Nucleophilic components

Retrosynthetic path b in Scheme 3.1 corresponds to reversal of the electrophilic and nucleophilic components with respect to the Madelung synthesis and identifies o-acyl-iV-alkylanilines as potential indole precursors. The known examples require an aryl or EW group on the iV-alkyl substituent and these substituents are presumably required to facilitate deprotonation in the condensation. The preparation of these starting materials usually involves iV-alkyla-tion of an o-acylaniline. Table 3.3 gives some examples of this synthesis. 

In stepwise additions, ketenes are usually the nucleophilic component, so that such additions can be catalyzed by Lewis acids, such as the additions of trimethylsilylketenes to aldehydes, catalyzed by BF3 (Scheme 14) (79JOC733). However, the roles can be reversed, such as in the addition of chlorocyanoketene to benzaldehyde (79JA5435). 

It is not difficult to incorporate this result into the general mechanism for hydrogen halide additions. These products are formed as the result of solvent competing with halide ion as the nucleophilic component in the addition. Solvent addition can occur via a concerted mechanism or by capture of a carbocation intermediate. Addition of a halide salt increases the likelihood of capture of a carbocation intermediate by halide ion. The effect of added halide salt can be detected kinetically. For example, the presence of tetramethylammonium... 

Due to mechanistic requirements, most of these enzymes are quite specific for the nucleophilic component, which most often is dihydroxyacetone phosphate (DHAP, 3-hydroxy-2-ox-opropyl phosphate) or pyruvate (2-oxopropanoate), while they allow a reasonable variation of the electrophile, which usually is an aldehyde. Activation of the donor substrate by stereospecific deprotonation is either achieved via imine/enamine formation (type 1 aldolases) or via transition metal ion induced enolization (type 2 aldolases mostly Zn2 )2. The approach of the aldol acceptor occurs stereospecifically following an overall retention mechanism, while facial differentiation of the aldehyde is responsible for the relative stereoselectivity. 

The formation of diazosulfones and diazosulfonates can also be described as S-coupling. Here the sulfur atom of the sulfinic acid or the sulfite ion, respectively, appears as the basic centre of the nucleophilic component, whereas the oxygen atoms do... 

Aldol Reactions of Lithium Enolates. Entries 1 to 4 in Scheme 2.1 represent cases in which the nucleophilic component is a lithium enolate formed by kinetically controlled deprotonation, as discussed in Section 1.1. Lithium enolates are usually highly reactive toward aldehydes and addition occurs rapidly when the aldehyde is added, even at low temperature. The low temperature ensures kinetic control and enhances selectivity. When the addition step is complete, the reaction is stopped by neutralization and the product is isolated. 

Selenylation can also be done under conditions in which another nucleophilic component of the reaction captures the selenium-bridged ion. For... 

Carbonylation reactions can be carried out with a boronic acid as the nucleophilic component.251... 

Quite recently, not only Lewis adds, but also Bronsted adds were found to be effedive catalysts for the three-component Mannich-type reactions in water with the aid of a surfadant. For example, Akiyama and co-workers1301 have reported that a combination of HBF4 and SDS is effedive for the readions of aldehydes, amines, and silyl enolates. We have found that dodecylbenzenesulfonic add (DBSA), a Bronsted add with a surfadant moiety, also catalyzes the reactions in water.1311 Furthermore, DBSA can be used for the dired Mannich-type reactions of aldehydes, amines, and ketones, without using silyl enolates as nucleophilic components (Eq. 8).1321... 

Aldol addition and condensation reactions involving two different carbonyl compounds are called mixed aldol reactions. For these reactions to be useful as a method for synthesis, there must be some basis for controlling which carbonyl component serves as the electrophile and which acts as the enolate precursor. One of the most general mixed aldol condensations involves the use of aromatic aldehydes with alkyl ketones or aldehydes. Aromatic aldehydes are incapable of enolization and cannot function as the nucleophilic component. Furthermore, dehydration is especially favorable because the resulting enone is conjugated with the aromatic ring. 

Coupling of organometallic reagents with hahdes in a carbon monoxide atmosphere leads to ketones by incorporation of a carbonylation step.147 148 These reactions involved a migration of one of the organic subsituents to the carbonyl carbon, followed by reductive elimination. These reactions can be carried out with stannanes149 or boronic acids150 151 as the nucleophilic component. 

Of key importance in the Lewis acid promoted living anionic polymerization of methacrylic esters with aluminum porphyrin is how to suppress the undesired reaction between the nucleophile (2j ) and the Lewis acid, leading to termination of polymerization (Fig. 11). As mentioned in previous sections, one of our approaches was to make use of sterically crowded Lewis acids such as methyla-luminum bis(ort/zo-substituted phenolates). This section focuses attention on the steric bulk of the nucleophile component (2 ), by using strategically designed aluminum porphyrins and some other methacrylates, for the purpose of understanding the scope and limitation of this method (Fig. 12). 

The combination of his-electrophilic and his-nucleophilic components is the basis of general pyrimidine synthesis. A reaction between an amidine (urea or thiourea or guanidine) and a 1,3-diketo compound produces corresponding pyrimidine systems. These reactions are usually facilitated by acid or base catalysis. 

In the presence of weak nucleophiles (water, acetic acid, methanol) in acetonitrile, F-Teda BF4 (6) reacts with styrene derivatives to introduce a fluorine atom and the nucleophile component on adjacent carbon atoms giving products 18.88,89... 

Reactions of this type in which carbonyl compounds combine together to form longer carbon chains are (loosely) known as condensation reactions. So far we have considered only self-condensations, that is ones in which both the nucleophilic component and the electrophilic component are forms of the same molecule. How would you make this compound ... 

Controversy remains in the determination of substrate tolerance for KdgA/KhgA aldolases from different sources. Early assay studies with KhgA prepared [127-129] from rat liver concluded that the catalyst had an unusually wide ranging tolerance for nucleophilic components, including a number of 3-substituted pyruvate derivatives as well as pyruvaldehyde, acetaldehyde, and pyruvic esters [135], Later, other workers using enzymes from rat or bovine liver and from E. coli reported their inability to reproduce these results but noted a rather limiting specificity [136]. 

Phosphoramide Catalysis. In a series of elegant studies, Denmark has described a process utilizing trichlorosilyl enolates 27 and 28 as the nucleophilic component in catalytic, enantiose-lective aldol addition reactions (Scheme 8B2.3) [151. These enoxysilanes are prepared by treatment of stannyl enolates with SiCl4. Although trichlorosilyl enolates are sufficiently reactive entities to undergo addition to aldehydes rapidly at -78°C, Denmark documented that... 

---