A thermal fragmentation of 1,2,4-oxadiazole-4-oxides to nitriles and nitrosocarbonyls

Article abstract of DOI:10.1016/S0040-4039(00)00093-9

1,2,4-Oxadiazole-4-oxides undergo clean thermal cleavage in refluxing chlorobenzene or xylene to nitriles and nitrosocarbonyl intermediates, which are either trapped with suitable olefins to afford ene adducts or dimerize and rearrange to anhydrides. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00093-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2019–2022
A thermal fragmentation of 1,2,4-oxadiazole-4-oxides to nitriles
and nitrosocarbonyls†
P. Quadrelli, G. Campari, M. Mella and P. Caramella ∗
Dipartimento di Chimica Organica, Università degli Studi di Pavia, Viale Taramelli, 10 I-27100 Pavia, Italy
Received 3 December 1999; accepted 11 January 2000
Abstract
1,2,4-Oxadiazole-4-oxides undergo clean thermal cleavage in refluxing chlorobenzene or xylene to nitriles and
nitrosocarbonyl intermediates, which are either trapped with suitable olefins to afford ene adducts or dimerize and
rearrange to anhydrides. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: ene reactions; nitroso compounds.
We have recently reported that 1,2,4-oxadiazole-4-oxides 1 undergo a clean photochemical cleavage1
to nitriles 2 and nitrosocarbonyls 3, highly reactive intermediates2 which can be quantitatively trapped
with dienes or alkenes to afford the hetero Diels–Alder (HDA) adducts 4 or the ene adducts 5 (Scheme 1).
The HDA3 and ene4 reactions of nitrosocarbonyls have recently acquired a broad synthetic significance
because of the easy manipulation of both the HDA and ene adducts, allowing the introduction of
functionality into the diene and ene components. The photochemical cleavage of 1,2,4-oxadiazole-4-
oxides offers a very mild entry to the nitrosocarbonyls, which are usually generated by oxidation of
hydroxamic acids2,3,5 or nitrile oxides6 or by thermal cycloreversion of their HDA adducts.2,4
In spite of its photochemical lability the 3,5-diphenyl-1,2,4-oxadiazole-4-oxide 1a proved to be ther-
mally stable and could be recovered unchanged after 2 h in boiling benzene or toluene. However, when
we recently dealt with the dimesityl derivative 1b, readily available by the BF3-catalyzed dimerization
of mesitonitrile oxide,7 the thermal instability of the 1,2,4-oxadiazole-4-oxides became manifest. The
dimesityl derivative 1b did not undergo the usual8 deoxygenation to 1,2,4-oxadiazole with trimethyl
phosphite in refluxing benzene, presumably because of the bulky substituents around the oxygen. When
we tested the stability of 1b in refluxing toluene for 2 h, we found that a smooth fragmentation had taken
place affording a 2:1 mixture of mesitonitrile 2b and the mesitoic anhydride 6b. The fragmentation of 1b
also takes place in refluxing benzene, albeit more slowly (24 h).
∗
†
Corresponding author.
Dedicated to Prof. Rolf Huisgen on the occasion of his 80th birthday.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00093-9
tetl 16366

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Scheme 1.
The formation of the anhydride 6b suggests the intermediacy of the nitrosocarbonyl 3b in the thermal
cleavage, since anhydrides 6 are the typical products of the decay of nitrosocarbonyls, when generated
thermally in the absence of trapping agents, e.g. in the thermolysis of the HDA adducts to 9,10-
dimethyl anthracene.2,9 A reasonable mechanism6,9 for their formation involves the dimerization of the
nitrosocarbonyl to the azo N,N-dioxide 7, a 1,2 shift of the acyl group to the acyloxy azo N-oxide 8 or
a 1,3 acyl shift to the N-nitroso O-benzoyl benzhydroxamic acid 9, and final collapse to the anhydride
6 with loss of nitrous oxide (Scheme 2). Indeed, on performing the thermolysis of 1b in benzene, in the
presence of 10 equiv. of tetramethylethylene, we obtained a 1:1 mixture of mesitonitrile and the known6
ene adduct 5b (R,R0,R00=CH3).
Scheme 2.
Fragmentation of the 3,5-diphenyl-1,2,4-oxadiazole-4-oxide 1a takes place similarly but under more
vigorous conditions. On refluxing in chlorobenzene (bp 132°C) or xylene for 4 h, 1a afforded a 2:1
mixture of benzonitrile and benzoic anhydride while in the presence of a suitable ene component, cyclo-
octene (bp 145°C, 10 equiv.), afforded instead a 1:1 mixture of benzonitrile 2a and the nitrosocarbonyl
ene adduct 10a (Scheme 3). The latter is identical to a sample prepared by generating the nitrosocarbonyl
according to the nitrile oxide route6and its structure can be proved by comparison of the spectroscopic
data10 as well as on the ready deoxygenation (PCl3, benzene, rt, 8 h, 83%) to 11a, mp 151–152°C, and
its further conversion by catalytic hydrogenation (Pd/C 10%, AcOEt, rt, 95%) to N-cyclooctylbenzamide
12a, mp 112–113°C, identical to an authentic specimen11 obtained from benzoylation of cyclooctyl

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amine. Alternatively, the ene adduct 10a afforded on hydrogenation the N-cyclooctyl benzhydroxamic
acid 13a (86%), mp 84–85°C, which was then deoxygenated to 12a (91%).
Scheme 3.
A few other 1,2,4-oxadiazole-4-oxides 1c–g, with the same or different aryl substituents in positions 3
and 5 on the heterocyclic ring, easily available by cycloaddition of nitrile oxides to amidoximes,8 behaved
similarly. Refluxing in chlorobenzene for 4 h afforded a mixture of nitriles and anhydrides while in the
presence of 10 equiv. cyclooctene the nitriles and the ene adducts 10a–e were formed (Table 1).
Table 1
Ene adducts 10a–e by thermolysis of 3,5-diaryl-1,2,4-oxadiazole-4-oxides 1 in chlorobenzene (4 h)
The isomeric 1,2,5-oxadiazole 5-oxides (furoxans) undergo cleavage under significantly harsher con-
ditions (>200°C) and afford nitriles and nitrile oxides, which may be trapped with suitable dipolarophiles
or isomerize to isocyanates.12 With bulky substituents the fragmentation is, however, more facile.13 The
relatively easy cleavage of the 3,5-dimesityl-1,2,4-oxadiazole-4-oxide 1b could be similarly ascribed to
an increase of strain due to the o,o0-phenyl substituents.
The 3,5-diphenyl-1,2,4-oxadiazole-4-oxide 1a was first described by Wieland in 190614 and has
attracted some attention in connection with the acid- and base-catalyzed dimerizations of nitrile oxides.15
Its chemistry remained, however, essentially unexplored. The results discussed here and the ones
previously reported1 show that these heterocycles undergo a clean thermal or photochemical cleavage and
are ideal precursors of nitrosocarbonyls, a class of fleeting intermediates which are awaiting detection.

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Acknowledgements
Financial support by MURST and the University of Pavia (FAR) are gratefully acknowledged.
References
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arom.), 9.69 (s, 1H, OH). The other adducts show similar spectra.
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