Nitriles, reaction with ester enolates

Reaction of sugar lactone with ester enolate (the Claisen condensation) gives -keto ester, the resulting 1,3-dicarbonyl compound immediately reacts with the hydroxyl group present in the same molecule to afford a lactol with an axial hydroxyl group. In a recent example shown in O Scheme 4 [8], the product of the reaction was further transformed to the corresponding nitrile or amide by addition of cyanide or a Ritter reaction with benzonitrile in the presence of TMSOTf as a Lewis acid. 

The condensation reaction of ester enolates with nitriles are an important general source of alkenyl-P-amino acids. In a simple example, the reaction of t-bulyl acetate with magnesium diisopropylamide and then propanenitrile led to /-butyl 3-amino-hex-2-enoate, 4.81. In addition, /-butyl 3-aminobut-2-enoate (66%), 3-amino-4-methylpent-2-enoate (74%), 3-amino-4,4-dimethylpent-2-enoate (43%), 3-amino-4-phenyIpent-2-enoate (25%) and other 4-aryl and 2-alkyl- ubstituted alkenylamino... 

Enolates of aldehydes, ketones, and esters and the carbanions of nitriles and nitro compounds, as well as phosphorus- and sulfur-stabilized carbanions and ylides, undergo the reaction. The synthetic applications of this group of reactions will be discussed in detail in Chapter 2 of Part B. In this section, we will discuss the fundamental mechanistic aspects of the reaction of ketone enolates with aldehydes md ketones. 

Many types of carbonyl compounds, including aldehydes, ketones, esters, thioesters, acids, and amides, can be converted into enolate ions by reaction with LDA. Table 22.1 lists the approximate pKa values of different types of carbonyl compounds and shows how these values compare to other acidic substances we ve seen. Note that nitriles, too, are acidic and can be converted into enolate-like anions. 

An alkylation reaction is used to introduce a methyl or primary alkyl group onto the a position of a ketone, ester, or nitrile by S 2 reaction of an enolate ion with an alkyl halide. Thus, we need to look at the target molecule and identify any methyl or primary alkyl groups attached to an a carbon. In the present instance, the target has an a methyl group, which might be introduced by alkylation of an ester enolate ion with iodomethane. 

Ketones and carboxylic esters can be a hydroxylated by treatment of their enolate forms (prepared by adding the ketone or ester to LDA) with a molybdenum peroxide reagent (MoOs-pyridine-HMPA) in THF-hexane at -70°C. The enolate forms of amides and estersand the enamine derivatives of ketones can similarly be converted to their a hydroxy derivatives by reaction with molecular oxygen. The M0O5 method can also be applied to certain nitriles. Ketones have also been Qc hydroxylated by treating the corresponding silyl enol ethers with /n-chloroperoxy-... 

In summary, reactions of nitronates with acid anhydrides or acyl chlorides give the O-acylated products, and reactions with acyl imidazoles, phenyl esters, acyl nitriles, and enol-lactones gives the C-acylated products, (see Eq. 5.13).25 The C/O selectivity of nitronate acylation by RCOX is qualitatively correlated with strength (pKJ of the acid HX conjugated to the leaving group X .25... 

By reaction of a base with compound 251, attack of the ester enolate at the adjacent nitrile occurs, to give the amino-substituted thienoindolizine 252 <1987CL2043> (Equation 34). 

Most solid-phase syntheses of pyrazoles are based on the cyclocondensation of hydrazines with suitable 1,3-dielectrophiles. The reported examples include the reaction of hydrazines with support-bound a,(3-unsaturated ketones, 1,3-diketones, 3-keto esters, a-(cyano)carbonyl compounds, and a, 3-unsaturated nitriles (Table 15.19). Pyrazoles have also been prepared from polystyrene-bound 3-(hydrazino)esters, which are generated by the addition of ester enolates to hydrazones (Entry 7, Table 15.19 see also Section 10.3). Benzopyrazoles can be prepared from support-bound hydra-zones using the reaction sequence outlined in Figure 15.11. Oxidation of a polystyrene-bound benzophenone hydrazone yields an a-(acyloxy)azo compound. Upon treatment with a Lewis acid, this intermediate is converted into a 1,2-diazaallyl cation,... 

The Michael reaction involves the addition of a nucleophilic carbon species to an electrophilic multiple bond. The electrophilic partners are typically a,fi-unsaturated ketones, esters or nitriles, but other electron-withdrawing substituents can be used to activate the carbon—carbon double bond to nucleophilic attack. A tandem aldol-Michael reaction has been recently described. Wachter-Jurcsak and coworkers66 reported that the reactions involving 2-pyridinecarboxaldehyde, 71, and 2-quinolinecarboxaldehyde with the enolates of acetophenone, 70, afforded the unexpected symmetric l,5-diphenyl-3-(2-heteroaryl)-1,5-pentanediones (Scheme 24). 

The preparation of a-selenoketones, esters, nitriles and related compounds can easily be performed via alkylation of the corresponding enolates or stabilized carbanions [21]. These compounds have found many synthetic applications in radical chemistry. In Eq. (9), a typical example involving a ketone is depicted [22]. The stability of a-selenoketones such as 41 is remarkable. Similar reactions with lactones have been performed. For instance, this approach has been applied to the stereoselective synthesis of oxygen-containing rings to either faces of a bicyclic structure [23]. The approach based on a-selenenylation/radical allyla-tion compares favorably with classical enolate allylation procedures, which usually leads to mixture of mono- and diallylated compounds. Furthermore, this strategy is excellent for the preparation of quaternary carbon centers [24] as shown by the conversion of 43 to 45, a key intermediate for the synthesis of fredericamycin A, [Eq. (10)] [25]. Similar reactions with sulfoxides [26] and phosphonates [27] have also been reported. 

The same catalyst is also effective in three-component reactions between aldehydes, amines, and silylated nucleophiles, leading to amino ketone, amino ester, and amino nitrile derivatives, respectively (Eq. 30) [114]. It is reported that 103 can be recovered and that continuous use is possible without any loss of activity. More interestingly, in competitive reaction of aldehyde, aldimine and silyl enolate, the less reactive aldimine reacted exclusively with silyl enolate in the presence of 103. This unique selectivity was explained by the polymer effect [115]. 

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