Synthesis Gabriel

Synthesis of primary amines using potassium phthaiimide and aikyi haiides. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 114, Springer International Publishing Switzerland 2014 

Goldberg, I. J. Chem. Soc., Perkin Trans. 1 1993,2357-2361. 

Gabriel synthesis. In Name Reactions for Functional Group Tran or-mations, Li, J. J., Ed. Wiley Hoboken,NJ,2007, pp438-450. (Review). 

The first step of the Gabriel synthesis, the alkylation of potassium phthalimide with alkyl halides, proceeds via an Sn2 reaction. The second step, the hydrazinolysis of the A/-alkylphthalimide, proceeds by a nucleophilic addition of hydrazine across one of the carbonyl groups of the phthalimide. Subsequently, the following steps occur ringopening then proton-transfer followed by an intramolecular SnAc reaction, another proton-transfer and finally, the breakdown of the tetrahedral intermediate to give the desired primary amine and the side product phthalyl hydrazide. 

The total synthesis of the insect feeding deterrent peramine was accomplished by D.J. Dumas at du Pont laboratories. The Gabriel synthesis was successfully employed in the last steps of the synthesis. The primary alkyl chloride was treated with potassium phthalimide in DMF at 77-82 °C for 1.5h. The resulting A/-alkylphthalimide was cleaved in high yield using the Ing-Manske procedure. 

A dynamic kinetic resolution was utilized for the highly stereoselective Gabriel synthesis of -amino acids by K. Nunami and co-workers. The substrate, f-butyl-(4S)-1-methyl-3-2-(bromoalkanoyl)-2-oxoimidazolidine-4-carboxylate, smoothly reacted with potassium phthalimide at room temperature to give only one diastereomer in good yield. The removal of the chiral auxiliary afforded an A/-phthaloyl-L- -amino acid. 

The reaction of potassium phthalimide 1 with an alkyl halide 2 leads to formation of a N-alkyl phthalimide 3/ which can be cleaved hydrolytically or by reaction with hydrazine (Ing-Manske variant) to yield a primary amine 5. This route owes its importance as a synthetic method to the fact that primary amines are prepared selectively, not contaminated with secondary or tertiary amines. 

The two-step procedure includes formation of a N-substituted phthalimide 3, and its subsequent cleavage to the primary amine 5. Phthalimide (which can be obtained from reaction of phthalic acid with ammonia) shows NH-acidity, since the negative charge of the phthalimide anion (the conjugated base) is stabilized 

Named Organic Reactions, Second Edition T. Laue and A. Plagens 2005 John Wiley Sons, Ltd ISBNs 0-470-01040-1 (HB) 0-470-01041-X (PB) 

A further alkylation of the nitrogen is not possible. In a second step the TV-substituted phthalimide 3 is hydrolyzed to give the desired amine 5 and phthalic acid 4  

The hydrolytic cleavage is usually slow, and requires drastic reaction conditions. A more elegant method is presented by the Ing-Manske procedure, where the A-alkylated imide is treated with hydrazine under milder conditions. In addition to the desired amine 5, the cyclic phthalic hydrazide 6 is then formed  

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An important laboratory use involves the Gabriel synthesis of a-amino-acids. 

Benzylamine may be obtained by the Gabriel synthesis, which depends upon the use of potassium phthalimide. The latter upon heating with benzyl... 

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. 

Chapter IV. a-Chloromethylnaphthalene (IV,23) benzylamine (Gabriel synthesis) (IV,39) i r.N -dialkylanilines (from amines and trialkyl orthophosphates) (IV,42) a-naphthaldehyde (Sommelet reaction) (IV,120) a-phenyl-cinnamic acid (Perkin reaction using triethylamine) (IV,124) p-nitrostyrene (IV,129) p-bromonaphthalene and p naphthoic acid (from 2 naphthylamine-1 -sulphonic acid) (IV,62 and IV,164) diphenic acid (from phenanthrene) (IV,165). 

Gabriel synthesis Gattermaim aldehyde reaction Gattermann reaction Gattermann-Kocll reaction Gomberg-Hey reaction Grignard reaction... 

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... 

The Gabriel synthesis is based on work carried out by Siegmund Gabriel at the Uni versity of Berlin in the 1880s A detailed discussion of each step in the Gabriel synthesis of benzylamine can be found in the October 1975 Journal of Chemical Education (pp 670-671)... 

Aryl halides cannot be converted to arylammes by the Gabriel synthesis because they do not undergo nucleophilic substitution with N potassiophthalimide m the first step of the procedure... 

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... 

In Its overall design this procedure is similar to the Gabriel synthesis a nitrogen nude ophile IS used m a carbon-nitrogen bond forming operation and then converted to an ammo group m a subsequent transformation... 

Alkylation of phthalimide The Gabriel synthesis (Section 22 8) The potassium salt of phthalimide reacts with alkyl hal ides to give N alkylphthalimide deriva fives Hydrolysis or hydrazinolysis of this derivative yields a primary alkylamine... 

Isobutylamine and 2 phenylethylamine can be prepared by the Gabriel synthesis ten butyl amine N methylbenzylamine and aniline cannot... 

Gabriel synthesis (Section 22 8) Method for the synthesis of primary alkylamines in which a key step is the formation of a carbon-nitrogen bond by alkylation of the potassium salt of phthalimide... 

Ethyleneimine was fkst piepaied commeicially in 1938 from 2-chloioethylaniine and NaOH by a modified Gabriel synthesis (21). 

Gabriel synthesis, 7, 33 aziridines, 7, 81-82 thiazoles, 6, 302 Galanthamine structure, 4, 548 Galbacin NMR, 4, 574 Gelatin hardeners for... 

Ring transformations heterocyclic compounds reviews, 1, 70 Ring-chain tautomerism polyheteroatom six-membered rings, 3, 1056 Ripariochromene A synthesis, 3, 751, 755 Robinson-Gabriel synthesis oxazoles, 6, 216... 

An alternative to Gabriel synthesis is based on the alkylation of tnfluoro-acetamide [770, 777[ or Al-benzyl triflamide [772] in place of the classical phtalimide (equations 96 and 97). 

Onaka demonstrated the utility of a modified Fisher method in the one-step synthesis of oxazole alkaloid Halfordinol (16) in higher overall yield than previously reported by Robinson-Gabriel synthesis. ... 

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