Phthalimides conditions

The 4-nitro-A -phthalimide, prepared by heating the amine with the anhydride to 130° for 30 min, is cleaved with MeNHCH2CH2NH2 (71-92% yield). These cleavage conditions were compatible with cephalosporins, where the phthalim-ide was removed in 92% yield at —50° in 30 min. ... 

The anion of A-nitromethyIphthalimide 17 also acts as a formyl anion equivalent with Michael acceptors to afford 1,4-dicarbonyl compounds 18 in good to excellent yields, although difficulty was experienced in isolating the products under the conditions required for removal of the phthalimide group (77CJC2919). 

Fig. 23 Microwave-promoted SPOS of substituted phthalimides. Reagents and conditions a phthalic acid (R = H, F, Br, CH3, C4H4), DIAD, PPha, THF, rt, 24h b primary amine (R =C3H6Ph, CH(CH3)C2H4Ph, CsH, 4-CH3 0Bn,4-ClBn, C5H9) amine, EDC HCl, HOAt, CH2CI2, rt, 18 h c MW, DMF, 170 °C, 20 min, closed vessel...

The transformation of isoquinoline has been studied both under photochemical conditions with hydrogen peroxide, and in the dark with hydroxyl radicals (Beitz et al. 1998). The former resulted in fission of the pyridine ring with the formation of phthalic dialdehyde and phthalimide, whereas the major product from the latter reaction involved oxidation of the benzene ring with formation of the isoquinoline-5,8-quinone and a hydroxylated quinone. 

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... 

The most successful approach to producing an aminomethyl derivative was the Gabriel synthesis. A phthalimide substituent can be introduced by Sn2 displacement of the chloride on 17 with potassium phthalimide under homogeneous conditions in DMF. The reaction is quantitative in all D.F. ranges and the phthalimldo-methyl intermediates, 18, are quite soluble in organic solvents. 

The 7-bromopropylphthalimide was prepared from potassium phthalimide and trimethylene bromide in 78% yields, using the conditions and molar quantities specified for the preparation of (3-bromoethylphthalimide.1 7-Bromopropylphthalimide can also be prepared from phthalimide, potassium carbonate, and trimethylene bromide.2... 

Phenothiazines are well-known as intermediates for pharmaceuticals, and are also active as insecticides and antioxidants. These compounds are usually prepared by the thiation of diphenylamines with elemental sulfur. In this context, the group of Toma has elaborated a synthesis of 3-phthalimidophenothiazine, as shown in Scheme 6.265 [455]. Using a variety of high-boiling solvents under conventional thermal reflux conditions, low isolated yields of the desired product were obtained. The highest conversion and isolated product yield (55%) was achieved by microwave irradiation of a mixture of the starting N-(4-phenylaminophenyl)phthalimide with... 

For the cydative cleavage step, it turned out that aprotic conditions were definitely superior to the use of protic media. Thus, employing N,N-dimethylformamide as solvent at somewhat elevated temperatures furnished the desired compounds in high yields and excellent purities. Having established the optimized conditions, various phthalic acids and amines were employed to prepare a set of phthalimides (Scheme 7.51). However, the nature of the amine was seen to have an effect on the outcome of the reaction. Benzyl derivatives furnished somewhat lower yields, probably due to the reduced activities of these amines. Aromatic amines could not be included in the study as auto-induced ring-closure occurred during the conversion of the polymer-bound phthalic acid. 

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]. 

Heterocycles having highly acidic NH sites, e.g. phthalimide, 2-pyridone, imidazole, react with ethylene carbonate under conditions analogous to those employed for the synthesis of p-hydroxyethyl esters (3.3.1.E) to give the (V-p-hydroxyethyl heterocycles [89]. 

Of particular interest was the reaction of two equivalents of potassium phthalimide with PFB using 18-crown-6 in refluxing acetonitrile. This reaction with either small molecules or the polymeric analogs represents a novel approach to arylimide synthesis via PTC. After 4 hr. under nonoptimized PTC reaction conditions, disubstitution afforded the bisimide 6 in ca. 50% yield. This shows that phthalimide anion, a considerably poorer nucleophile than either the phenoxide or thiophenoxide, is a strong enough nucleophile in the presence of 18-crown-6 to displace aryl fluoride with facility, and demonstrates that the synthesis of polyimides, an important class of thermally stable polymers, is feasible by this PTC polycondensation route. 

The observed catalytic effect of the crown ether appears to be dependent on the nucleophile employed in both polymerization and corresponding model reactions. Not surprisingly, it appears that the stronger the nucleophile employed, the smaller the catalytic influence of the crown ether. For example, with potassium thiophen-oxide yields of polymer or model products were almost quantitative with or without catalyst. By contrast, the reaction of PFB with potassium phthalimide, a considerably weaker nucleophile, affords 6 in 50% with catalyst and in 2-3% without catalyst under identical conditions. However, it may be that this qualitative difference in rates is, in fact, an artifact of different solubilities of the crown complexed nucleophiles in the organic liquid phase. A careful kinetic study of nucleophilicity in catalyzed versus non-catalyzed reactions study is presently underway. 

Scheme 3 Thomas synthesis of the larger fragment of lb (part 2). Reagents and conditions a 15, LDA, -78°C b TBSOTf, 42% from 14 c DIBALH, 82% d (COCl)2, DMSO, Et3N, 95% e 10, SnCh, 83% f AT-phenylselenenyl phthalimide, ZnC, CH2CI2, 54% g BujSnH, AIBN, 85% h Na naphthalenide, -60°C, 84% i B0C2O, Et3N, 80% j H2, Pd/C k Dess-Martin periodinane 1 NaCl02, NaH2P04,85% over the last three steps...

Scheme 4 Thomas synthesis of the smaller fragment of lb. Reagents and conditions a ent-10, SnCl4,80% b p-nitrobenzoic acid, DEAD, Ph3P, 68% c NaOH, 94% d N-phenylselenenyl phthalimide, SnCl4,60% e Bu3SnH, AIBN, 89% f H2,10% Pd/C, 70% g Dess-Martin peri-odinane h NaCl02, NaH2P04 i z-Pr2NEt, BnBr, 81% from 27 j cone. aq. HCl, MeOH, 49%...

Substitutions with N,N-diacylamines are best carried out under salt-free conditions in order to minimize the concentration of base in the reaction medium and to circumvent the low solubility of salts in THF. For example, potassium phthalimide could not be reacted in THF because of its insolubility. The reaction under salt-free conditions proceeded smoothly even with LI as the ligand (Table 9.3). 

The additions of ammonia equivalents, i.e. nitrogen nucleophiles like dibenzylamine (Scheme 27) which are essentially a protected primary amino group, are of special synthetic interest with respect to their possible subsequent chemical transformations. Poorly nucleophilic ammonia equivalents like acetamide or the classical phthalimide, did not add or originally gave low yields of 92a (Scheme 28) [9],but later phthalimide was found to add to 1-Me very well under mild conditions [53]. However, the a-chlorine in 92a could neither be substituted nor could the phthalimido group be cleaved without destroying the cyclopropane ring. The potassium bis(alkoxycarbonyl)amides (Boc)2NK and (Moc)(Boc)NK add to 1-Me in satisfactory yields, but the a-chlorine atom in... 

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. 

Scheme 36. Reaction conditions i, Bu00H-Ti(0 Pr)4, (+)-L-diethyltartarate ii, (MeOCH2-CH20)2A H iii, PhCOCl-EtjN iv, phthalimide, PhjP v, KjCOj-MeOH vi, NH2NH2H2O vii, aq HCIO4 viii, NaBCNH3-THF-MeOH-20% AcOH ix, DMSO oxidation x, Me(CH2>2CH2-CH=PPh3i xi, H2-Pt02.

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