Alumina promoted cyclization of α-nitro-oximes: A new entry to the synthesis of 1,2,5-oxadiazoles N-oxides (furoxans)

Article abstract of DOI:10.1016/S0040-4039(00)01422-2

A convenient method for the synthesis of 1,2,5-oxadiazole-N-oxides (furoxans) from α-nitro-ketoximes using acidic alumina as catalyst is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01422-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8817–8820
Alumina promoted cyclization of a-nitro-oximes: a new
entry to the synthesis of 1,2,5-oxadiazoles N-oxides
(furoxans)
Massimo Curini,a,* Francesco Epifano,a Maria Carla Marcotullio,a Ornelio Rosati,a
Roberto Ballini*b and Giovanna Bosicab
aDipartimento di Chimica e Tecnologia del Farmaco-Sezione di Chimica Organica, Facolta` di Farmacia,
Universita` di Perugia, Via del Liceo, I-06123 Perugia, Italy
bDipartimento di Scienze Chimiche dell’Universita`, Via S. Agostino 1, I-62032 Camerino (MC), Italy
Received 17 August 2000; accepted 23 August 2000
Abstract
A convenient method for the synthesis of 1,2,5-oxadiazole-N-oxides (furoxans) from a-nitro-ketoximes
using acidic alumina as catalyst is described. © 2000 Elsevier Science Ltd. All rights reserved.
Only few years ago furoxan derivatives were found to play an important pharmacological role,
as they are able to increase the cytosolic level of cGMP in human platelets,1 to activate the rat
liver soluble guanylate cyclase and to release NO when treated with thiol compounds under
physiological conditions2 resulting in a potent vasodilating effect.3 Very recently it has also been
discovered that furoxan derivatives exert anti-HIV1, antitrypanosomal and cytotoxic activities.4–7
Furoxans have been synthesized by oxidation of a-dioximes with sodium or t-butyl hypochlo-
rite,8,9 by thermolysis of o-nitro-azides, by dimerization of nitrile-N-oxides, by oxidation of
aromatic o-amino-nitro derivatives and by reaction of alkenes with N2O3.10,11 Unfortunately
many of these procedures suffer some limitations such as difficulty of handling, high tempera-
tures, use of strong oxidating agents and hazardous materials. Best results were obtained by
treatment of readily available a-nitro-oximes or b-nitro-nitroso derivatives with polyphosphoric
acid at 110°C, but there are only few examples of the application of this reaction.12
Surface-mediated solid phase reactions are of growing interest because of their advantages of
ease of set-up, mild conditions, rapid reactions, selectivity, increased yields, high purity of
compounds and low cost compared with their homogeneous counterpart.13–21 Based on our
previous experience in the use of alumina as the solid surface,22–27 we found that acidic alumina
* Corresponding authors. E-mail: curini@unipg.it; ballini@camserv.unicam.it
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01422-2

8818
is an excellent heterogeneous catalyst for the conversion of a-nitro-oximes into their correspond-
ing 1,2,5-oxadiazoles N-oxides (furoxans) (Scheme 1).
Scheme 1.
The reaction was carried out by adding a solution of the a-nitro-oxime in acetonitrile to a
suspension of acidic alumina (Brockmann I) in acetonitrile at 60°C. The reaction takes from 1
to 5 hours (see Table 1) and after a simple work-up affords furoxan derivatives in good yield
from both cyclic and acyclic a-nitro-oximes. All furoxans showed absorptions, in IR their
spectra, in the range of 1600–1620 cm−1 and a typical fragmentation pattern in their mass
spectra (M+, M+−30, M+−60).28 The mechanism of the reaction probably involves an initial
tautomeric equilibrium of the a-nitro-oxime with the b-nitro-nitroso isomer and subsequent
elimination of water with the formation of the furoxan ring system.4,12
In summary, acidic alumina, has proved to be a useful reagent for the preparation of furoxans
from readily available a-nitro-oximes and the reported method represents the first example of
the application of heterogeneous catalysis in this area.
Experimental. Typical procedure: To a well stirred suspension of acidic Al2O3 (4 g) in
acetonitrile (25 ml) a solution of a-nitro ketoxime29 (4 mmol) in acetonitrile (5 ml) was added
and the resulting mixture was stirred at 60°C for the appropriate time (see Table 1). The mixture
was filtered under vacuum and the solution was evaporated under reduced pressure. The crude
material was purified by flash chromatography on SiO2 (eluent CH2Cl2) affording the desired
furoxan.
4,5,6,7-Tetrahydro-2,1,3-benzoxadiazol-N-oxide (1b): yellow oil; IR (CH2Cl2): w=1620 cm−1;
1H NMR (CDCl3): l 1.65–1.82 (m, 4H), 2.42–2.51 (m, 2H), 2.63–2.75 (m, 2H); 13C NMR
(CDCl3): l 156.20, 113.04, 22.06, 21.21, 20.99, 19.38; GC/MS: M+=140.
6-(tert-Butyl)-4,5,6,7-tetrahydro-2,1,3-benzoxadiazol-N-oxide (2b): yellow oil; IR (CH2Cl2):
1
w=1625 cm−1; H NMR (CDCl3): l 0.87 (s, 9H), 1.05–3.02 (m, 7H); 13C NMR (CDCl3): l
156.33, 114.11, 44.22, 32.58, 27.07, 23.32, 22.52, 21.22; GC/MS: M+=196.
5,5,7,7-Tetramethyl-4,5,6,7-tetrahydro-2,1,3-benzoxadiazol-N-oxide (3b): yellow oil; IR
1
(CH2Cl2): w=1620 cm−1; H NMR (CDCl3): l 1.10, 1.13, 1.17, 1.39 (4s, 12H), 1.68 (s, 2H), 2.52
(s, 2H); 13C NMR (CDCl3): l 155.31, 117.46, 46.21, 42.15, 39.87, 33.22, 28.12, 26.65, 25.99,
25.45; GC/MS: M+=196
5,6,7,8-Tetrahydro-4H-cyclohepta[c][1,2,5]oxadiazol-N-oxide (4b): yellow oil; IR (CH2Cl2):
1
w=1620 cm−1; H NMR (CDCl3): l 1.18–1.63 (m, 6H), 2.32–2.47 (m, 2H), 2.61–2.73 (m, 2H);
13C NMR (CDCl3): l 153.67, 115.21, 28.10, 27.42, 26.29, 26.01, 24.79; GC/MS: M+=154.
4,5,6,7,8,9,10,11,12,13-Decahydrocyclododeca[c][1,2,5]oxadiazol-N-oxide (5b): yellow oil; IR
1
(CH2Cl2): w=1620 cm−1; H NMR (CDCl3): l 1.05–1.60 (m, 16H), 2.07–2.26 (m, 2H), 2.48–2.61
(m, 2H); 13C NMR (CDCl3): l 152.89, 111.13, 25.79, 24.94, 24.75, 24.63, 24.62, 23.49, 23.19,
22.66, 21.94; GC/MS: M+=224.
1
3-Ethyl-4-methyl-1,2,5-oxadiazol-N-oxide (6b): yellow oil; IR (CH2Cl2): w=1610 cm−1; H
NMR (CDCl3): l 1.32–1.45 (t, 3H, J=7.6 Hz), 2.17 (s, 3H), 2.65–2.78 (q, 2H, J=7.6 Hz); 13C
NMR (CDCl3): l 159.17, 112.76, 19.27, 10.62, 7.51; GC/MS: M+=128.

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Table 1
Al2O3 promoted synthesis of furoxans from a-nitro-oximes
1
3-Ethyl-4-phenethyl-1,2,5-oxadiazol-N-oxide (7b): yellow oil; IR (CH2Cl2): w=1615 cm−1; H
NMR (CDCl3): l 0.94–1.05 (t, 3H, J=6.5 Hz), 2.12–2.95 (m, 6H), 7.05–7.20 (m, 5H); 13C NMR
(CDCl3): l 155.84, 141.11, 128.56, 128.26, 126.32, 109.43, 32.44, 31.93, 29.44, 8.61; GC/MS:
M+=218.
1
4-Isopropyl-3-propyl-1,2,5-oxadiazol-N-oxide (8b): yellow oil; IR (CH2Cl2): w=1615 cm−1; H
NMR (CDCl3): l 0.89–1.07 (t, 3H, J=7.1 Hz), 1.32–1.42 (d, 6H, J=7.0 Hz), 1.75–3.02 (m, 5H);
13C NMR (CDCl3): l 150.02, 114.11, 26.48, 24.49, 20.39, 18.88, 13.72; GC/MS: M+=170.

8820
Acknowledgements
The authors wish to thank MURST ‘Progetto Chimica dei Composti Organici di interesse
biologico’ and CNR (Rome) for financial support.
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