Cyclohexanone axial attack

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. 

In the case of substituted cyclic ketones, particularly cyclohexanones, the stereochemical outcome of an addition reaction is determined by the predominance of either equatorial or axial attack of the nucleophile, leading to axial or equatorial alcohols, respectively 25 -27 (Figure 8). 

The stereochemical outcome of nucleophilic addition reactions to cyclic ketones is the subject of numerous experimental and theoretical studies, with substituted cyclohexanones and cy-clopcntanones having been intensively studied. In addition reactions to substituted cyclohexanones 1 the problem of simple diastereoselectivity is manifested in the predominance of cither axial attack of a nucleophile, leading to the equatorial alcohol 2 A. or equatorial attack of the nucleophile which leads to the axial alcohol 2B. 

Although it might be expected that a larger substituent at the 2-position of cyclohexanone would hinder axial attack to a greater extent, addition reactions to 2-methyl-, 2-ethyl- and... 

Similar to cyclohexanones, substituted cyclopentanones also adopt a conformation with the substituents in a sterically favorable position. In the case of 2-substituted cyclopentanones 1 the substituent occupies a pseudoequatorial position and the diastereoselectivity of nucleophilic addition reactions to 1 is determined by the relative importance of the interactions leading to predominant fra s(equatorial) or cw(axial) attack of the nucleophile. When the nucleophile approaches from the cis side, steric interaction with the substituent at C-2 is encountered. On the other hand, according to Felkin, significant torsional strain between the pseudoaxial C-2—H bond and the incipient bond occurs if the nucleophile approaches the carbonyl group from the trans side. 

The LUMO of cyclohexanone 3 is an out-of-phase combination of the carbonyl It orbital with the orbital (5 in Fig. 4). The out-of-phase enviromnent disfavors attack from the face of the bonds (motif ii in Fig. 1). This leads to the axial attack of nucleophiles. The observed selectivities are in agreement with the orbital... 

The simplest case of substrate-controlled diastereoselection is the incorporation of the controlling stereocenter and the prostereogenic center into a cyclohexane or cyclopentane ring. In the classical example of nucleophilic attack on a conformationally anchored cyclohexanone, axial and equatorial attack are possible, leading to diastereomers 1 and 2, respectively. 

Addition of R2CuIa to >C—0.1 Ordinarily cuprates do not undergo 1,2-addition to ketones, but this reaction can be effected in the presence of added ClSi(CH3)3 (1-2 equiv.) in THF (but not in ether) to give the silyl ether formed by axial attack in the case of cyclohexanones (equation I). 

In contrast, sterically undemanding hydride donors such as NaBH4 or LiAlH4 reduce 4-fert-butylcyclohexanone preferentially through an axial attack. This produces mainly the cyclohexanol with the equatorial OH group (Figure 8.8, middle and bottom reactions). This difference results from the fact that there is also a stereoelec-tronic effect which influences the diastereoselectivity of the reduction of cyclohexanones. 

Epoxide openings are not alone in always giving diaxial products. We can give the general guideline that, for any reaction on a six-membered ring that is not already in the chair conformation, axial attack is preferred. You will see in later chapters that this is true for cyclohexenes, which also have the half-chair conformation described in the next section. Cyclohexanones, on the other hand, already have a chair conformation, and so can be attacked axially or equatorially. 

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. 

Consideration of the two half-chair conformations of 76 shows that a transition state resulting from axial attack on 76a would be destabilized relative to one resulting from attack on 76b. Both half-chair conformations of 75 (not shown) can undergo axial alkylation, thus leading to a mixture of R- and -substituted cyclohexanones, and the... 

Frenking next examined the reaction of LiH with cyclohexanone. The Hartree-Fock (HF)/3-21G transition structures for axial (31ax) and equatorial (31eq) attack are shown in Figure 6.17. Axial attack is lower than equatorial... 

The stereochemical product ratio for the reduction of cyclic ketones by hydrides is affected by the structure of the cyclic ketone and the nature of the hydride used. The reduction of substituted cyclohexanones avoids product interconversion by conformational ring flip because of conformationally locked cyclohexanones. In such cases, axial attack is preferred over equatorial attack. 4-fert-Butylcyclohexanone (6.50) is reduced by NaBH4 and by LiAlH4 to give 86% and 92% of trans-4-fert-butylcyclohexanol (6.51), respectively. Hindered hydrides such as f-BusBHLi show more selectivity. 

Consideration of the stabilizing interaction between the low-lying CT "-orbital associated with the bond forming between the incoming hydride and the carbonyl carbon, and remote electron-donor o-orbitals led Cieplak to an explanation for many kinetic and stereochemical effects in cyclohexanones that were previously unexplained. The normal preference for axial attack in simple cyclohexanones was attributed to the improved electron-donor ability of carbon-hydrogen bonds over carbon-carbon bonds that would be antiperiplanar to the incoming nucleophile in the transition state. 

Felkin identified torsional effects in cyclohexanone reductions that accounted for the observed stereoselectivity. Minimization of these torsional effects, in the absence of steric hindrance, led to the predominance of axial attack (equation 2).- Recently, a computational approach has provided quantitative support for this model.- The eclipsing interactions between the incoming nucleophile and the bonds a to... 

Axial versus equatorial attack of magnesium tertiary-enolates on substituted cyclohexanones is affected by solvent (i.e., HMPA increases axial substitution) [18]. Increased basicity favors axial attack. The enolates were generated by reaction of j-PrMgCl with r-butylacetate [Eq. (14)]. 

Addition to cyclohexanones is considered to be influenced by two factors (i) the steric interaction of the incoming groups with 3,5-axial substituents and (ii) the torsional strain of the incoming groups with 2,6-axial substituents. Steric strain hinders axial attack, whereas torsional strain hinders equatorial attack. The actual stereochemistry of the addition depends upon which factor is greater in a particular case. The production of the desired isomer in high stereoselectivity is required from the synthetic point of view. 

There are two possible modes of delivery of the hydride to the carbonyl carbon of cyclohexanone (1) axial attack with formation of the equatorial alcohol and (2) equatorial attack with formation of the axial alcohol. Two factors are competing with each other (1) steric interaction of the incoming hydride with the 3,5-diaxial hydrogens in the axial attack and (2) torsional strain of the incoming hydride with the 2,6-diaxial hydrogens in the equatorial attack. 

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