Synthesis of 1-azaspiro[4.4]nonan-1-oxyls via Intramolecular 1,3-Dipolar Cycloaddition

Abstract

Sterically shielded nitroxides of pyrrolidine series are known to demonstrate the highest stability to reduction. Here we report on the synthesis of new pyrrolidine nitroxides from 5,5-dialkyl-1-pyrroline N-oxides via the introduction of pent-4-enyl group to nitrone atom followed by intramolecular 1,3-dipolar cycloaddition reaction and isoxazolidine ring opening. Kinetics of reduction of the new nitroxides with ascorbate was studied and compared to that of previously published 1S,2R,3′S,4′S,5′S,2″R-dispiro[(2-hydroxymethyl)-cyclopentan-1,2′-(3′,4′-di-tert-butoxy)pyrrolidine-5′,1″-(2″-hydroxymethyl)cyclopentane]-1′-oxyl (1).

The Reactions of 6-(Hydroxymethyl)-2,2-dimethyl-1-azaspiro[4.4]nonanes with Methanesulfonyl Chloride or PPh3-CBr4

“…After evaporation of the solvent under reduced pressure the crude residue was purified by column chromatography (SiO 2 , hexane-diethyl ether 1:1 mixture as an eluent) to give 3,3-dimethyloctahydrocyclopenta[c]pyrrolo[1,2-b]isoxazole ( 2 ): 0.119 g, yield 65%. Physical properties and spectral characteristics coincide to the literature data [ 4 ].…”

“…Conversion into alkoxy groups is a convenient way of the protection of nitroxide groups from reactions onto the oxygen atom [ 23 ]. We have previously reported on the synthesis of alkoxyamine 9 via treatment of corresponding nitroxide 8 with benzyl bromide in the presence of in situ formed Cu (I) using Matyjaszewski’s procedure [ 4 ]. Alkaline hydrolysis of 9 afforded 1c with nearly quantitative yield, and subsequent treatment with MsCl in the presence of a base gave a mixture of products ( Scheme 4 ).…”

“…The heterocycles with spiro-(2-hydroxymethyl)cyclopentane moieties can be easily prepared from cyclic nitrones via addition of pent-4-enylmagnesium bromide-oxidation-intramolecular cycloaddition-isoxazolidine ring opening sequence [ 4 , 34 , 35 ]. Here, we demonstrated an example of conversion of these spirocyclic structures into azepane derivatives.…”

“…An excess of KOH suspension in methanol- iso -propanol 1:3 mixture (8 mL) was added to a solution of alkoxyamine 9 [ 4 ] (0.342 g, 1.03 mmol) in iso-propanol (25 mL). The reaction mixture was left at room temperature for 12 h to complete the reaction.…”

“…Activation of a hydroxyl group towards nucleophilic substitution via reaction with methanesulfonyl chloride or PPh 3 -CBr 4 system is a commonly used pathway to various functional derivatives [ 1 , 2 , 3 ]. Recently, we reported on simple synthesis of (5 R ( S ),6 R ( S ))-2,2-dimethyl-6-(hydroxymethyl)-1-azaspiro[4.4]nonane-1-oxyl 1a from commercially available 5,5-dimethyl-1-pyrroline N -oxide (DMPO) [ 4 ]. The above nitroxide and its analogs were prepared as single enantiomeric pair with hydroxymethyl group close to the nitroxide one.…”