Cyclohexanones deprotonation

A number of studies of the acid-catalyzed mechanism of enolization have been done. The case of cyclohexanone is illustrative. The reaction is catalyzed by various carboxylic acids and substituted ammonium ions. The effectiveness of these proton donors as catalysts correlates with their pK values. When plotted according to the Bronsted catalysis law (Section 4.8), the value of the slope a is 0.74. When deuterium or tritium is introduced in the a position, there is a marked decrease in the rate of acid-catalyzed enolization h/ d 5. This kinetic isotope effect indicates that the C—H bond cleavage is part of the rate-determining step. The generally accepted mechanism for acid-catalyzed enolization pictures the rate-determining step as deprotonation of the protonated ketone ... 

The reaction of a cyclic ketone—e.g. cyclohexanone 1—with methyl vinyl ketone 2 resulting in a ring closure to yield a bicyclic a ,/3-unsaturated ketone 4, is called the Robinson annulation This reaction has found wide application in the synthesis of terpenes, and especially of steroids. Mechanistically the Robinson annulation consists of two consecutive reactions, a Michael addition followed by an Aldol reaction. Initially, upon treatment with a base, the cyclic ketone 1 is deprotonated to give an enolate, which undergoes a conjugate addition to the methyl vinyl ketone, i.e. a Michael addition, to give a 1,5-diketone 3 ... 

For cyclic ketones conformational factors also come into play in determining enolate composition. 2-Substituted cyclohexanones are kinetically deprotonated at the C(6) methylene group, whereas the more-substituted C(2) enolate is slightly favored... 

Such enantioselective deprotonations depend upon kinetic selection between prochiral or enantiomeric hydrogens and the chiral base, resulting from differences in diastere-omeric TSs.27 For example, transition structure E has been proposed for deprotonation of 4-substituted cyclohexanones by base D.28 This structure includes a chloride generated from trimethylsilyl chloride. 

The stereoselective intramolecular Henry reactions have been reported by Seebach. The Michael addition of doubly deprotonated acetyl acetaldehyde to l-methylenedioxyphenyl-2-nitroethene followed by subsequent intramolecular nitro-aldol cyclization leads to the diastereomerically pure cyclohexanone derivative, where the nitro and OH groups are cis as shown in Eq. 3.73.114 This reaction is applied to the synthesis of l-desoxy-2-lycorinone as shown in Eq. 3.74.115... 

Before the emergence in the mid-1980s of the asymmetric deprotonation of cA-dimethyl cyclohexanone using enantiomerically pure lithium amide bases, few reports pertaining to the chemistry of these chiral reagents appeared. Although it is not the focus of this chapter, the optically active metal amide bases are still considered to be useful tools in organic synthesis. Readers are advised to consult the appropriate literature on the application of enantiomerically pure lithium amides in asymmetric synthesis.6... 

The loss of optical activity accompanying deprotonation of (/f)-2,2,6-trimethyl-cyclohexanone by lithium diisopropylamide (LDA, which exists as a dimer) in THF is governed by the rate equation v = /c [ketone] [LDA]°-, which is consistent with a rate-determining proton transfer involving amine monomer. ... 

Scheme 37a illustrates a carbamate substrate that has three possible sites for deprotonation the benzylic sites a to either nitrogen or oxygen and the methylene attached to nitrogen. Of these three, the site least likely to deprotonate is the latter. Scheme 37b shows that this organolithinm, inaccessible by deprotonation, can be made readily by tin-lithium exchange. The derived organolithinm compound can be added to electrophiles snch as cyclohexanone in good yields. 

It is also possible to achieve enantioselective enolate formation by using chiral bases. Enantioselective deprotonation requires discrimination between two enantiotopic hydrogens, such as in (7.v-2,6-dirncthylcyclohcxanonc or 4-(/-butyl)cyclohexanone. 

Since the bases used for the metallation of the acetylenes are much stronger (in a thermodynamic sense) than the acetylides, the deprotonations are essentially complete, a condition that has to be met for most functionalization reactions. Some ethynyladons form an excepdon. Ethynylcyclohexanol, for example, can be obtained in yields greater than 90% by adding cyclohexanone to a suspension of potassium acetylide (or even KOH) in THF while introducing acetylene [2], The farmadon of potassium acetylide is likely to be an equilibrium ... 

Substituted cyclohexanones, bearing a methyl, isopropyl, tert-butyl or phenyl group, give, on deprotonation with various chiral lithium amides in the presence of chlorotrimethylsilane (internal quench), the corresponding chiral enol ethers with moderate to apparently high enantioselec-tivity and in good yield (see Table 2)13,14,24> 29 36,37,55. Similar enantioselectivities are obtained with the external quench " technique when deprotonation is carried out in the presence of added lithium chloride (see Table 2, entries 5, 10, and 30)593. 

The feasibility of a deprotonation of cyclohexanone derivatives bearing a chiral heterocyclic substituent in the 4-position with the C2-symmetric base lithium bis[(/f)-l-phenylethyl]amide with internal quenching of the lithium enolate formed with chlorotrimethylsilane is shown in entries 32 and 33 of Table 229,25a. The silyl enol ethers are obtained in a diastereomeric ratio of 79.5 20.5. By using lithium bis[(1S)-l-phenylethyl]amide the two diastereomers are formed in a ratio of 20 80 indicating that the influence of the chirality of the substituent is negligible. 

Enantioselective deprotonation can also be successfully extended to 4,4-disubstituted cyclohexanones. 4-Methyl-4-phenylcyclohexanone (3) gives, upon reaction with various chiral lithium amides in THF under internal quenching with chlorotrimethylsilane, the silyl enol ether 4 having a quaternary stereogenic carbon atom. Not surprisingly, enantioselectivities are lower than in the case of 4-tm-butylcyclohexanone. Oxidation of 4 with palladium acetate furnishes the a./i-unsaturated ketone 5 whose ee value can be determined by HPLC using the chiral column Chiralcel OJ (Diacel Chemical Industries, Ltd.)59c... 

Enantioselective deprotonation of 4-(p-tolyl)-4-methyl cyclohexanone with lithium bis[(S)-l-phenylethyl]amide in THF at 100 C in the presence of chlorotrimethylsilane gives (R)-4-methyl-4-... 

Asymmetric deprotonation of monocyclic cycloalkanones is not restricted to cyclohexanones. Thus, deprotonation of 3-phenylcyclobutanone with lithium bis[(S)-l-phenylethyl]amide in THF at — 100 °C in the presence of chlorotriethylsilane affords (—)-(/ )-3-pheny 1-1 -(triethylsi-lyloxy)-l-cyclobutene with 92% ee in 70% yield59d. Interestingly, with lithium (/ )-2,2-dimethyl-A-[( / )-2-(4-methyl-l-piperazinyl)-l-phenylethyl]propylamidc in THF/HMPA an ee value of only 47 % for the enol ether is recorded. 

Enantioselective deprotonation has also been used for the kinetic resolution of 2-substituted cyclohexanones rac-298. This procedure has been applied to a number of related cyclohexanones and a high level of enantioselectivity has been obtained. 

Cyclohexanone derived imines are deprotonated using LDA under standard conditions ( — 20 °C, THF, 1 h)7, then treated with the appropriate alkyl halide to provide, after hydrolysis, the 2-alkylcyclohexanones (see Table 2). 

To circumvent side reactions and racemization of the chiral auxiliary in metalation reactions of cyclohexanone imines derived from the tert-butyl esters of valine and tm-leucine, deprotonation is performed using LDA at low temperatures (— 78 °C, THF, 0.5 h). 

Alkylation of cyclohexanone imines derived from /i-methoxy-a-phenylbenzeneethanamine depends on the metal and the temperature. In order to generate zinc azaenolates, deprotonation is performed under optimized conditions (LDA, THF. —23 "C, 1 h) followed by the addition of zinc bromide and refluxing for 0.5 hours16. Alkylation of these azaenolates proceeds best at 0 C at lower temperatures ( — 78 C) yields are drastically decreased. 

Magnesium amides have also found good utility in enantioselective deprotonation processes. A range of chiral amines has been prepared by Henderson and coworkers and it was found after conversion to their Mg-bisamide derivatives that it react with 4- and 2,6-substituted cyclohexanones with good to excellent selectivities (see Section m). Structures of some chiral magnesium amides are given in Chart 1. 

Deprotonation of carbonyl compounds by chiral amide bases followed by trapping with silylating agents or aldehydes has become a common method for de-symmetrizing prochiral and conformationally locked 4-substituted cyclohexanones and bicyclic ketones. The literature through 1997 has been reviewed [45]. 

Deprotonation at room temperature leads to the thermodynamically more stable enoiate 20. Treatment with methyl iodide produces cyclohexanone 7 doubly methylated in the 2-position (see Chapter 12). 

An eight-membered cyclic transition has been proposed to account for the enantioselectivity observed on deprotonation of 4-substituted cyclohexanones by chiral bidentate lithium amides in THF, in presence of excess Me3 SiCl.132... 

Another concise route to 107 featured the facile construction of the cyclohexanone derivative 109 via the Michael addition of triply deprotonated methyl dioxohexanoate to the nitrostyrene (108 (Scheme 9) (115). Ketalization of 109 followed by hydrogenation of the nitro function and then cyclization of the resulting amino ester by thermolysis in refluxing xylene furnished the lactam 110, which was reduced LiAlH4 to the amine 111. All attempts to cyclize 111 via a Pictet-Spengler reaction led to complex mixtures of products. However, when the unstable enone 112, which was obtained by acid-catalyzed hydrolysis of 111,... 

An alternative approach that we examined involved the conceptual joining of the terminal ends of both the 2 and 6 substituents of requisite cyclohexanone 12 (Eq. 5).27 For example, known bicyclo[3.2.1]nonenone 1358 is incapable of deprotonation by the olefination reagent and indeed bis(trimethylsilyl)methyllithium55 provided pivotal vinyl silane 14 (Eq. 6). 

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