One-pot three-component heteroannulation of β-oxo dithioesters, amines and hydroxylamine: Regioselective, facile and straightforward entry to 5-substituted 3-aminoisoxazoles

Article abstract of DOI:10.1002/ejoc.201300038

An efficient and highly regioselective one-pot three-component synthesis of previously inaccessible and synthetically demanding 3-(cycloalkyl/alkyl/ arylamino)-5-aryl/alkylisoxazoles has been achieved by the cyclocondensation of β-oxo dithioesters, amines and hydroxylamine in ethanol at reflux. This transformation proceeds via an in situ generated β-oxothioamide by the reaction of the β-oxo dithioester and amine, which undergoes nucleophilic attack by hydroxylamine followed by intramolecular cyclization with the oxo functionality and subsequent dehydration to give 5-substituted 3-aminoisoxazoles as a single regioisomer in good yields. Furthermore, the mechanism of the reaction has been established experimentally and shown to be in agreement with the hard and soft (Lewis) acid and base (HSAB) theory. A highly regioselective synthesis of 5-substituted 3-aminoisoxazoles has been achieved by a one-pot three-component coupling of β-oxo dithioesters, amines and hydroxylamine in ethanol at reflux via an in situ generated β-oxo thioamide intermediate. The mechanism of the reaction has been established experimentally and shown to be in agreement with the HSAB theory. Copyright

Full text of DOI:10.1002/ejoc.201300038

Job/Unit: O30038
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Date: 15-05-13 17:21:56
Pages: 7
FULL PAPER
Isoxazole Synthesis
S. Samai, T. Chanda, H. Ila,
M. S. Singh* ..................................... 1–7
One-Pot Three-Component Heteroannul-
ation of β-Oxo Dithioesters, Amines and
Hydroxylamine: Regioselective, Facile and
Straightforward Entry to 5-Substituted 3-
Aminoisoxazoles
A highly regioselective synthesis of 5-sub-
stituted 3-aminoisoxazoles has been
achieved by a one-pot three-component
coupling of β-oxo dithioesters, amines and
hydroxylamine in ethanol at reflux via an
in situ generated β-oxo thioamide inter-
mediate. The mechanism of the reaction
has been established experimentally and
shown to be in agreement with the HSAB
theory.
Keywords: Amines / Multicomponent reac-
tions / Heteroannulation / Heterocycles /
Regioselectivity
0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O30038
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Date: 15-05-13 17:21:56
Pages: 7
S. Samai, T. Chanda, H. Ila, M. S. Singh
FULL PAPER
DOI: 10.1002/ejoc.201300038
One-Pot Three-Component Heteroannulation of β-Oxo Dithioesters, Amines
and Hydroxylamine: Regioselective, Facile and Straightforward Entry to
5-Substituted 3-Aminoisoxazoles
Subhasis Samai,[a] Tanmoy Chanda,[a] Hiriyakkanavar Ila,[b] and Maya Shankar Singh*[a]
Keywords: Amines / Multicomponent reactions / Heteroannulation / Heterocycles / Regioselectivity
An efficient and highly regioselective one-pot three-compo-
nent synthesis of previously inaccessible and synthetically
demanding 3-(cycloalkyl/alkyl/arylamino)-5-aryl/alkylisox-
azoles has been achieved by the cyclocondensation of β-oxo
dithioesters, amines and hydroxylamine in ethanol at reflux.
This transformation proceeds via an in situ generated β-
oxothioamide by the reaction of the β-oxo dithioester and
amine, which undergoes nucleophilic attack by hydroxyl-
amine followed by intramolecular cyclization with the oxo
functionality and subsequent dehydration to give 5-substi-
tuted 3-aminoisoxazoles as a single regioisomer in good
yields. Furthermore, the mechanism of the reaction has been
established experimentally and shown to be in agreement
with the hard and soft (Lewis) acid and base (HSAB) theory.
azoles also serve as versatile building blocks in organic syn-
thesis as they can be converted into several valuable syn-
thons, such as β-hydroxy ketones, β-hydroxy nitriles, γ-
amino alcohols and α,β-unsaturated oximes.[7]
Introduction
Of the five-membered nitrogen heterocycles, isoxazole
and its derivatives have received considerable attention dur-
ing the last few decades because of their rich chemistry[1]
and broad spectrum of pharmacological properties, such as
analgesic, anti-inflammatory, hypoglycemic, anti-bacterial,
antinociceptive and anti-cancer activities.[2] Substituted
isoxazoles, which are embedded as core structures in several
natural products (e.g., ibotenic acid, muscimol and isox-
azole-4-carboxylic acid) and commercial drugs[3] (e.g., val-
decoxib, bradykinin, leflunomide and oxacillins), are im-
portant synthetic targets. Some isoxazole derivatives also
serve as linkers in probes for live cells.[4] Furthermore, isox-
azoles containing aryl and carboxamide groups have been
shown to have potent in vivo anti-thrombotic efficacy and
to be a platelet-activating factor (PAF) antagonist.[4c] In ad-
dition, many substituted isoxazoles are used in the agroch-
emical industry[5] as pesticides and insecticides. Notably,
many isoxazole derivatives have been utilized as semi-con-
ductors, single-walled nanotubes, liquid crystals, chiral li-
gands, scaffolds for peptidomimetics, dyes and high-tem-
perature lubricants.[6] Moreover, suitably substituted isox-
Several elegant approaches to isoxazoles have been re-
ported in the literature, and the major routes typically in-
volve the 1,3-dipolar cycloaddition of alkenes/alkynes and
nitrile oxides,[8] the intramolecular cyclization of ketoximes/
propargylic oximes[9] and the reaction of hydroxylamine
with α-acetylenic ketones/aldehydes, β-oxo esters, α,β-un-
saturated ketones, propargylic alcohols and β-oxo ni-
triles.[10] Although various synthetic methods for the syn-
thesis of disubstituted isoxazoles have been developed,[11]
regioselective control of the functionalization of isoxazole
is still the main concern. Recently, Carreira and co-workers
synthesized substituted isoxazoles by base-mediated re-
arrangement of oxetanes.[12] Delft and co-workers devel-
oped a metal-free regioselective synthesis of 3,5-disubsti-
tuted isoxazoles by the hypervalent iodine-induced cycload-
dition of nitrile oxides to alkynes.[13] Chen and co-workers
revealed a palladium-catalysed cascade cyclization/alkenyl-
ation sequence for the synthesis of 3,4,5-trisubstituted isox-
azoles,[14a] and in a recent paper Xie and co-workers re-
ported the synthesis of 2,3-dihydroxyisoxazoles by domino
reactions in water.[14b] Nitro/dinitro dienes have been suc-
cessfully used to synthesize 3,5-disubstituted isoxaz-
oles.[14c–14h] Despite their high biological activity, there are
very few reports on the synthesis of substituted 3-amino-
isoxazoles,[15] and very few of these methods are general,
regioselective and high yielding, the majority of them not
being very reliable or efficient. Typical problems incurred
in the synthesis of aminoisoxazoles include poor yields,
multiple steps and low selectivity between the formation of
[a] Department of Chemistry, Faculty of Science, Banaras Hindu
University,
Varanasi 221005, India
Fax: +91-542-2368127
E-mail: mssinghbhu@yahoo.co.in
Homepage: Hompage: http:\\drmssinghchembhu.com
[b] New Chemistry Unit, Jawahar Lal Nehru Centre for Advanced
Scientific Research,
Jakkur, Bangalore 560064, India
Fax: +91-80-22082766
E-mail: hila@jncasr.ac.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300038.
2
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Regioselective Synthesis of 5-Substituted 3-Aminoisoxazoles
3-amino- and 5-aminoisoxazoles.[16] Therefore a robust, 71% yield (Scheme 1; Table 1, Entry 1). An alternative step-
practical, catalyst-free, regioselective method for the synthe- wise approach was also performed. Thus, in another experi-
sis of aminoisoxazoles with broad scope is highly desirable. ment, 1a (1.0 equiv.) was treated with morpholine (2a;
The concept of multicomponent reactions (MCRs) in- 1.2 equiv.) in ethanol at reflux for 2 h to afford β-oxo
volving a domino process with at least three different simple thioamide 3aa in 86% yield, which was found to be iden-
substrates has experienced exponential growth over the last tical to our previously reported sample.[20d] Treatment of
decade and emerged as a powerful strategy for the rapid the pure thioamide 3aa with neutral hydroxylamine
generation of molecular complexity and diversity.[17] There
has been a considerable revival of interest in the synthesis
Table 1. One-pot synthesis of 3-alkylamino-5-aryl/alkylisoxazoles
4.
of amino-substituted isoxazoles,[18] because they are key
building blocks in many naturally occurring molecules and
pharmaceutically active synthetic compounds[19] and serve
as useful precursors for condensed bioactive heterocycles.
During the course of our one-pot reactions directed
towards synthetic applications of β-oxo dithioesters in
heterocyclic synthesis,[20] we have developed a highly re-
gioselective one-pot three-component protocol for the facile
synthesis of 5-substituted 3-aminoisoxazoles by the cou-
pling of β-oxo dithioesters, amines and hydroxylamine un-
der mild reaction conditions. The results of these studies
are reported herein.
Results and Discussion
β-Oxo dithioesters are not commercially available and
were prepared according to reported procedures.[21a,21b]
Their use as versatile intermediates in organic synthesis is
well recognized due to the presence of two electrophilic and
three nucleophilic reactive sites, which can be exploited in a
regioselective manner.[20,21] Although isoxazole derivatives
have been synthesized from S,S-/N,S-acetals[22a–22e] and β-
oxo esters,[22f] so far, to the best of our knowledge, there is
no report on the synthesis of isoxazoles from β-oxo dithio-
esters. Therefore, we set out to explore the feasibility of β-
oxo dithioesters as 1,3-dielectrophilic synthons to access
isoxazoles.
Thus, when methyl 3-oxo-3-phenylpropanedithioate (1a;
1.0 equiv.) was treated with morpholine (2a; 1.2 equiv.) and
neutral hydroxylamine (4.0 equiv., generated by the reaction
of equimolar amounts of NH2OH·HCl and KOH in water)
in ethanol at reflux for 2 h (monitored by TLC) in a one-
pot three-component procedure, workup of the reaction
mixture afforded 3-morpholino-5-phenylisoxazole (4aa) in
Scheme 1. One-pot and stepwise syntheses of 3-morpholino-5-
phenylisoxazole (4aa).
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S. Samai, T. Chanda, H. Ila, M. S. Singh
FULL PAPER
(4.0 equiv.) in ethanol at reflux for 2 h furnished isoxazole Table 2. Synthesis of 3-arylamino-5-arylisoxazoles 4.
4aa in a comparable yield (73%) as a single regioisomer
(Scheme 1).
To elaborate the scope of the reaction, the above one-pot
three-component procedure was applied to the synthesis of
other 5-substituted 3-(cycloamino)isoxazoles 4 as single re-
gioisomers in good yields by using various β-oxo dithioes-
ters 1a–h and cyclic secondary or primary aliphatic amines
2a–2f (Scheme 2; Table 1). The reaction tolerated a broad
range of functional groups on both the β-oxo dithioester
and amine. The cyclocondensation protocol was found to
be equally facile with aliphatic β-oxo dithioesters 1g and 1h
derived from isopropyl methyl ketone and tert-butyl methyl
ketone, respectively, and furnished the corresponding 3-cy-
cloamino-5-alkylisoxazoles 4ag and 4bh in yields of 69 and
64% under conditions identical to those described above
(Table 1, Entries 7 and 12).
Scheme 2. Different amine substrates 2 used in the synthesis of 3-
alkylamino-5-aryl/alkylisoxazoles 4.
We then extended our study to aromatic amines with a
view to adding further diversity at the 3-position of the
isoxazole ring. Thus, when β-oxo dithioester 1a was treated
with aniline 2g and NH2OH under the previously described
one-pot conditions, 3-anilino-5-phenylisoxazole (4ga) was
obtained in 66% yield (Table 2, Entry 1). The generality of
the reaction was established by synthesizing 12 different 3-
arylamino-5-arylisoxazoles 4 by cyclocondensation of the
appropriate β-oxo dithioesters 1a–f with aromatic amines
2g–i and hydroxylamine under identical reaction conditions
(Table 2). Notably, the reactions of the aromatic amines
took longer to complete than the reactions with aliphatic
amines.
The structures of all the synthesized isoxazoles 4 were
confirmed by spectral studies, and their regiochemistry was
Figure 1. ORTEP diagrams of 4ac, 4af, 4bh and 4gc.
confirmed by single-crystal X-ray analysis of representative
compounds 4ac, 4af, 4gc and 4bh (Figure 1).[23] Thus, by
using this three-component one-pot procedure, we have
synthesized a small library (32 compounds) of previously
unknown 5-substituted 3-(cycloamino/alkylamino/aryl-
amino)isoxazoles in good yields and with high purity.
quantitative yields with no traces of the desired isoxazoles.
Furthermore, the thioamide 3ai thus obtained was treated
with excess of the neutral hydroxylamine (6.0 equiv.) in eth-
To illustrate the broad synthetic utility and generality of anol at reflux for 18 h, and still no trace of the desired isox-
our developed methodology, we undertook the formal syn- azole was formed, but the thioamide was completely reco-
thesis of annulated isoxazoles. Thus, we treated cyclic β-oxo vered (Scheme 3). The X-ray crystal structure of β-oxo
dithioesters derived from α-tetralone and cyclohexanone (1i thioamide 3ai displays an anti orientation of the carbonyl
and 1j, respectively) with cyclic secondary amines 2a, 2b and thiocarbonyl groups.[23] Thus, it may be inferred that
and 2c separately and hydroxylamine under the previously the formation of isoxazole is not possible due to the orien-
described conditions. Unfortunately, workup of the reaction tation of the carbonyl and thiocarbonyl groups, limiting the
provided the corresponding thioamides 3ai, 3ci and 3bj in scope of the reaction to some extent.
4
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Regioselective Synthesis of 5-Substituted 3-Aminoisoxazoles
of diversity at the 3- and 5-positions. By using this new
protocol, a small library (32 compounds) of hitherto unre-
ported and synthetically demanding 5-substituted 3-amino-
isoxazoles has been achieved, which is useful for the parallel
synthesis of libraries of isoxazole analogues. The mecha-
nism of the reaction has been established experimentally by
the isolation of a thioamide intermediate and shown to be
in agreement with HSAB theory.
Experimental Section
General: All reagents were commercial and purchased from Merck,
Aldrich and Fluka, and were used as received. Solvent ethanol was
dried and distilled according to a conventional procedure. β-Oxo
dithioesters were prepared according to a known procedure.[21a,21b]
1H and 13C NMR spectra were recorded with a JEOL AL 300
FT-NMR spectrometer. Chemical shifts are given as δ values with
reference to tetramethylsilane (TMS) as the internal standard. IR
spectra were recorded with a Varian 3100 FT-IR spectrophotome-
ter. Electrospray ionisation mass spectra were recorded with a
Waters-Q-Tof Premier-HAB213 instrument. XRD data were mea-
sured with an Xcalibur Oxford CCD diffractometer. All the reac-
tions were monitored by TLC on precoated sheets of silica gel G/
UV-254 of 0.25 mm thickness (Merck 60F254) using UV light for
visualization. Melting points were determined with a Buchi B-540
melting point apparatus and are uncorrected.
Scheme 3. Attempted synthesis of annulated isoxazoles.
Based on literature reports and our experimental results,
we propose the reaction mechanism outlined in Scheme 4.
The carbonyl and thiocarbonyl carbon atoms in β-oxo di-
thioester 1 can be regarded as relatively hard and soft elec-
trophilic centres, respectively, because the carbonyl carbon
atom is adjacent to the hard oxygen centre and the thiocarb-
onyl carbon atom is flanked by the soft thiomethyl group.
First, β-oxo dithioester 1 reacts with amine 2 to generate β-
oxo thioamide 3, which was isolated and shown to be the
reactive species in these reactions.[20d] Hydroxylamine hy-
drochloride, being an ambident nucleophile, has been
shown to exist in neutral media at pH = 7 in the NH2OH
form, in which the nitrogen centre is softer as well as more
nucleophilic in nature than the oxygen centre. Next, β-oxo
thioamide 3, behaving as a 1,3-dielectrophilic synthon,
readily undergoes nucleophilic attack by the NH2 group of
the heterobinucleophile NH2OH preferentially at the soft
electrophilic centre of the intermediate β-oxo thioamide 3,
in agreement with the hard and soft (Lewis) acid and base
(HSAB) principle,[24] followed by cyclization with the oxo
functionality and subsequent dehydration via intermediate
4Ј to form the 5-substituted 3-aminoisoxazoles 4.
General Method for the Synthesis of 3-Alkyl/Arylamino-5-alkyl/
arylisoxazoles 4: β-Oxo dithioester 1 (1.0 mmol) was added to dry
ethanol (5 mL) in a 25 mL round-bottomed flask. Cyclic second-
ary/primary alkyl/arylamine 2 (1.2 mmol) was added, and the reac-
tion mixture was heated at reflux for 1–10 h. When β-oxo dithio-
ester 1 had been fully converted into the corresponding β-oxo di-
thiamide
3
(reaction monitored by TLC), hydroxylamine
(4.0 mmol; generated from 4.0 mmol of NH2OH·HCl and
4.0 mmol KOH in 2 mL of water) was added to the reaction mix-
ture, which was heated at reflux for a further 2–4 h. The ethanol
was removed under vacuum, and water (20 mL) was added to the
residue. Then the reaction mixture was extracted with ethyl acetate
(3ϫ 20 mL). The combined organic layers were dried with anhy-
drous Na2SO4, and the solvent was evaporated under vacuum. The
crude reaction mixture was purified by column chromatography
using a mixture of ethyl acetate/n-hexane in an appropriate ratio as
determined by TLC analysis.
5-(4-Chlorophenyl)-3-(morpholin-4-yl)isoxazole (4ac): White solid.
M.p. 168–169 °C. IR (KBr): ν = 1629, 1599 cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 7.66 (t, J = 6.9 Hz, 2 H), 7.42 (t, J =
9.6 Hz, 2 H), 6.15 (s, 1 H), 3.83 (t, J = 4.5 Hz, 4 H), 3.32 (t, J =
4.8 Hz, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.4, 167.5,
136.0, 129.1, 128.9, 127.8, 126.8, 126.1, 90.3, 66.2, 65.9, 47.4,
46.6 ppm. HRMS: calcd. for [M + H]+ 265.0738; found 265.0742.
5-Phenyl-3-(4-phenylpiperazinyl)isoxazole (4ba): White solid. M.p.
200–201 °C. IR (KBr): ν = 1625, 1595, 1545 cm–1. 1H NMR
Scheme 4. Mechanism for the formation of 5-substituted 3-amino-
isoxazoles 4.
˜
(300 MHz, CDCl3): δ = 7.75–7.72 (m, 2 H), 7.44–7.42 (m, 3 H),
7.32–7.26 (m, 3 H), 6.99–6.88 (m, 2 H), 6.21 (s, 1 H), 3.51 (t, J =
4.5 Hz, 4 H), 3.27 (t, J = 5.1 Hz, 4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 169.6, 167.4, 151.2, 130.0, 129.2, 128.8, 127.8, 125.6,
120.4, 116.6, 90.3, 48.9, 47.4 ppm. HRMS: calcd. for [M + H]+
306.1601; found 306.1609.
Conclusions
We have developed an efficient and highly regioselective
one-pot three-component synthesis of 5-substituted 3-
5-(4-Chlorophenyl)-3-(phenylamino)isoxazole (4gc): White solid.
aminoisoxazoles from β-oxo dithioesters with a wide range M.p. 180–181 °C. IR (KBr): ν = 3386, 2921, 1738, 1625, 1555 cm–1.
˜
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1H NMR (300 MHz, CDCl3): δ = 7.70 (d, J = 8.1 Hz, 2 H), 7.44
(d, J = 8.1 Hz, 2 H), 7.37–7.32 (m, 4 H), 7.02 (br. s, 1 H), 6.30 (s,
1 H), 6.21 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.7,
161.5, 140.4, 136.2, 129.3, 129.2, 126.9, 125.9, 122.0, 117.7,
92.2 ppm. HRMS: calcd. for [M + H]+ 271.0633; found 271.0634.
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Supporting Information (see footnote on the first page of this arti-
1
cle): Synthetic procedures, characterization data and copies of H
and 13C NMR spectra of all the final compounds.
Acknowledgments
Financial support from the Council of Scientific and Industrial Re-
search (CSIR), the Department of Science and Technology (DST)
and the University Grants Commission (UGC), New Delhi are
gratefully acknowledged.
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Job/Unit: O30038
/KAP1
Date: 15-05-13 17:21:56
Pages: 7
Regioselective Synthesis of 5-Substituted 3-Aminoisoxazoles
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Received: January 10, 2013
Published Online: ᭿
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