Phthaloyl group amines

Gabriel synthesis, which is most often considered as a classical approach to primary amines, can be generalized as monoalkylation of a suitably protected ammonia derivative with subsequent removal of the phthaloyl group from nitrogen. Despite its wide applicability this procedure suffers, however, from several drawbacks ... 

The N -phthaloyl group (Phth), well known for the preparation of primary amines in the Gabriel synthesis,P was used more extensively as a temporary backbone amine protecting group in the early period of amino acid and peptide chemistry.t The resulting phthalimides ensure exhaustive substitution of the primary amine, i.e. removal of both acidic hydrogens, thus, moderating the nucleophilic character. 

Several methods have been developed for phthaloylation of primary amines. Originally, the phthaloyl group was introduced by treatment of anoino acids with phthalic anhydride at elevated temperatures of around The harsh reaction conditions of this... 

After converting A -Phth-protected amines into the corresponding 2-(pyrrolidinocarbon-yl)benzamide derivative, Dieckmann reactions, ester hydrolysis, and transesterfication can be carried out. This strategy of pyrrolidine-based deactivation of phthaloyl-protected anoines followed by reclosure of the phthaloyl group has successfully been applied in the synthesis of (3-lactam antibiotics.P l... 

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). ... 

Cleavage of phthaloylpeptides. The conventional method of removing the N-protective phthaloyl group of a peptide involves reaction with hydrazine in alcoholic solution and heating the intermediate formed with dilute acid to effect hydrolysis. Boissonnas found that cleavage can be effected more easily and in one step by heating in alcoholic solution with phenylhydrazine and a tertiary amine. For example, a solution of 535 mg. (2.05 mmoles) of phthaloyl-L-leucine, 0.5 ml. (2.1 mmoles) of Iri-n-butylamine, and 0.405 ml. (4.1 mmoles) of phenylhydrazine in 3 ml. of ethanol... 

Most other methods are based on o-azido or o-nitro derivatives of aromatic aldehydes and ketones. Thus, thermolysis of o-azidobenzalhy-drazone (19) protected by the o-phthaloyl group leads to 2-phthaloylami-doindazole (21), which, under the action of hydrazine, affords 2-aminoin-dazole (22). Both stages give almost quantitative yields. Supposedly, this reaction takes place via nitrene 20. In contrast to amine 22, 2-amino-3-methylindazole can be obtained in a yield of 80% in one step on heating... 

The sequence provides a useful alternative to the Gabriel synthesis particularly for preparation of amines containing nitrile, ester, or amide groups, which are hydrolyzed to a carboxylic acid group when the phthaloyl group is removed. 

Allylic amines 54 have also been synthesised using the Mitosunobu protocol. Sen and Roach describe the formation of such amines from allylic alcohols 29 The phthaloyl group can be removed cleanly by hydrazine at room temperature, while for more bulky groups (e.g., nerol, famesol) phthaloyl cleavage was better effected with methylamine. Deprotection with methylamine was found to be exceptionally mild, and in substrates... 

In the procedure presented here, the phthaloyl group is chosen as an amino protecting group to avoid internal amine participation.13 Amine diprotection is necessary since the same reaction conducted on the N-benzyloxycarbonyl (NHCbz) and the N-tert-butyloxycarbonyl (NHBoc) analogues did not led to clean a-chlorination but rather to unidentified products. This protection was performed using a standard procedure.14... 

Allylic amines. With phthalimide as nucleophile in the modified Mitsunobu reaction, high yields of the A -allylated phthalimides are prepared. The phthaloyl group can be removed with methylamine in methanol. 

A second non-selective addition of vinyl Grignard to 661 produces a mixture of alcohols 662 and 665. The hydroxyl center is inverted with phthalimide under Mitsunobu conditions, after which the phthaloyl group is cleaved with hydrazine and the resulting amine acylated to give 664 and 667 (separable by HPLC). Compound 667 is then debenzylated, the acetonide group is hydrolyzed, and the olefin is ozonolyzed to give 668 as a crystalline solid. Likewise, 664 is converted to 669. By a parallel sequence of reactions, 660 is transformed to 670 and 671. Ozonolysis as the last step is a critical feature of these syntheses, because the A-acetyl-hexosamines are generated very cleanly, and such compounds are notoriously difficult to purify. 

In the fourth method phthaloyl-L-glutamic anhydride is condensed with an amine, an amino acid or an amino acid ester with subsequent removal of the phthaloyl group by hydrazinolysis. This method gives exclusively — or mainly the y-derivative (but compare Section VI. 4.). 

Ring closure of 8 to recover the starting material can be achieved by treatment with thionyl chloride or methanolic HCl . The phthaloyl group is removed by hydrazinolysis, using hydrazine hydrate, to yield the amine and phthalhydrazide (9) (equation 8)... 

The phthaloyl group can be introduced by heating an alkyl halide with potassium phthalimide (4) alone or in a non-polar solvent (equation 4) , or by heating the amine with phthalic anhydride ... 

The phthaloyl group has been used for a long time as a protecting group in the course of the synthesis of various amines . The most important example of its use is in the synthesis of penicillin V (10). ... 

For the protection of primary amines the succinoyl and phthaloyl groups may be introduced by heating a mixture of the amine and the acid anhydride to temperatures in the region... 

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