In the Gabriel synthesis

The Gabriel synthesis is based on work carried out by Siegmund Gabriel at the Uni versity of Berlin in the 1880s A detailed discussion of each step in the Gabriel synthesis of benzylamine can be found in the October 1975 Journal of Chemical Education (pp 670-671)... 

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

In the Gabriel synthesis, care must be taken to insure that the... 

In the Gabriel synthesis, potassium phthalimide is reacted with an alkyl halide to produce an N-alkyl phthalimide. This N-alkyl phthalimide can be hydrolyzed by aqueous acids or bases into the primary amine. 

The Gabriel synthesis is a classical but useful preparative method for primary amines. Reaction of an alkyl bromide (24) with potassium phthalimide (25) gives the corresponding A -alkylphthalinude (26), which upon treatment with hydrazine followed by KOH affords the primary amine (27). When a chiral alkyl halide is used in the Gabriel synthesis, a chiral primary amine is obtained. However, preparation of optically active alkyl halides is not easy. If optical resolution of 26 which has a chiral alkyl group can be done, a new preparative method for optically active amines can be established by a combination of the resolution with the Gabriel synthetic method. Some examples of the combination method are described. 

Saccharin in the Gabriel synthesis of primary amines 91ACR285. 

Silacyclopentane derivatives in Peterson olefination 91SL764. 2,2,6,6-Tetramethyl-2,6-disilapiperidine in the Gabriel synthesis of primary amines 91ACR285. 

In a similar manner the conjugate base of phthalimide is used as the synthetic equivalent of amide ion for the preparation of primary amines in the Gabriel synthesis (see Section 10.6 and Figure 10.5). 

Alkylation of phthalLmide is the first step in the Gabriel synthesis of primary amines. The scope of this alkylation is discussed in method 452 because the phthalimides are often hydrolyzed directly, without purification, to primary amines. 

The N -phthaloyl group (Phth), well known for the preparation of primary amines in the Gabriel synthesis,P was used more extensively as a temporary backbone amine protecting group in the early period of amino acid and peptide chemistry.t The resulting phthalimides ensure exhaustive substitution of the primary amine, i.e. removal of both acidic hydrogens, thus, moderating the nucleophilic character. 

Zwierzak and co-workers have reported on the use of a phosphoramidate as an alternative to the phthalimide in the Gabriel synthesis.22 "0 However, several drawbacks to their method led to revisions in the original method. In particular, the use of toxic benzene as a solvent, deprotection by gaseous HC1 in benzene, and low yields were discouraging. The modified procedure reaction involves nucleophilic amination by diethyl yV-sodio-./V-(r-butoxycarbonyl)phosphoramidate 37 with tetrabutylammonium bromide as a catalyst in acetonitrile. Carrying out the reactions in tetrahydrofuran led... 

Amides appear in such diverse compounds as penicillin V (a (3-lactam and an amide) and polypeptides (a-amino adds linked by amide bonds) and an imide, 1,2-benzenecarboxylic imide, is used in the Gabriel synthesis of amines. An imide is prepared in Experiment [24] and anhydrides are prepared in Experiments [25A] and [25B].The polyamide polymer, nylon, is prepared in Chapter 7, Sequence B. 

Thus, as shown in Scheme 10.2, in the Gabriel synthesis," the anion of phthalimide [1,2-benzenedicarboximide or lH-isoindole-l,3(2H)-dione] generated by treatment of the imide with sodium ethoxide (Na" OCH2CH3) in ethanol (CH3CH2OH) is... 

In the Gabriel synthesis, the nitrogen atom comes from phthalimide, which serves as the starting material. The process requires three steps (1) deprotonation to form potassium phthalimide, (2) nucleophilic attack with an alkyl halide, and (3) hydrolysis. Draw the reagents for all three steps of the Gabriel synthesis ... 

In Summary Amines can be made from ammonia or other amines by simple alkylation, but this method gives mixtures and poor yields. Primary amines are better made in stepwise fashion, employing nitrile and azide groups, or protected systems, such as 1,2-benzenedicarboxylic imide (phthalimide) in the Gabriel synthesis. 

Potassium phthalimide is a commercially available reagent, which is usually used in the Gabriel synthesis of amines (50). Halomethylsilanes interact with potassium phthalimide to form N-silylmethylphthalimides 32—48 (Scheme 24.4, Table 24.2)... 

There are also many syntheses that involve nucleophilic substitution using a synthon for ammonia. Thus, the azide anion is an excellent nucleophile, and alkyl azides are readily reduced to amines (Figure 22.5), either by hydrogenation, as in this example, or by reduction with lithium aluminum hydride. Hexamethylenetetramine is also an excellent nucleophile and a synthon for ammonia in this case, the final product is released by hydrolysis (Figure 22.6). In the Gabriel synthesis, phthalimide acts as a synthon for ammonia (Figure 22.7). 

In the Gabriel synthesis, phthalimide is the starting material, and three steps are required. In the first step, phthalimide is deprotonated by hydroxide to give potassium phthalimide, which can serve as a nucleophile and attack the alkyl halide above in an 8 2 process. Subsequent treatment with hydrazine (or aqueous acid) releases the desired amine ... 

---