Reductive heterocyclizations via indium/iodine-promoted one-pot conversion of 2-nitroaryl aldehydes, ketones, and imines

Article abstract of DOI:10.1016/j.tetlet.2006.08.027

2-Nitroaryl aldehydes, ketones, and imines were reductively cyclized to 2,1-benzisoxazoles with good yields in the presence of indium and iodine in MeOH. Under a similar condition, N-(2-nitrobenzylidene)anilines were produced mixtures of 2,1-benzisoxazoles and 3-anilino-2-phenyl-2H-indazoles.

Full text of DOI:10.1016/j.tetlet.2006.08.027

Tetrahedron Letters 47 (2006) 7295–7299
Reductive heterocyclizations via indium/iodine-promoted
one-pot conversion of 2-nitroaryl aldehydes, ketones, and imines
Rongbi Han,a,b Kee In Son,a Gil Hwan Ahn,a Young Moo Jun,a Byung Min Lee,c
Younbong Parkd and Byeong Hyo Kima,*
aDepartment of Chemistry, Kwangwoon University, Seoul 139-701, Republic of Korea
bKey Laboratory of Organism Functional Factors of the Changbai Mountain, MOE, Yanbian University, Jilin 133002, China
cKorea Research Institute of Chemical Technology, Taejon 305-600, Republic of Korea
dDepartment of Chemistry, Chungnam National University, Taejon 305-764, Republic of Korea
Received 17 July 2006; revised 4 August 2006; accepted 10 August 2006
Available online 1 September 2006
Abstract—2-Nitroaryl aldehydes, ketones, and imines were reductively cyclized to 2,1-benzisoxazoles with good yields in the pres-
ence of indium and iodine in MeOH. Under a similar condition, N-(2-nitrobenzylidene)anilines were produced mixtures of 2,1-benz-
isoxazoles and 3-anilino-2-phenyl-2H-indazoles.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Since the past decade, indium has been receiving increas-
ing interest due to its applications in organic transfor-
mations.1 In particular, indium-mediated reactions in
aqueous media have been focused on synthetic applica-
tions because of environmental issues and the ease of
reactions that obviate the need for inflammable anhy-
drous organic solvents and inert atmosphere.1b Indium
can be used in various reactions in aqueous conditions
without requiring inert atmosphere: in alkylation of
aldehydes and ketones,2 reductive coupling of aldi-
mines,3 Reformatsky and aldol reactions,4 allenylation
or allylation of aldehydes and ketones,5 and ring expan-
sion of carbocycles.6
method, and it can initiate the heterocyclization toward
nitrogen-containing heterocycles such as 2,1-benz-
isoxazoles and benzotriazoles when it has a proper
functional group at the ortho position. Moreover,
reductive heterocyclizations using indium were also
successfully transformed into heterocyclic compounds
such as 2,1-benzisoxazoles,10a benzimidazoles,10b and
quinolines.10c
In recent years, iodine has been used for various organic
transformations including Lewis acid catalyst.11 Fur-
thermore, iodine has been known to make a reactive
intermediate reacting with indium metal under proper
conditions.12 A combination of indium and iodine has
been recently used for atom-transfer cyclizations such
as the reductive cyclizations of iodoalkyne to the 5-exo
cyclized product.13 Therefore, it would be interesting
to apply and make use of the environmentally favorable
indium and iodine. Thus, we examined the combined use
of indium and additives such as iodine to develop useful
reductive condition for the heterocyclization in terms of
green chemistry. We hereby report on the utilization of
indium and iodine for the preparation of 2,1-benz-
isoxazoles, which can be useful in pharmaceuticals.
Of special interest to us is the possibility of utilizing the
indium-promoted reaction for the preparation of various
nitrogen-containing heterocyclic compounds as an
extension of the study on reductive cyclization reaction
of 2-nitroarenes,7 as only a limited number of applica-
tions of indium, other than carbon–carbon bond forma-
tion, are found in the literature.1a,8 In our study of
heterocyclic compound formation via reductive cycliza-
tion reaction of nitroarenes,7,9 we have found that the
nitro group can bereduced by chemicalorelectrochemical
Prior to the study of reductive cyclization reaction, the
reduction of nitrobenzene was attempted to examine
the reductive power of some indium-related reagents.
As we somehow expected, no reaction occurred at
Keywords: Indium and compounds; Reduction; Nitro compounds.
*
Corresponding author. Tel.: +82 2 940 5247; fax: +82 2 942 4635;
e-mail: bhkim@daisy.kw.ac.kr
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.027

7296
R. Han et al. / Tetrahedron Letters 47 (2006) 7295–7299
all when indium (Table 1, entry 1), iodine (entry 2) or
indium(III) iodide (entry 3) was used as the only
reagent. Although the indium itself did not reduce the
nitro group, indium(I) iodide showed a reasonable
reductive power and the reaction produced a mixture
of aniline and azoxybenzene (entries 4 and 5). Unlike
indium(I) iodide reactions, the combined use of indium
and iodine in MeOH produced aniline as a major prod-
uct with hydrazobenzene and a trace amount of azo- or
azoxybenzene by-products (entry 6), which was a good
indication for the possibility of reductive cyclization of
o-nitro-substituted arenes.
to the reaction mixture did not help to increase the
2,1-benzisoxazole product; instead, it facilitated the
acetal formation (entry 2). However, the reaction of 2-
nitrobenzaldehyde in the presence of indium and iodine
in MeOH at 50 ꢁC gave better results, that is, it pro-
duced the 2,1-benzisoxazole as a predominant product
(entries 3 and 4). Both a combined use of indium/iodine
and the use of indium(I) iodide showed comparable
reductive abilities. However, the combined use of
indium/iodine was proved to be better for synthetic
utility as it produced better yield with much less
by-products and is relatively cheap and easy to handle
compared with indium(I) iodide. The role of iodine
would be both acting as Lewis acid11 and acting as an
activating reagent for the electron transferring ability
of indium.12
As indium and related reagents turned out to have rea-
sonable reductive power, reductive conditions that were
attempted with nitrobenzene were applied for the reduc-
tive cyclization of 2-nitrobenzaldehyde, which was
expected to produce 2,1-benzisoxazoles similar to the
results of our previous studies. The representative
indium-mediated reductive cyclizations are summarized
in Table 2. The reaction of 2-nitrobenzaldehyde using
indium(I) iodide in MeOH gave 76% of 2,1-benz-
isoxazole, along with 9% of 2-aminobenzaldehyde
(Table 2, entry 1). The addition of indium(III) iodide
To test the synthetic utility of the indium/iodine-pro-
moted reductive reaction for the synthesis of 2,1-benz-
isoxazole derivatives, heterocyclizations of substituted
2-nitrobenzaldehydes, 20-nitroacetophenone, and 2-
nitrobenzophenones were examined using the optimized
reaction conditions (Table 3, entries 1–11). In most
cases, cyclization reaction appears to be generally
Table 1. Indium-mediated reductive reaction of nitrobenzene under various reaction conditions at 50 ꢁC in MeOH
NO2
MeOH
50 oC, 12 h
+ In, I2 and/ or InXn
Reductive Products
Product (yield, %)a
Entry
Molar equivalent
In:I2:InI:InI3
O
N
H
H
PhNH2
N
N
Ph
Ph
Ph
N
Ph
1
2
3
4b
5b
6b
3:0:0:0
0:1:0:0
0:0:0:2
0:0:2:0
0:0:2:2
3:1:0:0
No reaction
No reaction
No reaction
16
17
69
—
—
ꢀ20
75
70
Trace
a GC yield with an internal standard.
b Trace amount of azobenzene was observed on GCMS.
Table 2. Indium-mediated reductive reaction of 2-nitrobenzaldehyde under various reaction conditions at 50 ꢁC in MeOH
O
H
MeOH
50 oC
In, I2 and/ or InXn
+
Reductive Products
Product (yield, %)a
NO2
Entry
Molar equivalent
In:I2:InI:InI3
Time (h)
OMe
O
O
H
OMe
NO2
N
NH2
1
2
3
4
5
6
0:0:2:0
0:0:2:2
3:1:0:0
3:0.8:0:0
0:0:0:2
0:1:0:0
2
2
1
1
2
76
55
83
87
—
—
9
10
Trace
—
Trace
—
Trace
21
—
—
94
72
12
a Isolated yield.

R. Han et al. / Tetrahedron Letters 47 (2006) 7295–7299
7297
Table 3. Reductive cyclization of 2-nitroacylbenzenes or 2-nitroiminobenzenes (1.0 mmol) in the presence of indium (3.0 equiv)/I2 (0.8 equiv) in
MeOH (3 mL) at 50 ꢁC
R1
R1
X
NHPh
N Ph
1 In (3 equiv)/ I2 (0.8 equiv)
MeOH, 50 oC
In (3 equiv)/ I2 (0.8 equiv)
MeOH, 50 oC
(X= O, R1= H, Me, Aryl)
R
O
+
O
N
N
NO2
N
(X= N-Ph, R1= H)
Entry
1
Substrate
CHO
Time (h)
Product(s) (yield, %)a
O
1.5
6
(1a, 87%)
N
N
NO2
Cl
Cl
CHO
NO2
2
3
(2a, 85%)
O
Cl
CHO
NO2
Cl
2
(3a, 95%)
O
N
CHO
NO2
O
N
b
(4a, 50% )
4
5
6
7
5
5
6
5
OMe
OMe
CHO
NO2
O
O
O
(5, 80%)
O
O
N
N
Me
CHO
NO2
Me
(6, 87%)
(7, 42%)
O
CHO
NO2
O
O
N
N
Me
NO2
Me
NO2
CHO
NO2
c
8
24
(8, 18% )
Me
O
COMe
NO2
9
4
4
(9, 88%)
N
OMe
O
10
(10, 81%)
O
NO2
OMe
Me
N
Me
O
Me
(11, 88%)
11
12
6
4
Me
NO2
O
O
N
N
NHPh
N Ph
Ph
N
(1a, 56%)
(1b, 27%)
+
NO2
N
(continued on next page)

7298
R. Han et al. / Tetrahedron Letters 47 (2006) 7295–7299
Table 3 (continued)
Entry
Substrate
Cl
Time (h)
6
Product(s) (yield, %)a
Cl
Cl
NHPh
N Ph
Ph
N
13
O
(2b, 25%)
(2a, 56%)
+
N
NO2
N
NHPh
Cl
Ph
Cl
N
Cl
14
15
6
O
(3a, 70%)
(3b, 15%)
N Ph
+
NO2
N
N
NHPh
N Ph
Ph
N
d
O
(4a, 68%)
(4b, 13% )
6
6
+
NO2
N
N
OMe
OMe
OMe
Ph
O
O
N
(5, 76%)
16
O
O
O
N
NO2
a
b
c
Isolated yield.
2-Amino-3-methoxybenzaldehyde was formed (16%).
Substrate was remained.
d
Trace amount of N-[(2-amino-3-methoxyphenyl)methylene]benzenamine was observed.
applicable, as all of the substrates were consumed within
1.5–6 h to give the corresponding 2,1-benzisoxazoles
in 80–95% yields independent of the electronic effect
of the substituents. In the case of chloro-substituted
2-nitrobenzaldehydes, the corresponding chloro-substi-
tuted 2,1-benzisoxazole was obtained in high yield (en-
tries 2 and 3) without giving any of the dechlorinated
product, which was a promising indication of its mild
reductive condition. Moreover, the indium/iodine-pro-
moted reductive reaction could also be useful for the
reductive cyclization of nitroarenes substituted with acid
labile alkoxy groups as well. In addition, similar to the
reactions of 2-nitrobenzaldehydes, the indium/iodine-
promoted reductive reaction of 2-nitroaryl ketones such
as 20-nitroacetophenone and 2-nitrobenzophenones
worked well giving the corresponding 3-substituted
2,1-benzisoxazoles in 81–88% yields (entries 9–11).
However, 3-substituted 2-nitroarenes, that is, ortho-
substituted arenes relative to the nitro group (entries 4
and 7), produced relatively low yields of the desired
product compared with others, presumably because of
the steric effect of the groups that may interfere with
the reductive reaction of the nitro group. The reductive
cyclization of 2,6-dinitrobenzaldehyde (entry 8) was
strongly retarded possibly because of the inhibitory
effect of the secondary nitro functionality that may
inhibit the single electron transfer processes.
of 2,1-benzisoxazole (56%) and 3-anilino-2-phenyl-
2H-indazole (27%) (entry 12). The formation of
3-anilino-2-phenyl-2H-indazole was somehow unex-
pected and the reactions of halo or methoxy substituted
N-(2-nitrobenzylidene)anilines also exhibited similar
results, producing mixtures of 2,1-benzisoxazoles and
3-anilino-2-phenyl-2H-indazoles (entries 13–15). We
presumed that 3-anilino-2-phenyl-2H-indazoles might
come from the effect of in situ formed anilines, which
are leaving groups when 2,1-benzisoxazoles are formed.
As indazole derivatives have also attracted much atten-
tion for their pharmaceutical activities, such as anti-
inflammatory, anti-tumor, and anti-HIV properties,
and our indazole derivatives are unknown compounds,
it would be valuable to investigate the reductive reac-
tions of N-(2-nitrobenzylidene)aniline derivative with
the indazole derivative as a major product. Thus, we
are now focusing on the 3-anilino-2-phenyl-2H-indazole
formation reaction to develop as a new synthetic meth-
odology for the indazole synthesis and to solve mecha-
nistic considerations.
A typical procedure for the reductive heterocyclization
is as follows: 2-nitrobenzaldehyde derivative or N-(2-
nitrobenzylidene)aniline derivative (1.0 mmol) was
added to a mixture of indium powder (345 mg,
3.0 mmol) and iodine (203 mg, 0.8 mmol) in MeOH
(3 mL). The reaction mixture was stirred at 50 ꢁC under
a nitrogen atmosphere. After the reaction was complete,
the reaction mixture was diluted with CH2Cl2 (30 mL),
filtered through Celite, and poured into 10% NH4Cl
solution and extracted with CH2Cl2 (30 mL · 3). The
combined organic extracts were dried over MgSO4, fil-
tered, and concentrated. The residue was eluted with
ethyl acetate/hexane (v/v = 2/98–20/80) through a silica
gel column to give the corresponding 2,1-benzisoxazoles
and indazoles. Structures of 2,1-benzisoxazoles and
As an extension of the indium/iodine-promoted
reductive cyclization reaction, heterocyclizations of
N-(2-nitrobenzylidene)aniline derivatives were examined
(entries 12–16). In our previous study, the reductive
cyclizations of both 2-nitrobenzoyls and N-(2-nitrobenz-
ylidene)anilines produced the same products, 2,1-benz-
isoxazoles, with similar yields.7a,b Interestingly, reduc-
tive cyclization of N-(2-nitrobenzylidene)aniline in the
presence of indium/iodine in MeOH produced a mixture

R. Han et al. / Tetrahedron Letters 47 (2006) 7295–7299
7299
3. Kalyanam, N.; Rao, G. V. Tetrahedron Lett. 1993, 34,
1647–1648.
4. Chan, T. H.; Li, C. J.; Lee, M. C.; Wei, Z. Y. Can. J.
Chem. 1994, 72, 1181–1192.
5. (a) Chan, T. H.; Isaac, M. B. J. Chem. Soc., Chem.
Commun. 1995, 1003–1004; (b) Alcaide, B.; Almendros, P.;
Rodriguez-Acebes, R. J. Org. Chem. 2005, 70, 3198–3204;
(c) Kaur, P.; Singh, P.; Kumar, S. Tetrahedron 2005, 61,
8231–8240; (d) Min, J.-H.; Jung, S.-Y.; Wu, B.; Oh, J. T.;
Lah, M. S.; Koo, S. Org. Lett. 2006, 8, 1459–1462.
6. Li, C. J.; Haberman, J. X. Tetrahedron Lett. 1997, 38,
4735–4736.
7. (a) Kim, B. H.; Jun, Y. M.; Kim, T. K.; Lee, Y. S.; Baik,
W.; Lee, B. M. Heterocycles 1997, 45, 235–240; (b) Kim, B.
H.; Lee, Y. S.; Kwon, W.; Jin, Y.; Tak, J. A.; Jun, Y. M.;
Baik, W.; Lee, B. M. Heterocycles 1998, 48, 2581–2592; (c)
Baik, W.; Yoo, C. H.; Koo, S.; Kim, H.; Hwang, Y. H.;
Kim, B. H.; Lee, S. W. Heterocycles 1999, 51, 1779–1783.
8. (a) Moody, C. J.; Pitts, M. R. Synlett 1998, 1028; (b)
Moody, C. J.; Pitts, M. R. Synlett 1998, 1029–1030; (c)
Moody, C. J.; Pitts, M. R. Synlett 1999, 1575–1576; (d)
Ranu, B. C.; Guchhait, S. K.; Sarkar, A. J. Chem. Soc.,
Chem. Commun. 1998, 2113–2114; (e) Ranu, B. C.; Dutta,
P.; Sarkar, A. J. Chem. Soc., Perkin Trans. 1 1999, 1139–
1140; (f) Reddy, G. V.; Rao, G. V.; Iyengar, D. S.
Tetrahedron Lett. 1999, 40, 3937–3938; (g) Pitts, M. R.;
Harrison, J. R.; Moody, C. J. J. Chem. Soc., Perkin Trans.
1 2001, 955–977, and references therein.
9. (a) Baik, W.; Park, T. H.; Kim, B. H.; Jun, Y. M. J. Org.
Chem. 1995, 60, 5683–5685; (b) Kim, B. H.; Kim, S. K.;
Lee, Y. S.; Jun, Y. M.; Baik, W.; Lee, B. M. Tetrahedron
Lett. 1997, 38, 8303–8306; (c) Kim, B. H.; Jun, Y. M.;
Choi, Y. R.; Lee, D. B.; Baik, W. Heterocycles 1998, 48,
749–754; (d) Kim, B. H.; Lee, D. B.; Kim, D. H.; Han, R.;
Jun, Y. M.; Baik, W. Heterocycles 2000, 53, 841–850.
10. (a) Kim, B. H.; Jin, Y.; Han, R.; Baik, W.; Lee, B. M.
Tetrahedron Lett. 2000, 41, 2137–2140, 4244; (b) Kim, B.
H.; Han, R.; Kim, J. S.; Jun, Y. M.; Baik, W.; Lee, B. M.
Heterocycles 2004, 62, 41–54; (c) Han, R.; Chen, S.; Lee,
S. J.; Qi, F.; Wu, X.; Kim, B. H. Heterocycles 2006, 68,
1675–1684.
Figure 1. The molecular structure of (4-chloro-2-phenyl-2H-indazol-3-
yl)phenylamine (2b) with an atom-labeling scheme.
indazoles were fully characterized by 1H NMR, 13C
NMR, FTIR, MS, and HRMS. X-ray crystal structure
of
(4-chloro-2-phenyl-2H-indazol-3-yl)phenylamine
(one of the indazoles) was obtained for the decisive
structure determination (Fig. 1).14
In conclusion, we have described a simple and efficient
method for a one-pot preparation of 2,1-benzisoxazoles
from nitroarenes using indium/iodine in MeOH under
mild conditions. Under a similar condition, N-(2-nitro-
benzylidene)anilines produced mixtures of 2,1-benz-
isoxazoles and 3-anilino-2-phenyl-2H-indazoles. The
development of a new methodology for the indazole
synthesis from N-(2-nitrobenzylidene)anilines is now
under investigation.
11. Bhosale, R. S.; Bhosale, S. V.; Bhosale, She. V.; Wang, T.;
Zubaidha, P. K. Tetrahedron Lett. 2004, 45, 7187–7188,
and references therein.
12. Freeland, B. H.; Tuck, D. G. Inorg. Chem. 1976, 15, 475–
476.
Acknowledgments
13. (a) Yanada, R.; Nishimori, N.; Matsumura, A.; Fujii, N.;
Takemoto, Y. Tetrahedron Lett. 2002, 43, 4585–4588; (b)
Yanada, R.; Koh, Y.; Nishimori, N.; Matsumura, A.;
Obika, S.; Mitsuya, H.; Fujii, N.; Takemoto, Y. J. Org.
Chem. 2004, 69, 2417–2422; (c) Yanada, R.; Obika, S.;
Nishimori, N.; Yamauchi, M.; Takemoto, Y. Tetrahedron
Lett. 2004, 45, 2331–2334.
This work was supported by the Korean Government
through
a
Korea Research Foundation Grant
(MOEHRD, KRF-2005-C00250) and partly by Kwang-
woon University in the year 2005.
14. Spectroscopic data of (4-chloro-2-phenyl-2H-indazol-3-
yl)phenylamine: TLC (30% ethyl acetate/hexane) Rf 0.46;
References and notes
1
mp 178–180 ꢁC; H NMR (300 MHz, CDCl3) d 7.67–7.58
1. (a) Yamamoto, H.; Oshima, K. In Main Group Metals in
Organic Synthesis; Wiley-VCH: Weinheim, 2004; Vol. 1,
Chapter 8, pp 323–386; (b) Li, C. J.; Chan, T. H. Organic
Reactions in Aqueous Media; Wiley-Interscience: New
York, 1997; (c) Li, C. J. Tetrahedron 1996, 52, 5643–
5668; (d) Podlech, J.; Maier, T. C. Synthesis 2003, 633–
655; (e) Nair, V.; Ros, S.; Jayan, C. N.; Pillai, B. S.
Tetrahedron 2004, 60, 1959–1982; (f) Kumar, S.; Pervin-
der, K.; Vijay, K. Curr. Org. Chem. 2005, 9, 1205–1235.
2. (a) Chan, T. H.; Li, C. J. Tetrahedron Lett. 1991, 32, 7017–
7020; (b) Paquette, L. A.; Bennett, G. D.; Chhatriwalla,
A.; Isaac, M. B. J. Org. Chem. 1997, 62, 3370–3374; (c)
Bose, A. K.; Jayaraman, M.; Manhas, M. S. Tetrahedron
Lett. 1997, 38, 709–712.
(m, 3H), 7.40–7.29 (m, 3H), 7.21–7.11 (m, 3H), 7.00 (d,
1H, J = 7.2 Hz) 6.82 (t, 1H, J = 7.2 Hz) 6.57 (d, 2H,
J = 7.7 Hz) 5.92 (s, 1H); 13C NMR (75 MHz, CDCl3) d
149.2, 145.5, 138.6, 132.5, 129.2, 129.0, 128.5, 127.1, 125.3,
124.5, 121.8, 120.3, 116.8, 115.1, 114.7; IR (nujol) 3225,
3036, 1601, 1256, 749, 690 cmꢁ1; GC–MS m/z (rel
intensity) 319 (M+, 100), 283 (11), 207 (9), 178 (7), 77
(23); HRMS (EI) calcd for C19H14ClN3 319.0876, found
319.0874. The crystallographic data for the structure of
(4-chloro-2-phenyl-2H-indazol-3-yl)phenylamine in this
paper have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication num-
ber CCDC 614941.