Radical Cyclization Reactions Research Articles

Silver‐Catalyzed Decarboxylative Radical Cyclizations: Developments and Insights

Transition‐metal‐catalyzed decarboxylative cross‐coupling reaction provides a powerful method for the construction C‐C, C‐N, C‐O bonds, which have great impact on synthetic chemistry. The use of silver salts as catalyst in decarboxylative reaction gradually increases because of their easy availability, low toxicity, biocompatibility and adequate stability. In fact, various radical cyclization reactions have been accomplished by exploiting single electron transfer (SET) ability of silver salts. The present review highlights recent advances (2015‐mid 2023) in the silver‐catalyzed decarboxylative radical cyclizations for the construction of cyclic molecular scaffolds. The content of the review is organized on the basis of decarboxylative reagents, such as, α‐keto acids, aliphatic/aromatic carboxylic acids, α,α‐difluoroacetic acids, amino acids, alkynyl carboxylic acids, oxamic acids and miscellaneous acids. Additionally, mechanistic insights of most of the reactions are highlighted for well understanding of the reaction mode.

Radicals as Chiral Catalysts for Asymmetric Radical Cyclization Reactions

Radicals as Chiral Catalysts for Asymmetric Radical Cyclization Reactions

Boryl Radical as a Catalyst in Enabling Intra- and Intermolecular Cascade Radical Cyclization Reactions: Construction of Polycyclic Molecules.

Cascade radical cyclization constitutes an atom- and step-economic route for rapid assembly of polycyclic molecular skeletons. Although an array of redox-active metal catalysts has recently shown robust applications in enabling various catalytic cascade radical processes, the use of free organic radical as the catalyst, which is capable of triggering strategically distinct cascades, has rarely been developed. Here, we disclosed that the benzimidazolium-based N-heterocyclic carbene (NHC)-boryl radical is capable of catalyzing cascade cyclization reactions in both intra- and intermolecular pathways, assembling [5,5] fused bicyclic and [6,6,6] fused tricyclic molecules, respectively. The catalytic reactions start with the chemo- and regioselective addition of the boryl radical catalyst to a tethered alkene or alkyne moiety, followed by either an intramolecular formal [3+2] or an intermolecular [2+2+2] cycloaddition process to construct bicyclo[3.3.0]octane or tetrahydrophenanthridine skeletons, respectively. Eventually, a β-elimination occurs to release the boryl radical catalyst, completing a catalytic cycle. High to excellent diastereoselectivity is achieved in both catalytic reactions under substrate control.

Boryl Radical as a Catalyst in Enabling Intra‐ and Intermolecular Cascade Radical Cyclization Reactions: Construction of Polycyclic Molecules

AbstractCascade radical cyclization constitutes an atom‐ and step‐economic route for rapid assembly of polycyclic molecular skeletons. Although an array of redox‐active metal catalysts has recently shown robust applications in enabling various catalytic cascade radical processes, the use of free organic radical as the catalyst, which is capable of triggering strategically distinct cascades, has rarely been developed. Here, we disclosed that the benzimidazolium‐based N‐heterocyclic carbene (NHC)‐boryl radical is capable of catalyzing cascade cyclization reactions in both intra‐ and intermolecular pathways, assembling [5,5] fused bicyclic and [6,6,6] fused tricyclic molecules, respectively. The catalytic reactions start with the chemo‐ and regioselective addition of the boryl radical catalyst to a tethered alkene or alkyne moiety, followed by either an intramolecular formal [3+2] or an intermolecular [2+2+2] cycloaddition process to construct bicyclo[3.3.0]octane or tetrahydrophenanthridine skeletons, respectively. Eventually, a β‐elimination occurs to release the boryl radical catalyst, completing a catalytic cycle. High to excellent diastereoselectivity is achieved in both catalytic reactions under substrate control.

Visible-Light-Triggered Difluoroacetylation/Cyclization of Chromone-Tethered Alkenes Enabling Synthesis of Tetrahydroxanthones.

Hydroxanthones have attracted considerable attention due to their significance in organic and biological chemistry, yet their synthesis remains a great challenge. In this study, a series of chromone-tethered alkenes are designed, and a radical cyclization reaction of these chromone derivatives has been achieved under photoredox conditions. The reaction uses bromodifluoroacetamides or bromodifluoroacetates as coupling partners, affording a broad range of functionalized tetrahydroxanthone products with up to 85% yields. The reaction is triggered via the generation of difluoroacetate radicals or alkene radical cations with fac-Ir(ppy)3 or 2,3,5,6-tetrakis(carbazol-9-yl)-1,4-dicyanobenzene as a photocatalyst. This approach offers access to various tetrahydroxanthone derivatives from readily available starting materials and enriches the research content of heteroarene-tethered alkenes.

Synthesis of the Cyclopentane Core Skeleton of Cranomycin and Jogyamycin.

Cranomycin and jogyamycin, two aminocyclopentitol natural products, possess complex structures and potential medicinal properties. This review describes synthetic studies about the process of making an advanced intermediate of cranomycin and jogyamycin. This highly functionalized intermediate, featuring three contiguous amine-substituted stereocenters, was constructed from cyclopentadiene through a series of reactions including the nitroso Diels-Alder reaction, nitrogen radical cyclization reaction, 1,2-nitrogen migration, and stereoselective nitrogen addition.

Divergent total synthesis of sesquiterpene (hydro)quinone meroterpenoids dysideanones A and E–G

The first total synthesis of marine sesquiterpene (hydro)quinone meroterpenoids dysideanones A and E–G (1 and 4–6) has been accomplished in an enantioselective and divergent way. The sesquiterpene fragment and the aromatic moiety were efficiently connected via a site-selective and diastereoselective intermolecular alkylation of Wieland–Miescher ketone derivative 9 and benzyl bromide 10. The core 6/6/6/6-fused backbone of dysideanones was efficiently constructed through an intramolecular radical cyclization reaction. Dysideanone G (6) was easily prepared on a gram-scale and dysideanones A, E, and F (1, 4, and 5) were divergently transformed from dysideanone G (6) in one or two steps

Photocatalytic Site‐Selective Cascade Radical Addition of Biaryl Ynones for the Construction of Spiro‐ and Fused Carbon Rings

Comprehensive SummaryFunctionalized free radical addition/cyclization reactions represent an efficient way for introducing new functionality or coupling fragments to molecules. Ynones are good regional selectivity radical acceptors in organic synthesis, and many of bio‐relevant cyclic compounds could be easily obtained by direct radical cyclization reaction. Here, we report a photocatalytic cascade radical addition of biaryl ynones, for the divergent synthesis of privileged carbon cycles. Additionally, further transformation of the multi‐functional group product into a variety of other derivatives demonstrates the synthetic value of this developed method.

Visible light-induced radical cyclization of o-alkenyl aromatic isocyanides with thioethers: direct synthesis of 2-thioquinolines

A novel visible-light-induced regioselective radical cyclization reaction of isocyanides with thioethers has been developed. This reaction provides an efficient method for the construction of highly functionalized quinolines in a single step.

Visible-light-induced synthesis of 2,4-disubstituted quinolines from o-vinylaryl isocyanides and oxime esters.

A visible-light-induced radical cyclization reaction of o-vinylaryl isocyanides and oxime esters to access various 2,4-disubstituted quinolines was disclosed. Oxime esters were employed as acyl radical precursors via the carbon-carbon bond cleavage. It provided an effective way for the synthesis of 2-acyl-4-arlysubstituted quinolines under mild conditions and exhibited good functional group tolerance and substrate applicability.

Photoredox radical cyclization reaction of o-vinylaryl isocyanides with acyl chlorides to access 2,4-disubstituted quinolines.

We herein report an efficient photoredox radical cyclization reaction of o-vinylaryl isocyanides with acyl chlorides to access a wide range of 2,4-disubstituted quinolines. Preliminary mechanism experiment results suggested that this reaction was initiated by an acyl radical generated from acyl chlorides through a single-electron-transfer (SET) process. This transformation showed good substrate suitability and functional group compatibility at room temperature.

Visible-light-promoted cyclization of 3-indolylallylamides enabling synthesis of tetrahydrocarbolinones

A novel visible-light promoted radical cyclization reaction of 3-indolylallylamides with sulfonyl chlorides as coupling partners has been described, which provides a unique approach toward the synthesis of functionalized tetrahydrocarbolinones. This reaction involves the reduction of sulfonyl chlorides to sulfonyl radicals, addition of sulfonyl radicals to alkenyl moiety, and following cycloaddition to indolyl at the C2 position. This photocatalytic reaction tolerates a broad range of aryl and alkyl sulfonyl chlorides with diverse functional groups, which provides a direct and operationally simple protocol to construct functionalized tetrahydrocarbolinones.

Photochemically Induced Hydrogen Atom Transfer and Intramolecular Radical Cyclization Reactions with Oxazolones.

Photochemically induced intramolecular hydrogen atom transfer in oxazolones is reported. An acetal or thioacetal function at the side chain acts as a hydrogen donor while the photochemical exited oxazolone is the acceptor. A one-step process─the electron and the proton are simultaneously transferred─is productive, while electron transfer followed by proton transfer is inefficient. Radical combination then takes place, leading to the formation of a C-C or C-N bond. The regioselectivity of the reaction is explained by the diradical/zwitterion dichotomy of radical intermediates at the singlet state. In the present case, the zwitterion structure plays a central role, and intramolecular electron transfer favors spin-orbit coupling and thus the intersystem crossing to the singlet state. The reaction of corresponding thioacetal derivatives is less efficient. In this case, photochemical electron transfer is competitive. The photoproducts resulting from C-C bond formation easily undergo stepwise thermal decarboxylation in which zwitterionic and polar transition states are involved. A computational study of this step has also been performed.

Non‐native Intramolecular Radical Cyclization Catalyzed by a B12‐Dependent Enzyme**

AbstractDespite the unique reactivity of vitamin B12 and its derivatives, B12‐dependent enzymes remain underutilized in biocatalysis. In this study, we repurposed the B12‐dependent transcription factor CarH to enable non‐native radical cyclization reactions. An engineered variant of this enzyme, CarH*, catalyzes the formation γ‐ and δ‐lactams through either redox‐neutral or reductive ring closure with marked enhancement of reactivity and selectivity relative to the free B12 cofactor. CarH* also catalyzes an unusual spirocyclization by dearomatization of pendant arenes to produce bicyclic 1,3‐diene products instead of 1,4‐dienes provided by existing methods. These results and associated mechanistic studies highlight the importance of protein scaffolds for controlling the reactivity of B12 and expanding the synthetic utility of B12‐dependent enzymes.

Non-native Intramolecular Radical Cyclization Catalyzed by a B12 -Dependent Enzyme.

Despite the unique reactivity of vitamin B12 and its derivatives, B12 -dependent enzymes remain underutilized in biocatalysis. In this study, we repurposed the B12 -dependent transcription factor CarH to enable non-native radical cyclization reactions. An engineered variant of this enzyme, CarH*, catalyzes the formation γ- and δ-lactams through either redox-neutral or reductive ring closure with marked enhancement of reactivity and selectivity relative to the free B12 cofactor. CarH* also catalyzes an unusual spirocyclization by dearomatization of pendant arenes to produce bicyclic 1,3-diene products instead of 1,4-dienes provided by existing methods. These results and associated mechanistic studies highlight the importance of protein scaffolds for controlling the reactivity of B12 and expanding the synthetic utility of B12 -dependent enzymes.

Redox-Neutral Radical Cascade Cyclization of N-Arylacrylamides with Unactivated Alkyl and Aryl Chlorides.

Herein, we report the first metal-free, redox-neutral strategy for radical cascade alkylative radical addition, cyclization of N-arylacrylamides with unactivated alkyl chlorides to give corresponding 3,3-disubstituted oxindoles in moderate to good yields. This transformation's salient features are the utilization of an organo photocatalyst, mild reaction conditions, and broad substrate scope. Moreover, this methodology is suitable for hetero cycle derived acrylamides and further allowed to utilize aryl chlorides for radical cyclization reaction. Finally, DFT studies allow us to shed light on the reaction mechanism.

Regioselective electrochemical oxidative radical ortho-(4 + 2)/ipso-(3 + 2) cyclization

Achieving regioselectivity in radical cyclization reactions is of central importance, yet extremely challenging. Although Baldwin's rules provided guidance on the addition of radical species with alkenes/alkynes, the ortho-/ipso-selectivity of the cyclic reaction between radical species (especially alkyl and alkenyl radical) and aryl groups is still ambiguous. Herein, we develop an electrochemically enabled regioselective ortho-(4 + 2)/ipso-(3 + 2) cyclization of alkyl/alkenyl radicals with aryl groups, which provides a series of tetrahydronaphthalene and spirocarbocycle derivatives, exhibiting a broad substrate scope and functional group tolerance. Alkyl/alkenyl radicals are generated by Cp2Fe-mediated electrochemical oxidative radical addition of benzylic malonates with alkenes and alkynes. The method avoids the use of chemical oxidant/base/noble metal, the pre-functionalization of substrates, and the over-oxidation of compounds. Theoretical studies reveal that the dominant factor promoting the alkene-preferred ortho-addition is the favorable interaction energy; the alkyne-preferred ipso-addition regioselectivity is controlled by the distortion energy. Notably, this strategy is regarded as an important supplement to Baldwin's rules for radical cyclization.

Synthesis of O-Heterocycle Spiro-Fused Cyclopentaquinolinones and Cyclopentaindenes through Visible Light-Induced Radical Cyclization Reactions.

Presented herein is an effective and sustainable synthesis of O-heterocycle spiro-fused cyclopentaquinolinone and cyclopentaindene derivatives through light-driven cascade reactions of N-(o-ethynylaryl)acrylamides or 2-(2-(phenylethynyl)benzyl)acrylate with various O-heterocycles. Experimental mechanistic studies revealed that these reactions are initiated by visible light-induced radical formation from O-heterocycle and its regioselective addition onto the acrylamide or acrylate moiety followed by 6-exo-dig and 5-endo-trig cascade radical annulation, which is terminated by single electron oxidation and proton elimination. Compared with previously reported synthetic methods for similar purposes, this newly developed protocol has advantages such as a broad substrate scope, extremely mild reaction conditions, excellent atom-economy, high efficiency, and good compatibility with diverse functional groups. With all of these merits, this method is expected to find wide applications in the related research arena.

NHC-Catalyzed Regioselective Intramolecular Radical Cyclization Reaction for the Synthesis of Benzazepine Derivatives.

A novel and efficient strategy for the synthesis of a series of structurally interesting benzazepine derivatives via an N-heterocyclic carbene-catalyzed regioselective intramolecular radical cyclization has been developed. This protocol features good regioselectivity, good functional-group compatibility, and wide substrate scope, providing a transition-metal- and oxidant-free pathway to access the seven-membered rings under mild reaction conditions. Additionally, further transformation of benzazepines and a large-scale experiment were also conducted.

Unique solvent effect of water in radical cyclization reaction

The radical cyclization reaction in the aqueous environment by Yorimitsu et al. is revisited using the RISM-SCF-cSED method, a hybrid of quantum chemistry and statistical mechanics theory for molecular liquids. The difference between the barrier height of the forward reaction from the intermediate E-rot, the cyclization step, and that of the backward reaction is crucial to the reaction yield. Considering the effect of hydrogen bonding through the RISM theory, we found that the barrier height for the forward reaction is lower, especially in water. In other words, considering microscopic solvation effects clearly shows the difference between water and DMSO solvents, explaining the remarkable acceleration of the reaction in the aqueous environment.