Cyclohexanones, alkylation preference

Their stability at low temperature means that lithium enolates are usually preferred, but sodium and potassium enolates can also be formed by abstraction of a proton by strong bases. The increased separation of the metal cation from the enolate anion with the larger alkali metals leads to more reactive but less stable enolates. Typical very strong Na and K bases include the hydrides (NaH, KH) or amide anions derived from ammonia (NaNH2, KNH2) or hexamethyldisilazane (NaHMDS, KHMDS). The instability of the enolates means that they are usually made and reacted in a single step, so the base and electrophile need to be compatible. Here are two examples of cyclohexanone alkylation the high reactivity of the potassium enolate is demonstrated by the efficient tetramethylation with excess potassium hydride and methyl iodide. 

Dicyclohexylarnine may be selectively generated by reductive alkylation of cyclohexylamine by cyclohexanone (15). Stated batch reaction conditions are specifically 0.05—2.0% Pd or Pt catalyst, which is reusable, pressures of 400—700 kPa (55—100 psi), and temperatures of 75—100°C to give complete reduction in 4 h. Continuous vapor-phase amination selective to dicyclohexylarnine is claimed for cyclohexanone (16) or mixed cyclohexanone plus cyclohexanol (17) feeds. Conditions are 5—15 s contact time of <1 1 ammonia ketone, - 3 1 hydrogen ketone at 260°C over nickel on kieselguhr. With mixed feed the preferred conditions over a mixed copper chromite plus nickel catalyst are 18-s contact time at 250 °C with ammonia alkyl = 0.6 1 and hydrogen alkyl = 1 1. 

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. ... 

The anion of cyclohexanone /V,/V-dimclhyl hydrazone shows a strong preference for axial alkylation.122 2-Methylcyclohexanone N,N-dimethylhydrazonc is alkylated by methyl iodide to give d.v-2,6-dimclhylcyclohcxanone. The 2-methyl group in the hydrazone occupies a pseudoaxial orientation. Alkylation apparently occurs anti to the lithium cation, which is on the face opposite the 2-methyl substituent. 

The E-boron enolate from cyclohexanone shows a preference for the anti aldol product. The ratio depends on the boron alkyl groups and is modest (2 1) with di-n-butylboron but greater than 20 1 for cyclopentyl- -hexylboron.16... 

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. 

Chiral sulfinimines 236 are very useful intermediates for the preparation of enantiomer-ically pure primary amines 237 (equation 158) . This reaction has been applied to the synthesis of a-amino acids . For sulfinimines obtained from simple ketones, lithium reagents are preferable for the addition , while for cyclic ketones organomagnesium compounds gave the best results. Addition of alkyl and aryl Grignard compounds to sulfinimines, derived from 3- and 4-substituted cyclohexanones, proceeds with excellent diastereoselectivity, depending on the stereochemistry of the ring substituents rather than the sulfinyl group . 

With alkyl methyl ketones (R-CH2,CO,Me) the reaction is complicated by the presence of two alternative sites of oxidation in practice the methyl group appears to be oxidised in preference to the methylene group for reasons which have not been adequately clarified, but in any case the yields are usually poor. Unsubstituted, or symmetrically substituted cyclic ketones possessing of course an a-methylene group, are similarly converted into 1,2-diketones (e.g. the formation of cyclohexane-l,2-dione from cyclohexanone, Expt 5.99, cognate preparation) unsymmetrically substituted cyclic ketones would normally give rise to regioisomers. 

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. 

Pyridine A-oxides are readily deprotonated at C(2) using LDA or -butyllithium as base in THF and the reagents thus produced react in the usual way in high yields with a variety of electrophiles including iodine, alkyl halides, aldehydes, and ketones < 1995J(P 1 )2503>. For example, -lithio derivative 361 can be generated and intercepted by various electrophiles, e.g., carbon dioxide, elementary sulfur, or cyclohexanone giving 362 note that the lithiation prefers the carbon to the oxide rather than that ortho to the chlorine. 

The stereochemistry of addition of an allylic organozinc reagent to a carbonyl group has received considerable attention. Both diallyl- and dicrotylzinc in their reactions with alkyl-substituted cyclohexanones display a strong preference for equatorial attack (formation of the rfl -alcohol) on the carbonyl group (5, 6), e.g.,... 

The hydroxylation of cyclohexane, of potential interest for the production of cyclohexanone, is exceedingly slow at near room temperature and has low selectivity at 100 °C [27, 28]. Tertiary C—H bonds yield tertiary alcohols, with little or no oxidation observed at the secondary carbons that may be present in the alkyl chain t-C—H sec-C—H (Table 18.3). The steric constraints introduced by alkyl substitution strongly favor the competition of side reactions, at the expense of hydroxylation. On arylalkanes, oxidation occurs on both the aromatic ring and the alkyl chain, with a general preference for the latter. Consistently, the competitive hydroxylation of benzene and n-hexane or cyclohexane mainly occurs on the alkane. However, benzylic methyls, despite the relative weakness of their C—H... 

Enolates derived from cyclic compounds such as cyclohexane carboxylic acid or cyclohexane carboxalde-hyde generate enolates that are unique. These enolates have an exocyclic double bond that can exist as ( ) and (Z) isomers. The facial and orientational bias in alkylation and condensation reactions of such enolates is influenced by the conformation of the ring it is attached to. Alkylidene cyclohexane enolates show a preference for equatorial attack, just as cyclohexanone derivatives do (sec. 4.7.C,D). 

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