Oximes dimerization

Figure 14 One-dimensional tapes linked via R2(6)0-H-N hydrogen-bonded oxime dimers in (a) [Ag(3-aldoximepyridine)2]PF6 (cf. XVII) and (b) [Ag(3-acetoximepyridine)2]PF6 (cf. XVIII) [50b]. Cross-linking of tapes via C-H O and C-H F hydrogen bonds not shown. Oxygen, nitrogen and key hydrogen atoms are shaded.

Primary amines, with at least one a-C—H bond, undergo consecutive oxidation to yield unstable alkylnitroso intermediates. These can isomerize to corresponding oximes, dimerize to nitroso dimers and produce nitro derivatives by further oxidation (Scheme 18.15). The selectivity depends on the oxidant system and the reaction conditions. The size restrictions of TS-1 allow a greater selectivity to the... 

Scheme 7 Infinite chain of Ag(I)(3-aldoximepyridine)2 cations held together by oxime-. -oxime dimeric hydrogen bonds.

In the 19-nor series, the reaction with NOF is more complex and there is isolated in addition to the fluoro nitrimine corresponding to (31) a 20% yield of the nitroso dimer (34), which dissolves in methanol-methylene dichloride solution to give the pure blue color characteristic of the monomer (35). The latter then isomerizes to the oxime (36). 

The formation of insoluble nitroso dimers is only observed in reactions involving fuctionalization at C-19 whereas 18-nitroso compounds apparently rearrange rapidly to the 18-oximes. However in most cases it is recommended that rearrangement be completed by brief treatment of the crude irradiation product in boiling isopropanol. 

Note 1. The same result is obtained when the corresponding 19-oxime is used as starting material, instead of the nitroso dimer. 

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). 

For nitrosyl chloride (Entry 8) and nitrosyl formate (Entry 9), the electrophile is the nitrosonium ion NO+. The initially formed nitroso compounds can dimerize or isomerize to the more stable oximes. 

A choice between mechanisms (b) and (c) was achieved by photolyzing a mixture of a 14N-nitrite in the pregnane series and the 15N-nitrite (29) to half-completion. Rearrangement of the nitroso dimers thus obtained to a mixture of oximes followed by oxidation of the pure oxime from (29) to the ketonitrile and mass spectrometric analysis indicated the N15/N14 ratio to be 1.15 1.00. Analysis of pure unreacted (29) gave a ratio of 1.00 0.00. These results indicate that mechanism (c) is operative in nitrite photolyses. 

Soufiaoui reported that arylnitrile oxides 10 can be generated under microwaves not only from aromatic oxime chlorides, such as 174, by the action of alumina (Method A) but also from aryloximes, such as 176, by the addition of a chlorination agent, N-chlorosuccinimide (NCS), supported on alumina (Method B) (Scheme 9.54) [29a]. Both methods afforded identical cydoadducts in similar yields - when indene was used as the dipolarophile the yield was 86%. In the absence of alumina, method B fails (reagents are less reactive and decompose) and method A does not yield any cydoadduct but a dimer of the dipole. 

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>. 

The nitrile oxide generated in situ by oxidation of oxime 325 gives the dimer 326 in 15% yield (Equation 72) <2001J(P1)415>. 

Starting from the Ni mrao-formyloctaethylporphyrin oxime complex, the meso-cyanooctaethylporphyrin N-oxide complex has been synthesized for the first time. The double addition of the nitrile oxide to 2,5-norbornadiene afford a porphyrin dimer, whose structure has been established by X-ray diffraction analysis (485). The 1,3-dipolar cycloaddition reaction of w< .so-tetraarylporphyrins with 2,6-dichlorobenzonitrile oxide yields isoxazoline-fused chlorins and stereoiso-metric bacteriochlorins. The crystal structure of one of bacteriochlorins has been characterized by X-ray diffraction (486, 487). 

Cyclization of oximes containing y-,d-, or oo-alkenyl substituents, upon treatment with /V-bromosuccinimide (NBS) or iodine leads in good yields to the corresponding cyclic nitrones or their dimeric H- bonded hydriodide salts (290). 

Azaurolic acid 137 is a compound that displays antithrombotic activity and that, both in solution and in the solid state, releases N2O, which is the product of dimer-ization/dehydration of HNO, giving the stable compound 138 (R=Ri=CH3, Scheme 6.27). This latter product also displays anthitrombotic activity [173]. These findings prompted the synthesis ofa series of 1,3,4-triazol-l-oles 138 which were obtained by cyclisation of the parent oximes 139 in aqueous alkali. 

FIGURE 3.17 Reagents for protection of amino groups as the ferf-butoxycarbonyl derivatives. terf-Butyl chloroformate is rarely used because of its low boiling point. The oxime is 2-ferf-butoxycarbonyloximino-2-phenylacetonitrile,45 Boc20 = di-ferf-butyl dicarbonate, or di-terf-butyl pyrocarbonate.46 (Tarbell et al., 1972 Pozdvev, 1974). Acylations are carried out at pH 9 to avoid dimerization. 

Reductive cross-dimerization has been established with ketones and 0-meth-oximes upon reduction in isopropanol with a Sn cathode as a convenient route to yS-amino alcohols, diastereoselectivities of up to 85 15 were obtained. A chiral ligand was obtained this way from the coupling of (-) - menthone with O-methyl acetaldoxime. Similarly, ketones could be coupled to hydrazones and nitrones. Also, intramolecular couplings were achieved with good yields and diastereoselectivity (Fig. 56) [308]. 

The asymmetric reduction of C=N double bonds in prochiral oximes afforded a maximum of 18% ee [380, 384, 385]. Prochiral azomethines were reduced to the corresponding 1,2-diamines and secondary amines using 36 optically active supporting electrolytes. The dimers were optically inactive, while the monomers showed low optical inductions (<11% ee). The effect of electrolyte, substrate concentration, temperature, pH, and cathode potential on the induction was studied. It was proposed that the enantioselectivity... 

In non-polar solvents many aminolysis reactions show a third-order dependence on the amine, B. This may be explained by catalysis of leaving-group departure by hydrogen-bonded homoconjugates, BH+B. Evidence for this pathway has been adduced from studies of the reactions of some nitro-activated (9-aryl oximes (7) with pyrrolidine in benzene, chlorobenzene, and dioxane, and with piperidine and hexylamine in cyclohexane. The third-order dependence on amine of the reaction of 2,6-dinitroanisole with butylamine in toluene and toluene-octanol mixtures has been interpreted in terms of a mechanism involving attack by dimers of the nucleophile. ... 

CoH(CN)5] catalyses the hydrogenation of nitro compounds either to amines (aliphatic substrates) or to products of reductive dimerization, i.e. to azo and hydrazo derivatives. Ketoximes and oximes of 2-oxo-adds are hydrogenated to amines. This latter reaction gives a possibihty to directly produce a-amino-acids in the reductive amination of 2-oxo-acids in aqueous ammonia at a temperature of40-50 °C and 70 bar H2 (Scheme 3.1). Yields are usually high (approximately 90%) [18]. 

Interestingly, treatment of a-nitrostilbene in water-ethyl acetate mixture by the cation-radical of A,A -dioctyl-4,4 -bipyridinium (the octylviologen cation radical) leads to the formation of products derived from the nitro group reduction. No dimerization is observed (Tomioka et al. 1986). Water is responsible for the fixation of transferred electron within the nitro group. Further reactions result in the formation of the corresponding oxime and ketone as shown in Scheme 2.10. 

The Ponzio reaction provides a useful route to gem-dinitro compounds and involves treating oximes with a solution of nitrogen dioxide or its dimer in diethyl ether or a chlorinated solvent. The Ponzio reaction works best for aromatic oximes where the synthesis of many substituted aryldinitromethanes have been reported. Compound (56), an isomer of TNT, is formed from the reaction of dinitrogen tetroxide with the oxime of benzaldehyde (55) followed by mononitration of the aromatic ring with mixed acid. Yields are usually much lower for aliphatic aldoximes and ketoximes. " The parent carbonyl compound of the oxime is usually the major by-product in these reactions. 

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