Enamines axial alkylation

The stereochemistry of the alkylation of enamine 482 has been reported by Karady, Lenfant, and Wolff (149) to give mainly the axial alkylated product... 

Alkylations of enolates, enamines, and silyl enol ethers of cyclohexanone usually show substantial preference for axial attack. The enamine of 4-f-butylcyclohexanone, which has a fixed conformation because of the i-butyl group, gives 90% axial alkylation and only 10% equatorial alkylation with n-Prl. 

Interactive mechanism for axial alkylation of cyclohexanone enamine... 

Because of the same preference for coplanarity in the enamine system, a alkyl substituents adopt an axial conformation to minimize steric interaction with the amino groi. ... 

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. 

As pointed out by Stork and coworkers in their definitive 1963 paper3, the reaction with electrophilic alkenes is especially successful since reaction at nitrogen is reversible. Reaction at the /2-carbon is (usually) rendered irreversible by, in the case of cyclohexanone enamines, internal proton transfer of the axial C-/2 proton to the anionic centre of the initially formed zwitterionic intermediate (34), under conditions of stereoelectronic control (Scheme 22). When this intramolecular proton transfer cannot occur in aprotic solvents, or when the product produced in protic solvents is a stronger carbon acid than adduct 35 (i.e. when Z = COR, N02), then carbon alkylation is also reversible and surprising changes in the regioselectivity of reaction may be observed (vide infra see also Section VI.D and Chapter 26). Cyclobutanes (36) and, in the case of a,/ -unsaturated... 

On the basis of distribution of products obtained in these reactions with the change of solvents, temperature and molar ratio of reactants, a mechanism has been suggested for the anomalous annulation which does not involve an initial attack of the tetrasub-stituted isomer of the enamine (equation 16)51. Alkylation of the more stable cis isomer of the enamine (80) with methyl vinyl ketone (MVK) would afford zwitterion 81 (attack by the other side of the enamine leads to strong steric interactions in the transition state). Reaction of the thermodynamically less favorable trans isomer 83 gives rise to zwitterions 84 and 89 (both without axial-axial interactions), and ion 84 is sterically able to undergo intramolecular proton shift to afford enamine 85. Zwitterionic intermediates 81 and 89 can be stabilized by conversion to dihydropyrans 82 and 90, or protonated to immonium ions. The pair 81-82 will lead to enamine 85, while the pair 89-90 will afford enamine 91. Then, cyclization of 85 or 91 will afford the enone expected from the normal enamine version of the Robinson annulation. 

Now the newly formed enamine 117 can be alkylated by the allylic bromide in the side chain. To do this reaction, the molecule must put the side chain in an axial position 118. The resulting iminium salt 119 is hydrolysed on work-up to the bridged bicyclic product 114. 

An interesting and useful property of enamines of 2-alkylcyclohexanone is the substantial preference for the less-substituted isomer to be formed. This tendency is especially pronounced for enamines derived from cyclic secondary amines such as pyrrolidine, a preference that can be traced to Ai allylic strain. In order to maximize conjugation between the nitrogen lone pair and the carbon-carbon double bond, the nitrogen substituent must be coplanar with the double bond. This creates a steric repulsion when the enamine bears a 6-substituent and leads to a preference for the unsubstituted enamine. Because of the same preference for coplanarity in the enamine system, a-alkyl substituents adopt an axial conformation to minimize steric interaction with the amino group. 

Acetaldehyde 34, which is the simplest of all enolizable carbonyl compounds but highly reactive as an electrophile, is an inexpensive and versatile two-carbon nucleophile in enamine-based Mannich reactions. Mannich reactions of acetaldehyde as a donor with aryl or alkyl substituted N-Boc-imines 90 are effectively catalyzed by (S) -proline (13) in moderate yield but excellent enantioselectivity (Table 28.6, entries 1 and 2) [47]. Chemical yields are improved up to 87% when N-benzoyl (Bz)-imine is employed in the presence of diaryl prolinol silyl ether 85 with p-nitrobenzoic acid (entry 3) [48]. To suppress side reactions, such as self-aldol reactions, the moderate nucleophilicity of the axially chiral amino sulfonamide 23 is particularly useful for this type of Mannich reaction these conditions give the corresponding adducts 91 in good yield and excellent stereoselectivity (entries 4 and 5) [49]. 

Both of these reactions result in the alkylation of 4-t-butylcyclohexanone, but the selectivity obtained is very different. The lithium enolate produced on reaction with LDA is sterically undemanding, and hence approach of the methyl iodide is possible either axially or equatorially there is a marginal preference for the more stable equatorial product. However, the pyrrolidine ring of the enamine is much bulkier and inhibits approach to the equatorial position more than it does to the axial position. 

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