1.2.4- Oxadiazoles nitrile oxides

Figure 5 1,2,4-Oxadiazoles that undergo fragmentation by loss of a nitrile oxide fragment.

The cycloaddition of nitrile oxides to nitriles in the presence of a Pd(ll) center allowed the isolation of the previously unknown l,2,4-oxadiazole-Pd(n) species 227 (Equation 44) <2005EJI845>. 

The Mukaiyama-Hoshino reaction between a nitroalkane and phenyl isocyanate generates a nitrile oxide, and this method has been used in the synthesis of 1,2,4-oxadiazoles as discussed in CHEC-II(1996) <1996CHEC-II(4)179>. In a more recent advance, nitroethane undergoes ultrasound-mediated cycloaddition with trichloroacetonitrile to give the extremely useful (see Equation 11) 5-trichloromethyl-l,2,4-oxadiazole 228 (Equation 45) <1995TL4471>. 

The oxidation of aromatic aldoximes with ceric ammonium nitrate produces nitrile oxides which undergo subsequent cycloaddition to nitriles to produce 1,2,4-oxadiazoles (Equation 47) <1997PJC1093>. The anodic oxidation of aromatic aldoximes in the presence of acetonitrile has been reported to give low yields of either 3-aryl-5-methyl-1,2,4-oxadiazoles (2-25%) or 3,5-bis-aryl-l,2,4-oxadiazoles (6-28%), although the synthetic utility of this route is limited by competitive deoximation to the carbonyl being the major reaction pathway <1997MI3509>. 

The cycloaddition of nitrile oxides to amidoximes 234 leads to 1,2,4-oxadiazole 4-oxides which can then be deoxygenated with trimethyl phosphite (Equation 48) <1997T1787>. 

The cycloaddition of nitrile oxide 235 to the 4-iminobenzopyran-2-one 236 gave the fully conjugated 1,2,4-oxadiazole 238 directly, a reaction that most likely proceeds via loss of methanol from the intermediate 237 (Scheme 36) <1996JHC967>. Similarly, nitrile oxide 239 reacted with imine 240 to give the 1,2,4-oxadiazole 242 via the nonisolable intermediate 241 <2002PJC1137>. 

In a significant addition to the synthesis of 1,2,4-oxadiazoles (Scheme 41), Itoh et al. discovered that the treatment of nitriles with iron(lll) nitrate in the presence of acetone or acetophenone gives the 3-acetyl- or 3-benzoyl-l,2,4-oxadiazoles 260, proposing that enolization and nitration gives an a-nitroketone, which then undergoes an acid-catalyzed dehydration to give the nitrile oxides 259 <2005S1935>. 

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>. 

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>. 

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>. 

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>. 

Glycosyl nitrile oxides 315, generated in situ by reaction of hydroxamoyl chlorides with DBU, participate in 1,3-dipolar cycloaddition with substituted alkenes leading to glycosyl isoxazolines the l,2,5-oxadiazole-2-oxides 316 are isolated as by-products in low yields (Scheme 79) <2004CHC353>. 

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). 

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). 

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. 

Dipolar cycloaddition of nitrile oxide at the C=N bond of indole imino esters 130, followed by elimination of the alcohol moity gives oxadiazole derivatives 131 (Scheme 1.26) (298). Reaction of N-arylbenzamidines with arenenitrile N-oxides (generated in situ from oximoyl chlorides) produce unstable 5-amino-4,5-dihydro-1,2,4-oxadiazoles which, on aqueous acidic treatment hydrolyze to open-chain N-benzoyloxy-N -arylareneamidines (299). 

Dipolar cycloadditions of 2-ethoxy- and 2-ethylthio-l-azetines 146 (Z = O, S) with nitrile oxides give 4,5,6,6a-tetrahydroazeto[l,2-d]oxadiazoles, for example 147 (315, 316). 

The carbon-nitrogen triple bond of aryl thiocyanates acts as a dipolarophile in 1,3-dipolar cycloadditions. Reactions with nitrile oxides yield 5-arylthio-1,2,4-oxadiazoles 227 (X = O Y = S). Aryl selenocyanates behave similarly forming 5-arylseleno-l,2,4-oxadiazoles 227 (X = 0 Y = Se). Reactions of 5-aryl-... 

A significant acceleration of 1,3-dipolar cycloaddition of nitriles with nitrile oxides is shown, in the absence of solvent, at microwave irradiation (395). The reactions are finished within 2 to 10 min, to give 1,2,4-oxadiazoles in good yields. 

A new route to 1,2,4-oxadiazoles and their complexes via Pt- and Pd-mediated 1,3-dipolar cycloaddition of nitrile oxides to organonitriles, has been reported. The sequence of the metal-mediated [2 + 3] cycloaddition offers an alternative route for the preparation of oxadiazoles. 

The benzyl ligand of benzylbis(dimethylglyoximato)pyridine cobalt complex has been selectively converted to 3,5-dibenzyl-l,2,4-oxadiazole by a reaction with alkyl nitrite in the presence of light (426). The reaction proceeds by the in situ formation of an oxime and a nitrile oxide (Scheme 1.44). 

Sealants obtained by curing polysulfide liquid polymers with aryl bis(nitrile oxides) possess stmctural feature of thiohydroximic acid ester. These materials exhibit poor thermal stability when heated at 60°C they soften within days and liquefy in 3 weeks. Products obtained with excess nitrile oxide degrade faster than those produced with equimolar amounts of reagents. Spectroscopic studies demonstrate that, after an initial rapid addition between nitrile oxide and thiol, a second slower reaction occurs which consumes additional nitrile oxide. Thiohydroximic acid derivatives have been shown to react with nitrile oxides at ambient temperature to form 1,2,4-oxadiazole 4-oxides and alkyl thiol. In the case of a polysulfide sealant, the rupture of a C-S bond to form the thiol involves cleavage of the polymer backbone. Continuation of the process leads to degradation of the sealant. These observations have been supported by thermal analysis studies on the poly sulfide sealants and model polymers (511). 

Acyl nitroso compounds react with 1, 3-dienes as N-O heterodienophiles to produce cycloadducts, which have found use in the total synthesis of a number of nitrogen-containing natural products [21]. The cycloadducts of acyl nitroso compounds and 9,10-dimethylanthracene (4, Scheme 7.3) undergo thermal decomposition through retro-Diels-Alder reactions to produce acyl nitroso compounds under non-oxidative conditions and at relatively mild temperatures (40-100°C) [11-14]. Decomposition of these compounds provides a particularly clean method for the formation of acyl nitroso compounds. Photolysis or thermolysis of 3, 5-diphenyl-l, 2, 4-oxadiazole-4-oxide (5) generates the aromatic acyl nitroso compound (6) and ben-zonitrile (Scheme 7.3) [22, 23]. Other reactions that generate acyl nitroso compounds include the treatment of 5 with a nitrile oxide [24], the addition of N-methyl morpholine N-oxide to nitrile oxides and the decomposition of N, O-diacylated or alkylated N-hydroxyarylsulfonamides [25-29]. 

Substituted 1,2,4-oxadiazoles were prepared by addition of nitrile oxides to imines or hydrazones. It has been reported that interaction of hydroximoyl chlorides 262 with chiral hydrazones 263 in the presence of EtsN leads to intermediates 264 with diastereoselectivity up to 97%. A subsequent N-N bond cleavage to remove chiral auxiliary by formic acid leads to 1,2,4-oxadiazolines 265 with ee up to 91% (equation 113). ... 

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. ... 

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