Nitrile oxides, cycloaddition with furoxans

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. 

Dipolar cycloadditions of nitrile oxides 216 onto 1 gave much poorer yields of cycloadducts 217 than those of nitrones 205. The cycloadditions of 216 to 1 require higher temperatures and unfavorably compete with their dimerization to furoxanes. However, stable nitrile oxides 216 with bulky substituents R that hamper dimerization, can be used. The thermal rearrangements of 5-spirocyclopropane-annelated isoxazolines 217 always required higher temperatures than the isoxazolidine counterparts. Under these conditions the second cyclopropane ring was also cleaved to give furopyridines 218 (Scheme 48) [136, 137]. 

A special case involves the thermal decomposition of 3,4-dinitrofuroxan (104). The cycloreversion is already observed at room temperature and the nitroformo-nitrile oxide could be trapped with electron-deficient nitriles. The cycloadditions with styrene, phenylacetylene, frani-stilbene, and cyclohexene, however, led to complex mixtures of products that could not be separated (104). In the related case of a furoxan with an a-hydrogen adjacent to the sulfonyl group, the reaction was proposed to proceed according to course (b) (Scheme 6.7). 

Control of reaction selectivities with external reagents has been quite difficult. Unsolved problems remaining in the held of nitrile oxide cycloadditions are (a) Nitrile oxide cycloadditions to 1,2-disubstituted alkenes are sluggish, the dipoles undergoing facile dimerization to furoxans in most cases (b) the reactions of nitrile oxides with 1,2-disubstituted alkenes nonregioselective (c) stereo- and regiocontrol of this reaction by use of external reagents are not yet well developed and (d) there are few examples of catalysis by Lewis acids known, as is true for catalyzed enantioselective reactions. 

Nitromethyl ketones react with p-toluenesulfonic acid (PTSA) in refluxing toluene to give the corresponding furo-xans in 97% yield [20]. When refluxed several hours in xylene or mesitylene in the presence of dipolarophiles and catalytic PTSA, not only activated nitro compounds but also phenylnitromethane and 1-nitropropane afforded the expected isoxazole derivatives, as a result of nitrile oxide cycloadditions [21]. Microwave irradiation in the presence of catalytic PTSA has been successfully applied to condensations between methyl nitroacetate and dipolarophiles [22]. Nitroacetic esters have been converted into the corresponding furoxans with cold sulfuric acid [23], while phenylnitromethane and phenylacetylene in ethereal boron trifluoride etherate are reported to give 3,5-diphenylisoxazole [24]. 

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-... 

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). 

The first examples of furazan and furoxan nitrile oxides have been reported in the early 1990s. 4-Aminofurazan-3-carbonitrile oxide (65) was generated from the hydroximoyl chloride with base and its cycloaddition reactions investigated <92KGS687>, and the 4-phenyl analogue (66) is formed via the nitrolic acid derivative by treatment of the aldoxime with dinitrogen tetroxide <93LA44i>. Furazan-3-amidoximes react in the usual way with nitriles to yield 3-(furazan-3-yl)-1,2,4-oxadiazoles <9013941 >. 

Heating furoxans with alkenes may also yield 2-isoxazolines as a result of initial fragmentation to nitrile oxides and subsequent 1,3-dipolar cycloaddition (see Section 4.22.3.2.2) ... 

Acetyl- and 3-benzoylisoxazoles 389 (and isoxazolines) have been prepared by one-pot reactions of alkynes (and alkenes) with ammonium cerium(iv) nitrate (CAN(lv)) or ammonium cerium(lll) nitrate tetrahydrate (CAN(m))-formic acid, in acetone or acetophenone. These processes probably involve 1,3-dipolar cycloaddition of nitrile oxides produced via nitration of the carbonyl compound by cerium salts. The existence of nitrile oxides as reaction intermediates was proved by the formation of the dimer furoxan 390 when the above reaction was carried out in absence of any dipolarophile (Scheme 95) <2004T1671>. An analogous improved procedure has been applied to alkynyl glycosides as dipolarophiles for the preparation of carbohydrate isoxazoles <2006SL1739>. 

Decarboxylation and ring cleavage, followed by cycloaddition of the nitrile oxide 118, probably account for the formation of adducts (119) from 4-methylfuroxan-3-carboxylic acid (117).361 Analogously, 4-phenylfuroxan forms an adduct (or adducts) with mesityl oxide, apparently derived via the nitrile oxide 120, which is produced from the furoxan under a variety of extremely mildly basic conditions.362... 

Nitrile oxides are usually prepared in the presence of the olefin or acetylene acceptor. Most nitrile oxides are highly reactive and in the absence of trapping agents they undergo rapid dipolar cycloaddition with themselves to give furoxans (Scheme 5.38). 

Nitrile oxides as starting materials or intermediates in cycloaddition reactions with dipolarophiles produce variable amounts of furoxans 3 (Scheme 8.1) as side products, as recalled before. In order to reduce the amount of furoxan, such reactions are usually carried out with an excess of dipolarophUe or under gradual reagent supply. 

The above results indicate that dehydration of a-nitro-ketones to nitrile oxides occurs (at least in part) prior to cycloaddition, leading to the corresponding furoxans together with the cycloadducts. It is worth remembering that enhanced dehydration of a-nitroketones to nitrile oxides has been noticed previously in more drastic conditions (heating with PTSA) and related to tautomerization [16] or by treatment with concentrated mineral acids [17]. Both reaction pathways (Scheme 8.2) are possible, depending on relative reaction rates and on the base employed. 

The competition between condensation and conjugate addition, observed with electron-poor dipolarophiles, suggests cycloaddition of nitronic acid to dipolarophile to be the next step toward condensation. Direct dehydration to nitrile oxides possibly gives a partial contribution to the process since minor amounts of furoxans have been detected in some cases. When condensation competes with conjugate addition. 

Addition of Cu salts to the base allows nitroalkanes to undergo condensations with dipolarophiles it is reasonable to relate this catalytic effect to the known existence of complexes with nitronates [92]. Formation of such complexes might affect conversion of nitro compound into a species prone to cycloaddition and possibly catalyzes cycloaddition. Dehydration to nitrile oxide must be considered, too. In fact, furoxans can be detected in the presence of dipolarophile, while in their absence furoxans can be prepared, at least from nitroacetates or other activated nitro compounds [83]. The Mn nitronate from ethyl nitroacetate has been reported to generate the corresponding nitrile oxide [81]. 

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