Acylation of enolate anions

Now this is exactly the same situation we encountered when we compared the reactivity of aldehydes and ketones with that of carboxylic acid derivatives (see Section 7.8). The net result here is acylation of the nucleophile, and in the case of acylation of enolate anions, the reaction is termed a Claisen reaction. It is important not to consider aldol and Claisen reactions separately, but to appreciate that the initial addition is the same, and differences in products merely result from the absence or presence... 

T. H. Black, Recent Progress in the Control of Carbon Versus Oxygen Acylation of Enolate Anions , Org. Prep. Pmced. Int. 1988, 21, 179-217. 

The combination of fluoride ions and enol silyl ethers provides a useful method for the generation of enolate anions [9]. Watts, Haswell and coworkers applied a borosilicate glass microreactor, having channel dimensions of 100 pm x 50 pm and equipped with an electrosmotic flow (EOF) pumping system, to the C-acylation of enolate anions, which leads to 1,3-diketones [10,11]. A THF solution of tetrabutyl-ammonium fluoride (TBAF) was placed in reservoir A, a THF solution of benzoyl... 

Control of carbon versus oxygen acylation of enolate anions of heterocyclic carbonyl derivatives 890PP179. 

Complementary to the acylation of enolate anions is the acid-catalyzed acylation of the corresponding enols, where the regiochemistry of acylation can vary from that observed in base-catalyzed reactions. Although the reaction has been studied extensively in simple systems, it has not been widely used in the synthesis of complex molecules. The catalysts most frequently employed are boron trifluoride, aluminum chloride and some proton acids, and acid anhydrides are the most frequently used acylating agents. Reaction is thought to involve electrophilic attack on the enol of the ketone by a Lewis acid complex of the anhydride (Scheme 58). In the presence of a proton acid, the enol ester is probably the reactive nucleophile. In either case, the first formed 1,3-dicarbonyl compound is converted into its borofluoride complex, which may be decomposed to give the 3-d>ketone, sometimes isolated as its copper complex. 

Higher Alkyl Cyanoformates. A range of other alkyl cyanoformates has been successfully utilized for the acylation of enolate anions, including ethyl, allyl, benzyl, and p-methoxybenzyl, but not r-butyl cyanoformate, which appears to be insufficiently reactive. Enantiomerically enriched cyanoformates derived from (+)-menthol, (-)-bomeol, and the Oppolzer alcohol were reported to furnish good chemical yields, but the level of enantioselectivity was disappointingly low (eq 18). ... 

Anions derived from malonates are ambident nucleophiles, which can react at the carbon or oxygen atom. Therefore, carbon-carbon bond-forming reactions by alkylation or acylation of enolates have been encountered with difficulties. Side reactions which may cause problems are the above-mentioned competiting O-reaction and dialkylation . 

Several important reactions of arenols involve aromatic substitution of arenolate ions with carbon electrophiles. In a sense, these reactions are alkylation and acylation reactions as discussed for arenes (Sections 22-4E and 22-4F). In another sense, they are alkylation and acylation reactions of enolate anions and therefore could give rise to products by C- and O-alkyla-tion, or C- and O-acylation (Section 17-4). Thus ... 

Alkylation and acylation of ketones and nitriles. DMSO greatly enhances the rate of alkylation of enolate anions. " Dialkylation of malononitrile and of pentane-2,4-... 

Alkylation of enolate anions usually gives C-alkylation and is therefore not suitable for the preparation of enol ethers. The exception is when triethyloxonium tetrafluoroborate is used as the alkylating agent in a dipolar aprotic solvent. 0-Alkylation can be regioselectiveiy achieved if the enolate anion is derived from acetoacetate or a similar compound. On the other hand, 0-acylation of enols or enolate anions is quite common. Enol esters can therefore be prepared readily from the parent carbonyl compounds. For... 

Enolates formed by organocopper conjugate addition may be acylated cleanly by acid chlorides to give 3-diketones.146 Although O- and C-acylation are both possible, the latter is favored by the use of acid chlorides rather than anhydrides and by the use of diethyl ether as solvent, rather than DME. Good yields of 3-diketones have been obtained by acylation of the anions derived from both acyclic and cyclic unsaturated ketones with cuprates, or in copper-catalyzed Grignard reactions. Some synthetic applications are given in Scheme 54. 

The condensation reaction of enolate anions and carbonyl derivatives is one of the most useful of all reactions in organic chemistry. The condensation is nothing more than an acyl addition reaction of the nucleo-... 

This chapter will discuss carbanion-like reactions that utilize enolate anions. The acid-base reactions used to form enolate anions will be discussed. Formation of enolate anions from aldehyde, ketones, and esters will lead to substitution reactions, acyl addition reactions, and acyl substitution reactions. Several classical named reactions that arise from these three fundamental reactions of enolate anions are presented. In addition, phosphonium salts wiU be prepared from alkyl halides and converted to ylids, which react with aldehydes or ketones to form alkenes. These ylids are treated as phosphorus-stabilized car-banions in terms of their reactivity. 

The acyl addition and acyl substitution reactions of enolate anions presented in this chapter clearly show that enolate anions are nucleophiles. In Chapter 11 (Section 11.3), various nucleophiles reacted with primary and secondary alkyl halides via Sn2 reactions. Enolate anions also react with alkyl halides via 8 2 reactions in what is known as enolate alkylation. 

Ethers are relatively unreactive and will not react in an acyl addition reaction or with the reactions of enolate anions. However, when a benzyl ether is treated with hydrogen gas and a palladium catalyst, hydrogenolysis leads to 2-butanol and toluene (see Chapter 19, Sections 19.3.4,19.3.5, and Chapter 21, Section 21.6, for hydrogenolysis). The benzyl ether is a good projecting group for an alcohol and a few other ethers may also be used. 

Thio- and Seleno-Carbonyl Compounds.—a-Arylthio- and a-alkylthio-carbonyl compounds have become established synthons in organic chemistry. A new regio-specific route to a-phenylthioketones (an alternative to direct thiolation of enolate anions ) involves the treatment of an aldehyde with a lithio a,a-bisthiophenyIal-kane, and aqueous acid-promoted decomposition of the adduct (Scheme 8). Alternatively, trifluoroacetic acid treatment of the bisphenylthioalkanols leads to the elimination of diphenyl disulphide and the formation of simple ketones in the latter sequence, the lithiated bisphenylthioalkanes act as acyl anion equivalents (Scheme 8). ... 

The most generally used carbonyl compounds for the acylation of enolate ions are esters. Here, nucleophilic addition of the anion to the carbonyl group is followed by loss of alkoxide from the tetrahedral intermediate. A classic example of this type of reaction is the Claisen condensation—the base-catalyzed self-condensation... 

Even though ketones have the potential to react with themselves by aldol addition recall that the position of equilibrium for such reactions lies to the side of the starting materials (Section 18 9) On the other hand acylation of ketone enolates gives products (p keto esters or p diketones) that are converted to stabilized anions under the reaction conditions Consequently ketone acylation is observed to the exclusion of aldol addition when ketones are treated with base m the presence of esters... 

Acetylenedimagnesium bromide, 66, 84, 137 Acyl-alkyl diradical disproportionations, 299 Acyl-alkyl diradical recombination, 296 Alkaline hydrogen peroxide, 10, 12, 20 Alkylation of formyl ketones, 93 Alkylation via enolate anions, 86 17a-Alkynyl steroids from 17-ketones, 67 2a-Al]yl-17jS-hydroxy-5a-androstan-3 -one, 9 5 Allylic acetoxylation, 242 Allylmagnesium bromide, 64 17 -Aminoandrost-5-en-3 -ol, 145 17 a-Aminomethy 1-5 a-androstane-3, 1718-diol, 387... 

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