Sodium ethoxide, reaction with nitriles

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... 

This Reaction should be carefully distinguished from the Claisen Conden-tation, which is the condensation of an ester, under the influence of sodium ethoxide, with (i) another ester, (ii) a ketone, or (iii) a nitrile, with the elimination of alcohol. For details of this condensation, see Ethyl Acetoacetate, p. 264. 

Nucleophilic attack by carbanion occurs in the reaction of 2-nitrobenzamides 154 treated with sodium ethoxide (72JCS(P1)835). The reaction mixtures usually contain small amounts of nitrile 155 and carboxamide 156, the product of decarboxylation 158 being usually the principal product (Scheme 24). The corresponding bromo derivatives under the used conditions did not react. 

A novel synthesis of alkylsulfanylisothiazoles 230 starts with sodium a-cyanoketene dithiolates 227, obtained by the reaction of cyanoacetamides 226 with carbon disulfide in the presence of sodium ethoxide <06SC825>. Treatment of 227 with sulphur and piperidine acetate generates sodium isothiazole-3,5-dithiolates 229. The formation of 229 is assumed to arise from the addition of anionic sulphur to the nitrile group in 227 to give the intermediate 228, which cyclizes upon elimination of anionic sulphur to yield 229. Salts 229 are readily alkylated to furnish 3,5-bis(alkylthio)isothiazole derivatives 230. 

Aldehydo nitriles are readily available and can be used to prepare 4-amino-6-unsubstituted pyrimidines carrying one or more substituents in any of the other positions. Equivalents of the formyl group are also often used, for example, a 3-ethoxy-, 3-amino-, or 3-haloacrylonitrile. Most syntheses with /3-keto nitriles are carried out with equivalents thereof Such equivalents are /3-substituted /3-alkoxy-, /3-amino-, or /3-haloacrylonitriles. /3 -Ester nitrile reactions are also well established. Malononitriles and substituted malononitriles react readily with thiourea and N-substituted thioureas in refluxing ethanolic sodium ethoxide to form pyrimidine-4,6-diamines. An example is the reaction of N2-malononitrile 680 with N2-thiourea 681 to give N4- 4,6-diamino-2-(l//)-pyrimidinethione 682 which was then used in the synthesis of Ns-labeled adenine derivatives <2001JOC5463>. 

A one-pot synthesis of 3,5-disubstituted 7-hydroxy-3//-l,2,3-triazolo[4,5-d]pyrimidines (130) has been carried out by using benzyl azide, cyano-acetamide, ethyl or methyl esters of the appropriate carboxylic acid, and sodium ethoxide as catalyst. The reaction proceeds via a 5-amino-l-benzyltriazole-4-carboxamide intermediate (85JHC1607). 7-Amino-3H-l,2,3-triazolo[4,5-d]pyrimidines 133 (R2 = H) were prepared starting from benzyl azide, malononitrile, and an aliphatic or aromatic nitrile, or by reaction of 130 with phosphorus oxychloride followed by amination. Compound 132 was formed in most reactions from two molecules of the 5-amino-4-cyano-l-benzyltriazole intermediate by an intermolecular nucleophilic at-... 

Another field of research is concerned with the one-pot synthesis of this system from readily available starting materials. In Scheme 12, reaction of phenyl azide and malononitrile in the presence of sodium ethoxide leads, via the intermediate triazole (139), to the self-condensation product (140), itself a triazolopyrimidine. In the presence of other nitriles the preferred formation of the more useful compounds (141) occurs in low to moderate yields with small amounts of dimer <87JHC997>. Direct synthesis of the 5,7-dione derivatives (143) (60-90%) is achieved by the reaction of the readily available aminopyrimidinedione (142) with an azide iminium salt in dichloromethane at moderately high dilution <87JHC1493>. 

In the presence of sodium ethoxide, nitriles having reactive a methylene groups may be acylated with esters to form /S-keto nitriles. The method is general and is illustrated by the reaction of alkyl cyanides, where R is C, to with ethyl benzoate to form the corresponding alkylbenzoyl-... 

A similar reaction sequence condenses iV-cyanoiminodithiocarbamic esters (7) with a-cyanoammonium salts (e.g. sarcosine nitrile sulfate) (Scheme 2.3.2). The isothiourea product (8) readily cyclizes to give 4-amino-5-cyanoimidazoles when heated with sodium ethoxide in DMF solution. It is possible to convert the dithiocarbamic esters directly into imidazoles if they are heated in DMF solution with sarcosine ethyl ester hydrochloride or methylaminoacetophenone in the presence of triethyamine [3]. These direct cyclizations arc, however, examples of both 1,2 and 1,5 bond formation. (See also Section 3.2). 

Treatment with sodium ethoxide of thioethers 316, prepared by the reaction of l,2,5,6,7,8-hexahydro-l,6-naphthyridine-2thiones 317 with halo ketones, esters, amides or nitriles, resulted in the synthesis of thieno[2,3-Z>]-l,6-naphthyridines 318 (1993BCJ3716). 

Reaction of compound 8 with a-halo nitriles (R CHHalCN) gave the 3-amino compounds 7 after cyclization of the intermediate S-alkylated products 12 with aqueous potassium hydroxide. Similarly reaction of 2-amino-3-chloropyrazine (13) with the mercapto esters 14 in the presence of sodium ethoxide gave the 3-oxo derivatives 16 on refluxing in dioxan. The intermediates 15 are involved in the reaction. The most convenient synthesis of these compounds involves reaction of 2-amino-3-chloropyrazines with thioglycollic acid in alkali and acid-catalyzed cyclization of the carboxymethylthio derivative. ... 

The ease of reaction depends both on the CH acidity of the addend and on the polarizability of the ethylenic double bond of the acceptor. Thus, in general, only such compounds function as addend in which a methylene or methine group is activated by two neighboring carbonyl or nitrile groups, as, for example, in malonic esters, malonodinitrile, cyanoacetic esters, 1,3-dioxo compounds and 3-oxo carboxylic esters, and their monoalkyl substitution products. The ethylenic double bond of the acceptor is polarized by conjugation with a polar multiple bond, so that the olefinic component is usually an unsaturated ketone, an, / -unsaturated ester, or an, / -unsaturated nitrile. The addition is catalysed by bases such as potassium hydroxide solution, sodium ethoxide, and amines. 

However, Claisen found in 1889 that a second molecule of ethyl acetate (with CH3 hydrogen atoms activated by COOEt) was not the only possible partner for a condensation reaction It could be replaced by a variety of other molecules, such as aldehydes and ketones (activation by CO group) and methyl cyanide and its derivatives (activation by CN group). Many condensation reactions of esters with nitriles were discovered, e.g. diethyl oxalate reacts with methyl cyanide in the presence of sodium ethoxide (Fleischhauer, 189320) ... 

Kim and co-workers showed that the nitrile group of 3-methyl-2-cyano-4(3//)quinazolinones could readily exchange with a number of thio-, amino- and oxo-based nucleophiles to produce the corresponding 2-substituted quinazolinones in good to excellent yields." For example, reaction of 3-methyl-2-cyano-4(3//)quinazolinone with sodium ethoxide in ethanol gave the desired 2-ethoxy substituted product in 96% yield. 

Type J (C—S—C—N—C) Syntheses.—In common with their ir-isoelectronic pyrylium analogues (32), 1,3-oxathiazolium salts (33) are convertible into other ring-systems under the influence of nucleophiles. Their reaction with cyanamide in the presence of sodium ethoxide produces substituted 4-aminothiazoles (36) it probably involves the initial addition of the nitrile moiety at C-2, followed by ring-scission to (35), and recyclization to (36). ... 

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