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

• substrate 1 in the presence of a base to form Cu(II) complex 5, which undergoes anodic oxidation to generate Cu(III) intermediate 6. Carboxylate-assisted C–H activation of the benzamide subsequently leads to the formation of Cu(III) species 7. Metalation of the terminal alkyne 2, followed by reductive

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

Synthesis of fluorinated acid-functionalized, electron-rich nickel porphyrins

• Mike Brockmann,
• Jonas Lobbel,
• Lara Unterriker and
• Rainer Herges

Beilstein J. Org. Chem. 2024, 20, 2954–2958, doi:10.3762/bjoc.20.248

• . After metalation with Ni(acac)2 and hydrolysis electron-rich porphyrins were obtained, that are equipped with covalently attached long chain acid substituents. The target compounds have potential applications in catalysis, sensing, and materials science. The fluorinated aliphatic carboxylic acids (TfO

• Williamson ether synthesis to yield 22 (78%), 23 (44%), and 24 (44%). Compounds 22, 23, and 24 were used as aldehyde components in the Rothemund-type synthesis of metal-free porphyrins 26 (9%), 27 (18%), and 28 (21%) (see Scheme 3). Metalation was achieved with nickel acetylacetonate to obtain the ester

• ester-functionalized aldehydes 22, 23, and 24. Conditions: a) NIS, TFA, Na2CO3, MeCN, reflux, 18 h; b) Cu2O·H2O, 2-pyridinaldoxime, TBAB, CsOH, H2O, N2, rt, 18 h; c) Cs2CO3, DMAc, N2, rt, 3 h. Porphyrin synthesis. a) Rothemund porphyrin synthesis of metal-free porphyrins 26, 27, and 28; b) metalation of

Multicomponent synthesis of α-branched amines using organozinc reagents generated from alkyl bromides

• Baptiste Leroux,
• Alexis Beaufils,
• Federico Banchini,
• Olivier Jackowski,
• Alejandro Perez-Luna,
• Fabrice Chemla,
• Marc Presset and
• Erwan Le Gall

Beilstein J. Org. Chem. 2024, 20, 2834–2839, doi:10.3762/bjoc.20.239

• ]. Thus, whereas Rieke et al. reported the insertion of activated zinc into alkyl bromides in THF at room temperature [16][17], Knochel et al. described the direct metalation of alkyl iodides in THF at 30 °C [18]. More recently, Knochel et al. improved their original method by the use of zinc dust in the

• presence of LiCl in THF for the metalation of alkyl bromides at room temperature [19]. Besides, Huo described the insertion of zinc dust into alkyl bromides at 80 °C in DMA or DMF [20]. Despite the high synthetic interest in mixed organozinc compounds, their use in the preparation of α-branched amines

• ][27][28], we observed that this solvent was not well-suited for the preparation of the organozinc species from the corresponding bromides, with no metalation being observed after 16 h at 80 °C (Table 1, entry 1). Conversely, the organozinc compound was formed in THF in nearly quantitative yield after

C–C Coupling in sterically demanding porphyrin environments

• Liam Cribbin,
• Brendan Twamley,
• Nicolae Buga,
• John E. O’ Brien,
• Raphael Bühler,
• Roland A. Fischer and
• Mathias O. Senge

Beilstein J. Org. Chem. 2024, 20, 2784–2798, doi:10.3762/bjoc.20.234

• previously, enrichment to the αβαβ, isomer may be necessary to remove the impact of opposing bromine atoms on the coupling reaction. Separation of the four individual atropisomers (αβαβ, α2β2, α3β, α4) has been accomplished before in dodecasubstituted porphyrins through Ni(II) metalation [15]. The core

• metalation effect prevents inner core N–H tautomerism [64] and thus increases the structural symmetry of the macrocycle [65][66], leading to more facile atropisomeric separation. However, in the case of compound 11 the atropisomers could not be separated due to low rotational barriers and similar polarities

• , even with Ni(II) metalation. There are many other methods available to achieve different desired atropisomeric ratios. These include thermal enrichment [67][68], photoracemization [69][70], axial-ligand coordination [71], precise separation techniques [50] or a combination of the procedures mentioned

A laterally-fused N-heterocyclic carbene framework from polysubstituted aminoimidazo[5,1-b]oxazol-6-ium salts

• Andrew D. Gillie,
• Matthew G. Wakeling,
• Bethan L. Greene,
• Louise Male and
• Paul W. Davies

Beilstein J. Org. Chem. 2024, 20, 621–627, doi:10.3762/bjoc.20.54

• -step ynamide annulation and imidazolium ring-formation sequence. Metalation with Au(I), Cu(I) and Ir(I) at the C2 position provides an L-shaped NHC ligand scaffold that has been validated in gold-catalysed alkyne hydration and arylative cyclisation reactions. Keywords: annulation; carbene; gold

(E,Z)-1,1,1,4,4,4-Hexafluorobut-2-enes: hydrofluoroolefins halogenation/dehydrohalogenation cascade to reach new fluorinated allene

• Nataliia V. Kirij,
• Andrey A. Filatov,
• Yurii L. Yagupolskii,
• Sheng Peng and
• Lee Sprague

Beilstein J. Org. Chem. 2024, 20, 452–459, doi:10.3762/bjoc.20.40

• important synthons, which are widely used in agrochemicals, pharmaceuticals and other fields [24][25][26]. Fluoroorganic lithium and Grignard reagents have been obtained by the metalation reactions of organofluorine compounds containing bromine and iodine atoms with alkyllithium and Grignard reagents

Mono or double Pd-catalyzed C–H bond functionalization for the annulative π-extension of 1,8-dibromonaphthalene: a one pot access to fluoranthene derivatives

• Nahed Ketata,
• Linhao Liu,
• Ridha Ben Salem and
• Henri Doucet

Beilstein J. Org. Chem. 2024, 20, 427–435, doi:10.3762/bjoc.20.37

• (Table 1, entries 14–16). The decisive influence of the base for this reaction is probably due to a concerted metalation–deprotonation mechanism [27][28][29][30]. Then, the scope of the Pd-catalyzed direct arylation for access to fluoranthenes was investigated (Scheme 2). The first step of the catalytic

• cycle involves the oxidative addition of 1,8-dibromonaphthalene. Then, a concerted metalation–deprotonation of the arene, which usually occurs at the ortho-position of an activating group such as a fluorine or a chlorine atom, followed by reductive elimination, gives the corresponding intermediate 1

Tying a knot between crown ethers and porphyrins

• Maksym Matviyishyn and
• Bartosz Szyszko

Beilstein J. Org. Chem. 2023, 19, 1630–1650, doi:10.3762/bjoc.19.120

• attraction between the two parts. Boitrel developed a crown ether-double-capped zinc(II) porphyrin 11 (Figure 9) [42]. The tritopic receptor incorporated symmetrically positioned diaza-crown-6 units above and below the central porphyrin core. The metalation of the tetrakis(o-aminophenyl)porphyrin (TAPP) core

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

• polyunsaturated analogues, the reaction started with the metalation of tert-butyl methyl ether according to the conditions reported by Corey and Eckrich [140], followed by the nucleophilic addition on unsaturated or polyunsaturated aldehyde to produce, as an example, 31.5. Then, the alkylation of the secondary

Pyridine C(sp²)–H bond functionalization under transition-metal and rare earth metal catalysis

• Haritha Sindhe,
• Malladi Mounika Reddy,
• Karthikeyan Rajkumar,
• Akshay Kamble,
• Amardeep Singh,
• Anand Kumar and
• Satyasheel Sharma

Beilstein J. Org. Chem. 2023, 19, 820–863, doi:10.3762/bjoc.19.62

• , displaying broad substrate scope and high yields (Scheme 20c). Based on literature reports and experimental studies, a possible mechanism (Scheme 20d) was proposed in which coordination of the DG 102 to the rhodium cationic species followed by ortho-metalation and migratory insertion of 103 into the Rh–C

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

Transition-metal-catalyzed C–H bond activation as a sustainable strategy for the synthesis of fluorinated molecules: an overview

• Louis Monsigny,
• Floriane Doche and
• Tatiana Besset

Beilstein J. Org. Chem. 2023, 19, 448–473, doi:10.3762/bjoc.19.35

• C(sp2)–H bond activation involving a concerted metalation–deprotonation pathway affords the metallacycle K. After an oxidative addition in the N-SCF3 bond of the Munavalli reagent V, the palladium(IV) species L is obtained. Finally, the reductive elimination affords the product and regenerates the

• isolated in 70% yield. Mechanistic studies indicated that the C–H bond activation event was the rate-limiting step and the authors suggested a similar mechanism to the one depicted in Scheme 20: formation of a palladacycle thanks to a concerted metalation deprotonation (CMD) process followed by oxidation

CuAAC-inspired synthesis of 1,2,3-triazole-bridged porphyrin conjugates: an overview

• Dileep Kumar Singh

Beilstein J. Org. Chem. 2023, 19, 349–379, doi:10.3762/bjoc.19.29

• °C [34] (Scheme 8). Further, nickel derivatives 44b–48b were also obtained from their zinc analogues by demetallation with concentrated HCl and metalation with nickel acetate. The preliminary photophysical results revealed a significant intramolecular energy transfer between the porphyrin core and

• porphyrin 126 was accomplished in four steps as shown in Scheme 24. First, porphyrin 123 was obtained by zinc metalation of the free-base porphyrin 122 using zinc acetate in a chloroform-methanol mixture. Further, the azide–alkyne click reaction between porphyrin 123 and 6-azido-6-deoxy-PM-β-CD 124 in the

1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

• Bram Ryckaert,
• Ellen Demeyere,
• Frederick Degroote,
• Hilde Janssens and
• Johan M. Winne

Beilstein J. Org. Chem. 2023, 19, 115–132, doi:10.3762/bjoc.19.12

• blocks with respect to their homologous counterparts. This is mainly due to their problematic metalation reactions (Scheme 2). Many ‘olane-type’ saturated heterocycles do not afford stable metalated species [12][13][14][15]. The most well-known example of this is tetrahydrofuran, which decomposes in a

• highly reactive electrophiles. The homologous 1,4-dithianes or 1,4-dioxanes are readily available as simple building blocks, but also undergo a swift β-elimination following the metalation of one of their ring carbons, again limiting their appeal as building blocks [16][17]. In his landmark synthesis of

• acetylacetone (19, Scheme 5c) [39]. As mentioned in the Introduction, the metalation of 1,4-dithianes is quite problematic [12][16]. In the unsaturated 1,4-dithiin series, however, the metalation of the cyclic vinyl-1,2-disulfide moiety is somewhat more feasible. Even though linear vinyl-1,2-disulfides such as

Synthetic strategies for the preparation of γ-phostams: 1,2-azaphospholidine 2-oxides and 1,2-azaphospholine 2-oxides

• Jiaxi Xu

Beilstein J. Org. Chem. 2022, 18, 889–915, doi:10.3762/bjoc.18.90

• hindrance of the N-alkyl group, although several regio- and diastereoisomers were generated in the reactions (Scheme 22) [19]. They further investigated the influences of the time of metalation, the concentration of base, cosolvents (additives), and the time of contact with the electrophiles on the regio

Synthesis of sulfur karrikin bioisosteres as potential neuroprotectives

• Martin Pošta,
• Václav Zima,
• Lenka Poštová Slavětínská,
• Marika Matoušová and
• Petr Beier

Beilstein J. Org. Chem. 2022, 18, 549–554, doi:10.3762/bjoc.18.57

• compounds 8, 20 and 21 albeit in low yields. Due to the extremely low isolated yield of compounds 20 and 21, we looked for an alternative more efficient procedure. In 2008 Sun et al. [32] described a method of karrikin alkylation in position 7 via direct metalation with lithium bis(trimethylsilyl)amide

• (LiHMDS), followed by the addition of an alkyl halide. Application of this method to 8 provided the target molecule 21 in good yield (Scheme 4). It has to be mentioned that the metalation proceeds exclusively at C7, and thus cannot be used for the preparation of 20 via alkylation at C5. Our attempt to

Efficient N-arylation of 4-chloroquinazolines en route to novel 4-anilinoquinazolines as potential anticancer agents

• Rodolfo H. V. Nishimura,
• Thiago dos Santos,
• Valter E. Murie,
• Luciana C. Furtado,
• Leticia V. Costa-Lotufo and
• Giuliano C. Clososki

Beilstein J. Org. Chem. 2021, 17, 2968–2975, doi:10.3762/bjoc.17.206

• of the anticancer agent verubulin. Thus, after regioselective 4-chloroquinazoline metalation by an in situ trapping metalation strategy, reaction quenching with iodine allowed us to isolate 4-chloro-8-iodoquinazoline in 83% yield. Surprisingly, further reaction of 4-chloro-8-iodoquinazoline with 4

Synthesis of highly substituted fluorenones via metal-free TBHP-promoted oxidative cyclization of 2-(aminomethyl)biphenyls. Application to the total synthesis of nobilone

• Ilya A. P. Jourjine,
• Lukas Zeisel,
• Jürgen Krauß and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2668–2679, doi:10.3762/bjoc.17.181

• activated derivatives (intramolecular Friedel–Crafts acylation) [29][30][31] found wide application here. In a different approach, a total synthesis of dengibsin (1a) was accomplished by Wang and Snieckus in 15 steps by means of a directed remote metalation [32], using a benzamide residue as the directing

Copper-catalyzed monoselective C–H amination of ferrocenes with alkylamines

• Zhen-Sheng Jia,
• Qiang Yue,
• Ya Li,
• Xue-Tao Xu,
• Kun Zhang and
• Bing-Feng Shi

Beilstein J. Org. Chem. 2021, 17, 2488–2495, doi:10.3762/bjoc.17.165

• development of efficient methods to access multifunctional ferrocenes has attracted tremendous attention. Conventionally, functionalized ferrocenes were derived via electrophilic aromatic substitution mediated by strong Lewis acids or direct metalation using strong bases, such as alkyllithium reagents [3][9

Advances in mercury(II)-salt-mediated cyclization reactions of unsaturated bonds

• Sumana Mandal,
• Raju D. Chaudhari and
• Goutam Biswas

Beilstein J. Org. Chem. 2021, 17, 2348–2376, doi:10.3762/bjoc.17.153

• -metalation followed by a regioselective mercuri-cyclization reaction (Scheme 60). During the total syntheses of (±)-fastigilin C and (–)-fastigilin C (201), 2 equiv of Hg(TFA)2 were used to synthesize key intermediate tricyclic furan compounds 199, 200, and 203. Hg(TFA)2 helped in the desired ring-formation

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• organometallic chemistry and catalysis [128]. The first example of a stoichiometric manganese-mediated C–H activation, reported by Stone, Bruce, and co-workers (1970) [129], was an ortho-metalation in azobenzenes. In recent years, with the expansion of the C–H activation field, manganese catalysts have been

A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• . Later, carboxylate-ligand-assisted C–H bond activation takes place through a concerted metalation–deprotonation transformation to produce the next intermediate. Finally, the corresponding product 142 is formed by a reductive elimination process, along with the regeneration of the active catalytic

Copper-mediated oxidative C−H/N−H activations with alkynes by removable hydrazides

• Feng Xiong,
• Bo Li,
• Chenrui Yang,
• Liang Zou,
• Wenbo Ma,
• Linghui Gu,
• Ruhuai Mei and
• Lutz Ackermann

Beilstein J. Org. Chem. 2021, 17, 1591–1599, doi:10.3762/bjoc.17.113

• in terms of a concerted metalation deprotonation (CMD) mechanism [50]. Interestingly, electron-rich alkyne 2f displayed a higher reactivity in the copper-promoted C−H activations as compared to the electron-poor analog 2h (Scheme 4b). A significant H/D scrambling was not detected in the ortho

One-step synthesis of imidazoles from Asmic (anisylsulfanylmethyl isocyanide)

• Louis G. Mueller,
• Allen Chao,
• Embarek AlWedi and
• Fraser F. Fleming

Beilstein J. Org. Chem. 2021, 17, 1499–1502, doi:10.3762/bjoc.17.106

• 3 that readily cyclizes to afford imidazole 4 (Scheme 1). The excellent efficiency is somewhat countered by requiring isocyanides that are readily deprotonated; metalation of alkylisocyanides is challenging except for methyl isocyanide which is why most isocyanides employed in accessing imidazoles