Spirocyclic Nitroxides as Versatile Tools in Modern Natural Sciences: From Synthesis to Applications. Part I. Old and New Synthetic Approaches to Spirocyclic Nitroxyl Radicals.

Elena Zaytseva,Dmitrii Mazhukin

doi:10.3390/molecules26030677

Abstract

Spirocyclic nitroxyl radicals (SNRs) are stable paramagnetics bearing spiro-junction at α-, β-, or γ-carbon atom of the nitroxide fragment, which is part of the heterocyclic system. Despite the fact that the first representatives of SNRs were obtained about 50 years ago, the methodology of their synthesis and their usage in chemistry and biochemical applications have begun to develop rapidly only in the last two decades. Due to the presence of spiro-function in the SNRs molecules, the latter have increased stability to various reducing agents (including biogenic ones), while the structures of the biradicals (SNBRs) comprises a rigid spiro-fused core that fixes mutual position and orientation of nitroxide moieties that favors their use in dynamic nuclear polarization (DNP) experiments. This first review on SNRs will give a glance at various strategies for the synthesis of spiro-substituted, mono-, and bis-nitroxides on the base of six-membered (piperidine, 1,2,3,4-tetrahydroquinoline, 9,9′(10H,10H′)-spirobiacridine, piperazine, and morpholine) or five-membered (2,5-dihydro-1H-pyrrole, pyrrolidine, 2,5-dihydro-1H-imidazole, 4,5-dihydro-1H-imidazole, imidazolidine, and oxazolidine) heterocyclic cores.

Highlights

Stable nitroxyl radicals (NRs), first obtained more than 150 years ago (Figure 1, 1a, R1,2 = SO3K, Frémy’s salt), became widely known with the development of electron paramagnetic resonance (EPR) spectroscopy methods and thanks to the discovery in 1959 of extremely stable cyclic derivatives (Figure 1, 1b, R1–4 = Me) of piperidine series (TEMPO) [1]
Due to the presence of spiro-function in the spirocyclic nitroxyl radicals (SNRs) molecules, the latter have increased stability to various reducing agents, while the structures of the biradicals (SNBRs) comprises a rigid spiro-fused core that fixes mutual position and orientation of nitroxide moieties that favors their use in dynamic nuclear polarization (DNP) experiments
This first review on SNRs will give a glance at various strategies for the synthesis of spiro-substituted, mono, and bis-nitroxides on the base of six-membered (piperidine, 1,2,3,4tetrahydroquinoline, 9,9 (10H,10H )-spirobiacridine, piperazine, and morpholine) or five-membered (2,5-dihydro-1H-pyrrole, pyrrolidine, 2,5-dihydro-1H-imidazole, 4,5-dihydro-1H-imidazole, imidazolidine, and oxazolidine) heterocyclic cores

Summary

Introduction

It is worth noting that the reactio of the acetonine with cyclic ketones may be the weak link in the whole synthetic scheme monospiroamines 21a–c are obtained as products of the interaction of 5 with cy clopentanone, cyclohexanone, and cycloheptanone, respectively, in the presence o NH4Cl or NH4Br with rather low yields (from 6% to 14%). Those authors have stated tha desired spiro compounds 21a–c are isolated chromatographically or by vacuum distilla tion from a complicated reaction mixture. Synthesis of diphenyl-substituted mono- and di-SNRs of the imidazolidine typ40e.of 64

Peculiar SNRs of the imidazolidine series were obtained from

Parent Diketone

Findings

11. Conclusions