2-Alkyl-5-methylcyclohexanones

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 reactions of pyrrolidinocyelohexenes with acid have also been Considered from a stereochemical point of view. Deuteration of the 2-methylcyclohexanone enamine gave di-2-deuterio-6-methylcyclohexanone under conditions where ds-4-/-butyI-6-methyIpyrrolidinocycIohexene was not deuterated (2J4). This experiment supported the postulate of Williamson (2JS), which called for the axial attack of an electrophile and axial orientation of the 6 substituent on an aminocyclohexene in the transition state of such enamine reactions. These geometric requirements explain the more difficult alkylation of a cyclohexanone enamine on carbon 2, when it is substituted at the 6 position, as compared with the unsubstituted case. 

The illumination of enamines as general activa ting derivatives of ketones in alkylation reactions also threw light on their special usefulness for controlling alkylations (3), particularly in the formation of monosubstituted cyclohexanones. Thus 2-methylcyclohexanone could be obtained in 80% yield from the pyrrolidine enamine of cyclohexanone, and further alkylation, which required more drastic conditions, gave only 2,6-dimethylcyclo-hexanone (1,237). 

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). 

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... 

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. 

FORMATION AND ALKYLATION OF SPECIFIC ENOLATE ANIONS FROM AN UNSYMMETRICAL KETONE 2-BENZYL-2-METHYLCY-CL0HEXAN0NE AND 2-BENZYL— 6-METHYLCYCLOHEXANONE, 52,... 

The present procedure is a general method for the preparation of monoalkylated ketones from enamines of aldehydes and ketones with electrophilic olefins. There are many advantages in this method of alkylation. Only monoalkylation occurs, even when such reactive species as acrylonitrile are used and, when a cyclic ketone like 2-methylcyclohexanone is used, reaction occurs only at the lesser substituted center. In a general base-catalyzed reaction, substitution occurs on the more substituted center. 

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 ... 

A simple Sn2 alkylation reaction serves as example. As we have already seen, treating cyclohexanone with LDA gives the enolate anion, which can then be allowed to react with methyl iodide to give 2-methylcyclohexanone. 

Alternatively, cyclohexanone may initially be transformed into an enamine with a secondary amine, here pyrrolidine. This intermediate enamine can act as a nucleophile and can be alkylated at the P-position using methyl iodide. Finally, 2-methylcyclohexanone may be generated by hydrolysis of the iminium system, effectively a reversal of enamine formation. This gives us two routes to 2-methylcyclohexanone, a short process using the very strong base LDA and... 

Back in Section 10.5 we saw two methods of synthesizing 2-methylcyclohexanone, i.e. by direct alkylation of the enolate anion derived from cyclohexanone and by using an enamine derivative as the nucleophilic species. The latter route had the advantage of not using a strong base to generate the... 

The preparation of 2-isopropyl-6-methylcyclohexanone is strongly dependent on the sequential order of introducing the methyl and the isopropyl group. Metalation of the chiral 2-isopropyl-cyclohexanone imine and alkylation with iodomethane furnished only 18% yield, whereas a 95 % yield was obtained by first introducing the methyl group and alkylating in the last step with 2-iodopropane8. 

Alternatively, metalation of cyclohexanone imines can be performed with isopropylmagnesium bromide by refluxing in THF for 2 hours1,24. Alkylation of the magnesium azaenolate of the (E)-2-amino butyl ether derivative at —78 °C provides (E)-2-methylcyclohexanone in an overall yield of 52% and 81% enantiomeric excess24. 

The dependency of asymmetric induction on the nature of the electrophile has been demonstrated in the synthesis of (7 )-2-methylcyclohexanone. Thus, the enantiomeric excess dropped from 99% to 67% wheniodomethane was used instead of dimethyl sulfate as alkylating agent6 and the use of methyl 4-methylbenzenesulfonate as electrophile resulted in a dramatic increase to >98% ee from that of 61 -75% ee when iodomethane was used9. 

These alkoxytitanium homoenolates show high propensity for equatorial attack in their ir reactions with substituted cyclohexanones (Table 6). The basic trend of their chemical behavior is similar to that of simple titanium alkyls [35]. Chemo-selectivity of the reagent 19 is also noteworthy. The alkoxytitanium homoenolate reacts preferentially with an aldehyde even in the presence of a ketone Eq. (32). A notable difference of rate between the reaction with cyclohexanone and that with 2-methylcyclohexanone was also observed, the latter being far less reactive toward the homoenolate. 

Chiral 2,2-disubstituted cycloalkanones.1 The imine 2 prepared from racemic 2-methylcyclohexanone and (S)-( - )-l, reacts with methyl vinyl ketone to form an adduct that is hydrolyzed to the (R)-( + )-diketone 3 in 91% ee with recovery of 1 in almost quantitative yield. The reaction is described as a deracemizing alkylation. ... 

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). 

The deprotonation of an iminium ion (formula A in Figure 7.27) to give an enam-ine is reversible under the usual reaction conditions. Therefore, the most stable enam-ine possible is produced preferentially. Figure 7.28 emphasizes this using the example of an enamine formation from a-methylcyclohexanone (i.e., from an asymmetrical ketone). The enamine with the trisubstituted double bond is produced regioselectively and not the enamine with the tetrasubstituted double bond. Since the stability of olefins usually increases with an increasing degree of alkylation, this result is at first... 

---