Pyrrolidine A -oxides

A series of 2//-imidazole-l-oxides, isoquinoline-A-oxides and pyrrolidine-A-oxides were investigated as to their specificity and efficiency at spin trapping HO and 02 as well as the stability of the corresponding spin-trapped adducts. 2,2-Dimethyl-4-methoxycarbonyl-2A-imidazole (42) has been found to be the most selective of the spin traps investigated for the in vivo, in situ detection of HO at the expense of 02. ... 

Allylthiols376 and unsaturated lithio sulfones377 have been found to react as nucleophiles with nitrones to yield intermediate hydroxylamines which undergo reverse-Cope cyclization to provide 1,3-thiazolidine N-oxides and pyrrolidine A-oxides, respectively. In the case of derivatives of C-phenyl nitrone (321 R2 = Ph), thermolysis was found to result in smooth Meisenheimer rearrangement leading to 1,5,2-oxathiazinane (322) (see Scheme 76). 

The addition of allylamine to the benzaldehyde nitrone 17 gave mainly the //wi.v-3,6-disubs tituted 1,2,5-oxadiazinane 20 via the cyclization of the ci.y-unsaturated hydroxylamine 18 to give the pyrrolidine A-oxide 19, and a final rearrangement step77. The product 20 was relatively sensitive to chromatographic purification, but could be converted to the more stable A -Boc and iV-(4-ni-trobenzoyl) derivatives (X-ray). 

The addition of benzenesulfonylmethyllithium to nitrones 25 containing a vinyl group can lead to pyrrolidine A -oxides 27 after workup through the intermediacy of 26 (Hanrahan and Knight 1998) (Scheme 7.9). 

For pyrrolidine A -oxides, one might a priori anticipate iminium ion formation to occur by a syn elimination process, since the N—O and adjacent Ca—H bonds cannot become antiperiplanar to each other. However, the A(-oxide (29a) of the steroid alkaloid conanine reacts with acetic and trifluoroacetic anhydride exclusively by the anti pathway to give the exocyclic enamine (30 Scheme 6). Release of steric strain between the C-16 methylene and the ring methyl substituent is undoubtedly a major driving force in this reaction. More revealing is the reaction of A -oxide (29b), which would give the same enamine product if a syn pathway is favored. The observed formation of compounds (31) and (32) argues in favor of the anti elimination. 

Nucleophilic addition of lithiated sulfones to nitrones made it possible to develop new stereoselective approaches to the synthesis of pyrrolidine-N -oxides based on a reverse-Cope-type elimination. One method is based on the reaction of lithiated sulfones with nitrones (386) (Scheme 2.168) (625). 

The /V -hydroxylamino compounds (404) and (405), obtained from the reaction of tert-butyl acetate with 3,4-dihydroisoquinoline-A-oxide or 5,5-dimethyl-pyrroline-/V-oxide, when boiled in methylene chloride in the presence of triphenylphosphine, carbon tetrachloride and triethylamine, are transformed to (1,2,3,4- tetrahydroisoquinolin-l-ilidene) acetate (406) or (pyrrolidin-2-ilidene) acetate (407) (Scheme 2.181) (645). 

Nitrogen heterocycles continue to be valuable reagents and provide new synthetic approaches such as NITRONES FOR INTRAMOLECULAR -1,3 - DIPOLAR CYCLOADDITIONS HEXAHYDRO-1,3,3,6-TETRAMETHYL-2,l-BENZISOX AZOLINE. Substituting on a pyrrolidine can be accomplished by using NUCLEOPHILIC a - sec - AM IN O ALKYL ATION 2-(DI-PHENYLHYDROXYMETHYL)PYRROLIDINE. Arene oxides have considerable importance for cancer studies, and the example ARENE OXIDE SYNTHESIS PHENANTHRENE 9,10-OXIDE has been included. An aromatic reaction illustrates RADICAL ANION ARYLATION DIETHYL PHENYLPHOSPHONATE. 

High enantioselectivity has been achieved on addition of diethylzinc to benzaldehyde catalysed by a chiral diamine, (,S )-2-(A,A -disubstitutcd aminomethyl)pyrrolidine,116 and by chiral helical titanate complexes of tetradentate ligands.117 Enantioselective additions of dialkylzinc reagents to A,-(diphcnylphosphiiioyl)imines, promoted by aziridino alcohols,118 and to the carbon-nitrogen double bond of the nitrone 3,4-dihydroisoquinoline A-oxide, promoted by dicyclopentyl(R,R)-tartrate,119 have also been reported. 

Although in cyclic systems studied to date the N-oxide function has been for the most part incorporated into a six-membered ring system, there are several examples where pyrrolidine or dihydropyrrole A -oxides are the substrates. For instance, the reaction of amine oxide (55) with acetic anhydride at 0 C provides a convenient route to the 7V-alkylisoindole (56 equation 16). ... 

Zhang et al. [32] have reported the formation of a series of radical cations via the sonolysis of aqueous A-tetraalkyl-p-phenylenediamines. It is suggested that on sonolysis the aqueous solution forms hydroxyl radicals and via a single electron transfer the corresponding alkyl radical cation is produced. In this study both hydroxyl and the jV-tetraalkyl-p-phenylenediamine radicals were identified by ESR techniques. Christman et al. [33] obtained evidence for the production of free radicals in aqueous solutions due to microsecond pulsed ultrasound. Employing spin traps such as 5,5-dimethyl- 1-pyrrolidine-jV-oxide (DMPO) and 4-pyridyl-l-oxide-A-rert-butylnitrone (4-POBN) the ESR spectra obtained provided evidence for the formation of the free radicals OH- and H-. 

Scheme V. Reaction of 5,5-dimethyl-l-pyrrolidine-N-oxide superoxide ion in the presence of a proton source to give radical hydroperoxide 10. ...

Dimethyl-2-pyrrolidine-1 -oxide Electron paramagnetic resonance Electrochemical step followed by a chemical reaction step... 

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