Acyl nucleophilic substitution, carbanion

Surprisingly carbonyl-substituted carbanions of phosphonates, in which the negative charge is delocalized over two oxygen atoms, are much more nucleophilic than the corresponding phosphoranes. This effea has first been observed by Homer, and has often been utilized in the synthesis of acylated olefins (R.D. Clark, 1975). 

The net result is that Nu replaces Z—a nucleophilic substitution reaction. This reaction is often called nucleophilic acyl substitution to distinguish it from the nucleophilic substitution reactions at sp hybridized carbons discussed in Chapter 7. Nucleophilic substitution with two different nucleophiles—hydride (H ) and carbanions (R )— is discussed in Chapter 20. Other nucleophiles are examined in Chapter 22. 

CHBr3 or iodoform, CHI3). Note that the second step of the reaction is a nucleophilic acyl substitution of CX3 by OH. That is, a halogen-stabilized carbanion acts as a leaving group. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

Being aware of the fact that a hetero-substituted carbon-carbon double bond is convertible into a carbonyl group, one can use a-hetero-substituted lithio-alkenes 2 as nucleophilic acylation reagents 142 and 143, which display the umpoled d reactivity, provided that the carbanionic character is effective. Depending on the hetero-snbstitnent X, the conversion of the vinyl moiety into a carbonyl gronp can be effected either by hydrolysis or by ozonolysis. The former procednre has been applied preferentially in the case of lithiated vinyl ethers, whereas the latter has been nsed in particnlar for cleavage of the double bond in such products that result from the reaction of hthiated vinyl bromides with electrophiles (Scheme 17). 

As noted in Section 4.2.1, the gas phase has proven to be a useful medium for probing the physical properties of carbanions, specifically, their basicity. In addition, the gas phase allows chemists to study organic reaction mechanisms in the absence of solvation and ion-pairing effects. This environment provides valuable data on the intrinsic, or baseline, reactivity of these systems and gives useful clues as to the roles that solvent and counterions play in the mechanisms. Although a variety of carbanion reactions have been explored in the gas phase, two will be considered here (1) Sn2 substitutions and (2) nucleophilic acyl substitutions. Both of these reactions highlight some of the characteristic features of gas-phase carbanion chemistry. 

In continuation of our investigations on asymmetric nucleophilic acylations with lithiated a-aminonitriles [40], we envisaged the asymmetric synthesis of 3-substituted 5-amino-4-oxo esters A, bearing both a-amino ketone and 5-amino ester functionalities (Scheme 1.1.14) [41]. Since a-amino ketones are precursors of chiral p-amino alcohols [42, 43] and chiral amines [43], their asymmetric synthesis has the potential to provide valuable intermediates for the synthesis of biologically active compounds, including peptidomimetics [44]. The retrosynthetic analysis of A leads to the a-aminoacyl carbanion B and p-ester carbocation... 

Most SN reactions of hydride donors, organometallic compounds, and heteroatom-stabi-lized carbanions at the carboxyl carbon follow the mechanism shown in Figure 6.2. Thus, the substitution products, i.e., the aldehydes and ketones C, form in the presence of the nucleophiles. Thus, when the nucleophile and the acylating agent are used in a 2 1 ratio, alcohols F are always produced. 

Next, we shall turn to reactions in which the carbonyl group plays both its roles the aldol condensation, in which a carbanion generated from one molecule of aldehyde or ketone adds, as a nucleophile, to the carbonyl group of a second molecule and the Claisen condensation, in which a carbanion generated from one molecule of ester attacks the carbonyl group of a second molecule, with acyl substitution as the final result. 

Like the aldol condensation and related reactions, the Claisen condensation involves nucleophilic attack by a carbanion on an electron-deficient carbonyl carbon. In the aldol condensation nucleophilic attack leads to addition the typical reaction of aldehydes and ketones in the Claisen condensation, nucleophilic attack leads to substitution, the typical reaction of acyl compounds (Sec. 20.4). 

If excess base and halogen are used, a methyl ketone is triply hali genated and then cleaved by base in the haloform reaction. The produc are a carboxylic acid plus a so-called haloform (chloroform, CHClg bromo-form, CHBrg or iodoform, CHL<). Note that the. second step of the reaction is a nucleophilic acyl substitution of CX3 by OH. That is, a carbanion acts as a leaving group. 

Using this method, synthesis of functionalized substituted cyclopropanes can be achieved via nucleophilic alkylation of the monoacetates of but-2-ene-l,4-diols 18 with malonates (and similar stabilized) carbanions in the presence of a palladium(0) catalyst. Subsequent acylation of the second hydroxyl function and subsequent treatment with base in the presence of the palladium(0) catalyst leads to intramolecular nucleophilic alkylation. This method and similar conversions have been applied to numerous other cyclopropane ring constructions. - - ... 

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