Oxidation of 2-arylindoles for synthesis of 2-arylbenzoxazinones with oxone as the sole oxidant

Article abstract of DOI:10.1039/c3cc44215b

A novel and efficient method for the oxidation of 2-arylindoles to synthesize 2-arylbenzoxazinones utilizing oxone as the sole oxidant has been developed. The reaction tolerates a wide range of functional groups and allows quick and atom-economical assembly of a variety of valuable 2-arylbenzoxazinones in high yields.

Full text of DOI:10.1039/c3cc44215b

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Oxidation of 2-arylindoles for synthesis of
2-arylbenzoxazinones with oxone as the sole oxidant†
Cite this: DOI: 10.1039/c3cc44215b
Xiao-Li Lian, Hao Lei, Xue-Jing Quan, Zhi-Hui Ren, Yao-Yu Wang and
Zheng-Hui Guan*
Received 5th June 2013,
Accepted 17th July 2013
DOI: 10.1039/c3cc44215b
www.rsc.org/chemcomm
A novel and efficient method for the oxidation of 2-arylindoles to of anthranilic acid or N-acetylanthranilic acid,5 palladium cata-
synthesize 2-arylbenzoxazinones utilizing oxone as the sole oxidant lyzed carbonylation reactions have emerged for the synthesis of
has been developed. The reaction tolerates a wide range of func- benzoxazinones. Alper and co-workers6 and Wu and Beller7 have
tional groups and allows quick and atom-economical assembly of a independently developed palladium catalyzed carbonylation of
variety of valuable 2-arylbenzoxazinones in high yields.
ortho-haloanilines to synthesize benzoxazinones. Palladium-
catalyzed direct carbonylation of benzanilides or aryl urea deriva-
Benzoxazinones are some of the most important fused hetero- tives for the synthesis of benzoxazinones has been developed by the
cycles in many biological compounds and pharmaceutical drugs Yu group8 and the Lloyd-Jones and Booker-Milburn group,9 respec-
(Fig. 1).1 They are also versatile building blocks in organic tively. Recently, Liu and co-workers have developed an interesting
synthesis and medicinal chemistry.2 For example, 2-aryl-benzox- palladium catalyzed CRC triple bond cleavage of 2-azidoalkynyl-
azinones are valuable synthetic intermediates for the synthesis benzenes for the synthesis of benzoxazinones.10 Despite these
of bioactive quinazolin-4(3H)-one derivatives (Fig. 1).3 Therefore, advances, novel and efficient methods for the synthesis of benzox-
the methods for the synthesis of benzoxazinones have received azinones that are compatible with various functional groups and
intensive attention over the past decade.4 In addition to cyclization proceed under mild conditions remain highly desirable.
The selective oxidation is one of the most useful reactions for
organic transformations.11 Particularly, oxidation reactions that
utilize environmentally benign peroxides or O2 as the oxidants are
preferable according to the principles of green chemistry.12 Oxone
(2KHSO5ÁKHSO4ÁK2SO4), which is a stable, nontoxic and inexpensive
oxidant, shows great efficiency in many oxidative transformations,13
for example oxidation of aldehydes to carboxylic acids,14 epoxida-
tion of alkenes,15 and oxidative cleavage of alkenes or alkynes to
carboxylic acids.16 In this communication, we report the direct oxida-
tion of 2-arylindoles for the synthesis of 2-arylbenzoxazinones using
oxone as the sole oxidant under transition-metal-free conditions.
Initially, 2-phenylindole 1a was chosen as a test substrate to
optimize the reaction conditions (Table 1). A variety of oxidants
such as K2S2O8, (NH4)2S2O8, TBHP, m-CPBA and tBuOOtBu were
screened (Table 1, entries 1–5). 2-Phenylbenzoxazinone product 2a
was observed when (NH4)2S2O8 was used as the oxidant, albeit in
Fig. 1 Some bioactive benzoxazinones and their applications in the synthesis of
only 20% yield. H2O2 which is a good oxidant in Baeyer–Villiger
bioactive quinazolin-4(3H)-ones.
oxidation was also screened.17 However, only a trace of 2a was
obtained (Table 1, entry 6). Further screening of oxidants revealed
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry
of Education, Department of Chemistry & Materials Science, Northwest University,
Xi’an 710069, P. R. China. E-mail: guanzhh@nwu.edu.cn
that oxone showed great efficiency for this transformation. The
yield of 2-phenylbenzoxazinone 2a improved dramatically to
91% in the presence of oxone (Table 1, entry 7). Optimization of
different solvents revealed that DCE and CH3CN were inferior to
CH3NO2 in the reaction (Table 1, entries 8 and 9). It should be
noted that a slightly low yield of 2-phenylbenzoxazinone 2a was
† Electronic supplementary information (ESI) available: Experimental procedure,
characterization data, CIF of compound 2a, 1H and 13C NMR spectra of com-
pounds 2. CCDC 942843. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c3cc44215b
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Table 1 Optimization reaction conditions for direct oxidation of 2-phenylindolesa
Table 2 Oxidation of 2-phenylindoles for the synthesis of 2-phenylbenzox-
azinones with oxonea
Entry
Oxidant
Solvent
T (1C)
Yieldb (%)
Entry
1
Substrate 1
Product 2
Yieldb (%)
93
1
2
3
4
5
6
7
8
K2S2O8
(NH4)2S2O8
TBHP
tBuOOtBu
m-CPBA
H2O2
Oxone
Oxone
Oxone
Oxone
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
DCE
CH3CN
CH3NO2
CH3NO2
CH3NO2
CH3NO2
80
80
80
80
80
80
80
80
80
80
60
100
120
nr
20
16
nr
7
5
91
45
70
78c
10
93
90
2
90
52
76
84
83
80
50
85
88
9
10
11
12
13
Oxone
Oxone
Oxone
3
a
Reaction conditions: 1a (0.2 mmol), oxidant (3.0 equiv.) in solvent
4
b
c
(2 mL), under air. Isolated yield. K2CO3 (2.0 equiv.) was added.
obtained when the reaction was conducted under basic condi-
tions (Table 1, entry 10). The reaction temperature was also varied,
and 100 1C gave the best result (Table 1, entries 11–13).
5
With the optimized reaction conditions established, the scope
and generality of the reaction were investigated (Table 2). The
reaction showed high functional group tolerance and proved to be
a quite general methodology for the preparation of 2-phenylbenzox-
azinones. It is noteworthy that the reaction was insensitive to the
electronic effects of the substrates. 5-Methyl, fluoro, chloro or bromo
substituted indoles 1b–1f reacted smoothly to give the corresponding
products 2b–2f in high yields (Table 2, entries 2–6). Methoxyl
substituted 2-phenylindoles gave moderate yields of benzoxazinones
due to the partial decomposition of the products (Table 2, entries 3
and 8). Both 6- and 7-substituted indoles showed similar reactivity to
that of 5-substituted indoles in the transformations. Satisfactorily, a
wide range of valuable 6- or 7-substituted 2-phenylbenzoxazinones
2g–2m were synthesized in high yields (Table 2, entries 7–13). In
addition, 2-phenyl-4H-naphtho[1,2-d][1,3]oxazin-4-one 2n was also
obtained in 60% yield when 2-phenyl-1H-benzo[g]indole 1n was
used as the substrate (Table 2, entry 14).
6
7
8
9
10
11
12
13
92
80
Next, the effects of the substituents on the aryl ring of 2-aryl-
indoles were examined (Table 3). Similarly, the reaction was insensi-
tive to the electronic effects of the substituents. As shown in Table 3,
2-arylindoles with methyl, methoxyl, fluoro, chloro and bromo
groups on the aryl rings all gave the corresponding benzoxazinones
2o–2u in good to excellent yields. Moreover, 2-(5,6,7,8-tetrahydro-
naphthalen-1-yl)-1H-indole 1v reacted smoothly to give the desired
benzoxazinone 2v in 75% yield implying that this transformation
was insensitive to steric hindrance. However, simple indole was inert
in the reaction. Indol-2-yl pivalate 1w was transformed into indolin-
2-one 3 in 86% yield under the standard conditions. And isatoic
anhydride 4 was obtained in 78% yield when 2-imidazole substituted
indole 1x was used as the substrate (Scheme 1). It should be noted
that the obtained 2-arylbenzoxazinones can be further transformed
into a variety of pharmaceuticals, which are anti-bacterial, anti-fungal
70
60
14
a
Reaction conditions: 1a (0.2 mmol), oxone (3.0 equiv.) in CH3NO2
b
(2 mL) at 100 1C for 8–10 h. Isolated yield.
To gain more insight into the mechanism of the reaction,
and anti-tumor agents, through simple operations.18 Therefore, our oxidation of 2-phenyl-3H-indol-3-one A was performed under
oxidation reaction could provide a useful route for drug discovery.
the standard conditions. The 2-phenylbenzoxazinone 2a was
c
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2-phenylindole 1 by oxone gives 2-phenyl-3H-intermediate A.13,19
Then, Baeyer–Villiger oxidation of the intermediate A generates
the product 2.20
Table 3 Oxidation of 2-arylindoles for the synthesis of 2-arylbenzoxazinones
with oxonea,b
In summary, we have developed a simple, efficient and
practical method for the oxidation of 2-arylindoles to synthesize
2-arylbenzoxazinones. Environmentally benign, inexpensive,
and safe oxone was found to be a particularly effective terminal
oxidant in the reaction. The reaction tolerates a wide range
of functional groups and is a reliable method for the rapid
assembly of a variety of valuable 2-arylbenzoxazinones in high
yields under mild conditions.
We thank the National Natural Science Foundation of China
(NSFC-21272183, 21002077) and the Rising Stars Foundation of
Shanxi Province (2012KJXX-26) for financial support.
Notes and references
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c
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