Enolates, nitrile, condensation

Carboxylic acids (511) and their chlorides, anhydrides, amides, esters and nitriles, condense with o-aminothiophenols (507) or their zinc salts, affording 2-substituted benzothiazoles (513), the only exception being acetic acid. The intermediate o -acylaminothioph-enols (512) could be isolated and readily cyclized. The activation of carboxylic acids in... 

B.iv. Nitrile Enolates. Nitrile enolates are formed by reaction of a nitrile with LDA or another suitable base. Both alkylation 30 and condensation reactions with aldehydes 3 or ketones are known. 32 in addition to alkyl halides and carbonyl derivatives, condensation can occur with another nitrile. The base-catalyzed condensation of two nitriles to give a cyano-ketone, via an intermediate cyano enolate, is known as the Thorpe reaction. 33.109e Reaction of butanenitrile with sodium ethoxide gave a nitrile enolate, which reacted with a second molecule of butanenitrile at the electrophilic cyano carbon to give 206. Hydrolysis gave an intermediate imine-nitrile (207), which is in equilibrium with the enamine form (208, sec. 9.6.A). Hydrolysis led to the final product of the Thorpe reaction, an a-cyano ketone, 209. 33 Mixed condensations are possible when LDA and kinetic conditions are used to generate the a-lithionitrile (a mixed Thorpe reaction). When pentanenitrile was treated with LDA and condensed with benzonitrile, 2-cyano-l-phenyl-1-pentanone was the isolated product after acid hydrolysis. Nitrile enolates can also be alkylated with a variety of alkyl halides. 34... 

Thus the sodio derivative (I) of the enol form of ethyl acetoacetate is obtained. This mechanism can clearly apply also to the condensation of an ester with a suitable ketone or nitrile, as in the above reactions (ii) and (iii) respectively. 

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

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 experimental conditions for the syntheses starting from acid chlorides of hydroxamic acids and from nitrile oxides are somewhat different. In the former case the other component of the reaction is organometallic, usually an organomagnesium derivative of an acetylene or, less frequently, a sodium enolate of a /8-diketone. Nitrile oxides condense directly with unsaturated compounds. 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

A two-step sequence of nitrile oxide-olehn cycloaddition and reduction of the resulting A -isoxazolines offers a unique and attractive alternative to the classical aldol reaction and its many variants (2J). The procedure bypasses traditional problems, including enolate equilibrium and cross condensation (20). 

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. 

In a more recent publication the same research group described a Cu(OTF)2/(POEt)3-catalyzed two-component Michael/aldol protocol of 2-112 and ZnEt2 leading to annulated cyclopentanols [46]. They showed that the enolate formed in the 1,4-addition can be trapped not only by a keto moiety, but also by an ester (Dieckmann condensation) or a nitrile functionality present in the molecule. Thus, as depicted in Scheme 2.26, there is a broad product variety. Starting from 2-112, compounds of type 2-114, 2-115 and 2-116 can be obtained via the enolate 2-113. 

Murahashi and co-workers developed an aldol-type condensation between various activated nitriles and aldehydes or ketones, catalyzed by cyclopentadienylruthenium enolate complexes (Equation (30)).351,351a 351b... 

This aldol condensation is assumed to proceed via nucleophilic addition of a ruthenium enolate intermediate to the corresponding carbonyl compound, followed by protonation of the resultant alkoxide with the G-H acidic starting nitrile, hence regenerating the catalyst and releasing the aldol adduct, which can easily dehydrate to afford the desired a,/3-unsaturated nitriles 157 in almost quantitative yields. Another example of this reaction type was reported by Lin and co-workers,352 whereas an application to solid-phase synthesis with polymer-supported nitriles has been published only recently.353... 

Among the compounds capable of forming enolates, the alkylation of ketones has been most widely studied and used synthetically. Similar reactions of esters, amides, and nitriles have also been developed. Alkylation of aldehyde enolates is not very common. One limitation is the fact that aldehydes are rapidly converted to aldol condensation products by base (see Chapter 2 for more discussion of this reaction). Only when the enolate can be rapidly and quantitatively formed is aldol condensation avoided. Success has been reported using potassium amide in liquid ammonia55 and potassium hydride in THF. Alkylation via enamines or enamine anions provides a more general method for alkylation of aldehydes. These reactions will be discussed in Section 1.9. 

The enolates of other carbonyl compounds can be used in mixed aldol condensations. Extensive use has been made of the enolates of esters, thioesters, amides, nitriles, and nitroalkanes. Scheme 2.4 gives a selection of such reactions. 

A condensation reaction leads to a product with a new C—C bond. Most often the new bond results from a nucleophilic addition of a reasonably stable carbanion-enolate to the C=0 group (acceptor) of an aldehyde less frequently the 0=0 group belongs to a ketone or acid derivative. Another acceptor is the C=N group of a nitrile. 

C-Acylations of C,H-acidic compounds have also been realized on insoluble supports. The few examples that have been reported include the C-acylation of support-bound ester enolates with acyl halides [9], Claisen condensations of polystyrene-bound ketones with benzoic acid esters, the C-acylation of nitriles with acyl nitriles or anhydrides, and the C-acylation of phosphonates with acyl halides (Entries 5-9, Table... 

With an aromatic aldehyde as the electrophilic partner, the nucleophilic enolate ion can also be derived from a ketone or a nitrile. As illustrated in the following examples, this enables the aldol condensation to be used to form a wide variety of compounds ... 

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