2-Methylcyclohexanone, formation

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 magnitude of the preference for the formation of the less substituted enamine from unsymmetrical ketones as expressed by the general rule given above is not entirely clear. House and Schellenbaum 48) have reported that 2-methylcyclohexanone and pyrrolidine produce a product mixture of tetra- and trisubstituted enamines in a ratio of 15 85. The estimate of this ratio was made from NMR data. In contrast Stork and co-workers (9) report the formation of 100% trisubstituted enamine as determined by NMR spectroscopy. 

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). 

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

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... 

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

Another example of the formation of a rearranged product is the palladium(0)-catalysed reaction of the enolate ion of 2-methylcyclohexanone with 3-methyl-3-nitro-l -butene... 

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... 

Ohmura, R. Uchida, T. Takeya, S. Nagao, J. Minagawa, H. Ebinuma, T. Narita, H. (2003 a). Clathrate hydrate formation in (methane + water + methylcyclohexanone) systems the first phase equilibrium data. J. Chem. Thermodynamics, 35, 2045-2054. 

Formation of CK-configurated cyclobutanones has also been observed with 2-methylcyclopen-tanone and 2-methylcyclohexanone/8 However, stereoreversed eyclobutanone formation can be achieved by opening the intermediate oxaspiropentane with sodium phenyl selenide, oxidation of the resulting / -hydroxy selenide with 3-chloroperoxybenzoic acid and subsequent rearrangement in the presence of pyridine/18 Thus, from one oxaspiropentane 8, either stereoisomeric eyclobutanone cis- or lrans-9 was produced. The stereoreversed eyclobutanone formation proceeds from a stereohomogenous / -hydroxy selenoxide and is thought to be conformationally controlled. 

Explain why ethyl formate condenses with 2-methylcyclohexanone in the presence of base at the unsubstituted position ... 

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. 

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... 

Garbisch (1965) explained predominant bromination (67%) on the methylene site of 2-methylcyclohexanone 1681 (6-position) in methanol (as opposed to 4% in ether) as due to easier formation of the more stable /F,6-enol ether from the acetal. Similar peculiar regioselectivities for acid-catalysed bromination, chlorination and deuteriation of [691-1731 have been reported... 

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... 

It was shown that the rate of formation of the enamine of 3,3-dimethylaziridine is 5 to 10 times faster than that of pyrrolidine with 2-methylcyclohexanone and 1-tetralone, probably due to decreased steric hindrance. However, the yields of monomethylated products are significantly lower with the azetidine enamine92. 

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