2-Methylcyclohexanone, reduction

Methylcyclohexanone is reduced to give 65 % of the tmns-2L cdho. However, the larger reagents, disiamylborane and diisopinocamphenylborane, give respectively 77 % and over 90 % of the cw-alcohol. Later work confirmed that reductions of 2-alkylcycloalkanones with dialkyl boranes give predominantly the less stable alcohol/ ... 

Hunig and Salzwedel (20) report that the acylation of the pyrrolidine enamine of 3-methylcyclohexanone with propionylchloride followed by the hydrolysis and the base cleavage of the resulting dione isomers (71) and (72) and subsequent reduction of the keto groups gave a 3 7 mixture of the carboxylic acids (73 and 74), respectively. Vig et al. (39), however, found o o o o... 

The direct conversion of 3-methylcyclohex-2-enone into 2-allyl-3-methylcyclohexanone provides an interesting example of the utility of the reduction-alkylation procedure. Synthesis of this compound from 3-methy I cyclohexanone would be difficult because the latter is converted mainly into 2-alkyl-5-methylcyelohexanones either by direct base-catalyzed alkylation11 or by indirect methods such as alkylation of its enamine (see Note 13) or alkylation of the magnesium salt derived from its cyclohexylimine.12... 

High-boiling products found in this procedure and in similar experiments involving cyclohex-2-enone derivatives5 probably result from bimolecular reduction processes.15 3-Methylcyclohexanone, which arises by protonation rather than alkylation of the enolate (and which made up ca. 12% of the volatile products), is probably the result of reaction of allyl bromide with liquid ammonia to form the acidic species allyl ammonium bromide.5 10... 

Further evidence for surface effects upon the stereochemistry of electrochemical reduction of ketones comes from the discovery that the nature of the cathode material may effect stereochemistry. Reduction of 2-methylcyclo-hexanone affords pure trans-2-methylcyclohexanone at mercury or lead cathodes, a mixture of cis and trans alcohols (mostly trans) at nickel, and pure cis alcohol at copper 81 >. Reduction could not be effected at platinum presumably hydrogen evolution takes place before the potential necessary for reduction of the ketone can be reached. 

Coleman, Kobylecki, and Utley studied the electrochemical reduction of the conformationally fixed ketones 4-tert-butylcyclohexanone and 3,3,5-tri-methylcyclohexanone 82>. Stereochemically, the cleanest reductions took place at a platinum cathode in a mixture of hexamethylphosphoramide and ethanol containing lithium chloride. Under these conditions the equatorial alcohol predominated heavily (95% from 4-fer/-butylcyclohexane and 91% from 3,3,5-trimethylcyclohexanone).In acidic media roughly equal quantities of axial and equatorial alcohol were produced. It was suggested that organo-lead intermediates are involved in the reductions in aqueous media. This is reasonable, based upon the probable mechanism of reduction in acid 83F Reductions in acid at mercury cathodes in fact do result in the formation of... 

Selected examples of the reduction of methylcyclohexanones with dithionite ... 

Reduction of 2-methylcyclohexanone gave the following percentage proportions of the less stable m-2-methylcyclohexanol (with axial hydroxyl) with lithium aluminum hydride 25%, with diborane in tetrahydrofuran 26%, with di-sec-amylborane in tetrahydrofuran 79%, with dicyclohexylborane in diglyme 94%, and with diisopinocampheylborane in diglyme 94% (the balance to 100% being the trans isomer) [837. ... 

Biochemical reduction of a,/3-unsaturated ketones using microorganisms (best Beauveria sulfurescens) takes place only if there is at least one hydrogen in the /3-position and the substituents on a-carbons are not too bulky. The main product is the saturated ketone, while only a small amount of the saturated alcohol is formed, especially in slightly acidic medium (pH 5-5.5). The carbonyl is attacked from the equatorial side. Results of biochemical reduction of 5-methylcyclohex-2-en-l-one are illustrative of the biochemical reduction by incubation with Beauveria sulfurescens after 24 hours 74% of the enone was reduced to 3-methylcyclohexanone and 26% to 3-methylcy-clohexanol containing 55% of cis and 45% of trans isomer. After 48 hours the respective numbers were 70% and 30%, and 78% and 22%, respectively [878]. 

Different stereoisomeric cyclohexanols resulted also from reduction of ethyl 4-/ r/-butyl-2-methylcyclohexanone-2-carboxylate with sodium borohydride (equatorial hydroxyl) or with aluminum isopropoxide (axial hydroxyl) [1088]. 

Bhattacharyya et al. reported the first total synthesis of clausenalene (90) to establish its structure (99). This total synthesis uses Japp-Klingemann and Fischer-Borsche reactions as key steps. The phenyl hydrazone 1000 required for the transformation to 1-0x0-tetrahydrocarbazole 1001 under Fischer-Borsche conditions was obtained by condensation of 2-hydroxymethylene-5-methylcyclohexanone (999) with diazotized 3,4-methylenedioxyaniline (998) using Japp-Klingemann conditions. Wolff-Kishner reduction of 1001 furnished 3-methyl-6,7-methylenedioxy-l,2,3,4-tetrahydrocarbazole (1002), which, on aromatization wifh 10% Pd/C in decalin, afforded clausenalene (90) (99) (Scheme 5.143). 

The fused tetrahydropyran-2-one (566) is obtained from 2-methylcyclohexanone by Michael addition to methyl prop-2-enoate and reduction of the resulting keto ester (565 Scheme 216) (63JOC34). When the enamine derived from the cyclohexanone reacts with the unsaturated ester, a mixture of keto esters (565) and (567) is formed. The pyranone (568) is formed by reduction of the latter. 

The fluoride ion-catalyzed reduction of 2-methylcyclohexanone by various hydrosilanes gives the corresponding silyl ethers in 40-99% yields (equation 27)41. The reactivity, markedly influenced by the steric bulk of hydrosilanes (see entry 30 of Table 1), decreases in the order of Ph2SiH2 >>PhMe2SiH > Ph2MeSiH > Ph3SiII. 

Reduction of cyclic and bicyclic ketones. This hydride reduces 4-r-butyl- and 3-methylcyclohexanone with some bias favoring formation of the more stable isomer. In contrast, 2-methylcyclohexanone is reduced preferentially to the less stable cis-isomer (72%). Essentially, only the ra-isomer is formed on reduction of 2-f-butylcyclohexanone (98% stereoselectivity). Norcamphor is reduced to the endo-alcohol in > 99% stereoselectivity, whereas the more hindered camphor is reduced to the exo-alcohol with 98% stereoselectivity. 

Ketones arise from phenols by isomerization of unsaturated alcohols (37). Palladium is the most suited for this type of reaction because of its high isomerization activity coupled with a very low rate of reduction of the resulting ketones (6). Excellent yields of ketones often may be obtained rhodium will give at times quite substantial yields of cyclohexanones (50-65% methylcyclohexanones from cresols) (38), but in other reductions such as resorcinol, little ketone accumulates over either rhodium or platinum under conditions where it is a major product over palladium (29). 

A very high stereoselectivity was observed in the reduction of 4-tert-butylcyclohexanone to the m-alcohol (> 95%), which is the industrially relevant product. The observed high selectivity to the thermodynamically unfavorable cis-alcohol was explained by a restricted transition-state for the formation of the trans-alcohol within the pores of the zeolites (Scheme 5). This reaction was found not only to be catalysed by Al-Beta, van der Waal et al. reported the catalytic activity of aluminum-free zeolite titanium beta (Ti-Beta) in the same reaction.74 Again, a very high selectivity to the cis-alcohol was observed indicating similar steric restrictions on the mechanism. Kinetically restricted product distributions were also reported for the 2-,3- and 4-methylcyclohexanone the cis, trans- and ds-isomers being the major products, respectively. In this case the tetrahedrally coordinated Ti-atom was assumed to behave as the Lewis acid metal center. Recent quantum-chemical calculations on zeolite TS-1 and Ti-Beta confirm the higher Lewis acidic nature of the latter one.75... 

In the reductive alkylation of ammonia with cyclohexanone, Skita and Keil found that, although cyclohexylamine was obtained in 50% yield over a nickel catalyst, over colloidal platinum dicyclohexylamine was produced as the predominant product even in the presence of an excess molar equivalent of ammonia. Steele and Rylander compared the selectivity to primary amine, secondary amine, and alcohol in the reductive alkylation of ammonia with 2- and 4-methylcyclohexanones over 5% Pd-, 5% Rh-, and 5% Ru-on-carbon as catalysts.18 As seen from the results shown in Table 6.2, the formation of secondary amine is greatly depressed by the methyl group at the 2 position. Thus over Pd-C the secondary amine was formed predominantly with cyclohexanone and 4-methylcyclohexanone while the primary amine was produced in 96% selectivity with 2-methylcyclohexanone. Over Ru-C the alcohol was formed quantitatively with 4-methylcyclohexanone without the formation of any amines, whereas with 2-methylcyclohexanone the alcohol was formed only to an extent of 57%, accompanied by the formation of 4 and 39% of the secondary and primary amines, respectively. These results indicate that secondary amine formation is affected by the steric hindrance of the methyl group to a much greater extents than is the formation of the primary amine or the alcohol. The results with Ru-C and Rh-C also indicate... 

Diastereoselective reduction of ketones. Trialkylsilanes can reduce aldehydes and ketones in the presence of a catalytic amount of tetrabutylammonium fluoride in HMPT (cf. reductions with activated hydrosilanes, 11, 554). Under these conditions esters and nitriles are not reduced. The reaction is stereoselective. Thus 2-methylcyclohexanone is reduced selectively to ds-2-methylcyclohexanol the cis-selectivity depends on the bulkiness of the hydrosilane, being highest (95%) with triphenylsilane. 

Reduction of ketones (8, 757). Reduction of methylcyclohexanones with sodium dithionite in a two-phase benzene-H20 mixture with Adogen 464 as a phase-transfer catalyst affords isomeric mixtures of methylcyclohexanols iq somewhat higher yield (70-82%) than that obtained when the reduction is conducted in aqueous solution only (15-68%). The stereoselectivity observed in the phase-transfer procedure is comparable to that reported with sodium borohydride. 

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