Indium mediated reductive heterocyclization of 2-nitroacylbenzenes or 2- nitroiminobenzenes toward 2,1-benzisoxazoles in aqueous media

Article abstract of DOI:10.1016/S0040-4039(00)00098-8

2-Nitro-substituted acylbenzenes or iminobenzenes such as 2- nitrobenzaldehydes, 2'-nitroacetophenone, and N(2-nitrobenzylidene)anilines were cyclized toward 2,1-benzisoxazoles in the presence of 2-bromo-2- nitropropane and indium in an MeOH/H₂O solution in excellent yields. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00098-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2137–2140
Indium mediated reductive heterocyclization of
2-nitroacylbenzenes or 2-nitroiminobenzenes toward
2,1-benzisoxazoles in aqueous media
Byeong Hyo Kim,a,∗ Youngoo Jin,a Young Moo Jun,a Rongbi Han,a Woonphil Baik b and
Byung Min Lee c
aDepartment of Chemistry, Kwangwoon University, Seoul 139-701, South Korea
bDepartment of Chemistry, Myong Ji University, Kyung Ki Do, South Korea
cKorea Research Institute of Chemical Technology, Taejon, South Korea
Received 7 December 1999; revised 5 January 2000; accepted 7 January 2000
Abstract
2-Nitro-substituted acylbenzenes or iminobenzenes such as 2-nitrobenzaldehydes, 20-nitroacetophenone, and N-
(2-nitrobenzylidene)anilines were cyclized toward 2,1-benzisoxazoles in the presence of 2-bromo-2-nitropropane
and indium in an MeOH/H2O solution in excellent yields. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: benzisoxazoles; cyclization; electron transfer; indium and compounds.
Compared to other metals, indium has not been explored much in organometallic reactions. Recently,
studies on indium-mediated reactions in aqueous media have focused on synthetic applications because
of environmental issues and the ease of reactions, obviating the need for inflammable anhydrous organic
solvents and an inert atmosphere.1 Indium has been applied to various reactions in aqueous conditions
without an inert atmosphere: alkylation of aldehydes and ketones,2 reductive coupling of aldimines,3
Reformatsky and aldol reactions,4 allenylation of aldehydes,5 and ring expansion of carbocycles.6
Without doubt, indium metal can be a suitable candidate for an electron donor in single electron
transfer (SET) processes and has some striking advantages over other metals, i.e., indium metal is
unaffected by air or oxygen at ordinary temperatures and is practically unaffected by water. Of special
interest to us was the possibility of utilizing an indium-promoted reaction for the preparation of various
nitrogen-containing heterocyclic compounds as an extension of studies on reductive cyclization reaction
of 2-nitroarenes,7 since the application of indium to other than carbon–carbon bond formation was
unprecedented elsewhere. Herein, we wish to report the utilization of indium for the preparation of 2,1-
benzisoxazoles, which are very useful in the pharmaceuticals.
∗
Corresponding author. E-mail: bhkim@daisy.kwangwoon.ac.kr (B. H. Kim)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00098-8
tetl 16379

2138
As control experiments, various reaction conditions were attempted to examine the use of indium
for the reductive cyclization of 2-nitrobenzaldehyde and the results are summarized in Table 1. The
reactions of 2-nitrobenzaldehyde (1) with indium (5 equiv.) in methanol (Table 1, entry 1), in water
(entry 2), or in a methanol/water co-solvent (entry 3) at 50°C did not exhibit any effective cyclizations
and 2-nitrobenzaldehyde was recovered completely in every case. However, addition of BNP to the
reaction mixture made the reductive cyclization of 2-nitrobenzaldehyde possible and the formation of
2,1-benzisoxazole was observed as expected.
Table 1
Reactions of 2-nitrobenzaldehyde in the presence of BNP/indium under the various reaction conditions
As shown in Table 1, reactions both in methanol and in water worked well when proper amounts of
BNP and indium were present. Usually, the reaction in an aqueous solution completed much faster than
in methanol. The optimum condition was obtained when 2 equiv. of BNP and 5 equiv. of indium were
applied in methanol/water (v:v=1:2) with 2-nitrobenzaldehyde at 50°C (entry 11) and the reaction time
was diminished dramatically compared to our previous zinc-mediated reaction.7a It produced almost a
quantitative yield of desired 2,1-benzisoxazole within 10 min!
The role of BNP is to be an electron acceptor due to its low-lying antibonding π-orbital and the
utility of BNP has been described by Russell et al.8 and by us.7 To ensure the electron accepting
ability of BNP, the cyclic voltammetric behavior of BNP was examined. BNP [−0.26 V, Pt cathode,
0.3 M LiClO4/MeOH/H2O (v:v=1:2) 40 mV/s] exhibited quite lower reduction potential compared
to 2-nitrobenzaldehyde [−0.64 V, Pt cathode, 0.3 M LiClO4/MeOH/H2O (v:v=1:2), 40 mV/s] in the
aqueous co-solvent medium. Furthermore, addition of di-tert-butyl nitroxide or m-dinitrobenzene has
shown strong inhibitory effects. Compared to the normal reaction of nitrobenzaldehyde in MeOH (entry
4), the reactions of nitrobenzaldehyde/BNP/indium in MeOH in the presence of 10 mol% of di-tert-
butyl nitroxide or m-dinitrobenzene had shown about 1 h initial retardation for each and completion time

2139
Table 2
The reactions of substituted 2-nitrobenzaldehydes, 20-nitroacetophenone, or N-(2-
nitrobenzylidene)anilines in the presence of BNP (2 equiv.)/indium (5 equiv.) in MeOH/H2O
(v:v=1:2) at 50°Ca
was delayed with decrement of yields (6 h, 75% and 62% each). This indicates that radical and radical
anion are involved during the reductive cyclization. Thus, BNP, a good electron acceptor, can easily take
the electron from indium to form BNP radical anion that dissociates immediately to 2-nitropropan-2-yl
radical and bromide anion. We believe 2-nitropropan-2-yl radical reacts with a nitro group to generate a
nitroso intermediate.
In order to test the synthetic utility of BNP/In conditions, we examined the reductive cyclizations
of various substituted 2-nitrobenzaldehydes, 20-nitroacetophenone, and N-(2-nitrobenzylidene)anilines
under the optimized condition. Our works concerning the reductive cyclizations using BNP/In are
summarized in Table 2. A trial for the Pd-catalyzed reduction of halogenated aromatic nitro compound
was reported to provide a dehalogenated product.9 In most of our cases, cyclizations were completed
within 10–60 min with excellent yields independent of the electronic effect of the substituent. However,
in the case of 3-methoxy-2-nitrobenzaldehyde which has an ortho-methoxy group relative to the nitro
group, the yield of the reductive cyclization toward 7-methoxy-2,1-benzisoxazole was drastically reduced

2140
to 61% and formation of the by-product, 2-amino-3-methoxybenzaldehyde, was observed in a large
amount (∼30%) which was not formed in other reactions (Table 2, entry 5). A similar trend was observed
for 3-methoxy-substituted N-(2-nitrobenzylidene)aniline (entry 11). This strongly indicates that steric
hindrance of the methoxy group retards the reaction between the nitro group and the 2-nitropropan-
2-yl radical generated from BNP radical anion, which will be a key step for the heterocyclization.
Consequently, a simple reduction of the nitro group can compete with the heterocyclization reaction
because electron and proton transfer processes are relatively free from the steric requirement. Despite
its accompanying low yielding problem with 3-substituted 2-nitroarenes, the reductive cyclization of
nitroarenes substituted with acid labile alkoxy functional groups using BNP/In in our neutral condition
provides an efficient and selective method for the synthesis of 2,1-benzisoxazole derivatives. Reductive
cyclization of 2,6-dinitrobenzaldehyde failed to obtain 4-nitro-2,1-benzisoxazole although all the starting
substrate was consumed (entry 12).
A typical procedure for the BNP-mediated reductive cyclization reaction is as follows. To a stirred
solution of 2-nitroarene derivative (1 mmol) and indium dust (0.574 g, 5 mmol) in MeOH/H2O (v:v=1.5:3
mL, for acylbenzenes, or v:v=0.75:1.5 mL, for imines) was added 2-bromo-2-nitropropane (0.336 g, 2
mmol) at 50°C. After the reaction was completed, the reaction mixture was taken up in CH2Cl2/10%
aqueous NH4Cl solution and extracted with CH2Cl2 (3×50 mL). The combined organic layer was
dried over MgSO4 and concentrated. If necessary, GC yield was determined with an internal standard.
Products were isolated by flash column chromatography with ethyl acetate:hexane (5:95–1:99) and are
fully characterized. For the full spectral data of products, see our previous reports.7
It is quite clear that the neutral condition in aqueous medium for the reductive heterocyclization
overwhelms any other methods shown in the literature, since our condition is mild and the reaction is
completed in a short reaction time. Further study of the application of BNP/In in an aqueous medium to
the heterocyclization reaction is underway.
Acknowledgements
Financial support from the Korea Research Foundation (1998-001-D00504) and partly from the
Kwangwoon University are gratefully acknowledged.
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