Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• is also oxidized to Mn(III)/L–N3. Azide radical addition to Mn(II)/L to form Mn(III)/L–N3 was considered as a possible route. Concurrently, the photocatalyst is irradiated by blue LED light to induce hydrogen atom transfer (HAT) at the C–H bond of substrate 12, generating alkyl radicals and enabling

Cerium-photocatalyzed aerobic oxidation of benzylic alcohols to aldehydes and ketones

• Girish Suresh Yedase,
• Sumit Kumar,
• Jessica Stahl,
• Burkhard König and
• Veera Reddy Yatham

Beilstein J. Org. Chem. 2021, 17, 1727–1732, doi:10.3762/bjoc.17.121

• benzylic alcohol selectively to the aldehyde or ketone is still desirable. Recently, cerium photocatalysis was introduced as a robust alternative to generate oxygen or carbon-centered radicals under mild reaction conditions [57][58][59][60][61][62][63][64]. CeCl3 reacts via ligand-to-metal charge transfer

• generating oxygen-centered radicals, that lead to carbon-centered radicals through intra/intermolecular hydrogen atom transfer (HAT) processes, radical decarboxylative or radical deformylation [57][58][59]. In continuation of our research interest on visible-light-driven cerium photocatalysis [59][65], we

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• cycloisomerizations initiated by the MHAT process in all-carbon quaternary synthesis The synthetic potential of carbon-centered radicals to construct new C(sp3)–C(sp3) bonds was considerably expanded by the development of MHAT strategies involving olefins as substrates. The regioselective transfer of the hydrogen

• (Scheme 17B). The proposed mechanism involves the formation of a cobalt hydride species that, upon transfer of a hydrogen atom to 32, generates a geminate radical pair containing a Co(II) species and a benzylic radical. The escape from the radical cage then generates the corresponding free radicals, which

• on the solvent radical cage efficiency and, consequently, on the concentration and “life-time” of the alkyl free radicals generated after the solvent cage collapse. In the latter case, the alkyl radical needed more time to cyclize before engaging in another solvent cage. After a β–H abstraction, it

Icilio Guareschi and his amazing “1897 reaction”

• Gian Cesare Tron,
• Alberto Minassi,
• Giovanni Sorba,
• Mara Fausone and
• Giovanni Appendino

Beilstein J. Org. Chem. 2021, 17, 1335–1351, doi:10.3762/bjoc.17.93

• observation was that the presence of radical traps, such as 4-hydroxy-substituted TEMPO, was detrimental for the reaction, which evidently involved free radicals. Anaerobic conditions (degassing with argon) inhibited the reaction, which could be restarted when oxygen was bubbled into the solution. This

• observation showed that oxygen, although not involved in the stoichiometry of the reaction, was critical. The alcohol corresponding to the alkyl residue was detected as a side product and became the main reaction product with substrates that generated stabilized radicals such as benzyl radicals. The formation

• ⋅mol−1) and favored over abstraction by a hydroperoxy radical, which would be only exothermic by 2 kcal⋅mol−1. The exothermicity of the hydrogen abstraction reaction is reduced with stabilized radicals, which have weaker C–H bonding. In this case, trapping by dissolved oxygen competes, generating a

Heterogeneous photocatalytic cyanomethylarylation of alkenes with acetonitrile: synthesis of diverse nitrogenous heterocyclic compounds

• Guanglong Pan,
• Qian Yang,
• Wentao Wang,
• Yurong Tang and
• Yunfei Cai

Beilstein J. Org. Chem. 2021, 17, 1171–1180, doi:10.3762/bjoc.17.89

• the generation of cyanomethyl radicals from readily available acetonitrile has not been reported yet. Herein, we disclose a CN-K-catalyzed cyanomethylarylation of both unactivated and activated alkenes with acetonitrile utilizing readily available alkyl N-hydroxyphthalimide (NHPI) esters as the

Manganese/bipyridine-catalyzed non-directed C(sp³)–H bromination using NBS and TMSN₃

• Kumar Sneh,
• Takeru Torigoe and
• Yoichiro Kuninobu

Beilstein J. Org. Chem. 2021, 17, 885–890, doi:10.3762/bjoc.17.74

• high temperatures in the absence of a catalyst (Scheme 1a) [14][15][16]. However, these reactions do not exhibit any selectivity due to the indiscriminate attack of bromine radicals on the C–H bonds in the substrate, which leads to the formation of a mixture of halogenated products. Electrophilic and

• (sp3)–H bromination reaction. The proposed reaction mechanism is shown in Scheme 5, which involves the following steps. (1) The reaction between NBS and TMSN3 generates bromine azide via the elimination of N-(trimethylsilyl)succinimide [52][53]; (2) bromine and azide radicals are then formed via

Highly regio- and stereoselective phosphinylphosphination of terminal alkynes with tetraphenyldiphosphine monoxide under radical conditions

• Dat Phuc Tran,
• Yuki Sato,
• Yuki Yamamoto,
• Shin-ichi Kawaguchi,
• Shintaro Kodama,
• Akihiro Nomoto and
• Akiya Ogawa

Beilstein J. Org. Chem. 2021, 17, 866–872, doi:10.3762/bjoc.17.72

• Innovation, Faculty of Agriculture, Saga University, 152-1 Shonan-cho, Karatsu, Saga 847-0021, Japan 10.3762/bjoc.17.72 Abstract The homolytic cleavage of the PV(O)–PIII bond in tetraphenyldiphosphine monoxide simultaneously provides both pentavalent and trivalent phosphorus-centered radicals with different

• was produced in 28% yield (Table 1, entry 2). However, 3a was obtained only in trace amounts upon irradiation with a tungsten lamp [51] (Table 1, entry 3). These results indicate that Ph2P• [52][53][54][55] and/or Ph2P(O)• [56][57][58][59] radicals were generated by the irradiation with light in the

• near-UV region. When benzene was used instead of CDCl3 under xenon lamp irradiation, the reaction did not proceed because 1 was less soluble in benzene than CDCl3 (Table 1, entry 4). The radical initiator, V-40, was found to be an appropriate initiator for the generation of phosphorus-centered radicals

Synthetic reactions driven by electron-donor–acceptor (EDA) complexes

• Zhonglie Yang,
• Yutong Liu,
• Kun Cao,
• Xiaobin Zhang,
• Hezhong Jiang and
• Jiahong Li

Beilstein J. Org. Chem. 2021, 17, 771–799, doi:10.3762/bjoc.17.67

• the excited state, causing an electron transfer to give radicals and to initiate subsequent reactions. Besides light as an external energy source, reactions involving the participation of EDA complexes are mild, obviating transition metal catalysts or photosensitizers in the majority of cases and are

• spectroscopy shows that phosphono radicals could proceed throughout the reaction. A halogen bond (XB) is a noncovalent interaction formed between a halogen atom and a neutral or negatively charged Lewis base. It is a kind of weak intermolecular interaction analogous to a hydrogen bond and basically can be

• aminosulfonylation, employing blue light as irradiation source (Scheme 5). It has to be said that nitrogen radicals played a coordinating role in the sulfonation step. Additionally, to verify the applicability of this approach, 1H-benzo[d][1,2]thiazine 2,2-dioxides have been prepared successfully. A possible

α,γ-Dioxygenated amides via tandem Brook rearrangement/radical oxygenation reactions and their application to syntheses of γ-lactams

• Mikhail K. Klychnikov,
• Radek Pohl,
• Ivana Císařová and
• Ullrich Jahn

Beilstein J. Org. Chem. 2021, 17, 688–704, doi:10.3762/bjoc.17.58

• ROESY investigations (see Supporting Information File 1). This corresponds to the previously reported data for N-benzylacetamides [82]. It can be assumed that the amide enolates after the Brook rearrangement and the α-amide radicals (4S,S)-19i–k and (4R,S)-19i, respectively, resulting after SET

• and the sterically more demanding phenyl ring of the 1-arylethyl group in (4R,S)-19i at the β-face shielding it in both radicals for the approach of TEMPO (3), but significantly more effectively in (4R,S)-19i (Scheme 7). The α-face is in contrast much less crowded and allows smooth radical coupling

• cyclized radicals 22 couple subsequently with TEMPO providing lactams 12a–k after deprotection of the TMS groups. The cyclized tertiary alkoxyamines (R3 = Me) are known to be thermally labile [89][90][91][92] and consequently 4-isopropenylpyrrolidones 12g,k are isolated as the exclusive products. The

Valorisation of plastic waste via metal-catalysed depolymerisation

• Francesca Liguori,
• Carmen Moreno-Marrodán and
• Pierluigi Barbaro

Beilstein J. Org. Chem. 2021, 17, 589–621, doi:10.3762/bjoc.17.53

• scission of C–C bonds into radicals, which leads to a complex mixture of olefinic and cross-linked compounds [143]. In a few cases, good selectivity to a liquid fraction was achieved. For instance, nanostructured BaTiO3 doped with Pb provided a mixture of liquid products, which includes alkanes (73.4

A new and efficient methodology for olefin epoxidation catalyzed by supported cobalt nanoparticles

• Lucía Rossi-Fernández,
• Viviana Dorn and
• Gabriel Radivoy

Beilstein J. Org. Chem. 2021, 17, 519–526, doi:10.3762/bjoc.17.46

• takes place to some extent, we assume that a competitive reaction pathway involving the participation of cobalt-superoxo active radicals (Co–O–O•) generated by interaction of the CoNPs with O2 [15] could not be disregarded. Conclusion To conclude, we have described a new and efficient heterogeneous

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

• disrotation at C2 and C3 during stereomutation in 1,1-difluorocyclopropanes [85]. An important feature in the fluorinated system was the stabilization of the intermediate 2,2-difluorotrimethylene radicals due to the conjugation of the radical centers with the σ*-orbital of C–F bond, which can be represented

• . Further applications of free radical chemistry have developed through the use of radical initiators under comparatively mild conditions to form cyclopropylmethyl radicals, which can readily release their strain by opening to give homoallyl radicals. gem-Difluorocyclopropanes, because of their

Amine–borane complex-initiated SF₅Cl radical addition on alkenes and alkynes

• Audrey Gilbert,
• Pauline Langowski,
• Marine Delgado,
• Laurent Chabaud,
• Mathieu Pucheault and
• Jean-François Paquin

Beilstein J. Org. Chem. 2020, 16, 3069–3077, doi:10.3762/bjoc.16.256

• used in the literature [34][35]. The use of the reagent allows the radicals to form, even at very low temperature, due to its strong reactivity with oxygen. However, the disadvantage for the use of the reagent comes from the same property: Et3B is an oxygen-sensitive and pyrophoric compound even at low

Metal-free synthesis of biarenes via photoextrusion in di(tri)aryl phosphates

• Hisham Qrareya,
• Lorenzo Meazza,
• Stefano Protti and
• Maurizio Fagnoni

Beilstein J. Org. Chem. 2020, 16, 3008–3014, doi:10.3762/bjoc.16.250

• intermediates (triplet aryl cations [28][29] or aryl radicals [30][31]). As for the former case, the intermolecular formation of a biaryl arose from the photoheterolysis of an Ar–N bond (in arene diazonium salts or their derivatives [32][33]), of an Ar–Cl bond [34][35], of an Ar–O bond (in aryl phosphates [36

• ], aryl sulfonates [36], and in aryl trifluoroethyl sulfate [37], Scheme 1a) followed by the reaction of the thus formed aryl cation with an aromatic substrate. In an alternative approach, aryl radicals may be generated under photoredox catalysis conditions (mostly from arene diazonium salts or aryl

• the presence of increasing amounts of TFE (up to 20% v/v, continuous line). Synthesis of biarenes via a) photogenerated triplet aryl cations and aryl radicals (PC = photocatalyst), b) intramolecular free radical ipso substitution, c) thermally catalyzed extrusion of CO and SO2, d) photoinduced

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

• electron transfer (SET) steps photoinitiated using visible light as the energy source, often leading to the generation of radicals and subsequent reaction of these radicals with the ground-state substrates [3]. Energy transfer catalysis is another significant branch of photocatalysis, in which

• dominant. Subsequent investigations by Yu expanded the scope to acyl radicals generated from carboxylic acids 56, affording enantioenriched 1,4-carbonyls 57 in excellent yields and good enantioselectivities (21 examples, up to 90:10 er) (Scheme 7b) [40]. The quantum yield was also measured to be <1 (Φ

• iminium ions 66 can be excited directly without formation of an EDA complex (Scheme 9a) [42]. The excited state iminium ion 66* can oxidise silanes 67 via a SET process to give radical cation 67•+ and alkyl radical 66•. Loss of the TMS group generates alkyl radicals 67• that can couple with 66

Host–guest interaction of cucurbit[8]uril with oroxin A and its effect on the properties of oroxin A

• Zhishu Zeng,
• Jun Xie,
• Guangyan Luo,
• Zhu Tao and
• Qianjun Zhang

Beilstein J. Org. Chem. 2020, 16, 2332–2337, doi:10.3762/bjoc.16.194

• addition of Q[8]. When the concentration of Q[8] was 1.0 × 10−4 mol·L−1, the solubility of OA was increased 22.47-fold. The solubility curve equation was S = 0.01c + 0.0575, R2 = 0.9986. Antioxidant activity OA has strong antioxidant activity and effectively eliminates ABTS+• radicals. If the antioxidant

• activity of OA was decreased significantly by the formation of the OA@Q[8] complex, the medicinal value of OA would be seriously affected. Figure 7 shows the results for OA and OA@Q[8] scavenging of ABTS+• radicals in the range of 1–20 μmol·L−1. The IC50 values of OA and OA@Q[8] were 4.65 × 10−6 mol·L−1

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

• formation of fluorine radicals. The generated alkyl radical could abstract fluorine atoms either from i) the AQN–F complex to regenerate AQN or ii) Selectfluor® to regenerate the Selectfluor® radical cation and thereby propagate a chain reaction. Following shortly after Tan’s report, Chen and co-workers

• (+)-sclareolide (C2 and C3) are remote from the lactone EWG and both form secondary radicals. Thus, the fluorination of these positions is presumably dictated by hindrance, given that the C3 position is neighbored by a gem-dimethyl group and is fluorinated to a lesser extent (22%). In both reports, the C2/C3

A complementary approach to conjugated N-acyliminium formation through photoredox-catalyzed intermolecular radical addition to allenamides and allencarbamates

• Olusesan K. Koleoso,
• Matthew Turner,
• Felix Plasser and
• Marc C. Kimber

Beilstein J. Org. Chem. 2020, 16, 1983–1990, doi:10.3762/bjoc.16.165

• radical cyclization of allenamides have been reported by Hsung and co-workers, where the radical adds principally to the central carbon of the allene (10) [45]; and (iii) the photoredox-catalyzed addition of radicals to enamides reported by Masson [46][47][48][49], and more recently by our own laboratory

• ]. Mechanistically, the formation of the key conjugated N-acyliminum 14a from α-aminoallyl radical 41 is analogous to the photoredox initiated addition of radicals to enamides [46][48][49]. Consequently, the formation of 14a can results from a SET event between the oxidized Ir(III) [55] and the α-aminoallyl radical

Metal-free synthesis of phosphinoylchroman-4-ones via a radical phosphinoylation–cyclization cascade mediated by K₂S₂O₈

• Qiang Liu,
• Weibang Lu,
• Guanqun Xie and
• Xiaoxia Wang

Beilstein J. Org. Chem. 2020, 16, 1974–1982, doi:10.3762/bjoc.16.164

• temperature at 70 °C based on the fact that K2S2O8 thermally decomposes forming sulfate radicals (SO4·−) [29][30], which may react with the substrates to furnish such a cascade cyclization. To our delight, the anticipated product 3aa was obtained in 42% yield in DMSO/H2O (4:1) as reaction medium in one pot

• , we successfully separated a small amount of byproduct 4 which was identified by NMR spectroscopy. These experiments clearly support a phosphorus-centered radical reaction pathway. It has been reported that phosphorus-centered radicals could be generated from phosphine oxides in the presence of

When metal-catalyzed C–H functionalization meets visible-light photocatalysis

• Lucas Guillemard and
• Joanna Wencel-Delord

Beilstein J. Org. Chem. 2020, 16, 1754–1804, doi:10.3762/bjoc.16.147

• mild heteroaromatic functionalizations. Last but not least, a HAT-type process inducing the generation of alkyl radicals via selective C–H abstraction from the aliphatic precursors may be combined with a Ni-catalyzed process, thus delivering cross-coupled products. The aim of this review is to present

• alkane products could be controlled by adjusting the acidity of the reaction media. As in the previously described examples, molecular oxygen plays a key role in the mechanism of the C–H functionalization (Figure 10). Indeed, both the photoexcited Ir-based catalyst and the superoxide radicals formed in

• activation of one substrate, and a two-electron activation by a transition-metal catalyst of the other. The main advantage of such a system is to promote highly regioselective reactions. Indeed, while radical transformations generally suffer from selectivity issues, interception of radicals by metal

Synthesis of new dihydroberberine and tetrahydroberberine analogues and evaluation of their antiproliferative activity on NCI-H1975 cells

• Giacomo Mari,
• Lucia De Crescentini,
• Serena Benedetti,
• Francesco Palma,
• Stefania Santeusanio and
• Fabio Mantellini

Beilstein J. Org. Chem. 2020, 16, 1606–1616, doi:10.3762/bjoc.16.133

• , namely pyrrolino-tetrahydroberberines, synthesized by some of us [68], exhibited enhanced antioxidant properties in comparison to THBER against a wide variety of pathophysiologically relevant oxidants such as peroxyl radicals, ferrous ion, and hydrogen peroxide [65]. In continuation of our ongoing

Photoredox-catalyzed silyldifluoromethylation of silyl enol ethers

• Vyacheslav I. Supranovich,
• Vitalij V. Levin and
• Alexander D. Dilman

Beilstein J. Org. Chem. 2020, 16, 1550–1553, doi:10.3762/bjoc.16.126

• source of hydrogen [21]. We thought that silane 1 could couple with silyl enol ethers in the presence of a photocatalyst affording fluoroalkylation products. Indeed, silyl enol ethers were found to be good acceptors of fluorinated radicals, and the resultant silyloxy-substituted radicals underwent single

Heterogeneous photocatalysis in flow chemical reactors

• Christopher G. Thomson,
• Ai-Lan Lee and
• Filipe Vilela

Beilstein J. Org. Chem. 2020, 16, 1495–1549, doi:10.3762/bjoc.16.125

• liquid medium are capable of breaking chemical bonds, including the sonolysis of water to hydrogen and hydroxyl radicals [159]. These conditions arise from a process known as acoustic cavitation in which the expanding phase of the acoustic wave creates microscopic voids within the solution, which

4-Hydroxy-3-methyl-2(1H)-quinolone, originally discovered from a Brassicaceae plant, produced by a soil bacterium of the genus Burkholderia sp.: determination of a preferred tautomer and antioxidant activity

• Dandan Li,
• Naoya Oku,
• Yukiko Shinozaki,
• Yoichi Kurokawa and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2020, 16, 1489–1494, doi:10.3762/bjoc.16.124

• the control reaction (Figure 3). Because the Fenton reaction catalyzed by Cu2+ was used to generate the hydroxy radicals, entrapment of Cu2+ by 1 was initially suspected as the mechanism of chemiluminescence inhibition. However, this speculation was ruled out by a titration experiment using Chrome