A-Methylcyclohexanone

Reagent 1 is preferred because of commercial availability, but it is less reactive than the amide acetal f-butoxybis(dimethylamino)methane 4 (Brederick s reagent). Thus 4 reacts with a-methylcyclohexanone to give the enaminone 2 in 99% yield. Trisdimethylaminomethane (5) is even more reactive than 4, but is not as readily available. 

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... 

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... 

Interesting examples of chelation-assisted C-C bond activation are found in the Rh(I)-promoted skeletal rearrangements of cycloaUcanones [30]. Reaction of cycloheptanone (56) with 2-amino-3-picoline (21) in the presence of (Ph3P)3RhCl (16) at 150°C was observed to generate a mixture of a-methylcyclohexanone (57) and a-ethylcyclopentanone (58) (Scheme 11). In this process, cycloheptanone... 

It is of course very tempting to combine sheer size of the proton acceptor with conditions of kinetic or thermodynamic control, as has been shown for a-methylcyclohexanone 71 [31b,c]... 

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. 

Display the lowest-unoccupied molecular orbital (LUMO) for equatorial methylcyclohexanone. This is the orbital into which the nucleophile s pair of electrons will go. Is it larger on the axial or equatorial face A clearer picture follows from the LUMO map, which gives the value of the LUMO on the electron density surface, that is, the accessible surface of the molecule. Display the LUMO map for equatorial methylcyclohexanone. Which face of the carbonyl group is more likely to be attacked by a nucleophile Which alcohol will result ... 

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 ... 

Methylcyclohexanone, pK 20, is typical of a weak acid that undergo H/D exchange. Identify the acidic protons of 2-methylcyclohexanone, i.e., those most susceptible to attack by base, as positions for which the value of the lowest-unoccupied molecular orbital (LUMO) is large. Use a LUMO map (the value of the LUMO mapped onto the electron density surface). Does this analysis correctly anticipate which of the anions obtained by deprotonation of 2-methylcyclohexanone is actually most stable Are any of the other ions of comparable stability, or are they aU much less stable ... 

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 ... 

This procedure appears to be general and has been successfully applied to the following examples ethyl acetoacetate from acetone (68 %) ethyl benzoylacetate from acetophenone (74%) ethyl a-propionylpropionate from diethyl ketone (81%) ethyl 2-methylcyclohexanone-6-carboxylate from 2-methylcyclohexanone (67%). 

Sodium hydride, 50% dispersion in mineral oil Alpha Inorganics 2-Carbethoxycyclooctanone (Chapter 10, Section I) 2-Methylcyclohexanone A, EK Methyl vinyl ketone MCB, A... 

However, 3- or4-methylcyclohexanone is less r Although 3-methylcyclohexanone does not react conchdons, under high pressure and a fluoride ioi 3-nitro alcohol in moderate yields fEq 3 1S "... 

Scheme 6.1 shows a simple preparation of f-i- -isominLlactone, isolated from a sample of peppermint oil. The addition of pytrolidino enamine of f/f -3-methylcyclohexanone to ni-... 

The situation is different for 2-methylcyclohexanone. 2-Methylcvclo-bexanone has no symmetry plane and is chiral because C2 is bonded to four different groups a -CH3 group, an —H atom, a -COCH2- ring bond (C1), and a —CH2CH2— ring bond (C3). 

Problem 19.4 How would you carry out the following reactions More than one step may be required, (a) 3-Hexvne 3-Hexanone, (b) Benzene —> m-Bromoacetophenone I (c) Bromobenzene —> Acetophenone (d) 1-Methylcyclohexene — 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). 

Problem 23,4 Aldol condensation of 3-methylcyclohexanone leads to a mixture of two enone products, not counting double-bond isomers. Draw them. 

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