Reduction of phthalimide

Electrolytic reduction of phthalimide and of phthalimidines which are at an oxidation level above that of isoindole, proceeds through the isoindole to the isoindoline stage, which is then stable to further... 

Results of reductions of cyclic anhydrides to lactones with sodium amalgam or with zinc are inferior to those achieved by complex hydrides [1020]. However, 95.6% yield of phthalide was obtained by reduction of phthalimide with zinc in sodium hydroxide [1021]. 

Phthalimide and substituted phthalimides are relatively easily reduced in DMF 1.4V (versus SCE)]. In alkaline or aprotic solution, two, one-electron reduction steps are observed in voltammetric experiments [134-137] anion radical formation at the first wave has been confirmed by esr spectroscopy [55,135,136]. Considerable attention has been given to the detailed mechanism of reduction of phthalimide derivatives [134— 137] ... 

Conditions for the formation of isoindoles by the reduction of phthal-imides have proved difficult to establish. Reduction of phthalimide itself with lithium aluminum hydride gives isoindoline. However, Garmaise and Ryan54 have shown that N-benzylphthalimide can be reduced with a modified hydride reductant [sodium bis(2-methoxyethoxy)aluminum hydride] to give 2-benzylisoindole in moderate yield under mild conditions. 

Alternative methods to remove the phthaloyl group have been developed over the years as the classical method is often deemed too harsh, sometimes leading to degradation of other functionalities present. An example is the two-stage one-pot method using sodium borohydride followed by acetic acid reported by Ganem and co-workers.8 Previously, NaBH4 reduction of phthalimides has been described but these examples... 

Addition of organolithium reagents to phthalamidines gives isoindoles with a 1-substituent derived from the lithium compound <79JOC15l9>. The phthalamidines can be prepared in a number of ways, including partial reduction of phthalimides by zinc (Scheme 90). 

Scheme 2 Cathodic reduction of phthalimide in ionic liquid with and without sonication...

An isoindol1 none moiety forms part of the aromatic moiety of yet another antiinflammatory propionic acid derivative. Carboxylation of the anion from -nitro-ethylbenzene (45) leads directly to the propionic acid (46). Reduction of the nitro group followed by condensation of the resulting aniline (47) with phthalic anhydride affords the corresponding phthalimide (48). Treatment of that intermediate with zinc in acetic acid interestingly results in reduction of only one of the carbonyl groups to afford the isoindolone. There is thus obtained indoprofen (49). ... 

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... 

Esters of (V-hydroxyphthalimide can also be used for decarboxylation. Photolysis in the presence of an electron donor and a hydrogen atom donor leads to decarboxylation. Carboxyl radicals are formed by one-electron reduction of the phthalimide ring. 

A useful approach for the preparation of chiral (3-aminophospho-nic acids from the naturally occurring a-amino acids has been reported.139 The overall scheme (Equation 3.4) involves formation of the phthalimide-acid halide from the starting a-amino acid followed by a Michaelis-Arbuzov reaction with triethyl phosphite to give the acylphosphonate. Complete reduction of the carbonyl group in three steps followed by hydrolysis of the ester and amide linkages provides the target material in very high yield without racemization (>99% ee). 

Carboxyl radicals are formed from one-electron reduction of the phthalimide ring. 

Decamethylenediamine has been obtained by reduction of sebaconitrile either catalytically 5 or by sodium and alcohol.7 It has also been obtained by hydrolysis of the condensation product from decamethylene iodide and phthalimide.8... 

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