Enolate anions from enol acetates

The reactions of ketenes or ketene equivalents with imines, discussed above, all involve the imine acting as nucleophile. Azetidin-2-ones can also be produced by nucleophilic attack of enolate anions derived from the acetic acid derivative on the electrophilic carbon of the imine followed by cyclization. The reaction of Reformatsky reagents, for example... 

If the violet color of the reaction solution is completely discharged, indicating that all the methyllithium has been consumed, addition of the enol acetate should be stopped at that point. The actual concentration of enolate anion in the solution can be calculated from the amount of enol acetate added. 

In Box 10.12 we saw that nature employs a Claisen reaction between two molecules of acetyl-CoA to form acetoacetyl-CoA as the first step in the biosynthesis of mevalonic acid and subsequenfiy cholesterol. This was a direct analogy for the Claisen reaction between two molecules of ethyl acetate. In fact, in nature, the formation of acetoacetyl-CoA by this particular reaction using the enolate anion from acetyl-CoA is pretty rare. 

A kind of enolic component we haven t mentioned yet is the acid anhydride. If you wanted to make the enolate anion from acetic anhydride, what base would you recommend ... 

Nucleophilic addition to the neutral activated acyl group is a favored process, and coenzyme A is a good leaving group from the tetrahedral intermediate. The occurrence of this process with the acetate anion, that is, acetate reacting with an enolate anion, again provides a sharp contrast with the... 

Considerable use has also been made of allyl carbonates as substrates for the allylation of Pd enolates.9 The reaction of Pd° complexes with allyl enol carbonates119,120 proceeds by initial oxidative addition into the allylic C—O bond of the carbonate followed by decarboxylation, yielding an allylpalladium enolate, which subsequently produces Pd° and the allylated ketone (equation 22). In like fashion, except now in an intermolecular sense, allyl carbonates have been found to allylate enol silyl ethers (equation 23),121 enol acetates (with MeOSnBu3 as cocatalyst) (equation 24),122 ketene silyl acetals (equation 25)123 and anions a to nitro, cyano, sulfonyl and keto groups.115,124 In these cases, the alkoxy moiety liberated from the carbonate on decarboxylation serves as the key reagent in generating the Pd enolate. 

So the synthesis could be done in one step by making the anion of methyl acetate and reacting it with bromocyclohexane. The polarities of the reaction partners match nicely, but the problem is that alkylations of secondary bromides with enolates often give poor yields. The enolate is a strong base, which promotes elimination in the secondary bromide rather than giving the substitution product needed in the synthesis. Thus elimination from cyclohexyl bromide to cyclohexene would be a major process if the reaction were attempted. While the retrosynthetic step seems reasonable, the synthetic step has known difficulties. It is important to work backward in the retrosynthetic analysis and then check each forward step for validity. 

By analogy, the chemical Claisen condensation using the enolate anion from diethyl malonate in Figure 2.10 proceeds much more favourably than that using the enolate from ethyl acetate. The same acetoacetic acid product can be formed in the malonate condensation by hydrolysis of the acylated malonate intermediate and decarboxylation of the gem-diacid. 

The synthesis of this starting material 73 X = SMe also uses interesting strategy. The first step was a Diels-Alder reaction between a cyelopentadiene 77 and the dienophile 62 used by Nicolaou in his taxol synthesis. The diene was made from the anion of cyclopentadiene 74 and ethyl formate,18 and the enolate 76 transformed into the enol acetate 77. Diels-Alder addition of 62 and hydrolysis of the enol ester gave the adduct19 78. 

The search for endothelin antagonists as potential compounds for treating cardiovascular disease was noted in Chapter 5 (see atrasentan). A composed with a considerably simpler structure incorporates a pyrimidine ring in the side chain. Condensation of benzophenone (94) with ethyl chloro-acetate and sodium methoxide initially proceeds to addition of the enolate from the acetate to the benzophenone carbonyl. The aUcoxide anion on the first-formed quaternary carbon then displaces chlorine on the acetate to leave behind the oxirane in the observed product (95). Methanolysis of the epoxide in the product in the presence of boron triflor-ide leads to the ether-alcohol (96). Reaction of this with the pyrimidine (97) in the presence of base leads to displacement of the methanesulfonyl group by the aUcoxide from 96. Saponification of the ester group in that product gives the corresponding acid, ambrisentan (98). " ... 

The enol acetates, in turn, can be prepared by treatment of the parent ketone with an appropriate reagent. Such treatment generally gives a mixture of the two enol acetates in which one or the other predominates, depending on the reagent. The mixtures are easily separable.An alternate procedure involves conversion of a silyl enol ether (see 12-17) or a dialkylboron enol ether (an enol borinate, see p. 645) to the corresponding enolate anion. If the less hindered enolate anion is desired (e.g., 126), it can be prepared directly from the ketone by treatment with LDA in THE or 1,2-dimethox-yethane (DME) at... 

C-aryl glycosides, 528 C-glycosides, 528 C-glycoside synthesis, 505 fronj enol ethers, 505 by free-radical methods, 507 from ketene acetals, 505 from malonate anion, 505 from 2-pyridylthio glycosides, 385... 

Organolithium con imds also react with acetals or oithoesters in the presence of BF3-OEt2. Dialkoxymethylations of lithium enolates with triethyl orthoformate are carried out by adding BF3-OEt2 to the mixture (equation 45). Prior mixture of an enolate and the Lewis acid results in a drastic decrease of the product yield. Lithium enolates are generated from silyl enol ethers and MeLi, and C—C bond formation proceeds legiospecifically with respect to the enolates. The condensation is applicable to a fully substituted enolate. Butenolide anions add to acetals or orthoesters pretreated with BF3-OEt2 at the C-S position (equation 46). ... 

House and Trost prepared an approximately IM solution of this reagent in 1,2-dimethoxyethane for use in an extensive study of compositions of enolate anions from ketones and enol acetates as follows. The solvent was removed from 15 ml. of a 1 Af ethereal solution of methyllithium under reduced pressure, and the residual solid was dissolved in 15 ml. of 1,2-dimethoxyethane. Triphenylmethane (18.3 mmoles) was added, and the mixture stirred under nitrogen until a test for methyl-lithium was negative. Reaction of an enol acetate with trityllithium can then be carried out as a titration and stopped when the solution is pale pink. 

In this section, we examine the formation of an enolate anion from one ester, followed by the nucleophilic acyl substitution of the enolate anion at the carbonyl carbon of another ester. One of the first of these reactions discovered was the Claisen condensation, named after its discoverer, German chemist Ludwig Qaisen (1851—1930). We illustrate a Claisen condensation by the reaction between two molecules of ethyl acetate in the presence of sodium ethoxide, followed by acidification, to give ethyl acetoacetate (note that, in this and many of the equations that follow, we abbreviate the ethyl group as Et) ... 

The above example illustrates the influence of the fS-stabdizing effect of silicon, which is well known for reactions involving carbocationic intermediates [70]. In contrast, less is known about the P-destabiUzing effect of siHcon on aUyic anions. In the present example, an allylic alkoxy anion is generated with methoxide from the silyl-substituted enol acetates 214 and 217 (Scheme 3.46) [71]. 

Davis and coworkers have exploited the reactions of chiral JV-sulfinyl-amines in the synthesis of numerous alkaloids. Their route to (—)-epimyr-tine (1098) began with the diastereoselective addition of the enolate anion of methyl acetate to the (Ss)-(4-)-sulfmimine (+)-1128, from which the (Ss,S)-p-amino ester derivative (- -)-1129 was obtained in better than 97% de (Scheme 144). After Claisen condensation of 1129 with ierf-butyl acetate, the sulfmyl group was removed from the resulting P-keto ester (4-)-1130 by treatment with acid, the desuhinylated product then undergoing Mannich cyclization with acetaldehyde. The relative stereochemistry of the sole product, 2,6-a5-disubstituted piperidine (4-)-1131, was corroborated by nOe experiments, which indicated that no epimerization at the stereogenic centers had occurred. After hydrolysis and decarboxylation of... 

Fused Heteroaromatic Compounds.— The halogen in 4-chloroquinoline is readily replaced by the enolate anions from isopropylidine alkylmalonates and acetic anhydride in the presence of the heterocycle acylation of the nitrogen provides the necessary activation of the system. Attempted overall methylation of 2-methylquinoline by MeSOCH2 and DMSO gives only a minute amount of the... 

Silyl enol ethers are other ketone or aldehyde enolate equivalents and react with allyl carbonate to give allyl ketones or aldehydes 13,300. The transme-tallation of the 7r-allylpalladium methoxide, formed from allyl alkyl carbonate, with the silyl enol ether 464 forms the palladium enolate 465, which undergoes reductive elimination to afford the allyl ketone or aldehyde 466. For this reaction, neither fluoride anion nor a Lewis acid is necessary for the activation of silyl enol ethers. The reaction also proceed.s with metallic Pd supported on silica by a special method[301j. The ketene silyl acetal 467 derived from esters or lactones also reacts with allyl carbonates, affording allylated esters or lactones by using dppe as a ligand[302]... 

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