O-iodoxy benzoic acid–mediated synthesis of 3,5-diarylisoxazoles and isoxazole-3-carboxylic acids

Article abstract of DOI:10.1080/00397911.2013.854916

A new, convenient, ecofriendly synthesis of 3,5-diarylisoxazoles is reported from a,b-unsaturated ketoximes. Similarly, a novel synthesis of isoxazole carboxylic acids is also reported. Both the methods use efficient, environmentally friendly, and nontoxic iodoxybenzoic acid (IBX) as an oxidative cyclizing reagent. Easy procedure, environmentally benign reaction conditions, and nontoxicity are advantages to the methodology.

Full text of DOI:10.1080/00397911.2013.854916

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o-Iodoxy Benzoic Acid–Mediated
Synthesis of 3,5-Diarylisoxazoles and
Isoxazole-3-carboxylic Acids
Vidya G. Desai a , Sneha R. Naik a & Kashinath L. Dhumaskar a
a Department of Chemistry , Dnyanprassarak Mandal's College of
Arts, Science, and Commerce, Assagao , Mapusa , Bardez-Goa , India
Accepted author version posted online: 10 Feb 2014.Published
online: 29 Apr 2014.
To cite this article: Vidya G. Desai , Sneha R. Naik & Kashinath L. Dhumaskar (2014) o-Iodoxy
Benzoic Acid–Mediated Synthesis of 3,5-Diarylisoxazoles and Isoxazole-3-carboxylic Acids, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
44:10, 1453-1460, DOI: 10.1080/00397911.2013.854916
To link to this article: http://dx.doi.org/10.1080/00397911.2013.854916
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Synthetic Communications1, 44: 1453–1460, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.854916
o-IODOXY BENZOIC ACID–MEDIATED SYNTHESIS
OF 3,5-DIARYLISOXAZOLES AND ISOXAZOLE-3-
CARBOXYLIC ACIDS
Vidya G. Desai, Sneha R. Naik, and Kashinath L. Dhumaskar
Department of Chemistry, Dnyanprassarak Mandal’s College of Arts,
Science, and Commerce, Assagao, Mapusa, Bardez-Goa, India
GRAPHICAL ABSTRACT
Abstract A new, convenient, ecofriendly synthesis of 3,5-diarylisoxazoles is reported from
a,b-unsaturated ketoximes. Similarly, a novel synthesis of isoxazole carboxylic acids is also
reported. Both the methods use efficient, environmentally friendly, and nontoxic iodoxyben-
zoic acid (IBX) as an oxidative cyclizing reagent. Easy procedure, environmentally benign
reaction conditions, and nontoxicity are advantages to the methodology.
Keywords Chalcone; isoxazoles; o-iodoxybenzoic acid; oxidative cyclization; a,b-
unsaturated ketoxime
INTRODUCTION
In recent years, the organic chemistry of hypervalent iodine compounds[1–4]
such as o-iodoxy benzoic acid (IBX) and iodobenzene diacetate (IBD) has experi-
enced immense development. This growing interest in iodine hypervalent compounds
is due to their mild and high chemoselective properties combined with benign
environmental character and commercial availability. Hence, numerous new chemi-
cal transformations effected by these hypervalent iodine reagents, as powerful
reagents, have recently been developed.[5–7] Isoxazoles[8–10] are an important class
Received August 26, 2013.
Address correspondence to Vidya G. Desai, Department of Chemistry, Dnyanprassarak Mandal’s
College of Arts, Science, and Commerce, Assagao, Mapusa, Bardez-Goa 403507, India. E-mail:
vidchem@gmx.net
1453

1454
V. G. DESAI, S. R. NAIK, AND K. L. DHUMASKAR
of heterocycles owing to their diverse applications. They act as intermediates in
the synthesis of natural products and as building blocks for construction of new
molecular systems.[11] Activity includes a wide range of applications as herbicides
and fungicides.[12,13] There are several routes by which 3,5-diaryl isoxazoles can be
synthesized. The [5 þ 0] routes involving oxidative cyclization of a,b-unsaturated
ketoximes using oxidizing agents such as 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ),[14] MnO2,[15] I2=KI in NaHCO3,[16] tetrakis(pyridine)cobalt dichromate
[20]
(TPCD),[17] KOH-dioxane,[18] N-bromosuccinimide,[19] and NOBF4
are some
of the few known. Microwave-assisted synthesis of isoxazoles has also been
reported.[21–24] There are few reports of one-pot synthesis of isoxazole.[25–29] However,
the mentioned methods involve use of expensive catalyst or high-temperature reac-
tion conditions and have limited applicability to a variety of substrates. Isoxazole-3-
carboxylic acids also possess various biological activities such as antitubercular,[30,31]
protein tyrosine phosphate IB(PT1B) inhibitory,[32] etc. 5-Phenylisoxazole-3-
carboxylic acid derivatives are found to be potent xanthine oxidase inhibitors.[33]
Either it is prepared from previously constructed isoxazole nucleus or by ring-closure
methods using appropriate starting compounds containing carboxyl or alkoxy car-
bonyl groups. In this, ring-construction of isoxazole has been a widely used method.
However, few syntheses of isoxazole carboxylic acids have been a reported.[33,34]
Despite the various methods of synthesis reported for disubstituted isoxazole
and isoxazole-3-carboxylic acid, development of newer ecofriendly and green
methodologies remains a challenging task for synthetic organic chemists. In our
earlier approaches we have developed novel strategies for synthesis of important
heterocycles.[14,15] o-Iodoxy benzoic acid (IBX) is a well-known, nontoxic, environ-
mentally benign reagent which has been extensively used for various organic func-
tional group transformations.[5–7,35] In view of this, we thought of trying IBX as a
reagent for oxidative cyclization.
RESULTS AND DISCUSSION
Herein, we describe a convenient methodology toward the synthesis of 3,5-
diaryl isoxazoles from a,b-unsaturated ketoximes. The parent chalcone (1a) prepared
by Claisen–Schmidt condensation was first converted into its corresponding oxime by
a reported literature procedure[36] via hydroxylamine hydrochloride treatment under
weakly basic conditions in good yield. The oxime, after isolation and purification, was
then subjected to oxidative cyclization in refluxing chloroform using 1 equivalent of
IBX. The reaction mixture was continuously monitored and the thin-layer chromato-
graphy (TLC) was checked with the authentic sample for the completion of the
reaction. The reaction reached completion in 4 h as indicated by TLC. The crude mix-
ture was then concentrated to remove chloroform, adsorbed over silica gel, and loaded
for column chromatographic separation. The product, 3,5-diphenylisoxazole, was
obtained as a white solid, which was recrystallized using ethanol to give pure isoxazole
(3a) in 78% yield. In its 1H NMR spectrum, it showed a singlet at d 6.8 ppm, a charac-
teristic signal indicating the presence of C-H at the 4-position of the isoxazole ring. To
check the generality of this reaction, various a,b-unsaturated ketoximes were tried for
oxidative cyclization using IBX as reagent. Besides the parent 3,5-diphenylisoxazole,
11 more differently substituted 3,5-diaryl isoxazoles were synthesized in moderate to

SYNTHESIS OF 3,5-DIARYLISOXAZOLES
1455
Scheme 1. IBX-mediated synthesis of 3,5-disubstituted isoxazole 3a–l from a,b-unsaturated ketoximes.
good yields after chromatographic separation (Scheme 1, Table 1). It was observed
that the nature and position of the substituent on the aryl ring did not make much dif-
ference in reactivity. All the compounds have been well characterized by comparison
with authentic sample melting points as well as spectroscopic data (IR, NMR).
Having successfully prepared the diarylisoxazoles, we thought of synthesizing
isoxazole-3-carboxylic acids starting from benzalacetone oxime and 3 equivalents of
IBX. Chromatographic separation and recrystallization gave 5-phenyl isoxazole-3-
carboxylic acid in 67% yield. Although the actual mechanistic pathway is not known,
we thought to propose the following putative mechanism[38,39] (Scheme 2) for the
conversion. Intramolecular Michael-type addition, insertion of hypervalent iodine
across the double bond, followed by the oxidation of the methyl group to carboxylic
acid group with the elimination of iodosobenzoic acid were performed. In its 1H NMR
spectrum, it showed a singlet at d 9.33 ppm, indicating the presence of a proton of
carboxylic acid, while in its 13C NMR spectrum, it showed a singlet at d 171 ppm,
indicating the carbonyl carbon of the carboxylic acid. This prompted us to extend this
methodology toward synthesizing more isoxazole carboxylic acids. We synthesized in
all five such isoxazole-3-carboxylic acids (Table 2). The melting points obtained for
the products compare well with the reported synthesis of isoxazole carboxylic acids
(Scheme 3). None of the reactions led to any kind of by product formation.
With the growing need to follow the trend of green chemistry, we also attempted
one-pot synthesis of 3,5-disubstitutedisoxazole (Scheme 4). Herein the substituted
Table 1. IBX-mediated green synthesis of 3,5-disubstituted isoxazole 3a–l from
a,b-unsaturated ketoximes
Entry
Producta
Isolated yield (%)b
Mp (ꢀC)
Lit. mpc (ꢀC)
R1
H
R2
H
3a
3b
3c
3d
3e
3f
78
69
73
61
61
86
68
72
81
76
60
64
140–142
85–86
141–142[14]
85–86[21]
2-Cl
4-OMe
4-Cl
H
4-OMe
4-OMe
4-OMe
4-OMe
4-Br
142–143
185–186
120–122
130–132
121–122
171–172
178–179
176–178
227–228
176–178
142–144[20]
185–186[28]
120–122[14]
130–132[27]
120–122[24]
170–172[17]
178–180[27]
176–178[27]
226–228[18]
176–178[37]
4-OMe
4-Cl
4-Cl
H
3g
3h
3i
4-Br
H
4-Br
3j
H
4-Cl
4-NO2
4-NO2
3k
3l
H
4-OMe
aAll products were characterized by 1H NMR, 13C NMR, and IR data.
bYields after purification by chromatography.
cIdentified by comparison with authentic samples (14, 15, 16, 17, 18, 19, 20, 21, 22,
23, 24, 25, 26, 27, 28, 29, 30, and 37).

1456
V. G. DESAI, S. R. NAIK, AND K. L. DHUMASKAR
Scheme 2. Proposed stepwise mechanism for the synthesis of isoxazole-3-carboxylic acids. Step 1:
synthesis of 3-methyl-5-phenyl isoxazole; Step 2: synthesis of 5-phenyl isoxazole-3-carboxylic acid.
Table 2. One-pot synthesis of isoxazole-3-carboxylic acid from benzalacetone oximes
Entry
Producta
Isolated yield (%)b
Mp (ꢀC)
162–163
156–157
Lit. mpc (ꢀC)
161–163[33]
156–157[34]
6a
6b
5-Phenylisoxazole-3-carboxylic acid
5-(4-Methoxyphenyl)isoxazole
-3-Carboxylic acid
67
75
70
61
62
6c
6d
6e
5-(4-Chlorophenylisoxazole
-3-Carboxylic acid
180
(decomposes)
162–163
180[34]
5-(2-Chlorophenyl)isoxazole
-3-Carboxylic acid
(decomposes)
162–162[34]
5-(4-Nitrophenyl)isoxazole
-3-Carboxylic acid
[31]
176–177
176–178
aAll products were characterized by 1H NMR, 13C NMR, and IR data.
bYields after purification by chromatography.
cIdentified by comparison with authentic samples (31, 33, 34, and 36).

SYNTHESIS OF 3,5-DIARYLISOXAZOLES
1457
Scheme 3. Synthesis of isoxazole-3-carboxylic acid (6a–e) from benzalacetone oximes.
Scheme 4. One-pot synthesis of 1,3-diaryl isoxazoles.
chalcone (7) was treated with excess of hydroxylamine under weakly basic conditions
in chloroform. After 4 h, TLC indicated the formation of oxime. To this, 3 equivalents
of IBX was added and the reaction mixture was further refluxed. After 15 h the
reaction reached completion and after purification gave the corresponding isoxazole
in 88% yield. Herein, this one-pot methodology involved three reactions: oxime
formation, cyclization, and oxidation. The method was tried for only one example.
All the products obtained were characterized by comparing melting points with
1
literature and spectroscopic data (IR, H NMR, and 13C NMR).
EXPERIMENTAL
The IR spectra were recorded on an IR Prestige-21 Shimadzu FTIR spectro-
1
photometer. H NMR spectra were obtained on a Avance Bruker 400-MHz spec-
trometer and 13C NMR were obtained on a Avance Bruker 75-MHz spectrometer.
Samples were analysed in CDCl3, and the chemical shift values are expressed relative
to Me4Si as an internal standard. The product isoxazoles were purified using glass
column and silica gel (60–120 Mesh). o-Iodoxybenzoic acid was prepared from
o-iodobenzoic acid by a literature known procedure.[40]
General Procedure for the Synthesis of 3,5-Disubstituted Isoxazole (3)
Ketoxime 2a (0.223 g, 1 mmol), IBX (0.280 g, 1 mmol), and chloroform (5 mL)
were placed in a 100-mL round-bottom flask. The reaction mixture was refluxed for
4 h. The product 3a was purified using column chromatography with petroleum ether
and ethyl acetate (9:1) as an eluent. The product was further recrystallized using
ethanol. 3,5-Diphenylisoxazole (3a)[14–20]: White solid, 78%, mp 140–141 ꢀC; IR
1
(KBr), t (cmꢁ1): 1250, 1430, 3010. H NMR (400 MHz, CDCl3), d (ppm): 6.8 (s,
1H), 7.21–8.05 (m, 10H).
General Procedure for the Synthesis of Isoxazole-3-carboxylic Acid (6)
Ketoxime 5a (0.161 g, 1 mmol), IBX (0.840 g, 3 mmol), and chloroform (5 mL)
were placed in a 100 mL round-bottom flask. The reaction was refluxed for 4 h. The

1458
V. G. DESAI, S. R. NAIK, AND K. L. DHUMASKAR
reaction was continuously monitored using TLC. The product 6a was purified using
column chromatography with petroleum ether and ethyl acetate (9:1) as an eluent.
5-Phenylisoxazole-3-carboxylic acid (6a)[34]: White solid, 67%, mp 162–163 ꢀC;
1
IR (KBr), t (cmꢁ1): 1450, 1550, 1690, 3000, 3200. H NMR (400 MHz, CDCl3),
d (ppm): 7.202–8.145 (m, 5H), 9.33(s, 1H). 13C NMR (75 MHz, CDCl3), d (ppm):
30.21, 97.88, 134–124, 142.45, 162.56, 171.54.
Procedure for One-Pot Synthesis of 3,5-(Bis-P-methoxyphenyl)-
isoxazole (8)
Chalcone 7 (0.268 g, 1 mmol), hydroxylamine hydrochloride (0.416 g, 6 mmol),
sodium acetate (0.5 g, 6 mmol), and chloroform (5 mL) were placed in a 100-mL,
round-bottom flask and refluxed for 4 h. Oxime formation was observed on TLC.
This was followed by addition of IBX (0.840 g, 3 mmol) for reaction. The reaction
was continuously monitored using TLC. After completion of the reaction, the
product 8 was separated and purified using column chromatography with petroleum
ether and ethyl acetate (9:1) as an eluent.
3,5-Bis (4-methoxyphenyl)isoxazole (8)[14,20]: White solid, 88%, mp 144 ꢀC; IR
(KBr), t (cmꢁ1): 1250, 1460, 1590, 3050. 1H NMR (400 MHz, CDCl3), d (ppm): 3.84
(s, 3H), 5.45 (s, 3H), 6.80 (s, 1H), 7.20–7.78 (m, 8H).
CONCLUSION
In conclusion, a convenient and an efficient method for the synthesis of 3,5-
diarylisoxazoles from a,b-unsaturated ketoximes have been developed for various
substrates. The significance of our synthesis of isoxazole carboxylic acid is that it
involves three reactions: cyclization, followed by oxidation, leading to isoxazole ring,
and then oxidation of side chain methyl group to carboxylic acid group. Also the one-
pot synthesis of 3,5-diarylisoxazole has been carried out effectively. Use of IBX for
oxidative cyclization signifies nontoxicity and ecofriendliness of the methodology.
All the reagents are used in stoichiometric amounts in view of the need for environ-
mentally benign synthesis. The sequence exhibits wide scope and is tolerant of various
substituted aromatic substrates.
FUNDING
The authors are grateful to the Department of Science and Technology,
Government of Goa, for the financial support for the research.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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