Formaldehyde surrogates in multicomponent reactions

• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Bernhard Westermann

Beilstein J. Org. Chem. 2025, 21, 564–595, doi:10.3762/bjoc.21.45

• reaction by metal catalysis is an option to avoid the problems regarding iminium or aminal stability. This is an important issue in AAA coupling when formaldehyde is used as the C1 source. Finally, a later work proposes a catalysis-free protocol for the synthesis of propargylamines by an AHA coupling

• secondary amines such as piperidine or pyrrolidine afford an aminal or an iminium ion, in general under high temperature or pressure conditions, which is not the case for the AHA coupling [69][70]. Despite these cases, the absence of evidence in terms of iminium ion generation confirms that the AHA coupling

• reaction [71]. Here, the reaction is carried out under mild conditions (CH2Cl2, 70 °C) without the need for catalysis or additional base for the activation of C–H and C–X bonds of the alkyne and dihalomethane compounds, respectively. However, this strategy has a limited scope in terms of the alkyne

Synthesis of N-acetyl diazocine derivatives via cross-coupling reaction

• Thomas Brandt,
• Pascal Lentes,
• Jeremy Rudtke,
• Michael Hösgen,
• Christian Näther and
• Rainer Herges

Beilstein J. Org. Chem. 2025, 21, 490–499, doi:10.3762/bjoc.21.36

• compared to parent diazocine [3][13]. Reaction conditions of the arylation of halogenated N-acetyl diazocines via Stille coupling reaction. Equivalents are normalized to the used amount of N-acetyl diazocine starting material. Vinylation of halogenated N-acetyl diazocines via Pd-catalyzed coupling

Red light excitation: illuminating photocatalysis in a new spectrum

• Lucas Fortier,
• Corentin Lefebvre and
• Norbert Hoffmann

Beilstein J. Org. Chem. 2025, 21, 296–326, doi:10.3762/bjoc.21.22

Synthesis of disulfides and 3-sulfenylchromones from sodium sulfinates catalyzed by TBAI

• Zhenlei Zhang,
• Ying Wang,
• Xingxing Pan,
• Manqi Zhang,
• Wei Zhao,
• Meng Li and
• Hao Zhang

Beilstein J. Org. Chem. 2025, 21, 253–261, doi:10.3762/bjoc.21.17

• reaction at 120 °C for 2 hours were determined as optimal conditions for the reaction (Table 1, entry 14). Under the optimized conditions, the coupling reaction of various sodium arylsulfinates was investigated to assess the scope and generality of this protocol. The results, shown in Scheme 2

Streamlined modular synthesis of saframycin substructure via copper-catalyzed three-component assembly and gold-promoted 6-endo cyclization

• Asahi Kanno,
• Ryo Tanifuji,
• Satoshi Yoshida,
• Sota Sato,
• Saori Maki-Yonekura,
• Kiyofumi Takaba,
• Jungmin Kang,
• Kensuke Tono,
• Koji Yonekura and
• Hiroki Oguri

Beilstein J. Org. Chem. 2025, 21, 226–233, doi:10.3762/bjoc.21.14

• -fluorobenzene (see Scheme 2 and Supporting Information File 1 for details). Copper(I)-catalyzed three-component coupling reaction of alkyne 8, THIQ 9, and benzaldehyde, proceeded with exquisite control of regioselectivity to afford 10 in an excellent yield of 92% [43][44][45][46]. This efficient cascade

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

• –heteroatom (C–X, where X = N, O, or halogens) bonds in organic synthesis. Copper was one of the first transition metals employed in cross-coupling to form C–C and C–X bonds [1][2]. In 1901, Ullmann reported the first cross-coupling reaction for the formation of biaryl compounds in the presence of

• undergoes reductive elimination to provide the desired enantioenriched nitrile product 111 and Cu(I) catalyst 116. The resulting Cu(I) catalyst 116 is reoxidized to Cu(II) 117 at the anode, completing the catalytic cycle. Coupling reaction (Chan–Lam coupling) Transition metal-catalyzed C–N bond formation

Nickel-catalyzed cross-coupling of 2-fluorobenzofurans with arylboronic acids via aromatic C–F bond activation

• Takeshi Fujita,
• Haruna Yabuki,
• Ryutaro Morioka,
• Kohei Fuchibe and
• Junji Ichikawa

Beilstein J. Org. Chem. 2025, 21, 146–154, doi:10.3762/bjoc.21.8

• equivalents of 2b to 1.0 equiv and K2CO3 to 1.2 equiv, we achieved the highest yield of 98% for 3bb (Table 1, entry 9). Under the optimized conditions, we investigated the substrate scope using 2-fluorobenzofurans 1 and arylboronic acids 2 (Scheme 2). The coupling reaction was efficient with 2

• optimized the coupling reaction using potassium phosphate as a base and increasing the nickel catalyst loading to 20 mol %, achieving a yield of 78% for the desired product 3bg. When 2-naphthylboronic acid (2i) was employed, its solubility was enhanced using a mixed solvent system of toluene, methanol, and

• , reductive elimination from G yields the coupling products 3. The following experiments were performed to elucidate the mechanism. Under the same conditions as the coupling reaction, stoichiometric amounts of Ni(cod)2, PCy3, and cod were treated with fluoronaphthofuran 1b at room temperature for 13 h

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

• 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

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

• organocatalytic cross-coupling reaction of 1-azonaphthalenes 238 with 2-naphthols 239 catalyzed by chiral N-triflylphosphoramide C56 was done in 2023 (Scheme 70) [104]. A remarkable number of axially chiral products 240 were prepared with excellent enantiomeric purities and high yields. Undiminished yields and

Emerging trends in the optimization of organic synthesis through high-throughput tools and machine learning

• Pablo Quijano Velasco,
• Kedar Hippalgaonkar and
• Balamurugan Ramalingam

Beilstein J. Org. Chem. 2025, 21, 10–38, doi:10.3762/bjoc.21.3

• were explored, using a total volume of 4.5 mL reaction mixture, and the screening results can be readily translated to continuous flow synthesis. The application of segmented flow or microslug reactors was demonstrated in the decarboxylative arylation cross-coupling reaction promoted by catalysts and

• drug molecules autonomously, and it does not include a closed-loop optimization framework. The Pfizer research team developed a custom-designed flow system for rapid reaction screening of the Suzuki–Miyaura coupling reaction on a nanomolar scale [50]. The platform included a modified HPLC system that

Synthesis, structure and π-expansion of tris(4,5-dehydro-2,3:6,7-dibenzotropone)

• Yongming Xiong,
• Xue Lin Ma,
• Shilong Su and
• Qian Miao

Beilstein J. Org. Chem. 2025, 21, 1–7, doi:10.3762/bjoc.21.1

• Abstract The polycyclic skeleton of tris(4,5-dehydro-2,3:6,7-dibenzotropone) is a key structural fragment in carbon schwarzites, a theoretical form of negatively curved carbon allotrope. This report presents a new synthesis of this compound using a Ni-mediated Yamamoto coupling reaction and structural

• synthesis of 1 using a Ni-mediated Yamamoto coupling reaction and the simultaneous crystallization of its two different conformers from the same solution. Expanding the π-skeleton of 1 through a Barton–Kellogg reaction followed by a subsequent Scholl reaction resulted in a new polycyclic arene (3 in Figure

• yield of 90%. Then, the Ni-mediated Yamamoto coupling reaction of 6 enabled cyclotrimerization to give trione 1 in a yield of 30%. It is worth mentioning that using 1,10-phenanthroline as the ligand in the Yamamoto coupling [25][26] led to a higher yield of compound 1 than using 2,2’-bipyridine. With

Synthesis of acenaphthylene-fused heteroarenes and polyoxygenated benzo[j]fluoranthenes via a Pd-catalyzed Suzuki–Miyaura/C–H arylation cascade

• Merve Yence,
• Dilgam Ahmadli,
• Damla Surmeli,
• Umut Mert Karacaoğlu,
• Sujit Pal and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2024, 20, 3290–3298, doi:10.3762/bjoc.20.273

• %). This cascade involves an initial Suzuki–Miyaura cross-coupling reaction between 1,8-dihalonaphthalenes and heteroarylboronic acids or esters, followed by an intramolecular C–H arylation under the same conditions to yield the final heterocyclic fluoranthene analogues. The method was further employed to

• analogues via a Pd-catalyzed reaction cascade that consists of a Suzuki–Miyaura cross-coupling reaction followed by an intramolecular C–H arylation. These heterocyclic fluoranthene analogues include a variety of acenaphthylene-fused heteroarenes such as thiophene, furan, benzofuran, pyrazole, pyridine and

Intramolecular C–H arylation of pyridine derivatives with a palladium catalyst for the synthesis of multiply fused heteroaromatic compounds

• Yuki Nakanishi,
• Shoichi Sugita,
• Kentaro Okano and
• Atsunori Mori

Beilstein J. Org. Chem. 2024, 20, 3256–3262, doi:10.3762/bjoc.20.269

• conditions. We carried out the palladium-catalyzed intramolecular coupling reaction of precursor 1a under similar conditions [23], which afforded smooth reaction with phenanthroline bisamide, with 10 mol % of palladium acetate as a catalyst in the presence of potassium carbonate and tetra-n-butylammonium

Synthesis of extended fluorinated tripeptides based on the tetrahydropyridazine scaffold

• Thierry Milcent,
• Pascal Retailleau,
• Benoit Crousse and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2024, 20, 3174–3181, doi:10.3762/bjoc.20.262

• LiOH, followed by a coupling reaction with ʟ-valine methyl ester hydrochloride, to give the corresponding four enantiomerically pure tripeptides 8 with satisfactory yields over two steps (Scheme 6). The absolute configuration (S,S,S) of the isomer 8f was unambiguously assigned by X-ray crystallographic

Extension of the π-system of monoaryl-substituted norbornadienes with acetylene bridges: influence on the photochemical conversion and storage of light energy

• Robin Schulte,
• Dustin Schade,
• Thomas Paululat,
• Till J. B. Zähringer,
• Christoph Kerzig and
• Heiko Ihmels

Beilstein J. Org. Chem. 2024, 20, 3061–3068, doi:10.3762/bjoc.20.254

• . Results and Discussion The norbornadiene derivatives 1h–l,n were synthesized by Sonogashira–Hagihara coupling reaction of 2-bromonorbornadiene (1g) [36] with the corresponding arylacetylenes 3a–g (Scheme 2). As an exception, 1,4-bis-norbornadienylnaphthalene (1m) could not be obtained by this route

Cyclodextrin-based rotaxanes for polymer materials: challenge on simultaneous realization of inexpensive production and defined structures

• Yosuke Akae

Beilstein J. Org. Chem. 2024, 20, 3026–3049, doi:10.3762/bjoc.20.252

• substitution/addition reactions became the standard for end-capping reactions, although a transition metal–catalyzed cross-coupling reaction has also been used to synthesize CD-based rotaxane. Typically, water-soluble components are prepared, after which the Suzuki coupling reaction in water is used to

• α-CD-based rotaxane comprising a stilbene axle that was synthesized by the Suzuki coupling reaction to light irradiation (Figure 6, right) [58]. In this structure, α-CD was first located on the trans-stilbene moiety, after which it moved to the benzene ring moiety via the cis-isomerization of the

• into the polymer system, further modification and structural analyses were performed [48][74]. The axle end was easily modified by bromination of the benzene ring and successive transition metal–catalyzed cross-coupling reaction, such as Suzuki or Sonogashira coupling (Figure 10A). Furthermore, the

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

• -unsaturated esters 143 and TBHP to afford α-peroxy-γ-diketones 145 was also disclosed under the catalysis of dirhodium(II) complex Rh2(esp)2 (esp = α,α,α′,α′-tetramethyl-1,3-benzenedipropanoate) (Scheme 45c) [109]. A three-component radical coupling reaction has been established for the assembly of β

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• -naphthols 21 by using iodonium salts 16 as the source of the aryl group (Scheme 7) [61]. Through optimization, it was determined that the presence of Na2CO3 as base and cyclohexane as solvent facilitated the C–C cross-coupling reaction. The products were obtained in satisfactory yields using various

• . Notably, the efficiency of the cross-coupling reaction was observed to increase with the transfer of electron-poor aryl groups from the hypervalent iodine salt. Thus, electron-withdrawing substituents such as trifluoromethyl, m-chloro, and fluorine on the aryl group promoted efficient coupling. Moreover

• 62. Acetonitrile was identified as a suitable solvent for this reaction, resulting in moderate to good yields of the products. The three main steps in the reaction were oxidation of the aryl iodide, addition of the TMP auxiliary, and C–O coupling reaction. Olofsson et al. worked towards the synthesis

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

• porphyrins [34] and tetrabromoanthracenyl porphyrins [35]. In general, the halogen atom needed for the Suzuki coupling reaction resides on the porphyrin; however, Suzuki–Miyaura reactivity has also been shown to be reversed whereby the synthesis of borolanylporphyrins leads to a different approach to

• Discussion Investigation of the Suzuki coupling reaction at the meso-phenyl position of dodecasubstituted porphyrins Synthesis of porphyrin precursors To investigate the Suzuki coupling at the ortho-, meta- and para-position of a dodecasubstituted saddle-shaped porphyrin, first the precursor porphyrins 11

• literature procedure [35]. With initial success in the synthesis porphyrin 26, this Suzuki coupling reaction was performed on 13, for a range of boronic acids/esters as shown in Figure 2 and Scheme 2. Boronic acids/esters were chosen based on their electronic properties (activating/deactivating) as well as

Computational design for enantioselective CO₂ capture: asymmetric frustrated Lewis pairs in epoxide transformations

• Maxime Ferrer,
• Iñigo Iribarren,
• Tim Renningholtz,
• Ibon Alkorta and
• Cristina Trujillo

Beilstein J. Org. Chem. 2024, 20, 2668–2681, doi:10.3762/bjoc.20.224

• fluoride ion, respectively. Volcanic 1.3.3, a Python package for the NaviCat platform, was used to generate 3D volcano plots, facilitating the identification of the most appropriate catalyst for the coupling reaction being considered [27]. Volcano plots Volcano plots are a visualisation of the Sabatier

• ), S1 is the substituent on the LB, and S2 is the substituent on the LA. Capture of CO2 and PO by an FLP Chemoselectivity Our investigations began by examining the uncatalysed coupling reaction between CO2 and PO (Scheme 1), which exhibits a calculated activation barrier (ΔG‡) greater than 55 kcal·mol−1

• chosen to avoid addressing asymmetry concerns at this stage. The capture exhibiting the lowest activation barrier was considered the first step of the coupling reaction for the remainder of the study. The free-energy profiles of both capture processes are depicted in Figure S1 (Supporting Information

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

• )–H functionalization C–N coupling reaction by developing an electrochemical method for the bioconjugation of tyrosine in proteins/polypeptides with phenothiazine residues, achieving excellent site- and chemoselectivity (Scheme 4a). This method was inspired by an earlier work from the Gouin group

Tandem diazotization/cyclization approach for the synthesis of a fused 1,2,3-triazinone-furazan/furoxan heterocyclic system

• Yuri A. Sidunets,
• Valeriya G. Melekhina and
• Leonid L. Fershtat

Beilstein J. Org. Chem. 2024, 20, 2342–2348, doi:10.3762/bjoc.20.200

• Information File 1 for details) [43]. As expected, amides 5 also undergo tandem diazotization/azo coupling reaction to form the target [1,2,5]oxadiazolo[3,4-d][1,2,3]triazin-7(6H)-ones 7. It should also be noted, that compounds 7 were obtained in similar yields as the corresponding furoxan analogues

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

• generates a stannylated imidoyl radical 20. The subsequent 5-exo cyclization, hydrogen abstraction from n-Bu3SnH, and aromatization successfully afforded the stannylated indole derivative 21 (Scheme 13) [8][54][55][56]. The stannyl group of 21 could be transferred to aryl or vinyl group by cross-coupling

• reaction. At the same time, Bachi et al. succeeded in synthesizing a 5-membered nitrogen-containing heterocycle based on the 5-exo cyclization of isocyanides with alkenyl or alkynyl groups using thiols as mediators (Scheme 14) [57]. The generated thiyl radical attacks the isocyano group and forms imidoyl

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• one-pot process (Scheme 43) [140]. This alkynone generation fulfills two functions: on the one hand, it acts as an activating reagent in the coupling reaction and, on the other, as a ring-forming component. Notably, this process can only be carried out as a domino reaction. For the coupling of

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• , Alcazar et al. developed continuous flow protocols for both the generation of alkylzinc halides and for the subsequent Negishi cross-coupling reaction [40][41][42][43][44]. We successfully adapted Alcazar’s protocols for the synthesis of otherwise challenging heteroaryl–alkyl connections (see Table S1 in

• decarboxylation during the hydrolysis step. Compounds 6j, 6l and 6r passed validation in moderate to good yields (Scheme 8). Conclusion In conclusion, by taking advantage of the recent advances in the Negishi cross-coupling reaction we obtained a broad range of heteroarylacetates starting from heteroaromatic