Preformed enol derivatives

In general the reaction of an aldehyde with a ketone is synthetically useful. Even if both reactants can form an enol, the a-carbon of the ketone usually adds to the carbonyl group of the aldehyde. The opposite case—the addition of the a-carbon of an aldehyde to the carbonyl group of a ketone—can be achieved by the directed aldol reaction The general procedure is to convert one reactant into a preformed enol derivative or a related species, prior to the intended aldol reaction. For instance, an aldehyde may be converted into an aldimine 7, which can be deprotonated by lithium diisopropylamide (EDA) and then add to the carbonyl group of a ketone ... 

The reactions with preformed enol derivatives provide a way to control the stereoselectivity of the aldol reaction. As with the Michael reaction (15-16), the aldol reaction creates two new chiral centers, and, in the most general case, there are four stereoisomers of the aldol product, which can be represented as... 

Among the preformed enol derivatives used in this way have been enolates of magnesium, lithium, titanium, zirconium, and tin, ° silyl enol ethers, enol borinates,and enol borates, R CH=CR"—OB(OR)2. The nucleophilicity of silyl enol ethers has been examined. In general, metallic Z enolates give the syn (or erythro) pair, and this reaction is highly useful for the diastereoselective synthesis of these products. The ( ) isomers generally react nonstereoselectively. However, anti (or threo) stereoselectivity has been achieved in a number of cases, with titanium enolates, with magnesium enolates, with certain enol bor-inates, and with lithium enolates at — 78°C. ... 

For some other aldol reactions with preformed enol derivatives, see Mukaiyama, T. Isr. J. Chem., 1984, 24, 162 Caine, D. in Augustine, Ref 564, p. 264. 

Among the preformed enol derivatives used in this way have been enolates of magnesium, lithium,526 titanium,527 rhodium,528 zirconium,522 and tin,529 silyl enol ethers,530 enol bori-nates,531 and enol borates R CH=CR"—OB(OR)2.532 In general, metallic Z enolates give... 

Tor a study of the rate and equilibrium constants in the reaction between acetone and benzaldehyde, see Guthrie, J.P. Cossar, J. Taylor, K.F. Can. J. Chem. 1984, 62, 1958. For a microwave induced reaction using aqueous NaOH, see Kad, G.L. Kaur, K.P. Singh, V. Singh, J. Synth. Commun. 1999, 29, 2583. " For some other aldol reactions with preformed enol derivatives, see Mukaiyama, T. Isr. J. Chem. 1984, 24, 162 Caine, D., in Augustine, R.L., Carbon-Carbon Bond Formation, Vol. 1, Marcel Dekker, NY, 1979, pp. 264-276. 

The reactions with preformed enol derivatives provide a way to control the... 

Among the preformed enol derivatives used for diastereoselective aldol condensations have been enolates of Mg, and silyl enol... 

At a glance, the descriptors Z and E might seem to be appropriate for O - metal-bound enolates like 6. Indeed, E/Z nomenclature causes no problems when the configuration of preformed enolates derived from aldehydes, ketones, and amides has to be assigned, because the O-metal residue at the enolate double bond has the higher priority. However, application of the E/Z descriptors to ester enolates leads to the dilemma that enolates with different metals but otherwise identical structures will be classified by opposite descriptors, as illustrated by lithium and magnesium enolates 9 and 10, respectively the former would have to be termed Z, and the latter E (Scheme 1.4). 

As long as nucleophilic addition of the preformed enolate to the second carbonyl component is rapid and the carbonyl electrophile is added after the enolate is formed, the product is predictable and is not a mixture. The rule of thumb to ensure success is that the carbonyl electrophile should be more reactive than the carbonyl compound from which the enolate is derived. If this condition is met, the carbonyl electrophile can have a protons and the structural possibilities are increased tremendously. Typical enolate-carbonyl pairs that have been condensed by this methodology include the following ... 

A number of methods have been developed for accomplishing aldol addition reactions in a stereoselective manner. The preformed lithium enolates of alkyl esters normally react with aldehydes to give mixtures of the two diastereomeric g-hydroxy esters (eq 1). However, the enolates derived from... 

In recent organic synthesis, stereoselective aldol condensations has been performed under two different conditions. Under the influence of acid, stabilized enol derivatives, enolsilanes (M = SiMe3), can condense with aldehydes or acetals in a stereoselective fashion [Eq. (12)]. In this reaction the role of the acid is to activate aldehydes or acetals. Alternatively, under basic conditions, the same process can be carried out directly with aldehydes and reactive, preformed metal enolates (M = Li, MgL, ZnL, AIL2, BL2, etc.) of defined geometry. 

Cocrystallization of either LiOCMc3 or KOCMc3 with preformed potassium or lithium enolate derived from MeCOCMc3 in the presence of THE yields a novel aggregate composed of four... 

Two mechanisms have been suggested. A radical mechanism was first proposed and its involvement is supported by the presence of dimeric products. However, the ligand coupling mechanism is now generally accepted. An enol-lead (IV) triacetate intermediate (7) is first formed by reaction of lead tetraacetate with the enol form. Its formation is accelerated by catalysis by boron trifluoride. 14,33 Treatment of the preformed enolate with lead tetraacetate performs a-acetoxylation at lower temperature and more rapidly than in the reaction with the corresponding enol. 4 Ligand coupling then takes place on this intermediate to lead to the a-acetoxycarbonyl derivative. 

As for preformed cationic enolate complexes, one decomposition pathway has been conclusively identified. Enolates derived from 3° alkyl esters are prone to loss of alkene to form cationic carboxylate complexes (Scheme Since donors such as THF partially impede this process, prior coordination of the ester oxygen may precede elimination. By the same token, the unhindered enolate [Me2Si(77-G5Me4)(TuN)Zr 0G(0 Bu)=CMe2 (THF)][B G6H3(GF3)2 4] decomposes at temperatures above —20°G to form the cationic carboxylate complex, even in the presence of excess... 

Aldol Reaction (Condensation) [24] Traditionally, it is the acid- or base-catalyzed condensation of one carbonyl compound with the enolate/enol of another, which may or may not be the same, to generate a P-hydroxy carbonyl compound— an aldol. The method is composed of self-condensation, polycondensation, generation of regioisomeric enols/enolates, and dehydration of the aldol followed by Michael addition, q.v. The development of methods for the preparation and use of preformed enolates or enol derivatives that dictate specific caibon-caibon bond formation have revolutionized the coupling of carbonyl compounds (Fig. 6.6) ... 

This effort has several components. First, the problem of more than one kind of a-proton (either in different reactants or on opposite sides of the same carbonyl in one reactant) can be controlled by preforming an enol, enolate anion, or enol derivative of one of the carbonyl components before the other is added. 

The problem of stereoselection, that is, to which face of the carbonyl component the preformed enol, enolate anion, or enol derivative will add, can then be analyzed as a steric problem. 

The catalytic enantioselective direct alkylation reaction of enolates is a less developed field. Early research from Evans group demonstrated that preformed titanium enolates derived from chiral Af-acyloxazolidinones reacted with orthoesters to provide the alkylated adducts with high levels of diastereo-control. In2005, the same group reported the enantioselective nickel-catalysed... 

Preformed enolates such as silyl enol ethers can he used as donors in the addition of a, 8-unsaturated aldehydes (Mukaiyama-type reaction). In this reaction the DNBA salt is preferred usually as stronger acids result in decomposition of the silyl ether. Both acyclic ejco-enolates and 2-silyloxy furan derivatives were seen to undergo 1,4 addition with enals in the presence of a catalytic amount of 1 (20 mol %). This latter transformation allows easy entry to enantiomerically enriched butenolides, and has been applied to the s)uithesis of spiculisporic acid (eq 8). 

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