Protective groups phthalimides

Simple amides are satisfactory protective groups only if the rest of the molecule can resist the vigorous acidic or alkaline hydrolysis necessary for their removal. For this reason, only amides that can be removed under mild conditions have been found useful as amino-protecting groups. Phthalimides are used to protect primary amino groups. The phthalimides can be cleaved by treatment with hydrazine. This reaction proceeds by initial nucleophilic addition at an imide carbonyl, followed by an intramolecular acyl transfer. 

Intermediate D-a-6 must now be converted into a form amenable to the crucial lactamization reaction. To this end, treatment of D-a-6 with hydrazine accomplishes the removal of the phthalimide protecting group and provides D-a-18 (Scheme 5) after acidification with dilute aqueous HC1. It is noteworthy that the acid-labile tert-butyl ester function withstands the latter step. Introduction of the... 

The phthalimide method (Chapter T8) was used to make the amine and cyclisation occurred spontaneously on removal of the protecting group. 

A similar sequence that takes place under milder conditions uses 4-nitrophthalimides as the protecting group and /V-melhylhydrazine for deprotection.234 Reduction by NaBH4 in aqueous ethanol is an alternative method for deprotection of phthalimides. This reaction involves formation of an o-hydroxybenzamide in the reduction step. Intramolecular displacement of the amino group follows.235... 

Protected primary allylic amines were generated from allylic carbonates and ammonia equivalents. Iridium-catalyzed allylic substitution has now been reported with sulfonamides [90, 91], imides [89, 91-93], and trifluoroacetamide [89] to form branched, protected, primary allylic amines (Table 5). When tested, yields and selectivities were highest from reactions catalyzed by complexes derived from L2. Reactions of potassium trifluoroacetamide and lithium di-tert-butyhminodi-carboxylate were conducted with catalysts derived from the simplified ligand L7. Reactions of nosylamide and trifluoroacetamide form singly-protected amine products. The other ammonia equivalents lead to the formation of doubly protected allylic amine products, but one protecting group can be removed selectively, except when the product is derived from phthalimide. 

Because of the polyfunctional nature of carbohydrates, protective-group strategy plays an important role in synthetic methodology involving this class of compounds. In the present Chapter, results are described from a study of the utility of N-trimethylsilyl- and N-tert-butyldimethylsilyl-phthalimide for the selective silylation of primary hydroxyl groups in carbohydrates. Also described, is a new, facile method for cleavage of acetals and dithioacetals in carbohydrate derivatives the method involves treatment of the derivatives with a dilute solution of iodine in methanol. 

In general, amino-containing compounds are poor partners in CM due to their tendency to coordinate to the metal catalyst, even when late-transition metal systems are employed. To preserve catalyst activity, amino groups are therefore typically masked as cyanides, carbamates, amides, or phthalimides. In substrates where iV-coordination to the catalyst is less favored, such as with hindered /V-aryl-/V-allylamines, no protecting group is required. 

Note that the first-formed product from the cycloaddition is actually the sodium tetrazolate salt 8.32. Protonation affords the neutral tetrazole 8.31. Prolonged acidic hydrolysis accomplishes several transformations hydrolytic removal of both the phthalimide and acetyl nitrogen protecting groups, and... 

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. 

Scheme 12.8 Synthesis of ferrocene amino acid according to Heinze (i) f-BuLi, -70°C (ii) quenching with iodine (iii) reaction in pyridine with phthalimide and Cu20 as catalyst (iv) hydrazinolysis in ethanol (v) A-acetylation with Ac20 (vi) selective Friedel-Crafts acylation with 2,6-dichlorobenzoyl chloride at the unsubstituted Cp ring (vii) base hydrolysis (viii) removal of the acetyl protection group with hydrochloric acid.

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