Radical chemistry in polymer science: an overview and recent advances

• Zixiao Wang,
• Feichen Cui,
• Yang Sui and
• Jiajun Yan

Beilstein J. Org. Chem. 2023, 19, 1580–1603, doi:10.3762/bjoc.19.116

• used in post-polymerization modification, including chemical crosslinking of polymers and polymer surface modification. Radicals are powerful tools for post-polymerization processes because of their exceptional reactivity. In contrast to the previous sections, we set the topic of section 4 on the

• based on the radical polymerization of catechol derivatives. Catechols are known as easily oxidizable compounds and are prone to undergo oxidation by losing one or two electrons [3]. This way, either semiquinone radicals or o-quinones are formed by single or double-electron oxidation, respectively [4

• ]. The semiquinone radicals formed during the oxidation of catechol can undergo a cross-coupling reaction to form polymers (Scheme 1). One example is the radical polymerization of urushiol. The earliest recorded application of natural radical polymerization can be traced back to the manufacture of

Synthesis of 5-arylidenerhodanines in L-proline-based deep eutectic solvent

• Stéphanie Hesse

Beilstein J. Org. Chem. 2023, 19, 1537–1544, doi:10.3762/bjoc.19.110

• recycled for several runs [20]. As some benzylidenerhodanine derivatives were already reported for their antioxidant activities [3], we investigated those compounds for their antioxidant activity expressed as percentage of 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) scavenging activity. DPPH free radicals

• solution of the corresponding synthesized compound (1.5 mL, 0.2 mM) was added to a DMSO solution of DPPH radicals (1.5 mL, 0.2 mM), so that the final concentration of DPPH radical and the synthesized compound in a solution was 0.1 mM. The mixture was shaken and allowed to stand at room temperature. After

N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• Scheme 31. Initially, homolytic cleavage of thiosulfonate 70 generated PhS· and PhSO2· radicals. The reduction of Ni(II) to Ni(0) in the presence of Cs2CO3 and the reaction with 68 formed alkynyl-Ni species I. Then, the PhS· radical reacted with I to generate alkenyl radical II, which can react with the

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

• alkylidenemalonates [9][10][11]. These reactions follow a free-radical chain process wherein alkyl radicals (R•) add across the C–C double bond of the 1,4-acceptor, activated by complexation with the dialkylzinc, to deliver an enoxyl radical that undergoes homolytic substitution at zinc (SH2) to produce a zinc

• radicals (Scheme 1, R1 = H) undergo readily homolytic substitution. By contrast, tertiary α-carbonyl radicals (Scheme 1, R1 ≠ H) are less prone, making additions to α-substituted 1,4-acceptors more challenging. Typically, ethyl methacrylate does not react with dialkylzinc reagents [12]. Notwithstanding

• , 1,4-additions of dialkylzinc reagents have been reported with dehydroamino ester derivatives [13][14] and α-bromoacrylates [15], which both involve an SH2 at zinc of tertiary α-alkoxycarbonyl radicals (Scheme 2, top). Here, the key to unlock the reactivity is the presence of a Lewis-basic substituent

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

• Hui Yu and
• Feng Xu

Beilstein J. Org. Chem. 2023, 19, 1259–1288, doi:10.3762/bjoc.19.94

• . Route b: the α-C(sp3)–H bonds are activated by a combination of transition metals and radical initiators to give the alkyl radicals, which are coupled with other radical receptors to afford the target product. Cu-catalyzed reactions Copper (common oxidation states are +I, +II and +III) has a

• oxidative alkylation of cyclic benzyl ethers with malonates or ketones. Oxygen is used as a terminal oxidant at atmospheric pressure. The key intermediate of this oxidative coupling reaction is benzyl alcohol intermediate C (Scheme 4) [52]. The generation of N–O radicals from NHPI in the presence of oxygen

• extract a hydrogen from the ether C (sp3)–H bond to form radicals. Subsequently, a single electron transfer (SET) leads to the oxonium species. Then, the enamine generated in situ from methyl aryl ketone and pyrrolidine undergoes a nucleophilic reaction with the oxonium species followed by hydrolysis to

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

• David T. Nemoto Jr Kang-Jie Bian Shih-Chieh Kao Julian G. West Department of Chemistry, Rice University, 6100 Main St MS 602, Houston, TX 77005, USA 10.3762/bjoc.19.90 Abstract The place of alkyl radicals in organic chemistry has changed markedly over the last several decades, evolving from

• engagement of alkyl radicals remains challenging. Among these functionalization approaches, a bio-inspired mechanistic paradigm known as radical ligand transfer (RLT) has emerged as a particularly promising and versatile means of forming new bonds catalytically to alkyl radicals. This development has been

• ; photocatalysis; radicals; Introduction The behavior of alkyl radicals has been studied rigorously for decades, though only recently have these come to be widely viewed as selective and useful synthetic intermediates [1][2][3][4]. This sea change has been driven by innovations in both the generation and

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

• radicals that often provide access to new dimensions of synthetic chemical space, the field of single electron transfer (SET) in organic synthesis has expanded considerably in the past two decades. Among this area, photoredox catalysis (PRC) is highly attractive due to its abilities i) to generate reactive

• 2.1.1 C(sp2)–X activation: In the rise of visible light-mediated PRC, the generation of aryl radicals for C(sp2)–C(sp2/3) couplings under mild conditions (room temperature, visible light activation of a catalyst) was heavily investigated [34][35][36]. However, initially the procedures were generally

• formation which corroborates the involvement of free radicals. The authors argued against radical chain propagation on the basis of lack of reactivity in the dark during the light ON-OFF cycle experiments (we note that this does not rule out chain propagation with an efficient chain death). Investigations

Photoredox catalysis enabling decarboxylative radical cyclization of γ,γ-dimethylallyltryptophan (DMAT) derivatives: formal synthesis of 6,7-secoagroclavine

• Alessio Regni,
• Francesca Bartoccini and
• Giovanni Piersanti

Beilstein J. Org. Chem. 2023, 19, 918–927, doi:10.3762/bjoc.19.70

• photocatalyst. Keywords: decarboxylative cyclization; DMAT; ergot alkaloids; photoredox catalysis; radicals; Introduction Visible-light photoredox catalysis is rapidly changing the way organic chemists approach the design and synthesis of molecules by offering new synthetic disconnection opportunities that

• their ability to participate in either redox step of the catalytic cycle [42][43][44][45]. For example, the main use of α-amino acids in syntheses via photoredox catalysis is as readily available precursors of regioselective α-amino radicals by decarboxylative transformations, by oxidation of the

• intramolecular decarboxylative cyclization with the formation of the 3,4-fused indole carbocycle rings (Figure 1b,c). In detail, the photocatalytic strategy for accessing the two C(sp3) radicals of DMAT derivatives envision the formation of a relatively stabilized allylic-benzylic carbon-centered radical by

Synthesis of aliphatic nitriles from cyclobutanone oxime mediated by sulfuryl fluoride (SO₂F₂)

• Xian-Lin Chen and
• Hua-Li Qin

Beilstein J. Org. Chem. 2023, 19, 901–908, doi:10.3762/bjoc.19.68

• esters and adopted the pre-acylation activation strategies [39][40][41]. Up to now, only one report employed an oxime for the generation of iminyl radicals to obtain the similar products, in which, substrates were limited to the electron-rich alkenes (Scheme 2b) [42]. On the other hand, sulfuryl fluoride

Photocatalytic sequential C–H functionalization expediting acetoxymalonylation of imidazo heterocycles

• Deepak Singh,
• Shyamal Pramanik and
• Soumitra Maity

Beilstein J. Org. Chem. 2023, 19, 666–673, doi:10.3762/bjoc.19.48

• boron complex (B2pin2), and using an expensive metal-based photocatalyst [fac-Ir(ppy)3] under inert atmosphere. We have recently demonstrated that aerial oxygen could be captured by alkyl radicals to install a keto-functionality onto alkenes in an organophotocatalytic way [23]. We aimed to extend this

• under optimized reaction conditions, the acetylated product 4a was produced with excellent conversion (>90%). These results suggest the involvement of compound 5 as an intermediate, and Zn(OAc)2 or AcOH may be effective acetylating agents via generation of acetyl radicals. Control experiments under

Direct C2–H alkylation of indoles driven by the photochemical activity of halogen-bonded complexes

• Martina Mamone,
• Giuseppe Gentile,
• Jacopo Dosso,
• Maurizio Prato and
• Giacomo Filippini

Beilstein J. Org. Chem. 2023, 19, 575–581, doi:10.3762/bjoc.19.42

• to photochemically generate electrophilic radicals that can drive the functionalization of suitable electron-rich substrates [23]. Exploiting this strategy, here we report a novel metal-free methodology for the direct homolytic aromatic substitution (HAS) reaction of indoles 1 with α-iodosulfones 2

• halogen-bonded EDA complex (Ia) between the sulfone 2a and DABCO (Figure 4). When irradiated, this photoactive aggregate led to the formation of reactive alkyl radicals (IIa), which may react with indole 1a eventually yielding the product 3a through a classical HAS pathway [31][32][33]. Then, we

• -iodosulfones and DABCO, that are able to produce reactive C-centered radicals under mild reaction conditions. (a) Exploitation of an EDA complex in organic synthesis. (b) This work: use of halogen-bonded complexes to photochemically initiate the C–H alkylation of indoles 1 with iodosulfones 2. Optical

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

•  7) instead of the more commonly, and expensive, metal-based photocatalysts. While broadly successful, tertiary radicals failed to deliver any desired product. Of note, the reaction was amenable to a broad scope of derivatized heterobicyclic alkenes with mono- and disubstituted bridgeheads having

• and Renaud expanded the scope of the photoredox/Ni dual-catalyzed coupling of alkyl nucleophiles 36 with heterobicyclic alkenes 30 to include α-amino radicals (Scheme 7) [40]. The authors noted the electron-rich oxabenzonorbornadiene derivatives provided the corresponding ring-opened adducts in good

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

• pleuromutilin tricyclic scaffold construction. Alternative reagents were thus explored to close the eight-membered ring via initial radical genesis. For instance, Bacqué et al. reported the insertion in the cyclization precursors of functional groups prone to form radicals (Scheme 35). In their investigations

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

• /cyclization cascades from acrylamides for the synthesis of oxindoles [39][40][41]. The radicals are typically generated from alkyl halides [42][43][44], carboxylic acids [45][46][47], simple alkanes [48], alkylboronic acids [49], isocyanides [50], or other [51][52][53]. In this context, the group of Fu

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• chemoselective manner [3]. The development of persistent radicals [4] as synthons in chemical synthesis, coupled with the advancements in generating and manipulating transient radicals [5] as cross-coupling partners in an array of chemical reactions, gives access to a wide variety of “new” retrosynthetic

• approach, excluding electrochemical methods for generating radicals. An exhaustive review on radical total synthesis or divergent total synthesis lies beyond the scope of this review, and the readers are advised to refer to excellent reviews on these topics [6][10][14]. This review covers the years 2018

• intermediates closely related to the biosynthetic origins of the family. On the other hand, radical retrosynthetic disconnections on common scaffolds are much less predictable and rarely similar due to the plethora of radical chemical transformations available nowadays. Although radicals stopped being

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

• aimed at overviewing the current state-of-art and perspectives of oxidative organocatalysis by redox-active molecules with the emphasis on challenging chemo-, regio- and stereoselective CH-functionalization processes. The catalytic systems based on N-oxyl radicals, amines, thiols, oxaziridines, ketone

• /peroxide, quinones, and iodine(I/III) compounds are the most developed catalyst types which are covered here. Keywords: CH-functionalization; free radicals; hypervalent iodine; N-oxyl radicals; redox-active molecules; Introduction Organocatalysis can be defined as catalysis by small organic molecules

• classified according to the catalytically active species or key intermediates: N-oxyl radicals, oxoammonium cations, amine cation radicals, thiyl radicals, quinones, dioxiranes and oxaziridines, hypervalent iodine compounds, etc. However, some examples of organocatalyzed oxidative processes, in which an

A one-pot electrochemical synthesis of 2-aminothiazoles from active methylene ketones and thioureas mediated by NH₄I

• Shang-Feng Yang,
• Pei Li,
• Zi-Lin Fang,
• Sen Liang,
• Hong-Yu Tian,
• Bao-Guo Sun,
• Kun Xu and
• Cheng-Chu Zeng

Beilstein J. Org. Chem. 2022, 18, 1249–1255, doi:10.3762/bjoc.18.130

•  1b). Alternatively, the oxidation of α-C–H of active methylene ketones generate α-carbon-centered radicals, thus providing another way to obtain thiazoles. Recently, Sun et al. reported a tert-butyl hydroperoxide/azodiisobutyronitrile-mediated synthesis of 2-aminothiazoles from active methylene

Polymer and small molecule mechanochemistry: closer than ever

• José G. Hernández

Beilstein J. Org. Chem. 2022, 18, 1225–1235, doi:10.3762/bjoc.18.128

• -known mechanophore that generates diarylacetonitrile radicals under force. Hence, when TASN derivative 8, bearing diarylurea moieties, was ball milled, the corresponding radical 9 was detected by electron paramagnetic resonance (EPR) spectroscopy. Similar treatment proved that 6 was 28 times less prone

• to generate radicals (Scheme 3) [67]. The difference in the C–C bond scission between 6 and 8 was explained based on the ability of diarylurea moieties in 8 to form strong self-assemblies through hydrogen bonding. In the solid state, this enabled the transduction of mechanical force to the

• mechanophores. Moreover, it was demonstrated that the hydrogen bonds of the diarylurea linkages also acted as supporting units to maintain the activated mechanophores (radicals) for a longer time [67]. Overall, this new strategy, which harnesses the power of noncovalent interactions by ball milling [68][69][70

Electro-conversion of cumene into acetophenone using boron-doped diamond electrodes

• Mana Kitano,
• Tsuyoshi Saitoh,
• Shigeru Nishiyama,
• Yasuaki Einaga and
• Takashi Yamamoto

Beilstein J. Org. Chem. 2022, 18, 1154–1158, doi:10.3762/bjoc.18.119

• , entry 2). On the other hand, the isolated yield of 3 was decreased by the addition of H2O (Table 2, entries 3 and 4). This is probably because the addition of H2O promoted the generation of hydroxyl radicals, and a decomposition reaction became dominant. These results indicated that the oxygen source is

A Streptomyces P450 enzyme dimerizes isoflavones from plants

• Run-Zhou Liu,
• Shanchong Chen and
• Lihan Zhang

Beilstein J. Org. Chem. 2022, 18, 1107–1115, doi:10.3762/bjoc.18.113

• host against oxidative radicals generated by UV irradiation [25][32]. To verify the antioxidative effect of the isoflavone dimers, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)-based antioxidant activity was performed [33]. The results showed that while 2 and 3 had an activity roughly

Radical cation Diels–Alder reactions of arylidene cycloalkanes

• Kaii Nakayama,
• Hidehiro Kamiya and
• Yohei Okada

Beilstein J. Org. Chem. 2022, 18, 1100–1106, doi:10.3762/bjoc.18.112

• at the β-position had a significant impact on the reaction. In general, tertiary radicals (or cations) are more stable than secondary ones and therefore, the additional methyl group seems to have a strong steric effect (Figure 3). If so, tying up the two methyl groups as a cyclopropane ring may

Cathodic generation of reactive (phenylthio)difluoromethyl species and its reactions: mechanistic aspects and synthetic applications

• Sadanobu Iwase,
• Shinsuke Inagi and
• Toshio Fuchigami

Beilstein J. Org. Chem. 2022, 18, 872–880, doi:10.3762/bjoc.18.88

• )difluoromethyl group (ArSCF2) have potential biological applications such as anti-HIV-1 reverse transcriptase inhibitors and agrochemical applications [3][4]. Reurakul and Pohmakotr et al. carried out the reaction of PhSCF2Br with SmI2 in THF/iPrOH to generate PhSCF2 radicals followed by trapping with various

• radicals such as n-perfluoropropyl radical have high reactivity to electron-rich olefins such as α-methylstyrene and styrene [26]. In fact, our cathodically generated reactive species also reacted with α-methylstyrene. However, electron-rich dihydrofuran did not provide any radical adduct at all (Table 1

• often employed. Médebielle et al. successfully carried out the cathodic reduction of ArCF2X and RCOCF2X with nitrobenzene as a mediator to generate the corresponding difluoromethyl radicals selectively, and they applied this electrocatalytic system to the synthesis of various heterocyclic compounds

Thiophene/selenophene-based S-shaped double helicenes: regioselective synthesis and structures

• Mengjie Wang,
• Lanping Dang,
• Wan Xu,
• Zhiying Ma,
• Liuliu Shao,
• Guangxia Wang,
• Chunli Li and
• Hua Wang

Beilstein J. Org. Chem. 2022, 18, 809–817, doi:10.3762/bjoc.18.81

• )benzene (5c), and S-shaped double helicenes DH-1–3 is shown in Scheme 1. The double oxidative photocyclization of 5a–c is the key step in the synthesis of DH-1–3 because oxidative photocyclization induces double radicals on a double bond, which led to the C=C bond rotation along the resulting single C

Synthesis of α-(perfluoroalkylsulfonyl)propiophenones: a new set of reagents for the light-mediated perfluoroalkylation of aromatics

• Durbis J. Castillo-Pazos,
• Juan D. Lasso and
• Chao-Jun Li

Beilstein J. Org. Chem. 2022, 18, 788–795, doi:10.3762/bjoc.18.79

• solubility of this class of molecules, perfluoroalkyl iodides have a tendency to be weakly soluble in common organic solvents (i.e., ethyl acetate and methanol) rendering their application troublesome [9]. Moreover, the homolysis of the perfluoroalkyl iodide produces iodine radicals that can result in stray

• halogenation reactions or oxidation. For these reasons, it would be ideal to develop an efficient methodology that allows for the generation of perfluoroalkyl radicals in a mild, redox- and pH-neutral manner, without the assistance of external photocatalysts, heavy metal catalysts, or further additives. Thus

• , trifluoromethyl radicals and its longer-chain analogues, share a common electrophilic character and a stabilizing stereoelectronic effect [14], we envisioned that the “dummy group” methodology could be translated into the formation of sought after perfluoroalkyl radicals (Scheme 1). In this work, we report the

Structural basis for endoperoxide-forming oxygenases

• Takahiro Mori and
• Ikuro Abe

Beilstein J. Org. Chem. 2022, 18, 707–721, doi:10.3762/bjoc.18.71

• , natural and (semi)synthetic endoperoxides with wide structural diversity show antimalarial activity against Plasmodium falciparum malaria. In this case, the reductive activation of the endoperoxide ring with the homolytic cleavage of the O–O bond leads to the generation of carbon-centered free radicals