Halo-nitriles, reaction with

The other main reaction in this class is the Dieckmann-type cyclization of the intermediates (163) from 4(6)-halo-5-ethoxycarbonylpyrimidines with AC-substituted /3-alanine esters and nitriles, and related compounds, to give 5,6,7,8-tetrahydro-5-oxopyrido[2,3-[Pg.221]

The imidazole nucleus is often found in biologically active molecules,3 and a large variety of methods have been employed for their synthesis.4 We recently needed to develop a more viable process for the preparation of kilogram quantities of 2,4-disubstituted imidazoles. The condensation of amidines, which are readily accessible from nitriles,5 with a-halo ketones has become a widely used method for the synthesis of 2,4-disubstituted imidazoles. A literature survey indicated that chloroform was the most commonly used solvent for this reaction.6 In addition to the use of a toxic solvent, yields of the reaction varied from poor to moderate, and column chromatography was often required for product isolation. Use of other solvents such as alcohols,7 DMF,8 and acetonitrile9 have also been utilized in this reaction, but yields are also frequently been reported as poor. 

Reaction of halo nitriles or diazo nitriles with boranes... 

A number of these alkylation reactions are illustrated in Scheme 9.2. Entries 1 and 2 are typical examples of a-halo ester reactions. Entry 3 is a modification in which the highly hindered base potassium 2,6-di-f-butylphenoxide is used. Similar reaction conditions can be used with a-halo ketones (Entries 4 and 5) and nitriles (Entry 6). Entries 7 to 9 illustrate the use of diazo esters and diazo ketones. Entry 10 shows an application of the reaction to the synthesis of an amide. 

This is a synthetically useful procedure because the a-halo acids are useful starting materials for other reactions. For example, the addition of hydroxide ion leads to the replacement of the halogen with an -OH group. The reaction with ammonia replaces the halogen with -NH2. The reaction with cyanide ion, CN , converts the halide to a nitrile. Figure 12-33 illustrates this reaction. 

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... 

The amide ions are powerful bases and may be used (i) to dehydrohalogenate halo-compounds to alkenes and alkynes, and (ii) to generate reactive anions from terminal acetylenes, and compounds having reactive a-hydrogens (e.g. carbonyl compounds, nitriles, 2-alkylpyridines, etc.) these anions may then be used in a variety of synthetic procedures, e.g. alkylations, reactions with carbonyl components, etc. A further use of the metal amides in liquid ammonia is the formation of other important bases such as sodium triphenylmethide (from sodamide and triphenylmethane). 

RC = CCH,X — RCX = C==CH,. /S.y- and 7,S-Acetylenic alcohols can be transformed to the halides in better yields by an alternative procedure, which consists in their esterification with p-toluenesulfonyl chloride and subsequent cleavage of the ester by the action of sodium iodide, lithium chloride, or calcium bromide in an appropriate solvent (60-90%). Halo ethers are prepared by the action of phosphorus tribromide on hydroxy ethers, as in the preparation of /3-ethoxyethyl bromide (66%). In a similar manner, /3-halo esters have been prepared without appreciable dehydration of the /3-hydroxy ester (40-60%). The reaction of cyanohydrins leads to a-halo nitriles. Treatment of 2-nitro-l-propanol with phosphorus pentachloride gives l-chloro-2-nitropropane (47%). ... 

Functionalized P-amino-a, -unsaturated lactones, esters and nitriles can be prepared by nucleophilic vinylic substitution of halogen atoms by amines on the corresponding 3-halo-a,3-unsaturated compounds (12), (13) and (15) (Scheme 9). 3-Bromo-2-butenoates ( )-(13) and (Z)-(13) reacted with secondary amines to give ( )-p-aminopropenoates ( )-(14) regardless of the initial stereochemistry, while the reaction with primary amines yielded a mixture of ( )- and (Z)-(14), when R = H, with the latter predominant. In contrast, the substitution of ( )- and (Z)-nitriles, ( )-(15) and (Z)-(15), with second-... 

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. ... 

Reactions with Azo Compounds. Meerwein reactions of diazoniiun halides with acrylonitrile take place at low temperatures, catalyzed by cupric chloride, to yield 2-halo-3-arylpropionitriles. Reactions with diazomethane compoimds lead to pyrazolines and finally cyclopropanes. Reactions with 9-diazofluorene produce a cyanocyclopropane derivative, with the generation of nitrogen. Phenyl azide reacts with acrylonitrile to 5deld a heterocyclic nitrile at room temperature or an open-chain nitrile at elevated temperatures. 

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