2 -Methylcyclohexanone, conformational

FIGURE 12. (a) (+)-trprojection diagrams. (b) CD spectra in methanol (-------) and isooctane (---). [Reproduced from D. A. Lightner,... 

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. 

It was assumed above that the methyl group adopts an equatorial conformation. Actually, methylcyclohexanone exists as a mixture of axial and equatorial conformations. 

Obtain the energy for axial methylcyclohexanone, and use equation (1) to calculate the room temperature equilibrium distribution of equatorial and axial conformers. Is the amount of the axial conformer significant (>5%) Perform a similar analysis as above and decide which face of the carbonyl in the axial conformer is more likely to undergo nucleophilic attack. Does addition lead to the same alcohol as before ... 

The enamines derived from cyclohexanones are of particular interest. The pyrrolidine enamine is most frequently used for synthetic applications. The enamine mixture formed from pyrrolidine and 2-methylcyclohexanone is predominantly isomer 17.106 A steric effect is responsible for this preference. Conjugation between the nitrogen atom and the tt orbitals of the double bond favors coplanarity of the bonds that are darkened in the structures. In isomer 17 the methyl group adopts a quasi-axial conformation to avoid steric interaction with the amine substituents.107 A serious nonbonded repulsion (A1,3 strain) in 18 destabilizes this isomer. 

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... 

In addition to the characteristic CH stretching VCD, a number of molecules that are strocturally similar to 3-methylcyclohexanone exhibit characteristic ROA features in the skeletal region below 700 cm. Figure 6 (11). In particular, a bisignate couplet near 500 cm is observed in six-membered ring compounds with a carbonyl substituent [(-F)-pulegone(73), (-F)-camphor (74), (-t-)-3-brom-ocamphor (74), (+)-nopinone (75)] and a broad low frequency couplet is observed in ketones with a 3-methyl substituent (75). The ROA of 3-methylcyclohexanone exhibits a third characteristic couplet near 400 cm. In all cases the sense of the observed couplets correlates with the absolute configuration of the most stable chair conformation. 

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. 

The possibility of ring conformational flexibility such as inversion (to afford the axial methyl isomer) or the intrusion of twist-boat isomers can be dismissed in (3R)-methylcyclohexanone because its n -> jr Cotton effect sign and magnitude (Ae +0.57)... 

Schaefer and Weinberg have reported (126) that the deuterolysis of 4-t-butyl-1-morpholino cyclohexene (477) produced specifically 2-8-deuterio-4-1 -butyl-cyclohexanone (478). Malhotra and Johnson (148) have shown that the enamine of 2-methylcyclohexanone gives on hydrolysis the oU-deuteromethylcyclohexanone 481. This enamine is known to exist in conformation 479 with the methyl group axial. Consequently, axial protonation must have taken place on 479 to give first the imini urn ion 480 which was then hydrolyzed to 481. 

Conformational control comes to the fore in the absence of highly polar substituents (as in propanal and a-methylcyclohexanones) and also in reactions with very early (reactant-like) or very late (product-like) transition states. Note that steric control is already incorporated in all models which assume that preferential attacks should come from the less hindered side.100... 

Figure 13. (a)-(d). Chair conformation (upper), approximate Ae (middle), and octant projection diagrams (lower) for a and 0-methylcyclohexanones. The Ae values are from refs 6-8, 1 and 12. (e)-(h). (3R)-Methylcyclohexanone with CH3 in an axial configuration (e) (15,3R)-4(a)-methyladamantan-2-one (f) and octant diagrams for back octants (g) and front octants (h). 

Conformationally mobile 3-methyl- and 4-methylcyclohexanone 179 and 182, respectively, react with CH3MgI (2 h, 22 °C) essentially non-selective, in contrast to 6 (distilled reactions in hexane, —15 °C->22 °C, 24h)77> as shown in Equations 61 and 62. 

The stereochemical course of the annulation process has been determined by reaction of acryloyl chloride with the morpholine enamine of 4-f-butyl-2-methylcyclohexanone. The bicyclic dione was obtained in 76% yield as a 4 1 mixture of two isomers (Scheme 150). X-ray analysis of the main isomer showed that reaction had occurred by axial attack from the same side as the C-2 methyl group. In order for regeneration of the enamine system to occur under conditions of stereoelectronic control, the intermediate ketene-iminium salt presumably adopts a twist conformation. Cyclization of the ketene... 

The pronounced magnetic anisotropy of benzene helps to reveal subtle solute-solvent interactions which otherwise could not be detected. For example, ASIS s can be used to differentiate between axial and equatorial H-atoms or methyl groups adjacent to carbonyl groups. A typical shift for an axial 2-methyl group in a cyclohexanone is 0.2... 0.3 ppm upheld, in benzene relative to tetraehloromethane as solvent, while that of the eorresponding equatorial 2-methyl group is 0.05. .. 0.10 ppm downfield [3]. This can be used to determine the configuration at the 2-position and to assess the position of the conformational equilibrium in 2-methylcyclohexanone. 

The reaction of 2-chloro-2-methylcyclohexanone with dimethyl sodiomalonate carried out at ice-bath temperature did not give the expected l-methylbicyclo[3.1.0]hexane derivative 24 (R = Me) but afforded only the substitution products 25 and 26 (R = Me) as a 52 48 mixture in 50% yield. The reaction with diethyl sodiomalonate likewise afforded a 27 73 mixture of the corresponding esters 25 and 26 (R = Et) in 43% yield. These results have been explained by the occurrence of a zwitterionic intermediate. By contrast, reaction of 2-chloro-4-methy 1-cyclohexanone with diethyl sodiomalonate under similar conditions gave 6-[bis(ethoxycar-bonyl]-3-methylbicyclo[3.1.0]hexan-6-ol (27) in 59% yield. This compound was tentatively assigned to have a more preferable boatlike conformation, which allows the bulky diester moiety to take the more favorable equatorial orientation. In a similar way, a 44 56 mixture of cn(/u-2-methyl- and exo-2-methyl-6-[bis(ethoxycarbonyl)methyl]-2-methylbicyclo-[3.1.0]hexan-6-ol (28) was obtained from the reaction of 2-chloro-5-methylcyclohexanone and diethyl sodiomalonate in 49% yield. 

Hickmott and coworkers have shown that the reaction of crotonoyl chloride with the pyrrolidino enamine of 4-benzoyl-4-methylcyclohexanone 117 gives a mixture of the three adamantane dione derivatives 118, 119 and 120 (equation 21). Surprisingly the main product obtained was the sterically most crowded 119, with the 6-phenyl and 9-methyl in mutually 1,3-diaxial position. This could be explained if the [3,3] sigmatropic rearrangement of 121 to 122 occurs via a boat transition state conformation from the same face of the cyclohexene moiety as the benzoyl group (equation 22). Although a boat conformation (125 126) normally is preferred for this type of rearrangement,... 

---