Reaction with potassium phthalimide

Finally the aminoquinoline bearing a primary amine at the terminal carbon atom of the side chain is itself an effective antimalarial drug. Ring opening of 2-methyltetrahydrofuran by bromine gives the dibromide, 99. The primary halide is sufficiently less hindered so that reaction with potassium phthalimide affords exclusively the product of displacement of that halogen (100). Alkylation of the aminoquinoline with lOO affords the secondary amine, 101. Removal of the phthalimide group by means of hydrazine yields primaquine (102). ... 

Scheme 44 Preparation of phthalated phospha sugars 137-136 by nucleophilic substitution reaction with potassium phthalimide...

For example (+)-43a was obtained after two purifications at 55 % ee and 10 % yield. Treatment of (+)-43a with hydrazine and KOH gave (+)-45a at 55 % ee and 40 % yield. The chiral host (S)-(—)-40 has been found to be extremely effective as a chiral selector towards comparatively bulky molecules of the phthalimide formed from of l- < r -butyl-3-chloro-azetidin-2-one, 47. A crystalline inclusion complex of 1 1 stoichiometry was formed between one mole of (S)-(—)-40 and two moles of rac-47 dissolved in benzene/hexane 1 1 solution. After one recrystallization, the complex was chromatographed on silica gel, and the crystalline product was treated with hydrazine. Optically pure (—)-3-amino-l-ieri-butyl-azetidin-2-one (—)-47, was obtained at 100% ee and 44% yield [51]. Primary diamines, like 1,3-dibromobutane (49), can undergo a similar reaction with potassium phthalimide, yielding diphthalimide, 50. The complexation process between rac-diphthalimide 50 and host (S,S)-(—)-6 gave a 1 1 complex containing (—)-50... 

Tertiary alkyl halides lose hydrogen halide in their reaction with potassium phthalimide. However, the t-alkylphthalimides are readily prepared by heating the corresponding t-alkylureas and phthalic anhydride to 200° to 240°. ... 

A different approach using alkene derivatives involved allylic substitution reactions. Ethyl cyclohex-3-en-l-carboxylate (7.51) reacted with N-bromosuccin-imide to give 7.52.26 This allowed reaction with potassium phthalimide to give 7.53 in an overall yield of 41%. Catalytic hydrogenation and treatment with methylamine led to ds-3-aminocyclohexane-l-carboxylic acid, 7.22.26... 

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. 

Gabriel amine synthesis (Section 24.6) A method for preparing an amine by SN2 reaction of an alkyl halide with potassium phthalimide. followed by hydrolysis. 

Bromoethylamine hydrobromide has been prepared by the reaction of potassium phthalimide with ethylene bromide, followed by hydrolysis,1 by the addition of hydrogen bromide to ethyleneimine,2 and by the present method.3... 

The Gabriel synthesis for converting halides to primary amines is based on this reaction. The halide is treated with potassium phthalimide and the product hydrolyzed (10-11) ... 

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 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. 

In the case of insoluble bis-4,4 -disubstituted perfluorobi-phenyls the reaction mixtures were poured into ca. 100 ml of H2O. The insoluble material was collected by filtration, and washed successively with H2O, EtOH and CH2C12 The crude products were dried (vac. oven at 80 ) and twice sublimed for purification. The model products were characterized by IR (neat liauid or KBr), mass spectrometry, and elemental analyses. and "f-NMR spectra we determined for all soluble products. Only minor modifications of this procedure were necessary with different haloaro-matics or nucleophiles. For reactions of potassium phthalimide no K2CO3 was used or needed. 

The reaction with ammonia or amines, which undoubtedly proceeds by the SNAr mechanism, is catalyzed by copper8" and nickel105 salts, though these are normally used only with rather unreactive halides.106 This reaction, with phase transfer catalysis, has been used to synthesize triarylamines.107 Copper ion catalysts (especially cuprous oxide or iodide) also permit the Gabriel synthesis (0-58) to be applied to aromatic substrates. Aryl bromides or iodides are refluxed with potassium phthalimide and Cu 0 or Cul in dimethylacetamide to give N-aryl phthalimides, which can be hydrolyzed to primary aryl amines.108... 

Most side-chain halobenzo [6 (thiophenes react normally with diethyl sodiomalonate 439,447,490,500,535 and its O-alkyl derivatives,499,536 but elimination may predominate in the case of a secondary halo compound.499 Halomethylbenzo [6]thiophenes react normally with potassium phthalimide in the Gabriel reaction (Section VI,H, 2). Where dehydrohalogenation is possible, alcoholic potassium hydroxide gives the corresponding olefin in good yield.469... 

Acetonide 133 is converted into the phthalimide derivative 135 and further reaction products 136 and 137 via substitution of mesylate 134 with potassium phthalimide (Scheme 44). 

The Gabriel synthesis is a classical but useful preparative method for primary amines. Reaction of an alkyl bromide (24) with potassium phthalimide (25) gives the corresponding A -alkylphthalinude (26), which upon treatment with hydrazine followed by KOH affords the primary amine (27). When a chiral alkyl halide is used in the Gabriel synthesis, a chiral primary amine is obtained. However, preparation of optically active alkyl halides is not easy. If optical resolution of 26 which has a chiral alkyl group can be done, a new preparative method for optically active amines can be established by a combination of the resolution with the Gabriel synthetic method. Some examples of the combination method are described. 

The present procedure is that described by the submitters.3 a-Phthalimido-o-toluic acid has also been prepared by the acidolysis of the corresponding ethyl ester, obtained from the reaction of ethyl a-bromo-o-toluate with potassium phthalimide.8... 

The Mannich reaction is readily applied to isatins. The products of this reaction, the N-aminomethylisatins (Mannich bases), can also be obtained from the A -hydroxymethyl derivatives by reaction with an amine95 or by reaction with acetyl chloride to yield N-chloromethylisatin which can be further treated with potassium phthalimide or alcohols to give the corresponding A-phthalimidomethyl or TV-alkoxymethyl isatins96. The Mannich reaction can also be performed with isatin derivatives, such as isatin-3-hydrazones97 and isatin-3-thiosemicarbazones98. 

Haloalkyl-l-silacycloalkanes were also used in the synthesis of fungicidal triazolopyrimidines (06WOP2006066873). Thus, 113 on treatment with potassium phthalimide in DMF, followed by hydrazinolysis afforded amines 114. Their reaction with 7-halotriazolo[l,5-fl]pyrimidines gave 115 (Scheme 22). 

The reagent is prepared by reaction of potassium phthalimide with S2CI2 to form the disulfide, which is then cleaved by CI2 in CHQ3. 

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