Reduction of ketoximes

The present preparation illustrates the general method for the synthesis of aziridines by reduction of ketoximes 4 having an aromatic ring attached to carbon a or /3 to the oximino function and of aldoximes 4 having the aromatic ring attached to the carbon atom j3 to the oximino group. It has also been applied... 

B. Reduction of Ketoximes and Ketoxime Ethers with Chiral Metal... 

In the asymmetric reduction of ketones, stereodifferentiation has been explained in terms of the steric recognition of two substituents on the prochiral carbon by chirally modified reducing agents40. Enantiomeric excesses for the reduction of dialkyl ketones, therefore, are low because of the little differences in the bulkiness of the two alkyl groups40. In the reduction of ketoxime ethers, however, the prochiral carbon atom does not play a central role for the stereoselectivity, and dialkyl ketoxime ethers are reduced in the same enantiomeric excess as are aryl alkyl ketoxime ethers. Reduction of the oxime benzyl ethers of (E)- and (Z)-2-octanone with borane in THF and the chiral auxiliary (1 R,2S) 26 gave (S)- and (R)-2-aminooctane in 80 and 79% ee, respectively39. 

Reduction of ketoximes is one of the most useful ways to primary amines. 

Reduction of cyclohexanone oxime with lithium aluminum hydride in tetra-hydrofuran gave cyclohexylamine in 71% yield [809], and reduction of ketoximes with sodium in methanol and liquid ammonia [945] or in boiling ethanol [946] afforded alkyl amines, usually in good to high yields. Stannous chloride in hydrochloric acid at 60° reduced the dioxime of 9,10-phenanthra-... 

Enantioselective reduction of ketoxime ethers with chiral boron hydrides produces chiral 0-alkylhydroxylamines with variable ee. Reduction of oxime ethers of type 94 (equation 65) with norephedrine-derived oxazoborolidine 95 proceeds with very high ee. However, an analogous reduction of acyclic aromatic oximes with chiral oxab-orazolidines produced a mixture of amine and hydroxylamine . 

Reduction of ketoximes.1 Ketoximes are reduced by LiAlH4 to a mixture of primary and secondary amines. In contrast, reduction with LiAlH4-HMPT in the molar ratio 1 10 in refluxing THF (130°, 3 hours) results in ketones. HMPT is believed to prevent further reduction of the imine intermediate and to facilitate hydrolysis. This method is not useful for reversion of aldoximes to aldehydes because of dehydration to nitriles. 

Isopropylamine is formed in the reduction of aeetoxime in sulphuric-acid solution at a lead cathode (Tafcl and Pfeffer-mann1). This process is a general one. The electrolytic reduction of ketoximes leads, like that of the aldoximes and phenylhydrazones, to the final formation of amines. About 66% of the theoretically possible quantity of isopropylamine is formed from aeetoxime acetonphenylhydrazone gives about the same yield. 

Oximes, Tosylhydrazones, and Related Derivatives.—Ketoximes afford enimides in refluxing acetic anhydride-pyridine.181 Theproduct (207) from 5a-cholestan-3-one oxime (206), for example, gave 3-acetylamino-5a-cholest-2-ene (208) in 93% yield after chromatography on alumina. Use of succinic instead of acetic anhydride, with pyridine, gave the enimide (209) which was stable to chromatography. A radical mechanism is proposed. Reduction of ketoximes by Cr11, V11, or Tiin salts in acetic anhydride affords the same enamides, by acetylation of the intermediate imines. The... 

Enantioselective Reduction of Imines and Ketoxime O-Ethers. In addition to the reduction of prochiral ketones, chiral oxazaborolidines have been employed as enantioselective reagents and catalysts for the reduction of imines (eq 11) and ketoxime O-ethers (eq 12) - to give chiral amines. It is interesting to note that the enantioselectivity for the reduction of ketoxime O-ethers is opposite that of ketones and imines. For more information, see 2-Amino-3-methyl-l,l-diphenyl-I-butanol. 

Although the metal-NHs reduction of unhindered cyclohexanones usually affords equatorial alcohols with greater stereoselectivity then metal hydride reductions, this method has not been used frequently in synthesis. An exception is the highly stereoselective reduction of ketoxime (19 equation 10), an intermediate in the synthesis of ( )-perhydrohistrionicotoxin, which gave an excellent yield of equatorial alcohol (20) on reduction with Na-NHs. This reduction is noteworthy in that the oxime survives the reduction, which was carried out below the boiling point of liquid NH3 for a relatively short period of time (30 min). ... 

The reduction of ketoximes to primary amines by zinc dust often proceeds better with coned, ammonia solution than with acid. " The reaction proceeds particularly well with diaryl ketoximes (80-90% yield) with aryl alkyl ketoximes yields are lower (50-60%). The oxime, zinc, ammonium acetate, and coned, ammonia solution are refluxed in ethanol. 

Asymmetric reduction of ketoxime O-alkylethers to chiral primary amines can be carried out with a high enantiomeric excess by borane or better by NaBH4-ZrCl4 in THF in the presence of a chiral amino alcohol [IS2, WM2, ZHl]. 

Graham and Williams9 found nickel-aluminum alloy with aqueous sodium hydroxide to be a useful reagent for the reduction of ketoximes to amines without rearrangements that often accompany aluminum hydride reductions. 

The enantioselective reduction of ketoximes and their O-tctrahydropyranyl and O-methyl derivatives with the lithium aluminum hydride-3-0-benzyl-l,2-0-cyclohexylidene-a-D-gluco-furanose complex yields optically active amines with up to 56% optical purity39. For O-sub-stituted and free oximes similar stereoselectivities have been observed. All the resulting amines have the S configuration. 

The reduction of ketoxime ethers by borane in the presence of (—)-norephedrine yields (S)-amines from a/ i-kctoximcs and (/ )-isomers from. s i/ -ketoximes, e.g. from phenyl-4-tolyl-methyl ketoxime methyl ether40. 

Figure 17 Hydrolysis and stereospecific reduction of ketoxime prodrugs of the aryloxypropanolamine P-adrenoreceptor antagonists in the eye.

Scheme11.17 la-induced borane reduction of ketoxime derivatives.

Based on a comparative study for asymmetric reduction of oxime ethers of acetophenone and 2-hepitanone using different classes of OABs, such as la, 2a, and 6a, Cho and Ryu reported the 6a-induced borane reduction of ketoxime O-trimethylsilyl ethers in moderate to good enantioselectivities (Scheme 11.19) [83a, bj. Similarly, ben-zylic amine derivatives were obtained with high enantioselectivities by stoichiometric reduction of oxime ethers using ent-6a-BHj or la-BH (Scheme 11.20) [84-86],... 

Scheme11.19 OAB-induced reduction of ketoxime ether derivatives.

The reduction of ketoximes with titanium(iu) chloride is noted in a partial synthesis of erythromycylamine in this case, the intermediate imine is stable and can be further reduced, though normally imine hydrolysis is rapid and ketones are obtained in high yield. This observation has been utilized to effect conversion of a nitro-compound into a ketone. In search of a route to 1,4-diketones via conjugate addition of a masked carbonyl anion to an ajS-unsaturated ketone, McMurry considered Michael addition with a nitro-alkane. Treatment of the resulting y-nitroketone with titanium(m) chloride afforded the required 1,4-diketone (148) in excellent yield, presumably by sequential intermediacy of the oxime and the imine this mild conversion avoids the harsh conditions of the alternative Nef procedure (Scheme 69). 

The synthesis of aziridines by the reduction of ketoximes with lithium aluminium hydride or sodium aluminium (dimethoxyethoxy) hydride ( Red-AI ) is possible when the oxime has a neighbouring double bond or phenyl group cyclohexanone oximes give amines under these conditions. A new simple, and rapid aziridine synthesis from cyclohexanones uses the above reducing agents on the trimethyl... 

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