Lithium diisopropylamide reaction with nitriles

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

The conversion of the polystyrene-supported selenyl bromide 289 into the corresponding acid 290 allowed dicyclohexylcarbodiimide (DCC)-mediated coupling with an amidoxime to give the 1,2,4-oxadiazolyl-substituted selenium resin 291 (Scheme 48). Reaction with lithium diisopropylamide (LDA) and allylation gave the a-sub-stituted selenium resin 292, which was then used as an alkene substrate for 1,3-dipolar cycloaddition with nitrile oxides. Cleavage of heterocycles 293 from the resin was executed in an elegant manner via selenoxide syn-elimination from the resin <2005JC0726>. 

Lithium salts of resonance-stabilized organic anions have also found a role in carbon-phosphorus bond formation by displacement at phosphorus. The generation of the lithium salt derived from acetonitrile (or other aliphatic nitriles by reaction with butyl lithium or lithium diisopropylamide) provides for carbon-phosphorus bond formation by displacement of halide from phosphorus (Equation 4.24).68... 

A somewhat different approach to this series of compounds involves the reaction between a carbanion and an aromatic nitrile. Thus, a series of methylpyrazines 253 is first treated with lithium diisopropylamide (LDA) to generate an anion at the methyl group. Addition of an aromatic nitrile produces 254 (Equation 89) <2003JME222, 2004EUP1388541>. Many other examples have been reported <2003JME222>, including some with substituents at the open position in structure 254. 

Alkyl and arylmagnesium halides react with 2-methylquinoxaline by addition of one mole of reactant to the 3,4-bond. After hydrolysis the 2-alkyl- or 2-aryl-l,2-dihydro-3-methylquinoxalines (52) are obtained. When ethylmagnesium bromide is used a dimeric by-product (53) is also isolatedReaction of 2,3-dimethylquinoxaline with benzonitrile and lithium amide gives l-amino-l-phenyl-2-(3-methyl-2-quinoxalinyl)-ethylene (54). The mono- and dilithium salts of 2,3-dimethylquinoxaline have been generated from the quinoxaline by reaction with one or two equivalents of lithium diisopropylamide (LiNPr, respectively. These salts have been reacted with a variety of electrophilic reagents such as alkyl halides, aryl ketones, esters, and nitriles. " ... 

The chemical operations described in the literature to introduce or into citric acid molecule are based essentially on the Grimaux and Adam synthesis. Labeled citric acid was prepared by Wilcox et al. [35] in the reaction of Na CN with 3-chloro-2-carboxy-2-hydroxybutyric acid and the formed nitrile was hydrolyzed directly with hydrochloric acid. From this solution, citric acid was isolated in the form of calcium citrate and finally converted to the acid. An alternative procedme was proposed by Rothchild and Fields [36] to obtain trimethyl citrate from labeled sodium cyanide and di-chloromethyl glycolate. A more complex synthesis of C labeled citric acid is described by Winkel et al. [39]. They used labeled methyl acetate and acetyl chloride (in the presence of hthium 1,1,1,3,3,3,-hexamethyldisilazide, [(CH3)2Si]2NLi which was dissolved in tetrahydiofuran) to obtain methyl acetoac-etate. It reacts in the presence of lithium diisopropylamide, [(CH3)2CH]2NLi, also dissolved in tetrahydrofuran, with dimethyl carbonate to give dimethyl 1,3-ace-tonedicaiboxylate. It is dicarboxylated by the action of bisulfite and potassium cyanide is converted to 3-cyano-3-hydroxy-l,5 pentanedioate and finally hydrolyzed by hydrochloric acid to citric acid. 

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