Nitroxide heterocyclic

Since Huisgen s definition of the general concepts of 1,3-dipolar cycloaddition, this class of reaction has been used extensively in organic synthesis. Nitro compounds can participate in 1,3-dipolar cycloaddition as sources of 1,3-dipoles such as nitronates or nitroxides. Because the reaction of nitrones can be compared with that of nitronates, recent development of nitrones in organic synthesis is briefly summarized. 1,3-Dipolar cycloadditions to a double bond or a triple bond lead to five-membered heterocyclic compounds (Scheme 8.12). There are many excellent reviews on 1,3-dipolar cycloaddition, in particular, the monograph by Torssell covers this topic comprehensively. This chapter describes only recent progress in this field. Many papers have appeared after the comprehensive monograph by Torssell. Here, the natural product synthesis and asymmetric 1,3-dipolar cycloaddition are emphasized.630 Synthesis of pyrrolidine and -izidine alkaloids based on cycloaddition reactions are also discussed in this chapter. 

Nitrone cycloaddition reactions with alkynes have been widely used for the synthesis of imidazolidine nitroxides (736) and (737), containing chelating enam-ino ketone groups (821). Different heterocyclic systems were obtained, such as 3-(2-oxygenated alkyl)piperazin-2-ones (738) (822), also compounds containing the isoxazolo[3,2-i]indole ring system (739) (823) and a new class of ene-hydroxylamino ketones- (l )-2-( 1-hydroxy-4,4,5,5-tetraalkylimidazolidin-2-ylidene)ethanones (740) (824) (Fig. 2.46). 

Scheme 35 Nitroxide-based access to nitrogen-containing heterocycles...

Mechanistic data obtained with the diarylnitroxide 56 have also mostly been extrapolated for nitroxides derived from heterocyclic amines DHQ, DHI, PT and HAS. The relative participation of the relevant nitroxides in the three principal pathways (Scheme 7), i.e. scavenging of R and ROO and disproportionation, has been determined by the chemical structure of the particular nitroxide and its stability reflected in the tendency to react in mesomeric forms. The adjacent aromatic moiety enhances participation of the mesomeric structures. The stability of the nitroxides diminishes in the series from HAS to DHQ or DHI and DPA and is the lowest in the PD series [4], As a consequence, the nitroxides derived from PD exist only in the form of bisnitrones (81 in Scheme 9). The ROO scavenging ability is involved only in the aromatic (DPA, PNA) and heterocyclic (DHQ, DHI) amines and cannot be included in the reactivity of HAS derived nitroxides. On the contrary, the most efficient R scavenging is in the HAS series. 

The ultimate loss of the HAS activity occurs by destruction of the heterocycle initiated thermally, photochemically, chemically or by high-energy radiation. An intramolecular H-abstraction from the p-carbon atom in thermolysis of 2,2,6,6-tetramethyl-4-oxo-piperidinyl-l-oxyl 133 via a general reaction (Eq. 8) was proposed as a pathway of thermal selfdestruction of the piperidine cycle [25] (Scheme 25). The respective hydroxylamine was isolated in the yield of 66.5%. The biradical intermediate 137 either dimerizes to nitroxide 138 or thermolyses via 139 to a nitrogen-free fragment 140 (phorone) and nitric oxide. 

The nitroxide (467), a free-radical species with potential value as a spin label, has been synthesized in three steps (Me2S04. CH2=CH—CH2MgBr, and m-chloroperbenzoic acid) from the lactam (468) The formation of some novel steroids with fused heterocyclic rings is described on pp. 326, 346,351,355, and 359 and a novel method for the introduction of thio- and nitrogen-containing substituents at C-5 on p. 357. 

Loss of the EPR signal during Fe(CN)g (hcf) oxidation of imidazolidine nitroxides having a hydrogen at position 4 of the heterocycle (HIMD) supports the assumption that the HIMD fragmentation is facilitated by proton abstraction from the position 4 of the oxoammonium cation formed as a result of the initial one-electron HIMD oxidation. ... 

The 4-pyridone (151), an analogue of maltol, has been isolated from the reaction of lactose or maltose with a hot aqueous solution of methylammonium acetate. The heterocyclic derivative (152) and the 1,2,4-triazine derivatives (153) have been obtained from 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide by standard routes. Bischler-Napieralski cyclization of the corresponding iV-acetyl-tryptamines and dehydrogenation (Pd-BaSO ) gave the )S-D-glucopyranosyl-carboline (154) and the related a-L-arabinopyranosylcarboline. The spin-labelled nitroxide derivative (155) has been prepared by reaction of the nicotinamide derivative with 2,3,5-tri-0-benzoyl-j8-D-ribofuranosyl bromide. ... 

The presence in the molecule of imidazoline nitroxides of an additional nitrogen atom or of an N-oxide group in combination with functional groups in position 4 of the heterocycle allows com-plexation, chelation, and cyclometalation without participation of the radical center. This made it possible to investigate for the first time the magnetic resonance spectra of multispin systems. 

Hence, polarization of the C=N bond of imidazolinium nitroxyl salts provides easy and unique addition of nucleophilic agents (i.e., cyanide ion, Grignard reagent, and hydride ion) with the formation of imidazolidine nitroxides, whereas the radical center participates when, in reactions of this type, as in the case of 3-imidazoline-3-oxides, the functional group becomes transformed and the heterocycle is opened. 

Polarization of the C=N bond also causes electrophilic substitution of the alkyl group hydrogen in the a-position. Interaction of 1-hydroxy-3-imidazoline-3-oxide (6a) with aromatic aldehydes in the presence of bases, similar to the case observed for heterocyclic iV-oxides (Ochiai, 1967 Katritzky and Lagowski, 1971 Hansen and Boyd, 1970), leads to l-hydroxy-4-arylvinyl-3-imidazoline-3-oxides (41), oxidation of which generates nitroxides 42. The action of an equimolar amount of amyl nitrite on l-hydroxy-4-methyl- and l-hydroxy-4-ethyl-3-imidazoline-3-oxides... 

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