Reactions of Enols and Enolates with Electrophiles

Most carbonyl compounds possessing hydrogens at the a-position can equilibrate with enol tautomers (unless the enol/enolate would be particularly unstable, for example, if it cannot be planar). 

Enolization may be catalyzed by acid or base the rate is slowest at neutral pH. 

Enols are formed in acid solution and enolates in basic solution. 

The stability of enols, and hence the position of the carbonyl/enol equilibrium, depends on their structure—conjugation, hydrogen bonding, aromaticity, and solvation are all important. 

The formation of enols may be detected (even where equilibrium constants are very low) by exchange of enolizable protons with DjO. 

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The enols and enolates undergo several types of reactions. The reaction of enolates with electrophiles is referred to as a-substitution of carbonyl compounds. 

Enolates of carbonyl compounds are ambident anions. Although the negative charge resides predominantly at the oxygen, reactions of enolates with electrophiles can take place at the carbon terminus. C-Monoalkylation of enolates is usually accompanied by di- and polyalkylation owing to a rapid... 

We had to be careful in chapter 25 when we wanted to add bromoketones 4 to enolates 3 to make the 1,4-dicarbonyl compound 5. We could not use a lithium enolate because it would be too basic. No such difficulties exist in the reaction of enolates with allylic halides such as 2. Any enol(ate) equivalent will do as there are no acidic hydrogens and allylic halides are good electrophiles for the Sn2 reaction. 

Fortunately, over the last three decades lots of thought has already gone into the problem of controlling the reactions of enolates with carbon electrophiles. This means that there are many excellent solutions to the problem our task in this chapter is to help you understand which to use, and when to use them, in order to design useful reactions. 

Ibuprofen is the generic name for the pain reliever known by the trade names of Motrin and Advil. Like aspirin, ibuprofen acts as an anti-inflammatory agent by blocking the synthesis of prostaglandins from ara-chidonic acid. One step in a commercial synthesis of ibuprofen involves the reaction of a nucleophilic eno-late with an electrophilic carbonyl group. In Chapter 24, we learn about the carbon-carbon bond-forming reactions of enolates with carbonyl electrophiles. 

REACTIONS OF ENOLATES WITH OTHER ELECTROPHILES HALOGENATIONS, AMINATIONS, ACYLATIONS AND OXIDATIONS... 

We shall be looking at these reactions in detail in Chapter 25. For the rest of this chapter we will turn to some simpler consequences of enolization and some reactions of enolates with simple heteroatom-based electrophiles. 

AldolCondensations. Cation-exchanged montmorillonites accelerate the aldol condensation of silyl enol ethers with acetals and aldehydes. Similarly, the aldol reaction of silyl ketene acetals with electrophiles is catalyzed by solid-acid catalysts. Neither report discussed the use of iron montmorillonite for these reactions however, some reactivity is anticipated. 

Perhaps the single most important reaction of enolate ions is their alkylation by treatment with an alkyl halide or tosylate, thereby forming a new C-C bond and joining two smaller pieces into one larger molecule. Alkylation occurs when the nucleophilic enolate ion reacts with the electrophilic alkyl halide in an SN2 reaction and displaces the leaving group by backside attack. 

Iron-acyl enolates such as 1, 2, and 3 react readily with electrophiles such as alkyl halides and carbonyl compounds (see Houben-Weyl, Vol. 13/9a p418). The reactions of these enolatc species with alkyl halides and similar electrophiles are discussed in Section D.1.1.1.3.4.1.3. To date, only the simple enolates prepared by a-deprotonation of acetyl and propanoyl complexes have been reacted with ketones or aldehydes. 

Although the reaction of ketones and other carbonyl compounds with electrophiles such as bromine leads to substitution rather than addition, the mechanism of the reaction is closely related to electrophilic additions to alkenes. An enol, enolate, or enolate equivalent derived from the carbonyl compound is the nucleophile, and the electrophilic attack by the halogen is analogous to that on alkenes. The reaction is completed by restoration of the carbonyl bond, rather than by addition of a nucleophile. The acid- and base-catalyzed halogenation of ketones, which is discussed briefly in Section 6.4 of Part A, provide the most-studied examples of the reaction from a mechanistic perspective. 

The wide diversity of the foregoing reactions with electron-poor acceptors (which include cationic and neutral electrophiles as well as strong and weak one-electron oxidants) points to enol silyl ethers as electron donors in general. Indeed, we will show how the electron-transfer paradigm can be applied to the various reactions of enol silyl ethers listed above in which the donor/acceptor pair leads to a variety of reactive intermediates including cation radicals, anion radicals, radicals, etc. that govern the product distribution. Moreover, the modulation of ion-pair (cation radical and anion radical) dynamics by solvent and added salt allows control of the competing pathways to achieve the desired selectivity (see below). 

Alkenes are scavengers that are able to differentiate between carbenes (cycloaddition) and carbocations (electrophilic addition). The reactions of phenyl-carbene (117) with equimolar mixtures of methanol and alkenes afforded phenylcyclopropanes (120) and benzyl methyl ether (121) as the major products (Scheme 24).51 Electrophilic addition of the benzyl cation (118) to alkenes, leading to 122 and 123 by way of 119, was a minor route (ca. 6%). Isobutene and enol ethers gave similar results. The overall contribution of 118 must be more than 6% as (part of) the ether 121 also originates from 118. Alcohols and enol ethers react with diarylcarbenium ions at about the same rates (ca. 109 M-1 s-1), somewhat faster than alkenes (ca. 108 M-1 s-1).52 By extrapolation, diffusion-controlled rates and indiscriminate reactions are expected for the free (solvated) benzyl cation (118). In support of this notion, the product distributions in Scheme 24 only respond slightly to the nature of the n bond (alkene vs. enol ether). The formation of free benzyl cations from phenylcarbene and methanol is thus estimated to be in the range of 10-15%. However, the major route to the benzyl ether 121, whether by ion-pair collapse or by way of an ylide, cannot be identified. 

Figure 3.25. Rh/(5)-binap-catalyzed asymmetric 1,4-addition of Ar-9-BBN to a,P-enones and subsequent reactions of the chiral boron enolates with electrophiles.

The reaction of enolate anions with electrophiles is one of the most important and most widely used C-C bond forming reactions. Compared to its immense importance there are relatively few reviews dealing with this subject1-5. 

C. Reactions of Magnesium Ester Enolates and Magnesium Lactone Enolates with Electrophiles... 

The reaction of a citronellic ester enolate with electrophilic agents gives open-chain fluorinated products 32 and 33 only.11 The absence of rearranged fluorinated products in this system, a potential precursor to a 5-hexenyl-type radical clock, indicates that free radicals are not intermediates in the path to fluorinated products.12... 

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 ... 

Acyliron complexes have found many applications in organic synthesis [40]. Usually they are prepared by acylation of [CpFe(CO)2] with acyl chlorides or mixed anhydrides (Scheme 1.13). This procedure affords alkyl, aryl and a,P-unsaturated acyliron complexes. Alternatively, acyliron complexes can be obtained by treatment of [Fe(C5Me5)(CO)4]+ with organolithium reagents, a,P-Unsaturated acyliron complexes can be obtained by reaction of the same reagent with 2-alkyn-l-ols. Deprotonation of acyliron complexes with butyllithium generates the corresponding enolates, which can be functionalized by reaction with various electrophiles [40]. 

More recently a stereoselective synthesis of (35)-7V-Pf-3-aminoaspartate (Pf = 9-phenylfluoren-9-yl) by reaction of TV-Pf-aspartate enolates with electrophilic animating reagents was reported by Sardina and co-workers [40]. Electrophilic animations were run using trisylazide or dialkylazodicarboxylates DTBAD and DBAD. N-Pf-... 

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