Other Means of Generating Enolates

CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON. ENOLATES AND ENAMINES 

Regioselective silylation of ketones by in situ enolate trapping 

Trimethylsilyl enol ethers can also be cleaved by tetraalkylammonium fluoride (Entry 2) The driving force for this reaction is the formation of the very strong Si-F bond, which has a bond energy of 142 kcal/mol.31 These conditions, too, lead to enolate equilibration. 

Sugasawa, M. Shindo, H. Noguchi, and K. Koga, Tetrahedron Lett., 37, 7377 (1996). 

Generation and Properties of Enolates and Other Stabilized Carbanions 

The composition of the enol ethers trimethylsilyl prepared from an enolate mixture reflects the enolate composition. If the enolate formation can be done with high regio-selection, the corresponding trimethylsilyl enol ether can be obtained in high purity. If not, the silyl enol ether mixture must be separated. Trimethylsilyl enol ethers can be prepared directly from ketones. One procedure involves reaction with trimethylsilyl 

Trimethylsilyl enol ethers can also be prepared by 1,4-reduction of enones using silanes as reductants. Several effective catalysts have been found.24 The most versatile of these catalysts appears to be a Pt complex of divinyltetramethyldisiloxane.25 This catalyst gives good yields of substituted silyl enol ethers. 

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Dipyridyldisulfide has been used as the electrophilic reagent by Williams and co-workers in their studies directed toward the synthesis of bicyclomycin (82JA6092). The enolate of (124) was generated by means of lithium diisopropyl amide (LDA) in tetrahydrofuran (THF) at -78°C and added to a solution of 2,2 -dipyridyldisulfide. This gave (125) as a single regio- and stereoisomer in 80-95% yield. Contrary to expectation, the two side chains of the piperazinedione in (125) were disposed cis to each other. 

Another recent application of CID is the generation of anions which cannot be obtained easily by other means. For example, the unsubstituted vinyl (C2H ), 2-propenyl (CH3C=CH2), 1-propenyl (CH3CH=CH-) and cyclopropyl (CH2)2CH anions have been prepared by CID of the corresponding carboxylate anions through loss of carbon dioxide (Froelicher et al., 1986) and the dimethylsilanone enolate anion by CID loss of methane... 

While the greater nucleophilicity of azaenolates means that they will react with a wider range of electrophiles, their basicity, like that of lithium enolates, means that they will not react with SNl-reactive electrophiles like tertiary alkyl halides. The solution to this problem is to use silyl enol ethers, which are less reactive and so require a more potent electrophile to initiate reaction. Carbocations will do, and they can be generated in situ by abstraction of a halide or other leaving group from a saturated carbon atom. 

The reaction of diethyl malonate (90) with sodium hydride generates enolate anion 91 as the conjugate base, and hydrogen gas is the conjugate acid. It has the three resonance contributors shown in the illustration, although 91A has the highest concentration of electron density, and 91 will react as a carbanion nucleophile. There is one extra resonance form in the malonate enolate anion relative to a simple ester due to the second carbonyl unit, and it means that 91 is more stable than the enolate derived from a monoester. In part, this accounts for the enhanced acidity and easier formation of the enolate anion using a weaker base. Once formed, 91 is a carbon nucleophile and it will react with both aldehydes and ketones, as well as with other esters. 

An alternate approach, which also uses enzyme-catalyzed ring-opening of a lactone to generate a mechanism-activated inhibitor, was developed by Katzenellenbogen and his co-workers [183], who found enol lactones, exemplified by (13-8) and (13-9), to be potent, selective inhibitors of HLE. The haloenol lactone (13-9) was an irreversible inactivator of HLE and chymotrypsin, and after exposure to (13-9), active enzyme could not be regenerated even upon treatment with hydrazine. Enol lactone (13-8), on the other hand, was an alternate-substrate inhibitor, which produced only transient inhibition of HLE and chymotrypsin. These results have been interpreted to mean that, with the halo-substituted compounds, ring opening results in formation of an acyl-enzyme that contains a reactive halomethyl ketone, which then alkylates His-57. That these compounds... 

One possible reaction for 60 is an intramolecular condensation with the other carbonyl (see Chapter 22, Section 22.6, for reactions of this type), but that would lead to a four-membered ring product, 61. The activation barrier to form this strained ring is high, so this reaction is slow (see Chapter 8, Section 8.5.3). The reaction conditions favor thermodynamic control (protic solvent, hydroxide, heat see Chapter 22, Section 22.4.2), which means that enolate anion 60 is in equilibrium with the neutral diketone. Further reaction with hydroxide generates the kinetic enolate anion 62 as part of the equilibrium mixture. If 62 attacks the carbonyl in an intramolecular aldol reaction (Chapter 22, Section 22.6), a six-membered ring is formed (63) in a rapid and highly favorable process. 

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