Gabriel synthesis, amines from imides

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

The success of the Gabriel synthesis depends on N-alkylation being favored over O-alkylation and SN2 being favored over E2. Polar, aprotic solvents such as methylsulfinylmethane, (CH3)2SO, are useful for the Gabriel synthesis. Hydrolysis of the alkylation product often is difficult and amide interchange (analogous to ester interchange, Section 18-7A) with hydrazine can be an effective way to free the amine from the imide. 

An alternative to the azide synthesis is the Gabriel amine synthesis, which uses a phthalimide alkylation for preparing a primary amine from an alkyl halide. Imides (-CONHCO-) are similar to ethyl acetoacetate in that... 

In Summary Amines can be made from ammonia or other amines by simple alkylation, but this method gives mixtures and poor yields. Primary amines are better made in stepwise fashion, employing nitrile and azide groups, or protected systems, such as 1,2-benzenedicarboxylic imide (phthalimide) in the Gabriel synthesis. 

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