Primary amines Gabriel synthesis

Where there are two carbonyl groups to stabilize the amide anion, as in the l,2-benzenedicarboximide (phthalimide) anion (Section 18-IOC), the acidity increases markedly and imides can be converted to their conjugate bases with concentrated aqueous hydroxide ion. We have seen how imide salts can be used for the synthesis of primary amines (Gabriel synthesis, Section 23-9D and Table 23-6). 

Also, reaction of an alkyl halide with phthalimide anion, followed by hydrolysis, gives a primary amine (Gabriel amine 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. 

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... 

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). 

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) ... 

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... 

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]. 

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 ... 

Gabriel synthesis is used for the preparation of primary amines. Phthalimide on treatment with ethanolic potassium hydroxide forms potassium salt of phthalimide which on heating with allqrl halide followed by alkaline hydrolysis produces the corresponding primary amine. Aromatic primary amines cannot be prepared by this method because aryl halides do not undergo nucleophilic substitution with the anion formed by phthalimide. 

Why cannot aromatic primary amines be prepared by Gabriel phthallmide synthesis ... 

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. 

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. 

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 reaction with ammonia or amines, which undoubtedly proceeds by the SNAr mechanism, is catalyzed by copper8" and nickel105 salts, though these are normally used only with rather unreactive halides.106 This reaction, with phase transfer catalysis, has been used to synthesize triarylamines.107 Copper ion catalysts (especially cuprous oxide or iodide) also permit the Gabriel synthesis (0-58) to be applied to aromatic substrates. Aryl bromides or iodides are refluxed with potassium phthalimide and Cu 0 or Cul in dimethylacetamide to give N-aryl phthalimides, which can be hydrolyzed to primary aryl amines.108... 

C. EtkyUnimine Ketones and Related Syntheses Closely related to the Gabriel synthesis is the reaction of /9-dihaloketones or cc-hslo-a -unsaturated ketones with primary amines... 

SAMPLE SOLUTION (a) The Gabriel synthesis is limited to preparation of amines of the type RCH2NH2, that is, primary alkylamines in which the amino group is bonded to a primary carbon. Butylamine may be prepared from butyl bromide by this method. 

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). 

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

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. 

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