Nitriles synthesis from halides

Both methods of nitrile synthesis—SN2 displacement by CN- on an alkyl halide and amide dehydration—are useful, but the synthesis from amides is more general because it is not limited by steric hindrance. 

The synthesis of nitriles from halides is valuable in medicinal chemistry because nitriles are flexible building blocks readily converted into carboxylic acids, amides, amines, or a variety of heterocycles, e. g. thiazoles, oxazolidones, triazoles, and tetrazoles. The importance of the tetrazole group in medicinal chemistry is easily understood if we consider that it is the most commonly used bioisostere of the carboxyl group. 

Sandmeyer s synthesis of aromatic nitriles is far more elegant than the removal of water from the ammonium salts of carboxylic acids, which latter reaction is also applicable to benzene derivatives. In particular, the former synthesis permits of the preparation of carboxylic acids via the nitriles, and so provides a complete substitute for Kolbe s synthesis (alkyl halide and potassium cyanide), which is inapplicable to aromatic compounds. The simplest example is the conversion of aniline into benzoic add. The converse transformation is Hofmann s degradation (benzamide aniline, see p. 152). 

Th synthesis of the acid from the nitrile thus becomes in reality a synthesis from sulphonic acids. An exactly analogous reaction takes place when an aryl halide, with the halogen in the side chain, is distilled with potassium cyanide, as discussed later (p. 678). 

Nitrile synthesis. Sodium salts of carboxylic acids when heated in a sealed tube with cyanogen chloride at 200-300° are converted into the corresponding nitriles, often in high yield. Tracer studies with cyanogen bromide have shown that the carbon dioxide liberated is derived from the cyanogen halide and that the bond... 

Symmetrical six-membered triazine rings can be synthesized from C-N units which are parts of nitrile groups, imidoyl halides, ureas, imido esters, amidines and guanidines. These reactants may be generated during the synthesis. 

A popular reaction type in recent years has been the conversion of alcohols into other compounds by use of an organophosphorus compound in the presence of a source of a nucleophile [reaction (8)]. PhsP plus diethyl azodicarboxylate has been a particularly popular form of organophosphorus reagent, and the product is formed with inversion of configuration. In 1977 there appeared a number of variations on this general theme, for the synthesis of halides, thiocyanates, thio-ethers, azides, and esters from alcohols.Similar systems have been used to convert amides and thioamides into nitriles. ... 

Dihalocarbenes produced under PTC conditions have been advantageously used in the classical isonitrile synthesis from primary amines, again giving higher yields than the classical procedure. Hydrazine affords diazomethane, amides are dehydrated to nitriles and sulfoxides are reduced to sulfides in high yields. Finally, alcohols are converted into halides (Table 17)... 

The Rosenmund-von Braun synthesis of aryl nitriles (40) from aryl halides (38) also shares some commonality with the Castro-Stephens reaction. This transformation was discovered nearly a century ago, and was mentioned in the initial Castro-Stephens publication where the authors noted potential mechanistic similarity. 

Replacement of one of the phenyl groups by an alkyl group of similar bulk, on the other hand, alters the biologic activity in this series. Alkylation of phenylacetonitrile with isopropyl bromide affords the substituted nitrile, 136. Treatment of the anion prepared from 136 with strong base with 2-dimethylamino-l-chloropropane gives isoaminile (137). It is of note that alkylation of this halide, isomeric with that used in the early methadone synthesis, is apparently unaccompanied by isomer formation. Isoaminile is an agent with antitussive activity. 

The synthesis of (hetero)aryl cyanides from (hetero)aryl halides via transition-metal catalysis is a very valuable reaction since a nitrile can be easily transformed into several other functional groups. Not until 2000 were the first examples on microwave-assisted cyanation reported in the literature. Alter-man and Hallberg found that 3-bromopyridine and 3-bromothiophene were... 

A single-mode microwave procedure has been reported for the palladium-catalyzed preparation of both aryl and vinyl nitriles from the corresponding bromides. The reaction times were short and full conversions were achieved in just a few minutes (Eq. 11.33) [50], The cycloadditions to yield the tetrazoles needed slightly longer reaction times, from 10 to 25 min, but only 20 W of power was required as a temperature of 220 °C was reached after 10 min heating. The yields in this step ranged from 36% to 96%. This method for transforming halides into tetrazoles has been used for the synthesis of a novel HIV-protease inhibitor [50],... 

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