Enolate as a nucleophile

Nature builds carbon-carbon bonds essentially by aldol or Claisen-type reactions, both involving a carbonyl group as an electrophile, and an enol or enolate as a nucleophile. A less-frequent reaction bears a formal analogy to the Claisen acyloin condensation. The aldol reaction of carbohydrates always involves an aldehyde as the electrophile, and an aldehyde or ketone as the nucleophile (see Eq. 1). 

Lately, Balme et al. reported on a new and completely different reaction mode leading to ring-annelated cyclohexadienes similar to those obtained from inter-intramolecular Heck reactions with subsequent 6tt-electrocyclizations (cf. Scheme 29). The method employs conjugated enynes with a tethered stabilized enolate as a nucleophilic carbon center, generated... 

The Robinson annulation involves two reactions occurring in tandem a Michael reaction followed by an aldol condensation (loss of water is normally expected in this reaction so the aldol product is typically dehydrated to give an a,P-unsaturated cyclohexenone product). The reaction of an enolate as a nucleophile attacking the beta carbon of methyl vinyl ketone as the electrophile (a Michael reaction) forms the first carbon-carbon bond in the Robinson annulation and results in a 1,5-dicarbonyl product. The methyl group from MVK serves as the nucleophile for the second part of the reaction when it finds a carbonyl electrophile six atoms away to undergo an intramolecular aldol reaction. After dehydration, an a,P-unsaturated cyclohexenone product is formed. Ultimately, two new carbon-carbon bonds are formed within the cyclohexenone moiety. 

Step 1 The aldehyde and its enolate are m equilibrium with each other m basic solution The enolate acts as a nucleophile and adds to the carbonyl group of the aldehyde ... 

Alkylation occurs by an 8 2 mechanism m which the enolate ion acts as a nucleophile toward the alkyl halide... 

Because the pK s of the aldehyde and water are similar, the solution contains significant quantities of both the aldehyde and its enolate. Moreover, their reactivities are complementary. The aldehyde is capable of undergoing nucleophilic addition to its carbonyl group, and the enolate is a nucleophile capable of adding to a carbonyl group. And as shown in Figure 18.4, this is exactly what happens. The product of this step is an alkoxide, which abstracts a proton from the solvent (usually water or ethanol) to yield a (3-hydroxy aldehyde. A compound of this type is known as an aldol because it contains both an aldehyde function and a hydroxyl group (aid + ol = aldol). The reaction is called aldol addition. 

Although the carbonyl condensation reaction appears different from the three processes already discussed, it s actually quite similar. A carbonyl condensation reaction is simply a combination of a nucleophilic addition step and an -substitution step. The initially formed enolate ion of one acetaldehyde molecule acts as a nucleophile and adds to the carbonyl group of another acetaldehyde molecule, as shown in Figure 5. 

The enolate ion adds as a nucleophile to the carbonyl group of a second acetaldehyde, producing a tetrahedral aikoxide ion. 

We ve now studied three of the four general kinds of carbonyl-group reactions and have seen two general kinds of behavior. In nucleophilic addition and nucleophilic acyl substitution reactions, a carbonyl compound behaves as an electrophile. In -substitution reactions, however, a carbonyl compound behaves as a nucleophile when it is converted into its enol or enolate ion. In the carbonyl condensation reaction that we ll study in this chapter, the carbonyl compound behaves both as an electrophile and as a nucleophile. 

The enolate ion acts as a nucleophilic donor and adds to the electrophilic carbonyl group of a second carbonyl compound. 

The prime functional group for constructing C-C bonds may be the carbonyl group, functioning as either an electrophile (Eq. 1) or via its enolate derivative as a nucleophile (Eqs. 2 and 3). The objective of this chapter is to survey the issue of asymmetric inductions involving the reaction between enolates derived from carbonyl compounds and alkyl halide electrophiles. The addition of a nucleophile toward a carbonyl group, especially in the catalytic manner, is presented as well. Asymmetric aldol reactions and the related allylation reactions (Eq. 3) are the topics of Chapter 3. Reduction of carbonyl groups is discussed in Chapter 4. 

The first part is a Birch reduction, with NH3 as the proton source. It gives the carboxylate enolate as the initial product. When the alkyl halide is added, the enolate acts as a nucleophile to give the C3-C7 bond in an Sn2 reaction. 

This resonance form can then act as a nucleophile, in much the same way as an enolate anion can. However, there is a marked difference, and this is what makes enamines such useful synthetic intermediates. Generation of an enolate anion requires the treatment of a carbonyl compound with a base, sometimes a very strong base (see Section 10.2). 

In the aldol reaction, we saw an enolate anion acting as a nucleophile leading to an addition reaction with aldehydes and ketones. 

These are reacted together in basic solution. It can be deduced that the 1,3-diketone is more acidic than the monoketone substrate, so will be ionized by removal of a proton from the carbon between the two carbonyls to give the enolate anion as a nucleophile. This attacks the a,P-unsaturated ketone in a Michael reaction. It is understandable that this large nucleophile prefers to attack the unhindered -position rather than the more congested ketone carbonyl. 

Hydroxycoumarin can be considered as an enol tautomer of a 1,3-dicarbonyl compound conjugation with the aromatic ring favours the enol tautomer. This now exposes its potential as a nucleophile. Whilst we may begin to consider enolate anion chemistry, no strong base is required and we may formulate a mechanism in which the enol acts as the nucleophile, in a simple aldol reaction with formaldehyde. Dehydration follows and produces an unsaturated ketone, which then becomes the electrophile in a Michael reaction (see Section 10.10). The nucleophile is a second molecule of 4-hydroxycoumarin. 

We can insert the heteroatom into the rest of the carbon skeleton, or attempt to join two units, one of which contains the heteroatom, by means of C-C and C-heteroatom linkages. To make the new bonds, two reaction types are most frequently encountered. Heteroatom-C bond formation is achieved using the heteroatom as a nucleophile to attack an electrophile such as a carbonyl group (see Section 7.7.1). Aldol-type reactions may be exploited for C-C bond formation (see Section 10.3), employing enamines and enols/enolate anions (see Section 10.5). 

It is conceptually easier to consider initially the aldol reaction rather than the reverse aldol reaction. This involves generating an enolate anion from the dihydroxyacetone phosphate by removing a proton from the position a to the ketone group. This enolate anion then behaves as a nucleophile towards the aldehyde group of glyceraldehyde 3-phosphate, and an addition reaction occurs, which is completed by abstraction of a proton, typically from solvent. In the reverse reaction, the leaving group would be the enolate anion of dihydroxyacetone phosphate. 

An interesting bifunctional system with a combination of In(OTf)3 and benzoyl-quinine 65 was developed in p-lactam formation reaction from ketenes and an imino ester by Lectka [Eq. (13.40)]. High diastrereo- and enantioselectivity as well as high chemical yield were produced with the bifunctional catalysis. In the absence of the Lewis acid, polymerization of the acid chloride and imino ester occurred, and product yield was moderate. It was proposed that quinine activates ketenes (generated from acyl chloride in the presence of proton sponge) as a nucleophile to generate an enolate, while indium activates the imino ester, which favors the desired addition reaction (66) ... 

The generation of an enolate (as a C(l) nucleophile) by a deprotonation step was achieved when the alternative mode of enolization towards C(3) was... 

The disulfide dimers of 2-aminothiophenols have also been used in the syntheses of benzothiazines. In this case, nitrogen acts as a nucleophile and sulfur as an electrophile. Reagents that have nucleophilic carbons adjacent to an electrophilic carbon can be reacted with these disulfides. Examples include a,(3-unsaturated esters that undergo conjugate addition followed by enolate addition to sulfur (Equation 86) <1983J(P1)567>, and 1,3-dicarbonyl compounds such as ethyl acetoacetate <2005AXEo2716> and dimethyl malonate <2006ARK(xv)68> (Scheme 63). 

Enolate 18 was prepared by two different methods either by deprotonation of the corresponding lactone 20 or 21 by LDA (method A) or by 1,4-addition of bis(methylthio)trimethylsilylmethyl-lithium as a nucleophile to the lactone 22 (method B)63,64... 

Methods for the preparation of the requisite -2,/l-unsaturaied iron-acyl complexes are presented in Section D.1.3.4.2.5., but it is noted here that several examples of 1,4-alkylative preparations of a-enolates from in situ generated fi-complexes, such as 9, have been reported in which the alkyllithium base employed acts both as a base to produce the unsaturated species via elimination and subsequently, as a nucleophile to afford alkylation products 10 and 1244. 

Conseqnently, the magnesinm chelate 71 can also react as a nucleophilic donor in aldol reactions. In the chemistry involving magnesium chelates, these two aspects model their mode of action as nucleophilic partners in aldol condensations. This is exemplified in aldol condensations of y-diketones . Thus, sodium hydroxyde catalyzed cyclization of diketone 73 to give a mixtnre of 3,5,5-trimethyl-cyclopent-2-enone 74 and 3,4,4-trimethyl-cyclopent-2-enone 75 in a 2.2/1 isomeric ratio (equation 100). When treated with magnesinm methanolate, the insertion of a a-methoxy carbonyl group as control element, as in 76, allows the formation of a chelated magnesium enolate 77, and the major prodnct is now mainly the aldol 78. This latter treated with aqueous NaOH provides the trimethylcyclopent-2-enones 74 and 75 in a 1/49 ratio. 

In aldol condensation, the enolate anion of one carbonyl compound reacts as a nucleophile, and attacks the electrophilic carbonyl group of another one to form a larger molecule. Thus, the aldol condensation is a nucleophilic addition reaction. 

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