Thermal fragmentation of 1,2,5-and 1,2,4-oxadiazoles

Thermolysis of 3,4-diphenyl-1,2,5-oxadiazole (diphenylfurazan) in tetradec-1-ene at 245 ºC afforded 5-dodecyl-3-phenyl-2-isoxazoline resulting from cycloaddition of benzonitrile oxide to the alkene. Similarly, the tetramethylene and decamethylene furazans 13 and 15 in 4-methoxybenzonitrile at 240 ºC fragmented to ω -cyanoalkanonitrile oxides, which were trapped as their 1,2,4-oxadiazole cycloadducts 17 and 19 , respectively. The flash vacuum pyrolysis (FVP, 550-650 ºC) technique was used to investigate the process in more detail using a range of mono and bicyclic furazans. In all cases the 1,2,5-oxadiazole ring cleaved cleanly at O(1) − N(2) and C(3) − C(4) to nitrile and nitrile oxide fragments. The nitrile oxides were trapped in high yield (81-100%) as their isoxazoline cycloadducts by reaction with hex-1-ene. The tetramethylene furazan 13 was converted into 4-cyanobutyl isocyanate by FVP and reaction of the condensate with sulfur dioxide. 3,5-Diphenyl-1,2,4-oxadiazole showed greater thermal stability under similar conditions (FVP, 600 ºC), but at higher temperatures (700-800 ºC) phenyl isocyanate was formed and trapped as its methyl urethane derivative. Attempts to trap the putative benzonitrile oxide intermediate were unsuccessful.


Results and Discussion
The furazans under investigation were prepared, as illustrated in Scheme 2, either by dehydration of the corresponding glyoxime using thionyl chloride after the method of Boulton and Mathur, 12 or by deoxygenation of the furoxan with triethyl phosphite as described by Mukaiyama et al. 21f the two synthetic approaches, deoxygenation of furoxans (Route B) is a more general method, whereas dehydration of glyoximes (Route A) is restricted to those glyoximes that do not undergo Beckmann rearrangement to the 1,2,4-oxadiazole.In the present context Route A was used successfully to prepare 3,4-dimethylfurazan 12 (52%) and the tetramethylenefurazan 13 (53%).
In contrast, an attempt to prepare 3,4-diphenylfurazan 5 by this approach afforded not 5 but 3,5diphenyl-1,2,4-oxadiazole in 85% yield.If the furoxan is readily available, as was the case for the present investigation, Route B is the method of choice with deoxygenation taking place in excellent yield (usually >90%), whereas Route A normally gave ca.50% yield of the furazan The products were identified from their analytical and spectroscopic properties.In particular, they showed 13 C NMR signals at 149-154 ppm, characteristic for C(3) and C(4) of the oxadiazole ring. 22

N
As the role of benzonitrile oxide in the original thermolysis of furazan 5 (Scheme 1) had not been firmly established, 8,9 we repeated the experiment in the presence of a dipolarophile in an attempt to trap it as its cycloadduct.A similar approach had been successful for trapping the same nitrile oxide formed on fragmentation of the corresponding furoxan 6 using tetradec-1-ene as the dipolarophile.3a Thus a solution of diphenylfurazan 5 was heated in tetradec-1-ene at reflux (245 ºC) for 6 hours, and from the reaction mixture was isolated in 75% yield 5-dodecyl-3-phenyl-2-isoxazoline 14, which was identified by comparison with an authentic sample prepared from benzohydroximoyl chloride and tetradec-1-ene.HPLC analysis of the reaction mixture gave the 2-isoxazoline 14 (83%) together with unreacted 5 (15%).The formation of cycloadduct 14 in high yield (98% based on consumed 5) shows that the 1,2,5-oxadiazole ring cleaves cleanly at O(1)−N(2) and C(3)−C(4).Under identical conditions the corresponding furoxan 6 was consumed in 2 hours, whereas the furazan reaction was incomplete even after 6 hours, suggesting that the furazan has greater thermal stability.3a Whereas bicyclic furoxans, both strained and unstrained, ring open on heating to bis(nitrile oxides) that can readily be trapped as their 1,3-dipolar cycloaducts, 2,3a,3d,3e,7 the corresponding reaction for furazans has so far been limited to those fused to five-membered rings. 12,13Two unstrained bicyclic furazans were selected for the present investigation: the tetramethylene compound 13 and the decamethylene analogue 15.The former was obtained, as indicated above, by dehydration of the commercially available cyclohexane-1,2-dione dioxime, whereas compound 15 was prepared by deoxygenation of the furoxan 3, which was itself readily prepared from cyclododecene via the known α-nitro-oxime 16. 23 A solution of the furazan 13 in 4methoxybenzonitrile as dipolarophile was heated at reflux (240 ºC) for 2 hours and from the reaction mixture was isolated the 1,2,4-oxadiazole 17 (72%) derived from 5-cyanopentanonitrile oxide 18. Oxadiazole 19 (67%) was prepared similarly from the decamethylene furazan 15.These results demonstrate that, as was found for furoxans, the thermolytic ring cleavage does not require special structural features such as ring strain, but is a general reaction for furazans, although it requires more forcing conditions.Furthermore, such bicyclic furazans provide a source of ω-cyanoalkyl nitrile oxides not readily accessible by other means.
These liquid phase studies demonstrate that nitrile oxides can be generated from furazans; however, the high temperatures involved limit the range of dipolarophiles that can be used.Previous studies 3b with furoxans had shown that using conventional flash vacuum pyrolysis (FVP) apparatus and technique 24,25 it was possible, not only to isolate and identify the nitrile oxide fragments, but also to trap them as their 1,3-dipolar cycloadducts by incorporating a dipolarophile in the cold trap.We therefore used the same approach for a selection of representative furazans.In a typical experiment diphenylfurazan 5 (1.8 mmol) was pyrolysed at 600 ºC/10 -3 mmHg and the pyrolysate condensed onto excess hex-1-ene (11.9 mmol) as the dipolarophile.The product mixture was worked up by removal of excess hexene and then vacuum distillation to afford benzonitrile (1.65 mmol, 92%).From the residue was obtained by sublimation 5-butyl-3-phenyl-2-isoxazoline 20 (96%), which was identified by comparison with an authentic sample.3a Similar results were obtained for the pyrolyses of the di-(4methoxyphenyl)-, di-(4-tolyl)-, and dimethyl-furazans 21, 22, 12.The results, which are summarised in Table 1, show that all the furazans afford nitriles and nitrile oxide cycloadducts 23-25 in high yield.In order to gain some insight into the mode of fragmentation of the heterocyclic ring three asymmetrically-substituted furazans 26-28 were investigated.These were prepared via the glyoxime and furoxan as outlined in Scheme 3.For such furazans there are two possible fragmentation pathways involving cleavage at C(3)−C(4) and at either O(1)−N(2) or O(1)−N (5).In all three cases FVP afforded mixtures of 2-isoxazolines and nitriles that were analysed by GC (Table 1, entries 5-7).For the 3-methyl-4-phenyl compound 26, the observed ratio (65:35) of 3phenyl-to 3-methyl-isoxazolines 20, 25 shows that the major pathway involves ring cleavage at O(1)−N(2) and C(3)−C(4), rather than O(1)−N(5) and C(3)−C(4).For 27 and 28 the ratio of products is more finely balanced, with only a slight preference for formation of 4methoxybenzonitrile oxide rather than benzonitrile oxide in the case of 28.Although these results are limited in scope, it is noted that fragmentation favours the more 'stable' nitrile oxide.Acetonitrile oxide is known to have a much shorter lifetime than benzonitrile oxide, 26 and it has also been reported that 4-methoxybenzonitrile oxide is longer lived that benzonitrile oxide, an effect attributed to the electron-donating methoxy substituent.We have previously established that ring-strained bicyclic furoxans can be converted into diisocyanates in good yield in the presence of sulfur dioxide.For example, the diisocyanate 30 was prepared from the norbornane furoxan 4 by heating in toluene saturated with SO 2 .3e The process is believed to involve fragmentation to the dinitrile oxide 2, which undergoes 1,3-dipolar cycloaddition to the SO 2 to form the bis-dioxathiazolone 31.Thermal fragmentation of 31 with extrusion of SO 2 then affords the diisocyanate 31, as illustrated in Scheme 4. The sulfur dioxide thus plays a key role by effecting the nitrile oxide to isocyanate conversion at temperatures lower than those normally required, and also by minimising competing polymerisation of the intermediate dinitrile oxide.3e The conversion of unstrained furoxans to isocyanates was also achieved by using FVP and reacting the condensate with sulfur dioxide.For example, using this approach phenyl isocyanate (93%) was prepared from diphenylfuroxan 6. 3c The corresponding reaction for bicyclic furazans has the potential to produce ω-cyanoalkyl isocyantes.Indeed, we have previously found that heating the strained trimethylenefurazan 32 in the presence of sulfur dioxide generated 3-cyanopropyl isocyanate 33, which could be trapped by aniline as its urea adduct 34. 28To extend the scope of this reaction we examined the tetramethylene compound 13 as an example of an unstrained bicyclic furazan.Furazan 13 was therefore subjected to FVP at 600 ºC and the pyrolysate condensed onto sulfur dioxide.Addition of toluene and heating the resulting solution at reflux afforded 4-cyanobutyl isocyanate 35, which was converted into the urea 36 by treatment with aniline.The reaction presumably proceeds via 5-cyanopentanonitrile oxide 18 and the dioxathiazolone 37, which on heating affords the isocyanate with expulsion of SO 2 .

ISSN 1551-7012
Page 206 © ARKAT USA, Inc.The early literature suggests that 3,5-aryl-1,2,4-oxadiazoles are more stable than the corresponding furazans, [18][19][20] but that at temperatures in excess of 300 ºC decomposition leads to nitriles and isocyanates.Three possible decomposition pathways are illustrated in Scheme 5: Path A, a retro-1,3-dipolar cycloaddition to nitrile and nitrile oxide fragments involving cleavage at O(1)−C(5) and C(3)−N(4), followed by the known 26 nitrile oxide to isocyanate rearrangement; Path B, a one-step process involving cleavage at O(1)−N(2) and C(3)−N(4) with concomitant migration of the aryl group at C(5) to N(4); and Path C, a two-step pathway involving fragmentation to the nitrile and an acylnitrene intermediate that rearranges to the isocyanate.Cotter and Knight 19 found only benzonitrile and phenyl isocyanate, together with unreacted starting material, when they heated 3,5-diphenyl-1,2,4-oxadiazole 38a at 340 ºC in an evacuated sealed ampoule, and they proposed the one-step mechnism (Path B) to explain the results.On the other hand, Ainsworth 20 found that thermolysis of the unsymmetricallysubstituted analogue 3-(4-chlorophenyl)-5-(4-methoxyphenyl)-1,2,4-oxadiazole 38b afforded 4chlorophenyl isocyanate and 4-methoxybenzonitrile, rather than 4-methoxyphenyl isocyanate and 4-chlorobenzonitrile; and he interpreted these results in terms of the nitrile oxide intermediate (Path A).Mass spectrometry studies have shown that electron impact-induced fragmentation of 38 also proceeds via Path A. 29 It was anticipated that by using the FVP technique which had successfully been applied to diphenylfuroxan 6 and diphenylfurazan 5, it might prove possible to isolate the putative benzonitrile oxide intermediate 7 formed on fragmentation of the 1,2,4-oxadiazole analogue 38a.
3,5-Diphenyl-1,2,4-oxadiazole 38a was prepared in good yield (85%) by thionyl chlorideinduced Beckmann rearrangement of benzil dioxime.Heating a solution of the oxadiazole 38a in excess tetradec-1-ene at 251 ºC yielded only recovered starting material and none of the isoxazoline cycloadduct 14 could be detected, thus confirming its greater thermal stability of 38a compared with the furazan 5. Similarly, FVP of 38a at 600 ºC onto hex-1-ene resulted only in recovered starting material (97%).At 700 ºC some decomposition did take place with 54% of 38a being recovered, but the isoxazoline 20 that would have been formed from benzonitrile oxide could not be detected in the product mixture.It had previously been established 30 that FVP of diphenylfuroxan 6 at 700 ºC afforded benzonitrile oxide 7 in very high yield (95%), thus demonstrating that the benzonitrile oxide to phenyl isocyanate rearrangement is slow under these conditions.The involvement of benzonitrile oxide as an intermediate in the formation of phenyl isocyanate from oxadiazole 38a therefore remains unproven.FVP of 38a at 800 ºC onto methanol was carried out in an attempt to trap benzoylnitrene, but failed to produce any Nbenzoyl-O-methylhydroxylamine that would have resulted from O−H bond insertion; the only product isolated was the phenyl isocyanate-derived urethane (PhNHCO 2 Me).

ISSN 1551-7012
Page 207 © ARKAT USA, Inc.In conclusion, these results show that the fragmentation of furazans to nitrile oxides and nitriles does not depend on special features such as ring strain or bulky substituents, and that using the FVP technique gives excellent yields of cleavage products (87-100%).It is also noteworthy that by using FVP a wider range of furazans and dipolarophiles can be used compared with liquid-phase reactions.Bicyclic furazans afford ω-cyanoalkyl nitrile oxides, which can be trapped as their 1,3-dipolar cycloadducts and using sulfur dioxide as the dipolarophile provides access to ω-cyanoalkyl isocyanates.Attempts to trap benzonitrile oxide from the decomposition of 3,5-diphenyl-1,2,4-oxadiazole were not successful.

Experimental Section
General.Melting points were determined on a Kofler hot-stage apparatus and are uncorrected.NMR spectra ( 1 H at 100 or 360 MHz, 13 C at 20 or 93 MHz) were recorded on solutions in CDCl 3 (unless otherwise stated) with Me 4 Si as internal standard and using Brucker WH360, Varian XL100 or Varian CFT-20 spectrometers.Mass spectra were obtained on an AEI M902 instrument and reaction mixtures analysed using a VG Micromass 12 mass spectrometer/gas chromatograph.A Perkin Elmer 157G spectrophotometer was used to record IR spectra.For qualitative and quantitative GC investigations were carried using Pye 104 and Perkin-Elmer F11 instruments, using SE30 as stationary phase.HPLC analyses were performed using either Spherisorb silica, Spherisorb alumina, or ODS-Hypersil supplied by Shandon-Southern Ltd.