Carbonyl enolate additions

Reaction of diphenylsulfoxide with triflic anhydride affords, as precedently mentioned, the corresponding sulfoxonium triflate, a powerful reagent for numerous reactions, such as a-arylation of carbonyls, enolate additions,or nucleophilic substitution on alkenes (102). ... 

Aldol Addition and Related Reactions. Procedures that involve the formation and subsequent reaction of anions derived from active methylene compounds constitute a very important and synthetically useful class of organic reactions. Perhaps the most common are those reactions in which the anion, usually called an enolate, is formed by removal of a proton from the carbon atom alpha to the carbonyl group. Addition of this enolate to another carbonyl of an aldehyde or ketone, followed by protonation, constitutes aldol addition, for example... 

Ketones are oxidatively cleaved by Cr(VI) or Mn(VII) reagents. The reaction is sometimes of utility in the synthesis of difunctional molecules by ring cleavage. The mechanism for both reagents is believed to involve an enol intermediate.206 A study involving both kinetic data and quantitative product studies has permitted a fairly complete description of the Cr(VI) oxidation of benzyl phenyl ketone.207 The products include both oxidative-cleavage products and benzil, 7, which results from oxidation a to the carbonyl. In addition, the dimeric product 8, which is suggestive of radical intermediates, is formed under some conditions. 

In this study, benzaldehyde and benzaldehyde-methyllithium adduct were fully optimized at HF/6-31G and their vibrational frequencies were calculated. The authors used MeLi instead of lithium pinacolone enolate, since it was assumed that the equilibrium IBs are not much different for the MeLi addition and lithium enolate addition. Dehalogena-tion and enone-isomerization probe experiments detected no evidence of a single electron transfer to occur during the course of the reaction. The primary carbonyl carbon kinetic isotope effects and chemical probe experiments led them to conclude that the reaction of lithium pinacolone enolate with benzaldehyde proceeds via a polar mechanism. 

The D-ring of steroids has been cleaved frequently by a Beckmann fragmentation. Typical strategy uses enolate chemistry to introduce an oximino group at the a-carbonyl carbon. Reduction of the carbonyl (or addition of a carbanion) produces an a-hydroxy oxime which serves as good substrate for the fragmentation. Two examples of this strategy are shown in equations 213 and 214. 

Condensation with enolntes of carbonyl compounds (r/. T richloroethylene, 9,479-480). The reagent can react in two ways with carbonyl enolates. The first one evidently is a direct addition-elimination (equation I) the second one is considered to involve perchlorobutenync (a) as an intermediate (equation II).1... 

The chemistry of the thiazoles does, of course, bear some similarity to that of the oxazoles. Metallated thiazoles and thiazole derivatives have found use, for example, both as carbonyl equivalents and masked acetaldehyde enolates. Additionally, as will be exemplified below, thiazole derivatives have served as catalysts for benzoin-type condensations, and they have provided access to a unique class of activated acid derivatives. 

Metzner reports that lithium dithioenolates, which are softer nucleophiles than the corresponding carbonyl enolates, add kinetically in a 1,4-mode exclusively to ot, 3-enones and the diastereoselectivity preferences are similar to that for ester enolate additions.l43a d Typically, kinetic deprotonation of dithioesters affords predominantly the (Z)-enethiolate (170) which is opposite to that for esters 139 thus, with ( )-enones, anti adducts (172) are obtained. In contrast, the addition of methyl dithioacetate to ot,P-disubstituted enones affords predominantly syn adducts (174 and 175) which is a consequence of intramolecular protonation of the resultant enolate (Scheme 68).143e... 

Vinyl sulfoxides (221), which are aldehyde a-cation equivalents, and vinylthiolium ions (230), which are a.jj-unsaturated carbonyl 3-cation equivalents, are also suitable acceptors for silyl ketene acetals and enol silyl ethers (Scheme 36). Kita reports that the bulky r-butyldimethylsilyl ketene acetals and tri-methylsilyl ketene acetals form 1 1 adducts (224) and 1 2 adducts (225) with (221), respectively 91 mechanistically, these additions proceed via an initial Pummerer rearrangement The vinylthiolium ion additions are notable for their synthetic flexibility for example, additions to the ketene dithioacetal (229) proceed with higher diastereoselectivity than the corresponding enolate additions to a,3-unsaturated esters.9 lc,91d... 

Metal enolate complexes have also been used to catalyze the allylation of carbonyl compounds ° °, addition of aldehydes to l,3-dienes ° and alkynes as well as the addition of alkenes to alkynes " and indoles ". In the latter study, 5 mol% of Pd(acac)2 (29) and 10 mol% of PPhs were found to be an effective catalyst system for the coupling of Ai-methylindole (93) with a variety of 2-acetoxymethyl-substituted electron-deficient alkenes, including methyl 2-(acetoxymethyl)acrylate (94) (equation 26). Substituted indoles (95) constitute an important class of biologically active natural products and synthetic routes to these valuable compounds have therefore attracted considerable attention. 

Directed lithiations of a,3- and -y.b-unsaturated amides " have been extensively studied. Illustrative examples are shown in Scheme 44. Prior complexation of the alkyllithium base with the amide carbonyl oxygen directs the base to the thermodynamically less acidic -position in a,3-unsaturated amide (31), which adds to benzophenone and subsequently lactonizes. Analysis of the NMR spectrum reveals that the organolithium added the benzophenone in the equatorial position. A Afferent kinetic deprotonation is seen in y,8-unsaturated amide (32), where -lithiation to form an allylic anion predominates over a-lithiadon to form an enolate. > Addition of the lithium anion to acetone affords poor regioselectivity, but transmetalation to magnesium before carbonyl addition yields a species which adds exclusively at the 8-position. ... 

The recognition of chiral carbonyl compounds, especially the substrates having a chiral stereogenic center at the a-carbon, have been a main subject of research for long time [81], since Curtin [82] and Cram [83] initially proposed a structural model for the diastereoselective addition to these molecules. There are in-depth studies related to this subject including chiral enolate addition, i.e., double asymmetric synthesis [84]. In this section, therefore, some other impressive topics of current interest are discussed briefly. 

The essential feature is the formation of a TiCl4—ketone complex which polarizes the carbonyl group. Addition of triethylamine yields a titanium enolate by proton abstraction. The enolate attacks a... 

Isatin is a stable, bright orange solid that is commercially available in large quantities. Because it readily undergoes clean aromatic substitution reactions at C-5, iV-alkylation via an anion, and ketonic reactions at the C-3-carbonyl group, for example enolate addition, it is a very useful intermediate for the synthesis of indoles and other heterocycles. 

The Mukaiyama version of the aldol reaction is well known a carbonyl-titanium tetrachloride complex reacts with a trimethylsilyl enol ether. Under these conditions there is no titanium enolate involved. Another procedure has been reported a trimethylsilyl enol ether reacts with titanium tetrachloride to give the titanium enolate addition of the carbonyl compound generates the aldol product (although with slightly lower diastereoselectivity than with Mukaiyama s procedure). (Z)-Enolsilanes from acyclic ketones react rapidly and stereospecifically with TiCU to form (Z)-configured CbTi enolates, while the ( )-isomers react slowly to afford low yields of mixtures of ( )- and (Z)-Cl3Ti enolates (Scheme 41). 

The Claisen rearrangement can be formally considered as an intramolecular SN2 addition of a carbonyl enol to an allylic alcohol. In contrast to the Cope rearrangement (see Section D.l. 6.3.1.2.), it is an irreversible, highly exothermic reaction with the exception of some special substrates, such as cyclopropane derivatives43,44 or some bicyclic compounds45-47. 

In addition to serving as a key stereochemical controlling element for synthesis of indinavir,5 the title compound has proven to be a remarkably versatile chiral ligand and auxiliary for a range of asymmetric transformations including Diels-Alder reactions,13 carbonyl reductions,14 diethylzinc additions to aldehydes,15 and enolate additions.16... 

Prior to the advent of organocatalysis, the asymmetric direct a-allqtlation reaction was relatively unknown. Classical methods to access a-allq lated carbonyl products required stoichiometric amounts of preformed aldehyde metal enolates. Additionally, side reactions such as aldol, Canizzaro- or Tischenko-type processes diminished the efficiency of these reactions. In this sense the asymmetric intermolecular Sjj2 a-alkylation of aldehydes with simple allq l halides has been a difficult feat to achieve. 

Control of Enantioselectivity. In the previous sections, the most important factors in determining the syn or anti stereoselectivity of aldol and Mukaiyana reactions were identified as the nature of the transition state (cyclic versus acyclic) and the configuration (E or Z) of the enolate. Additional factors affect the enantioselectivity of aldol additions and related reactions. Nearby chiral centers in either the carbonyl compound or the enolate can impose facial selectivity. Chiral auxiliaries can achieve the same effect. Finally, use of chiral Lewis acids as catalysts can also achieve enantioselectivity. Although the general principles of control of the stereochemistry of aldol addition reactions have been developed for simple molecules, the application of the principles to more complex molecules and the selection of the optimum enolate system requires analysis of the individual cases.Not infrequently, one of the enolate systems proves to... 

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