Nitrolic acids: Efficient precursors of nitrile oxides under neutral conditions

Article abstract of DOI:10.1016/S0040-4039(99)02278-9

Nitrolic acids are prepared in good yields from primary nitroalkanes or primary alkyl bromides. Upon heating in THF, they afford the corresponding nitrile oxides under neutral conditions. In the presence of dipolarophiles, isoxazoles are obtained in yield

Full text of DOI:10.1016/S0040-4039(99)02278-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1191–1194
Nitrolic acids: efficient precursors of nitrile oxides under neutral
conditions
Christophe Matt, Arnaud Gissot, Alain Wagner ∗ and Charles Mioskowski ∗
Laboratoire de Synthèse Bioorganique, Université Louis Pasteur de Strasbourg, UMR 7514 du CNRS, Faculté de Pharmacie,
74 route du Rhin-BP 24-67401 Illkirch, France
Received 25 November 1999; accepted 8 December 1999
Abstract
Nitrolic acids are prepared in good yields from primary nitroalkanes or primary alkyl bromides. Upon heating
in THF, they afford the corresponding nitrile oxides under neutral conditions. In the presence of dipolarophiles,
isoxazoles are obtained in yields up to 95%. For the less stable alkoxycarbonyl- and arylnitrolic acids the crude
nitrolic acids can be directly engaged in the cycloaddition reaction. © 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: nitrile oxides; alkyl halides; nitro compounds; cycloadditions; nitrolic acids.
Nitrolic acids, obtained by careful addition of dilute acid to a mixture of nitroalkane anion and
potassium nitrite, were first reported by Meyer in 1873.1 Since then, only scanty reports dealing with
their synthesis, stability and use are found in the literature.2
We recently reported the transformation of primary nitroalkanes or primary alkyl bromides into
carboxylic acids under mild conditions, using a mixture of acetic acid and sodium nitrite in DMSO
at 50°C.3 We noticed that, when the reaction is carried out at 20°C, the nitrolic acid, which is the
intermediate of the above transformation, could be isolated in good yield.
Nitrolic acids, prior to this work, were known to be highly unstable, difficult to handle and prone to
decomposition upon heating via formation of the corresponding nitrile oxides.4 For these reasons and
presumably because of the lack of a simple and reliable method for their synthesis, thermolytic fragmen-
tation of nitrolic acids has never been considered as a synthetically useful reaction for the generation of
nitrile oxides. Herein we demonstrate the synthetic potential of our novel preparative method of nitrolic
acids and investigate their use as precursors of nitrile oxides for 1,3-dipolar cycloadditions (Scheme 1).
Scheme 1.
∗
Corresponding authors. Fax: 33 3 88 67 88 91; e-mail: alwag@aspirine.u-strasbg.fr (A. Wagner),
mioskow@aspirine.u-strasbg.fr (C. Mioskowski)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02278-9
tetl 16206

1192
In a preliminary study, we prepared a series of nitrolic acids from nitro or bromo precursors. Upon
treatment with a mixture of acetic acid and sodium nitrite in DMSO,5 the conversion of the nitroalkyl
substrate is always higher than 80%, according to NMR analysis of the crude. However the stability of
the nitrolic acids proved to be dramatically dependent on their substituents. Alkylnitrolic acids can be
easily isolated and purified by silica gel chromatography in around 90% yield and stored for several
months at −20°C. In contrast, alkoxycarbonyl- or arylnitrolic acids are rather unstable and tend to
decompose during column chromatography. Moreover they have a strong tendency to give rise to the
corresponding nitrile oxide, as witnessed by the formation of furoxanes after a few days even at −20°C.
As a consequence, the alkoxycarbonyl- and arylnitrolic acids are isolated in 50% yield after purification.
Conversion of nitrolic acids into nitrile oxides is promoted by gentle heating. To perform the cycload-
ditions, we simply carried out the reactions by heating THF solutions of nitrolic acids in the presence of
dipolarophiles. The results obtained from reactions of purified nitrolic acids and various dipolarophiles
are summarized in Table 1.
Table 1
Thermolysis of alkylnitrolic acids in the presence of alkenes affords cycloadducts in almost pure forms
(entry 1). Since the conditions are neutral and do not require strong dehydrants or strong oxidants like
classical methods for generation of nitrile oxides, unprotected alcohols (entry 2) and highly oxidizable
sulfur moieties (entry 3) are compatible with the reaction conditions. The cycloadducts are obtained in
97 and 95% yield, respectively. Starting from an arylnitrolic acid, the cycloadduct is obtained in 53%
yield (entry 4). This moderate yield is due to the formation of 40% of furoxane derivative arising from
nitrile oxide dimerization. Similarly, reaction of alkoxycarbonylnitrolic acid give a mixture of the desired
cycloadduct in 55% isolated yield (entry 5), and of furoxane in 40% isolated yield.
Classical methods for the preparation of nitrile oxides use large excesses of reagent that lead to the
formation of by-products.6 Thermolytic generation of nitrile oxides operate under stoichiometric and
neutral conditions which avoid these drawbacks. At the end of the reaction no work-up is necessary, the
cycloadduct being directly obtained after concentration of the crude mixture.

1193
Thus, thermolytic generation of nitrile oxide from nitrolic acid appears to be an efficient reaction,
especially in the case of alkyl nitrolic acids and in all cases when neutral conditions are required. However
the instability of alkoxycarbonyl and arylnitrolic acids during the purification step restrains somewhat the
scope of the methodology. To overcome this drawback, we carried out cycloaddition reactions on crude
nitrolic acid mixtures obtained from standard work-up of the reaction of bromo or nitro precursors in a
mixture of acetic acid and sodium nitrite in DMSO (Table 2).
Table 2
Starting from ethylnitroacetate, the cycloadduct is obtained in 50% isolated yield (entry 1). The only
side-product of the reaction is the furoxane formed by dimerization of the nitrile oxide. Since under
our reaction conditions (mixture DMSO/AcOH/NaNO2) primary alkyl bromides are converted in situ
into their corresponding nitro derivatives, these bromides can directly be used as precursors of nitrile
oxides. Starting from ethyl bromoacetate (entries 2 and 3), the cycloadduct is obtained in 45% overall
yield as a result of three consecutive one-pot reactions. This result is especially of interest since classical
methods for the generation of alkoxycarbonyl nitrile oxides give low yields.7 Moreover, it is noteworthy
that nitroacetates are difficult to access, while bromoacetates are readily available.
In conclusion, nitrolic acids are easily prepared by reaction of primary bromo or nitro derivatives with
a mixture of acetic acid and sodium nitrite in DMSO. Purification on silica gel affords pure alkylnitrolic
acids in high yields. Alkoxycarbonyl- and arylnitrolic acids, which are less stable, partly decompose
during chromatographic purification. Thermolytic fragmentation of nitrolic acid in the presence of
dipolarophiles leads to the corresponding isoxazoles under neutral conditions suitable for sensitive
substrates. The less stable alkoxycarbonyl- and arylnitrolic acids can be engaged in cycloaddition
reactions as crude mixtures.
Acknowledgements
We thank the Ministère de la Recherche et de l’Enseignement for financial support of this work through
a MRE grant to Christophe Matt and Arnaud Gissot.

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