Microwave-assisted one-pot synthesis of benzo[b][1,4]oxazin-3(4H)-ones via Smiles rearrangement

Article abstract of DOI:10.1016/j.tetlet.2008.03.120

An efficient method for the synthesis of benzo[b][1,4]oxazin-3(4H)-ones via Smiles rearrangement using a microwave-assisted one-pot, three-step reaction has been developed. Various benzo[b][1,4]oxazin-3(4H)-ones are obtained in good yields (55-86%) from t

Full text of DOI:10.1016/j.tetlet.2008.03.120

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Tetrahedron Letters 49 (2008) 3827–3830
Microwave-assisted one-pot synthesis of benzo[b][1,4]oxazin-3(4H)-ones
via Smiles rearrangement
Hua Zuo a,c, Lijuan Meng a, Manjunath Ghate a, Kyu-Hyeon Hwang a, Yong Kweon Cho a,
S. Chandrasekhar b, Ch. Raji Reddy b, Dong-Soo Shin a,*
a Departments of Chemistry, Biochemistry and Health Science, Changwon National University, Changwon, 641-773, South Korea
b Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
c College of Pharmaceutical Sciences, Southwest University, Chongqing 400716, China
Received 22 January 2008; revised 18 March 2008; accepted 21 March 2008
Available online 28 March 2008
Abstract
An efficient method for the synthesis of benzo[b][1,4]oxazin-3(4H)-ones via Smiles rearrangement using a microwave-assisted
one-pot, three-step reaction has been developed. Various benzo[b][1,4]oxazin-3(4H)-ones are obtained in good yields (55–86%) from
the corresponding substituted 2-chlorophenols and primary amines in short reaction time (18–40 min).
Ó 2008 Published by Elsevier Ltd.
Benzo[1,4]oxazin-3(4H)-one derivatives are one of the
important classes of heterocyclic compounds and have
shown to exhibit a wide range of biological activities such
as anti-inflammatory, antiulcer, antipyretic, antihyperten-
sive, antifungal, as receptor antagonists, potassium channel
modulators, antirheumatic agents and antihypertensive
agents.1–9 Hence, the synthesis of this class of compounds
has been attracted by several synthetic organic chemists.
Most of the available methods in the literature involve
the use of either substituted 2-aminophenols or 2-nitro-
phenols as starting materials, which were transformed to
benzo[1,4]oxazin-3(4H)-one scaffold by the stepwise
sequential reactions.10,11 For example, in the case of
2-aminophenol, which was initially treated with 2-haloal-
kanoyl chloride or bromide to form 2-amidophenols, which
then underwent a base mediated intramolecular O-alkyl-
ation under heating condition. Later, a few one-pot meth-
ods have been developed using the same starting
materials.12 However, the use of these starting materials
is limiting the diversity of the products based on their avail-
ability. Recently, Yuan and co-workers have used 1,5-
difluoro-2,4-dinitrobenzene as a starting material for the
synthesis of a diverse benzo[1,4]-oxazin-3-one-based com-
pounds.13 In contrast to these existing methods, we herein
described an efficient one-pot method for the synthesis of
benzo[1,4]oxazin-3(4H)-one derivatives using 2-chloro-
phenols as starting materials. This one-pot reaction pro-
ceeds via a three-step sequence involving Smiles rearrange-
ment14 to provide the desired products in good yields.
The concept of our process, illustrated in Scheme 1, is
based on using simple starting materials, such as substi-
tuted 2-chlorophenol (1), 2-chloroacetyl chloride and
primary amine (2), to form a ring system (3) under micro-
wave irradiation (MW). The commercial availability of
such starting materials makes this approach sufficiently
diversity oriented, thus fulfilling the recent demand for
the generation of large combinatorial chemical libraries.
Moreover, this novel one-pot three-step reaction provides
a quick and efficient entry to functionalized benzo[1,4]oxa-
zin-3(4H)-one derivatives of biological interest.
In view of the high efficiency of Cs2CO3 in our earlier
work on the synthesis of the titled compounds,15 we have
chosen it as a base to perform this one-pot reaction16 and
the results are summarized in Table 1. We first examined
*
Corresponding author. Tel.: +82 55 213 3437; fax: +82 55 213 3430.
E-mail address: dsshin@changwon.ac.kr (D.-S. Shin).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.03.120

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H. Zuo et al. / Tetrahedron Letters 49 (2008) 3827–3830
R2
N
OH
Cl
O
Cs2CO3,DMF
Cl
R2NH2
+
Cl
+
i) 0 oC, ii) 150 oC, MW
R1
O
R1
O
1
( )
2
( )
3
( )
R1= Cl, Br, F
R2= alkyl, aryl
Scheme 1. One-pot synthesis of benzo[1,4]oxazin-3(4H)-ones.
Table 1
One-pot synthesis of benzo[1,4]oxazin-3(4H)-one derivativesa
Entry
1
Phenol
Amine
Productb
Time (min)
28
Yieldc (%)
70
Bn
N
OH
Cl
NH2
O
2a
X
X
O
X= Cl, 1a
X= Cl, 3a
2
3
X = Br, 1b
X = F, 1c
2a
2a
X = Br, 3b
X = F, 3c
18
35
70
64
OH
Cl
NH2
4
N
O
O
18
72
X
2b
X= Cl, 1a
X
X= Cl, 3d
5
6
X = Br, 1b
X = F, 1c
2b
2b
X = Br, 3e
X = F, 3f
35
30
70
86
OH
N
O
O
NH2
7
30
75
X
Cl
2c
X
X= Cl, 1a
X= Cl, 3g
8
9
X = Br, 1b
X = F, 1c
2c
2c
X = Br, 3h
X = F, 3i
35
35
65
78
OH
Cl
O
O
N
O
10
30
80
O
X
NH2
2d
1a
X= Cl,
X
3j
X= Cl,
11
12
X = Br, 1b
X = F, 1c
2d
2d
X = Br, 3k
X = F, 3l
40
25
72
82
Ph
NH2
N
O
O
13
1a
25
86
2e
3m
Cl
OH
Cl
NH2
2b
N
O
14
25
75
Cl
3n
1d
O
Cl

H. Zuo et al. / Tetrahedron Letters 49 (2008) 3827–3830
3829
Table 1 (continued)
Entry
Phenol
Amine
Productb
Time (min)
30
Yieldc (%)
Cl
OH
Cl
Bn
N
NH2
Cl
O
15
55
2a
3o
1e
1e
O
Cl
OH
Cl
NH2
2b
16
35
62
Cl
N
O
O
3p
a
Reaction conditions: ClCH2COCl, CS2CO3, (i) 0 °C; (ii) 150 °C, MW.
b
c
All the products were characterized by mp, MS, 1H and 13C NMR spectra.
Isolated yields after column purification.
the reaction of 2,4-dichlorophenol 1a with chloroacetyl
chloride and benzyl amine 2a in the presence of Cs2CO3
under microwave irradiation at 150 °C for 28 min to obtain
the desired benzo[1,4]oxazin-3(4H)-one 3a in 70% yield
(entry 1). This result encouraged us to explore the reactivity
of other 2-chlorophenol substrates 1b and 1c with benzyl
amine 2a independently in the presence of chloroacetyl
chloride and Cs2CO3 under microwave irradiation to yield
the corresponding products 3b and 3c (entry 2 and 3). After
this success, a few other amines viz., cyclohexyl amine 2b,
n-hexyl amine 2c and tetrahydrofurfuryl amine 2d were
also treated with chloroacetyl chloride and 2-chlorophenols
1a, 1b and 1c in the presence of Cs2CO3 under microwave
irradiation and it was found that the transformation pro-
ceeded well to give the desired products 3d to 3l in good
yields (entries 4–12). The synthesis of benzo[1,4]oxazin-
3(4H)-ones 3m to 3p from the corresponding 2-chlorophe-
nol and amine was also successful using the present proto-
col (entries 13–16). The GC–MS spectra of the all the
products clearly indicated the formation of the correspond-
ing product and IR, 1H and 13C NMR spectra further con-
firmed the structures of benzo[1,4]oxazin-3(4H)-ones 3a–p.
The formation of benzo[1,4]oxazin-3(4H)-one product
3o was confirmed by synthesizing it from the reaction of
4-chloro-2-amino phenol 4 with 2-chloroacetyl chloride
using a known stepwise method (Scheme 2). 2-Chloroacetyl
chloride was reacted with 4 to afford the intermediate 5,
which was cyclized to afford 6. Compound 6 was then trea-
ted with benzyl chloride to furnish compound 3o. Product
3o obtained by two different synthetic routes, that is, from
aminophenol 4 (Scheme 2) and from 2,5-dichlorophenol 1e
(Scheme 1) was compared using physical and spectral data.
Rf value (TLC), melting point, GC–MS and NMR spectral
data of the two compounds were found to be the same.
A mechanistic rationalization for this reaction is pro-
vided in Scheme 3 (exemplified by 3o). The cyclization of
O-alkylated product by Smiles rearrangement occurred
via two steps: the spiro-type intermediate was formed in
the first step, and was rearranged in the second step with
the loss of HCl yielding compound 3o.
In summary, we have developed a one-pot, three-step
synthesis of benzo[b][1,4]oxazin-3(4H)-one derivatives of
potential synthetic and pharmacological interest assisted
by microwave irradiation via Smiles rearrangement. The
use of simple starting materials and short reaction time
are the notable advantages of this method, which may find
applications in the synthesis of diversified benzo[b][1,4]oxa-
zin-3(4H)-one derivatives.
H
N
H
Cl
NH2
OH
Cl
Cl
O
N
Cl
K2CO3
ClCH2COCl, K2CO3
O
DMF, reflux
1h, 80 %
CH3CN, rt
3 h, 90%
O
OH
4
6
5
BnCl, K2CO3
DMF, reflux,
1 h, 82%
Bn
Cl
N
O
O
3o
Scheme 2. Alternative route for the synthesis of 3o.

3830
H. Zuo et al. / Tetrahedron Letters 49 (2008) 3827–3830
Cl
Bn
NH
O
HO
Cl
Cl
Cl
O
O
NHBn
Cl
Cl
1e
BnNH2
O
Cl
Cs2CO3
2a
Cl
N
H
O
H
O
O
Cs2CO3
- HCl
-Cl
Cl
O
N
Bn
Cl
O
N
Bn
Cl
Bn
O
3o
Scheme 3. Proposed mechanism.
S. G.; Giester, G.; Leban, I.; Kikelj, D. J. Org. Chem. 2001, 66, 7044;
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Acknowledgement
This work was supported by Grants from the Korea
Research Foundation (KRF200-005-D20016).
¨
¨
11. (a) Ozden, S.; Ozturk, A. M.; Go¨ker, H.; Altanlar, N. Il Farmaco
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Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.
03.120.
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