Methylcyclohexanones

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/ ... 

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... 

Since the conformational inversion of 2c-methylcyclohexanone is the key step in this sequence, the corresponding conformationally more stable system, i.e., cw-2-methyl-4-t-butylcyclohexanone (14), should fail to incorporate any deuterium. This was actually shown to be the case. Treatment of this ketone under identical conditions for d exchange did not show any d incorporation. This evidence also rules out the likelihood of any d incorporation via acid- or base-catalyzed enolization. 

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. 

Although the enamine (30) underwent addition reaction with ethyl azido-dicarboxylate, it failed to add another mole of jS-nitrostyrene. In a similar manner the morpholine enamine of 2-methylcyclohexanone also failed to react with this olefin, i.e., jS-nitrostyrene, which is undoubtedly due to the 1,3-diaxial interaction between the methyl group and the incoming electrophile in the transition state. 

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... 

Information regarding the position of the substituents can be obtained from the mass spectra of the enamines of cyclic ketones. For instance in the case of the morpholine enamine of 3-methylcyclohexanone, which is shown to be a 2 1 mixture of/ and isomers by NMR spectroscopy, the fragmentation of the radical ion from the /) isomer results in the loss of a methyl radical from the C-3 position. The d isomer gives a complicated spectrum due to the loss of the hydrogen radical. 

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 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). 

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