Nucleophiles ketone enolates

Alditol (Section 25 18) The polyol obtained on reduction of the carbonyl group of a carbohydrate Aldol addition (Section 18 9) Nucleophilic addition of an aldehyde or ketone enolate to the carbonyl group of an aide hyde or a ketone The most typical case involves two mole cules of an aldehyde and is usually catalyzed by bases... 

Not all carbon nucleophiles will add to arene chromium tricarbonyl complexes. For example, alkyllithium reagents and simple ketone enolates do not give adducts.325... 

In reactions with azides, ketones are directly converted to 5-hydroxytriazolines. Ketone enolate 247, generated by treatment of norbornanone 246 with LDA at 0°C, adds readily to azides to provide hydroxytriazolines 248 in 67-93% yield. Interestingly, l-azido-3-iodopropane subjected to the reaction with enolate 247 gives tetracyclic triazoline derivative 251 in 94% yield. The reaction starts from an electrophilic attack of the azide on the ketone a-carbon atom. The following nucleophilic attack on the carbonyl group in intermediate 249 results in triazoline 250. The process is completed by nucleophilic substitution of the iodine atom to form the tetrahydrooxazine ring of product 251 (Scheme 35) <2004JOC1720>. 

Scheme 16 Synthesis of ( )-phoracantholide based on nucleophilic opening of epoxides by ketone enolates...

Ketone Enolates Derived from Silyl Enol Ethers as Nucleophiles... 

Scheme 9.15 Alkylations with ketone enolates derived from silyl enol ethers as nucleophiles.

Thus, ketone enolates easily substitute chlorine in position 2 of the electrophilic nucleus of pyrazine (1,4-diazabenzene), and even in the dark, the reaction proceeds via the Sj l mechanism (Carver et al. 1981). It is expected that the introduction of the second chlorine in the ortho position to 4-nitrogen in the electrophilic nucleus of pyrazine promotes the ion-radical pathway even more effectively. However, 2,6-dichloropyrazine in the dark or subjected to light reacts with the same nucleophiles by Sr.,2 and not S nI mechanism (Carver et al. 1983). The authors are of the opinion that two halogens in the pyrazine cycle facilitate the formation of a-complex to the extent that deha-logenation of anion-radicals in solution and a subsequent nucleophilic attack of free pyrazine radical become virtually impossible. Thus, the reaction may either involve or exclude the intermediate a-complex, and only special identification experiments can tell which is the true one. 

Now let us look at the ease of forming the enolate anion nucleophiles. Ketones are more acidic than esters (see Section 10.7). Taken together, these factors mean the more favoured product is going to be the P-diketone (acetylacetone), formed from a ketone nucleophile by a Claisen reaction with an ester. This is the reaction observed. 

Conjugate addition can also be carried out by completely forming the nucleophilic enolate under kinetic conditions. Ketone enolates formed by reaction with LDA in THF react with enones to give 1,5-diketones (entries 1 and 2, Scheme 1.12). Esters of 1,5-dicarboxylic acids are obtained by addition of ester enolates to a,/J-unsaturated esters (entry 5, Scheme 1.12). 

The addition of the nucleophilic carbanion-enolate, usually of an aldehyde, to the C=0 group of its parent compound is called an aldol condensation. The product is a /3-hydroxycarbonyl compound. In a mixed aldol condensation the carbanion-enolate of an aldehyde or ketone adds to the 0=0 group of a molecule other than its parent. The more general condensation diagramed above is termed an aldol-type condensation. Since the C, not the O, is the more reactive site in the hybrid, the enolate contributing structure is usually omitted when writing equations for these reactions. This is done even though the enolate is the more stable and makes the major contribution. 

The procedure reported here is based on a reaction discovered by Bunnett and Creary, and was first employed for preparative purposes by Bunnett and Traber.3 It is attractive because of the high yield obtained, the ease of work-up, and the cleanliness of the reaction. The reaction is believed to occur by the SRN1 mechanism, which involves radical and radical anion intermediates.2,4 The SRN1 arylation of other nucleophiles, especially ketone enolate ions,5 ester enolate ions,6 picolyl anions,7 and arenethiolate ions,8 has potential application in synthesis. 

In a side-reaction 10-15% carboxylic acids are produced by oxidative cleavage of the ketone enolates. The cleavage is favoured by higher temperatures e.g. cyclo-hexanol leads to 80% cyclohexanone and 16% adipic acid at 25 °C, whilst at 80 °C 5% ketone and 42% diacid are found. These acidic by-products are easily separated, since they remain in the alkaline solution during workup. The oxidation of 6 gave the acetal 7 as main product (28%) together with 4% of the ketone 8 and 56% of unchanged 6. The acetal 7 is probably formed by nucleophilic addition of the alcohol 6 at the activated triple bond of ketone 8. 

More reactive carbon nucleophiles than enolates can also be prepared on insoluble supports (see Chapter 4) and are used to convert aldehydes or ketones into alcohols. Organolithium compounds have been generated on cross-linked polystyrene by deprotonation of formamidines and by metallation of aryl iodides (Table 7.5). Similarly, support-bound organomagnesium compounds can be prepared by metallation of aryl and vinyl iodides with Grignard reagents. The resulting organometallic compounds react with aldehydes or ketones to yield the expected alcohols (Table 7.5). 

Nucleophilic attack on a rt-allyl ligand of a metal complex occurs in general at one of the terminal carbons to afford allylated products. The attack, however, may be directed to the central carbon atom of the 7i-allyl group to produce cyclopropyl derivatives by appropriate choice of nucleophile, metal ligand and reaction conditions (equation 33). A variety of nucleophiles (pA"a > 20) including ester and ketone enolates and a-sulfonyl carbanions react with... 

This section describes the additions of stabilized carbon nucleophiles, such as cyanide, malonate, ketone enolates, enamines, etc., to alkenic ir-systems. These reactions are highly useful in organic synthesis since they are all carbon-carbon bond-forming reactions, and therefore have been used extensively in organic chemistry. 

Allyl esters of acetoacetates7-8-9-11 react with Pd° catalysts to generate initially a bisphosphine allylpal-ladium cation, with the 3-ketocarboxylate serving as counterion. Under the reaction conditions the (3-ketocarboxylate decarboxylates, yielding a -Tr-allylpalladium ketone enolate complex. The required nucleophile is thus formed in situ and is capable of Pd-mediated alkylation. A wide spectrum of reactions have been based on this chemistry which will be discussed in later sections. 

Ketoacids126,127 form the same intermediates as the allyl 3-ketoesters by nucleophilic addition of the carboxylate to a n-allylpalladium complex. Decarboxylation generates the allylpalladium enolate, which again yields Pd° and allylated ketone. Enol silyl ethers have also been employed with allyl arsenites93 to provide allylated ketones. 

The aldol condensation is the reaction of an aldehyde or ketone enolate with an aldehyde or ketone to give a /3-hydroxy aldehyde or ketone. A simple aldol reaction is one in which the enolate nucleophile is derived from the carbonyl electrophile. Very often the /3-hydroxy carbonyl product dehydrates to give an... 

The formation of C-C bonds in SN reactions using ketone enolates as nucleophiles has been reviewed.4... 

Trichlorosilylenolates of type 13 were used as nucleophiles. Such enolates are highly activated ketone derivatives and react spontaneously with several aldehydes at room temperature. At —78 °C, however, the uncatalyzed reaction can be suppressed almost completely (formation of the undesired racemic aldol adduct is only 4%). Thus, at —78 °C and in the presence of the chiral organocatalyst 14 the acetone-derived enolate and benzaldehyde gave the desired adduct in high yield... 

Several organic molecules have been found to catalyze this process efficiently. As described in Section 6.2.1.1, the syntheses can be performed as indirect or direct aldol reactions. Thus, as nucleophiles, ketones were applied directly or enolates can be used as starting materials. 

Aldol reactions using phosphoramides as organocatalysts The organic base-catalyzed asymmetric intermolecular aldol reaction with ketone-derived donors can be successfully applied to the construction of aldol products with two stereogenic centers [82-86]. Trichlorosilyl enolates of type 51 have been used as nucleophiles. Such enolates are strongly activated ketone derivatives and react spontaneously with several aldehydes at —80 °C. A first important result was that in the aldol reaction of 51 catalytic amounts of HMPA led to acceleration of the rate of reaction. After screening several optically active phosphoramides as catalysts in a model reaction the aldol product anti-53 was obtained with a diastereomeric... 

Equation 76) <1993OM3019>, which react as ester and ketone enolate equivalents, respectively. The latter reaction requires the use of fluoride ion activation (tetrabutylammonium fluoride, TBAF) to actuate the addition. Central carbon alkylation is less common for allylpalladium reactions despite this, nucleophilic alkylation of TMEDA-stabilized 1,3-diphenylallyl palladium complexes proceeds selectively to the central carbon (Equation 77) <1995AGE100>. 

Fig. 6.21. In situ activation of a carboxylic acid—i.e., the side chain carboxyl group of protected L-aspartic acid—as the mixed anhydride (B) and its aminolysis to a Weinreb amide. How this Weinreb amide acylates an organolithium compound is shown in Figure 6.44. The acylation of an H nucleophile by a second Weinreb amide is presented in Figure 6.42 and the acylation of a di(ketone enolate) by a third Weinreb amide in Figure 13.64. Figure 6.50 also shows how Weinreb amides of carboxylic acids can be obtained by C,C bond formation.

Intramolecular nucleophilic substitution of a chlorine atom in an a-chloro amide, by a ketone enolate, causes cyclization and this has been used in the synthesis of some alkaloid ring systems (equation 87)576. The product of this reaction is a key intermediate for the synthesis of Strychnos, Aspidosperma, Schizozygane and Eburnamine alkaloids. 

---