Enolate anions, amide reaction with aldehydes

Many types of carbonyl compounds, including aldehydes, ketones, esters, thioesters, acids, and amides, can be converted into enolate ions by reaction with LDA. Table 22.1 lists the approximate pKa values of different types of carbonyl compounds and shows how these values compare to other acidic substances we ve seen. Note that nitriles, too, are acidic and can be converted into enolate-like anions. 

Besides ordinary esters (containing an a hydrogen), the reaction can also be carried out with lactones and, as in 16-38, with the y position of a,p-unsaturated esters (vinylogy). There are also cases, where the enolate anion of an amide was condensed with an aldehyde. ... 

Reaction between Two Different Aldehydes. In the most general case, this will produce a mixture of four products (eight, if the alkenes are counted). However, if one aldehyde does not have an a hydrogen, only two aldols are possible, and in many cases the crossed product is the main one. The crossed-aldol reaction is often called the Claisen-Schmidt reaction. The crossed aldol is readily accomplished using amide bases in aprotic solvent. The first aldehyde is treated with LDA in THF at —78°C, for example, to form the enolate anion. Subsequent treatment with a second aldehyde leads to the mixed aldol product. The crossed aldol of two aldehydes has been done using potassium ferf-butoxide and Ti(OBu)4. ... 

Silyl enol ethers react with aldehydes in the presence of chiral boranes or other additives " to give aldols with good asymmetric induction (see the Mukaiyama aldol reaction in 16-35). Chiral boron enolates have been used. Since both new stereogenic centers are formed enantioselectively, this kind of process is called double asymmetric synthesis Where both the enolate derivative and substrate were achiral, carrying out the reaction in the presence of an optically active boron compound ° or a diamine coordinated with a tin compound ° gives the aldol product with excellent enantioselectivity for one stereoisomer. Formation of the magnesium enolate anion of a chiral amide, adds to aldehydes to give the alcohol enantioselectively. 

When primary or secondary amides are treated with a base, there is a complicating reaction that was not possible with esters, ketones, or aldehydes. The N—H moiety is acidic enough to react with the bases used for deprotonation. Treatment of 56 with base gave the A-lithio derivative, but the a-lithio derivative (57) can be generated by addition of two equivalents of base. Enolate anion formation is straightforward with tertiary amides, such as dimethylisobutyramide (56, R = Me) and the resultant enolate anion (58) reacted with butanal to give amido-alcohol 59 in 68% yield O (see sec. 9.4.B). 

When acetone reacts with NaOEt in ethanol to form enolate anion 27, it is a reversible acid-base reaction. Therefore, unreacted ketone or aldehyde always remains in the reaction, and this fact allows self-condensation to occur. Is it possible to choose a base that will generate the enolate anion, but the equilibrium is pushed far to the right (toward the enolate anion product) If such a base is available, self-condensation is much less of a problem, which is particularly important for mixed aldol condensation reactions. As chemists experimented to find such a base, it was discovered that amide bases (RaNr), derived from secondary amines (R2NH) accomplished this goal. 

By comparison, the acid-base reaction of 30 and 2 path b ) proceeds smoothly to give enolate anion 27 (the conjugate base) and diisopropylamine (the conjugate acid). There is little steric hindrance to the approach of the proton on the a-carbon, and 30 is a strong base. In other words, the acid-base reaction of 30 and 2 proceeds readily to form the enolate anion, but acyl addition to form 31 is so slow that virtually no 31 is formed. Since lithium diisopropylamide is a good base hut a poor nucleophile, it is termed a non-nucleophilic ha.se. Non-nucleophilic amide bases such as 30 are used when the acid is very weak, as with simple ketones and aldehydes, and acyl addition is a competitive reaction to deprotonation. When the pKj, of the aldehyde or ketone falls below 10, weaker bases can be used, but those reactions will be introduced when it is appropriate. 

Many a,P-unsaturated carbonyl compounds (aldehydes and ketones as well as esters and amides [this chapter]) undergo aldol reactions on the a-carbon of the unsaturated partner with the carbonyl of a second partner. This interesting reaction (the Baylis-Hillman reaction) depends upon the temporary addition of a hindered base (l,4-diazabicyclo[2.2.2]octane, DAB(70, is commonly used) to the P-carbon of the a,P-unsaturated system rather than the deprotonation of the a-carbon. The enolate anion, a to the carbonyl of what was the a,P-unsaturated system, then adds to the other reactant and subsequent elimination provides the condensation product and the base is eliminated. The process is shown in Scheme 9.52 for the reaction between ethanal (acetaldehyde) and the a,P-unsaturated ester ethyl propenoate (ethyl acrylate). 

Oxaziridines 14 transfer the NCOY group to enolates of ketones (see Eq. 90),153-156 esters (see Eq. no),153 155 157 158 amides,158 A -acyloxazolidino-nes,153,157 and (3-dicarbonyl compounds,155 anions stabilized by cyano (see Eq. 141),155 sulfonyl (see Eq. 145),158 and phosphinoyl154 groups, and ketone enol ethers.155 Yields are in the 20-60% range. The first step in these reactions is presumably attack of the enolate on nitrogen as in Eq. 11, followed by elimination of an aldehyde ArCHO and formation of the animation product. With esters,... 

All ketones, aldehydes, and esters mentioned so far have had an a-carbon that can lead to an enol, which means that there was a hydrogen on that carbon that could be removed by base. When a ketone does not have such a proton (it is a non-enolizable ketone), treatment with strong base can lead to a C—C bond cleavage reaction. Discovered by Semmeler,52 Haller and Bauer developed the reaction illustrated by reaction of 63 with NaNH2 to give amide 65. Acyl addition of the amide anion to the carbonyl of the ketone led to 64, and loss of the anion Ph" gave the amide product. Workup protonates the anion to give, in this case, benzene. This... 

Treatment of a-silyl esters with a base readily affords the corresponding enolates, which can be utilized for Peterson reactions (Scheme 2.70) [189-196]. LDA is the most widely used base for the deprotonation of a-silyl esters. The carbonyl compounds used in the above reactions are aldehydes, saturated and unsaturated ketones, amides, lactones, and lactams. The products, a,j8-unsaturated esters, are obtained as mixtures of the E- and Z-isomers in most cases. When another trimeth-ylsilyl group is present on the anionic carbon atom, the reactions of the carban-ion derived from the a,a-bis(trimethylsilyl) esters with ketones are unsuccessful, probably because of steric reasons, and result only in enolization [197]. 

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