Functionally Substituted Ketoximes

As a rule, such reaction involves splitting of the oxygen-containing radical to give a mixture of simpler pyrroles in low yields. Having no great synthetic value, these results, nevertheless, shed additional light on some peculiarities of this reaction as a whole. 

The simplest representative of a series of studied ketoximes, l-hydroxy-2-propanoe oxime, is unstable and completely resinifles under usual conditions of the reaction with acetylene. 

SCHEME 1.66 Functionally substituted ketoximes studied in the reactions with acetylene in superbase system KOH/DMSO. 

SCHEME 1.67 Reaction of l-ethoxy-2-propanone oxime with acetylene. 

SCHEME 1.68 Generation of alternative carbanions from l-ethoxy-2-propanone oxime under the action of KOH/DMSO system. 

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Extention of the reaction of ketoximes with acetylene to oximes of hydroxyalkyl ketones can lead to the synthesis of inaccessible, functionally substituted pyrroles and A-vinyl derivatives. However, the methyl a- and /3-hydroxyalkyl ketoximes used by Trofimov et al. (80ZOR410) appeared to react with acetylene in the KOH/DMSO system in an abnormal way. 

The extension of the reaction of ketoximes with acetylene over oximes of hydroxy, alkoxy, and vinyloxy alkyl ketones (Scheme 1.66) could lead to the synthesis of hardly accessible functionally substituted pyrroles. However, it turns out that oximes of such ketones react with acetylene in the system KOH/DMSO in a peculiar manner [253]. 

The addition of ZnBi 2 to die tandem 1,3-azaprotio cyclotransfer-cycloaddition of a ketoxime with divinyl ketone results in rate enhancement and the exclusive formation of l-aza-7-oxabicyclo[3.2.1]octan-3-ones.79 The 1,3-dipolar cycloaddition of 1-aza-l-cyclooctene 1-oxide with alkenes produces the corresponding isoxazolidines in high yields with a minimum of polymeric material.80 The cycloaddition of thiophene-2 -carbaldehyde oxime with acetonitrile and methyl acrylate produces the 1,3-dipolar adduct, substituted isoxazolidines, and not the previously reported 4 + 2-adducts.81 Density functional theory and semi-empirical methods have been used to investigate the 3 + 2-cycloaddition of azoxides with alkenes to produce 1,2,3-oxadiazolidines.82 The 3 + 2-cycloaddition of a-nitrosostyrenes (62) with 1,3-diazabuta-l,3-dienes (63) and imines produces functionalized cyclic nitrones (64) regioselectively (Scheme 22).83... 

Palacios et al. described the stereoselective synthesis of fluoroalkyl-substituted aziridine-phosphine oxides by the diastereoselective addition of Grignard reagents to functionalized ketoxime-phosphine oxides. Aziridines were used as intermediates for the regioselective S5mthesis of fluorine containing P-aminophosphine oxides. Products of the latter type could also be obtained by reduction of the ketoxime-phosphine oxides with sodium borohydride (Scheme 39). ... 

In 2013, Yoshikai and Wei developed a copper-catalyzed pyridines synthesis from oximes and enals [65]. Under redox-neutral reaction conditions, with 0-acetyl ketoximes and 0 ,/3-unsaturated aldehydes as the substrates and using copper(I) salt and a secondary ammonium salt (or amine) as the catalyst system, a variety of substituted pyridines were prepared with a broad range of functional groups tolerance (Scheme 3.29). By merging iminium catalysis and copper catalyst, imder the redox activity of the copper catalyst, the reaction started to reduce the oxime N—O bond to generate a nucleophilic copper(II) enamide and later oxidize a dihydropyridine intermediates to the final products. 

Recently, Guan et al. developed a novel Cu(OAc)2-promoted oxidative coupling of enamides with electron-deficient alkynes for the synthesis of multisubstituted NH pyrroles. This reaction tolerates a wide range of functional groups and is a reliable procedure for the rapid elaboration of readily available enamides into a variety of diester-substituted NH pyrroles. The reaction proceeded through C-H and N-H bond functionalization of enamides CU/O2 system [22]. They also developed an efficient CuBr-catalyzed homocoupling of ketoxime carboxylates for the synthesis of symmetrical pyrroles [23] (Scheme 8.10). 

The analysis of vast experimental material has revealed that the new reaction of ketones (ketoximes) with acetylene has a general character and allows diverse 2-, 2,3-, 2,3,4- and 2,3,5-substituted pyrroles and their N-vinyl derivatives to be synthesized in high yields. The reaction tolerates almost all ketones (ketoximes) having at least one methylene or methyl group in the a-position relative to the ketone (oxime) function. 

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