Ketones, reductive cleavage anions

Reductive cleavage of 6-ketosulfones [166], RC0CHR S02R", in DMF at mercury is a practical way of preparing alkyl ketones the primarily formed radical anion cleaved to a radical RCOCHR and a sulfinate ion R"S02. Since the anodic reaction was the oxidation of R"S02" to R"S03, an undivided cell could be used. 

In 1973, Johnson reported the use of (N-methylphenylsulfonimidoyl)methyllithium (26) for addition to carbonyls, followed reductive elimination to produce the methylene derivative (28 Scheme 7). As with the Tebbe and Oshima procedures discussed in Sections 3. l.S and 3.1.6, this method can be applied to enones, ketones and, with comparatively diminished efficiency, aldehydes. The anion appears to be more nucleophillic than methylenetriphenylphosphorane, and there are several examples, detailed below, in which the Wittig reaction failed but the Johnson procedure succeeded. The addition and reductive cleavage can be combined into a single operation without isolation of the p-hydroxysulfoximine. ... 

Reductive cleavage of a-substituted ketones, such as a-halo-, a-hydroxy- and a-acyloxy-ketones to the unsubstituted ketone can be carried out with zinc and acetic acid or dilute mineral acid. The reaction is thought to proceed by transfer of two electrons to the carbonyl group, followed by departure of the leaving group as the anion (7.39). This generates an enolate, which is converted into the ketone by acid. For a-halo-ketones, a different mechanism, with ahack by zinc on the halogen, is possible. 

One of the key pioneers in this area was Solladie, who thoroughly investigated the reactions of chiral sulfoxide carbanions [21], Their diastereoselec-tive additions to ketones and aldehydes are illustrative of the method (Scheme 13.16) [67]. Addition of 104 to cyclohexyl methyl ketone (105) thus furnished adduct 106. The sulfoxide, having fulfilled its role as an auxiliary, is subsequently subjected to reductive cleavage to afford hydroxy ester 107. After transesterification, alcohol 108 was produced in 95 % ee. Despite the numerous years that have transpired since these results were first published, such optically active tertiary alcohols remain otherwise difficult to prepare, a feature that attests to the potential value of chiral sulfoxide anions in asymmetric synthesis. 

Q , 8-Ethylenic sulfones exhibit a behavior that could be considered as specific and totally different from that of Q , 8-ethylenic ketones or nitriles. Thus, with the present series, there is practically no case of dimerization or double-bond saturation. This seems to be because of the fact that reduction of compounds of this series cannot be completed neither in acidic nor in aqueous solutions because a fast cleavage occurs at the level of the anion radical. 

Gribble and Saulnier (79) have extended their ellipticine synthesis 43) to the synthesis of 9-methoxyellipticine (2) (Scheme 24). One of the key features of this approach is the regioselective nucleophilic addition to the C-4 carbonyl group of pyridine anhydride 28. The other noteworthy transformation is the conversion of keto lactam 142 to the diol 143 with methyllithium, a process that presumably involves cleavage of the initial adduct to a methyl ketone which undergoes cyclization at the C-3 position of the indolyl anion. Reduction of 143 with sodium borohydride completes the synthesis of 2, in 47% overall yield from 5-methoxyindole (139). Gribble and students 80) have also used this method to synthesize 8-methoxyellipticine (134), 9-fluoroellipticine (144), and the previously unknown 7,8,9,10-tetrafluorellipticine (145), each from the appropriate indole. 

Formation of 170 from the reaction of dicyclopropyl ketone with Na was attributed to formation of a dianion which rearranged and added to another molecule of ketone (equation 36). An alternative route would involve cleavage of a radical anion and then reduction. 

The Sn2 mechanism is ruled out for reaction between the tertiary halide, r-BuBr, and radical anions derived from the more easialy reduced compounds cinnamonitrile (9) ethyl cinnamate (12a), methyl styryl ketone (23a), and phenyl styryl ketone (20a). Reduction of the activated alkenes in the presence of an excess of r-BuBr leads to mixtures of products where a r-Bu group has been introduced in a- or j0-position or in the phenyl ring. For 9 and 12a small amounts of butylated hydrodimers were obtained in addition, and for the enone 23a formation of the unsaturated alcohol with introduction of the /-Bu group at C-1 was a major product [192]. In this case the mechanism is unambiguously reduction of the activated alkene followed by electron transfer to r-BuBr concerted with halide cleavage, in... 

A slow cleavage of a benzylic C-O bond is observed in the reduction in DMF of 2-disubstituted 4-(4 -nitrophenyl)-l,3-dioxolanes and dioxanes the hemiketal thus formed is hydrolyzed to the ketone so these compounds may be used as protecting groups for ketones. On preparative reduction besides ketone some side products, formed by attack by the EGB promoted substrate anion on DMF, were isolated [79]. 

Lithium dimethylcuprate has also been used for the reduction of aryl cyclopropyl ketones and i -cyclopropyl enones. Cleavage of the intermediate radical anions was accompanied by methylation however, the extent of rearrangement was often rather small, which limits the synthetic usefulness of this reaction. 

The known bicyclo[3.1. Ojhexene 167 was hydroborated and oxidized to afford anti alcohol 168 in up to 80% yield. Chromic acid oxidation of 168 was followed by p elimination of malonate anion with EtaN to produce enone 169 (86%). Initial deprotonation of 169 followed by the addition of cuprate 166 afforded an 82% yield of 170. As expected, Michael addition to the enone occurred anti to the malonate unit. Reduction of ketone 170 with LiBH4 gave a 4 1 mixture of Cy alcohols, the major product being the desired a-hydroxy isomer. Chromatographic separation of the alcohols, followed by protection and ester cleavage, then gave the diacid 171. 

Synthesis of the acyclic portion began, as in the previous synthesis, with enantiomerically pure citronellol (25). Protection of the alcohol as the benzyl ether and oxidative cleavage of the olefin to the aldehyde gave 26 (85%). Chain extension via the masked acyl anion equivalent 27, alcohol protection, and concomitant -elimination and isomerization of the allene to die alkyne with butyl lithium gave 28. The resulting protected ketone must now be converted to the P-alcohol required for the completion of the synthesis. Thus hydrolysis to die ketone followed by enantioselective reduction with (—)-N-methylephedrine-... 

Cleavage of nitronate anions. Conversion of conjugated nitroalkenes to ketones can be accomplished through borohydride reduction and oxidation of the nitronate anions with 30% H2O2. 

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