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Named Reactions in Organic Synthesis
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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. Hence forward the mild two-step process, alkylation followed by hydrolysis, for the preparation of primary amines from their corresponding alkyl halides became known as the Gabriel synthesis.
The alkylation step can take place 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 sulphoxide (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 were 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 and this 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 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.
Mechanism of Gabriel Synthesis
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Reduction reactions NEW!
Some relevant Alfa Aesar products for Gabriel synthesis: