An indium mediated efficient chemoselective deoxygenation of N-oxides and nitrones

Article abstract of DOI:10.1016/S0040-4039(02)00020-5

A simple and inexpensive procedure for the deoxygenation of N-oxides, such as N-arylnitrones, azoxybenzenes and N-heteroarene N-oxides with indium trichloride in acetonitrile at ambient pressure is described. The procedure gives high yields of deoxygenated products.

Full text of DOI:10.1016/S0040-4039(02)00020-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1877–1879
An indium mediated efficient chemoselective deoxygenation of
N-oxides and nitrones
Md Ilias, Dhiren C. Barman, Dipak Prajapati and Jagir S. Sandhu*
Regional Research Laboratory, Jorhat-785006, Assam, India
Received 12 November 2001; revised 11 December 2001; accepted 20 December 2001
Abstract—A simple and inexpensive procedure for the deoxygenation of N-oxides, such as N-arylnitrones, azoxybenzenes and
N-heteroarene N-oxides with indium trichloride in acetonitrile at ambient pressure is described. The procedure gives high yields
of deoxygenated products. © 2002 Elsevier Science Ltd. All rights reserved.
tic reaction conditions which effect substituents,16
uncontrolled reduction of nitrones 16b or reductive
cleavage of azoxy compounds11 to amines rather than
to the expected imines or azo compounds, respectively.
Moreover, the titanium tetrachloride–NaBH4 complex,
used by Kano,17 was found to reduce the aromatic ring
in the substrate. Also, in a very recent finding,18
HCOONH4/10% Pd–C reduces pyridine N-oxides to
their corresponding piperidine derivatives. We report
herein, the utility of indium(III) chloride as an efficient
deoxygenating agent for N-oxides such as nitrones,
azoxybenzenes and N-heteroarene N-oxides to give the
corresponding aromatic derivatives. The reaction pro-
ceeds efficiently at ambient pressure and in high yields
(Scheme 1).
In recent years organic chemistry has witnessed the
increased use of indium reagents.1 It was found that the
low reactivity of trivalent organoindium reagents can
be increased by complex formation with organolithium
compounds.2 The tetraorgano-indates thus prepared are
sufficiently reactive to take part in reactions at ambient
temperature.2a Allylic indates react with imides and
nitriles regioselectively at the g-carbon to give homoal-
lylamines.2b Also, indium metal3 has been found to be
an effective reducing agent and indium(III) halide com-
plexes act4a as efficient Lewis acid catalysts in
Mukaiyama aldol reactions, Friedel–Crafts acylations,3
Diels–Alder reactions4b in water and hetero Diels–Alder
cycloadditions.4c Our interest in indium based reagents5
prompted us to investigate the use of indium in the
chemoselective deoxygenation of N-oxides. The selec-
tive deoxygenation of organic N-oxides is a subject of
considerable interest in heterocyclic synthesis and a
large number of reports are available on the reduction
of NꢀO bonds.6 Aromatic N-oxides are relatively more
stable than aliphatic ones. They are also resistant to
deoxygenation,7 although some undergo deoxygenation
with sulfurous acid followed by the liberation of sulfu-
ric acid.8 Several deoxygenating agents including
sodium hydrogen telluride,6a phosphorus,6b aluminium–
nickel alloy,9 titanium(0) reagents,10 tin derivatives,11
silanes,12 alkali metal hydrides,13 tetrathiomolybdate14
and aluminium iodide15 may be used for this purpose.
However, most of these methods are deficient in some
respects, such as low yields, difficult accessibility, dras-
In a typical case, to a solution of benzaldehyde N-
phenyl nitrone 1a (0.40 g, 2 mmol) in dry acetonitrile
(15 ml) was added anhydrous indium trichloride (0.45
g, 2 mmol) and the mixture was refluxed under a
nitrogen atmosphere for 1 h (monitored by TLC). After
completion of the reaction, the solvent was removed on
a rotary evaporator and the residue was treated with
water (50 ml). The resultant mixture was made basic
(pH 8) with 25% aqueous ammonia and extracted with
diethyl ether (2×30 ml), the extract dried over anhy-
drous Na2SO4 and the solvent distilled off to give the
Keywords: indium trichloride; deoxygenation; azoxybenzenes; N-aryl-
nitrones; N-oxides.
* Corresponding author. Fax: +91 0376 3370011; e-mail: drugs@
csir.res.in; drrljt@csir.res.in
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00020-5

1878
M. Ilias et al. / Tetrahedron Letters 43 (2002) 1877–1879
crude product, which was purified by column chro-
matography (pet. ether/benzene, 4:1) to afford the
imine 2a in 95% yield. Similarly, other nitrones (entries
2–7) were reacted and the corresponding imines were
isolated in high yields (Table 1), without the formation
of any rearranged amides or decomposition products.
The selectivity of this new method is demonstrated by
several examples and the results are summarised in
Table 1. A variety of nitrones, azoxybenzenes, pyridine
N-oxides and quinoline N-oxides were converted
efficiently to their corresponding deoxygenated deriva-
tives. The method is general and several reducible func-
tionalities such as methoxycarbonyl, methyl ether and
cyano remain unaffected, the chloro substituents in
4-chloroquinoline 1-oxide 8b and 3-chloropyridine 1-
oxide 6a remain unchanged, even though they are
prone to dehalogenation reactions.19 Extending the
methodology to azoxybenzenes 3 gave the correspond-
ing azobenzenes 4 as the sole products (Table 1). Simi-
larly, the reaction of indium trichloride with quinoline
and pyridine N-oxides, respectively, afforded the
deoxygenated products 6 and 8 in high yields without
the formation of any side products. It is worth men-
tioning here that aldonitrones rearrange to the isomeric
amides by treatment with a variety of Lewis acids20 and
2,4,4-trimethylpyrroline N-oxide gave decomposition
products with triphenylstibine or triphenylbismuthine.21
However, indium trichloride being a mild Lewis acid
gave only the corresponding deoxygenated products in
high yields without the formation of any undesirable
side products. To check the efficiency of indium trichlo-
ride in this reaction we carried out the deoxygenation
with a catalytic amount of indium trichloride (10 mg)
under reflux conditions and found that the reaction was
comparatively less effective and took 3–6 h to give 60%
yields of 2a. A further increase in the reaction time had
no significant effect on the yield and resulted in a minor
amount of decomposition. All the compounds obtained
were characterised by spectroscopic data and finally by
comparison with authentic samples (Schemes 2–4).
In conclusion, this new deoxygenative method using
indium trichloride offers a useful alternative to the
other methods available for the reduction of N-oxides.
Its main advantages are the avoidance of strong acid
media and harsh reagents, no side product formation
with groups like methyl ethers and chloro substituents
surviving under the reaction conditions, very mild con-
ditions and excellent yields for a wide variety of
products.
Scheme 2.
Scheme 3.
Scheme 4.
Table 1. Deoxygenation of N-oxides 1, 3, 5, and 7 with InCl3
Entry
Producta
R1/X
R2
Reaction time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
4a
4b
6a
6b
6c
6d
8a
8b
C6H5
4-ClC6H4
C6H5
4-OMeC6H4
2-Furyl
2-Thienyl
C6H5CHꢁCH-
H
4-Cl
Cl
H
COOMe
CN
H
H
H
4-Cl
H
H
H
H
H
4-Cl
–
1
1.5
1
1
1
1.5
1.5
1.5
1
1.2
1.2
1
1
1.5
1.2
95
90
85
90
80
78
80
80
82
75
80
78
75
80
76
9
10
11
12
13
14
15
–
–
–
–
Cl
–
a Most of the products are commercially available and were identified by comparison of their TLC, IR and mass spectra with those of authentic
samples.
b Yield of isolated products.

M. Ilias et al. / Tetrahedron Letters 43 (2002) 1877–1879
1879
9. Lunn, G.; Sansone, E. B.; Keefer, L. K. Synthesis 1985,
1104.
References
10. (a) Malinowski, M. Synthesis 1987, 732; (b) Malinowski,
M.; Kaczmarek, L. Synthesis 1987, 1013.
11. (a) Jousseaume, B.; Chanson, E. Synthesis 1987, 55; (b)
Kozuka, S.; Akasaka, T.; Furumai, S. Chem. Ind. (Lon-
don) 1974, 452.
12. (a) Naumann, K.; Zon, G.; Mislow, K. J. Am. Chem.
Soc. 1969, 91, 7012; (b) Vorbruggen, H.; Krolikiewicz, K.
Tetrahedron Lett. 1983, 24, 5337.
13. Hamer, J.; Macaluso, A. Chem. Rev. 1964, 64, 491.
14. In a recent report using tetrathiomolybdate where the
reaction time is 12–72 h and did not reduce the azoxy
compounds, see: Ilankumaran, P.; Chandrasekaran, S.
Tetrahedron Lett. 1995, 36, 4881.
1. For recent work, see: (a) Araki, S.; Jin, S. J.; Butsugan,
Y. J. Chem. Soc., Perkin Trans. 1 1995, 549; (b) Araki, S.;
Yamada, M.; Butsugan, Y. Bull. Chem. Soc. Jpn. 1994,
67, 1126; (c) Loh, T. P.; Xu, K. C.; Sook-Chrang, D. H.;
Sun, H. K. Synlett 1998, 369; (d) Li, X. R.; Loh, T. P.
Tetrahedron: Asymmetry 1996, 7, 1535; (e) Loh, T. P.; Li,
X. R. J. Chem. Soc., Chem. Commun. 1996, 1929.
2. (a) Jin, S. J.; Araki, S.; Butsugan, Y. Bull. Chem. Soc.
Jpn. 1993, 66, 1528; (b) Araki, S.; Simizu, T.; Jin, S. J.;
Butsugan, Y. J. Chem. Soc., Chem. Commun. 1991, 824.
3. For recent reviews on indium metal, see: (a) Li, C. J.;
Chan, T. K. Tetrahedron 1999, 55, 11149; (b) Li, C. J.;
Chen, D. L.; Lu, Y. Q.; Daberman, J. X.; Mague, J. T. J.
Am. Chem. Soc. 1996, 118, 4216.
4. (a) Loh, T. P.; Pai, J.; Cao, G. Q. J. Chem. Soc., Chem.
Commun. 1996, 1819; (b) Loh, T. P.; Pai, J.; Lin, M. J.
Chem. Soc., Chem. Commun. 1996, 2315; (c) Ali, T.;
Chauhan, K. K.; Frost, C. G. Tetrahedron Lett. 1999, 40,
5621.
5. (a) Prajapati, D.; Laskar, D. D.; Sandhu, J. S. Tetra-
hedron Lett. 2000, 41, 8639; (b) Gadhwal, S.; Sandhu, J.
S. J. Chem. Soc., Perkin Trans. 1 2000, 2827.
15. Konwar, D.; Boruah, R. C.; Sandhu, J. S. Synthesis 1990,
337.
16. Katritzky, A. R.; Lagowski, J. M. Chemistry of the
Heterocyclic N-Oxides; Academic Press: London, 1971.
17. (a) Kano, S.; Tanaka, Y.; Hibino, S. Heterocycles 1980,
14, 39; (b) Kano, S.; Tanaka, Y.; Sugino, E.; Hibino, S.
Synthesis 1980, 695.
18. Zacharie, B.; Moreau, N.; Dockendorff, C. J. Org. Chem.
2001, 66, 5264.
19. Katritzky, A. R.; Monro, A. M. J. Chem. Soc. 1958,
1263.
20. (a) Exner, O. Collection. Czech. Chem. Commun. 1951,
16, 258; Chem. Abstr. 1953, 47, 5884; (b) Brady, O. L.;
Dunn, F. P.; Goldstein, R. F. J. Chem. Soc. 1926, 129,
2386.
6. (a) Barton, D. H. R.; Fekih, A.; Lusinchi, X. Tetrahedron
Lett. 1985, 26, 4603; (b) Olah, G. A.; Gupta, B. G. B.;
Narang, S. C. J. Org. Chem. 1978, 43, 4503.
7. Ochiai, E. Proc. Imp. Acad. (Tokyo) 1943, 19, 307; CA,
1947, 41, 5880.
21. Umezawa, B. Chem. Pharm. Bull. (Tokyo) 1960, 8, 967;
Chem. Abstr. 1962, 57, 8537.
8. Hayashi, E.; Iijima, Ch. Yakugaku, Zasshi. 1962, 82,
1093; CA, 1963, 58, 4551.