ALIPHATIC CYANIDES NITRILES

By the dehydration of primary amides with phosphorus pentoxide or with thionyl chloride, for example  

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From Aryl Cyanides Acid Nitriles),— The aromatic cyanides which were simply referred to as substitution products (p. 521) are, of course, like the aliphatic cyanides, nitriles of acids which they yield on hydrolysis. 

Aliphatic nitriles (or alkyl cyanides) can be prepared by the following methods ... 

The physical properties of a number of aliphatic nitriles (cyanides) are given in Table 111,115. 

Hydrogen cyanide (HCN) and aliphatic nittiles (RCN) can be used to form imidazolines. For example, EDA and HCN form 2-imidazoline (38). In the presence of sulfur or polysulfides as catalysts, 2-aIkyl-2-imidazolines can be prepared from ahphatic nitriles and EDA (39,40). 

A particularly useful variation of this reaction uses cyanide rather than HCN. a-Amino nitriles can be prepared in one step by the treatment of an aldehyde or ketone with NaCN and NH4CI. This is called the Strecker synthesisand it is a special case of the Mannich reaction (16-15). Since the CN is easily hydrolyzed to the acid, this is a convenient method for the preparation of a-amino acids. The reaction has also been carried out with NH3-I-HCN and with NH4CN. Salts of primary and secondary amines can be used instead of NH to obtain N-substituted and N,N-disubstituted a-amino nitriles. Unlike 16-51, the Strecker synthesis is useful for aromatic as well as aliphatic ketones. As in 16-51, the Me3SiCN method has been used 64 is converted to the product with ammonia or an amine. ... 

The y-keto nitriles shown in Table I were prepared by the cyanide-catalyzed procedure described here. This procedure is generally applicable to the synthesis of y-diketones, y-keto esters, and other y-keto nitriles. However, the addition of 2-furancarboxaldehyde is more difficult, and a somewhat modified procedure should be employed. Although the cyanide-catalyzed reaction is generally limited to aromatic and heterocyclic aldehydes, the addition of aliphatic aldehydes to various Michael acceptors may be accomplished in the presence of thioazolium ions, which are also effective catalysts for the additions. 

Willhite, C.C. and R.P. Smith. 1981. The role of cyanide liberation in the acute toxicity of aliphatic nitriles. Toxicol. Appl. Pharmacol. 59 589-602. 

To enhance the efficiency of the cyanide addition, these workers subsequently reported a three-component asymmetric synthesis of amino nitriles that avoids the use of the previously mentioned undesirable stannane [74], Thus, as illustrated in Scheme 6.23, treatment of the requisite aniline and aldehyde with HCN (toxic but cheap and suitable for industrial use) at —45°C in the presence of 2.5 mol% 65 leads to the formation of 67 with 86 % ee and in 80 % yield. As was mentioned above in the context of catalytic asymmetric three-component alkylations of imines (see Scheme 6.18), the in situ procedure is particularly useful for the less stable aliphatic substrates (cf. 71—73, Scheme 6.23). The introduction of the o-Me group on the aniline is reported to lead to higher levels of asymmetric induction, perhaps because with the sterically less demanding aliphatic systems, the imine can exist as a mixture of interconverting cis and trans isomers. 

No structure-activity relationships were applicable for establishing AEGLs for HCN. It has been observed that the signs of intoxication associated with excessive exposure to HCN and with certain aliphatic nitriles are similar. While the toxic concentrations of acrylonitrile are similar to HCN when compared on the basis of cyanide content (Dudley et al. 1942), the time course of aliphatic nitrile intoxication is different. The authors also observed... 

Vesey et al. 1976) and a series of commercially important, simple, aliphatic nitriles (e.g., acetonitrile, propionitrile, acrylonitrile, n-butyronitrile, maleonitrile, succinonitrile) (Willhite and Smith 1981) release cyanide upon metabolism. These drugs and industrial chemicals have been associated with human exposure to cyanide and have caused serious poisoning and, in some cases, death. 

Trimethylsilyl trichloroacetate is a useful reagent for the A-trimethylsilylation of amines284. The combined action of primary aliphatic or aromatic amines and trimethylsilyl cyanide on aliphatic or aromatic aldehydes yields a-amino nitriles (equation 93)285,286. 

The acute toxicity of aliphatic nitriles, which are important industrial compounds, is ascribed mainly to the liberation of cyanide after oxidative de-nitrilation [118 - 120], The reaction involves cytochrome P450 mediated hy-droxylation of C(a) to form an intermediate cyanohydrin, which then breaks down to inorganic cyanide and an aldehyde ... 

There are a few data in the literature to suggest that the hydrolysis of aliphatic nitriles occurs in mammals, but only as a minor or even undetectable pathway in competition with oxidative denitrilation. For example, benzyl cyanide (11.80, Fig. 11.12) undergoes cytochrome P450 catalyzed hydroxy-lation to mandelonitrile (11.81), from which cyanide and benzaldehyde are produced, the latter being oxidized to benzoic acid (11.83) [118]. However, a careful metabolic study of mandelonitrile has shown that, in the rat, this pathway accounts for ca. 90% and not 100% of the dose [122], Only ca. 10% of orally administered benzyl cyanide was converted to mandelic acid (11.82, Fig. 11.12) by hydrolysis of the CN group. 

Stetter expanded Umpolung reactivity to include the addition of acyl anion equivalents to a,P-unsaturated acceptors to afford 1,4-dicarbonyls Eq. 5a [57-60]. Utilizing cyanide or thiazolylidene carbenes as catalysts, Stetter showed that a variety of aromatic and aliphatic aldehydes act as competent nucleophilic coupling partners with a wide range of a,p-unsaturated ketones, esters, and nitriles [61]. The ability to bring two different electrophilic partners... 

In humans there have been no reports of adverse effects. The probable reason for lack of systemic effects is that aromatic, unlike aliphatic, nitriles do not liberate cyanide in the body. 

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