Other Carbon Nucleophiles

Many other carbon nucleophiles have been developed. Only two additional types are introduced here, but both provide interesting variations on the themes that have been presented so far. 

The first of these nucleophiles is derived from a dithiane. A dithiane can be prepared by the reaction of an aldehyde with 1.3-propanedithiol. This reaction, described in Section 18.9, is the sulfur analog of acetal formation and requires a proton or Lewis acid catalyst  

The hydrogen on the carbon attached to the two sulfur atoms is weakly acidic (pAf, = 31) and can be removed by reaction with a strong base, such as butyllithium. (Butyl-lithium is also a nucleophile, and therefore it is not used to generate enolate anions from carbonyl compounds. However, the dithiane is not electrophilic, so butyllithium can be used as the base in this reaction.) 

The acidity of the dithiane can be attributed to the stabilization of the conjugate base by the inductive effect of the sulfurs. 

The dithiane anion is a good nucleophile in SN2 reactions. After it has been alkylated, the thioacetal group can be removed by hydrolysis using Hg2+ as a Lewis acid catalyst. 

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Formation of ketones. Ketones can be prepared by the carbonylation of halides and pseudo-halides in the presence of various organometallic compounds of Zn, B, Al, Sn, Si, and Hg, and other carbon nucleophiles, which attack acylpalladium intermediates (transmetallation and reductive elimination). 

Chapters 1 and 2 focus on enolates and other carbon nucleophiles in synthesis. Chapter 1 discusses enolate formation and alkylation. Chapter 2 broadens the discussion to other carbon nucleophiles in the context of the generalized aldol reaction, which includes the Wittig, Peterson, and Julia olefination reactions. The chapter and considers the stereochemistry of the aldol reaction in some detail, including the use of chiral auxiliaries and enantioselective catalysts. 

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. 

A variety of other carbon nucleophiles have been alkylated with alcohols including malonate esters, nitroaUcanes, ketonitriles [119, 120], barbituric acid [121], cyanoesters [122], arylacetonitriles [123], 4-hydroxycoumarins [124], oxi-ndoles [125], methylpyrimidines [126], indoles [127], and esters [128]. Selected examples are given in Scheme 35. Thus, benzyl alcohol 15 could be alkylated with nitroethane 147, 1,3-dimethylbarbituric acid 148, phenylacetonitrile 149, methyl-pyrimidine 150, and even f-butyl acetate 151 to give the corresponding alkylated products 152-156. 

Grignard reagents and other carbon nucleophiles can react with imidoyl halides 438 to produce imines 439 (equation 186). Other nucleophiles may be used to displace successfully the halide. 

Attempts to rationalize the regioselectivity of attack of nucleophiles on the aryl rings of nitrenium ions in terms of calculated properties of the ions (LUMO coefficients, localization energies, etc.) have been moderately successful. An adequate explanation of electrophilic reactivity of nitrenium ions at N with certain nucleophiles such as glutathione, C-8 of d-G, and other carbon nucleophiles has not yet appeared. ... 

Other carbon nucleophiles may also be employed in such a coupling reaction that provides (3-amino ketones and polyol intermediates. As shown in Scheme 32, aryl-Grignard reagents react at low temperature with the Ai-Boc p-lactam 96 to afford p-aminoketones 97 in 90-96% yields as the exclusive products. In no case over-addition is observed, even when an excess of the Grignard reagent is present in the reaction medium. On the other hand, when the reaction is performed at room temperature, only tertiary carbinols 98 are produced. 

The metal-bound carbon atom in organopalladium(II) complexes can formally react either as an electrophile or as a nucleophile. Treatment of arylpalladium(II) complexes with alkyl halides, for example, yields products of homo- or cross-coupling, possibly via intermediate formation of hexacoordinated Pd(IV) complexes [31,33] (Scheme8.1). Treatment of the same type of complex with alkyl Grignard reagents or other carbon nucleophiles, on the other hand, also yields the corresponding alkyl arenes via nucleophilic displacement of a ligand followed by reductive elimination (Scheme 8.1). 

Scheme8.5. Palladium-catalyzed cross-coupling reactions of stannanes and other carbon nucleophiles with aryl, allyl, and vinyl bromides [56, 69-72],...

Predicting the Products of the Reactions of Enolate and Other Carbon Nucleophiles... 

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