The Gabriel synthesis of amines is the chemical reaction that transforms primary alkyl halides into primary amines in a two-step reaction process. (i) Potassium phthalimide is first alkylated, and (ii) the resulting N- alkylphthalimide is subsequently hydrolyzed.
- DMF, DMSO, HMPA, chlorobenzene, acetonitrile, and ethylene glycol are commonly used solvents, being DMF the best (good for SN2 reactions).
- The best alkylating agents are alkyl sulfonates, α-halo ketones, esters, nitriles, and α,β-unsaturated compounds. Also, sterically unhindered alkyl halides (alkyl iodides being the most reactive) followed by allylic, benzylic, and propargylic halides. And aryl halides in the presence of Cu(I) catalyst.
- Strong alkaline hydrolysis is often incompatible with base-sensitive functional groups. The use of hydrazine hydrate in refluxing ethanol for the cleavage of the N-alkylphthalimide under mild and neutral conditions is often employed. It is also known as the Ing-Manske procedure.
- For a modified procedure, where a secondary alcohol is replaced by phthalimide via Mitsunobu-based conditions, followed by the Ing–Manske procedure to obtain the secondary amine and phthalhydrazide, see example 1.
Reaction mechanism of Gabriel synthesis
1. Alkylation of potassium phthalimide with alkyl halides via SN2 reaction.
2. Hydrazinolysis of the N-alkylphthalimide by nucleophilic addition of hydrazine across one of the carbonyl groups of the phthalimide.
3. Ring-opening, proton transfer, intramolecular SNAc reaction, proton transfer, and breakdown of the tetrahedral intermediate gives the primary amine and phthalyl hydrazide.
Examples and experimental procedures of Gabriel synthesis
Example 1: Chem. Eur. J. 2018, 24, 10069.
DIAD (1.2 equiv) was added to a solution of the racemic alcohol (9.5 mmol, 1.0 equiv), phthalimide (1.2 equiv), and tributylphosphine (1.2 equiv) in dry THF (30 mL) at 0 ºC under an argon atmosphere. After stirring at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure. The crude mixture was purified by flash column chromatography.
Hydrazine hydrate (50–60%, 18.0 equiv) was added to a solution of the racemic substrate (2.94 mmol, 1.0 equiv) in MeOH (15 mL) under an argon atmosphere, and the mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with Et2O, and the formed precipitate was filtered off on Celite. The filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography to afford the racemic amine.
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