Enolate anions, acylation alkylation

We have described what is commonly known as the acetoacetic ester synthesis and have illustrated the use of ethyl acetoacetate as the starting reagent. This same synthetic strategy is applicable to any j8-ketoester, as, for example, those that are available by the Claisen (Section 19.3A) and Dieckmann (Section 19.3B) condensations. For example, following are structural formulas for two jS-ketoesters available from Dieckmann and Claisen condensations that can be made to tmdergo (1) formation of an enolate anion, (2) alkylation or acylation, (3) hydrolysis followed by (4) acidification, and finally (5) decarboxylation just as we have shown for ethyl acetoacetate. 

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... 

Undesirable intermolecular reactions can be avoided during certain synthetic conversions. Thus it is often useful to carry out C-alkylation and C-acylation of compounds that form enolate anions, for example, esters with a-hydrogens. Such reactions are often complicated by self-condensation since the enolate anion can attack the carbonyl group of a second ester molecule. Attachment of the enolizable ester to a polymer support at low loading levels allows the alkylation and acylation reactions (Eq. 9-79) to be performed under... 

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 ... 

While the addition-oxidation and the addition-protonation procedures are successful with ester enol-ates as well as more reactive carbon nucleophiles, the addition-acylation procedure requires more reactive anions and the addition of a polar aptotic solvent (HMPA has been used) to disfavor reversal of anion addition. Under these conditions, cyano-stabilized anions and ester enolates fail (simple alkylation of the carbanion) but cyanohydrin acetal anions are successful. The addition of the cyanohydrin acetal anion (71) to [(l,4-dimethoxynaphthalene)Cr(CO)3] occurs by kinetic control at C-P in THF-HMPA and leads to the a,p-diacetyl derivative (72) after methyl iodide addition, and hydrolysis of the cyanohydrin acetal (equation 50).84,124-126... 

The enolization process, i,e. conversion of a carbonyl compound such as 438 into the intermediate enol 439 or enolate anion 440 is an important reaction in organic chemistry because these intermediates can further react with electrophiles to undergo either protonation, halogenation, alkylation, aldo-lization, or acylation type reactions. 

Because of the contribution of structures such as the one on the right to the resonance hybrid, the a-carbon of an enamine is nucleophilic. However, an enamine is a much weaker nucleophile than an enolate anion. For it to react in the SN2 reaction, the alkyl halide electrophile must be very reactive (see Table 8.1). An enamine can also be used as a nucleophile in substitution reactions with acyl chlorides. The reactive electrophiles commonly used in reactions with enamines are ... 

The formation constants of an actinium isopropyltropolonate complex were determined. Thermochemically relevant studies of thorium enolates generally involve bis(pentamethyl-cyclopentadienyl)thorium derivatives. Cp 2Th(Cl)(C(0)CFl2Bu-f) with an anionic acyl group that readily rearranges to the isomeric enolate Cp 2Th(Cl)OCH=CHBu-t. The Z-isomer is formed upon heating and the -isomer upon catalysis with Cp 2ThH2. Is the E or Z enolate thermodynamically more stable For the simple alkyl enolates MeCH=CHOR, the equilibration reaction of the Z- and E-isomers is nearly thermo-neutral . Consider the two species Cp 2Th(H)OCH(Bu-t)2 and Cp 2Th(H)0-2,6-C6H3 (Bu-f)2. The reversible addition of CO yields the rp- formyl derivative in reactions that are 19 4 and 25 6 kJmoR exothermic. These formyl species dimerize to form the classical enediolate, Cp 2Th(OR)OCH=CHO(OR)ThCp 2. This product is formed as the Z-isomer, plausibly thermodynamically preferred over the -isomer, much as (Z)-MeOCH=CHOMe is preferred over its E-counterpart by 6.0 0.2 kJmoR. ... 

The copper-mediated 1,4-addition of alkyl groups to a,P-unsaturated ketones affords regiochemically pure enolate anions (see also Section 7.5) which may be trapped at oxygen with silyl halides, acyl halides, or dialkylcarbonates to provide silyl enol ethers, enol acetates, or enol carbonates, respectively. These can be unmasked at a later stage by reaction with MeLi to regenerate the enolate for further elaboration. ... 

Alkylation or acylation of ketones, sulfides, and amines. This reagent generally reacts with alcohols or carboxylic acids to form 2,2,2-trifluoroethyl ethers or esters in satisfactory yields, except in the case of alcohols prone to dehydration. The reaction of these ethers provides a simple synthesis of unsymmetrical sulfides (equation I). A similar reaction can be used for preparation of secondary amines or amides (equation II). Enolate anions (generated from silyl enol ethers with KF) can be alkylated or acylated with a or b (equation III). Use of Grignard reagents in this type of coupling results in mediocre yields. 

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... 

For acylations with reactive esters, such as formate or oxalate (see Section 3.6.4.5), sodium alkoxides are still the bases of choice, but sodium hydride, dimsyl sodium, sodium or potassium amide or sodium metal have all been used for the in situ generation of the enolate anion. A typical example is shown in Scheme 47. Acylation by esters results in the production of 1 equiv. of the alkoxide ion, along with the p-dicarbonyl compound proton transfer then results in the production of the conjugate base of the dicarbonyl compound. This process normally leads to the more stable anion in the acylation of an unsymme-trical ketone. The acyl group thus becomes attached to the less-substituted a-position of the ketone. The less stable 0-acylated products are normally not observed in such reversible base-catalyzed reactions. Methyl alkyl ketones are normally acylated on the methyl group where both a-carbons are substituted to the same extent, acylation occurs at the less-hindered site. Acylation is observed only rarely at a methine carbon as the more stable p-diketone enolate cannot be formed. 

The magnesium enolate (216) generated from copper(i)-catalysed conjugate addition of MeMgl to 3-methylcyclohex-2-enone in ether at 0°C has been used as a substrate in a study of acylation, alkylation, and the aldol condensation, particularly with respect to regiospecificity. With acetyl chloride in ether the ratio of C-alkylated (217) to 0-alkylated (218) product was 62 38 in a total yield of 39—53%, whereas in dimethoxyethane (218) only was formed in 63% yield. Predominant C-acylation also occurred with crotonyl chloride in ether, where the isolated product contained 86% of (219) in dimethoxyethane the extent of 0-acylation was 95 %. No evidence was adduced for intermediacy of the equilibrated enolate anion (216b). Product ratios were discussed in terms of hardness and softness of the reaction sites. 

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. 

A variation of the malonic ester synthetic uses a P-keto ester such as 116. In Section 22.7.1, the Claisen condensation generated P-keto esters via acyl substitution that employed ester enolate anions. When 116 is converted to the enolate anion with NaOEt in ethanol, reaction with benzyl bromide gives the alkylation product 117. When 117 is saponified, the product is P-keto acid 118, and decarboxylation via heating leads to 4-phenyl-2-butanone, 119. This reaction sequence converts a P-keto ester, available from the ester precursors, to a substituted ketone in what is known as the acetoacetic acid synthesis. Both the malonic ester synthesis and the acetoacetic acid synthesis employ enolate alkylation reactions to build larger molecules from smaller ones, and they are quite useful in synthesis. 

Compound 58 clearly offers more possibilities for disconnection. Disconnections are available at or near the carbon atom bearing the OH group, but also at or near both carbonyl carbons. The larger number of functional groups leads to more choices. Does the chemistry of the alcohol, the aldehyde, or the ketone offer the best choice for a disconnection The chemistry of alcohols is associated with oxidation and reduction (Chapter 17, Section 17.2 Chapter 19, Sections 19.2,19.3.4,19.4.1), formation and reactions of alkoxides as nucleophiles (Chapter 11, Section 11.3.2) and as bases (Chapter 12, Section 12.1), and formation of esters (Chapter 20, Section 20.5). Alcohols are converted to alkyl halides (Chapter 11, Section 11.7). Aldehydes and ketones are formed by the oxidation of alcohols (Chapter 17, Section 17.2), are reduced to alcohols (Chapter 19, Sections 19.2, 19.3.4, 19.4.1), undergo acyl addition (Chapter 18, Sections 18.1-18.7), and participate in enolate anion reactions (Chapter 22, Sections 22.2, 22.4, 22.6). Based on these reactions, several disconnections are shown, but several more are possible. 

This chapter introduced the use of enolates and/or enamines as nucleophiles in several reactions, including aldol reactions, Claisen condensations and Michael additions, alkylations, and acylations. We can also use LDA to generate the enolate anions and perform the same reactions, as shown here for cyclohexanone and a few specific electrophiles. Similar reactions are possible for aldehydes and esters with a-hydrogens. The synthetic versatility of this approach has made LDA a very popular and important reagent in modem synthetic organic chemistry. 

Preformed enolate anions using LDA can be used to carry out a wide variety of crossed enolate reactions, including aldol reactions, Claisen condensations, Michael additions, alkylations, and acylations. 

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