Alkylation of esters and nitriles

The Alkylation of Esters and Nitriles Arthur C. Cope. H. I.. Holmes, and Herbert O. House... 

All lation of Garbanions. Concentrated N a OH—hen syl triethyl amm onium chloride is the base/catalyst system normally used for this type of process (20). Classes of compounds alkylated in this way include phenylacetonitriles, ben2ylketones, simple aUphatic ketones, certain aldehydes, aryl sulfones, P-ketosulfones, P-ketoesters, malonic esters and nitriles, phenylacetic esters, indene, and fluorene (see Alkylation). 

Ketones, esters, and nitriles can all be alkylated using LDA or related dialkyl-amide bases in THE. Aldehydes, however, rarely give high yields of pure products because their enolate ions undergo carbonyl condensation reactions instead of alkylation. (We ll study this condensation reaction in the next chapter.) Some specific examples of alkylation reactions are shown. 

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 reductive capability of CgK has been a subject of interest (LA). Uses for CgK include the reductive cleavage of carbon-sulfur bonds (S5), the reductive alkylation of nitriles and esters (S6), and the reductive alkylation of aldehydes and ketones (S7). The activity of CgK has... 

Scheme 1.6 gives some examples of alkylation of esters, amides, and nitriles. Entries 1 and 2 are representative ester alkylations involving low-temperature... 

Scheme 1.9. Alkylation of Esters, Amides, Imides and Nitriles... 

Activated nitro and halo substituents have been efficiently replaced by a variety of alkyl groups via SsAx reaction with carbanions. Examples include the displacement of the nitro group in compounds (10 X = 4-PhCO, 4-MeOCO, 4-CN, 4-N02, 4-PhS02, 3,5-(CF3>2) by the anion of 2-nitropropane in HMPA at room temperature (equation 2),83 and the reaction of p-dinitrobenzene with several ketones, esters and nitriles (RH equation 3) in Bu OK/liquid NH3 at -70 C.84 Interestingly, under the latter reaction conditions, p-chloronitrobenzene gave the product of alkylation rather than of SNAr displacement of chloride, as in equation (4).85 Further examples include the dehalogenation of p-halonitrobenzenes by 9-fluorenyl anions in DMSO at room temperature,34 and dehalogenation and denitration reactions by the carbanions of phenyl- and diphenyl-acetonitrile in DMSO or under PTC conditions.86... 

Reaction of N-substituted bromomethanesulfonamides with 2 equiv of potassium carbonate and an cr-haloketone, ester, or nitrile leads directly to the /3-sultams 187 substituted at the C-3 position by an EWG. This base-promoted condensation can be used with a-halo ketones, esters, and nitriles where a second Sn2 intramolecular displacement can operate in tandem fashion (Scheme 60). This domino alkylation sequence exhibits a reactivity order where ketone > nitrile > ester (Table 14). The process is particularly efficient when diethyl bromomalonate or 3-chloro-2-butanone are involved <2004CJC113>. 

Iron-catalyzed Suzuki-Miyaura coupling reactions were also reported by Nakamura and colleagues (entry 27) [67]. Alkyl halides 1 and mixed pinacol aryl(butyl)borates, generated in situ from arylboronates and butyllithium, were used as the reagents and 10 mol% of the iron complexes 16a or 16b as the catalysts. The addition of 20 mol% of MgBr2 was essential for the success of the reaction. Products 3 were isolated in 65-99% yield. The methodology tolerates ester and nitrile functions. The reaction starts probably by initial boron-iron transmetalation to generate a diaryliron(II) complex. 

Enolate anions generated from ketones, esters, and nitriles can be used as nucleophiles in Sn2 reactions. This results in the attachment of an alkyl group to the a-carbon in a process termed alkylation. Aldehydes are too reactive and cannot usually be alkylated in this manner. Alkylation of cyclohexanone is illustrated in the following equation ... 

Alkylation of Ketones, Aldehydes, Nitriles, and Carboxylic Esters a-Acylalkyl-de-halogenation, and so on... 

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