Aldoximes oxidation, nitrile oxide generation

A nitrile oxide generated from a sugar derived aldoxime 30 underwent INOC reaction to the chiral pyranoisoxazoline 31 (Eq. 4) [20]. Reductive cleavage of isoxazoline 31 followed by acetylation provided the tetrasubstituted pyran 32. 

Poly(ethylene glycol) supported liquid-phase syntheses by both the reaction of (polyethylene glycol (PEG))-supported imines with nitrile oxides, generated in situ from aldoximes, (300) and 1,3-dipolar cycloadditions of nitrile oxide, generated in situ on soluble polymers with a variety of imines (301, 302) have been described. The solid-phase synthesis of 1,2,4-oxadiazolines via cycloaddition of nitrile oxide generated in situ on solid support with imines has also been elaborated (303). These syntheses of 1,2,4-oxadiazolines provide a library of 1,2,4-oxadiazolines in good yields and purity. 

Cycloaddition reactions of nitrile oxides continue to be the source of new isoxazoles and dihydroisoxazoles. The oxidation of a-hydroxyimino acids 1 by ammonium hexanitratocerium(IV) has provided a new method of generation of benzonitrile oxide and other nitrile oxides on the other hand the oxime 2 is simply dehydrogenated by this oxidant to produce benzoylnitrile oxide <99BSJ2277>. Manganese dioxide has also been used to oxidise aldoximes to nitrile oxides the reaction is most efficient with methyl (hydroxyimino)acetate <99TL5605>. ... 

Isoxazolines.1 Reaction of aldoximes with chloramine-T generates nitrile oxides, which can be trapped by alkenes to give 2-isoxazolines. 

Table I presents data from McFarlane al, (8) showing that the multi-step oxidation of L-tyroslne to p-hydroxymandelonltrlle requires only 02 and a source of reducing power, most effectively supplied by an NADFH generating system. The table also shows that some of the L-tyroslne Is converted to p-hydroxyphenylacetaldoxime (aldoxime) as well as a trace of p-hydroxyphenylacetonltrlle (nitrile). The production of the aldoxime and nitrile In this experiment was the first Indication that the microsomal preparation from sorghum might constitute an organized enzyme entity Involved In the synthesis of dhurrln. If this were true, it should be possible to demonstrate each individual step of the reaction sequence between tyrosine and p-hydroxymandelontrlle.

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. 

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>. 

Oxidation of aldoximes 327 with sodium hypochlorite or NBS is one of the best-known methods for generation of nitrile oxides (Equation 73) <1999BCJ2277>. 

Nitrile oxides were also readily generated by reaction of aldoximes 172 with icri-butyl hydroperoxide and bis(tributyltin) oxide. The reaction proceeded nnder mild conditions, in which 0-stannylated aldoximes 173 were the key intermediates. This reaction system was applicable to the one-pot synthesis of isoxazoline 174 or isoxazole 175 derivatives... 

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 >. 

Diammonium hexanitratocerate (IV) (CAN) has also been used as an oxidizing agent for aldoximes. This approach is especially useful for the preparation of ahphatic 2-oxo-carbonitrile oxides (99). Another useful reagent for the generation of nitrile oxides from aldoximes is 1-chlorobenzotriazole (100). Due to its reactivity toward both aldoximes and olefins, this reagent can only be used to prepare stable... 

Chlorination of aldoximes. NCS converts aryl aldoximes to hydroxamic acid chlorides without significant chlorination of the aryl group. This reaction has been used for a novel synthesis of nitrile oxides. Thus reaction of salicylaldoxime (1) with NCS followed by dehydrochlorination with pyridine generates a nitrile oxide, which is trapped by styrene to give the isoxazoline 2. The N-O bond can be cleaved by catalytic hydrogenation to 3, which is converted into the chalcone 4 on elimination of water. This product can be converted by classical methods to the flavanone 5 and the flavone 6. An analogous route can be used to synthesize 2-... 

The Brown allylboration was used in the enantioselective total synthesis of (-)-calicheamicinone 3318 (Scheme 3.1o). Thus the lactol 34, readily prepared from tetronic acid, was treated with the allylborane d35 to give 36 in a highly stereoselective manner (95% ee, > 98% de). Compound 36 was converted to the aldoxime 37 by standard chemistry. Generation of the nitrile oxide with aqueous sodium hypochlorite was accompanied by spontaneous [3 + 2]-dipolar cycloaddition to afford 38 in 65% yield. 

Apart from a few stable species, nitrile oxides exhibit a high tendency toward dimerization to furoxans for this reason, several methods have been developed for the in situ generation of such dipoles in the presence of the desired acceptor. The most common procedures involve thermal or base-mediated deydrohalogenation of hydroxymoyl halides, oxidation of aldoximes, and dehydration of primary nitroalkanes <1984CHEC(6)1>. 

An SPS of substituted benzopyranoisoxazoles 427 in high yields and purity has been developed. The procedure exploits very mild conditions for the generation of nitrile oxides from aldoximes on a polymer support followed by an intramolecular 1,3-dipolar cycloaddition with a tethered alkyne to assemble the isoxazoles (Scheme 102) <20020L323>. 

Nitrile oxides could also be prepared from nitroalkanes by reaction with (Boc)20 in the presence of catalytic amounts of DMAP at room temperature under N2 [276]. Alternatively they could also be prepared via base-induced dehydrohalogenation from hydroximinoyl chlorides, which can be either purchased or generated hy chlorination of the corresponding aldoximes with N-chlorosucdnimide. 

Isothiocyanates. Both a-chloro aldoximes and nitroalkanes give isothiocyanates on reaction with thiourea. The former needs a base (e.g., E N) to generate nitrile oxides in situ, and the latter requires both a base and a dehydrating agent, such as 4-chlorophenyl isocyanate. 

Aldoximes derived from an o-protected vanillin 321, when treated with TCCA in the presence of olefins as dipolarophiles, afford nitrile oxides 322. Subsequent 1,3-dipolar cycloaddition generates the corresponding isoxazo-lines 323 (Scheme 72) <2001SC3075>. 

Here, nitrile oxide intermediates (56) are generated in situ via the corresponding aldoxime and halogenation/deprotonation by Chloramine-T [130], Capture of the intermediate nitrile oxide by copper(I) acetylides occurs, presumably, before dimerization. In this case, the Cu catalyst was obtained from copper metal and copper(II) sulfate, and the products were isolated by simple filtration or aqueous work-up. Trace amounts of toluenesulfonamide and unreacted acetylene are easily removed by recrystallization or by passing the product through a short plug of silica gel. 

The addition of nitrile oxides to a,P-unsaturated carboxylic acid derivatives opens up a route to chiral, substituted isoxazoline derivatives. The nitrile oxides are generated in situ via deprotonation with a base (e.g. triethylamine) starting from the chlorinated aldoxime as the precursor (solvents CHCI3, CH2CI2, ether, benzene, toluene temperature -78°C up to 110°C). In most cases only one of two possible regioisomeric adducts is formed. 

Owing to their tendency to dimerize to furoxans (1,2,5-oxadiazole 2-oxides), nitrile oxides 5 are usually generated in situ, i.e., in the presence of suitable dipolarophiles such as alkenes, alkynes, etc., from stable precursors such as aldoximes 12 (X = H) or from primary nitroalkanes 13 (Scheme 2) [5,57-67]. Generation of nitrile oxides 5 from aldoximes 12 (X = H) involves either direct oxidation or halogenation of aldoximes 12 (X = H) to hydroximoyl halides 12 (X = Cl or Br) followed by dehydrohalogenation [5,57-67,79,80]. Alternatively, nitrile oxides 5 are conveniently generated via dehydration of primary nitroalkanes 13 [ 17,38,39,65,66,81-95]. This review covers the literature in the last 10-15 years pertaining to the chemistry of isoxazoHnes synthesized from primary nitroalkanes 13. 

---