Gabriel synthesis, modifications

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]. 

A. The Oalrid and. Wenker Reactions The preparation of an aziridino derivative is most frequently accomplished in a two-step synthesis from a suitably substituted 0-aminn alcohol. When the reaction is carried out via the /MialGabriel synthesis (Eq. 1). in honor of the discoverer of the prototype reaction. A convenient modification of this sequence, called the Wenker synthesis (Eq, 2), was published in 1936" and almost simultaneously reported independently in the patent literature."4- SR This involves the conversion of the amino alcohol into tb 0-amino hydrogen auifete (which undoubtedly exists as the zwitterion)... 

Detailed examples of modifications in the technique of the Gabriel synthesis are to be found in the literature. 11... 

Better yields are generally obtained by the Gabriel phthalimide synthesis (Problem 11, p. 744) the a-halo esters are used instead of a-halo acids (Why ). A further modification, the phthalimidomalonic ester method, is a combined malonic ester-Gabriel synthesis. 

A commonly used modification of the Gabriel synthesis is the Ing-Manske procedure.10 Instead of removal of the phthaloyl group with aqueous base or acid, the Ing-Manske modification utilizes hydrazinolysis. It has been used in the synthesis of optically active a-amino acids 17, as illustrated by Guifa and Lingchong.11... 

Liberation of amines. A modification of the classical Gabriel synthesis to gain access to a-amino acids using chiral a-bromoalkanoic esters to react with potassium phthalimide catalyzed by a chiral phase transfer agent has been reported. Unfortunately, the results are not very satisfactory. 

While side-reactions of the primary aromatic amine with the maleimide moiety were to be feared, none are in fact observed. Thus, N-butylamine amminolyzes succinimides readily in a modification of the time-honored (1887) Gabriel synthesis of eunino acids by contrast, aniline does not react with succinimides, even in hot DMF. This contrast in behavior between primary aliphatic and aromatic amines is ascribed)le to their vastly different basicities (pl s of 3.3 and 9.3, respectively). 

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 ... 

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. 

The expected synthesis of a-S-diaminovalerianic acid, which was attempted by Willstatter in 1900, by the action of ammonia upon a-B-dibromovalerianic acid, led to the synthesis of a-pyrrolidine-carboxylic acid, and only in the following year was the synthesis of this important naturally occurring diamino acid accomplished by E. Fischer. He made use of Gabriel s phthalimide method with a slight modification and obtained ornithine by the following series of reactions —... 

The intermediate in the Gabriel-Posner synthesis of quinazolin-2(lH)-one (fusion of o-aminobenzaldehyde with excess of urea), was found to be o-ureidobenzylidene urea (19), which then cyclized on heating, or in the presence of acid, with elimination of urea. The intermediate reacted with aniline, iV-methylaniline, and N,V-dimethylaniline to form 4-p-aminophenyl, 4-p-methylaminophenyl, and 4-p-dimethylaminophenyl quinazolin-2(lH)-ones in an unusual manner. Several quinazolin-2(li/)-ones were prepared by converting o-acylanilines into o-ureidophenyl ketones followed by cycli-zation in acetic acid medium for long periods at 55°C. A novel modification of this cyclization involved a Curtius or Hofmann reaction on 2 -benzoyl-oxanilic acid chlorides (20 = Cl) or amides (20 = NH2), respectively. 

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