Cyclohexanone enolates

Endocyclic cyclohexanone enolates with 2-alkyl groups show a small preference (1 1-5 1) for approach of the electrophile from the direction that permits the chair conformation to be maintained. ... 

Compare the geometries of the cyclohexanone enolate and the cyclohexanone lithium enolate. Do both molecules show delocalized structures, or is the bonding in one of them more localized For comparison, examine the geometries of 1-hydroxycyclohexene md cyclohexanone. 

HOMO of cyclohexanone enolate reveals most nucleophilic sites. 

Obtain the energies of the products resulting from metihylation of cyclohexanone enolate the CCproduct (shown above) and the OCproduct. Does methylation give the more stable product Repeat this analysis for the CSi and OSi silylation products. 

For simple, conformationally biased cyclohexanone enolates such as that from 4-t-butylcyclohexanone, there is little steric differentiation. The alkylation product is a nearly 1 1 mixture of the cis and trans isomers. 

Fig. 1 Charge-transfer absorption spectra of enol silyl ethers complexes with re-acceptors. (a) Spectral changes accompanying the incremental additions of cyclohexanone enol silyl ether [2] to chloranil in dichloromethane. Inset Benesi-Hildebrand plot, (b) Charge-transfer absorption spectra of chloranil complexes showing the red shift in the absorption maxima with decreasing IP of the enol silyl ethers, (c) Comparative charge-transfer spectra of EDA complexes of a-tetralone enol silyl ether [6] showing the red shift in the absorption maxima with increasing EAs of the acceptors tetracyanoben-zene (TCNB), 2,6-dichlorobenzoquinone (DCBQ), chloranil (CA), and tetracyanoqui-nodimethane (TCNQ). Reproduced with permission from Ref. 37.

DDQ ( red = 0.52 V). It is noteworthy that the strong medium effects (i.e., solvent polarity and added -Bu4N+PFproduct distribution (in Scheme 5) are observed both in thermal reaction with DDQ and photochemical reaction with chloranil. Moreover, the photochemical efficiencies for dehydro-silylation and oxidative addition in Scheme 5 are completely independent of the reaction media - as confirmed by the similar quantum yields (d> = 0.85 for the disappearance of cyclohexanone enol silyl ether) in nonpolar dichloromethane (with and without added salt) and in highly polar acetonitrile. Such observations strongly suggest the similarity of the reactive intermediates in thermal and photochemical transformation of the [ESE, quinone] complex despite changes in the reaction media. 

Scheme 2-5 is one of such examples in which stereoelectronic control has to be taken into account in diastereoselective alkylation of substituted cyclohexanone enolates.12... 

In a frequently cited investigation, House studied the condensations of a variety of metal enolates with aldehydes under conditions of thermodynamic control (14). In the cyclohexanone enolate-benzaldehyde condensation (eq. [5]), it was observed that the zinc enolate (14°C, 5 min) afforded a 5 1 ratio of aldol adducts 5T and... 

A large number of studies have addressed the condensation of cyclic ketones with both aliphatic and aromatic aldehydes under conditions that reflect both thermodynamic (cf. Table 2) and kinetic control of stereochemistry. The data for cyclohexanone enolates are summarized in Table 8. Except for the boryl enolates cited (6), the outcome of the kinetic aldol process for these enolates... 

Kinetic Aldol Condensations of Cyclohexanone Enolates with Aromatic Aldehydes (eq. [18])... 

The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the reaction which is crucial in many cases is the stereoselectivity. The alkylation step has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, since the electrons which are involved in bond formation are the n electrons. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile will approach from the less hindered of the two faces, and the degree of stereoselectivity depends upon the steric differentiation. For simple, conformationally based cyclohexanone enolates such as that from 4 - /- b u ty I eye I o h cx an o ne, there is little steric differentiation. The alkylation product is a nearly 1 1 mixture of the cis and trans isomers. 

Steric control elements are also important for the diastereoselectivity in alkylations of mono-cyclic cyclohexanone enolates. However, electronic control becomes more evident in these systems compared to monocyclic cyclopentanone enolates The flexibility of the six-membered ring system, and the large number of possible ring conformations, makes predictions of the diastereoselectivity difficult. In general, one may conclude that the diastereoselectivity in alkylations of enolates derived from monocyclic cyclohexanones is not as high as in alkylations of cyclopentanone enolates. The syntheses of compounds 21-27 demonstrate the effect of substitution in each position of the six-membered ring49,61 -7°. 

Like enamines, dihalocarbenes add smoothly to enol ethers and in many cases it is possible to isolate the dihalocyclopropyl intermediates which are valuable synthons for chloroenones (cf. Section 4.7.3.7.1). The earliest example of the addition of a dihalocarbene to an enol ether was provided by Parham,6,79 who studied the addition of dichlorocaibene to dihydropyran (equation 22). An example which illustrates the synthetic potential of the process is the conversion of the cyclohexanone enol ether (6) to the dichlorocy-clopropane (7 equation 23).80 The latter served as a useful intermediate in a stereospecific synthesis of Prelog-Djerassi lactonic acid. 

Ring contractions are not frequent among the 5-alkoxytriazolines469,521 however, under pressure arylsulfonyl azides react with sterically congested silyl enol ethers to give clean one-carbon, ring-contracted products (Scheme 183).528 For example, cyclohexanone enol ethers give cyclopentanes in 62-87% yield. 

Subsequently, certain authors (126-128) have supported this interpretation, but alternative explanations have also been proposed (129-132). Another early discussion of the stereochemistry of the enolization process was that of Vails and Toromanoff (133). They proposed that if stereoelectronic effects are an important parameter, the cyclohexanone enolate should react by two different pathways, one involving a chair-like transition state (443 444) and the other a boat-like transition state (443 445 446) Thus, both of these reactions proceed by perpendicular attack (134) of the electrophile. Their energy difference results from the difference in strain between the chair (444) and the twist-boat (445) forms. 

Lastly, in a very similar ring expansion process, bicyclic compounds, formed by reaction of mono- or dihalocarbenes with cyclohexanone enols, undergo ring expansion to give cyclohexenones (equation 194)1015-1017. 

Acidity constants (p-Kjjj) of cyclopentanone and cyclohexanone enols have been determined by the halogen-titration method from the variations of the enol + enolate sum as a function of pH (Bell and Smith, 1966). However, since the values of the keto-enol equilibrium constants are questionable, these pflra-values (11.8 and 11.3, respectively) are doubtful as well, although they are in fair agreement with those expected. 

The mechanism begins with the Michael addition of the cyclohexanone enolate to MVK, forming a 8-diketone. 

Thienolactam 205 was prepared from thioaroylketene 6, Ar-acctal 203, Hg(OAc)2, and cyclohexanone enol ether 204 in the presence of either tris(dimethylamino)(trimethylsilyl)sulfur difluoride (TASF), or TBAF, with a yield of 30% and 28%, respectively (Scheme 86 <2001J(P 1)2774>). 

Nucleophilic attack on ( -alkene)Fp+ cations may be effected by heteroatom nucleophiles including amines, azide ion, cyanate ion (through N), alcohols, and thiols (Scheme 39). Carbon-based nucleophiles, such as the anions of active methylene compounds (malonic esters, /3-keto esters, cyanoac-etate), enamines, cyanide, cuprates, Grignard reagents, and ( l -allyl)Fe(Cp)(CO)2 complexes react similarly. In addition, several hydride sources, most notably NaBHsCN, deliver hydride ion to Fp(jj -alkene)+ complexes. Subjecting complexes of type (79) to Nal or NaBr in acetone, however, does not give nncleophilic attack, but instead results rehably in the displacement of the alkene from the iron residue. Cyclohexanone enolates or silyl enol ethers also may be added, and the iron alkyl complexes thus produced can give Robinson annulation-type products (Scheme 40). Vinyl ether-cationic Fp complexes as the electrophiles are nseful as vinyl cation equivalents. ... 

An elegant synthesis of ( )-hirsutene (32) was developed by Cohen and coworkers . The key step of the synthesis is the one pot, completely stereoselective, oxidative cyclopen-tannulation of dienolate 31 with two equivalents of FeCls in dmf (equation 17). CuCl2 was also tested, but proved inferior. The formation of a single diastereoisomer of the triquinane intermediate (31 ) is useful and suggests that stereochemical equilibration may occur at some stage. This annulation procedure can also be extended to cyclohexanone enolates. 

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