The Gabriel Synthesis of Amines

The azide anion (Ns ) can also be used as a synthetic equivalent of ammonia. Sodium azide (NaNs) is commercially available, and the azide anion can do an Sn2 substitution with an alkyl halide. Like using phthalimide, this introduces nitrogen in place of the halogen leaving group. Reduction of the resulting azide by catalytic hydrogenation provides an amine product. 

The availability of these ammonia synthetic equivalents provides two good options when considering an amine TM. The -NH2 group can be converted to either the phthalimide group or an -N3 group. After this FGI, disconnection of the resulting structure at the C-N bond leads to reasonable starting materials. 

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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. 

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. 

One of the best methods of amino acid synthesis is a combination of the Gabriel synthesis of amines (Section 19-20) with the malonic ester synthesis of carboxylic acids (Section 22-16). The conventional malonic ester synthesis involves alkylation of diethyl malonate, followed by hydrolysis and decarboxylation to give an alkylated acetic acid. 

This method, a modification of the Gabriel synthesis of amines (Section 20.4A), uses potassium phthalimide and diethyl a-bromomalonate to prepare an imido malonic ester. The example shown is a synthesis of methionine ... 

Gabriel Synthesis of Amines. )V-Benzyltriflamide was originally introduced as a new nitrogen source for the Gabriel synthesis of amines. Based on its pKa of 6.8 in 67% DMF-water and a gas phase acidity of AGacid = 318.8, due to the powerful electron-withdrawing effect of the triflate function, it was reasoned that a weak base should be sufficient to induce the necessary A deprotonation. Typical conditions (eq 1) for W alkylation... 

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. 

In Summary Racemic amino acids are made by the amination of 2-bromocarboxylic acids, applications of the Gabriel synthesis of amines, and the Strecker synthesis. The last method proceeds through an imine variation of the preparation of cyanohydrins, followed by hydrolysis. 

One of the best methods for synthesizing amino acids is based on the chemistry of malonate esters (Section 22.17) and a modification of the Gabriel synthesis of amines (Section 23.7). Diethyl acetamidomalonate has a nitrogen atom bonded to the a-carbon of the malonate ester. This nitrogen eventually becomes the nitrogen of the final amino acid product. 

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)... 

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]. 

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]. 

Fig. 6.20. Mechanism of the second step of the Gabriel synthesis of primary alkyl amines.

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. 

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. 

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

Identify the lettered intermediates in the following reaction scheme. This is an alternative method to synthesize amino acids, based on the Gabriel synthesis of 1 ° amines (Section 25.7A). 

Tris(dimethylamino)phosphine added to a soln. of N-benzylthiophthalimide in benzene whereupon an exothermic reaction ensues N-benzylphthalimide. Y 87%. - This method provides an alternative to the Gabriel synthesis of prim, amines. F. e. s. D. N. Harpp and B. A. Orwig, Tetrah. Let. 1970, 2691. 

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... 

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