Alkyl bromides, reaction with sodium cyanide

The synthesis of zolpidem began with an alkylation/condensation reaction of amino-pyridine 5 and bromide 6 to give imidazopyridine 7 (Scheme 15.1). Mannich-type reaction with formaldehyde and dimethylamine provided 8. Treatment of 8 with methyliodide to form the quaternary salt 9, followed by reaction with sodium cyanide, gave 10. Acidic hydrolysis followed by reaction of the resultant acid 11 with carbonyldiimidazole (GDI) and dimethylamine afforded zolpidem (1) in 46% overall yield (George et al., 1991 Rossey and Long, 1988). 

Of the synthetic reactions of the alkyl halides that with potassium cyanide, which enabled H. Kolbe to synthesise acetic acid from a methane derivative, has already been mentioned (cf. the preparations on pp. 137 and 254). Of the simpler syntheses that of Wiirtz may be mentioned here. Metallic sodium removes the halogen from two molecules and the two radicles combine. Thus, in the simplest case, ethane is formed from methyl bromide ... 

Reeves and Hilbrich288 have reported the catalysis by pyridines of benzyl ketone alkylation they are less efficient than aliphatic trialkylamines. Reeves and White289 have also described the reaction of alkyl bromides with sodium cyanide, where pyrazine is a better catalyst (99% yield) compared to pyridine (12% yield). Isakawa et al.289 have also carried out addition of dichloro-carbene to cyclohexene under biphasic conditions, using heterocyclic amines as catalysts (e.g., iV-butylpiperidine gives 76% yield). 

The ready replacement of the halogen in an alkyl or an aralkyl halide illustrated in Expt 5.157 by reaction with sodium or potassium cyanide is inapplicable in the case of aryl halides wherein the halogen is relatively inert. However, aryl bromides can be converted into nitriles in good yield by heating them for several hours at about 200 °C with copper(i) cyanide in the presence of pyridine (e.g. 1-naphthonitrile, Expt 6.168). This displacement may be achieved more readily by using dimethylformamide as the solvent, when reaction is usually completed in a few hours at reflux temperature.63... 

Displacements. Primary and secondary alkyl chlorides react rapidly and exother-mally with sodium cyanide in partial solution in dimethyl sulfoxide to give the corresponding nitriles in excellent yield. - The reactions are faster and the yields better than in the reactions of the corresponding bromides or iodides in aqueous alcohol. Neopentyl and neophyl halides can be converted by this method to... 

Vinylic copper reagents react with CICN to give vinyl cyanides, though BrCN and ICN give the vinylic halide instead." Vinylic cyanides have also been prepared by the reaction between vinylic lithium compounds and phenyl cyanate PhOCN." Alkyl cyanides (RCN) have been prepared, in varying yields, by treatment of sodium trialkylcyanoborates with NaCN and lead tetraacetate." Vinyl bromides reacted with KCN, in the presence of a nickel complex and zinc metal to give the vinyl nitrile. Vinyl triflates react with LiCN, in the presence of a palladium catalyst, to give the vinyl nitrile." ... 

The classical procedure for the reaction involves heating the alkyl halide (usually the chloride or bromide) with sodium or potassium cyanide in metha-nolic or ethanolic solution. The method is clearly of value for the extension of the carbon chain by one carbon atom, since the cyano group may be converted into a carboxyl group by hydrolysis (Section 5.11.2, p. 671) or into an amino-methyl group (—CH2-NH2) by reduction (Section 5.16.1, p. 771), or into a formyl group by controlled reduction to the imine followed by hydrolysis (Section 5.7.4, p. 594). ... 

On keeping the resin in contact with an aqueous phase, such as a solution of sodium cyanide, and an organic phase, such as an alkyl bromide, alkyl cyanides were formed by nucleophilic substitution (Scheme 13-6). The basic difference between the common heterogeneous catalytic reaction and the one being discussed is that in the latter, the catalyst and each pair of reactants are located in separate phases. 

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