Brominated isoindolines: precursors to functionalised nitroxides

Abstract

A new, convenient method for the preparation of functionalised precursors to stable tetraalkylisoindoline nitroxides (aminoxyls) is presented. Simple treatment of 2-benzyl-1,1,3,3-tetramethylisoindoline 2 with Br 2 in CCl 4 gives rapid oxidative debenzylation, generating benzaldehyde and an unusual bromamine, 2-bromo-1,1,3,3-tetramethylisoindoline 4, in high yield. Treatment of the bromamine 4 with FeSO 4 / H 2 SO 4 results in bromination of the aromatic ring in varying yield, while rapid treatment with peroxide / tungstate causes debromination, generating 1,1,3,3-tetramethylisoindoline 3. Bromination of the isoindoline aromatic ring is more readily afforded by treatment of 2-benzyl-1,1,3,3-tetramethylisoindoline 2 with Br 2 and AlCl 3 in CCl 4 , producing 2,5-dibromo-1,1,3,3-tetramethylisoindoline 7 and/or 2,5,6-tribromo-1,1,3,3-tetramethylisoindoline 6 in varying yields depending upon the exact reaction conditions. Rapid treatment with peroxide / tungstate generates the corresponding bromine substituted isoindolines, 5-bromo-1,1,3,3-tetramethylisoindoline 5 and 5,6-dibromo-1,1,3,3-tetramethylisoindoline 8. Prolonged peroxide / tungstate treatment oxidises the substituted bromamines to the corresponding nitroxides, 5-bromo-1,1,3,3-tetramethylisoindolin-2-yloxyl 9 and 5,6-dibromo-1,1,3,3-tetramethylisoindolin-2-yloxyl 10. SQUID magnetic susceptibility measurements of crystalline 10 reveal strong antiferromagnetic interradical spin coupling. The crystal structures of 10, 2-bromo-1,1,3,3-tetramethylisoindoline 4 and the hydrobromide dihydrate salt of 1,1,3,3-tetramethylisoindoline 3 (3a) have also been determined, with 10 displaying an interesting molecular packing arrangement.2

The Synthesis of Novel Isoindoline Nitroxides Bearing Water‐Solubilising Functionality

“…The dibromination of 8 with bromine, aluminium trichloride and catalytic pyridine to give 11 was found to proceed in a significantly higher yield (91 % compared to ca. 50 % previously) [25] when only 7 equiv. of bromine were used in chloroform rather than carbon tetrachloride (Scheme 2).…”

“…[24] Treatment of 2-benzyl-1,1,3,3-tetraethylisoindoline (7) with bromine in the presence of anhydrous aluminium trichloride gave 2,5-dibromo-1,1,3,3-tetraethylisoindoline (8) in modest yield (30 %) (Scheme 1) after purification by column chromatography to remove the benzaldehyde which results from oxidative cleavage of the benzyl group by bromine. [25] Subsequent reduction of bromoamine 8 with hydrogen peroxide in the presence of sodium hydrogen carbonate afforded 5-bromo-1,1,3,3-tetraethylisoindoline (9) in high yield (98 %). The corresponding tetramethyl derivative could, at this stage, be separated from the benzaldehyde side-product by acid-base extraction.…”

“…Therefore, in order to suppress potential ring opening of the tetraethyl-substituted pyrrolidine moiety during the bromination process, the use of a suitable protecting group was required (the benzyl group is known to be cleaved by bromine before aromatic bromination occurs). [25] As the final desired product is a nitroxide, it seemed logical to continue the synthesis with a protected www.eurjoc.orgnitroxide. Accordingly, 1,1,3,3-tetraethylisoindolin-2-yloxyl (18) was prepared using literature methods by debenzylation of 7 and subsequent oxidation to the nitroxide.…”

“…Lithiation of bromoamine 9, reaction with carbon dioxide and subsequent oxidation with hydrogen peroxide in the presence of a tungstate catalyst gave the desired nitroxide 5-carboxy-1,1,3,3-tetraethylisoindolin-2-yloxyl (3) in modest yield (21 %). Scheme 1. The reported synthesis of DCTMIO (2) entails double bromination of 2-benzyl-1,1,3,3-tetramethylisoindoline (10) to give dibromoamine 11, [25] oxidation to the nitroxide, [25] palladium(0)-catalysed coupling of the nitroxide with zinc cyanide to afford dinitrile 12 [26] and final hydrolysis of 12 to furnish DCTMIO (2). [27] Optimisation of this procedure for the synthesis of DCTMIO (2) was required before it could be applied to prepare 5,6-dicarboxy-1,1,3,3-tetraethylisoindolin-2-yloxyl (4, DCTEIO).…”

The First Example of an Azaphenalene Profluorescent Nitroxide

“…[18] Anhydride 1 was heated at reflux (3 h) with benzylamine (1.6 equiv.) in CH 3 COOH, poured onto ice and recrystallised from EtOH to give imide 2 (Ͼ95 %, m.p.…”