Nitrile oxides dimerization

Fig. 3 Fx synthetic approaches. Left nitrile oxides dimerization. Right a-nitrooxime de-hydration/cyclization...

As a new utility of nitrile oxide in organic synthesis, synthesis of medium and large rings by intramolecular nitrile oxide dimerization is reported (Eq. 8.67).102... 

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). 

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). 

The yields of the first and the second stages were 53% and 48%, respectively. The yields of the para-analog of 414 were similar (55% and 35%, respectively). A one-pot reaction with pyridine-2,6-biscarbohydroximinoyl dichloride gives a pyridine analog of 414 as a minor product (8%). The main product 416 (25% yield) arises from an intramolecular nitrile oxide dimerization. The macrocyclic cycloadducts have been characterized spectroscopically and by X-ray crystallography (452). 

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))... 

Bicyclic derivatives of furazan A-oxide are prepared by nitrile oxide dimerization reaction. Dioxime 272 (R, R = Me) undergoes cyclization to the corresponding 4,4-tetramethylperhydrocycloocta[c]furazan A-oxide 273 (84% yield) by treatment with NaOCl/HaO/CHaCla at 0°C and then refuxing in toluene (equation 117). However, in the cases of sterically less hindered oximes 272 (R = H, Me R = H) only complex mixtures of oligomerization and cyclization products could be obtained ". Interestingly, the reaction of pyridyl oxime -274 with TsCl afforded 1,2,5-oxadiazole 275 as single product (equation 118). On the other hand, the reaction of Z-isomer of oxime 274 leads only to 0-tosylated oxime. ... 

The ready accessibility of 1,2-dioximes (glyoximes) and the ease with which they are dehydrated has ensured that this is the most common route to furazans. The starting materials are usually prepared by oximation of the appropriately substituted 1,2-diketone or, more often, by a-nitrosation of an alkyl ketone followed by oximation of the resulting 1,2-dione monooxime (Scheme 16). 1,2-Dioximes can also be prepared by reduction of furoxans (Section 4.05.5.2.4) and, in cases where the furoxan is more readily available than the furazan, for example, by nitrile oxide dimerization, this furoxan-> glyoxime-> furazan sequence represents a viable synthetic strategy for symmetrically substituted derivatives. 

Cycloaddition rates range over several orders of magnitude and to predict the likely success of a reaction, when alternative reaction pathways such as nitrile oxide dimerization are possible, it is necessary to understand the reactivity of the system. 

Aminium hexachloroantimonate, tris-4-bromophenyl-, effect of on nitrile oxide dimerization, 60, 266 Aminoacids... 

Furazan-A-oxides (furoxanes) 104 (Scheme 30) are isolated as a result of the nitrile oxide dimerization when chloro-oximes 101 are treated with bases in the absence of dipolarophiles [21,49, 50]. Oxidation of aldoxime 99 with nitric acid gives furoxan 104 [Rp=H(CF2)8] in 50 % yield [51]. Similarly, furoxane 104 (RF=CgF5)... 

From 3-picoline A -oxide and phenyl isocyanate the cycloadduct can be isolated Also, nitrile oxides, generated from arylhydroxamoyl chloride and triethylamine, react with phenyl isocyanate to give 2,4-diaryl-l,2,5-oxadiazol-3-ones and nitrile oxide dimers". Mesitonitrile oxide reacts with a l-oxa-3-azonia-butatriene salt 419 (R = 2,4,6-MesPh) by addition across the C=0 bond of the isocyanate to give a 1,2,5-oxadiazole derivative 420" ". ... 

Nitrile oxides are considerably more reactive than nitrones, and nitrile oxide dimerization is a prominent side reaction that can effectively compete with dipolar cycloaddition. To overcome this obstacle, nitrile oxides are typically generated in situ under conditions that lead to their participation in 1,3-dipolar cycloaddition reactions. The resulting isoxazolines constitute a versatile class of heterocycles, which are amenable to extensive manipulation. Confalone s synthesis of biotin (16) includes clever use of an intramolecular nitrile oxide cycloaddition reaction [46] that sei-ves to install the requisite relative configuration as well as the necessary side chain (Scheme 18.4) [47]. 

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). 

Irradiation of l//-indazoles under nonacidic conditions resulted in isomerization to benzimidazoles and also ring opening to isomeric benzonitriles. With 1-substituted benzimidazoles and sensitized irradiation, nitriles were formed, but these are only minor products with other substitution patterns 67HCA2244, 64TL2999). Irradiation of benzimidazoles leads to oxidative dimerization. 

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 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 usually prepared via halogenation and dehydrohalogenation of aldoximes [11] or via dehydration of primary nitro alkanes (Scheme 1) [12]. However, it is important to note that nitrile oxides are relatively unstable and are prone to dimerization or polymerization, especially upon heating. 1,3-Dipolar cycioaddition of a nitrile oxide with a suitable olefin generates an isoxazoline ring which is a versatile synthetic intermediate in that it provides easy access to y-amino alcohols, )5-hydroxy ketones, -hydroxy nitriles, unsaturated oximes, and a host of other multifunctional molecules (Scheme 1) [5a]. Particularly for the formation of )5-hydroxy ketones, nitrile oxide-olefin cycioaddition serve as an alternative to the Aldol reaction. 

Chiral tricyclic fused pyrrolidines 29a-c and piperidines 29d-g have been synthesized starting from L-serine, L-threonine, and L-cysteine taking advantage of the INOC strategy (Scheme 4) [19]. L-Serine (23 a) and L-threonine (23 b) were protected as stable oxazolidin-2-ones 24a and 24b, respectively. Analogously, L-cysteine 23 c was converted to thiazolidin-2-one 24 c. Subsequent N-allylation or homoallylation, DIBALH reduction, and oximation afforded the ene-oximes, 27a-g. Conversion of ene-oximes 27a-g to the desired key intermediates, nitrile oxides 28 a-g, provided the isoxazolines 29 a-g. While fused pyrrolidines 29a-c were formed in poor yield (due to dimerization of nitrile oxides) and with moderate stereoselectivity (as a mixture of cis (major) and trans (minor) isomers), corresponding piperidines 29d-g were formed in good yield and excellent stereoselectivity (as exclusively trans isomers, see Table 3). 

Contrary to other Af-oxide containing heterocycles, Bfx and Fx are not formed by direct oxidation of the parents systems, benzofurazan (Bfz) and furazan (Fz), respectively. Even though each kind of heterocycle possesses individual synthetic procedures, some common approaches should be mentioned, i.e., thermo or photochemical intramolecular cychzation of 1,2-azidonitro derivatives and oxidative cychzation of 1,2-dioximes. Some other synthetic procedures, such as oxidation of o-nitroanUines to Bfx or dimerization of nitrile oxides and dehydration of a-nitrooximes to Fx, have been depicted. The following sections provide the most recent descriptions. 

The intermolecular dimerization of nitrile oxides has been described as a procedure to prepare Fx with identical substituent both in the 3 and 4 position (Fig. 3). This procedure is a [3 -F 2] cycloaddition where one molecule of nitrile oxide acts as 1,3-dipole and the other as dipolarophile [24-26]. Yu et al. has studied this procedure in terms of theoretical calculus [27,28]. Rearrangement of isocyanates competes with the bimolecular dimerization, with the former becoming dominant at elevated temperatures. 

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],... 

Adducts 380-383 of nitrile oxides to highly hindered bicyclopropylidene (3) can be obtained, despite the lower reactivity of the tetrasubstituted double bond which reduces the yields favoring the dimerization of reactive nitrile oxides (Table 31, entries 1-2) [80a, b]. 

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>. 

Nitrile oxides are widely used as participants in 1,3-dipolar cycloadditions leading to five-membered heterocycles. Nitrile oxides (especially for lower aliphatic and acyl nitrile oxides) can dimerize easily to form l,2,5-oxadiazole-2-oxides (Equation 67) <2003JA15420>. 

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>. 

Di-(2,3,4,6-tetra-0-acetyl-a-D-mannopyranosyl)-l,2,5-oxadiazole 2-oxide 306 was synthesized from D-mannose 305 by a route involving dimerization of mannopyranosyl nitrile oxide as the key step. Three methods were used for the generation of the nitrile oxide isocyanate-mediated dehydration of nitromethylmannose derivatives, treatment of aldoxime with aqueous hypochlorite, and base-induced dehydrochlorination of hydroximoyl chloride (Scheme 76) <2001TL4065, 2002T8505>. 

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>. 

Dimerization under neutral conditions takes place upon refluxing a concentrated solution (1.0 M) of nitrile oxide 308 in benzene for 18 h resulting in clean formation of dimer 309 (Equation 69) <2001JOC6410>. 

---