Benzyl halides cyanide

This method is particularly applicable to the more reactive benzyl halides which are easily hydrolyzed in the aqueous media usually employed for the metathetical reaction with alkali cyanides. For example, anisyl chloride treated with sodium cyanide in aqueous dioxane gives, as a by-product, 5-10% of anisyl alcohol as determined by infrared analysis. The use of anhydrous acetone not only prevents hydrolysis to the alcohol but also decreases the formation of isonitriles. This method was also applied successfully by the submitters to the preparation of -chlo-rophenylacetonitrile in 74% yield. 

The reaction works well with primary alkyl halides, especially with allylic and benzylic halides, as well as other alkyl derivatives with good leaving groups. Secondary alkyl halides give poor yields. Tertiary alkyl halides react under the usual reaction conditions by elimination of HX only. Nitriles from tertiary alkyl halides can however be obtained by reaction with trimethylsilyl cyanide 4 ... 

Benzylic halides produce isonitriles (80-90%) with tetramethylammonium cyanoargentate, prepared from tetramethylammonium chloride and silver cyanide [20]. The reaction fails with simple haloalkanes. 

The data for the reactions of potassium cyanide with benzyl halides at 85 C and 25 C are summarized in Tables I-III and graphical representations of these data are shown in Figures 1-3. The reactions carried out at 85 C were followed to 70% completion, while those at 25 C were followed to 50% completion. In general, excellent first-order kinetic plots were obtained. Each point on the graphs represents an average of at least three kinetic determinations. It is interesting to note that in the absence of added water (solid-liquid phase transfer catalysis), the rates of benzyl halide disappearance were more accurately described by zero-order kinetics. 

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... 

Three PTC methods are worthy of note. In the first the alkyl halide is treated with sodium cyanide in decane solution in the presence of catalytic amounts of hexadecyltributylphosphonium bromide.1673 In the second tetraethylammo-nium cyanide in molar quantities is used in dichloromethane solution with the alkyl halide.1676 In the third method, which is reported to be most satisfactory in the case of allylic and benzylic halides, a solid/liquid system of potassium cyanide and 18-crown-6 ether is employed.168... 

Benzyl cyanide is the product of nucleophilic substitution by cyanide ion on benzyl bromide or benzyl chloride. The benzyl halides are prepared by free-radical halogenation of the toluene side chain. 

Potassium tellurocyanate, prepared from potassium cyanide and tellurium in DMSO, reacts with benzyl halides to produce benzyl tellurium cyanides in good yields. Because of the sensitivity of potassium tellurocyanate to oxygen and of some of the benzyl tellurium cyanides to light, the reactions must be carried out in an inert atmosphere (nitrogen or argon) under red light. 

Ben2 yl-type chlorides are converted to the corresponding cyanides much more rapidly (85-90%). Ring substituents include alkyl, halo, carbethoxy and nitro groups. The more reactive benzyl halides, particularly the p-methoxy derivatives, are subject to extensive alcoholysis when ethanol is employed as the solvent. The successful use of acetone, acetonitrile, and phenylacetonitrile as solvents has been described. Conversion by cuprous cyanide and pyridine has been successfully applied to benzyl chloride as well as to di-o-tolylchloro-methane. It is interesting to find that treatment of a-chloroethylbenzene, C,H,CH(C1)CH, with cuprous cyanide gives 1,3-diphenyI-l-butene,... 

An alternative route involves the nucleophilic substitution of an alkyl or benzyl halide with a cyanide ion. Two reactions are possible, leading to an isocyanide (R N=C) or a cyanide (R -ON). 

Tellurocyanate ion reacts with benzyl halides aryl iodides , arenediazonium tetraflu-oroborates, and with azulene" to form aryl tellurium cyanides. 

The transformation of alkyl halides with cyanides (equation 1) represents not only the classical route to nitriles, but, if modified properly, is still of very great practical importance even today. A whole series of review articles stress the scope and value of this reaction. Although the substituent R may be varied to a large extent, the primary as well as the benzylic halides generally give higher yields than secondary and tertiary ones, as, with the latter, the formation of alkenes gains in importance. This side reaction as well as the undesired formation of alcohols and ethers, which sometimes takes place in aqueous media or with alcohols as solvent, is of course due to the basicity of the cyanide ion. Under deleterious conditions one may even observe carboxylic acids, which result fi-om the hydrolysis of the nitriles. - Some of these undesired side reactions may be avoided by the use of CuCN instead of sodium or potassium cyanide. ... 

A general method for the preparation of a-cyano ketones from acid halides was developed recently (equation 43).i57.i58 trimethylsilyl cyanide as reagent a great number of acyl cyanides can be prepared under mild conditions in high yield. In particular the synthetically useful aliphatic derivatives have become accessible by this reaction. Table 13 lists examples for aliphatic, a, -unsaturated and benzylic acyl cyanides. The procedure is very simple in that trimethylsilyl cyanide and acid chloride are mixed and kept without solvent. The reaction is followed by IR spectroscopy. As soon as all of the trimethylsilyl cyanide is consumed, the product can be isolated, normally by distillation, or directly used for fruther reactions. 

Primary amines are not usually made by reduction of amides (15) but by other reductive processes which are minor variations on this scheme. For unbranched amines (16) we can reduce cyanides. This method is especially suitable for benzylic amines since aryl cyanides (17) can be made from diazonium salts (see Chapter 2), and for the homologous amines (18) since cyanide ion reacts easily with benzyl halides. 

In many PTC systems, a third phase can form where reaction occurs and rates are enhanced. This third phase can form in many multiphase systems, and has been termed the omega phase [18]. The first example of an omega phase was discovered in the ITC reaction of cyanide ion on a benzyl halide in the presence of a crown ether as phase transfer catalyst. This liquid-solid PTC system was found to have rates dependent on the amount of water present. It was determined that in the absence of either water or the... 

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