One-pot synthesis of functionalized nitrones from nitro compounds

Article abstract of DOI:10.1055/s-2001-16042

The zinc-mediated reduction of nitroalkanes and nitroarenes in the presence of aldehydes is an efficient method to synthesize a wide range of nitrones. This method is mild enough to accommodate a variety of functional groups. It is particularly useful when the intermediate hydroxylamines are unstable and/or water-soluble. We used it to prepare several aromatic, aliphatic and highly functionalized sugar-derived nitrones.

Full text of DOI:10.1055/s-2001-16042

LETTER
1281
One-Pot Synthesis of Functionalized Nitrones from Nitro Compounds
Valérie Gautheron-Chapoulaud, Shashi U. Pandya, Pascale Cividino, Géraldine Masson, Sandrine Py, Yannick Vallée*
LEDSS, UMR CNRS-Université Joseph Fourier, B.P.53X, 38041 Grenoble, France
Fax +33 (4) 76514382, E-mail: yannick.vallee@ujf-grenoble.fr
Received 17 January 2001
sterically hindered groups on the nitrogen atom and/or the
Abstract: The zinc-mediated reduction of nitroalkanes and ni-
electrophilic carbon. A wide range of nitro compounds
being commercially available, we turned our attention to
a one-pot preparation of nitrones from nitroalkanes or ni-
troarenes in the presence of aldehydes is an efficient method to syn-
thesize a wide range of nitrones. This method is mild enough to
accommodate a variety of functional groups. It is particularly useful
when the intermediate hydroxylamines are unstable and/or water- troarenes and aldehydes under reductive conditions.
soluble. We used it to prepare several aromatic, aliphatic and highly
Such a process has been previously used to prepare cyclic
functionalized sugar-derived nitrones.
nitrones by reduction-intramolecular condensation be-
Key words: zinc reductions, nitro derivatives, hydroxylamines,
tween a nitro group and a carbonyl functionality.15 Inter-
carbohydrate derivatives, nitrones
molecular examples of this reaction are also known.16
However, this method received only moderate attention to
prepare aliphatic nitrones.
In the last decade, there has been a great deal of interest in
The usual reduction procedure of the nitro compound into
the chemistry of nitrones.1 These compounds are sub-
hydroxylamine is carried out by a mixture of zinc/acetic
strates of choice for 1,3-dipolar cycloadditions2 with alk-
acid in ethanol or zinc/ammonium chloride in water. Re-
enes and alkynes, to yield isoxazolidines and
cently, Kende described a way to reduce nitro derivatives
isoxazolines, which are easily converted to the corre-
with the more expensive, air-sensitive samarium diio-
sponding amino-alcohols by N-O bond cleavage.
dide.17
Another interesting feature of nitrones is their higher sta-
bility and better electrophilicity when compared to the
corresponding imines which prompted their use as precur-
In this paper, we demonstrate that the in situ zinc mediat-
ed reduction of nitro compounds in presence of aldehydes
(Scheme 1) is mild enough to accommodate a variety of
sors of hydroxylamines and amines through nucleophilic
functional groups. We used it to prepare aromatic, aliphat-
additions onto the C=N bond.3 Nitrones are also well
ic and highly functionalized sugar-derived nitrones.
known as radical spin-trapping agents,4 thus allowing
their use as antioxidants.5 Recently, they have also been
considered as substrate analogs for inhibiting enzymes
such as thermolysin.6
Several general methods have been proposed for the syn-
thesis of nitrones.7 The first procedures involved N-alky-
lation of oximes but proved to be poorly selective and
Scheme 1
significant amounts of O-alkylated products contaminated
product mixtures.8 Oxidation of secondary amines,9
The results obtained from various aromatic aldehydes and
hydroxylamines,10 or imines11 also leads to nitrones. How-
nitro derivatives are summarized in Table 1. Depending
ever, in the cases of unsymmetric substrates a regio-
on the nature of both starting materials, nitrones were iso-
selectivity problem cannot be avoided.
lated with moderate to very good yields.
To date, it seems that the mildest and the most selective
The general reaction conditions required the use of 1
route to prepare nitrones is the condensation of N-alkylhy-
equivalent of nitro derivative and 2-4 equivalents of zinc
droxylamines with carbonyl compounds.12 The major
at 0 °C during two days. Yield improvements could be
drawback of this method is that only very few N-alkyl-hy-
achieved by either increasing the temperature (entries 7-8,
droxylamines are commercially available. The prepara-
Table 1) or the number of equivalents of nitro compound
tion of N-monoalkylhydroxylamines is often not
and/or zinc (entries 2-3 and 7-9, Table 1).
straightforward, and the most general process involves
three steps from primary amines.13 Moreover, N-
monoalkylhydroxylamines are usually prone to oxidize or
disproportionate on standing, and need to be stored as
their salts (hydrochloride or oxalate).
Representative results with different aliphatic and glyco-
syl aldehydes (Schemes 2 and 3) and the sterically hin-
dered 2-methyl-2-nitropropane are gathered in Table 2.
Again, the corresponding nitrones were obtained in mod-
erate to very good yields. Some results could be optimized
by increasing the number of equivalents of t-BuNO2 and/
or zinc. Increasing the temperature or reaction time was
not an adequate way to improve yields in these cases.
In the course of synthetic studies carried out in our labo-
ratories,14 we were interested in an efficient and general
method to prepare aromatic and aliphatic nitrones bearing
Synlett 2001, No. 8, 1281–1283 ISSN 0936-5214 © Thieme Stuttgart · New York

1282
V. Gautheron-Chapoulaud et al.
LETTER
Table 2 Synthesis of nitrones from aliphatic aldehydes and 2-me-
Table 1 Synthesis of nitrones from aromatic aldehydes and various
thyl-2-nitropropane
nitro derivatives
(a) : R1 = o-(2’-Br-PhCH2O)-Ph-
It is worth pointing out that attempts to prepare such func-
tionalized nitrones by the usual condensation reaction
(aldehyde / t-butylhydroxylamine)12 were unsatisfactory;
at room temperature, very slow conversions were ob-
served, and degradation of the starting materials occurred
on heating.
i. Numbers of nitro compounds are commercially avail-
able or easily synthesized.
ii. It can easily be scaled up to prepare large amounts of
The method described herein allowed the synthesis of an
, -unsaturated nitrone derived from cinnamaldehyde
(entry 15, Table 2) with a satisfactory yield (58%). No
product resulting from cyclization was observed.
nitrones (50 mmol).
iii It is compatible with sensitive functionalities like
, -unsaturated or sugar-derived aldehydes.
iv. It has proved to be especially useful for the prepara-
tion of nitrones derived from: - quaternary and aromatic
hydroxylamines which are usually not commercially
available and are unstable;18 - low molecular weight and/
or water soluble hydroxylamines which are difficult to
isolate.
Scheme 2
General procedure
To a stirred solution of the aldehyde (1 mmol) in 10 mL of 95% eth-
anol were added the nitroalkane or the nitroarene (x equiv, see Ta-
bles 1 and 2) and zinc powder (y equiv, see Tables 1 and 2) at 0 °C
under argon atmosphere. Glacial acetic acid (6 mmol) was then in-
troduced dropwise. Reaction temperature was kept at 0 °C during
evolution of the reaction or raised to room temperature. The conver-
sion of the starting materials was followed by TLC. After filtration
on a celite pad and evaporation of the filtrate under vacuum, the
Scheme 3
Concerning the sugar-derived nitrones (entries 16, 17 and crude material was purified by flash chromatography on silica gel.
All new compounds gave spectroscopic and analytical data in
agreement with the assigned structures.
18, Table 2), they were obtained as glycosyl hydroxy-
lamines, resulting from the cyclization of the C5 oxygen
onto the C1 carbon of the nitrone.
References and Notes
In conclusion, we have demonstrated that the one-pot re-
duction-condensation of nitroalkanes or nitroarenes with
aldehydes constitutes a direct and efficient method to syn-
thesize a wide range of nitrones. The major advantages of
this method are the following:
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Synlett 2001, No. 8, 1281–1283 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
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1437-2096,E;2001,0,08,1281,1283,ftx,en;D10101ST.pdf
Synlett 2001, No. 8, 1281–1283 ISSN 0936-5214 © Thieme Stuttgart · New York