An Efficient Deoxgenation of Heteroaromatic N-Oxides Using Zinc Dust/Ammonium Formate Reagent System

Article abstract of DOI:10.1081/SCC-120026355

Heteroaromatic N-oxides were readily and selectively deoxygenated to the corresponding bases with zinc/ammonium formate reagent system.

Full text of DOI:10.1081/SCC-120026355

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An Efficient Deoxygenation of Heteroaromatic N-Oxides
Using Zinc Dust/Ammonium Formate Reagent System
Roman Balicki a , Marcin Cybulski a & Grzegorz Maciejewski a
a Pharmaceutical Research Institute , Warsaw, Poland
Published online: 16 Aug 2006.
To cite this article: Roman Balicki , Marcin Cybulski & Grzegorz Maciejewski (2003) An Efficient Deoxygenation of
Heteroaromatic N-Oxides Using Zinc Dust/Ammonium Formate Reagent System, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 33:23, 4137-4141, DOI: 10.1081/SCC-120026355
To link to this article: http://dx.doi.org/10.1081/SCC-120026355
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 23, pp. 4137–4141, 2003
An Efficient Deoxygenation of Heteroaromatic
N-Oxides Using Zinc Dust/Ammonium Formate
Reagent System
*
Roman Balicki, Marcin Cybulski, and Grzegorz Maciejewski
Pharmaceutical Research Institute, Warsaw, Poland
ABSTRACT
Heteroaromatic N-oxides were readily and selectively deoxygenated
to the corresponding bases with zinc/ammonium formate reagent
system.
Key Words: Deoxygenation; N-Oxide; Ammonium formate.
Selective, mild, and cheap deoxygenation of amine N-oxides is still
area of considerable interest, particularly when a molecule has other
reducible and labile groups. A survey of the literature reveals that many
methods have been reported for reduction of hetroaromatic N-oxides,
*Correspondence: Roman Balicki, Pharmaceutical Research Institute, PL-01-793
Warsaw, Poland; E-mail: cybul@poczta.fm.
4137
DOI: 10.1081/SCC-120026355
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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4138
Balicki, Cybulski, and Maciejewski
including agents such as: trivalent phosphorus compounds,[1,2] sulphur or
selenium compounds,[3,4] metals in acids,[5] aluminium iodide,[6] and
catalytic hydrogenation.[7] In general, these traditional procedures often
require severe reaction conditions and prolonged reaction times, and
afford products of insufficient purity in moderate or low yield.
Previously, we reported that amine N-oxides may be easily and efficiently
reduced to the corresponding bases with low-valent titanium, generated
through the reaction TiCl4 with lithium aluminium hydride[8] or stannous
chloride[9] in tetrahydrofuran.
Excellent results were obtained when the deoxygenation of amine
N-oxides was performed in neutral medium using some hydrogen
transfer agents in the presence of palladium on carbon as catalyst.[10,11]
However, our last methods appear to be inappropriate for large-
scale preparation due to necessity of using LiAlH4 or expensive
palladium.
In this communication we report a new and efficient method for
deoxygenation of the N–O function to the corresponding bases using
zinc dust/ammonium formate reagent system. The application of this
cheap and simple agent was till now limited to the reduction of nitro
group[12] and reductive cleavage of azo compounds.[13] A variety of
amine N-oxides were treated with zinc dust/ammonium formate system,
and the corresponding bases were obtained in high yields; the results are
summarized in Table 1. The reaction proceeds readily upon addition of
anhydrous ammonium formate to a suspention of N-oxide and activated
zinc dust in boiling methanol within 2–7 h. The optimum ratio reagent
was found to be 1:3:2 (substrate 1/ammonium formate/ zinc dust) for
monooxides (1a–l) or 1:6:4 for dioxides (1m,n). Acetic acid is also accep-
table solvent in some cases, but the reaction was slower in this medium.
Among the metals tested, zinc appear to be the most effective, while
magnesium and iron powder gave much lower yields. The selectivity
of our method is demonstrated by several examples. Substituents, like
halogen (1b,d), methoxy (1g), cyano (1h), acetyl (1f ) or esters (1i,j)
remained unchanged; however nitro group (1e) was easily reduced
under the reaction conditions to 4-aminopyridine.
The progress of the reaction was monitored by TLC, and the
corresponding products 2 were isolated by the usual work-up and
identified by IR, MS, and TLC.
We believe that the present procedure offers an attractive
alternative for other method available for the reduction of N-oxides.
Its principal advantages are: the ease of manipulation, mild reaction
conditions, selectivity, cheap reagents, and good yields for a wide variety
of heteroaromatic N-oxides.

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Deoxygenation of Heteroaromatic N-Oxides
4139
Table 1. Deoxygenation of heteroaromatic N-oxides using zinc dust/ammonium
formate reagent system.
Reaction
time (h)
Yieldb
(%)
Substrate
Producta
1a 4-t-Butylpyridine
N-oxide
4
3
5
3
5
6
6
5
3
4
3
4
7
6
2a 4-t-Butylpyridine
81
85
77
72
70
65
68
54
78
76
81
76
62
69
1b 4-Chloropyridine
N-oxide
2b 4-Chloropyridine
2c 3-Picoline
1c 3-Picoline
N-oxide
1d 3,5-Dibromopyridine
N-oxide
2d 3,5-Dibromopyridine
2e 4-Aminopyridine
2f 3-Acetylpyridine
2g 3-Methoxypyridine
2h 4-Pyridinecarbonitrile
2i 4-Carbomethoxypyridine
2j 3-Carbomethoxypyridine
2k Quinoline
1e 4-Nitropyridine
N-oxide
1f 3-Acetylpyridine
N-oxide
1g 3-Methoxypyridine
N-oxide
1h 4-Pyridinecarbonitrile
N-oxide
1i
Methyl isonicotinate
N-oxide
1j
Methyl nicotinate
N-oxide
1k Quinoline
N-oxide
1l
Isoquinoline
N-oxide
1m Phenazine
2l Isoquinoline
2m Phenazine
N,N-dioxide
1n 2,20-Bipyridine
N,N0-dioxide
2n 2,20-Bipyridine
aAll products are commercially available and were identified by comparison of
their IR and MS spectra as well as their Rr values (TLC) with those of authentic
samples.
bYield of isolated product based on a single experiment and not optimized.

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4140
Balicki, Cybulski, and Maciejewski
EXPERIMENTAL
Infrared spectra were obtained on a Beckman 4240 spectrophot-
ometer and MS spectra was recorded on a LKB-9000A instrument.
Deoxygenation of N-Oxides (General Procedure)
To a magnetically stirred suspension of the appropriate amine
N-oxides 1 (2 mmol for monooxides or 1 mmol for dioxides) and freshly
activated zinc dust (4 mmol) in methanol (8 mL) was introduced
anhydrous ammonium formate (6 mmol). The resulting reaction mixture
was refluxed for 2–6 h. The catalyst was then removed by filtration
through celite and washed with methanol (2 mL). The residue obtained
by evaporation of solvent was purified by flash column chromatography
on silica gel (eluent:hexane/AcOEt, 8:1) or crystallized to give pure
product 2. The results are summarized in Table 1.
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Deoxygenation of Heteroaromatic N-Oxides
4141
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Received in Poland April 8, 2003

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