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Summary tert-(Hetero)cyclobutanols are important synthetic building blocks. However, previous synthesis of these compounds has mainly focused on the nucleophilic addition of organometallic reagents to (hetero)cyclobutanones. Herein, we disclose a single-electron process for preparing allyl tert-(hetero)cyclobutanols with readily available organosilicon reagents. The success of the reaction is attributed to the favored radical 1,2-silyl transfer over β-carbon elimination of the alkoxyl radicals. The mechanism of the generation of carbon radicals from alkoxyl radicals is distinct from previous photoredox-mediated oxidation of hypervalent silicates. Our reaction shows broad substrate scope and wide functional-group tolerance. With the highly functionalized allyl tert-(hetero)cyclobutanols, we have achieved ring-opening reactions to synthesize thiolated 1,4-diketones and ring-expansion reactions to prepare seven-membered ring compounds.

Four diastereomers of 2-[(trimethylammonium)-methyl]-5-methyltetrahydrofuran-3-ol, trivially named isomuscarine, allo-isomuscarine, epi-isomuscarine, and epiallo-isomuscarine, were prepared as bromide salts from 2,4-like and 2,4-unlike diastereomers of 3-(4-hydroxyhex-5-en-2-oxy)-4-methylthiazole-2(3H)-thione. The strategy for constructing the tetrahydrofuran nucleus of the isomuscarines uses alkenoxyl radical 5-exo-bromocyclization, occurring 2,3-cis-selectively for the 2,4-like-4-hydroxyhex-5-en-2-oxyl radical, and 2,3-trans-selectively for the 2,4-unlike diastereomer. A fraction of 4-hydroxyhex-5-en-2-oxyl radicals cyclizes 6-endo-selectively providing 5-bromo-2-methyltetrahydropyran-4-ols in yields between 3 and 15%. Substituting trimethylamine for bromide in 5-exo-bromocyclized products furnishes isomuscarine bromides, which were structurally characterized by X-ray diffraction and NMR-spectroscopy.

The reaction of dihydroartemisinin (DHA) with solvated electrons (e(solv)(-)) generated under radiolytic conditions showed high pH dependence. The reduction performed under neutral conditions led to the formation of compound P1 deriving from the initial alkoxyl radical as the only detectable product. (C) 2013 Elsevier Ltd. All rights reserved.

The primary alkoxyl radical generated by reaction of 1-(2-hydroxyethyl)-glycosides with (diacetoxyiodo)benzene (DIB) and iodine can undergo regioselective intramolecular hydrogen abstraction (IHA) reactions to furnish four different dioxabicyclic systems derived from carbohydrates. The results strongly suggest that the regiocontrol and feasibility of the cyclisation are dependant not only on geometric and stereoelectronic factors, but also on polar and thermochemical factors. The correct selection of the substituents at the precursors can favour the 1,6-IHA against the 1,5-IHA pathway.

Primary, secondary, and tertiary alkoxyl radicals add exo -selectively to the olefinic π-bond in bicyclo[2.2.1]heptene to afford exo -2-alkoxybicyclo[2.2.1]hept-3-yl radicals, which are trapped with BrCCl 3 preferentially from the endo face to furnish β-bromohydrine ethers in 23–67% yield.

The product distributions observed after visible light irradiation of a series of 1-alkylcycloalkanols ( 1 – 3 ) and bis(pyridine)iodonium tetrafluoroborate (IPy 2 BF 4 ), have been compared with those observed after irradiation of the same substrates in the presence of (diacetoxy)iodobenzene (DIB) and I 2 , i.e. under bona fide conditions for alkoxyl radical generation. The observation of very similar product distributions with the two systems strongly supports the previous hypothesis that alkoxyl radical intermediates are formed after photolysis of substrates 1 – 3 in the presence of IPy 2 BF 4 .

1,1,1-Trihaloalkanes of the types R–CCl 2 I, R–CClBrI, and R–CBr 2 I belonging to 1,1,1-trihalo-1-deoxy- d -arabinitol series of alditols were prepared and fully characterized by anomeric alkoxyl radical fragmentation of the corresponding 2,2-dihalo-2-deoxy- d - arabino -hexopyranose derivatives. The analogous diiodohalo compounds R–CClI 2 and R–CBrI 2 could not be prepared by this methodology. The results strongly suggest that the stability of the mixed trihalo alditols decreases with increasing bulkiness of the halogen atoms.

Novel entry to synthesize medium-sized cycloalkanones is described. Thus, employment of catalytic (2+2)-cycloaddition for cyclic silyl enol ether followed by radical mediated ring-opening reaction provided medium-sized γ-halocycloalkanones.

A new synthesis of (−)-muscarine, (+)- allo -muscarine, (−)- epi -muscarine, and (−)- epiallo -muscarine has been devised which utilizes selective alkoxyl radical cyclizations for constructing tri-substituted tetrahydrofuran units. Photolysis of (2 R ,3 S )- N -(3-benzoyloxy-5-hexen-2-oxy)-4-methylthiazole-2(3 H )thione in the presence of BrCCl 3 provided (2 R ,3 S ,5 S )-3-benzoyloxy-5-bromomethyl-2-methyltetrahydrofuran as the major product and the corresponding (2 R ,3 S ,5 R )-isomer as the minor. These building blocks were converted into enantiomerically pure (+)- allo -muscarine (from the major alkoxyl radical cyclization product) and (−)-muscarine (from the minor product). Temperature and substituent effects on the diastereoselectivity of the underlying alkoxyl radical cyclization have been investigated. (−)- epi -Muscarine and (−)- epiallo -muscarine have been prepared likewise, starting from (2 R ,3 R )- N -(3-benzoyloxy-5-hexen-2-oxy)-4-methylthiazole-2(3 H )thione.

The reactivity of 2,2-dimethyl-5-methoxyindan-1-ol ( 1 ) and 2,2-dimethyl-6-methoxytetral-1-ol ( 2 ) radical cations has been studied both in acidic and basic solution. At pH≤4 both 1 + and 2 + undergo C α H deprotonation as the exclusive reaction with k =4.6×10 4 and 3.2×10 4 s −1 , respectively. In basic solution 1 + and 2 + behave as oxygen acids undergoing − OH-induced αOH deprotonation in a diffusion controlled process ( k −OH ≈10 10 M −1 s −1 ). An intermediate alkoxyl radical is formed which undergoes a 1,2-hydrogen atom shift in competition with CC β-scission (with 1 + ) or as the exclusive pathway (with 2 + ). A behavior which is interpreted in terms of the greater ease of ring-opening of a five membered ring as compared to a six-membered one.

The oxidation of proteins by free radicals is thought to play a major role in many oxidative processes within cells and is implicated in a number of human diseases as well as ageing. This review summarises information on the formation of radicals on peptides and proteins and how radical damage may be propagated and transferred within protein structures. The emphasis of this article is primarily on the deleterious actions of radicals generated on proteins, and their mechanisms of action, rather than on enzymatic systems where radicals are deliberately formed as transient intermediates. The final section of this review examines the control of protein oxidation and how such damage might be limited by antioxidants.

Substituted 5-hexen-1-oxyl radicals have been generated from N -(5-hexen-1-oxy)-5-( p -methoxyphenyl)-4-methylthiazole-2(3 H )-thiones under tin-free conditions and have been successfully applied as reactive intermediates in a mechanistic study on the formation of bromomethyl-substituted tetrahydropyrans via 6- exo - trig selective cyclizations.

Biologically/medicinally important compounds, when metabolized, can generate free radicals from which electronically excited products—often in the triplet state—are generated. Peroxidases are particularly apt to catalyze such processes, which usually entail oxidations by electron transfer. In the latter case, the chemiluminescence may derive from peroxyl and alkoxyl radicals or excited states derived from dioxetanes. Besides peroxidases, prostaglandin-H synthase and lipoxygenase may catalyze the formation of excited carbonyls. The pronounced similarity in the chemical behavior and reactivity of radicals and excited species derives in part from the biradical nature of the latter. Usually in analyzing the biological effects of xenobiotics, only radicals and/or reactive ground state products have been considered. However, in such processes the generation of excited species is possible, which should be tested for by direct and/or sensitized emission or by photochemical transformation.

Acetyl hypoiodite and a number of alkyl hypoiodites have been characterized as intermediates in the conversion of alcohols into alkoxyl radicals under Suarez (photostimulated iodosobenzenediactetate/iodine reagent) and Beebe (photolysed acetyl hypoiodite/alcohol) conditions.

The representative photostimulated hypoiodite reaction of cyclopentanol with mercury(II) oxide and iodien gives products formed by a sequence of iodoaldehyde formation, followed by consumption to give Baeyer-Villiger and hydrolysis products.

A new general synthesis of γ-substituted γ-lactones and δ-substituted δ-lactones including dihydro-5-octyl-2(3H)-furanone, a natural pheromone, is described. The synthesis involves the regioselective β-scission of alkoxyl radicals generated from transannular hemiacetals as the key step.

New general methods are described for the synthesis of phthalides, 3-monosubstituted, and 3,3-disubstituted phthalides including naturally-occurring phthalides such as pierardine based on a regioselective single or double β-scission of the alkoxyl radicals generated by the photolysis of the hypoiodites of 1-ethyl benzocyclobuten-1-ols or 1,2-catacondensed benzocyclobuten-1-ols or 1,3-dihydro-1,3-alkanoisobenzofuran-1-ols. The formation paths of the phthalides, which involve a regioselective single or double β-scission of the alkoxyl radicals generated from 1-alkylbenzocyclobuten-1-ols and from catacondensed benzocyclobuten-1-ols, are discussed.

EPR spectroscopic observations and product studies showed that the trimethylsilyl group undergoes 1,2-migration from carbon to nitrogen in aminyl radicals, Me 3 SiCh 2 O . → . CH 2 NHSiMe 3 , and from carbon to oxygen in alkoxyl radicals, Me 3 SiCh 2 O . → . CH 2 OSiMe 3 .

3 beta-Hydroxy-5 alpha-androstan-17-one was transformed into 17-oxa-5 alpha-androstan-3 beta-ol in five steps involving conversion of the 17-ketone via the corresponding lactol to its hypoiodite and thence a regioselective beta-scission under irradiation to give ring D seco iodoformate, from which the 17-oxasteroids were derived. Four bisheterosteroids 3,17-dioxa-5 alpha-androstane, 3-thia-17-oxa-5 alpha-androstane, 3-aza-17-oxa-5 alpha-androstane, and 3-selena-17-oxa-5 alpha-androstane) were synthesized from 17-oxa-5 alpha-androstan-3 beta-ol via 5, 8, 8, and 9 steps, respectively, involving a second regioselective beta-scission of an alkoxyl radical as the key step.

The inhibition of the autoxidation of hydrocarbons and polypropylene by aliphatic, aromatic, sterically hindered and cyclic phosphites has been studied by means of volumetric and 31P-NMR techniques. The antioxidant activity of phosphites depends on the rate of their reactions with peroxyl radicals and on the way they react with alkoxyl radicals. Only those phosphites which react by substitution to give free aryloxyl radicals are effective as chain-breaking antioxidants. The reaction modes of various phosphites with various peroxyl and alkoxyl radicals have been studied in some model reactions and the relationship between structure, reaction mechanism and antioxidant activity has been elucidated.

The low-pressure gas-phase thermolysis of several dialkyl peroxides has been investigated in the 250–350°C range. The free radicals were trapped at 77 K and identified by ESR. No primary alkoxyl radicals have been detected. There is evidence for the decomposition of methoxyl and ethoxyl radicals with formation of H and CH 3 radicals, respectively, which readily combine with traces of O 2 to yield HO 2 and CH 3 O 2 . For higher homologues only RCH 2 O 2 radicals have been detected and identified from the hyperfine structure.

Methanethiyl radicals (CH3S.) are shown to react with cyclic ethers containing double bonds to give addition and hydrogen abstraction from the allylic positions. The esr spectra of the corresponding radicals have been determined. In some cases radicals arising from a rearrangement (probably 1,4 H-shift) were observed. t-Butoxyl radicals also give abstraction and addition with the same substrates. In two cases the barriers to ring inversion for six-membered ring radicals have been determined.

The e.s.r. spectra derived from 7-bromo-5,6-epoxyheptene derivatives such as epoxygeranyl bromide (7) showed that the main free radical intermediates were tetrahydrofuranylmethyl radicals (11), formed by ring opening of the epoxide and subsequent exocyclisation of the unsaturated alkoxyl radicals. The 7-oxabicyclo[2.2.1]heptanyl methyl radicals (12) were also formed via a double cyclisation. Products derived from both these intermediates were isolated from the reaction of (7) with tri-n-butyltin hydride.

A simple new method for the synthesis of phthalides and their 3-alkyland 3,3′-spiroalkyl derivatives including (±)-3-butylphthalide, a racemic form of a constituent of celery oil, through the β-scission of alkoxyl radicals generated from hypoiodites of benzocyclobutenols by the photolysis, is described.

The alkyl radical products of β-scission of a cyclic tetraalkoxyphosphoranyl radical are independent of its source.