Lithium aluminum hydride, reducing alkyl azides

Alkyl azides prepared by nucleophilic substitution of alkyl halides by sodium azide as shown m the first entry of Table 22 3 are reduced to alkylammes by a variety of reagents including lithium aluminum hydride... 

Alkyl azides prepared by nucleophilic substitution by azide ion in primary or secondary alkyl halides are reduced to primary alkylamines by lithium aluminum hydride or by catalytic hydrogenation... 

The use of acyl azides in the preparation of amines by the Curtius rearrangement has been discussed previously (Section 23-12E). Alkyl azides can be reduced readily by lithium aluminum hydride to amines and, if a pure primary amine is desired, the sequence halide — azide — amine may give as good or better results than does the Gabriel synthesis (Section 23-9D). 

Formation and Reduction of Nitriles Like the azide ion, cyanide ion (- C=N ) is a good Sn2 nucleophile it displaces leaving groups from unhindered primary and secondary alkyl halides and tosylates. The product is a nitrile (R—C=N), which has no tendency to react further. Nitriles are reduced to primary amines by lithium aluminum hydride or by catalytic hydrogenation. 

Primary alkyl amines. a-Alkoxy azides are reduced to primary amines by lithium aluminum hydride in ether. A side reaction noted occasionally, reduction to an ether, can be suppressed by addition of TMEDA. Sodium bis(2-methoxy-ethoxy)aluminum hydride cannot replace lithium aluminum hydride in this reductive amination. The a-alkoxy azides are available by reaction of aldehydes with azidotrimethylsilane, by addition of hydrazoic acid to an enol ether, or by reaction of ketals with the l8-crown-6 complex of sodium azide. 

Alkylation of Azide Ion and Reduction A much better method for preparing a primary amine from an alkyl halide is first to convert the alkyl halide to an alkyl azide (R — N3) by a nucleophilic substitution reaction, then reduce the azide to a primary amine with lithium aluminum hydride. 

Aikyiation of Azide ion Foiiowed by Reduction (Section 23.7B) Azides are prepared by treatment of a primary or secondary alkyl halide or an epoxide with KNj and are reduced to primary amines by a variety of reducing agents, including lithium aluminum hydride. 

Several years ago, we reported the synthesis and synthetic utility of lithium aminoborohydrides (LABs) a new class of powerful, safe, and highly selective reducing agents (2, 3). These reagents performed many of the transformations for which lithium aluminum hydride is usually used. Thus, the following reduction reactions were carried out with LABs aldehydes and ketones to alcohols, esters to alcohols, oc,P>unsaturated ketones to allylic alcohols, a,P-unsaturated esters to allylic alcohols, alkyl halides to hydro-carbons, azides to amines, and epoxides to alcohols. These reduction reactions are summarized in Figure 3. 

There are also many syntheses that involve nucleophilic substitution using a synthon for ammonia. Thus, the azide anion is an excellent nucleophile, and alkyl azides are readily reduced to amines (Figure 22.5), either by hydrogenation, as in this example, or by reduction with lithium aluminum hydride. Hexamethylenetetramine is also an excellent nucleophile and a synthon for ammonia in this case, the final product is released by hydrolysis (Figure 22.6). In the Gabriel synthesis, phthalimide acts as a synthon for ammonia (Figure 22.7). 

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