Hydrazine Gabriel synthesis

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. 

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. 

It was originally thought that one should be able to remove the succinic acid group by treatment of 7 with hydrazine in the same way one is able to produce a primary amine by treating a phthalimide with hydrazine in the classical Gabriel synthesis (12). This was not the case, though, since 7 did not react with hydrazine. However, it was found that treatment of 7 with dilute sodium hydroxide readily hydrolyzed the succinimide to produce the amino alcohol, 1, in 90% yield and having a 98 - 99% ee. 

The success of the Gabriel synthesis depends on N-alkylation being favored over O-alkylation and SN2 being favored over E2. Polar, aprotic solvents such as methylsulfinylmethane, (CH3)2SO, are useful for the Gabriel synthesis. Hydrolysis of the alkylation product often is difficult and amide interchange (analogous to ester interchange, Section 18-7A) with hydrazine can be an effective way to free the amine from the imide. 

An alternative reagent equivalent for the amide anion synthon is the potassium salt of phthalimide which can only react with one molecular proportion of alkyl halide. The resulting JV-alkylphthalimide is then cleaved to the primary amine (the Gabriel synthesis). The preliminary preparation of potassium phthalimide (from a solution of phthalimide in absolute ethanol and potassium hydroxide in 75% ethanol) may be avoided in some cases by boiling phthalimide with the halide in the presence of anhydrous potassium carbonate. The cleavage of the JV-substituted phthalimide is best effected by reaction with hydrazine hydrate and then heating the reaction mixture with hydrochloric acid. The insoluble phthalylhydrazide is filtered off, leaving the amine hydrochloride in solution from which the amine may be liberated and isolated in the appropriate manner. 

The enantioselective complexation technique can also be applied as one step in the reaction sequence, providing chiral substrates for the next step. We will now discuss the example of Gabriel synthesis between potassium phthalimide 41 and alkyl bromide 42, which leads to optically active amines (Scheme 1) [51], Instead of the complicated preparation of chiral alkyl bromides (halides), imides (43), which are reaction intermediates, have been resolved. Upon treatment with hydrazine and KOH, these gave optically active amines. The chiral host (S,S)-(-)-6 or the chiral biaryl host (,S>(-j-40 was used for the effective resolution of the intermediates 43. Racemic mixtures 43a-d were resolved by complex formation with the host (S,S)-(-)-6 in a mixture of diethyl ether and light petroleum. 

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. 

Further transamidation reactions are depicted in Scheme VI/6. In some respects, even the Gabriel synthesis, [15] [16] [17]3), a method for preparation of primary amines from N-substituted phthalimides by treatment with hydrazine,... 

The first step of the Gabriel synthesis, the alkylation of potassium phthalimide with alkyl halides, proceeds via an Sn2 reaction. The second step, the hydrazinolysis of the A/-alkylphthalimide, proceeds by a nucleophilic addition of hydrazine across one of the carbonyl groups of the phthalimide. Subsequently, the following steps occur ringopening then proton-transfer followed by an intramolecular SnAc reaction, another proton-transfer and finally, the breakdown of the tetrahedral intermediate to give the desired primary amine and the side product phthalyl hydrazide. 

The phthalimide anion is a strong nucleophile. It can react easily with primary alkyl halides to form substituted phthalimides. One advantage when working with substituted phthalimides is that when treated with hydrazine, primary amines are furnished through this alkylation protocol (Gabriel synthesis). For both synthetic pathways (a) and (b), suggest a suitable mechanism. 

One variation of the Gabriel synthesis employs hydrazine to free the amine in the final step of the synthesis. Draw the by-product obtained in this process. 

Gabriel synthesis Phthalimide is the starting material for the Gabriel synthesis, which can be used to prepare primary amines. Phthalimide is treated with KOH to give potassium phthalimide, which is then treated with an alkyl halide, giving an Sn2 reaction. The product of the Sn2 process is then hydrolyzed (upon treatment with hydrazine or aqueous acid) to release the amine. 

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 ... 

Next the product is acylated with bromoacetyl chloride and the glycine equivalent is constructed in place by a Gabriel amine synthesis (phthalamide anion followed by hydrazine) subsequent to which cyclization to benzodiazepine occurs. The synthesis of the tranquilizer quazepam (88) is finished by thioamide conversion with phosphorus pentasulfide. ... 

A variant of Gabriel amine synthesis where hydrazine is used to release the amine from the corresponding phthalimide ... 

Gabriel amine synthesis Synthesis of primary amines by alkylation of the potassium salt of phthalimide, followed by displacement of the amine by hydrazine, (p. 915)... 

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