Alkyl halides. Gabriel synthesis

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. 

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... 

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... 

GABRIEL Amine Synthesis Synthesis ol primary amines from alkyl halides... 

Alkylation of phthalimide. The Gabriel synthesis (Section 22.8) The potassium salt of phthalimide reacts with alkyl halides to give A/-alkylphthalimide derivatives. Hydrolysis or hydrazinolysis of this derivative yields a primary alkylamine. 

Primaty amines may be prepared from alkyl halides using phthalimide. This is called the Gabriel amine synthesis. 

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 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 ... 

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

Gabriel amine synthesis (Section 24.6) A method for preparing an amine by SN2 reaction of an alkyl halide with potassium phthalimide. followed by hydrolysis. 

An alternative to the Gabriel synthesis, in which alkyl halides can be converted to primary amines in good yields, involves treatment of the halide with the strong base guanidine followed by alkaline hydrolysis. There are several alternative... 

Amides are weakly nucleophilic and react only slowly with alkyl halides. The anions of amides are substantially more reactive. The classical Gabriel procedure for synthesis of amines from phthalimide is illustrative.58... 

Gabriel s synthesis org chem A synthesis of primary amines by the hydrolysis of n-alkylphthallmldes the latter are obtained from potassium phthalimide and alkyl halides. ga-bre-alz, sin-tha-sas ... 

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. 

Problem 18.8 Prepare ethylamine by (a) Gabriel synthesis, (6) alkyl halide amination, (c) nitrile reduction, (d) reductive amination, (e) Hofmann degradation. ... 

Primary amines can be prepared from alkyl halides by 0-44, by 0-63, by 0-61 followed by reduction of the azide (9-53), or by the Gabriel synthesis (0-58). 

The use of acyl azides in the preparation of amines by the Curtius rearrangement has been discussed previously (Section 23-12E). Alkyl azides can be reduced readily by lithium aluminum hydride to amines and, if a pure primary amine is desired, the sequence halide — azide — amine may give as good or better results than does the Gabriel synthesis (Section 23-9D). 

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. 

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 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. 

The overall reaction involves replacing the halogen atom of the alkyl halide with an NH, unit. Another method is the Gabriel synthesis of amines. This involves treating phthalimide with KOH to abstract the N-H proton. The N-H proton of phthalimide is more acidic (pK9) than the N-H proton of an amide since the anion formed can be stabilised by resonance with both neighbouring carbonyl groups. The phthalimide ion can then be alkylated by treating it with an alkyl halide in nucleophilic substitution. 

Potassium phthalimide, CgH CO NK Reacts with alkyl halides to yield N-alkyl-phthalimides, which are hydrolyzed by aqueous sodium hydroxide to yield amines (Gabriel amine synthesis Section 24.6). 

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