And the Gabriel synthesis

Among compounds other than simple alkyl halides a halo ketones and a halo esters have been employed as substrates m the Gabriel synthesis Alkyl p toluenesul fonate esters have also been used Because phthalimide can undergo only a single alkyl ation the formation of secondary and tertiary amines does not occur and the Gabriel synthesis is a valuable procedure for the laboratory preparation of primary amines... 

Several additional amine syntheses are effectively limited to making primary amines. The reduction of azides and nitro compounds and the Gabriel synthesis leave the carbon chain unchanged. Formation and reduction of a nitrile adds one carbon atom. Show how these amine syntheses can be used for the following conversions. 

Nucleophilic substitution is the key step in two different methods for synthesizing amines direct nucleophilic substitution and the Gabriel synthesis of 1° amines. 

Primary amines can also be prepared by the reaction of an alkyl halide with azide ion, followed by catalytic hydrogenation. What advantage do this method and the Gabriel synthesis have over the synthesis of a primary amine using an alkyl halide and ammonia ... 

Amino acids can be synthesized with much better yields than those obtained by the previous two methods via an A-phthalimidomalonic ester synthesis, a method that combines the malonic ester synthesis (Section 18.18) and the Gabriel synthesis (Section 16.18). 

The modified procedure involves refluxing the N-substituted phthaUmide in alcohol with an equivalent quantity of hydrazine hydrate, followed by removal of the alcohol and heating the residue with hydrochloric acid on a steam bath the phthalyl hydtazide produced is filtered off, leaving the amine hydrochloride in solution. The Gabriel synthesis has been employed in the preparation of a wide variety of amino compounds, including aliphatic amines and amino acids it provides an unequivocal synthesis of a pure primary amine. 

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... 

In Its overall design this procedure is similar to the Gabriel synthesis a nitrogen nude ophile IS used m a carbon-nitrogen bond forming operation and then converted to an ammo group m a subsequent transformation... 

Isobutylamine and 2 phenylethylamine can be prepared by the Gabriel synthesis ten butyl amine N methylbenzylamine and aniline cannot... 

The hydrazinolysis is usually conducted in refluxing ethanol, and is a fast process in many cases. Functional groups, that would be affected under hydrolytic conditions, may be stable under hydrazinolysis conditions. The primary amine is often obtained in high yield. The Gabriel synthesis is for example recommended for the synthesis of isotopically labeled amines and amino acids. a-Amino acids 9 can be prepared by the Gabriel route, if a halomalonic ester—e.g. diethyl bromomalonate 7—is employed as the starting material instead of the alkyl halide ... 

The Gabriel synthesis represents another indirect but highly valuable approach to amines. Trost has demonstrated a method for the asymmetric ring-opening of butadiene monoepoxide by use of one equivalent of phthalimide, 7t-allylpalladium chloride dimer, and the chiral bisphosphine 22 (Scheme 7.37). The dynamic kinetic asymmetric transformation proceeded through a putative achiral intermedi-... 

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 sulphonyl chloride 23 is proposed as a protecting group for the Gabriel synthesis of secondary amines from primary amines. At the deprotecting stage, carbon-sulphur bond cleavage is achieved using zinc and acid as the electron source [109]. 

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. 

Since the 2-nitrobenzenesulfonamide group is stable under acidic [HCI (10 eq), MeOH, 60°C, 4 hr] as well as basic [NaOH (10 eq), MeOH, 60°C, 4 hr] conditions, it can be used extensively for protection of primary and secondary amines. Because of the mild conditions and easy procedure, the submitters believe that the use of 2-nitrobenzenesulfonamides serves as a method of choice for the preparation of a wide variety of secondary amines comparable to the Gabriel synthesis for primary amines. 

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