Synthesis of nitrogen-containing heterocycles using exo- and endo-selective radical cyclizations onto enamides

The effect of positional change of the carbonyl group of enamides on Bu₃SnH-mediated alkyl radical cyclization leading to five-, six-, seven-, and eight-membered nitrogen-containing heterocycles was examined. A 5-exo cyclization is generally preferred over a 6-endo ring closure in systems having an alkyl radical center on the enamide-acyl side chain, whereas enamides having an alkyl radical center opposite to the acyl side chain predominantly gave 6-endo cyclization products. These results suggest that the exo or endo selectivity of radical cyclization onto the alkenic bond of enamides can be controlled by positional change of the carbonyl group. For an understanding of these selectivities, heat of formation for each transition state was calculated. 6-endo-Selective radical cyclization was applied to the radical cascade, enabling a concise synthesis of a cylindricine skeleton. A 7- or 8-endo alkyl radical cyclization, however, predominated over a corresponding 6- or 7-exo ring closure regardless of the positional change of the carbonyl group of enamides.     

Physico-chemical aspects of polyethylene processing in an open mixer. Part 28: Formal kinetics of aldehyde and carboxylic acid formation in the advanced stages

The rate of acid formation at high temperature is constantly increasing but temperature independent. Two main mechanisms can account for this behavior in the advanced stages of polyethylene processing. The first mechanism is based on free radical induced oxidation of aldehyde pairs that are formed on acid-catalyzed decomposition of allylic hydroperoxides. The last will be formed essentially on mechanical stress-induced oxygen addition to trans-vinylene groups. Peroxidation of one of the aldehydes might yield an acyl-peroxy radical that is likely to abstract the labile hydrogen atom from the second aldehyde. The acyl radical formed in the reaction will abstract a hydroxyl group from the peracid formed in the same reaction. This yields an acid and an acyl-oxy radical that will give a primary alkyl radical on decarboxylation. The second mechanism involves oxidation of ketones and alcohols that accumulate in the oxidizing melt. Acid-catalyzed decomposition of the α-keto-hydroperoxides yields simultaneously an acid and an aldehyde. Formal kinetics based on each mechanism shows that they do not involve significant activation energy, as it is required by the experimental data. The dependency on the oxygen concentration deduced from the formal kinetics for the oxidation of aldehyde pairs is in agreement with the experiments.     

6-endo Versus 5-exo radical cyclization: streamlined syntheses of carbahexopyranoses and derivatives by 6-endo-trig radical cyclization

Three factors that can direct 6-endo radical cyclization over 5-exo ring closure: substitution at C-5, vinyl radical cyclization and ring strain, have been considered in the context of the preparation of carbapyranoses from carbohydrate derivatives. As a result, alkyl radicals in substrates containing a strain inducing 2,3-O-isopropylidene ring, and vinyl radical in non-strained compounds undergo a completely regioselective 6-endo-trig ring closure leading to carbasugar derivatives.     

On-line high-performance liquid chromatography-diode array detection-electrospray ionization-mass spectrometry-chemiluminescence assay of radical scavengers in Epimedium

An on-line analysis method for the simultaneous detection and identification of radical scavenging compounds in plant extracts was developed by combining HPLC with hydrogen dioxide radical scavenging and HPLC-DAD-MS-CL system. The structural identification and activity characteristics of various constituents could be rapidly achieved by the on-line assay of UV, MS and CL in one run. In 4 species of Epimedium studied 32 compounds, including phenolic acids, 8-isopentenyl-flavonoid glycosides and flavonoid glycosides containing a ortho-hydroxyl group, were identified by comparison with authentic standards and published mass data. Among these compounds, phenolic acids and flavonoid glycosides containing an ortho-hydroxyl group could obviously inhibit CL, which suggested their strong radical scavenging activity. These four species each exhibited different active properties, which might correlate to their respective quality. The results indicated that the on-line HPLC-DAD-MS-CL system would be a potential method to rapidly and sensitively screen radical scavengers in herbal medicines, and could display an integrated fingerprint based on different detectors.     

Regioselective alkylation of 3,4-dihydro-2H-pyran by xanthate-mediated free radical nonchain process

An intermolecular xanthate-mediated free radical nonchain addition reaction is introduced for the regioselective alkylation of 3,4-dihydro-2H-pyran. Additionally, we observed that the free radical nonchain reaction depends on the nature of the radical precursor.     

Rapid stereoselective access to the tetracyclic core of puupehenone and related sponge metabolites using metal-free radical cyclisations of cyclohexenyl-substituted 3-bromochroman-4-ones

The tetracyclic nucleus of puupehenone, 15-oxopuupehenol and other sesquiterpene-phenol natural products can be assembled stereoselectively in three steps, the last of these being the 6-endo-trig cyclisation of an alpha-keto radical generated from a substituted 2-(2-cyclohexenyl)ethyl 3-bromo-4-chromanone under metal-free conditions.     

Asymmetric radical cyclization reactions of axially chiral N-allyl-o-iodoanilides to form enantioenriched N-acyl dihydroindoles

Radical cyclizations of enantiomerically enriched N-allyl-o-iodoanilides provide N-acyl-3-alkyl-2,3-dihydroindoles in good yields and with good to excellent levels of chirality transfer from the N-Ar axis to the new stereocenter. In competitive cyclizations of N-acryloyl-N-allyl-o-iodoanilides, the addition of an o-methyl group reverses the regioselectivity of the radical cyclization from the acryloyl group to the allyl group. Approximate rate constants for representative radical cyclizations have been measured to provide insight into the origin of these observations.     

A radical mediated first total synthesis from ‘diacetone glucose’ and determination of the absolute stereochemistry of xylobovide

The first total synthesis by an intramolecular radical cyclisation protocol on a carbohydrate derived 5-hexynyl system, and determination of the absolute stereochemistry of xylobovide are reported.     

An efficient synthesis of furano analogs of duocarmycin C1 and C2: seco-iso-cyclopropylfurano[e]indoline-trimethoxyindole and seco-cyclopropylfurano[f]quinoline-trimethoxyindole

seco-Iso-cyclopropylfurano[e]indoline-trimethoxyindole 1 and seco-cyclopropylfurano[f]quinoline-trimethoxyindole 2 are potent cytotoxic agents. Previous synthesis of these compounds was inefficient and the approach required separation of a mixture containing the isomeric indoline and quinoline intermediates 11 and 12, formed from radical cyclization of allylic bromide 10. Reported herein is an efficient and selective synthesis of either intermediate 11 or 12, thus product 1 or 2, as needed. The conditions of the Stobbe condensation, bromination, 5-exo-trig radical cyclization, amine-carboxylic acid coupling, and debenzylation were optimized for multi gram scale. As a result, the reaction times were shortened, the products were readily isolated, and the yields and purity improved.     

A new access to C-arylglycosides related to the gilvocarcins

A new strategy has been developed for the synthesis of C-aryl glycosides based on a xanthate-mediated free radical addition-cyclization sequence of an acetophenone xanthate to a vinylic carbohydrate followed by aromatization.     

Radical cyclisation approach for the synthesis of (+)dihydrocanadensolide, (+)dihydrosporothriolide and their C-3 epimers from d-xylose

Intramolecular radical cyclisation protocol on 5-hexenyl systems derived from d-xylose, was utilized for the synthesis of (+)dihydrocanadensolide, (+)-dihydrosporothriolide and their C-3 epimers, wherein a study on the impact of C-2′ stereocentre on radical cyclisation was conducted.     

Hindered, 1,1-disubstituted monomers. Chain transfer to benzene in the radical polymerisation of di-n-butyl itaconate

The transfer constant to benzene in the radical polymerisation of di-n-butyl itaconate, DBI, was measured at 60 °C and found to have the value of 2.2 × 10⁻³. This value is surprisingly high considering that benzene has no readily extractable hydrogen atoms and is usually considered to be a relatively inert solvent in radical polymerisations. The high values of transfer constants in the radical polymerisation of itaconates must be taken into consideration when planning the tailored polymerisation of these monomers.     

Synthesis of oxa-aza spirobicycles by intramolecular hydrogen atom transfer promoted by N-radicals in carbohydrate systems

The nitrogen-centred radical generated by reaction of an N-phosphoramidate or N-cyanamide, attached to a tri- or tetramethylene tether extended from the C-1 of a carbohydrate, with (diacetoxyiodo)benzene (DIB) and iodine can undergo a regio- and stereoselective intramolecular hydrogen atom transfer (HAT) reaction to furnish four different oxa-azaspirobicyclic systems: 1-oxa-6-azaspiro[4.4]nonane, 1-oxa-6-azaspiro[4.5]decane, 6-oxa-1-azaspiro[4.5]decane and 1-oxa-7-azaspiro[5.5]undecane. A tandem 1,5- or 1,6-HAT-oxidation-nucleophilic cyclisation mechanism is proposed.     

Iron-chelating agents never suppress Fenton reaction but participate in quenching spin-trapped radicals

Hydroxyl radical formation by Fenton reaction in the presence of an iron-chelating agent such as EDTA was traced by two different assay methods; an electron spin resonance (ESR) spin-trapping method with 5,5-dimethyl-1-pyrroline N-oxide (DMPO), and high Performance liquid chromatography (HPLC)-fluorescence detection with terephthalic acid (TPA), a fluorescent probe for hydroxyl radicals. From the ESR spin-trapping measurement, it was observed that EDTA seemed to suppress hydroxyl radical formation with the increase of its concentration. On the other hand, hydroxyl radical formation by Fenton reaction was not affected by EDTA monitored by HPLC assay. Similar inconsistent effects of other iron-chelating agents such as nitrylotriacetic acid (NTA), diethylenetriamine penta acetic acid (DTPA), oxalate and citrate were also observed. On the addition of EDTA solution to the reaction mixture 10 min after the Fenton reaction started, when hydroxyl radical formation should have almost ceased but the ESR signal of DMPO-OH radicals could be detected, it was observed that the DMPO-OH signal disappeared rapidly. With the simultaneous addition of Fe(II) solution and EDTA after the Fenton reaction ceased, the DMPO-OH signal disappeared more rapidly. The results indicated that these chelating agents should enhance the quenching of [DMPO-OH] radicals by Fe(II), but they did not suppress Fenton reaction by forming chelates with iron ions.     

Free radical polymerization of glycidyl methacrylate in plasticized Poly(vinyl chloride)

Kinetic of free radical in-situ polymerization of glycidyl methacrylate (GMA), was studied in a complex evolutionary system: poly(vinyl chloride) (PVC) plastisols. A predictive model of conversion-time profile based on free radical mechanism was proposed and structure of the modified PVC system developed was investigated by NMR analyses. In order to elucidate the mechanism of the reaction, model molecules for PVC were used with NMR and MALDI-TOF characterization. It was found that in-situ polymerization of GMA in PVC plastisols leads to both homopolymerization and grafting of GMA onto PVC backbone by hydrogen abstraction. For 33 wt% GMA loaded, grafting efficiency is 67% with an amount of grafted poly-glycidyl methacrylate (pGMA) equals to 22 wt%. Thus, this article discloses a new type of PVC plastisols called reactive plastisols where, in addition to usual plasticizers, PVC is modified by polymerizable GMA monomer.     

The O-neophyl rearrangement of 1,1-diarylalkoxyl radicals. Experimental evidence for the formation of an intermediate 1-oxaspiro[2,5]octadienyl radical

A product study on the reactivity of a 1,1-diarylalkoxyl radical bearing 2,2-diphenylcyclopropyl groups in the para-positions has been carried out. The exclusive formation of a product deriving from cyclopropyl ring-opening has been observed, indicating that 1,1-diarylalkoxyl radicals exist in equilibrium with a bridged 1-oxaspiro[2,5]octadienyl radical. This represents the first experimental evidence in support of the stepwise nature of the O-neophyl rearrangement of 1,1-diarylalkoxyl radicals.     

Synthesis of the Tolerance-Inducing Oligosaccharide Lacto-N-Fucopentaose III Bearing an Activated Linker

A concise synthetic route to an immunomodulatory pentasaccharide, lacto-N-fucopentaose III (1) and its corresponding human serum albumin conjugate, is described. Key transformations of the strategy include two highly regio- and stereoselective glycosylations for the construction of disaccharide 10 and pentasaccharide 12, a Birch reduction for deprotection of benzyl ethers, and a UV-promoted radical addition of a thiol to an alkene for modification of the aglycone.     

Free radical and isomerisation processes during the electrochemical fluorination of n-butyryl chloride, i-butyryl chloride and pivaloyl chloride in anhydrous hydrogen fluoride

Electrochemical perfluorination (ECPF) of the title compounds containing primary, secondary and tertiary carbon atoms was carried out in anhydrous hydrofluoric acid (AHF). Detailed analysis of major and minor products suggest that carbon chain isomerisation involving cyclo-propane intermediate is more prevalent during ECPF of i-butyryl chloride when compared to n-butyryl chloride. Simple statistical probability involving free radical intermediates also support this observation. ECPF involving cyclo-propane intermediate is even more prevalent in pivaloyl chloride containing three methyl substituents. In this case, perfluorinated cyclo-propane intermediates were also observed in the product sample. Distribution of minor perfluorinated and partially fluorinated products also suggest the predominant role of normal free radical pathway involving single-electron transfer.     

Synthesis of highly substituted pyrroles via oxidative free radical reactions of β-aminocinnamates

Oxidative free radical reactions of β-aminocinnamates are described. Imine radicals produced by tetra-n-butylammonium cerium(IV) nitrate (TBACN) oxidation of enamines undergo efficient addition to the C-C double bond of β-aminocinnamates. This TBACN mediated free radical reaction between β-aminocinnamates and enamines provides a novel method for the synthesis of highly substituted pyrroles. The direct TBACN oxidation of β-aminocinnamates gave the dimerization products effectively.