Synthesis of novel isoxazole-benzoquinone hybrids via 1,3-dipolar cycloaddition reaction as key step

Article abstract of DOI:10.1016/j.tetlet.2012.05.123

An efficient method for the preparation of novel 2-(5-arylisoxazol-3-yl) cyclohexa-2,5-diene-1,4-dione hybrids via 1,3-dipolar cycloaddition followed by an oxidation reaction using ceric ammonium nitrate (CAN) has been described. Using this method, various aryl as well as alkyl substituted isoxazole-benzoquinone hybrids were synthesized in high yields.

Full text of DOI:10.1016/j.tetlet.2012.05.123

Tetrahedron Letters 53 (2012) 4108–4113
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel isoxazole-benzoquinone hybrids via 1,3-dipolar
cycloaddition reaction as key step
P. Ravi Kumar a,b, Manoranjan Behera a, K. Raghavulu a, A. Jaya Shree b, Satyanarayana Yennam a,
⇑
a Department of Medicinal Chemistry, GVK Biosciences Pvt. Ltd., Plot No. 28, IDA, Nacharam, Hyderabad 500 076, AP, India
b Centre for Chemical Sciences & Technology, Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500 072, AP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the preparation of novel 2-(5-arylisoxazol-3-yl)cyclohexa-2,5-diene-1,4-dione
hybrids via 1,3-dipolar cycloaddition followed by an oxidation reaction using ceric ammonium nitrate
(CAN) has been described. Using this method, various aryl as well as alkyl substituted isoxazole-benzo-
quinone hybrids were synthesized in high yields.
Received 5 March 2012
Revised 24 May 2012
Accepted 25 May 2012
Available online 1 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Oxime
Cycloaddition
Hybrid molecule
Isoxazole
Benzoquinone
Huisgen reaction
The search for new antitumor agents having less toxicity and
more cytotoxicity potency is the major interest in the present
day research.1 The quinone containing compounds have been
widely used for their antitumor and anticancer activities.2 But
the problems associated with these compounds such as toxicity
and drug resistance have stimulated an intense demand for the dis-
covery of new and novel antitumour agents.3 In the last few dec-
ades significant progress has been made in the screening of
quinone containing compounds for antitumour activity.4
Among a number of cytotoxic antibiotics, a few are clinically
tolerable as antitumor agents.5 While antibiotics display an enor-
mous diversity in chemical structures, quinone antibiotics such
as adriamycin, mitomycin C, and streptonigrin6 deserve special
attention (Fig. 1). Although they share a common trait of interfer-
ence with the synthesis of DNA as well as RNA investigations on
their mode of action have revealed an intrinsic characteristic fea-
ture of each compound, that is intercalation between stacked base
pairs for quinone antibiotics, covalent binding to DNA after the
intracellular reduction and superoxide formation through the oxi-
do-reduction cycle.7 In this context, search of new class of mole-
cules containing quinone moiety has always fascinated the
organic as well as medicinal chemist.
ure.8 Isoxazole derivatives show hypoglemic, analgesic, anti-
inflammatory, antifungal, anti-bacterial and HIV-inhibitory activi-
ties.9 Synthesis of hybrid natural products has gained momentum
in recent years.10 It is expected that combining features of more
than one biologically active natural segment in a single molecule
may result in pronounced pharmacological activity while retaining
high diversity and biological relevance.11 There are a few reports
describing the preparation of quinone-hybrid with other natural
products. For example, quinone-amino acids,12 sugar-oxasteroid-
quinone,13 quinone-annonaceous acetogenins,14 conduritol-
carba-sugar15 hybrids have been described using different
synthetic protocol. Quinone–isoxazole hybrid shows significant
antifungal activity as well as agricultural application.16 Arylated
quinones possess unique visual and electronic properties that
make them useful in photosynthesis and appealing structures to
the dye industry.17
Depending on the substitution pattern, arylated quinones were
prepared by a few general methods.18 Meerwin reactions with
aryldiazonium salts and oxidation of the corresponding aromatics
are among the most popular. But the disadvantage of this method
is that aryldiazonium salts are difficult to prepare, are unstable and
have been shown to be explosives. Other methods such as the
Pummerer arylation and direct arylation protocols have also been
used for the installation of electron rich aryl or hetero aromatics.
When these reactions are carried out on mono-substituted 1,4-
benzoquinones, an issue of regioselectivity arises, as the arylation
can lead to a 2,5 or to a 2,6-disubstituted 1,4-benzoquinone. Most
Compounds containing the quinone group present an important
class of biologically active molecules that are wide spread in nat-
⇑
Corresponding author. Tel.: +91 40 6628 1375.
E-mail address: satya@gvkbio.com (S. Yennam).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.123

P. Ravi Kumar et al. / Tetrahedron Letters 53 (2012) 4108–4113
4109
O
O
MeO
H2N
O
O
O
OH
OH
N
COOH
CH3
N
OH
O
O
O(CO)NH2
OMe
NH
OH
O
H2N
HO
H2N
Me
H
OMe
O
CH3
OH
N
MeO
OMe
NH2
Mitomycin C
Streptonigrin
Adriamycin
Figure 1. Quinone antibiotics.
OH
N
NO2
NO2
N
NO2
O
NH2OH.HCl,
NaOAc in MeOH
NaOCl (9-12% in
Water), TEA /DCM
CHO
25 OC, 2 h
25 OC, 20 h
2
3
1
Fe, NH4Cl
EtOH/Water(8:2)
Reflux, 2 h
O
O
N
O
Fremy's salt
NH2
N
O
in phosphate buffer
CH3CN
0
OC - 25 OC, 16 h
5a
4
Scheme 1. Attempted 1,3-dipolar cycloaddition and oxidation reactions using 2-nitrobenzaldehyde as starting material.
OH
OCH3
CHO
MeI / K2CO3
in acetone
OCH3
CHO
NH2OH.HCl,
OH
NaOAc in MeOH
N
25 OC, 20 h
25 OC, 2 h
OH
OCH3
OCH3
6
8
7
NaOCl (9-12% in
Water), TEA in DCM
25 0C, 20 h
O
N
O
OCH3
N
CAN in
CH3CN / Water(8:2)
O
25 OC, 1 h
O
OCH3
9a
5a
Scheme 2. 1,3-Dipolar cycloaddition and oxidation reactions using 2,5-dihydroxybenzaldehyde as starting material.
of these procedures take place with low regioselectivities and give
poor yields with electron-deficient aryl groups. In this respect,
transition metal mediated cross-couplings are wider in scope than
the other procedures.19 However, their application requires the
previous selective functionalization of the starting quinones with
a halogen or triflate group suitable for coupling. Also, the ability
of quinones to act as ligands and oxidants to transition metals,
such as palladium, poses additional challenge to cross-coupling ap-
proaches.20 Alternate strategy employing protected halo-dihydro-
quinones followed by deprotection21 has proven both lengthy
and inefficient, as have Diels–Alder/functionalization/retro Diels–
Alder sequence.22 For this reason, a more general method for the
functionalization of quinones is in demand. There are some reports
of fused benzoquinones such as pyrrolobenzimidazoles (PBI) and
indolobenzoquinones by Skibo et al.23 Recently, Baran’s group
has developed a practical C–H functionalization of quinones with
boronic acids.24 In a similar approach Csaky and co-workers have
reported a mild method for the direct arylation of 2-aryl-1,4-ben-

4110
P. Ravi Kumar et al. / Tetrahedron Letters 53 (2012) 4108–4113
Table 1
During our research program involving preparation of aziridinyl
Methods for 1,3-dipolar cycloaddition reaction
benzoquinones, we required to synthesize a number of 2-heterocy-
clic benzoquinones with various degrees of substitution on hetero-
cyclic ring system which can be regarded as hybrids of the
pharmacologically relevant subunits of isoxazole and quinone.
Herein, we wish to report for the first time that 1,3-diploar cyclo-
addition reaction combined with oxidation reaction can be used to
prepare 2-isoxazole-1,4-benzoquinone derivatives in a simple
four-step synthetic protocol (Scheme 2). It is well known that
isoxazole can be prepared from aromatic aldehyde via cycloaddi-
tion reaction through oxime intermediate using the Huisgen
Entry
Reaction conditions
Yield (%)a
1
2
3
NCS/NaHCO3/EtOAc/reflux
(Bu3Sn)2O/t-BuOCl/rt
NaOCl/Et3N/DCM/rt
80
48
88
a
Isolated yields.
zoquinones with good regioselectivities.25 But there are no reports
of direct synthesis of 2-isoxazole-1,4-benzoquionone system as per
the literature search.
Table 2
List of compounds prepared using 2,5-dihydroxybenzaldehyde as starting material
S. no.
3,5-Di-aryl isoxazole
Yield
88
Quinone–isoxazole hybrid
Yield
88
OMe
O
N
N
O
O
1
5a
OMe
OMe
O
O
9a
N
N
O
O
2
89
92
Cl
9b
Cl
O
O
O
OMe
OMe
5b
N
N
N
N
N
O
3
4
5
6
7
8
9
86
75
80
84
86
71
64
88
88
86
91
93
78
75
Cl
Cl
9c
O
O
OMe
OMe
5c
N
O
O
O
O
O
O
O
O
F
F
9d
OMe
OMe
O
O
5d
N
O
OPh
OPh
9e
OMe
OMe
O
O
5e
N
O
9f
O
O
OMe
OMe
CF3
CF3
5f
N
N
N
N
O
S
S
9g
OMe
OMe
O
O
5g
N
O
9h
OMe
OMe
O
O
5h
N
O
9i
OMe
OMe
O
O
5i
N
Cl
N
Cl
O
10
71
85
O
Cl
5j
9j
OMe
Cl

P. Ravi Kumar et al. / Tetrahedron Letters 53 (2012) 4108–4113
4111
OH
OH
NH2OH.HCl,
OCH3
CHO
OCH3
CHO
MeI / K2CO3
in acetone
NaOAc in MeOH
OH
N
25 OC, 2 h
25 OC, 20 h
OCH3
OCH3
10
12
11
NaOCl (9-12% in
Water), TEA / DCM
25 OC, 20 h
O
O
OCH3
N
O
N
O
CAN in
CH3CN / Water(8:2)
25 OC, 1 h
13a
14a
OCH3
Scheme 3. 1,3-Dipolar cycloaddition and oxidation reactions using 4-methyl-2,5-dihydroxybenzaldehyde as starting material.
Table 3
List of compounds prepared using 2,5-dihydroxy-4-methylbenzaldehyde as starting material
S. no.
3,5-Di-aryl isoxazole
Yield
Quinone-isoxazole hybrid
Yield
OMe
O
N
N
O
O
1
82
83
93
14a
OMe
OMe
O
O
13a
N
N
O
O
2
77
Cl
Cl
OMe
OMe
O
O
13b
14b
N
N
O
O
3
4
5
6
7
8
82
74
71
67
71
67
93
88
95
81
88
Cl
Cl
13c
OMe
OMe
O
O
14c
N
N
N
N
N
N
O
O
F
F
13d
OMe
OMe
O
O
14d
N
O
O
OPh
OPh
13e
OMe
OMe
O
O
14e
N
O
O
13f
OMe
OMe
CF3
O
O
CF3
14f
N
O
O
S
S
13g
O
O
OMe
OMe
14g
N
O
O
83
13h
O
OMe
14h
(continued on next page)

4112
P. Ravi Kumar et al. / Tetrahedron Letters 53 (2012) 4108–4113
Table 3 (continued)
S. no.
3,5-Di-aryl isoxazole
Yield
84
Quinone-isoxazole hybrid
Yield
84
OMe
O
N
N
O
O
9
13i
OMe
OMe
O
O
14i
N
Cl
N
Cl
O
O
10
67
87
O
OMe
Cl
Cl
14j
13j
protocol.26 We envisioned that suitably placed amine precursor or
methoxy group in the aromatic ring can be utilized for oxidation
reaction after the introduction of isoxazole ring.
pounds 5a–5j were well characterized by 1H NMR, IR, MS, and
13C NMR spectrum. The purity of the 2-isoxazole-1,4-benzoqui-
none derivatives was obtained by HPLC analysis.
To begin with, 2-nitrobenzaldehyde 1 (Scheme 1) was reacted
with hydroxylamine hydrochloride (NH2OHÁHCl) to produce the
oxime derivative 2. Compound 2 was subjected to the key 1,3-
dipolar cycloaddition reaction with phenyl actetylene in the
presence of NaOCl/Et3N in DCM as solvent. The isoxazole 3 was
smoothly formed using this Huisgen’s one pot protocol. We did
not observe the formation of any other isomer and nitrile oxide
dimerization product in this reaction. Any undesired by-products
resulting from aromatic halogenations were not observed in our
case. After obtaining the cycloaddition product 3, the next task
was to convert it into benzoquinone. In this regard, the reduction
of nitro group gave the amine derivative 4 ready for benzoquinone
synthesis. Unfortunately several attempts to oxidize the amine
derivative 4 to produce benzoquinone 5a using Fremy’s salt,
DDQ, CAN, etc., were not successful. Maybe the presence of isoxaz-
ole ring at the ortho position is detrimental to oxidation reaction in
the compound 4. Then we turned our attention to 2,5-dimethoxy-
benzaldehyde 7 as the starting material to get the target molecule
5a (Scheme 2).
Compound 7 was prepared from corresponding phenol 6 by
treatment with MeI/K2CO3 in acetone as solvent for 20 h at rt. Then
the compound 7 was reacted with NH2OHÁHCl to produce the
oxime derivative 8. Subsequent one pot reaction of oxime deriva-
tive with phenyl acetylene in the presence of NaOCl/Et3N in DCM
as solvent gave the isoxazole moiety 9a cleanly.27 Then the com-
pound 9a was oxidized with CAN to give the desired target 2-isox-
azole-1,4-benozoquinone 5a in very good yield.28 The compound
5a was characterized by 1H NMR, 13C NMR, and HRMS data. The
characteristic quinone proton at 6.9 d in 1H NMR spectrum con-
firms the oxidation of compound 9a to generate compound 5a. IR
spectrum of the compound 5a shows the carbonyl peaks at
1655 cmÀ1. The two carbonyl peaks at 186.7 and 185.1 d in 13C
NMR spectrum validate the benzoquinone moiety. All the benzo-
quinones are characteristic yellowish solids.
It is noteworthy to mention here that previously inaccessible
thiophene, cyclopentyl, and isopropyl analogues were synthesized
in very good yield (entries 7–9). As indicated in Table 2, F and CF3
substituted phenyl acetylene gave the products in very good yield.
Using the condition above, ortho substitution is tolerated (entry 2)
to give the product 5b without any difficulties. Although both alkyl
as well as aryl acetylene undergo the two step reaction protocol
smoothly to generate 2-isoxazole-benzoquinone derivatives, it
was observed that aryl substitution gave better yield compared
to alkyl group.
Similar approach was adapted to synthesize the 5-methyl-2-
isoxazole-benzoquinone derivatives (Scheme 3) and the results
are given in Table 3. All the substrates reacted well under these
conditions and did not produce any by-products.
In conclusion, we have developed an efficient and simple meth-
od to synthesize 2-isoxazole-benzoquinone derivatives using 1,3-
dipolar cycloaddition and oxidation reactions as key steps in good
yields. We believe that this methodology will find a widespread
application for the synthesis of 2-aryl-benzoquinone and its deriv-
atives. Further applications of this methodology for introduction of
aziridine in quinone ring system of 2-aryl-benzoquinone are in
progress in our group.
Acknowledgments
Authors are grateful to the GVK Biosciences Pvt. Ltd., for the
financial support and encouragement. Help from the analytical
department for the analytical data is appreciated. We thank Dr.
Balaram Patro for his invaluable support and motivation.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.05.
123.
The 1,3-dipolar cycloaddition reaction was tried using various
reaction conditions and the results are summarized in Table 1.
Among the conditions screened we found that NCS/NaHCO3/EtOAc
gave little less yield compared to NaOCl/Et3N/DCM, while (Bu3S-
n)2O gave 48% yield. Also in NaOCl condition, it was easy to purify
the product by simple solvent washing whereas column purifica-
tion is necessary in NCS/NaHCO3 condition.
Once the reaction condition was standardized, various highly
substituted phenyl acetylenes were subjected to cycloaddition
reaction to give the compounds 9a–9j (Table 2). The required phe-
nyl acetylenes were either commercially available or prepared
from corresponding iodo derivatives by two step Sonogashira cou-
pling with TMS acetylene and deprotection strategy. All com-
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27. Typical experimental Procedure for the preparation of compound 9a: To a solution
of compound 8 (1 g, 5.52 mmol) in DCM (10 mL), phenyl acetylene (0.67 g,
6.62 mmol), TEA (0.83 g, 8.28 mmol), and sodium hypochlorite (9–12% in
water) (10 ml) were added at 0 C under nitrogen atmosphere. Then the
reaction mixture was stirred at rt 0 °C for 20 h. The progress of the reaction was
monitored by TLC analysis (15% EA/pet ether). Then, water (50 ml) was added
and the reaction mixture was extracted with DCM. The combined organic layer
was washed with water followed by brine and dried over anhydrous Na2SO4.
Evaporation of the solvent in high vacuum gave the compound 9a (1.32 g, 88%
yield) as off white solid. MP 77–79 °C; 1H NMR (400 MHz, CDCl3):d 7.82–7.88
(m, 2H), 7.42–7.54 (m, 4H), 7.08 (s, 1H), 6.94–7.02 (m, 2H), 3.80 (s, 3H), 3.60 (s,
3H); 13C NMR (100 MHz, CDCl3): d 169.3, 160.4, 153.6, 151.6, 129.8, 128.8,
127.7, 125.7, 118.4, 117.2, 113.5, 113.0, 101.0, 56.2, 55.8; MS (EI) m/z 281
(M+1, 100); HRMS calcd for C17H16NO3 (M+1) = 282.1052, found 282.0273.
28. Typical experimental procedure for the preparation of compound 5a: To a solution
of compound 9a (0.3 g, 1.06 mmol) in acetonitrile (10 mL), H2O (2 ml), CAN
(1.75 g, 3.20 mmol) was added and the reaction mixture was stirred at rt for
1 h. The progress of the reaction was monitored by TLC analysis (15% EA/pet
ether). Then, water (20 ml) was added and extracted with ethyl acetate. The
combined organic layer was washed with water followed by brine and dried
over anhydrous Na2SO4. Evaporation of the solvent in high vacuum gave the
compound 5a (0.22 gm, 88% yield) as yellow solid. MP 142–144 °C; 1H NMR
(400 MHz, CDCl3): d 7.82–7.86 (m, 2H), 7.46–7.53 (m, 4H), 7.14 (s, 1H), 6.88-
6.92 (m, 2H); 13C NMR (100 MHz, CDCl3): d 186.7, 185.1, 170.8, 156.4, 136.7,
136.5, 134.3, 133.2, 130.5, 129.0, 126.8, 125.8, 100.8; MS (EI) m/z 251 (M+1,
100), HRMS calcd for C15H10NO3 (M+1) = 252.0582, found 251.9927.
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