Gabriel synthesis reaction

Chapter IV. a-Chloromethylnaphthalene (IV,23) benzylamine (Gabriel synthesis) (IV,39) i r.N -dialkylanilines (from amines and trialkyl orthophosphates) (IV,42) a-naphthaldehyde (Sommelet reaction) (IV,120) a-phenyl-cinnamic acid (Perkin reaction using triethylamine) (IV,124) p-nitrostyrene (IV,129) p-bromonaphthalene and p naphthoic acid (from 2 naphthylamine-1 -sulphonic acid) (IV,62 and IV,164) diphenic acid (from phenanthrene) (IV,165). 

Gabriel synthesis Gattermaim aldehyde reaction Gattermann reaction Gattermann-Kocll reaction Gomberg-Hey reaction Grignard reaction... 

A method that achieves the same end result as that desired by alkylation of ammonia but which avoids the formation of secondary and tertiary amines as byproducts is the Gabriel synthesis Alkyl halides are converted to primary alkylamines without contam mation by secondary or tertiary amines The key reagent is the potassium salt of phthal imide prepared by the reaction... 

A related aziridine synthesis is the Gabriel reaction (a.k.a. Gabriel-Cromwell reaction), which involves an intramolecular Sn2 reaction of a P-amino halide. However, the reaction has become so common that the name Gabriel is not tightly related to the transformation. 

Reaction of alkyl halides 1 with hexamethylenetetramine 2 (trivial name urotropine) followed by a hydrolysis step, leads to formation of primary amines 3 free of higher substituted amines. This method is called the Delepine reaction, a comparable method is the Gabriel synthesis. 

The Gabriel synthesis is often carried out by heating the starting materials without a solvent for several hours at a temperature of 150 °C or higher. The use of solvents like dimethylformamide can lead to better results. In a number of solvents—e.g. toluene—the phthalimide is insoluble the reaction can however be conducted in the presence of a phase transfer catalyst." ... 

Scheme 2.16 Synthesis of vinylaziridines by the Gabriel-Cromwell reaction.

The Gabriel-Cromwell reaction is a convenient strategy for the synthesis of vinylaziridines. Treatment of 4,5-dibromopent-2-enoate 50 with primary amines 51 in the presence of DBU afforded the corresponding conjugated aziridines 52 in 63-80% yields (Scheme 2.16) [28]. The use of DBU has proven to be essential for the successful conversion. 

The Gabriel synthesis for converting halides to primary amines is based on this reaction. The halide is treated with potassium phthalimide and the product hydrolyzed (10-11) ... 

The reaction with ammonia or amines, which undoubtedly proceeds by the SnAt mechanism, is catalyzed by copper and nickel salts, though these are normally used only with rather unreactive halides. This reaction, with phase-transfer catalysis, has been used to synthesize triarylamines. Copper ion catalysts (especially cuprous oxide or iodide) also permit the Gabriel synthesis (10-61) to be... 

The most successful approach to producing an aminomethyl derivative was the Gabriel synthesis. A phthalimide substituent can be introduced by Sn2 displacement of the chloride on 17 with potassium phthalimide under homogeneous conditions in DMF. The reaction is quantitative in all D.F. ranges and the phthalimldo-methyl intermediates, 18, are quite soluble in organic solvents. 

A wide variety of M W-assisted aldol [59, 60] and Knoevenagel condensation reactions have been accomplished using relatively benign reagents such as ammonium acetate [61], including the Gabriel synthesis of phthalides with potassium acetate [62],... 

The simplicity of the two-phase modification of the Gabriel synthesis of primary amines, via the N-alkylation of potassium phthalimide, makes the procedure considerably more convenient than the traditional method, which normally requires the use of anhydrous dipolar aprolic solvents. The reaction can be conducted under solid liquid conditions using potassium hydroxide in toluene [25], or with preformed potassium phthalimide [26, 27] (cf ref. 28). As is normal for acylation reactions, relatively mild conditions are required for the preparation of the A-ethoxycarbonyl derivative [29], whereas a reaction temperature of 100°C is generally used for N-alkylation (Table 5.16). The reaction time for the soliddiquid two-phase system can be reduced dramatically with retention of the high yields, when the reaction mixture is subjected to microwave irradiation [30]. 

Cf. Gabriel synthesis, where the product is also amine and Sommelet reaction, where the product is aldehyde. The Delepine works well for active halides such as benzyl, allyl halides, and a-halo-ketones. 

Brooks, D. A. Robinson-Gabriel Synthesis in Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 249-253. (Review). 

The Gabriel synthesis of amines uses potassium phthalimide (prepared from the reaction of phthalimide with potassium hydroxide). The structure and preparation of potassium phthalimide is shown in Figure 13-13. The extensive conjugation (resonance) makes the ion very stable. An example of the Gabriel synthesis is in Figure 13-14. (The N2H4 reactant is hydrazine.) The Gabriel synthesis employs an 8, 2 mechanism, so it works best on primary alkyl halides and less well on secondary alkyl halides. It doesn t work on tertiary alkyl halides or aryl halides. 

Gabriel Synthesis The reaction of an alkyl halide with potassium phthalimide to form, after hydrolysis, a primary amine. 

Problem 21.2 Synthesize leucine, (CH,),CHCH,CH(NH,)COO, by (a) Hell-Volhard-Zelinsky reaction (Section 16.3) followed by ammonolysis. (b) Gabriel synthesis, (c) phthalimidomalonic ester synthesis, (d) reductive amination of a keto acid, (e) Strecker synthesis (addition of NH, HCN to RCH=0), (/) acetylaminomalonic ester. 

---