A mild deoxygenation of heteroaromatic N-oxides by formamidinesulfinic acid

Article abstract of DOI:10.1007/s007060070044

Various heteroaromatic N-oxides were efficiently deoxygenated to the corresponding bases under mild conditions using formamidinesulfinic acid (thiourea S,S-dioxide).

Full text of DOI:10.1007/s007060070044

Monatshefte fuÈr Chemie 131, 1105±1107 (2000)
A Mild Deoxygenation of Heteroaromatic
N-Oxides by Formamidinesul®nic Acid
Ã
Roman Balicki and Urszula Chmielowiec
Pharmaceutical Research Institute, PL-01793 Warsaw, Poland
Summary. Various heteroaromatic N-oxides were ef®ciently deoxygenated to the corresponding
bases under mild conditions using formamidinesul®nic acid (thiourea S,S-dioxide).
Keywords. Deoxygenations; Amine N-oxides; Thiourea S,S-dioxide.
Introduction
Many reports on the deoxygenation of heteroaromatic N-oxides, which are important
in the synthesis of nitrogen containing heterocyclic compounds, exist in literature [1].
For example, metals in acids [2±3], various selenium and sulfur compounds [4±5],
trivalent phosphorous compounds [6±7], zinc in sodium hydroxide [8], low-valent
titanium reagents [9], aluminum iodide [10], and catalytic hydrogenation [11] have
been utilized for the deoxygenation of amine N-oxides. Many of these methods are
de®cient with respect to costs, availability of reagents, reaction conditions, yields, or
reaction time.
In connection with another investigation we have required a satisfactory route for
the simple reduction of the N-oxide function of an N-heteroaromatic ring. Exellent
results have been previously obtained when the deoxygenation was carried out in a
neutral medium using hydrogen transfer agents in thepresence of palladium on carbon
[12]. However, the methodology described has appeared to be inappropriate for large-
scale preparations due to the necessity of using the expensive palladium catalyst.
In this communication, we report a new and ef®cient method for the
deoxygenation of amine N-oxides to the corresponding bases using formamidine-
sul®nic acid [13, 14]. This agent, which is easily prepared by the oxidation of thiourea
with hydrogen peroxide, is known to be a strong reducing compound for inorganic
metal ions [15]. However, its application in organic synthesis is rather limited to the
reduction of nitro groups [16], sulfoxides [17], or carbonyl compounds [18].
Results and Discussion
A variety of heteroaromatic N-oxides were treated with thiourea dioxide, and the
corresponding amines were obtained in high to excellent yields; the results are
Ã
Corresponding author

1106
R. Balicki and U. Chmielowiec
Table 1. Deoxygenation of heteroaromatic N-oxides by formamidinesul®nic acid (thiourea dioxide)
Substrate
Reaction
time/h
Producta
Yieldb/%
1a 4-t-butylpyridine N-oxide
1b 2,6-dimethylpyridine N-oxide
1c 4-acetylpyridine N-oxide
1d 4-pyridinecarbonitrile N-oxide
1e 4-chloropyridine N-oxide
1,0
1,5
3,5
3,5
1,5
2,0
2,5
4,0
2,0
2,5
3,0
1,5
1,5
3,0
2a 4-t-butylpyridine
2b 2,6-dimethylpyridine
2c 4-acetylpyridine
84
85
52
66
80
81
82
63
90
86
74
80
81
76
2d 4-pyridinecarbonitrile
2e 4-chloropyridine
1f
3,5-dibromopyridine N-oxide
2f
3,5-dibromopyridine
1g 3-methoxypyridine N-oxide
1h 4-nitropyridine N-oxide
2g 3-methoxypyridine
2h 4-aminopyridine
1i
1j
quinoline N-oxide
2i
2j
quinoline
isoquinoline N-oxide
isoquinoline
1k acridine N-oxide
1l
2k acridine
2l
2,20-bipyridine N,N-dioxide
2,20-bipyridine
1m 4,40-bipyridine N,N-dioxide
1n phenazine N,N-dioxide
2m 4,40-bipyridine
2n phenazine
a
All products are commercially available and were characterized by comparison of their IR and MS
spectra as well as their Rf values (TLC) with those of authentic samples; b yield of isolated product
based on a single experiment and not optimized
summarized in Table 1. The reaction is very simple and proceeds upon addition of
thiourea dioxide to a suspension of N-oxide and 3 N sodium hydroxide in ethanol at
80±85ꢀC. The optimum ratio of reagents was found to be 1:2 (substrate 1 to thiourea
dioxide) or 1:4 when the substrate 1 contained two N!O moieties (1l,n).
Acetonitrile is also an acceptable solvent in some cases, but the reaction was slower
in this medium. Among the alkali tested, NaOH was the most effective, although
KOH gave also good results. The selectivity of our method is demonstrated by
several examples. Substituents like halogen (1e,f), methoxy (1g), cyano (1d), or
acetyl (1c) remained unaffected; however, the nitro group (1h) was reduced under
the reaction conditions giving 4-aminopyridine contaminated by side-products. After
completion of the reaction the corresponding amines were isolated by the usual
work-up and identi®ed by IR, MS, and TLC.
In conclusion, we believe that the present procedure offers an attractive
alternative to other methods available for the reduction of N-oxides. Its principal
advantages are ease of manipulation, relatively smooth reaction conditions,
selectivity, mild reagents, and high yields for a wide variety of heteroaromatic N-
oxides.

Deoxygenation of Heteroaromatic N-Oxides
1107
Experimental
IR spectra were obtained on a Beckman 4240 spectrophotometer, mass spectra were recorded on a
LKB-9000A instrument. Formamidinesul®nic acid (thiourea dioxide) is commercially available.
Deoxygenation of N-oxides (general procedure)
A mixture of N-oxide 1 (4 mmol for monooxides or 2 mmol for dioxides), 10 cm3 3 N sodium
hydroxide, and 12 cm3 ethanol was stirred at 80±85ꢀC. Thiourea dioxide (0.864 g, 8 mmol) was then
added portionwise over 5 min, and the mixture was stirred for 1±4 h before being poured into H2O.
The aqueous solution was extracted continuously with CH2Cl2 or CHCl3. The combined organic
layers were washed with H2O, the solvent was removed, and the residue was puri®ed by ¯ash
chromatography on silica gel (eluent:hexane/ethyl acetate ˆ 9:1) to give the pure base 2. The results
are summarized in Table 1.
Acknowledgments
We are grateful to Dr. è. Kaczmarek for a generous gift of some amine N-oxides.
References
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Received March 24, 2000. Accepted April 18, 2000