and references cited therein (b) Dong, K.-Y.;
Qin, H.-T.; Bao, X.-X.; Liu, F.; Zhu, C. Oxime-Mediated Facile Access
to 5-Methylisoxazoles and applications in the Synthesis of Valdecoxib
and Oxacillin. Org. Lett. 2014, 16, 5266−5268. and references cited
therein
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Hiriyakkanavar Ila − New Chemistry Unit, Jawaharlal Nehru
Centre for Advanced Scientific Research, Bangalore 560064,
India; orcid.org/0000-0002-6971-8374; Email: hila@
jncasr.ac.in
Authors
Mary Antony P − New Chemistry Unit, Jawaharlal Nehru
Centre for Advanced Scientific Research, Bangalore 560064,
India
Gantala L. Balaji − New Chemistry Unit, Jawaharlal Nehru
Centre for Advanced Scientific Research, Bangalore 560064,
India
Pethaperumal Iniyavan − New Chemistry Unit, Jawaharlal
Nehru Centre for Advanced Scientific Research, Bangalore
560064, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02216
Notes
(5) Review: (a) Sahani, R. L.; Ye, L.-W.; Liu, R.-S. Synthesis of
Nitrogen-Containing Molecules via Transition Metal-Catalyzed
Reactions on Isoxazoles, Anthranils and Benzoisoxazoles. Advances
in Organometallic Chemistry; Perez, P. J., Ed.; Elsevier Inc., 2019; Vol.
72, pp 1−57. See also. (b) Lohrer, B.; Bracher, F. Novel access to 2-
substituted quinolin-4-ones by nickel boride-mediated reductive ring
transformation of 5-(2-nitrophenyl)isoxazoles. Tetrahedron Lett. 2019,
60, 151327−151330. (c) Galenko, E. E.; Linnik, S. A.; Khoroshilova,
O. V.; Novikov, M. S.; Khlebnikov, A. F. Isoxazole Strategy for the
Synthesis of α-Aminopyrrole Derivatives. J. Org. Chem. 2019, 84,
11275−11285. (d) Galenko, E. E.; Novikov, M. S.; Shakirova, F. M.;
Shakirova, J. R.; Kornyakov, I. V.; Bodunov, V. A.; Khlebnikov, A. F.
Isoxazole Strategy for the Synthesis of 2,2’-Bipyridine Ligands:
Symmetrical and Unsymmetrical 6.6’-Binicotinates, 2,2’-Bipyridine-5-
carboxylates, and Their Metal complexes. J. Org. Chem. 2019, 84,
3524−3536. (e) Charest, M. G.; Lerner, C. D.; Brubaker, J. D.; Siegel,
D. R.; Myers, A. G. A Convergent Enantioselective Route to
Structurally Diverse 6-Deoxytetracycline Antibiotics. Science 2005,
308, 395−398. (f) Manning, J. R.; Davies, H. M. L. One-Pot Synthesis
of Highly Functionalized Pyridines via a Rhodium Carbenoid Induced
Ring Expansion of Isozaxoles. J. Am. Chem. Soc. 2008, 130, 8602−
8603.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge Professor C. N. R. Rao, FRS, for encourage-
ment and support of our research. We thank University Grants
Commission (UGC, New Delhi) for UGC-SRF (to M.A.P.),
Science and Engineering Research Board (SERB, New Delhi)
for National Post-doctoral fellowship (NPDF) (to P.I. and
G.L.B.), and JNCASR for Hindustan Lever Research
Professorship (to H.I.).
DEDICATION
■
This paper is dedicated to Prof. Paul Knochel on the occasion
of his 65th Birthday.
REFERENCES
■
(1) Recent reviews: (a) Morita, T.; Yugandar, S.; Fuse, S.;
Nakamura, H. Recent progresses in the synthesis of functionalized
isoxazoles. Tetrahedron Lett. 2018, 59, 1159−1171. and references
therein (b) Hu, F.; Szostak, M. Recent Developments in the Synthesis
and Reactivity of Isoxazoles: Metal Catalysis and Beyond. Adv. Synth.
Catal. 2015, 357, 2583−2614. (c) Pinho e Melo, T. Recent Advances
on the Synthesis and Reactivity of Isoxazoles. Curr. Org. Chem. 2005,
9, 925−958. (d) Vitale, P.; Scilimati, A. Five-membered ring
heterocycles by reacting enolates with dipoles. Curr. Org. Chem.
2013, 17, 1986−2000. (e) Cicchi, S.; Cordero, F. M.; Giomi, D. Five-
Membered Ring Systems with O and N Atoms. In Progress in
Heterocyclic Chemistry; Gribble, G., Joule, J., Eds.; Elsevier:
Amsterdam, 2011; Vol. 23, pp 303−320.
(6) (a) Svejstrup, T. D.; Zawodny, W.; Douglas, J. J.; Bidgeli, D.;
Sheikh, N. S.; Leonori, D. Visible-light-mediated generation of nitrile
oxides for the photoredox synthesis of isoxazolines and isoxazoles.
Chem. Commun. 2016, 52, 12302−12305. and references cited
́
therein (b) Poh, J.-S.; García-Ruiz, C.; Zuniga, A.; Meroni, F.;
̃
Blakemore, D. C.; Browne, D. L.; Ley, S. V. Synthesis of
trifluoromethylated isoxazoles and their elaboration through inter-
and intra-molecular C-H arylation. Org. Biomol. Chem. 2016, 14,
5983−5991. (c) Kesornpun, C.; Aree, T.; Mahidol, C.; Ruchirawat,
S.; Kittakoop, P. Water-Assisted Nitrile Oxide Cycloadditions:
Synthesis of Isoxazoles and Stereoselective Syntheses of Isoxazolines
and 1,2,4-Oxadiazoles. Angew. Chem., Int. Ed. 2016, 55, 3997−4001. .
See also: (d) Chalyk, B. A.; Hrebeniuk, K. V.; Gavrilenko, K. S.;
Shablykin, O. V.; Yanshyna, O. O.; Bash, D.; Mykhailiuk, P. K.;
Liashuk, O. S.; Grygorenko, O. O. Synthesis of Bi- and Polyfunctional
Isoxazoles from Amino Acid Derived halogenoximes and Active
Methylene Nitriles. Eur. J. Org. Chem. 2018, 2753−2761. (e) Lai, Z.;
Li, Z.; Liu, Y.; Yang, P.; Fang, X.; Zhang, W.; Liu, B.; Chang, H.; Xu,
H.; Xu, Y. Iron-Mediated Synthesis of Isoxazoles from Alkynes: Using
Iron (III) Nitrate as a Nitration and Cyclization Reagent. J. Org.
Chem. 2018, 83, 145−153. (f) Chalyk, B. A.; Hrebeniuk, K. V.; Fil, Y.
(2) (a) Giomi, D.; Cordero, F.; Machetti, F. In Comprehensive
Heterocyclic Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E.
F. V., Taylor, R. J. K., Joules, J., Eds.; Elsevier: Oxford, U.K., 2008;
Vol. 4, pp 365−378. (b) Sutharchanadevi, M.; Murgan, R. In
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Elsevier: Oxford, U.K., 1996; Vol. 3, pp 221−
2260. (c) See also: Wakefield, B. J. In Science of Synthesis: Houben−
Weyl Methods of Molecular Transformations; Schaumann, E., Ed.;
Georg Thieme Verlag: Stuttgart, 2001; Vol. 11, pp 229−288.
́
(3) Reviews: (a) Sysak, A.; Obminska-Mrukowicz, B. Isoxazole ring
as a useful scaffold in search for new therapeutic agents. Eur. J. Med.
Chem. 2017, 137, 292−309. (b) Zhu, J.; Mo, J.; Lin, H.-z.; Chen, Y.;
M
https://dx.doi.org/10.1021/acs.joc.0c02216
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
V.; Gavrilenko, K. S.; Rozhenko, A. B.; Vashchenko, B. V.; Borysov,
O. V.; Biitseva, A. V.; Lebed, P. S.; Bakanovych, I.; Moroz, Y. S.;
Grygorenko, O. O. Synthesis of 5-(Fluoroalkyl)isoxazole Building
Blocks by Regioselective Reactions of functionalized halogenoximes. J.
Org. Chem. 2019, 84, 15877−15899. (g) Xu, H.; Fan, G.-P.; Liu, Z.;
Wang, G.-W. Catalyst- and solvent-free mechanochemical synthesis of
isoxazoles from N-hydroxybenzimidoylchlorides and enamino carbon-
yl compounds. Tetrahedron 2018, 74, 6607−6611. (h) Iwai, K.;
Asahara, H.; Nishiwaki, N. Synthesis of Functionalized 3-Cyanoisox-
azoles Using a Dianionic Reagent. J. Org. Chem. 2017, 82, 5409−
5415. and references cited therein (i) Studer, A.; Hadida, S.; Ferritto,
R.; Kim, S.-Y.; Jeger, P.; Wipf, P.; Curran, D. P. Fluorous Synthesis: A
Fluorous- Phase Strategy for Improving Separation, Efficiency in
Organic Synthesis. Science 1997, 275, 823−826.
(7) (a) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.;
Noodleman, L.; Sharpless, K. B.; Fokin, V. V. Copper(I)-
CatalyzedSynthesis of Azoles. DFT Study Predicts Unprecedented
Reactivity and Intermediates. J. Am. Chem. Soc. 2005, 127, 210−216.
(b) Hansen, T. V.; Wu, P.; Fokin, V. V. One-Pot Copper(I)-
CatalyzedSynthesis of 3,5-Disubstituted Isoxazoles. J. Org. Chem.
2005, 70, 7761−7764. (c) Kuribayashi, S.; Shida, N.; Inagi, S.;
Fuchigami, T. Synthesis of fluorinated triazole and isoxazole
derivatives by electrochemical fluorination. Tetrahedron 2016, 72,
5343−5349. (d) Grecian, S.; Fokin, V. V. Ruthenium-Catalyzed
Cycloaddition of Nitrile Oxides and Alkynes: Practical Synthesis of
Isoxazoles. Angew. Chem., Int. Ed. 2008, 47, 8285−8287.
(8) (a) Yoshimura, A.; Middleton, K. R.; Todora, A. D.; Kastern, B.
J.; Koski, S. R.; Maskaev, A. V.; Zhdankin, V. V. Hypervalent Iodine
Catalyzed Generation of Nitrile Oxides from Oximes and their
Cycloaddition with Alkenes or Alkynes. Org. Lett. 2013, 15, 4010−
4013. . See also: (b) Minakata, S.; Okumura, S.; Nagamachi, T.;
Takeda, Y. Generation of Nitrile Oxides from Oximes Using t-BuOI
and Their Cycloaddition. Org. Lett. 2011, 13, 2966−2969.
(9) (a) Nieto, C. I.; Cornago, M. P.; Cabildo, M. P.; Sanz, D.;
Claramunt, R. M.; Torralba, M. C.; Elguero, J. Synthesis, structure
and NMR study of fluorinated isoxazoles derived from hemi-
curcuminoids. J. Fluorine Chem. 2019, 219, 39−49. (b) Silva, R. G.
M.; da Silva, M. J. V.; Jacomini, A. P.; Moura, S.; Back, D. F.; Basso, E.
A.; Rosa, F. A. Development of methodologies for the regioselective
synthesis of four series of regioisomer isoxazoles from β-enamino
diketones. RSC Adv. 2018, 8, 4773−4778. (c) Harigae, R.; Moriyama,
K.; Togo, H. Preparation of 3,5-Disubstituted Pyrazoles and
Isoxazoles from Terminal Alkynes, Aldehydes, Hydrazines, and
Hydroxylamine. J. Org. Chem. 2014, 79, 2049−2058. (d) Pei, Y.;
Wickham, B. O. S. Regioselective synthesis of 3-aminomethyl-5-
substituted isoxazoles: A facile and chemoselective reduction of azide
to amine by sodium borohydride using 1,3-propanedithiol as catalyst.
Tetrahedron Lett. 1993, 34, 7509−7512.
ref cited therein. See also: (c) Tu, K. N.; Hirner, J. J.; Blum, S. A.
Oxyboration with and without a Catalyst: Borylated Isoxazoles via B-
O σ-Bond Addition. Org. Lett. 2016, 18, 480−483. . See also:
(d) Sau, P.; Santra, S. K.; Rakshit, A.; Patel, B. K. tert-Butyl Nitrite-
Mediated Domino Synthesis of Isoxazolines and Isoxazoles from
Terminal Aryl Alkenes and Alkynes. J. Org. Chem. 2017, 82, 6358−
6365.
(12) (a) Anand, D.; Patel, O. P. S.; Maurya, R. K.; Kant, R.; Yadav,
P. P. Substrate Controlled Synthesis of Benzisoxazole and
Benzisothiazole Derivatives via PhI(OAc)2-Mediated Oxidation
Followed by Intramolecular Oxidative O-N/S-N Bond Formation. J.
Org. Chem. 2015, 80, 12410−12419. and references cited therein
(b) Prakash, O.; Saini, R. K.; Singh, S. P.; Varma, R. S. Hypervalent
iodine oxidation of o-aminochalcones: A novel synthesis of 3-(β-
styryl)-2,1-benzisoxazoles. Tetrahedron Lett. 1997, 38, 3147−3150.
(c) Stokes, B. J.; Vogel, C. V.; Urnezis, L. K.; Pan, M.; Driver, T. G.
Intramolecular Fe(II)-Catalyzed N-O or N-N Bond Formation from
Aryl Azides. Org. Lett. 2010, 12, 2884−2887. (d) Smith, P. A. S.;
Brown, B. B.; Putney, R. K.; Reinisch, R. F. TheSynthesis of
Heterocyclic Compounds from Aryl Azides. III. Some Six membered
Rings and Some Azidobiaryls. J. Am. Chem. Soc. 1953, 75, 6335−
6337.
(13) (a) Zheng, Y.; Yang, C.; Zhang-Negrerie, D.; Du, Y.; Zhao, K.
One-pot synthesis of isoxazoles from enaminones: an application of
Fe(II) as the catalyst for ring expansion of 2H-azirine intermediates.
Tetrahedron Lett. 2013, 54, 6157−6160. and references therein
(b) Singh, B.; Zweig, A.; Gallivan, J. B. Wavelength-Dependent
Photochemistry of 2-Aroyl-3-aryl-2H-azirines. Mechanistic Studies. J.
Am. Chem. Soc. 1972, 94, 1199−1206. (c) Padwa, A.; Stengel, T.
Transition metal-catalyzed ring opening reactions of 2-phenyl-3-vinyl
substituted 2H-azirines. Tetrahedron Lett. 2004, 45, 5991−5993.
(d) Brahma, S.; Ray, J. K. Synthesis of Azirines Containing Aldehyde
Functionality and their Utilization as Synthetic Tools for Five
Membered Oxazoles and Isoxazoles. J. Heterocycl. Chem. 2008, 45,
311−317.
(14) (a) Auricchio, S.; Bini, A.; Pastormerlo, E.; Truscello, A. M.
Iron Dichloride Induced Isomerization or Reductive Cleavage of
Isoxazoles: AFacileSynthesis of 2-Carboxy-azirines. Tetrahedron 1997,
53, 10911−10920. . See also: (b) Serebryannikova, A. V.; Galenko, E.
E.; Novikov, M. S.; Khlebnikov, A. F. Synthesis of Isoxazole-and
Oxazole-4-carboxylic Acids Derivatives by Controlled Isoxazole-
Azirine-Isoxazole/Oxazole Isomerization. J. Org. Chem. 2019, 84,
15567−15577. (c) Li, C.; Yuan, J.; Zhang, Q.; Bhujanga Rao, C.;
Zhang, R.; Zhao, Y.; Deng, B.; Dong, D. Oxidative Cyclization of β-
AminoacrylamidesMediated by PhIO: ChemoselectiveSynthesis of
Isoxazoles and 2H-Azirines. J. Org. Chem. 2018, 83, 14999−15008.
(15) (a) Kumar, G. R.; Kumar, Y. K.; Reddy, M. S. A direct access to
isoxazoles from ynones using trimethylsilyl azide as amino surrogate
under metal/catalyst free conditions. Chem. Commun. 2016, 52,
6589−6592. . See also: (b) Andreev, M. V.; Medvedeva, A. S.; Larina,
L. I.; Demina, M. M. Synthesis of 5-aminoisoxazoles from 3-
trimethylsilylprop-2-ynamides. Mendeleev Commun. 2017, 27, 175−
177. (c) Ning, Y.; Otani, Y.; Ohwada, T. Contrasting C- and O-Atom
Reactivities of Neutral Ketone and Enolate Forms of 3-Sulphonylox-
yimino-2-methyl-1-phenyl-1-butanones. J. Org. Chem. 2018, 83, 203−
219.
(10) (a) Gao, W.-C.; Cheng, Y.-F.; Chang, H.-H.; Li, X.; Wei, W.-L.;
Yang, P. Synthesis of 4-Sulfenyl Isoxazoles through AlCl3-Mediated
Electrophilic Cyclization and Sulfenylation of 2-Alkyn-1-one O-
Methyloximes. J. Org. Chem. 2019, 84, 4312−4317. and references
cited therein (b) Waldo, J. P.; Larock, R. C. Synthesis of Isozaxoles via
Electrophilic Cyclization. Org. Lett. 2005, 7, 5203−5205. (c) Waldo, J.
P.; Larock, R. C. The Synthesis of Highly Substituted Isoxazoles by
Electrophilic Cyclization: An Efficient Synthesis of Valdecoxib. J. Org.
Chem. 2007, 72, 9643−9647. (d) Liu, X.; Hong, D.; She, Z.; Hersh,
W. H.; Yoo, B.; Chen, Y. Complementary regioselective synthesis of
3,5-disubstituted isoxazoles from ynones. Tetrahedron 2018, 74,
(16) (a) Kumar, S. V.; Yadav, S. K.; Raghava, B.; Saraiah, B.; Ila, H.;
Rangappa, K. S.; Hazra, A. Cyclocondensation of Arylhydrazines with
1,3-Bis(het)arylmonothio-1,3-diketones and 1,3-Bis (het)aryl-3-
(methylthio)-2-propenones: Synthesis of 1-Aryl-3,5-bis(het)-
arylpyrazoles with complementary Regioselectivity. J. Org. Chem.
2013, 78, 4960−4973. (b) Acharya, A.; Parameshwarappa, G.;
Saraiah, B.; Ila, H. Sequential One- Pot Synthesis of Tri-and
Tetrasubstituted Thiophenes and Fluorescent Push- Pull Thiophene
Acrylates involving (Het)aryl Dithioesters as thiocarbonyl Precursors.
J. Org. Chem. 2015, 80, 414−427. (c) Yugandar, S.; Konda, S.;
Parameshwarappa, G.; Ila, H. One-Pot Synthesis of 2,4,5-Trisub-
stituted Imidazoles via [2+2+1] Cycloannulation of 1,3-Bis(het)aryl-
monothio-1,3-diketones,α-Substituted Methylamines and Sodium
6593−6606. (e) Speranca̧ , A.; Godoi, B.; Zeni, G. Iron(III) Chloride/
Diorganyl Diselenides: A Tool for Intramolecular Cyclization of
Alkynone O-Methyloximes. J. Org. Chem. 2013, 78, 1630−1637.
(11) (a) Okitsu, T.; Sato, K.; Potewar, T. M.; Wada, A.
Iodocyclization of Hydroxylamine Derivatives Based on the Control
of Oxidative Aromatization Leading to 2,5-Dihyhydroisoxazoles and
Isoxazoles. J. Org. Chem. 2011, 76, 3438−3449. (b) Gayon, E.;
Quinonero, O.; Lemouzy, S.; Vrancken, E.; Campagne, J.-M.
Transition-Metal-CatalyzedUninterruptedFour-Step Sequence to Ac-
cess Trisubstituted Isoxazoles. Org. Lett. 2011, 13, 6418−6421. and
N
https://dx.doi.org/10.1021/acs.joc.0c02216
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Nitrite through α-Nitrosation of Enaminones. J. Org. Chem. 2016, 81,
5606−5622. (d) Yugandar, S.; Konda, S.; Ila, H. Synthesis of
Substituted Benzo[b]thiophenes via Sequential One-Pot, Copper-
Catalyzed Intermolecular C-S Bond Formation and Palladium-
Catalyzed Intramolecular Arene-Alkene Coupling of Bis(het)aryl/
alkyl-1,3-monothiodiketones and o-Bromoiodoarenes. Org. Lett. 2017,
19, 1512−1515. . See also: (e) Acharya, A.; Gautam, V.; Ila, H.
Synthesis of Thieno-Fused Five- and Six-Membered Nitrogen and
Oxygen Heterocycles via Intramolecular Heteroannulation of 4,5-
Substituted3-Amino or 3-Hydroxy 2-Functionalized Thiophenes. J.
Org. Chem. 2017, 82, 7920−7938.
(17) Li, J.; Ma, W.; Ming, W.; Xu, C.; Wei, N.; Wang, M. Divergent
Reactivity in the Reaction of β-Oxodithioesters and Hydroxylami-
ne:Access to β-Ketonitriles and Isoxazoles. J. Org. Chem. 2015, 80,
11138−11142. and references cited therein
(18) Thotutumkara, A. P.; Bowsher, A. P.; Vinod, T. K. In Situ
Generation of o-Iodoxybenzoic acid (IBX) and the Catalytic Use of it
in Oxidation Reaction in the Presence of Oxone as a Co-oxidant. Org.
Lett. 2005, 7, 2933−2936.
(19) Andrews, P. C.; Blair, V. L.; Ferrero, R. L.; Junk, P. C.;
Kedzierski, L.; Peiris, R. M. Bismuth(III) β-thioxoketonates as
antibiotics against Helicobacter pylori and as anti-leishmanial agents.
Dalton Trans. 2014, 43, 1279−1291.
(20) (a) Mathew, P.; Asokan, C. V. Cyclization of functionalized
ketene-N,S-acetals to substituted pyrroles: applications in the
synthesis of marine pyrrole alkaloids. Tetrahedron Lett. 2005, 46,
475−478. (b) Singh, G.; Bhattacharjee, S. S.; Ila, H.; Junjappa, H. A
Facile One-Step Synthesis of Methyl β-Oxodithiocarboxylates.
Synthesis 1982, 693−694.
O
https://dx.doi.org/10.1021/acs.joc.0c02216
J. Org. Chem. XXXX, XXX, XXX−XXX