Gabriel Synthesis

The alkylation of phthalimide with alkyl halides was first reported in 1884, but in 1887 S. Gabriel realized that the process was a general one and developed a synthesis for primary amines. Henceforward, the mild two-step process for the preparation of primary amines from their corresponding alkyl halides, i.e., alkylation followed by hydrolysis, became known as the Gabriel synthesis.

The alkylation step can take place either neat or in the presence of a solvent. If a solvent is used, dimethyl formamide (DMF) is often considered the best choice; however, other solvents can be used including dimethyl sulfoxide (DMSO), Hexamethyl phosporamide (HMPA), acetonitrile, and ethylene glycol.

Several issues limited the use of the original Gabriel synthesis. Firstly, when the reaction of the potassium phthalimide and alkyl halide required high temperatures, heat-sensitive substrates could not be used. Secondly, the hydrolysis step was usually performed in the presence of a strong acid such as sulfuric, hydrobromic, or hydroiodic acids, further preventing the use of substrates that were sensitive to acid conditions. Alternatively, where strong alkali could be used for hydrolysis, base-sensitive functional groups had to be excluded.

In 1926, H.R. Ing and R.H.F. Manske developed a modification using hydrazine hydrate in refluxing ethanol to cleave the N-alkylphthalimide under milder and neutral conditions, which became known as the Ing-Manske procedure.

Since then, several other modifications have been developed, such as the development of novel Gabriel reagents that replace the phthalimide with other nitrogen sources, the addition of catalytic amounts of crown ether or a cryptand to improve yields, and the use of sodium borohydride in isopropyl alcohol (IPA) for exceptionally mild cleavage of the phthalimide.

The total synthesis of peramine, an alkaloid produced by a fungus that protects grasses against grazing by mammals and insects, successfully employed the Gabriel synthesis in the latter stages.