3-Imidazoline-3-oxide nitroxide

An alternative method of synthesizing 3-imidazoline-3-oxide nitroxides is oxidation with hydrogen peroxide of 2,2,5,5,-tetraalkyl-3-imidaz-oline-3-oxides (8) containing a sterically hindered secondary amino group (Martin and Volodarsky, 1979). Compounds 8 are derived from a-aminooximes generated from olefinic nitrosochlorides (Michael and... 

Imidazoline-3-oxide nitroxides (7a,c) can also be derived by oxidation of 1,2-iV-isopropylhydroxylaminooximes with excess lead dioxide... 

Thus, various 3-imidazoline-3-oxide nitroxides proved to be accessible, including bicyclic compounds, spiro derivatives, and compounds with functional groups in position 2. 

Interaction of 3-imidazoline-3-oxide nitroxides with Grignard reagent proceeds with the involvement of the radical center and leads to reduction products 6a,c and methoxy derivatives 35a,c. Meanwhile, in the interaction of methylmagnesium iodide with the methoxy derivatives 1,3-addition to the nitrone group occurs, and 1-methoxy-3-hydroxy-4-alkyl (aryl)-... 

Alkali treatment of 4-dihalomethyl derivatives 65a leads not to aldehyde 83a, but to acid 46. Nitroxyl aldehyde 83a was prepared by acid hydrolysis of 4-iminomethyl-3-imidazoline-3-oxide nitroxide (78). Alkaline hydrolysis of 4-a,a-dichloroethyl nitroxide (65b, X = Cl) leads to ketone 83b (Grigor ev et al, 1979b). 

Thus, the interaction of 4-dihaloalkyl-3-imidazoline-3-oxides with nucleophiles affords a wide range of functional derivatives of 3-imidazoline and 3-imidazoline-3-oxide nitroxides. 

Mitasov MM. Structural Inverstigations of 3-imidazoline-3-oxides, 3-imidazolines and Corresponding Nitroxides by the Methods of Vibration Spectroscopy, PhD Dissertation, Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, Novosibirsk, 151, 1984. 

Nitronyl nitroxide 1070 is reduced in the presence of thiourea to imino nitroxide 1071, which is further reduced to 2-imidazoline A -oxide 1072 in high yields (Scheme 258) <2003TL6397, 2005TL3599>. 

A pair of Ullman s nitronyl nitroxide radicals carrying m- and p-ethynylphenyl groups at position 2 of the imidazoline ring (7 and 8) are quite stable at room temperature under air and the unpaired electrons withstand the catalyzed polymerization conditions (see Section 11.4.3) [6]. The terminal ethynyl groups are not susceptible to Pb02 in benzene/metha-nol at room temperature, which is used for the oxidation of the bis(hydroxylamine)s to the nitronyl nitroxides [6, 7]. Fremy s salt gives the best result for the oxidation of the hydroxyl-amine 14 carrying a terminal 1,3-butadiyne moiety [9]. 

The formation of l-hydroxy-3-imidazolines proceeds under mild weakly alkaline or weakly acidic conditions, in contrast to the strongly acidic media usually employed for obtaining precursors of doxyl radicals (Keana, 1978). l-Hydroxy-3-imidazolines are easily oxidized to nitroxides by molecular oxygen, Pb02, Mn02, etc. 

The presence of an imine or imine-iV-oxide (nitrone) group in the molecule of imidazoline nitroxides dictates both their stability... 

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. 

Oxidation of 1-hydroxy derivatives (6a-g) with lead dioxide in nonpolar organic solvents leads smoothly to nitroxides, namely 2,2,5,5-tetra-alkyl-3-imidazoline-3-oxide-l-oxyls (7a-g) (Volodarsky and Kutikova, 1971). In the crystalline state radicals 7 can be stored for a long time without decomposition. Both radical precursors 6 and the radicals themselves enter into various substitution, condensation, and other reactions. 

Nitroxides of the imidazoline series, however, proved to be stable in acid media. Thus, 3-imidazoline-3-oxide-l-oxyl 7c and 3-imidazoline-l-oxyl 13c are soluble in concentrated aqueous acids and give paramagnetic, orange-colored solutions (Golubev et al., 1974). Dilution of the freshly prepared solutions with water results in quantitative regeneration of the... 

Treatment of l-hydroxy-3-imidazoline-3-oxides (6a,c) with Grignard reagent opens the cycle and forms 1,2-iV-t rt-butylhydroxylaminooximes (38a,c). Oxidation of the latter leads to acyclic stable nitroxides (39a,c)... 

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... 

For less reactive 3-imidazoline derivatives containing no iV-oxide oxygen only a nitrosation reaction has been realized, and its results depend on the conditions under which the reaction is conducted. Slow addition of two equivalent amounts of amyl nitrite to nitroxides 13a,b or to 1-hydroxy-4-methyl-3-imidazoline (12a) in liquid ammonia in the presence of sodium amide produces nitroxyl oximes 52a,b. The immediate treatment... 

Numerous derivatives of imidazoline nitroxides with various functional groups have been obtained in the investigations of reactions of 4-alkyl-halide- and 4-alkyl-dihalide-3-imidazoline-3-oxides. The interaction of compounds 7a,b with an equimolar quantity of iV-bromo- and N-chloro-succinimide leads to 4-bromomethyl-, 4-a-bromoethyl-, and 4-a-chloro-ethyl-3-imidazoline-3 oxides (64a,b) (Kutikova and Volodarsky, 1973 Grigor ev and Volodarsky, 1975). With the addition of excess iV-succinimide halide 4-dibromomethyl-, 4-dichloromethyl-, and 4-a,a-dichloroethyl-3-imidazoline-3-oxides (65a,b) are formed (Grigor ev and Volodarsky, 1974 Grigor ev et a/., 1975 Mitasov et ai, 1978). Nitroxides 64 and 65 are reduced by zinc to diamagnetic 1-hydroxy-derivatives 66 and 67. 

The interaction of 64a with sodium amide in liquid ammonia gives dinitroxide 51, and the interaction of 64b with 1,5-diazabicyclo- [5,4,0] undecene-5 (DBU) in THF yields 4-vinyl-3-imidazoline-3-oxide-l-oxyl (73). This vinyl nitroxide (73) easily adds a molecule of bromine, giving dibromo derivative 74, and it regenerates 6b on treatment with NaBH4. Dehydrobromination of 75 under similar conditions leads to nitroxide 76 (Grigor ev et al, 1979a). 

Thus, the interaction of a-haloalkylnitrones 64a,b with amines and hydrazine leads to products that contain no iV-oxide oxygen atom. This allows aldehyde and ketone derivatives of 3-imidazoline nitroxide to be synthesized the latter are of interest as spin labels for biological systems (Schlude, 1973). The interaction of the same compounds (64a,b) with nitrogenous nucleophiles, which contain a more electronegative nitrogen atom than that in amines or hydrazine, as well as the interaction with C-, S-, and O-nucleophiles, proceeds with the preservation of the nitrone group and leads to nucleophilic substitution products. Dehydrobromination of 4-bromoalkyl derivatives leads to reactive a,j8-unsaturated nitrones... 

The nitroxide also oxidizes the alcoholic group of 4-hydroxymethyl-(84a) and 4-(l-hydroxyethyl)- (84b) 3-imidazoline-l-oxyls obtained by reduction of aldehyde 71a and ketone 71b with NaBH4 (Grigor ev and Volodarsky, 1978). 

Dissociation of molecular ions of l-hydroxy-3-imidazoline-3-oxides (6) (Scheme 4) and of corresponding nitroxides (7) (Scheme 5) proceeds in a more complicated manner (Ivanovskaja et al, 1979). 

Estimating the potential of the mass spectrometry method for the analysis of stable nitroxides and their precursors in the series of penta-substituted 3-imidazoline, it is possible to emphasize two main points. In the first place, the compositions of molecular ions, characteristic fragmentation ions, and losses make it possible to determine the compositions of substituents at all the carbon atoms of the imidazoline cycle (only in the case of AT -oxides are the overall values of the substituents R, and R obtained rather than complete information). In the second place, the... 

Easy transformation of 1,2-hydroxylaminoketones to l-hydroxy-3-imidazolines and then to nitroxides allowed introduction of a nitroxyl group into molecules containing a ketone group, similar to the method suggested by Keana et al (1967). The method of Keana is based on the condensation of a compound containing a ketone group with 2-amino-2-methylpropanol-l in the presence of p-toluenesulfonic acid and subsequent oxidation of the resulting oxazolidine derivative with m-chloroper-... 

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