Amines Gabriel method

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. 

Gabriel method based on the cyclization of 2-haloalkyl amines with a base. This method was used for the first commercial production of ethyleneimine. 

The Gabriel method of making primary amines (Scheme 2.33) rests on the fact that the imide hydrogen of phthalimide is rendered acidic by the two carbonyl groups. It therefore forms a potassium salt, which is a powerful nucleophile and may be alkylated. Hydrolysis of the amide generates the primary amine. The cleavage of the phthalimide may be carried out with hydrazine (H NNHj). 

The Gabriel synthesis is a classical but still useful procedure for the preparation of primary amines. The method consists of alkylation of phthalimide anion with an appropriate alkylating reagent and subsequent removal of the phthaloyl group to generate primary amines (Scheme 36). ... 

The addition of amines to activated cyclopropanes with opening of the three-membered ring was also applied for the preparation of bicyclic systems with the nitrogen as bridgehead atom. These transformations involved the intramolecular nucleophilic attack of a primary amine which was generated by the Gabriel method. 

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... 

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. 

The Gabriel synthesis represents another indirect but highly valuable approach to amines. Trost has demonstrated a method for the asymmetric ring-opening of butadiene monoepoxide by use of one equivalent of phthalimide, 7t-allylpalladium chloride dimer, and the chiral bisphosphine 22 (Scheme 7.37). The dynamic kinetic asymmetric transformation proceeded through a putative achiral intermedi-... 

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 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. 

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. 

Die Alkylierungen konnen mit oder ohne Isolierung der Zwischenstufen durchgefuhrt werden. Insgesamt stellt diese Methode eine Alternative zur Gabriel-Synthese dar und eignet sich dariiber hinaus auch zur Herstellung sekundarer Amine. 

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. 

In practice the most common method is the one based upon obtaining a,(3-dihalogen derivatives of unsaturated ketones with their subsequent interaction with ammonia or primary amines, known as the Gabriel reaction (Scheme 1.1). 

The alkylation of ammonia, Gabriel synthesis, reduction of nitriles, reduction of amides, reduction of nitrocompounds, and reductive amination of aldehydes and ketones are methods commonly used for preparing amines. 

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. 

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. 

Aminooxindols (11/153) are rearranged to 3-cinnolinols 11/154, if treated with equimolar amounts of /-butyl hypochlorite [106] [107] [108]. Compound 11/153 is known as Neber s lactam , and is formed from 11/154 with zinc and sulfuric acid. The mechanism preferred for the 11/153 —> 11/154 transformation involves nitrene formation [106]. - As already mentioned, the Gabriel synthesis (11/155 11/157) is a method for synthesis of primary amines. But the side product is the ring enlarged hydrazide, compare Chapter IV... 

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,... 

A milder alternative to the classical Gabriel synthesis, which allows the appendage of a protected primary amine to a secondary alkyl group, exploits the Mit-sunobu inversion2 as illustrated in Scheme 8.15.27 The method can also be adapted to the synthesis of -protected hydroxylamines [Scheme 8,16)22... 

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. 

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