Abstract
Two novel, unsubstituted, pyridine-annulated pyrrolidine nitroxides; 1,1,3,3-tetramethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-2-yloxyl and 1,1,3,3-tetramethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-5-oxide-2-yloxyl were synthesized in overall yield of ~15% (5 steps starting from pyridine-3,4-dicarboxyic acid) via a Grignard approach. Grignard methylation of N-benzylcinchomeronic imide that was derived from pyridine-3,4-dicarboxylic anhydride, furnished the tetramethylpyrrolidine precursor in an isolated yield of 18%. Hydrogenation of the tetramethyl pyrrolidine precursor followed by oxidation afforded, depending on the oxidation conditions, each of the two nitroxides.
Highlights
Isoindoline nitroxides, a commercially valuable class of nitroxides have gained widespread attention mainly due to some advantages they possess over the commercially available other classes of nitroxides
Some of the uses of monocyclic heteroaromatic nitroxides such as EPR probes in biomedicine and related fields to monitor oxidative stress and reactive radical species in biological systems (Bobko et al, 2012; Zhelev et al, 2019), pH sensitive spin probes (Khlestkin et al, 2005), contrast enhancing agents (Keana et al, 1987) for magnetic resonance imaging (MRI) applications and molecular units (Vaz et al, 1999; Laget et al, 1998) in the synthesis of molecular magnetic materials are of notable importance
Since tetraalkylation of N-benzylphthalimide provides reasonable yields and involves limited reaction steps for the formation of commercially valuable isoindoline nitroxides, 1,1,3,3-tetraethylisoindolin-2-yloxyl (TEIO) and 1,1,3,3-tetramethylisoindolin-2-yloxyl (TMIO) compared to other methods, the synthesis of pyridine annulated tetraalkyl nitroxides through the Grignard alkylation of N-benzylcinchomeronic imide followed by hydrogenation and oxidation is an attractive approach
Summary
Isoindoline nitroxides, a commercially valuable class of nitroxides have gained widespread attention mainly due to some advantages they possess over the commercially available other classes of nitroxides. Hideg and co-workers synthesized a pyridine-fused paramagnetic nitroxide system 3 using hetero Diels-Alder reactions (Scheme 1) (Kalai et al, 2000; Krishna et al, 1996). Scheme 1: Synthesis of pyridine annulated pyrroline nitroxide using hetero Diels-Alder reaction.
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