Reactions of Enolates

The enolates of methyl ketones may be generated regiospecifically from esters by reaction with two equivalents of trimethyl- or triphenyl-stannylmethyllithium [equation (49)]. The 

The alkylation of a-hetero substituted aldehydes and ketones is often a far from simple process. However methods for both the a and a -alkylation of fluoroacetone by way of its lithium N-cyclohexyl enamide,1 0 and the alkylation of formamido ketones1 1 have been reported. The allylation of ketones has received a 

The conjugated thionium ylids are prepared by the Pummerer reaction of an allyl sulphoxide, with trimethylsilyl triflate in the presence of ethyl diisopropylamine, and give products of ketone allylation [equation (52) 

The otherwise rather difficult carbon alkylation of cyclohexane - 1,3-diones may be achieved photochemically although in rather variable yield, by irradiation through pyrex of a benzene solution of the dione and an enol ether, the alkyl portion of which is transferred [equation (53)l.1  

The formation of chiral enol derivatives by the enantioselective deprotonation of symmetrically substituted ketones under kinetically controlled conditions has been studied. The best 

Similar results have been reported using the phenolic 

The conjugate reduction of enones is a well known route to enolates and the conformational preferences of acyclic enones are now found to determine the geometry of the enolate produced 

R and R on the s-cis to s-trans ratio are well known, this provides a potentially useful route to enolates of defined 

Molecular mechanics studies aimed at predicting the cis-trans 

Both enol silanes and tin(II) enolates have been found to react in a Michael sense with nitro-alkenes with high anti- 

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Reaction of Enolate Anions. In the presence of certain bases, eg, sodium alkoxide, an ester having a hydrogen on the a-carbon atom undergoes a wide variety of characteristic enolate reactions. Mechanistically, the base removes a proton from the a-carbon, giving an enolate that then can react with an electrophile. Depending on the final product, the base may be consumed stoichiometricaHy or may function as a catalyst. Eor example, the sodium alkoxide used in the Claisen condensation is a catalyst ... 

The alkylation reactions of enolate anions of both ketones and esters have been extensively utilized in synthesis. Both very stable enolates, such as those derived from (i-ketoesters, / -diketones, and malonate esters, as well as less stable enolates of monofunctional ketones, esters, nitriles, etc., are reactive. Many aspects of the relationships between reactivity, stereochemistry, and mechanism have been clarified. A starting point for the discussion of these reactions is the structure of the enolates. Because of the delocalized nature of enolates, an electrophile can attack either at oxygen or at carbon. 

Enolates can also serve as carbon nucleophiles in carbonyl addition reactions. The addition reaction of enolates with carbonyl compounds is of very broad scope and is of great synthetic importance. Essentially all of the enolates considered in Chapter 7 are capable of adding to carbonyl groups. The reaction is known as the generalized aldol addition. 

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. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

The acid-catalyzed reaction of enol ethers 2 (X = OR) and enamines 2 (X = NR2) to form y-lactol derivatives proceeds with great ease even on silica gel chromatography. Vinyl sulfides 2 (X = SR) or vinyl chlorides 2 (X = Cl) are difficult to hydrolyze. 

A high degree of syn selectivity can be obtained from the addition of enamines to nitroalkenes. In this case, the syn selectivity is largely independent of the geometry of the acceptor, as well as the donor, double bond. Next in terms of selectivity, are the addition of enolates. However, whether one obtains syn or anti selectivity is dependent on both the geometry of the acceptor and the enolate double bond, whereas anti selectivity of a modest and unreliable level is obtained by reaction of enol silyl ethers with nitroalkenes under Lewis acid catalysis. 

Addition of ( )-enolates to ( )-l-nitropropene favors products with the syn stereochemistry while products with the anti stereochemistry are favored from the reaction of ( )-enolates with (Z)-1 -nitropropene. 

The Andersen sulphoxide synthesis allows one also to synthesize a variety of a-heteroatom substituted sulphoxides starting from a-heteroatom stabilized carbanions and (—)-(S)-276. The selected examples shown in Scheme 3 are the best illustration of the generality of this approach. The reaction of enolates or enolate like species with (—)-(S)-276 has been used for the synthesis of optically active a-carbalkoxy sulphoxides. For example, treatment of (—)-(S)-276 with the halogenomagnesium enolates of -butyl acetate, t-butyl propionate or t-butyl butyrate resulted in the formation of ( + )-(R)-t-butyl p-toluenesulphinylcarboxylates 298367 (equation 163). 

Phenyl 2-(trimethylsilyl)ethynyl sulfone (118) can act as a vinyl cation synthon (equations 93 and 94)78 79. Thus, the reaction of enolates with 118 and subsequent desulfonylation of the adduct gives a-vinyl ketone, such as 119 and 120. 

The SET mechanism is chiefly found where X = I or NO2 (see 10-104). A closely related mechanism, the SrnE takes place with aromatic substrates (Chapter 13). In that mechanism the initial attack is by an electron donor, rather than a nucleophile. The Srn 1 mechanism has also been invoked for reactions of enolate anions with 2-iodobicyclo[4.1.0]heptane. An example is the reaction of l-iodobicyclo[2.2.1]-heptane (15) with NaSnMe3 or LiPPh2, and some other nucleophiles, to give the substitution product. Another is the reaction of bromo 4-bromoacetophenone (16) with Bu4NBr in cumene. " The two mechanisms, Sn2 versus SET have been compared and contrasted. There are also reactions where it is reported that radical, carbanion, and carbene pathways occur simultaneously. ... 

Summary of the Relationship between Diastereoselectivity and the Transition Structure. In this section we considered simple diastereoselection in aldol reactions of ketone enolates. Numerous observations on the reactions of enolates of ketones and related compounds are consistent with the general concept of a chairlike TS.35 These reactions show a consistent E - anti Z - syn relationship. Noncyclic TSs have more variable diastereoselectivity. The prediction or interpretation of the specific ratio of syn and anti product from any given reaction requires assessment of several variables (1) What is the stereochemical composition of the enolate (2) Does the Lewis acid promote tight coordination with both the carbonyl and enolate oxygen atoms and thereby favor a cyclic TS (3) Does the TS have a chairlike conformation (4) Are there additional Lewis base coordination sites in either reactant that can lead to reaction through a chelated TS Another factor comes into play if either the aldehyde or the enolate, or both, are chiral. In that case, facial selectivity becomes an issue and this is considered in Section 2.1.5. 

Aldol Addition Reactions of Enolates of Esters and Other Carbonyl Derivatives... 

II and 12 indicate, the selenenylation of ketones can also be effected by reactions of enol acetates or enol silyl ethers. 

The stereochemistry of these reactions depends on the lifetime of the dipolar intermediate, which, in turn, is influenced by the polarity of the solvent. In the reactions of enol ethers with tetracyanoethylene, the stereochemistry of the enol ether is retained in nonpolar solvents. In polar solvents, cycloaddition is nonstereospecific, as a result of a longer lifetime for the zwitterionic intermediate.177... 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

It has been postulated that secophthalideisoquinoline ene lactams and hydroxy lactams are most probably artifacts of isolation resulting from the reaction of enol lactones or keto acids with ammonia during the extraction process. The hydroxy lactams are probably formed initially and then undergo dehydration to give ene lactams (5,8). For this reason, this section covers the hydroxy lactams in addition to the ene lactams. The hydroxy lactams are... 

In a similar manner, reaction of enol ether 2-787, hydroxycoumarin (2-781), and a-diketone 2-786 led to the cycloadduct 2-788 in 79% yield using Yb(OTf)3 as catalyst (Scheme 2.174). 2-788 could be transformed into the natural product preethulia coumarin (2-789). 

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). 

This result, associated with those on substituent effects, supports previous conclusions to the effect that the position of the transition state depends on the reactivity in agreement with RSP. In particular, stabilization of the intermediate as a result of conjugation, such as that in the reaction of enol ethers, makes the transition state very early. The few available KSIEs also suggest that the transition states for aromatic series are earlier than those for alkenes. 

Commensurately with the development of various catalyst systems, the Pd-catalyzed G-O cross-coupling has found a number of synthetic applications. Examples include the syntheses of the protein kinase G (PKC) activator (+)-decursin,104 the natural product heliannuol E,105 a chiral 2-methyl chroman,106 and a series of aryloxy and alkoxy porphyrins.107 The Buchwald-Hartwig coupling has also been utilized in the preparation of a heterocycle library.108 Intramolecular O-arylation has also been achieved in the reactions of enolates with aryl halides leading to benzofur-ans.109,110 Finally, a double cross-coupling between an 0-dibromobenzene and a glycol has also been applied for the preparation of benzodioxanes (Equation (16)).1... 

T.-H. Chan, Formation and Addition Reactions of Enol Ethers In Comprehensive Organic Synthesis (Ed. B. M. Trost), Pergamon Press, New York, 1991, vol. 2, pp. 595-628. 

Alkoxy ketones. These ketones can be prepared by an aldol-type reaction of enol ethers with acetals catalyzed by a trityl salt. Methoxymethyl (MOM) enol ethers are more reactive than methyl enol ethers. 

The aldol reactions of enol silyl ethers, (16), with unprotected aromatic aldehydes also give good yields of the adducts (isolated as the silyl ether) but with... 

A review of aromatic substitution by the 5 rnI reaction has been published. The reactions of enolate ions of 2-acetyl-(147) and 3-acetyl-1-methylpyrroles (148) with aryl iodides and neopentyl iodides under irradiation conditions afforded good yields of substitution products by 5rn1 mechanisms, without the need for initiator. These... 

The relative reactivities of the enolate ions of acetophenone and 2-acetylnaphthalene towards phenyl radicals have been explored in order to determine their suitability as electron donor initiatiors of 5 rnI reactions of enolate ions of 2-acetylthiophene and 2-acetyl fiiran with aryl halides Phl. ... 

Aldol reactions of silyl enolates are promoted by a catalytic amount of transition metals through transmetallation generating transition metal enolates. In 1995, Shibasaki and Sodeoka reported an enantioselective aldol reaction of enol silyl ethers to aldehydes using a Pd-BINAP complex in wet DMF. Later, this finding was extended to a catalytic enantioselective Mannich-type reaction to a-imino esters by Sodeoka s group [Eq. (13.21)]. Detailed mechanistic studies revealed that the binuclear p-hydroxo complex 34 is the active catalyst, and the reaction proceeds through a palladium enolate. The transmetallation step would be facilitated by the hydroxo ligand transfer onto the silicon atom of enol silyl ethers ... 

The catalytic activity of the oxoisoindolium salt 54 and 55 was compared to that of trityl tetrakis[pentafluorophenyl]borate salts in the addition reaction of enol acetate to benzaldehyde and glycosylation reaction (Scheme 59) [151, 152]. 

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