3,5-dimethylcyclohexanone isomers

That the methyl group in the less substituted isomer of the enamine (20) is axial was borne out by the work of Johnson et al. (18) in the total synthesis of the glutarimide antibiotic //-dehydrocycloheximide (24). The acylation of the morpholine enamine of 2,4-dimethylcyclohexanone (25) with 3-glutarimidylacetylchloride (26), followed by the hydrolysis of the intermediate product (27) with an acid buffer, led to the desired product in 35 % yield. The formation of the product in a rather low yield could most probably be ascribed to the relatively low enamine-type aetivity exhibited by the tetrasubstituted isomer, which fails to undergo the acylation reaction, and also because in trisubstituted isomer one of the CHj groups is axial. Since the methyl groups in the product are trans to each other, the allylic methyl group in the less substituted isomer of the enamine should then be in the axial orientation. 

The versatility of host 1 allows discrimination not only between isomeric planar, aromatic compounds but also between quite bulky derivatives of cyclohexane. For example, host 1 will include selectively the diequatorial isomer of 3,5-dimethylcyclohexanone (65), but not 66 or isomer 67 from a mixture of 67-69 [67],... 

While it is probably reasonable to draw general trends from this series, it should be kept in mind that most of the data came from different laboratories, as indeed there are four different reports for the simple pyrrolidine enamine that account for the range from 85 to 96%. Some of the factors that contribute to determining the regioisomeric composition of enamines are A -strain, which destabilizes the more substituted isomer, and A - -strain, which destabilizes the less substituted isomer (Scheme 6). The former effect was used by Johnson to effectively convert c/j-2,4-dimethylcyclohexanone to the trans isomer through formation of the less substituted pyrrolidine enamime, where a pseudo-axial orientation of the 2-methyl group reduces the level of A - -strain (equation... 

The lithium enolate of (2/ ,4/ )-2,4-dimethylcyclohexanone has been condensed with an appropriate aldehyde to prepare several isomers of the antibiotic cycloheximide (equation 61). The major isomer results from reaction on the unsubstituted face of the cyclohexanone ring, and has the same relative stereochemistry at the two new stereocenters as the major isomer in Scheme 1. The second most abundant isomer is o a syn aldol, and results from attack on the more-substimted face of the dimethylcyclohexa-none. 

A valuable feature of the enamine reaction is that it is regioselective. In the alkylation of an unsymmetrical ketone, the product of reaction at the /ess-substituted a-carbon atom is formed in greater amount, in contrast to direct base-mediated alkylation of unsymmetrical ketones, which usually gives a mixture of products. For example, reaction of the pyrrolidine enamine of 2-methylcyclohexanone with iodomethane gives 2,6-dimethylcyclohexanone almost exclusively. This selectivity derives from the fact that the enamine from an unsymmetrical ketone consists mainly of the more-reactive isomer in which the double bond is directed toward the less-substituted carbon atom. In the more-substituted enamine, there is decreased interaction between the nitrogen lone pair and the -ir-system of the double bond because of steric interference between the a-substituent (the methyl group in Scheme 1.33) and the a-methylene group of the amine. 

Dimethylcyclohexanone is an industrial, high-boiling mixture of cis and irons isomers [54396-54-2] and [54396-55-3], respectively. It is comparable to methylcyclohexanone as regards solvency and miscibility. 

When cis-2,4-dimethylcyclohexanone is dissolved in aqueous ethanol containing a trace of NaOH, a mixture of cis and trans isomers results. Propose a mechanism for this isomerization. 

The hydrolysis and isomer content of enamines of 2,3- and 2,5-dimethylcyclohexa-nones falls into a broadly similar pattern. Enamines of 2,6 dimethylcyclohexanones can exist only as (234), with the 6-methyl group axial or equatorial. Both pyrrolidine and morpholine enamines undergo hydrolytic decomposition to give ca. 50 50 mixtures of cis- and trans-ketones. The 4-t-butyl derivative (235), on hydrolysis, gave... 

Hanessian resolved alkylqrclohexanones by benzylidenation with a chiral olefination reagent arising from R,R)-103 [71]. Treatment of ( )-2-methylcyclohexanone 104 with 0.5 Molar equiv of the anion of 103 gave ( ,2S)-(2-methylcyclohexane)-benzylidene 105 (together with <2% of the Z-isomer), in 34% yield, based on the ketone (63% based on the chiral reagent). Analogously, ( )-cts-2,4-dimethylcyclohexanone 106 afforded the 3-hydroxyphosphonamide 107, then the ( ,2R,4i )-(2,4-dimethylcyclohexane)-benzylidene 108 in 30% yield and over 99% ee. 

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