Generation Of Alkoxyl Radicals Research Articles

Microwave-assisted generation of alkoxyl radicals and their use in additions, β-fragmentations, and remote functionalizations

Microwave irradiation (2.45 GHz, 300-500 W) of N-(alkoxy)thiazole-2(3H)-thiones in low-absorbing solvents affords alkoxyl radicals, which were identified by (i) spin adduct formation (EPR-spectroscopy) and (ii) fingerprint-type selectivities in intramolecular additions (stereoselective synthesis of disubstituted tetrahydrofurans), beta-fragmentations (formation of carbonyl compounds), and C,H-activation of aliphatic subunits, by delta-selective hydrogen atom transfer. C-Radicals formed from oxygen-centered intermediates were trapped either by Bu(3)SnH, L-cysteine ethyl ester, the reduced form of glutathione (reductive trapping), or by bromine atom donor BrCCl(3) (heteroatom functionalization) The results suggest that microwave activation is superior to UV/Vis-photolysis and conductive heating for alkoxyl radical generation from N-(alkoxy)thiazolethiones. It offers by far the shortest reaction times along with the option to reduce the amount of trapping reagent significantly.

Generation of Alkoxyl Radicals from N-Alkoxy-2-pyridones

Alkoxyl radicals have unique characteristic properties such as a facile β-fragmentation and a hydrogen abstraction due to their high reactivity. Various alkoxyl radical precursors are normally prepared from alcohols and include nitrites, nitrates, hypohalites, sulfenyl ethers, and Nalkoxyphthalimides. Especially, N-alkoxypyridine-2thiones 3 have attracted a great deal of attention as synthetically useful alkoxyl radical precursors. However, preparations of N-alkoxypyridine-2-thiones 3 are problematic due to competing Oand S-alkylation (eq. 1). Even under carefully controlled conditions, the desired product 3 is normally obtained in poor yields with a significant amount of undesired S-alkylated side product 4. In addition, the radical precursor is also unstable in light. Thus, some improved procedures have been reported, but the chemical yields were not very high. Since radical precursors are needed to be stable for safe handling and better chemical yields, we have been interested in N-alkoxy-2-pyridones 5 as new alkoxyl radical precursors.

Selectivity in the Chemistry of Oxygen‐Centered Radicals — The Formation of Carbon—Oxygen Bonds.

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Selectivity in the Chemistry of Oxygen-Centered Radicals - The Formation of Carbon-Oxygen Bonds

In recent years, powerful new methods for the generation of alkoxyl radicals under mild and neutral conditions have been developed. This progress has led to a thorough investigation of most O-radical elementary reactions.Today, sufficiently reliable thermodynamic and kinetic data are available either from experimental or from theoretical studies in order to predict alkoxyl radical reactivities and selectivities in synthesis. For instance, alkoxyl radicals readily add to carbon-carbon and carbon-nitrogen double bonds. Due to generally low activation barriers and strongly negative reaction enthalpies, inter- and intramolecular addition reactions proceed under kinetic control and are associated with high rate constants. Nevertheless, intramolecular 5-exo-trig additions, i.e. cyclizations, proceed with an astonishing degree of diastereoselectivity and often provide complementary selectivities if compared to commonly used methods such as the bromine cyclization of alkenols. Therefore, several useful applications of O-radical cyclizations in the synthesis of functionalized tetrahydrofurans have been discovered in the last few years. A second major reaction channel of alkoxyl radicals is associated with the homolysis of a β-C-C bond. This fragmentation proceeds under thermodynamic control and affords a carbonyl compound besides an alkyl radical from the starting alkoxyl radical. Regioselectivities for C-C bond homolysis may be predicted by considering strain release (cyclic carbon framework) and the stability of the newly formed carbon radical (cyclic and open chain carbon skeletons). The third major group of alkoxyl radical-based transformations are connected with homolytic substitutions such as intramolecular 1,5-hydrogen shifts which have been applied with considerable success to remote functionalization reactions. In view of the diversity of alkoxyl radical reactions it is the aim of this review to organize basic principles of this type of chemistry and to present its latest useful application in organic synthesis.

Laser flash photolysis studies of alkoxyl radical kinetics using 4-nitrobenzenesulfenate esters as radical precursors

4-Nitrobenzenesulfenate esters were used as precursors for the generation of alkoxyl radicals under laser flash photolysis conditions. The esters were efficiently cleaved using the Nd:YAG third harmonic (355 nm) to produce alkoxyl radicals and the 4-nitrobenzenethiyl radical. Rate constants for beta-scission and 1, 5-hydrogen abstraction reactions of alkoxyl radicals were measured.

On the radical brook rearrangement. Reactivity of alpha-silyl alcohols, alpha-silyl alcohol nitrite esters, and beta-haloacylsilanes under radical-forming conditions

Two alkoxyl radical generation methods, lead tetraacetate treatment of alcohols and photolysis of nitrites, were applied to alpha-silyl alcohols 21 and to the corresponding nitrites 25 with a view to forming alpha-silyl alkoxyl radicals 23 and studying their possible radical Brook rearrangement to alpha-silyloxy carbon radicals 24. LTA treatment of 21 led to their quick and efficient conversion into mixed acetyl-silyl acetals 33 under very mild conditions. Photolysis of alpha-alkylmonosubstituted alpha-silyl nitrites 25 to the corresponding aldehydes is considered to proceed through alpha-silyl alkoxyl radical intermediates 23. A concerted process is, however, proposed for the case of the benzyl nitrites analogues. On the basis of these results, it is postulated that resonance stabilization can have a major influence on the evolution of alpha-silyl alkoxyl radicals: should this stabilization be possible, they quickly evolve by alpha-silyl fragmentation; otherwise, they tend to undergo radical Brook rearrangement. It was also found that the radical Brook rearrangement of alpha-silyl cyclopropyloxyl radicals generated from beta-bromoacylsilanes under standard tin-radical conditions is too slow to compete with beta-fragmentation.

New Strategies in Carbonylation Chemistry: The Synthesis of δ-Lactones from Saturated Alcohols and CO

This paper describes the δ-carbonylation of saturated alcohols which uses a 1,5-hydrogen-transfer reaction of alkoxyl radicals and subsequent carbonylation at the δ-carbon atoms as the key. The carbonylation reactions of five classes of saturated alcohols, namely, primary alcohols having primary δ-carbons, primary alcohols having secondary δ-carbons, primary alcohols having tertiary δ-carbons, secondary alcohols having primary δ-carbons, secondary alcohols having secondary δ-carbons, were carried out, in which lead tetraacetate (LTA) was used as a one-electron oxidant to generate the alkoxyl radicals. Carbonylation of these saturated alcohols, except for primary alcohols having tertiary δ-carbons, took place to afford δ-lactones in moderate to good yields. The mechanism of the remote carbonylation likely involves (1) alkoxyl radical generation via LTA oxidation of a saturated alcohol, (2) conversion of this alkoxyl radical to a δ-hydroxyalkyl radical by a 1,5-hydrogen-transfer reaction, (3) CO trapping of the δ-hydroxyalkyl radical yielding an acyl radical, and (4) oxidation and cyclization of the acyl radical to give a δ-lactone. A metal salt-free system was also tested for a substrate derived from a tertiary alcohol having a secondary δ-carbon; the photolysis of an alkyl 4-nitrobenzenesulfenate under CO pressures gave a δ-lactone in moderate yield.

Alkoxyl Radical Generation Following Nitric Oxide Synthase Inhibition 179

Background: Previous studies suggest that peroxynitrite is a mediator of lipid peroxidation. Hypothesis: Nitric oxide (NO) synthase inhibition by Nω-nitro-L-arginine (NNLA) will result in decreased peroxynitrite, leading to decreased alkoxyl radical, an index of lipid peroxidation during cerebral hypoxia. Subjects: 20 piglets Vn: vehicle, normoxia; Vh: vehicle, hypoxia; Nn: NNLA (40 mg/Kg), normoxia and Nh: NNLA, hypoxia. (n=5, each). Method: Tissue hypoxia was documented by measuring levels of ATP and phosphocreatine. Free radicals, trapped with PBN were measured by electron spin resonance spectroscopy (ESR). Signal characteristics were compared with chemically produced alkoxyl and hydroxyl radical. Results: Hyperfine splitting constant (Hfsc) of brain sample (αN=13.5-13.8 G, αH=2.1-2.3 G) were closely identical to reported Hfsc of alkoxyl and hydroxyl radical. The alkoxyl radical(αN=13.7 G, αH=2.2 G) was identical to those observed in hypoxic brain. Hypoxic brain tissue addition to the hydroxyl radical generating system decreased the signal by 63%, and increased signal 2500% for alkoxyl radical. Free radical intensity in Vn, Vh, Nn and Nh was 11.6 ± 4.4, 27.7± 18.8, 15.3 ± 6.5, and 11.6 ± 2.0, respectively. Free radical production was increased in Vh vs Vn and Nn (p<0.05). NNLA reduced predominantly alkoxyl radical in Nh vs Vh (p<0.05).Conclusion: Decreased generation of alkoxyl radical by NNLA suggests that peroxynitrite is a mediator of lipid peroxidation during hypoxia and NO is a limiting factor. (By NIH-HD-20337)

EFFECT OF 100% OXYGEN AND 21% OXYGEN DURING RESUSCITATION ON CEREBRAL CELLULAR FUNCTION FOLLOWING NEONATAL ASPHYXIA. † 1279

Previous studies have shown that hypoxia and severe repeated asphyxia modify the N-methyl-D-aspartate (NMDA) receptor, decrease Na+,K+-ATPase activity, and increase lipid peroxidation and free radical production. The present study investigates the effect of hyperoxic and normoxic reventilation following asphyxia in piglets on NMDA receptor activation, lipid peroxidation and free radical generation. Asphyxia was induced in 8 anesthetized and paralyzed piglets by discontinuing mechanical ventilation for 6-12 min until the heart rate was 120mmHg and PO2<5mmHg). After asphyxia, animals in Grp 1 (n=4) and Grp 2 (n=4) were reventilated with 21% oxygen and 100% oxygen for 20 min. The cerebral cortices were removed for analysis.3[H]MK-801 binding, an index of NMDA receptor activation, showed the Bmax (number of receptors) in Grp 1 and Grp 2 to be 1.32±0.13 and 1.57±0.34 pmol/mg protein (mean±SD). Kd for the same groups were 4.45±1.45 and 3.79±0.96 nM. Bmax and Kd in controls were 1.23±0.06 pmol/mg protein and 5.8±0.5 nM. Na+,K+-ATPase activity in Grps 1 and 2 were 23.5±0.9 and 24.4±3.9 μmol Pi/mg protein/hr, as compared to control(49.9±0.5, p<0.05). Lipid peroxidation products, conjugated dienes(0.07 vs. 0.05 μmol/g brain) and fluorescent compounds (0.78 vs. 0.54 μg quinine sulfate/g brain) were similar. Electron spin resonance spectroscopy performed after trapping spin adducts in α-phenyl-N-tert-butylnitrone for the detection of alkoxyl radical showed similar spin adduct signal height intensity (10.39 vs. 13.68 mm/g tissue). The results show that NMDA receptor activation, lipid peroxidation. Na+,K+-ATPase activity and alkoxyl radical generation were similar following reventilation with 100% and 21% oxygen. These data did not reveal immediate cerebral cellular dysfunction with either normoxic or hyperoxic reventilation following asphyxia. Since previous data have shown a 48 h delay in the appearance of neuronal membrane injury, the long term effect of reventilation with oxygen on neuronal membrane function remains unknown. (Funded by NIH HD-20337, MOD-6FY940135, UCP#R-506-93).

Generation of alkoxyl radicals from O-alkyl benzenesulphenates

Representative examples (1,2, and 3) of primary, secondary, and tertiary alkyl benzenesulphenates, when treated with tributylstannane, generate alkoxy radicals which undergo characteristic β-scission or intramolecular addition reactions; the rate constants of these processes have been determined.