Nitriles furoxans

Phototransformation of pyridazine 1,2-dioxides sharply contrasts with that of pyridazine 1-oxides. Pyridazine 1,2-dioxide derivatives give 3a,6a-dihydroisoxazolo[5,4- f]isoxazoles (53) through postulated bisiminoxyl radicals. 3,6-Diphenylpyridazine 1,2-dioxide gives, besides the corresponding bicyclic derivative (53), 3-phenylisoxazole (54) and 4,5-diphenyl-furoxan (55). The last two products can be explained by generation of the nitrile oxide from the intermediate (53) with subsequent dimerization to the furoxan (55 Scheme 18) (79T1267). 

The rate of dimerization of nitrile A-oxides is strongly influenced by the nature of R. When R = Cl, Br, CO2 alkyl or COR, the nitrile A-oxide cannot be isolated nor obtained in solution for any appreciable time. Table 11 gives the approximate time required for complete dimerization of some nitrile A-oxides (335) to furoxans (336) in benzene solution at 18 °C (70E1169). Evidently, steric and electronic effects dramatically increase the stability... 

Table 11 Stability of Some Nitrile Af-Oxides, R—C=N—O, towards Dimerization to Furoxans <70EU69)...

Nitrile oxides react with a wide variety of alkenic compounds and this reaction may be complicated by dimerization of the nitrile oxide to furoxan in the presence of unreactive double bonds (Scheme 98). 

Nitrile groups attached to the furazan and furoxan rings are susceptible to nucleophilic reagents. The nitrile group was easily reacted with azides (68USP3386968,... 

The type of the thermolysis process depends on the nature of the acyl group. Thus, other types of thermolysis processes involve reversible fragmentation of the furoxan ring to give two molecules of the corresponding nitrile oxide followed... 

In contrast to other furoxans, the cycloreversion of 3,4-dinitrofuroxan to nitro-formonitrile oxide was observed even at room temperature. The nitrile oxide could be trapped in situ with electron-deficient nitriles (Scheme 149) (95MC231). Attempts to obtain cyclo adducts with styrene, phenylacetylene, rran.s-stilbene, and cyclohexene failed. 

Few reactions of sulfonylfuroxans with olefins have been reported. Depending on the substituents at the furoxan ring, nature of dipolarophile, and temperature, different types of products may be obtained. It is relatively simple to cyclore-vert disulfonylfuroxans to a-sulfonyl nitrile oxides on thermolysis (81TL3371, 85T727). These nitrile oxides were trapped by dipolarophiles to yield sulfonyl-substituted isoxazole derivatives. For example, 3,4-bis(phenylsulfonyl)furoxan reacts with an excess of styrene in xylene under reflux to afford the corresponding isoxazoline 290 (Scheme 189). 

NITRILE OXIDES. Nitrile oxides are a well known class of compds represented by R.C N- 0, and are usually prepd by treating hydroxamic acid chlorides with a mild alkali, thus eliminating HQ (Ref 2). Wieland (Refs 1 3) was responsible for the first isolation of free nitrile oxides. These compds are somewhat unstable, showing a marked tendency to dimerize to (he corresponding furoxanes (1,3-dipolar addition) (Refs 2 3). The nitrile oxides add to a considerable number of carbenes, as benzonitrUe oxide (for example) to a large number of olefins in ether at 20° (Ref 3)... 

Nitrile oxides are very reactive dipoles which, apart a few members, need to be prepared in situ for their tendency to dimerize to furoxans [86], This behaviour represents a limit to their use with alkylidenecyelopropanes that is only in part compensated by their reactivity. The cycloadditions of several nitrile oxides with alkylidenecyelopropanes were extensively studied in connection with the rearrangement process leading to dihydropyrid-4-ones 336 [64, 87],... 

Aroylnitrile oxides can also be generated from diaroyl furoxans 183 under micro-wave irradiation [33]. Formation of the nitrile oxide intermediate 184 and its cycloaddition with dipolarophiles proceeds at atmospheric pressure within minutes in the absence of solvent and in good yields (Scheme 9.56). The reaction occurs by the rear-... 

The major fragmentation in mass spectra of 1,2,5-oxadiazoles is attributed to the loss of nitrile and nitrile oxide or expulsion of NO. The conversion of 3,4-dicyano-l,2,5-oxadiazole-2-oxide (3,4-dicyanofuroxan) 10 to cyanogen iV-oxide 11 (Equation 5) was investigated under the conditions of collisional activation (CA) and neutralization-reionization (NR) mass spectrometry. Flash vacuum thermolysis mass-spectrometry (FVT-MS) and flash vacuum thermolysis infra-red (FVT-IR) investigations of furoxans 10, 12, and 13 reveal that small amounts of cyano isocyanate accompany the formation of the main thermolysis product 11 <2000J(P2)473>. 

The reaction of 3,4-diacyl-l,2,5-oxadiazole 2-oxides (furoxans) with activated nitriles in ionic liquids and in ethanol unexpectedly resulted in 3-acyl-4-acylamino-l,2,5-°xadiazoles (furazans) <2003MC230>. 3-Formyl-4-phenyl-l,2,5-oxadiazole Ar-oxide 105 is a good precursor for the synthesis of functional substituted furoxans (Scheme 28) <1999JME1941, 2000MOL520, 2000JFA2995>. 

Although the Capdevielle reaction for one-pot conversion of aldehydes to nitriles is a very convenient and widely applicable synthetic procedure, 3-substituted furoxans appear to be susceptible to rearrangement when substitutions with amine nucleophiles are attempted, even under relatively mild conditions (Scheme 29) <1999JOC8748>. The formation of the final product 107 in this reaction was explained via phenyl abstraction by carbamoyl radical cation from the second molecule of intermediate product 106 < 1999JOC8748>. 

Dimerization of nitrile oxides derived from 4-amino- and 4-R-substituted l,2,5-oxadiazole-3-carbohydroximoyl chlorides 201 leads to the formation of tricyclic furoxans 200 or compound 202 (Scheme 45) <2001RJ01355>. 

The side products of the reaction between benzoylnitromethane 279 and dipolarophiles (norbornene, styrene, and phenylacetylene) in the presence of l,4-diazabicyclo[2.2.2]octane (DABCO) were identified as furazan derivatives (Scheme 72). The evidence reported indicates that benzoylnitromethane gives the dibenzoylfuroxan as a key intermediate, which is the dimerization product of the nitrile oxide. The furoxan then undergoes addition to the dipolarophile, hydrolysis, and ring rearrangement to the final products (furazans and benzoic acid) <2006EJ03016>. 

Several examples of the synthesis of furoxans by dimerisation of nitryl oxides are shown below. The treatment of oximes 302 with iV-bromosuccinimide (NBS) and then with triethylamine leads to the formation of nitrile oxides 303, as shown by the presence of a strong IR absorption band at around 2300 cm 1 typical of the CNO group stretching. Slow dimerization of nitrile oxides 303 took place at room temperature leading to the furoxans 304 in good yields (Scheme 75 and Table 4) <2002S1701>. 

Nitrile oxides are readily formed upon treatment of hydroximoyl halides with a base such as Et3N <1998T791, 2000ARK683>. Usually nitrile oxides are unstable and easily dimerize to form furoxans in the absence of a dipolarophile. For example, an almost quantative yield of furoxan 307 is formed in the absence of the trapping reagents (Equation 68) <1998T791>. 

These routes are dimerization to furoxans 2 proceeding at ambient and lower temperatures for all nitrile oxides excluding those, in which the fulmido group is sterically shielded, isomerization to isocyanates 3, which proceeds at elevated temperature, is practically the only reaction of sterically stabilized nitrile oxides. Dimerizations to 1,2,4-oxadiazole 4-oxides 4 in the presence of trimethylamine (4) or BF3 (1 BF3 = 2 1) (24) and to 1,4,2,5-dioxadiazines 5 in excess BF3 (1, 24) or in the presence of pyridine (4) are of lesser importance. Strong reactivity of nitrile oxides is based mainly on their ability to add nucleophiles and particularly enter 1,3-dipolar cycloaddition reactions with various dipolarophiles (see Sections 1.3 and 1.4). 

Stable furoxans are convenient starting compounds for generating short-lived nitrile oxides XCNO (X = ONC, NC, Cl, Br, and Me) by thermolysis (10, 11, 80, 81). The thermolysis of benzotrifuroxan (200°, in excess PhCN) proceeds (Scheme 1.6) with the cleavage of the C-C and 0-N(0) bonds in only one furoxan ring to give bifuroxan bis(nitrile oxide). The latter undergoes further reactions such as cycloaddition with PhCN or conversion to bisisocyanate (82). 

Cycloreversion with nitrile oxide formation is known not only in furoxans but also in isoxazolines, 1,2,4-oxadiazoles, furazans, and some other live-membered heterocycles (76). Such process, eliminating nitrile oxide fragment 3-R CeHiC N+Cr ", was observed mass spectrometrically in 3a,4,5,6-tetrahydro-[ 1,2,4 oxadiazolo[4,5-a J [ 1,5 benzodiazepine derivatives 11 (83). 

In alkali solutions, 5-nitro-2-furaldehyde forms an anion of (5-nitrofuran-2-yl)methanediol, which undergoes an irreversible redox ring-opening reaction to give mono(nitrile oxide) of a-ketoglutaconic acid H02CCOCH=CH-CNO,°o the latter was identified as furoxan (91). 

Ammonium cerium(IV) nitrate on reaction with acetone or acetophenone generates acetyl- or benzoylformonitrile oxides, respectively (99). These nitrile oxides dimerize to furoxans and give, in the presence of alkenes and alkynes, 3-acetyl- or 3-benzoyl-4,5-dihydroisoxazoles and 3-acetyl- or 3-benzoylisoxazoles, respectively the yield of the isoxazole derivatives was improved on using ammonium cerium(III) nitrate tetrahydrate-formic acid (99). 

Some routes of chemical transformations of nitrile oxides connected with the problem of their stability were briefly discussed in Section 1.2. Here only two types of such reactions, proceeding in the absence of other reagents, viz., dimerization to furoxans and isomerization to isocyanates, will be considered. All other reactions of nitrile oxides demand a second reagent (in some cases the component is present in the same molecule, and the reaction takes place intramolecularly) namely, deoxygenation, addition of nucleophiles, and 1,3-dipolar cycloaddition reactions. Also, some other reactions are presented, which differ from those mentioned above. 

The stability of o-sulfonylbenzonitrile oxides and their thiophene analogs probably depends on electronic factors. The same factors do not prevent dimerization, as can be seen from data concerning several differently substituted nitrile oxides of the thiophene series (103). Sterically stabilized 3-thiophenecarbonitrile oxides 18 (R = R1 = R2 = Me R = R2 = Me, R1 = i -Pr), when boiled in benzene or toluene, isomerized to isocyanates (isolated as ureas on reaction with aniline) while nitrile oxides 18 with electron-withdrawing substituents (R1 and/or R2 = SOiMe, Br) dimerized to form furoxans 19. 

Diaryl- (85), diaroyl- (71), bis(4-substituted-l,2,5-oxadiazol-3-yl)furoxans (104) as well as exotic l,2,2,5,5-pentamethyl-4-(nitromethyl)-3-imidazoline 3-oxide-derived furoxan 22 (105) were obtained via corresponding nitrile oxides. 

Deoxygenation by NO proceeds rather slowly, and nitrile oxides take part simultaneously in two other reactions (a) dimerization to furoxans 23 and (b) interaction with NO2 which is formed in the reaction, to give aryltrini-tromethanes. The most unstable of the known arenecarbonitrile oxides, benzonitrile oxide, owing to its fast dimerization gives no phenyltrinitromethane but only furoxans. Products similar to both cited reactions are formed with N2O3 because of its known equilibrium with NO and NO2 (112). 

DFT studies of the intramolecular ene-like (or the so-called 1,3-dipolar ene) reaction between nitrile oxides and alkenes show that this reaction is a three-step process involving a stepwise carbenoid addition of nitrile oxide to form a bicyclic nitroso compound, followed by a retro-ene reaction of the nitrosocyclopropane intermediate. The competitive reactions, either the intramolecular [3 + 2] cycloaddition between nitrile oxides and alkenes or the intermolecular dimerization of nitrile oxides to form furoxans, can overwhelm the intramolecular 1,3-dipolar ene reaction if the tether joining the nitrile oxide and alkene is elongated, or if substituents such as trimethylsilyl are absent (425). 

I.4.2.I. Synthesis and Modification of Polymers Unstable bis(nitrile oxide), generated by dichloroglyoxime dehydrochlorination, polymerizes in solution to give poly(furoxan) or (in the presence of 1,3-dienes) gives rise to their being cross-linked (500). Polymerization of terephthalonitrile dioxide and its... 

In this reaction, isoxazole (173) rather than the corresponding aziridine was isolated in good yield. It was stated (223) that acyl nitronate (172) rather than the corresponding nitrile oxide is a precursor of isoxazole (173). This interpretation is supported by the fact that the corresponding nitrile oxide dimer (furoxan (174))... 

In general, furoxans are fairly stable compounds in acid solution but are sensitive to bases [6, 9]. This is true in particular for the parent ring and for the 4- and 3-monosubstituted compounds. The former undergoes extensive decomposition, while the latter two produce a-hydroxyimino substituted nitrile oxides 5 and a-nitro substituted nitriles 6, respectively. 4-Aryl-3-methylfuroxans 7, unlike their 4-methyl isomers, give Angeli s rearrangement, namely they are converted to the corresponding 3-arylisoxazolin-4-one oximes 8, by the action of concentrated alkali hydroxides or alkoxides (Scheme 6.1). 

This is the principal route to obtain symmetrically substituted furoxans. The reaction normally occurs by heating the isolated nitrile oxide 11 or by keeping it in a neutral medium. This reaction is fast and is the main reason why it is difficult to conserve isolated nitrile oxides. 

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