Visible-light-promoted radical cyclisation of unactivated alkenes in benzimidazoles: synthesis of difluoromethyl- and aryldifluoromethyl-substituted polycyclic imidazoles

• Yujun Pang,
• Jinglan Yan,
• Nawaf Al-Maharik,
• Qian Zhang,
• Zeguo Fang and
• Dong Li

Beilstein J. Org. Chem. 2025, 21, 234–241, doi:10.3762/bjoc.21.15

• 2019, Gouverneur and co-workers reported a hydrodifluoromethylation of unactivated alkenes, wherein a CF2H radical was generated from CF2HCOOH using (diacetoxyiodo)benzene (PIDA) and light [21]. This CF2H radical then added to the double bond to form a new alkyl radical, which underwent hydrogen atom

• abstraction to yield the hydrodifluoromethylation product. Building upon this work, we hypothesized that if the newly formed alkyl radical could undergo intramolecular cyclization with an aromatic ring, instead of hydrogen abstraction, it could enable the construction of polycyclic structures. Thus, as part

Recent advances in electrochemical copper catalysis for modern organic synthesis

• Yemin Kim and
• Won Jun Jang

Beilstein J. Org. Chem. 2025, 21, 155–178, doi:10.3762/bjoc.21.9

• reacts with the alkene 97 to produce an alkyl radical 104, which undergoes ligand transfer from Cu(II)(N3)2 (102) to yield the diazidation product 99 and Cu(I)(N3) (100). The Cu(I)(N3) (100) is reoxidized to Cu(III)(N3)3 (101) on the anode in the presence of N3- to complete the catalytic cycle. In 2024

• radical, which adds to the alkene 97 to form carbon-centered radical intermediate 106 (Figure 17). The resulting alkyl radical intermediate 106 then reacts with the Cu(II)(CN)2 catalyst 109 to produce a Cu(III) species 107, which undergoes reductive elimination to deliver the desired product 105 and the

Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• reaction proceeds through an initial single-electron transfer from NFBS assisted by the active copper species, followed by intermolecular hydrogen-atom transfer from the carbazate. The nitrogen radical intermediate I thus formed is decomposed into the acyl or alkyl radical intermediates II and III

• , respectively. The latter interacts with the alkene generating an alkyl radical IV that converts to the cationic intermediate V by single-electron oxidation by the Cu(II) species. Finally, the attack of the nucleophile leads to the desired products 6. Starting from aryl carbazates, intermediate II, adds

• alkyltrifluoroborate into its corresponding alkyl radical. o-Halo-substituted aryl selenides and sulfides 13 can be achieved by a three-component coupling reaction performed with an aryne precursor, potassium halides and electrophilic chalcogen species as reactants, in the presence of Cu(OTf)2 (Scheme 10) [23]. Under

Giese-type alkylation of dehydroalanine derivatives via silane-mediated alkyl bromide activation

• Perry van der Heide,
• Michele Retini,
• Fabiola Fanini,
• Giovanni Piersanti,
• Francesco Secci,
• Daniele Mazzarella,
• Timothy Noël and
• Alberto Luridiana

Beilstein J. Org. Chem. 2024, 20, 3274–3280, doi:10.3762/bjoc.20.271

• derivatives. Upon abstraction of a hydride from tris(trimethylsilyl)silane (TTMS) by an excited benzophenone derivative, the formed silane radical can undergo a XAT with an alkyl bromide to generate an alkyl radical. Consequently, the alkyl radical undergoes a Giese-type reaction with the Dha derivative

• photocatalytic activation (Figure 1b) [17][18][19][20][21]. A photocatalytic HAT or SET generates the corresponding boryl, α-amino or silyl radical, which can abstract a halogen atom from alkyl halides to form the corresponding alkyl radical. However, the use of TTMS as a XAT reagent had already been established

• strategy to generate alkyl radicals and explored the feasibility of a Giese-type reaction (Figure 1c). More recently, Gaunt et al. [25] showed that irradiation of alkyl iodides combined with TTMS leads to the formation of an alkyl radical, which can be used in a Giese-type reaction without the need of a

Advances in radical peroxidation with hydroperoxides

• Oleg V. Bityukov,
• Pavel Yu. Serdyuchenko,
• Andrey S. Kirillov,
• Gennady I. Nikishin,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2024, 20, 2959–3006, doi:10.3762/bjoc.20.249

• generate the nucleophilic carbon radical B. The intramolecular 1,5-HAT of B provided the alkyl radical C, which then cross-coupled with the in situ-generated high-valent Mnn+1OO-t-Bu species to form the 1,6-difunctionalized product 42 via peroxy-ligand transfer. The remote trifluoromethylthiolation

• , which transforms into alkyl radical D via CO elimination. Radical D adds to the double bond of alkene 130, to form the C-centered radical E, which recombines with radical B to yield the target product 132. Later, the same authors reported a four-component radical coupling of two different alkenes 133

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• anodic oxidation cleaves the diazene, resulting in the formation of an acyl radical and the release of molecular nitrogen. The subsequent step involves the decarboxylation of the acyl radical to produce an alkyl radical. This method was successfully applied to the late-stage functionalization of

• undergoes hydrogen-atom transfer (HAT) leading to alkyl radical formation. The manganese-catalyzed azide radical transfer then delivers the product. Unactivated secondary and tertiary C–H bonds, as well as benzylic C–H bonds, were prone to azidation, with the reactivity order being: benzylic > tertiary

• form a cyclic alkyl radical. The alkyl radical is further oxidized by [Co(III)] to produce the target amination product and a [Co(II)–H] species via direct hydrogen transfer or β-hydride elimination. Deprotonation of [Co(II)–H] by MeO− regenerates the [Co(I)] complex, which is subsequently oxidized

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• generated from Togni’s reagent (145) to a double bond of the δ-alkenylamine, followed by intramolecular hydrogen atom transfer and a single-electron oxidation of the intermediate alkyl radical to form an imine that is then reduced by hydrogen donor 147 catalysed by CPA (R)-VAPOL (148). The

Efficacy of radical reactions of isocyanides with heteroatom radicals in organic synthesis

• Akiya Ogawa and
• Yuki Yamamoto

Beilstein J. Org. Chem. 2024, 20, 2114–2128, doi:10.3762/bjoc.20.182

• substituents on the heteroatom. For this reason, the 1,1-addition is less likely to proceed as with group 16 or 15 heteroatom radicals. In the case of stannyl and silyl radicals, the alkyl group of the isocyanide is eliminated as an alkyl radical from the imidoyl radical intermediate 2 [42]. The formed alkyl

• radicals abstract hydrogen from the tin hydride or hydrosilane, and the reduction reaction proceeds with the concomitant formation of stannyl or silyl cyanide 15 as byproducts (Scheme 9a) [38][43]. In the presence of acrylonitrile, the formed alkyl radical can add to acrylonitrile, affording the addition

Electrophotochemical metal-catalyzed synthesis of alkylnitriles from simple aliphatic carboxylic acids

• Yukang Wang,
• Yan Yao and
• Niankai Fu

Beilstein J. Org. Chem. 2024, 20, 1497–1503, doi:10.3762/bjoc.20.133

• then extrude CO2 to generate the alkyl radical. Concurrently, Cu(II)–CN species are produced in the presence of cyanide anion through anodic oxidation. At this stage, Cu(II)–CN species are believed to capture alkyl radicals and the product would be readily generated via reductive elimination from the

Generation of alkyl and acyl radicals by visible-light photoredox catalysis: direct activation of C–O bonds in organic transformations

• Mithu Roy,
• Bitan Sardar,
• Itu Mallick and
• Dipankar Srimani

Beilstein J. Org. Chem. 2024, 20, 1348–1375, doi:10.3762/bjoc.20.119

• photocatalysts, transition-metal photoredox catalysts, and metallaphotocatalysts to produce acyl and alkyl radicals driven by visible light. Keywords: acyl radical; alkyl radical; sustainable catalysis; visible light; Introduction The growing awareness of the necessity for sustainable developments has been

• acyl radical. This acyl radical eventually leads to the formation of expected product. Reactions involving alkyl radical obtained via C–O bond cleavage C–O bond activation of prefunctionalized alcohols Alkyl radicals play a crucial role as intermediates in various chemical transformations involving C–H

• ][40][41][42]. However, these protocols have a limited scope and suffer from prefunctionalization and waste generation. Photons are considered the greenest reagent in organic synthesis. Thus, photomediated alkyl radical generation from easily accessible alcohols for organic synthesis is highly

Transition-metal-catalyst-free electroreductive alkene hydroarylation with aryl halides under visible-light irradiation

• Kosuke Yamamoto,
• Kazuhisa Arita,
• Masami Kuriyama and
• Osamu Onomura

Beilstein J. Org. Chem. 2024, 20, 1327–1333, doi:10.3762/bjoc.20.116

• alkene 2 to provide alkyl radical species B. Further single-electron reduction by 1,3-DCB•− or at the cathode followed by protonation of B provides hydroarylation product 3. Meanwhile, the sacrificial anode is oxidized to form Al cations. Although the exact role of visible-light irradiation in the

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• alkyl radical 12 is captured by intermediate 122, resulting in the formation of complex 123. At this point, the metal center has undergone a two-electron oxidation, making it well-suited for reductive elimination yielding the cross-coupling product 124. Under these catalytic conditions, various TM

• ester 10, regenerating pyridine 137 while forming alkyl radical 12, CO2 and phthalimide–B(pin) adduct 139. Subsequently, radical–radical coupling between 12 and one equivalent of 138 affords dihydropyridine 140, which upon re-aromatization, facilitated by ZnCl2 acting as a Lewis acid, yields product 141

• ] (Scheme 33A). The mechanism of this redox neutral reaction involves reductive fragmentation of the radical precursor 3 mediated by the cathode under constant-current electrolysis (Scheme 33B). The resulting alkyl radical 9 attacks the protonated quinoline 168, forming radical cation intermediate 169

Additive-controlled chemoselective inter-/intramolecular hydroamination via electrochemical PCET process

• Kazuhiro Okamoto,
• Naoki Shida and
• Mahito Atobe

Beilstein J. Org. Chem. 2024, 20, 264–271, doi:10.3762/bjoc.20.27

• this case, intramolecular radical trapping by the uracil nucleobase was preferred, leading to the formation of the cyclized alkyl radical D. Continuous radical recombination furnished dimer 4. Conclusion We observed additive-controlled inter- and intramolecular chemoselectivity in the hydroamination of

Recent advancements in iodide/phosphine-mediated photoredox radical reactions

• Tinglan Liu,
• Yu Zhou,
• Junhong Tang and
• Chengming Wang

Beilstein J. Org. Chem. 2023, 19, 1785–1803, doi:10.3762/bjoc.19.131

• smoothly delivered an electron donor–acceptor (EDA) complex II via coulombic interactions. Upon 456 nm blue LED light irradiation, the EDA complex II underwent a single electron transfer (SET) process, followed by subsequent decarboxylation to produce the alkyl radical intermediate A, accompanied by

• transformations, as depicted in Scheme 14. The dual-catalytic cycle comprised a photocatalytic cycle and a copper catalytic cycle, interconnected through an intermolecular single-electron transfer. Within the context of the photocatalytic cycle, the generation of the C(sp3)-centered alkyl radical A was

• depicted in Scheme 16. Initially, a photoactive EDA complex II was transiently formed through the combined action of NaI, PPh3, and the γ,σ-unsaturated phthalimide 33a. Upon irradiation with blue LEDs, the alkyl radical A was generated through a single-electron transfer from the iodide anion to the γ,σ

α-(Aminomethyl)acrylates as acceptors in radical–polar crossover 1,4-additions of dialkylzincs: insights into enolate formation and trapping

• Angel Palillero-Cisneros,
• Paola G. Gordillo-Guerra,
• Fernando García-Alvarez,
• Olivier Jackowski,
• Franck Ferreira,
• Fabrice Chemla,
• Joel L. Terán and
• Alejandro Perez-Luna

Beilstein J. Org. Chem. 2023, 19, 1443–1451, doi:10.3762/bjoc.19.103

• that α-(aminomethyl)acrylates are suitable acceptors for 1,4-additions of dialkylzincs in aerobic conditions. The air-promoted radical–polar crossover process involves the 1,4-addition of an alkyl radical followed by homolytic substitution at the zinc atom of dialkylzinc. Coordination of the nitrogen

Application of N-heterocyclic carbene–Cu(I) complexes as catalysts in organic synthesis: a review

• Nosheen Beig,
• Varsha Goyal and
• Raj K. Bansal

Beilstein J. Org. Chem. 2023, 19, 1408–1442, doi:10.3762/bjoc.19.102

• primary, secondary, and tertiary alkyl halides. The mechanistic investigation revealed the generation of a silyl–copper intermediate which activates the alkyl halides by a single electron transfer to form alkyl radical intermediates [54]. It was suggested that substituting B2pin2 for PhMe2Si-Bpin would

Visible-light-induced nickel-catalyzed α-hydroxytrifluoroethylation of alkyl carboxylic acids: Access to trifluoromethyl alkyl acyloins

• Feng Chen,
• Xiu-Hua Xu,
• Zeng-Hao Chen,
• Yue Chen and
• Feng-Ling Qing

Beilstein J. Org. Chem. 2023, 19, 1372–1378, doi:10.3762/bjoc.19.98

• pivalic anhydride as activator to afford Ni(II) intermediate F. Subsequently, trapping of the alkyl radical C generates high-valent Ni(III) intermediate G, which undergoes facile reductive elimination to furnish the final coupling product 3 and Ni(I) intermediate H. The single-electron transfer (SET

Radical ligand transfer: a general strategy for radical functionalization

• David T. Nemoto Jr,
• Kang-Jie Bian,
• Shih-Chieh Kao and
• Julian G. West

Beilstein J. Org. Chem. 2023, 19, 1225–1233, doi:10.3762/bjoc.19.90

• amenable to all radical generation approaches/substrate classes nor can they form all desired bonds from alkyl radical intermediates, limiting the toolkit of radical reactions. Recently, radical ligand transfer (RLT) [9][10][11] has emerged as a radical functionalization paradigm with the potential to

• alkyl C–H bond to a high valent iron oxo species, resulting in formation of iron hydroxo and alkyl radical intermediates [15]. Subsequent RLT of the hydroxo ligand to the alkyl radical produces a hydroxylated product, allowing for metabolism and excretion of previously diverse bioactive compounds

• charge transfer (LMCT) which, following cage escape, could add to the alkene to generate an alkyl radical. This alkyl radical could then be chlorinated via RLT from a second Cu(II) chloride species, furnishing the dichlorinated product. While copper was unable to be used catalytically in this early

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

• mechanism follows a ‘monophotonic’ oxidative quenching (OQ) route in which [FeIII(btz)3]3+ is oxidatively quenched to [FeIV(btz)3]4+ by the alkyl halide substrate after excitation with green light. After addition of the alkyl radical to the alkene or alkyne substrate, the catalyst is regenerated by

• strongly reducing 3MLCT excited state (*E1/2 = −1.6 V to −1.8 V vs Fc), which then induces SET to the alkyl halide generating an alkyl radical via cleavage of the C(sp3)–X bond. The authors propose that this radical then engages in a radical chain propagation pathway leading to product 30 and a new alkyl

• reducing enough to engage the model substrate perfluorooctyl iodide and instead *[FeII(btz)3]2+ was verified as the key catalytic species by transient absorption spectroscopy; even though the strongly reducing α-amino alkyl radical intermediate might also engage in the reduction of alkyl halides or act as

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

• of an alkyl halide to a carbonyl group, implementation of the Barbier-type ring closure relied thus on the preliminary introduction of both aldehyde and alkyl halide functional groups on a suitable substrate. The mechanism was first thought to involve the coupling of an alkyl radical and a ketyl

NaI/PPh₃-catalyzed visible-light-mediated decarboxylative radical cascade cyclization of N-arylacrylamides for the efficient synthesis of quaternary oxindoles

• Dan Liu,
• Yue Zhao and
• Frederic W. Patureau

Beilstein J. Org. Chem. 2023, 19, 57–65, doi:10.3762/bjoc.19.5

• reported a Ru(bpy)3Cl2-catalyzed synthesis of N-Boc proline oxindole derivatives under visible-light assistance [47]. Therein, N-hydroxyphthalimide (NPhth) esters were utilized as alkyl radical precursors, which can be readily prepared from highly available carboxylic acids. In 2015, Cheng and co-workers

• -membered ring structure 3ra could be successfully isolated with a good yield (66%). A number of alkyl radical precursors were then synthesized and evaluated in the reaction (Scheme 3). We found that redox-active esters derived from primary, secondary, and tertiary aliphatic carboxylic acids were all

• ][10][11][12][13]. Selected photocatalytic decarboxylative radical cascade reactions of N-arylamides. Arylamide substrate scope with isolated yields of products. Alkyl radical precursor scope with isolated yields of products. Selected mechanistic experiments. Optimization tablea. Supporting

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• -coupling involving aldehyde C–H bond cleavage. DABCO-derived cationic catalysts in inactivated C–H bond cleavage for alkyl radical addition to electron-deficient alkenes under photoredox catalysis conditions. Electrochemical diamination and dioxygenation of vinylarenes catalyzed by triarylamines

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

• of the alkyl radical generating the cross-coupled product cannot be ruled out [57][60]. In 2020, Gutierrez and co-workers developed a Fe-catalyzed intra- and intermolecular difunctionalization of vinyl cyclopropanes 14 with alkyl bromides 13 and aryl Grignard reagents 2 (Scheme 4) [61]. Using

• sterically hindered tertiary alkyl bromides, the authors were able to favor intermolecular radical addition of the generated alkyl radical 17 to the vinylcyclopropane, outcompeting radical rebound to an aryl Fe species. The incipient radical can then undergo ring-opening of the cyclopropane 18. Work by

• radical 28 (Scheme 5). Regioselective Giese addition to the π-system 21 would generate the transient 2° alkyl radical 29. Due to the high energetic barrier associated with direct cross-coupling between sterically hindered 3° alkyl radicals and aryliron complexes, it is assumed the persistent aryliron

Visible-light-mediated copper photocatalysis for organic syntheses

• Yajing Zhang,
• Qian Wang,
• Zongsheng Yan,
• Donglai Ma and
• Yuguang Zheng

Beilstein J. Org. Chem. 2021, 17, 2520–2542, doi:10.3762/bjoc.17.169

• generate a trifluoromethyl radical and LnCuIISO2Cl (intermediate A in Scheme 8). The formed trifluoromethyl radical adds to the alkene moiety to deliver a new alkyl radical, which is trapped by the LnCuII-SO2Cl species. Free SO2Cl– decomposes rapidly to SO2 and Cl–. However, in this transformation, SO2Cl

• – is stabilized by the copper complex. The alkyl radical reacts with LnCuII-SO2Cl to deliver the target product 5. A mechanistic study demonstrated that [Cu(dap)2]Cl can coordinate with the reactive intermediate SO2Cl and suppresses the extrusion of SO2. Thus, [Cu(dap)2]Cl achieves a unique

• to its triplet state CuICN*, in which the fluoroalkyl iodides were reduced to Rf• and I−. Subsequently, the radical Rf• attacks the alkene forming a new alkyl radical species. This radical species is then trapped by CuII(CN)n to generate a CuIII intermediate, which undergoes reductive elimination to

Photoredox catalysis in nickel-catalyzed C–H functionalization

• Lusina Mantry,
• Rajaram Maayuri,
• Vikash Kumar and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2021, 17, 2209–2259, doi:10.3762/bjoc.17.143

• oxidation of 4-V by the photoexcited iridium(III) photocatalyst 4-II results in the nickel(III) species 4-VI. Photolysis of 4-VI generates a chloride radical, which rapidly abstracts the α-oxy C(sp3)−H of the ether to provide the alkyl radical species. The alkyl radical rebound to 4-VIII produces the nickel

• ) species 6-VI generated from the nickel(II) pre-catalyst by a SET process, captures the alkyl radical 6-IV to furnish the nickel(I)–alkyl species 6-VII. Subsequently, the nickel(I)–alkyl species 6-VII undergoes oxidative addition into aryl bromide 3b followed by a reductive elimination to provide the

• ) photocatalyst 10-III. The active iridium(III) photocatalyst 10-I is regenerated by a SET process between 10-III and the nickel(I) species 10-X. The addition of the tertiary radical 10-IV to the terminal alkyne 34 followed by an intramolecular 1,5-HAT results in a nucleophilic secondary alkyl radical species 10