9. Improved Synthesis of 5-tert- Butoxycarbonyl 5-methyl-1-pyrroline N-oxide

Masaaki Sato, Kazunori Anzai, Nobuo Ikota, and Toshihiko Ozawa

Keywords: ESR spin trapping 5, 5-dimethyl-1-1-pyrroline N-oxide, superoxide, 5-tert-butoxycarbonyl 5-methyl-1-pyrroline N-oxide, improved synthesis

The spin trapping method is a useful method for the detection of unstable radicals. Radicals are trapped by non-radical spin trapping reagent and converted to stable radical adducts which can be observed with an ESR spectrometer. DMPO (1, 5,5-dimethyl-1-1-pyrroline N-oxide) has been widely used to trap superoxide and hydroxyl radical. A major disadvantage of DMPO is that the DMPO-superoxide adduct (DMPO-OOH) spontaneously decays to the DMPO-hydroxy adduct (DMPO-OH). The phosphorylated analog, DEPMPO (2, 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide), has been reported recently. In contrast to DMPO-OOH, DEPMPO-OOH does not decompose to DEPMPO-OH. However, ESR spectra of DEPMPO adducts are complicated due to the hyperfine coupling from an additional ³¹P and the existence of diastereomers. Substitution of the 5-methyl group in DMPO with an electron-withdrawing group increases the stability of superoxide adduct and has led to the synthesis of a carboxylated analogs. More recently, a new analog, BMPO (3, 5-tert-butoxycarbonyl 5-methyl-1-pyrroline N-oxide) has been reported. However, synthetic procedures for BMPO were not well established. Here, we describe an improved synthesis of BMPO.

The synthetic route for the preparation of (3) is illustrated in Fig. 8. The cyclic nitrone spin trap, BMPO, was prepared starting from 2-bromopropionic acid (4), which was converted to the corresponding tert-butyl ester (5) by treatment with isobutene in the presence of sulfuric acid in dioxane (yield 90%). This ester was also obtained from 2-bromopropionyl bromide and tert-butyl alcohol in the presence of silver cyanide in benzene at reflux temperature in comparatively low yield (30 %). Teatment of 5 with sodium nitrate and phloroglucinol in dimethylformamide at room temperature afforded tert-butyl 2-nitropropionate (6) in 56% yield. The nitro compound (6) was then treated with acrolein in the presence of triethylamine in acetonitrile under Ar atomosphere at 10 ^oC to give the desired Michael adduct, i.e. nitro aldehyde (7), almost quantitatively (99 %). Reduction of the nitro aldehyde (7) with zinc powder in MeOH-H₂O (1:1, v/v) in the presence of ammmonium chloride gave the BMPO (3) in 66 % yield as white needles ( mp 97-98^oC) after purification by column chromatography and recrystallization from hexane-dichloromethane.

The BMPO superoxide (BMPO-OOH) adduct was about 10 times more stable than DMPO-OOH in the spin trapping of superoxide anion generated by the hypoxanthine-xanthin oxidase system.

Fig.8.Synthetic scheme for the preparation of BMPO.

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