Alkylation of 2-methylcyclohexanone

Note in the ketone example that alkylation of 2-methylcyclohexanone leads to a mixture of products because both possible enolate ions are formed. In general, the major product in such cases occurs by alkylation at the less hindered, more accessible position. Thus, alkylation of 2-niethvTcyclohexanone occurs primarily at C6 (secondary) rather than C2 (tertiary). 

Regiochemistry, the preferential addition of the reagent in only one of two possible regions or directions, exemplified by the preferential alkylation of 2-methylcyclohexanone by the derived enolate at C(2) and not at C(6)... 

Some of the stereochemical aspects of the alkylation of 2-methylcyclohexanone are treated in Problem 20.74. 

What experimental conditions would favor formation of 2-ben2yl-2-methylcyclohexanone by alkylation of 2-methylcyclohexanone with ben2yl bromide ... 

The pyrrolidine enamine of 2-methylcyclohexanone (7) was in fact found to be quite inert toward further alkylation and was shown to consist only of the trisubstituted isomer (4) on the basis of the NMR spectral data. The... 

The presence of 1,3-diaxial interaction between the C-2 alkyl group and the C-4 axial hydrogen atom is reflected in the rate of enamine formation of 2-substituted cyclohexanone. It has been shown by Hunig and Salzwedel (20) that even under forcing conditions, the yield of pyrrolidine and morpholine enamines of 2-methylcyclohexanone does not exceed 58%, whereas the C-2 unsubstituted ketones underwent enamine formation under rather milder conditions in better than 80 % yield. 

The anion of cyclohexanone /V,/V-dimclhyl hydrazone shows a strong preference for axial alkylation.122 2-Methylcyclohexanone N,N-dimethylhydrazonc is alkylated by methyl iodide to give d.v-2,6-dimclhylcyclohcxanone. The 2-methyl group in the hydrazone occupies a pseudoaxial orientation. Alkylation apparently occurs anti to the lithium cation, which is on the face opposite the 2-methyl substituent. 

The most common rearrangement reaction of alkyl carbenes is the shift of hydrogen, generating an alkene. This mode of stabilization predominates to the exclusion of most intermolecular reactions of aliphatic carbenes and often competes with intramolecular insertion reactions. For example, the carbene generated by decomposition of the tosylhydrazone of 2-methylcyclohexanone gives mainly 1- and 3-methylcyclohexene rather than the intramolecular insertion product. 

Benzyl-6-methylcyclohexanone has been prepared by the hydrogenation of 2-benzylidene-6-methylcyclohexanone over a platinum or nickel catalyst, and by the alkylation of the sodium enolate of 2-formyl-6-methylcyclohexanone with benzyl iodide followed by cleavage of the formyl group with aqueous base. The 2,6-isomer was also obtained as a minor product (about 10% of the monoalkylated product) along with the major product, 2-benzyl-2-methylcyclohexanone by successive treatment of 2-methylcyclohexanone with sodium amide and then with benzyl chloride or benzyl bromide. Reaction of the sodium enolate of 2-formyl-6-methylcyclohexanone with potassium amide in liquid ammonia formed the corresponding dianion which was first treated with 1 equiv. of benzyl chloride and then deformylated with aqueous base to form 2-benzyl-2-methylcyclohexanone.i ... 

Metalation of unsymmetrical mines. Pioneering studies on the metalation and subsequent alkylation of unsymmetrical imines indicated that the reaction occurs predominantly at the less substituted a-position.5 This pattern has since been observed generally with lithium diethylamide, LDA, and ethylmagnesium bromide. Recent studies6 indicate that the site of alkylation is independent of the alkylating group but is dependent on the substituent on the imine and particularly on the basicity of the base. Butyllithium ( -, sec-, and /-) can abstract a proton from the more substituted a-carbon of the acyclic imine 1 to some extent. In the case of the cyclic imine 2, alkylation at the more substituted position is actually the main reaction. However, only substitution at the less substituted position of the dimethylhydrazone of 2-methylcyclohexanone is observed with either LDA or jcc-butyllithium (7,126-128). 

Similarly, the enamine of a 2-substituted cyclohexanone is alkylated by electrophilic alkenes such as acrylonitrile or methyl acrylate at the exposition in methanol or acetonitrile. However, prolonged reaction time (66 h) of the pyrrolidine enamine of 2-methylcyclohexanone with these reagents in dioxane or benzene under reflux gives a 1 1 mixture of 2,2- and 2,6-disubstituted cyclohexanones (38 and 39)82>83 (Scheme 23). 

TABLE 2. Regioselectivity of alkylation of the pyrrolidine enamine of 2-methylcyclohexanone... 

TABLE 5. Regio- and enantioselective alkylation of 2-methylcyclopentanone (31a) and 2-methylcyclohexanone (31b) with an optically active Lewis acid... 

Conversely, Hosomi and Sakurai have shown that deprotonation with alkyllithium reagents occurs predominantly at the more substituted side of the cyclohexylimine of 2-methylcyclohexanone (equation 41). However, the low yield in this sequence (as compared with, for example, equations 39 and 40) places this route to 2,2-disubstituted systems only equal with other techniques such as those that employ the more stable enolate-derived 2-alkyl cyclic ketones. Further, in no case did deprotonation of an unsymmetrical, acyclic ketone imine with an alkyllithium result in synthetically usable selectivity for the more substituted carbon. 

An illustration of this behavior is provided in equation (1). A 67 33 mixture of the less- and more-substituted potassium enolates was produced upon treatment of 2-methylcyclohexanone with tritylpotassium in DME. However, the major product of alkylation of this mixture with methyl iodide was 2,2-dimethyl-cyclohexanone and significant amounts of tri- and tetra-methylcyclohexanone were also obtained. ... 

Regioselective alkylations at C-6 of 2-methylcyclohexanone have been accomplished via the alkylation of thermodynamically unstable trisubstituted lithium, lithium triethanolamine borate, potassium triethylboron, tri- -butyltin and benzyltrimethylammonium enolates (c/. 2). Alkylation is faster than equilibration for the more reactive alkylating agents. Although enolate equilibration has been shown to compete with butylation using n-butyl iodide under certain conditions, butylation of the enolate (2 M = Li) in liquid ammonia-THF gave a mixture of cis- and /ra/ij-2-methyl-6-butylcyclohexanone along with 2-methylcyclohexanone in an 83 17 ratio in 90% yield no 2,2-dialkylcyclohexanone was obtained in this reaction (Scheme 8). ... 

This new reagent is an active reducing agent and reduces cyclic and bicyclic ketones with superstereoselectivity.1 Thus reduction of 2-methylcyclohexanone (1) gives m-2-methylcyclohexano) in 99.3 % purity. Note that reduction with lithium trimethoxy-aluminum hydride alone yields (2) in 69 % yield. Thus increasing the size of the alkyl substituents on boron enhances the stereoselectivity of the borohydride anion. Even... 

Because the amines are removed in the subsequent hydrolytic workup, enamines are obviously amenable to an auxiliary-based asymmetric synthesis using a chiral amine. It is additionally significant from a preparative standpoint that unsym-metrical ketones alkylate at the less substituted position via tertiary enamines e.g., Ce of 2-methylcyclohexanone) whereas the more hindered position is alkylated preferentially with secondary enamines (e.g., C2 of 2-methylcyclohexanone). 

Two different products can be formed when the ketone is not symmetrical, because either a-carbon can be alkylated. For example, methylation of 2-methylcyclohexanone with one equivalent of methyl iodide forms both 2,6-dimethylcyclohexanone and... 

Reductive alkylation of afi-unsaturated ketones (3, 179-181). An example of this useful method of Stork for alkylation of a,l3-unsaturated ketones via the less stable lithium enolate has been described in Org. Synf Direct base-catalyzed alkylation of 3-methylcyclohexanone leads mainly to 2-alkyl-5-methylcyclohexa-nones. The Stork reaction requires an added proton source as a buffer in the example shown water is used so that lithium hydroxide (a weak base) is present. 

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. 

Enolate alkylation can be difficult to carry out with simple aldehydes and ketones. It is not always possible to limit the reaction to monoalkylation, and aldol condensation competes with alkylation, especially with aldehydes. The formation of regioisomeric alkylation products is an issue with unsymmetrical ketones but can be minimized by selecting reaction conditions that favor either kinetic or thermodynamic control of enolate formation. The kinetic enolate of 2-methylcyclohexanone, for example, was prepared by deprotonation with lithium diisopropylamide then treated with benzyl bromide to give predominantly 2-benzyl-6-methylcyclohexanone,... 

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