Alkyl cyanides, 184 Table

This method has been reviewed recently (78RCR975). Alkyl cyanides are difficult to trimerize, needing both very high pressures and temperatures (Table 14). It is one of the few organic reactions which requires pressures above 1000 atm. In contrast to other nitriles, the alkyl cyanides will not trimerize in acid conditions thus in the presence of hydrogen chloride, alkyl cyanides form N-substituted amidines (73BCJ292). 

Alkyl cyanides with electron withdrawing substituents are more reactive and cyclotrimer-ize under both acidic and basic conditions as well as at high pressure (Table 14). Complexes of Lewis acids and hydrogen halides are particularly valuable catalysts. Two mechanisms for the acid-catalyzed cyclotrimerization have been postulated. Grundmann et al. suggest... 

Alkyl halides react with nucleophiles, reagents that can supply an electron pair to form a covalent bond, to give a product in which the nucleophile takes the place of the halogen. Table 6.1 gives fifteen examples of such nucleophilic substitution reactions, which can be used to convert alkyl halides to alcohols, ethers, esters, amines, thiols, alkyl cyanides, or acetylenes. 

Aryl cyanides are of similar activity to alkyl cyanides containing electron-withdrawing groups. A combination of hydrogen chloride and a Lewis acid is particularly valuable for the acid-catalyzed cyclization. Lewis acids alone are inefficient (Table 14), and hydrogen chloride alone forms the stable adduct (141). The presence of the Lewis acid, such as PCls, decreases the nucleophilicity of the chloride counter ion, permitting the reaction to go to completion (73BCJ306). 

Table 1 Alkyl Cyanides from the Reaction of Alkyl Halides with CN" Ions R-X + MCN -------------------------- R-CN + M-X...

Table 1 Alkyl Cyanides torn the Reaction of Alkyl Halules with CN Ions...

Nitriles contain the —C=N functional group We have already discussed the two mam procedures by which they are prepared namely the nucleophilic substitution of alkyl halides by cyanide and the conversion of aldehydes and ketones to cyanohydrins Table 20 6 reviews aspects of these reactions Neither of the reactions m Table 20 6 is suitable for aryl nitriles (ArC=N) these compounds are readily prepared by a reaction to be dis cussed m Chapter 22... 

Section 20 18 Nitnles are prepared by nucleophilic substitution (8 2) of alkyl halides with cyanide ion by converting aldehydes or ketones to cyanohydrins (Table 20 6) or by dehydration of amides... 

Kwiatek and Seyler were the first to report that many organopenta-cyanides, when treated first with acid and then with alkali, liberate nitriles 110). This reaction occurs with unsubstituted primary and secondary alkyl, benzyl, vinyl, and phenyl complexes, while allyl, 2-oxo-, 2-hydroxy-, and 2-alkoxy complexes simply release the organo-ligand on treatment with acid, and 1-cyanoalkyl and a-pyridyl complexes are stable 105) (see also Table IV). The yield of nitrile is usually far from quantitative and is... 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

Substrate selectivities in reactions of aqueous sodium cyanide with alkyl halides in toluene and 17% RS onium ion catalysts are shown in Table 1 84). The data are particularly instructive about how intraparticle diffusion affects reactions that occur... 

Table 14 Formation of Symmetrical 1,3,5-Triazines (RCN)3 by Cyclotrimerization of Alkyl and Aryl Cyanides...

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