Enolate anions, nitrile

Inductive and resonance stabilization of carbanions derived by proton abstraction from alkyl substituents a to the ring nitrogen in pyrazines and quinoxalines confers a degree of stability on these species comparable with that observed with enolate anions. The resultant carbanions undergo typical condensation reactions with a variety of electrophilic reagents such as aldehydes, ketones, nitriles, diazonium salts, etc., which makes them of considerable preparative importance. 

The alkylation reactions of enolate anions of both ketones and esters have been extensively utilized in synthesis. Both very stable enolates, such as those derived from (i-ketoesters, / -diketones, and malonate esters, as well as less stable enolates of monofunctional ketones, esters, nitriles, etc., are reactive. Many aspects of the relationships between reactivity, stereochemistry, and mechanism have been clarified. A starting point for the discussion of these reactions is the structure of the enolates. Because of the delocalized nature of enolates, an electrophile can attack either at oxygen or at carbon. 

C NMR studies of various heteroaromatic nitriles, including 1/7-1,2,3- and 2/7-1,2,3-triazolyl nitriles, reveal a correlation between a value derived from the chemical shifts, cn and c-cn and the reactivity of nitriles in forming the corresponding enaminoketones via reactions with the enolate anion of acetone. Based on the correlation, a new reactivity index y is proposed <82H(l9)22l>. 

The above system failed entirely when nonstabilized carbanions such as ketone or ester enolates or Grignard reagents were used as carbon nucleophiles, leading to reductive coupling of the anions rather than alkylation of the alkene. However, the fortuitous observation that the addition of HMPA to the reaction mixture prior to addition of the carbanion prevented this side reaction1 extended the range of useful carbanions substantially to include ketone and ester enolates, oxazoline anions, protected cyanohydrin anions, nitrile-stabilized anions3 and even phenyllithium (Scheme 3).s... 

Step 3b The resonance-stabilized enolate anion reacts both chemo- and regio-selectively iodide displacement occurs in preference to 1,2-addition alkylation occurs a to the nitrile moiety. 

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 ... 

Various electron-withdrawing groups can be used in almost any combination with good results. In this example an ester and a nitrile cooperate to stabilize an anion. Nitriles are not quite as anion-stabilizing as carbonyl groups so this enolate requires a stronger base (sodium hydride) in an aprotic solvent (DMF) for success. The primary alkyl tosylate serves as the electrophile. 

Recent general spectral studies of such nitriles include the vibration spectra of 2-pyrazinecarbonitrile and a (> 99%)15N-isotopic version 1172 the mass spectra of 2,3-pyrazinedicarbonitrile, its 5,6-diphenyl derivative, and 2,3,5,6-pyrazinetetracarboni-trile for comparison with those of analogous heterocyclic nitriles 1406 and the 15C NMR spectra of 2-pyrazinecarbonitrile and the like for correlation with their reactivities toward acetone enolate anions.251 The structure-activity relationship of pyrazinecarbonitriles as herbicides has been reported.1048... 

Quite a number of other electron withdrawing groups containing multiple heteroatomic bonds, such as the ester carbonyl, nitrile, carboxamide, etc., can likewise stabilize carbanions. The lithium salt of tert-butyl acetate 32 is an example of an enolate anion sufficiently stable as a salt to be used as a shelf reagent. Substituents containing easily polarizable atoms, such as sulfur or selenium, are also capable of stabilizing an adjacent anionic center. 

Introduction of a cyano group a to the carbonyl group of a ketone can be accomplished by prior formation of the enolate anion with LDA in THF and addition of this solution to p-TsCN at —78°C. The products are formed in moderate to high yields but the reaction is not applicable to methyl ketones. Treatment of TMSCH2N(Me)C=Nf-Bu with iec-butylhthium and R2C=0, followed by iodo-methane and NaOMe leads to the nitrile, R2CH-CN. ... 

You have already seen the tosyl group used in the inversion sequence on p. 000, where it was displaced by as weak a nucleophile as acetate. This should alert you to the fact that TsO can be displaced by almost anything. We choose some examples in which new carbon-carbon bonds are formed. This will be an important topic later in the book when we meet enolate anions (Chapter 21) but our two examples here use sp anions derived from nitriles and acetylenes. 

Alkylation and acylation of ketones and nitriles. DMSO greatly enhances the rate of alkylation of enolate anions. " Dialkylation of malononitrile and of pentane-2,4-... 

On reaction with Grignard reagents, p-keto nitriles are transformed into enamino ketones." The carbonyl group is protected as the enolate anion. To retain the nitrogen atom, a mild workup is required. 

In an extension of quinoline ring formation by reaction of enolate anions with o-trifluoromethylaniline, the enolate anion was replaced with anion of nitrile (44) to give quinoline (45) (Scheme 19) <94TL(35)7597). 

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