5.5- Dimethyl-1 -pyrroline-1 -oxide, reaction

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). 

The dimer of 1-methyl- -pyrroline (39) was obtained by reduction of N-methylpyrrole with zinc and hydrochloric acid (132) and, together with the trimer, by mercuric acetate dehydrogenation of N-methylpyrrolidine (131). J -Pyrroline-N-oxides form dimers in a similar manner (302). Treatment of 1,2-dimethyl-zl -piperideine with formaldehyde, producing l-methyl-3-acetylpiperidine (603), serves as an example of a mixed aldol reaction (Scheme 18). 

In related work, the reactions of hydrogen peroxide with iron(II) complexes, including Feu(edta), were examined.3 Some experiments were carried out with added 5.5"-dimethyl-1-pyrroline-N-oxide (DMPO) as a trapping reagent fa so-called spin trap) for HO. These experiments were done to learn whether HO was truly as free as it is when generated photochemically. The hydroxyl radical adduct was indeed detected. but for some (not all) iron complexes evidence was obtained for an additional oxidizing intermediate, presumably an oxo-iron complex. 

Volume 75 concludes with six procedures for the preparation of valuable building blocks. The first, 6,7-DIHYDROCYCLOPENTA-l,3-DIOXIN-5(4H)-ONE, serves as an effective /3-keto vinyl cation equivalent when subjected to reductive and alkylative 1,3-carbonyl transpositions. 3-CYCLOPENTENE-l-CARBOXYLIC ACID, the second procedure in this series, is prepared via the reaction of dimethyl malonate and cis-l,4-dichloro-2-butene, followed by hydrolysis and decarboxylation. The use of tetrahaloarenes as diaryne equivalents for the potential construction of molecular belts, collars, and strips is demonstrated with the preparation of anti- and syn-l,4,5,8-TETRAHYDROANTHRACENE 1,4 5,8-DIEPOXIDES. Also of potential interest to the organic materials community is 8,8-DICYANOHEPTAFULVENE, prepared by the condensation of cycloheptatrienylium tetrafluoroborate with bromomalononitrile. The preparation of 2-PHENYL-l-PYRROLINE, an important heterocycle for the synthesis of a variety of alkaloids and pyrroloisoquinoline antidepressants, illustrates the utility of the inexpensive N-vinylpyrrolidin-2-one as an effective 3-aminopropyl carbanion equivalent. The final preparation in Volume 75, cis-4a(S), 8a(R)-PERHYDRO-6(2H)-ISOQUINOLINONES, il lustrates the conversion of quinine via oxidative degradation to meroquinene esters that are subsequently cyclized to N-acylated cis-perhydroisoquinolones and as such represent attractive building blocks now readily available in the pool of chiral substrates. 

In this type of spin traps, 5,5-dimethyl-l-pyrroline-Af-oxide (DMPO) deserves particular mention. DMPO is widely employed as a spin trap in the detection of transient radicals or ion-radicals in chemical and biological systems (see, e.g., Siraki et al. 2007). Characteristic ESR spectra arising from the formation of spin adducts are used for identification of specific spin species. In common opinion, such identification is unambiguous. However, in reactions with superoxide ion (Villamena et al. 2004, 2007b), carbon dioxide anion-radical (Villamena et al. 2006), or carbonate anion-radical (Villamena et al. 2007a), this spin trap gives rise to two adducts. Let us consider the case of carbonate anion-radical. The first trapped product arises from direct addition of carbonate anion-radical, second adduct arises from partial decarboxylation of the first one. Scheme 4.25 illustrates such reactions based on the example of carbonate anion-radical. 

Oxidation of a sulfide to sulfoxide is known to be an electrophilic reaction, in contrast with nucleophilic oxidation of sulfoxide to sulfone. Since 2-nitrobenzenesulhnyl ehloride/K02 oxidizes sulfides to sulfoxides selectively, intermediate 48 must be the actual active intermediate. Moreover, in the presence of l,4-diazabicyclo[2.2.2.]octane (DABCO), which is a radical capturing reagent, the oxidation of methyl phenyl sulfide to the sulfoxide was inhibited. In order to further detect the intermediate 48, pure 5,5-dimethyl-1-pyrroline-l-oxide (DMPO) was used as a trapping reagent and spin adduct was obtained223. The ESR spectrum of the DMPO spin adduct was obtained by the reaction of 02 with 2-nitrobenzenesulfinyl chloride (hyperfine coupling constants, aH = 10.0 G and aN = 12.8 G). 

The reaction of cyclic nitrones with free radicals takes place as in Scheme 8.21 with 5,5-dimethyl-l-pyrroline IV-oxide (DMPO) as an example.119,120 The resulting stable nitroxide spin adducts can be detected and quantified by ESR. 

The reaction of 5,5-dimethyl-l-pyrroline 1-oxide with dimethylketene N-phenylimine leading to pyrrolo[l,2-a]imidazol-2(3H)-ones (190) proceeds via initial formation of zwitterion (188). Subsequent sigmatropic rearrangement of (188) gives zwitterion (189), capable of undergoing ring closure to (190) (79JOC4543). 

CuZnSOD has been demonstrated to act as a peroxidase, oxidizing various substrates, among them nitrite (to NO2) [57] and relatively bulky molecules such as 5,5-dimethyl- 1-pyrroline N-oxide (DMPO to DMPO-OH), tyrosine (to dityrosine) or 2,2 -azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS to a cation radical). However, the enzyme becomes inactivated in the presence of H2O2. Apparently, hydrogen peroxide reduces Cu- at the active site of the enzyme. Subsequent reaction of H2O2 with Cu generates a potent oxidant (Cu+-0 or Cu + CH) that can attack the adjacent histidine residue and thus inactivate the enzyme, or oxidize an alternative substrate [3]. Most authors assume that the mechanism of the peroxidative action of CuZnSOD, significantly accelerated in the presence of bicarbonate, consists in oxidation of bicarbonate to a carbonate radical anion able to oxidize other substrates [58,59] ... 

In a paper published along with that of Stevens and Wentland20 and in agreement with these authors, Keely and Tahk23 reported the independent synthesis of dl-mesembrine, also from I-methyl-3-(3,4-dimethoxyphenyl)-2-pyrroline and methyl vinyl ketone. In their work the cyclopropyl derivative 3b was prepared from the reaction of the anion of 3,4-dimethoxyphenylacetonitrile (lc) with ethylene dibromide in dimethyl sulfoxide and its sodium salt as solvent and base. Reduction with ethereal diisobutylaluminum hydride gave the aldehyde, which was condensed with excess methylamine in benzene-ether solution with calcium oxide as the dehydrating agent. 

As might be predicted on the basis of these data, a number of other thiol compounds have been shown to reduce Fe(IV)=0 Lb to the Fe(III) state with concomitant formation of thiyl radicals (detected by use of EPR spin trapping using 5,5-dimethyl-l-pyrroline IV-oxide) (135). In some cases, however, other species are formed, and these have been identified from their UV-vis absorption spectra as novel sulfur species formed by nucleophilic attack on the tetrapyrrole ring by the thiol group (135). The ability of a thiol to undergo two such competing reactions is dictated by steric and electronic characteristics... 

Let us report here the results of the reactions of 1-pyrroline-l-oxide and 5,5-dimethyl-1-pyrroline-l-oxide with acrylonitrile (Scheme 1 and Table 1) and maleonitrile (Scheme 2 and Table 2). In our regiochemical notation, A-adducts involve the a-carbon atom of the alkene in the new forming C - C bond, whereas... 

Other than giving a very good account of the experimental qualitative behaviour, the above results probably offer a reasonable quantitative evaluation of the leacbon parameters. The apparent activation free enthdpy of the reaction of 1-pyrroline-1-oxide and 5,5-dimethyl-1-pyrroline-l-oxide with acrylonitrile have been meas-ured 2 in cyclohexane (20.4 0.4 and 21.7 0.4 kcal mol, respectively) and in di-chloromethane (22.4 0.2 and 23.010.8 kcal mol ) at 298K the rate constants for the reactions of H-nitrone have not been measured, but it can be stressed that N-monosubstituted nitrone, e.g, t-Bu-nitrone, exhibits a high reactivity in 1,3-dipolar cycloadditions, which is similar to that of 1-pyrroline-l-oxide so that the evaluations of Table 6 emerge to be surprisingly good. Moreover, the activation entropy of the reaction of 5,5-dimethyI-1-pyrroline-l-oxide with acrylonitrile in cyclohexane has been estimated -31,9 eu, a value which is well reproduced by our calculations in the gas-phase (-33.4, -31.1, footnote of Table 6). 

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