Ketones, cyclopropyl methyl reduction

The hydrostannation of carbonyl compounds to give alkoxystannanes (equation 14-5) can follow a homolytic or heterolytic mechanism depending on the structure of the reactants and on the reaction conditions (Section 20.1.3). This existence of alternative mechanisms is elegantly demonstrated in the reduction of cyclopropyl methyl ketone by tributyltin hydride. In methanol, 1-cyclopropylethanol is formed in a polar process, but, with irradiation with UV light, the main product is pentan-2-one, which is formed by ring opening of the cyclopropylmethyl radical by P-scission (Scheme 14-1)14... 

Reduction of a-ketocyclopropanes. Cyclopropyl methyl ketone (1) is reduced by the reagent in methanol under the influence of radical initiators [hi/, azobisiso-butyronitrile, 1,45] to propyl methyl ketone as the only product of reduction (51 % yield). In the absence of an initiator the reaction is slow and results in reduction of the carbonyl group. ... 

Reduction of cyclopropyl methyl ketone has been attempted by four different methods 415 Only poor yields of the alcohol were obtained by use of sodium and alcohol on use of LiAlH4 difficulties were encountered for larger batches and catalytic hydrogenation with Raney nickel caused partial cleavage of the cyclopropane ring however, excellent yields of 1-cyclopropylethanol were obtained in the presence of a copper-chromium oxide catalyst activated by barium, at 100°. 

Unusual reduction of eyclopropyl phenyl ketone. Cyclopropyl ketones are reduced by Li-NHa with cleavage of the cyclopropane ring for example, cyclopropyl methyl ketone is reduced to pentanone-2 and pentanol-2. Unexpectedly cyclopropyl phenyl ketone is reduced without cleavage (equation I). ... 

The method is a modification of one used by Barton and McCombie.8 Reduction of ketones.9 Ketones can be reduced to alcohols by Bu3SnH in the presence of either AIBN or a Lewis acid, but this reaction is limited to unhindered ketones. However, even sterically hindered ketones, such as f-butyl methyl ketone, can be reduced under high pressure (10 kbar) in the absence of a catalyst. This method is particularly useful in the case of cyclopropyl and a,p-epoxy ketones, which are reduced to the corresponding alcohols. Reduction of these ketones with Bu3SnH under radical conditions results in ring-opened products. 

The first report on the reduction of a carbonyl substituted cyclopropane was published in 1949. Reactions of methyl cyclopropyl ketone (131) with sodium in liquid ammonia in the presence of ammonium sulfate yielded instead of the expected methyl cyclopropylcarbinol (132) only a mixture of 2-pentanone (133) and 2-pentanol (134). 

The cyclopropyl ketone system in 3a,7,7-trimethyloctahydrocyclopropa[c]inden-2-one (26, thujopsene) was converted to the 3-methyl ketone fragment 27 upon reduction with lithium. ... 

Lithium is the preferred metal for the reductive cleavage of cyclopropane bonds in cyclopropyl ketones. Sodium is less suited for this reaction because it tends to reduce the carbonyl group rather than open the three-membered ring. With sodium the cyclopropane ring in methyl-substituted benzoylcyclopropanes 1 was retained and the benzoyl group reduced to benzyl contrary to lithium which gave rise to the formation of cleavage products. ... 

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. 

In a paper published along with that of Stevens and Wentland20 and in agreement with these authors, Keely and Tahk23 reported the independent synthesis of dl-mesembrine, also from I-methyl-3-(3,4-dimethoxyphenyl)-2-pyrroline and methyl vinyl ketone. In their work the cyclopropyl derivative 3b was prepared from the reaction of the anion of 3,4-dimethoxyphenylacetonitrile (lc) with ethylene dibromide in dimethyl sulfoxide and its sodium salt as solvent and base. Reduction with ethereal diisobutylaluminum hydride gave the aldehyde, which was condensed with excess methylamine in benzene-ether solution with calcium oxide as the dehydrating agent. 

The alcohol dehydrogenase from Thermoanaerobium brockii is very suitable for the reduction of aliphatic ketones[18, 19L Even very simple aliphatic ketones can be reduced enantioselectively. An interesting substrate size-induced reversal of enantio-selectivity was observed. The smaller substrates (methyl ethyl, methyl isopropyl or methyl cyclopropyl ketones) were reduced to the (R)-alcohols, whereas higher ketones produced the (S -enantiomers. 

This reaction was first reported by Nenitzescu in 1931. It is the formation of an a,p-unsaturated ketone directly by aluminum chloride-promoted acylation of alkenes with acyl halides. Therefore, it is known as the Darzens-Nenitzescu reaction (or Nenitzescu reductive acylation), or Nenitzescu acylation. Under such reaction conditions, Nenitzescu prepared 2-butenyl methyl ketone from acetyl chloride and 1-butene and dimethylacetylcyclohex-ene from acetyl chloride and cyclooctene. However, in the presence of benzene or hexane, the saturated ketones are often resolved, as supported by the preparation of 4-phenyl cyclohexyl methyl ketone from the reaction of cyclohexene and acetyl chloride in benzene, and the synthesis of 3- or 4-methylcyclohexyl methyl ketone by refluxing the mixture of cycloheptene and acetyl chloride in cyclohexane or isopentane. This is probably caused by the intermolecular hydrogen transfer from the solvent. In addition, owing to its intrinsic strain, cyclopropyl group reacts in a manner similar to an oleflnic functionality so that it can be readily acylated. It should be pointed out that under various reaction conditions, the Darzens-Nenitzescu reaction is often complicated by the formation of -halo ketones, 3,)/-enones, or /3-acyloxy ketones. This complication can be overcome by an aluminum chloride-promoted acylation with vinyl mercuric chloride, resulting in a high purity of stereochemistry. ... 

Modhephene, 34, was the first isolated propellane natural product. As such, the Weiss-Cook reaction was the perfect method for its construction. The process began with the condensation of 2 with diketone 27. Standard conditions for decarboxylation produced the core scaffold 28. Hydrogenation of the mono-enol phosphate afforded the monoketone 29. The cyclopropyl derivative 30 was prepared by copper-catalyzed decomposition of a diazoketone. gem-Dimethylation to generate 31 preceded carboxylation and esterification to afford the advanced intermediate 32. Cuprate-induced cyclopropane ring opening and methylation of the 3-ketoester introduced the final carbon atoms giving rise to 33. Lithium iodide induced decarboxylation preceded reduction of the ketone followed by dehydration with Martin s sulfurane, thus producing 34. 

Methylation of the enolate (B) derived from a cyclopropyl ketone for stereospecific introduction of the two vicinal trans methyl groups in ring C further illustrates the concept of enolate trapping developed by Stork (ref. 2). In this instance, generation of the enolate has been accomplished by the reductive removal of an a-substitutent (i—ii) cf. W. G. Dauben and E. J. Deviny, J. Org. Chem., 31, 3794 (1966). 

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