The chemistry of α,β-ditosyloxy ketones: A new and convenient route to 4,5-diarylisoxazoles from α,β-chalcone ditosylates

Article abstract of DOI:10.1055/s-0031-1290109

The reaction of α,β-chalcone ditosylates with hydroxyl-amine hydrochloride under suitable conditions leads to a 1,2-aryl shift, thereby providing a new route to 4,5-disubstituted isoxazoles. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1290109

LETTER
93
The Chemistry of a,b-Ditosyloxy Ketones: A New and Convenient Route to
4,5-Diarylisoxazoles from a,b-Chalcone Ditosylates
C
a
hemistry of
a
,
b
a
j
K
etones Kamal,*a Deepak Sharma,b Deepak Wadhwa,a Om Prakasha
Department of Chemistry, Kurukshetra University, Kurukshrtra 136119, Haryana, India
E-mail: kamalraj_sharma@rediffmail.com
b
Govt. Post Graduate College, Ambala Cantt 133001, Haryana, India
Received 18 July 2011; revised 21 October 2011
el and convenient route to 4,5-diarylisoxazoles, for which
previous synthetic and structural studies are limited.
Abstract: The reaction of a,b-chalcone ditosylates with hydroxyl-
amine hydrochloride under suitable conditions leads to a 1,2-aryl
shift, thereby providing a new route to 4,5-disubstituted isoxazoles.
In the last decade it has been reported that 4,5-diarylisox-
azole derivatives can act as potential therapeutic agents
for the treatment of cancer,4 novel inhibitors of cyclooxy-
genase-2 with analgesic and anti-inflammatory activities,5
and can also inhibit metastasis of breast cancer cell lines.
These compounds also have potential for the treatment of
angiogenesis-related diseases including cancers, rheuma-
toid arthritis, and psoriasis.6
Key words: a,b-chalcone dibromides, a,b-chalcone ditosylates,
hydroxy(tosyloxy)iodobenzene, 4,5-diarylisoxazoles
The present study is in connection with our ongoing inter-
est in the synthetic potential of a,b-ditosyloxyketones in
the synthesis of 4,5-diarylisoxazoles. The chemistry of
a,b-chalcone dibromides has been well explored,1 and the
reactivity mode of a,b-chalcone ditosylates 1 has been
studied recently in our research group. The aim of this
study is to explore the potential of a,b-chalcone ditosyl-
ates 1 in heterocyclic synthesis with particular emphasis
on comparison with their dibromo analogues. In our pre-
liminary study it was reported that the reaction of a,b-
chalcone ditosylates 1 with various reagents such as phe-
nylhydrazine hydrochloride, semicarbazide hydrochlo-
ride, and thiosemicarbazide under suitable conditions
leads to a 1,2-aryl shift, thereby providing a novel route to
1,4,5-trisubstituted pyrazoles 2 (Equation 1).2 These re-
sults have shown that the reactivity pattern of a,b-chal-
cone ditosylates 1 is quite different from that of a,b-
chalcone dibromides, which are known to give
pyrazolines1j,3 under similar reaction conditions.
Various derivatives of a,b-chalcone ditosylates 1a–o were
prepared by treatment of the respective chalcones with
hydroxy(tosyloxy)iodobenzene (HTIB) according to the
method developed by Rebrovic and Koser7 (Scheme 1 and
Table 1).2,8,9
O
OTs
Ar2
O
HTIB
Ar1
Ar1
Ar2
CH2Cl2
OTs
3
1
Scheme 1 a,b-Ditosyloxylation of chalcones using HTIB
We first examined the reaction of a,b-chalcone ditosy-
lates 1 with hydroxylamine hydrochloride. Thus a,b-chal-
cone ditosylate 1a (0.001 mol) was heated with
hydroxylamine hydrochloride (0.002 mol) in the presence
of sodium acetate (0.002 mol) in ethanol (25 mL). The re-
action afforded a single colourless solid product in 72%
yield, which was characterised as 4,5-diphenylisoxazole
(4a) on the basis of its physical and spectroscopic data
X
O
OTs
Ar2
N
N
XNHNH2
Ar1
Ar1
OTs
Ar2
1
1
2
(IR, H NMR, mass). The IR spectrum of the product
X = Ph, CONH2, CSNH2
showed the disappearance of a peak at 1680 cm–1 arising
Equation 1
from the carbonyl group of a,b-chalcone ditosylate 1a.
1
The H NMR spectrum showed a sharp singlet at d =
Prompted by the foregoing observations and coupled to
our interest in the synthesis of heterocyclic compounds,
we became interested in investigating the reactivity of
a,b-chalcone ditosylates 1 with hydroxylamine hydro-
chloride with the hope of developing a convenient ap-
proach to the synthesis of 4,5-diarylisoxazoles. As
consequence of this investigation, we report herein a nov-
8.2 ppm, corresponding to a single proton that can be as-
cribed to the C(3)-H of the isoxazole ring. The mass spec-
trum of the product 4a showed the molecular ion, an
intense fragment corresponding to [PhCO]+ and a rear-
rangement peak at m/z 165 characteristic of 4,5-diphenyl-
isoxazole,10 as observed by Rao et al.14
To study the scope of the reaction, a wide range of substi-
tuted a,b-chalcone ditosylates (1b–o) were treated with
hydroxylamine hydrochloride under similar conditions. It
was observed that each of the substrates behaved in a sim-
ilar manner, affording the corresponding isoxazoles 4b–o
in good yield (64–78%; Scheme 2 and Table 2).11
SYNLETT 2012, 23, 93–96
x
x
.x
x
.2
0
1
1
Advanced online publication: 13.12.2011
DOI: 10.1055/s-0031-1290109; Art ID: D22611ST
© Georg Thieme Verlag Stuttgart · New York

94
R. Kamal et al.
LETTER
Table 1 Physical Data of a,b-Chalcone Ditosylates 1
Entry
1
Ar1
Ar2
Mp
Yield (%)a
(Lit.)2,7,8
1
2
1a
1b
1c
1d
1e
1f
Ph
Ph
134–136 (136–138)
113–114 (114–115)
138–139 (138–140)
101–102
67
61
73
62
62
68
67
67
64
66
65
62
57
62
58
Ph
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2-thienyl
Ph
3
Ph
4
Ph
5
Ph
120–122
6
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
113–114
7
1g
1h
1i
4-MeC6H4
2-thienyl
Ph
127–128 (128–129)
138–139
8
9
130–132 (132–133)
92–94 (93–94)
154–155
10
11
12
13
14
15
1j
4-MeOC6H4
2-thienyl
Ph
1k
1l
108–110 (108–110)
128–130
1m
1n
1o
2-thienyl
5-methyl-2-thienyl
Ph
144–145
134–135
a Yield was calculated with respect to the corresponding chalcones.
Table 2 Physical Data of 4,5-Disubstituted Isoxazoles 4
Entry
1
4
Ar1
Ar2
Mp (Lit.)12–15
74–76 (75–76)
82–84 (84–85)
68–70 (69–70)
108 (109)
105–107
Yield (%)a
4a
4b
4c
4d
4e
4f
Ph
Ph
72
76
78
73
53
68
64
55
69
66
61
74
48
52
72
2
Ph
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2-thienyl
Ph
3
Ph
4
Ph
5
Ph
6
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
109–110 (110)
88–89
7
4g
4h
4i
4-MeC6H4
2-thienyl
Ph
8
Oil
9
50–52 (53)
68–69
10
11
12
13
14
15
4j
4-MeOC6H4
2-thienyl
Ph
4k
4l
Oil
103–104 (103–104)
138–140
4m
4n
4o
2-thienyl
5-methyl-2-thienyl
Ph
121–22
73–75
a Yield was calculated with respect to the corresponding a,b-chalcone ditosylates.
Synlett 2012, 23, 93–96
© Thieme Stuttgart · New York

LETTER
Chemistry of a,b-Ditosyloxy Ketones
95
Ar2
remarkable difference in the reactivity pattern is not yet
clear. Nevertheless, the reaction offers a novel route for
the synthesis of 4,5-diarylisoxazoles. This newly devel-
oped route involves simple experimentation and yields are
good using a,b-chalcone ditosylate derivatives to effect
selective transformations that are not possible from a,b-
chalcone dibromides.
O
OTs
Ar2
NH2OH•HCl
Ar1
N
NaOAc, heat
Ar1
O
OTs
4
1
Scheme 2 Synthesis of 4,5-diarylisoxazoles from a,b-chalcone di-
tosylates
The exclusive formation of rearranged products reveals
that the conversion involves 1,2-aryl migrations. The
mechanism of this migration is closely related to that of
the pinacol rearrangement and is outlined in Scheme 3.
The first step of the reaction probably involves nucleo-
philic substitution of the OTs group, situated at position 3,
by the amino group of the reagent. The substitution is fol-
lowed by 1,2-aryl migration, resulting in the formation of
intermediate, which subsequently undergoes cyclization
in the usual manner to afford the rearranged product. Of
the various reported examples of rearrangement of this
sort, two important ones are bistosyloxylation of 1,1-
diphenylethylene leading to desoxybenzoin,7 and copper-
catalysed rearrangement of hydroxyl ketones.16 It is inter-
esting to note that bis-brominated homologues of 1 were
never reported to undergo such rearrangement.1c,j,3 In-
stead, the reaction of a,b-chalcone dibromides with
hydroxylamine hydrochloride is known to give 3,5-diaryl-
isoxazoles.1c
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We are grateful to the Council for Scientific and Industrial Research
(CSIR), New Delhi for financial support of this work.
References and Notes
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HO
O
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NH
HONH2
– TsOH
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OTs
OTs
1
(2) Prakash, O.; Sharma, D.; Kamal, R.; Kumar, R.; Nair, R. R.
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1,2-shift
– TsOH
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N
N
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Ar1
Ar2
4
Scheme 3 Plausible mechanistic pathway for the formation of rear-
ranged products
(9) Experimental procedure used to prepare a,b-chalcone
ditosylates 1: Prepared from the corresponding chalcones17–22
3 using a procedure similar to that reported previously by our
research group. Compounds 1a–c,g,i–j,l were previously
reported, whereas 1d–f,h,k,m–o are novel compounds.
Spectroscopic data of the latter compounds are given in the
Supporting Information.
It is worthy of note that synthetic and structural studies of
4,5-diarylisoxazoles in the literature are limited. One of
the literature reports includes a three-step synthesis of 4,5-
diarylisoxazoles, starting from the respective chalcones.14
In conclusion, this study further reveals that the reactivity
pattern of a,b-chalcone ditosylates 1 is quite different
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Spectrom. 1969, 2, 739.
© Thieme Stuttgart · New York
Synlett 2012, 23, 93–96

96
R. Kamal et al.
LETTER
(11) Experimental procedure used to prepare 4,5-diaryl-
isoxazoles 4: A mixture of chalcone ditosylate (1a; 0.550 g,
0.001 mol), hydroxylamine hydrochloride (0.138 g, 0.002
mol) and sodium acetate (0.164 g, 0.002 mol) in EtOH (25
mL) was heated at reflux for approximately 3 h. The reaction
mixture was then poured onto ice-cold water. The resulting
mixture was extracted with CH2Cl2 (3 × 50 mL) and the
combined organic extract was dried over anhydrous Na2SO4
and filtered. Evaporation of CH2Cl2 in vacuo gave the crude
product, which was purified by column chromatography on
silica gel (100–200 mesh; PE–EtOAc) to give pure pyrazole
4a (72%, 0.159 g). Other derivatives were prepared in a
similar manner. Compounds 4e,g,h,j,k,m–o are novel.
Spectroscopic data of these compounds are given in the
Supporting Information.
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Synlett 2012, 23, 93–96
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