Pyrrolidine N-oxides

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). 

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 N-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). 

Three deuterated analogues of 5-diethoxyphosphonyl-5-methyl-l-pyrrolidine N-oxide (DEPMPO) (494), (495) and (496) were synthesised and used to trap tert-butylperoxide radical (Figure 94b). ... 

For pyrrolidine N-oxides, one might a priori anticipate iminium ion formation to occur by a syn elimination process, since the N—O and adjacent Co—bonds cannot become antiperiplanar to each other. However, the N-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 N-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. 

Nicotine Pyrrolidine 5 -hydroxylation to cotinine Pyrrolidine N-oxidation (FMO) N-demethylation (nornicotine and... 

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. ...

The synthesis of desdanine (5), isolated from Streptomyces culture, has been accomplished (Scheme 1)2 Treatment of the pyrrolidine N-oxide (3) with the hemiacetal of glyoxylic acid ethyl ester provided (4) which upon successive ammonolysis, electrolytic reduction, and dehydration gave desdanine (5). The... 

Improved syntheses of (-l-)-lentiginosine (125) and (7R)-7-hydroxylen-tiginosine (126), inhibitors of amyloglucosidases, have been reported. In multi-step syntheses based upon a 1,3-dipolar cycloaddition of a pyrrolidine N-oxide derived from L-tartaric acid to 3-buten-l-ol, 125 and 126 were prepared in 25% and 37% overall yields from a common indolizidine intermediate. The enantiomers of these compounds could be similarly prepared using D-tartaric acid as a starting material. ... 

Hanrahan, J. R. and Knight, D. W. 1998. A new strategy for the elaboration of pyrrolidine n-oxides using the reverse-cope elimination. Chem. Commun. 20 2231-2232. 

Without additional reagents Tetrahydro-l,2-oxazines from pyrrolidine N-oxides... 

CgHi gCl4CuNg02, Creatininium tetrachlorocupratedi), 45B, 202 CbHigN02, (+)-2,2,5,5-Tetramethyl-3-hydroxy-pyrrolidine N-oxide,... 

Similarly, pyrroline N-oxides (12), pyrrolines, or pyrrolidines can be prepared from y-nitro ketones (13) in aqueous organic media at low temperatures the pyrroline N-oxide is obtained66 [Eq. (26)]. 

Ozone-nicotine surface chemistry has recently been identified by Destaillats et al. (2006a). Nicotine and other products of tobacco smoking adsorb strongly to indoor surfaces. In the presence of ozone, surface nicotine can form a variety of products (Scheme 13.7). On cotton, high humidity inhibits this reaction. Ozone attacks the pyrrolidinic N, suggesting that other indoor surface bound species with this functionality may be oxidized in this manner. Not only does this chemistry generate volatile by-products, it may explain why indoor nicotine concentrations correlate poorly with exposure to tobacco smoke. This raises the question, what other, similarly functionalized, surface amines may also react with ozone in indoor environments ... 

Pyrrolidines. LDA (THE, -78°) converts trimethylamine N-oxide into an ylide, CH2=N (CH,)CH2Li, which undergoes (3 -I- 2] cycloaddition with simple alkenes to form pyrrolidines. 

Oxid), 1412 (NH - N-oxid) 3H-Pyrrol-l-oxid 2-Methyl-4,5-dihydro- E14b, 146 (aus N02-Keton) Pyrrolidin... 

A - M e t h y 1 -. V- (4 - pen t e n v I) - and, V-methyl-A -(5-hexenyl)hydroxylamine, prepared by reduction or alkylation of nitrones, undergo spontaneous cyclization to pyrrolidine and piperidine N-oxide, respectively. The cyclization is reversible and the equilibrium is affected by the solvent and presumably by the nature and the position of substituents. The optimum solvent for the cyclization is chloroform. The stereochemical outcome, e.g., formation of 14 and 15, is consistent with a concerted mechanism. Cyclic amines can be obtained by catalytic hydrogenation, e.g., 16. 

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). ... 

The influence of water as a solvent on the rate of dipolar cycloadditions has been reported [76]. Thus the rate of the 1,3-dipolar cycloaddition of 2,6-dichloroben-zonitrile N-oxide with 2,5-dimethyl-p-benzoquinone in an ethanol/water mixture (60 40) is 14-fold that in chloroform [76b]. Furthermore the use of aqueous solvent facilitates the workup procedure owing to the low solubility of the cycloadduct [76b]. In water-rich solutions, acceleration should be even more important. Thus in water containing 1 mol% of l-cyclohexyl-2-pyrrolidinone an unprecedented increase in the rate of the 1,3-dipolar cycloaddition of phenyl azide to norbornene by a factor of 53 (relative to hexane) is observed [77]. Likewise, the 1,3-dipolar cycloaddition of C,Ar-diphenylnitrone with methyl acrylate is considerably faster in water than in benzene [78]. Similarly, azomethine ylides generated from sarcosine and aqueous formaldehyde can be trapped by dipola-rophiles such as N-ethylmaleimide to provide pyrrolidines in excellent yields... 

Metal Free Although transition metal catalysts are effective and selective for C—N bond formation via direct C—H bond functionalization, metal-free methodologies are more attractive. Molecular iodine acts as a radical initiator and can be used to direct y-/a-sp3 C—H bond oxidation of sulfonamides in the presence of PhI(OAc)2 (Equation 11.24) [56]. The reaction provides a practical route to pyrrolidines, N-sulfonylimines, and various sulfonamide derivatives. A tentative mechanism is... 

---