Benzylic Radical Intermediate Research Articles

Nickel/Titanocene-Catalyzed Electrophilic Acylation Coupling of Styrene Oxides.

The cross-coupling of epoxides with acyl chlorides or anhydrides by a nickel/titanocene dual catalytic system is established. A variety of synthetically useful β-hydroxy ketones were obtained in good to high yields by using modified pyridine-oxazoline ligand. The reaction proceeds via the cooperation of titanocene-catalyzed ring-opening of epoxides and nickel-catalyzed acylation of the benzylic radical intermediate.

Iron-Catalyzed Intermolecular Amination of Benzylic C(sp3)-H Bonds.

A catalytic system for intermolecular benzylic C(sp3)-H amination is developed utilizing 1,2,3,4-tetrazole as a nitrene precursor via iron catalysis. This method enables direct installation of 2-aminopyridine into the benzylic and heterobenzylic position. The method selectively aminates 2° benzylic C(sp3)-H bond over the 3° and 1° benzylic C(sp3)-H bonds. Experimental studies reveal that the C(sp3)-H amination undergoes via the formation of a benzylic radical intermediate. This study reports the discovery of new method for 2-pyridine substituted benzylamine synthesis using inexpensive, biocompatible base metal catalysis that should have wide application in the context of medicinal chemistry and drug discovery.

Enantioselective Copper-Catalyzed Trifluoromethylation of Benzylic Radicals via Ring Opening of Cyclopropanols

Summary The asymmetric trifluoromethylation of aryl-substituted cyclopropanols via a radical ring-opening pathway is reported herein, which provides an easy and straightforward access to structurally diverse β-CF3 ketones in good yields and excellent enantioselectivities under very mild conditions. Critical to the success of the copper-catalyzed radical relay is that a benzylic radical intermediate can be enantioselectively trapped by reactive (L∗)CuIICF3. In addition, a novel quinolinyl-containing bisoxazoline ligand plays a significant role in the asymmetric trifluoromethylation.

Copper(I)-Catalyzed Enantioconvergent Borylation of Racemic Benzyl Chlorides Enabled by Quadrant-by-Quadrant Structure Modification of Chiral Bisphosphine Ligands.

The first copper(I)-catalyzed enantioselective borylation of racemic benzyl chlorides has been realized by a quadrant-by-quadrant structure modulation of QuinoxP*-type bisphosphine ligands. This reaction converts racemic mixtures of secondary benzyl chlorides into the corresponding chiral benzylboronates with high enantioselectivity (up to 92 % ee). The results of mechanistic studies suggest the formation of a benzylic radical intermediate. The results of DFT calculations indicate that the optimal bisphosphine-copper(I) catalyst engages in noncovalent interactions that efficiently recognize the radical intermediate, and leads to high levels of enantioselectivity.

Copper(I)‐Catalyzed Enantioconvergent Borylation of Racemic Benzyl Chlorides Enabled by Quadrant‐by‐Quadrant Structure Modification of Chiral Bisphosphine Ligands

AbstractThe first copper(I)‐catalyzed enantioselective borylation of racemic benzyl chlorides has been realized by a quadrant‐by‐quadrant structure modulation of QuinoxP*‐type bisphosphine ligands. This reaction converts racemic mixtures of secondary benzyl chlorides into the corresponding chiral benzylboronates with high enantioselectivity (up to 92 % ee). The results of mechanistic studies suggest the formation of a benzylic radical intermediate. The results of DFT calculations indicate that the optimal bisphosphine‐copper(I) catalyst engages in noncovalent interactions that efficiently recognize the radical intermediate, and leads to high levels of enantioselectivity.

Cu-catalyzed regio- and stereoselective sulfonylation of multi-substituted allenes

Regio- and stereoselective sulfonylation of allenes under Cu catalysis is described. Allenyl sp carbons exclusively react with TsCN to give the corresponding alkenyl sulfones. The reaction is initiated by addition of tosyl radical to form benzyl radical intermediates, which determines the reaction pathway. The structure of the products is highly dependent on the substituents on allenes.

Rhodium‐Catalyzed Enantioselective Radical Addition of CX4 Reagents to Olefins

AbstractWe describe the synthetically useful enantioselective addition of Br−CX3 (X=Cl or Br) to terminal olefins to introduce a trihalomethyl group and generate optically active secondary bromides. Computational and experimental evidence supports an asymmetric atom‐transfer radical addition (ATRA) mechanism in which the stereodetermining step involves outer‐sphere bromine abstraction from a [(bisphosphine)RhIIBrCl] complex by a benzylic radical intermediate. This mechanism appears unprecedented in asymmetric catalysis.

Rhodium-Catalyzed Enantioselective Radical Addition of CX4 Reagents to Olefins.

We describe the synthetically useful enantioselective addition of Br-CX3 (X=Cl or Br) to terminal olefins to introduce a trihalomethyl group and generate optically active secondary bromides. Computational and experimental evidence supports an asymmetric atom-transfer radical addition (ATRA) mechanism in which the stereodetermining step involves outer-sphere bromine abstraction from a [(bisphosphine)RhII BrCl] complex by a benzylic radical intermediate. This mechanism appears unprecedented in asymmetric catalysis.

Enantioselective Copper-Catalyzed Intermolecular Amino- and Azidocyanation of Alkenes in a Radical Process.

Asymmetric copper-catalyzed intermolecular amino- and azidocyanation reactions of alkenes have been developed that proceed via a radical process in which a key benzylic radical intermediate is enantioselectively trapped by a chiral Box/CuII cyanide complex. A variety of enantiomerically enriched β-amino/azido alkylnitriles were efficiently synthesized. The β-azido alkylnitriles could be converted into a series of highly valuable optically active amine-based building blocks and bioactive compounds.

Enantioselective Copper‐Catalyzed Intermolecular Amino‐ and Azidocyanation of Alkenes in a Radical Process

AbstractAsymmetric copper‐catalyzed intermolecular amino‐ and azidocyanation reactions of alkenes have been developed that proceed via a radical process in which a key benzylic radical intermediate is enantioselectively trapped by a chiral Box/CuII cyanide complex. A variety of enantiomerically enriched β‐amino/azido alkylnitriles were efficiently synthesized. The β‐azido alkylnitriles could be converted into a series of highly valuable optically active amine‐based building blocks and bioactive compounds.

Carbon–Carbon σ-Bond Transfer Hydrogenation with DMF Catalyzed by Cobalt Porphyrins

Cobalt porphyrins were found to catalyze the transfer hydrogenation of the carbon–carbon σ bond of [2.2]paracyclophane (PCP) with the solvent DMF serving as the hydrogenating agent. Successful trapping experiments with benzene solvent and the kinetic isotope effect (4.9) suggested the presence of benzyl radical intermediates in undergoing hydrogen atom transfer from DMF as the rate-limiting step. The rate law was established by initial rate measurements to be rate = kobs[CoII(ttp)][PCP].

Photoinduced HBr-catalyzed C–Si bond cleavage of benzylsilanes and their subsequent oxidation into benzoic acids with air as the terminal oxidant

A photoinduced highly efficient C–Si bond cleavage reaction of benzylsilanes under the catalysis of HBr was developed. The in situ generated benzyl radical intermediates were aerobically oxidized into benzoic acids highly chemoselectively.

Light-induced Free Radical Oxidation of 2-Oxo-1,2,3,4-tetrahydropyrimidines

A variety of 4-substituted 5-acetyl- and 5-carboethoxy-2-oxo-1,2,3,4-tetrahydropyrimidines were oxidized under UV irradiation in the presence or absence of benzoyl peroxide. The nature of the substituents on the 4- and 5-positions of the heterocyclic ring affects the rate of photo-oxidation, and irradiation of these compounds in the presence of benzoyl peroxide decreases the time of reaction drastically. Removal of 4-H by a benzoyloxy radical under formation of a trihydropyrimidinoyl radical intermediate occurs in the rate-determining step. The stability of this benzylic and allylic radical intermediate is affected by the nature and the position of the additional substituent on the phenyl group located at C-4.

Reduction of base-stabilized difluoroboranes to induce rearrangement reactions

Lewis base-stabilized difluoroboranes 2, 4-pyr and 4-iPr, having an oxazoline- or amine-tethered amide ligand, were synthesized and fully characterized. The treatment of 2 with KC8 led to its complete consumption, and the rearranged product 5-H, probably originating from C–O bond cleavage and B–O bond formation, could be isolated as a major Dip-containing product in 18% yield. From deuterium labelling experiments and diffusion control reactions, the formation of 5-H could be explained by a radical mechanism. The reduction of 4-pyr and 4-iPr using one-electron reducing agents also gave the rearranged products 13-pyr and 13-iPr in 21 and 19% yields, respectively, via C–N bond cleavage and B–N bond formation. The mechanism for the formation of 13-pyr and 13-iPr is suggested to contain a benzylic radical intermediate.

Mechanistic Insights into the Cytochrome P450‐Mediated Oxidation and Rearrangement of Littorine in Tropane Alkaloid Biosynthesis

During the biosynthesis of certain tropane alkaloids, littorine (1) is rearranged to hyoscyamine (3). Recent evidence indicates that this isomerisation is a two-step process in which the first step is an oxidation/rearrangement to give hyoscyamine aldehyde (2). This step is catalysed by CYP80F1, a cytochrome P450 enzyme, which was recently identified from the plant Hyoscyamus niger; CYP80F1 also catalyses the hydroxylation of littorine at the 3'-position. The mechanisms of the reactions catalysed by CYP80F1 were probed with synthetic deutero and arylfluoro analogues of 1. Measurement of the primary kinetic isotope effects indicates that C3' hydrogen abstraction is the rate-limiting step for the oxidation/rearrangement of natural littorine, and for the 3'-hydroxylation reaction of the unnatural S enantiomer of littorine. The character of the intermediates in the oxidation/rearrangement and hydroxylation reaction was probed with the use of arylfluorinated analogues of (R)-littorine (natural stereoisomer) and (S)-littorine (unnatural stereoisomer) as substrates for CYP80F1. The relative conversions of ortho-, meta- and para-fluorolittorine analogues were used to obtain information on the likely intermediacy of either a benzylic radical or benzylic carbocation intermediate. The data suggest that hydroxylation takes place via a benzylic carbocation intermediate, whereas the product profile arising from rearrangement is more consistent with a benzylic radical intermediate.

Polarizability and Spin Density Correlate with the Relative Anaerobic Biodegradability of Alkylaromatic Hydrocarbons

Polarizability ((alpha) and spin density (SD) of benzyl radical intermediates calculated using Gaussian O3 were correlated with the extent of anaerobic biodegradation for 17 C1 to C4 parent alkylbenzenes. The percent anaerobic biodegradation of the hydrocarbon series was determined in a previous study using an inoculum from a gas condensate-contaminated aquifer incubated under sulfate-reducing conditions. Many of the parent compounds are known to be biodegraded in the absence of oxygen by fumarate addition reactions. Percent biodegradation over a 100 day incubation (predicted) = -1.044 <alpha> + 908.271SD - 586.197 (R2 = 0.839; all p-values < or = 0.058). This correlation suggests that compounds forming more stable alkylbenzyl radical intermediates biodegrade by fumarate addition more slowly than their counterparts forming less stable radicals. More highly substituted molecules including isopropylbenzene, 1-ethyl-2,6-dimethylbenzene and 1-ethyl-3,4-dimethylbenzene did not fit the model. The assumption of biodegradation by fumarate addition reaction was independently verified with several substrates. These findings help form a basis for predicting the relative rate of alkylbenzene metabolism in anaerobic environments.

Pyrolytic cleavage mechanisms of lignin-ether linkages: A study on p-substituted dimers and trimers

Abstract Pyrolytic cleavage mechanisms of lignin-ether linkages were studied with some dimers and trimers which have various p-substituted Cα-phenoxy groups (-H, -OCH3, -Cl or -COCH3). Pyrolysis of these model compounds provides phenols and isoeugenol type products. To determine whether the reactions mechanisms are heterolytic or homolytic, the reactivities were compared based on Hammett's substituent constant (σ p ) and the ΔBDE parameter, namely the bond dissociation energy (BDE) reduction. The α-ether-linkages in phenolic forms are cleaved in a heterolytic mechanism, while in non-phenolic forms the α-ether linkages are cleaved homolytically. Cleavage of these α-ether linkages is the rate-determining step for the scission of the Cβ-O bond in trimers. The β-ether-linkages in the non-phenolic trimers are cleaved through the β-scission type reaction from the benzyl radical intermediates. On the other hand, quinone methide formation through heterolytic cleavage of the α-ether linkages is the key step for following homolysis of the Cβ-O bonds in the phenolic trimers. Electron attracting character of the quinone methide structure reduces the BDE of the Cβ-O bond.

Photo‐oxidative dealkylation of α‐alkylbenzyl methyl ethers induced by titanium dioxide in acetonitrile

AbstractTiO2‐sensitised photo‐oxidation of α‐alkylbenzyl methyl ethers in deaerated CH3CN gives the expected corresponding ketone, whereas in an aerated medium a dealkylation compound (methyl benzoate) is obtained as the principal product, with respect to the ketone, or the exclusive product (when the alkyl group is tert‐butyl). The product analysis and distribution, together with a qualitative estimate of the relative reactivity, suggest that the mechanism in deaerated CH3CN is the same as that previously hypothesized for non‐α‐alkylated benzyl ethers; in particular, the carbonyl compound should be formed through oxidation of the benzylic radical (obtained by deprotonation of the cation radical) to the corresponding cation. To justify the formation of methyl benzoate in an aerated medium, a reasonable hypothesis is that the α‐alkyl‐α‐methoxybenzylperoxy radical (obtained from the competitive attack of oxygen on the benzylic radical) undergoes a dealkylation process; in particular, this intermediate, as a tertiary peroxy radical, could form a dimer that evolves into the corresponding oxy radical, giving the ester through a β‐scission process. The general mechanism suggested in aerated medium was confirmed by evaluating the relationship between the ester/carbonyl (E/C) molar ratio and the adiabatic ionization potential of the benzylic radical intermediate. To evaluate the influence of medium heterogeneity, the E/C ratio data were compared with those obtained from an electron‐transfer photosensitised [by 9,10‐dicyanoanthracene (DCA)] oxidation in a homogeneous phase. A significant confirmation of the mechanism, in both deaerated and aerated media, was obtained by the reaction performed from 4‐methoxy‐α‐ethylbenzyl methyl ether (as a model) in the presence of H218O, sensitised by either TiO2 or DCA. Copyright © 2005 John Wiley &amp; Sons, Ltd.

DIRECT SYNTHESIS OF γ-BUTYROLACTONES VIA γ-PHENYL SUBTITUTED BUTYRIC ACIDS MEDIATED BENZYL RADICAL CYCLIZATION

Synthesis of several γ-butyrolactones with aromaticsubstitution at carbon 5 from comparative γ-aryl acids with 25–85%yield are covered. The straight oxidation in the presence of peroxydisulphate-copper(II)chloridesystem in aqueous medium was applied. The reaction is highly regioselectiveand leads exclusively to γ-butyrolactone, through stable benzylic radicalintermediate.

Reactivity and reaction pathways of alkylalkoxybenzene radical cations. Part 2. Effects of 2-alkyl substituents on the relative importance of deprotonation over de-tert-butylation of 2-alkyl-5-tert-butyl-1,4-dimethoxybenzene radical cations

The 2-alkyl-5-tert-butyl-1,4-dimethoxybenzene radical cations 1+·a–e (2-alkyl = Me, Et, i-Pr, c-PrCH2 and PhCH2) generated in one-electron oxidation of their parent compounds 1a–e by pentafluorobenzoyl peroxide or cerium(IV) sulfate were characterized by EPR spectrometry. The product analysis shows that under certain conditions 1+·a–e may collapse through two competitive pathways, i.e. deprotonation and de-tert-butylation. The deprotonation of 1+·a–e is further assured by EPR observations of the corresponding benzyl radical intermediates. The relative importance of the two pathways is greatly dependent on the structure of the alkyl substituents, the nature of the solvents and the reaction temperature. For deprotonation, the reactivity order is found to be c-PrCH2 >Me >PhCH2 >Et ≫ i-Pr. Copyright © 1999 John Wiley & Sons, Ltd.