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

• model reaction was proposed (Scheme 6). First, 1a was acidified to form p-methylbenzenesulfinic acid A, and A was reduced by HI to form p-tolyl hypoiodothioite B, which then reacted with A to form the thiosulfonate C. 3a undergoes a cyclization reaction to form 3aa in an acidic environment. Compound B

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

• , Palestine 10.3762/bjoc.21.15 Abstract An efficient and eco-friendly approach for synthesizing difluoromethyl- and aryldifluoromethyl-substituted polycyclic imidazoles was established via a visible-light-promoted radical cyclization reaction. This method employed the readily accessible and inexpensive

• CF2HCO2H or PhCF2COOH, along with benzimidazoles bearing unactivated alkenes and PhI(OAc)2 as substrates, and proceeded without the need of any base, metal catalyst, photocatalyst or additive. In total, 24 examples were examined, and all of them successfully underwent cyclization reaction to produce the

• target products in good to excellent yields. Mechanistic studies revealed that the reaction proceeds via a radical pathway. Keywords: cyclization; difluoromethylation; hypervalent iodine; polycyclic imidazole; visible light; Introduction Organofluorine compounds continue to play important roles in

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

• coupling with gold(I)-mediated 6-endo cyclization streamlines the rapid and modular assembly of the substructure of bis-tetrahydroisoquinoline (THIQ) alkaloids. The design of the key synthetic intermediate bearing a 2,3-diaminobenzofuran moiety allows both gold(I)-mediated regiocontrolled 6-endo

• cyclization to efficiently construct the pentacyclic intermediate 7, as demonstrated in our previous study [15]. Following the pioneering total synthesis of saframycin A (1) by Fukuyama and co-workers taking advantage of the compatibility of phenolic hydroxy groups with PS-type cyclization [22], other groups

• , followed by gold(I)-promoted 6-endo cyclization between the internal alkyne and 2,3-diaminobenzofuran moieties with spontaneous transformations into the left THIQ segment in 14. Results and Discussion As outlined in our modular synthetic approach (Scheme 1c), the copper(I)-catalyzed three-component

Dioxazolones as electrophilic amide sources in copper-catalyzed and -mediated transformations

• Seungmin Lee,
• Minsuk Kim,
• Hyewon Han and
• Jongwoo Son

Beilstein J. Org. Chem. 2025, 21, 200–216, doi:10.3762/bjoc.21.12

• ) nitrenoid intermediate INT-7. Subsequent nitrene insertion, protodemetalation, and intramolecular cyclization furnish the desired 1,2,4-triazole. 1.3 Three-component formation of N-acyl amidines In 2019, N-acyl amidines were prepared from dioxazolones using a copper catalyst with terminal alkynes and

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

• reactions, particularly in controlling the high reactivity and selectivity of radical intermediates [13][14]. Early studies on copper-mediated radical reactions, such as Julia’s work on radical cyclization reaction [15], along with advancements in dimerization [16][17], oxidative cleavage [18][19], and

• elimination, produces C–H alkynylated arene 10, which then forms the final product 3 through intramolecular cyclization. Finally, the Cu(I) complex 9 produced via reductive elimination is reoxidized at the anode to regenerate the Cu(II) complex 4, completing the catalytic cycle. Yao and Shi developed the

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

• coupling between these components (Scheme 1b). Among aromatic fluorides, we have targeted 2-fluorobenzofurans 1 for C–F bond activation [19]. These compounds, which we prepared efficiently via 5-endo-trig cyclization of β,β-difluoro-o-hydroxystyrenes [20][21], possess a C–C double bond with an electron

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

• (Scheme 16) [33]. The reaction, which occurs with formation of C–C, C–N and C–O bonds, involves a nucleophilic addition of the activated alkyne XIV to the in situ-generated iminium ion XV, followed by cyclization to form a quinoxalin-2-one intermediate XVI. A subsequent 5-endo-dig cyclization involving

• the coupling with copper triflate as catalyst, without ligand, co-catalyst or other additives. The reaction involved the formation of the imine XVII followed by alkynylation to propargylamine XVIII, cyclization, and oxidation to quinoline 23 (Scheme 17) [34]. Three component oxidative annulation to

• , hydrazines and alkenes with Cu(OTf)2 (20 mol %) in CH2Cl2 at reflux is a useful tool to access substituted 4,5-dihydropyrazoles 31 (Scheme 23) [40]. The products reasonably result from a Mannich/cyclization/oxidative transformation of the substrates in which Cu(OTf)2 is involved in more steps. The reaction

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

• intermediate Int-9. As the assumed rate-determining step the intramolecular nucleophilic addition takes place, followed by further cyclization and finally, release of the organocatalyst to form the axially chiral product 9. Various aryl-substituted indolines 9 were obtained in good yields and high enantiomeric

• purities (Scheme 3). Sparr and co-workers developed an atroposelective synthesis for tetra-ortho-substituted biaryls 11 by non-canonical polyketide cyclizations [21]. This work was based on an earlier report of the team on the aldol cyclization of naphthyl-substituted unsaturated ketoaldehydes [22]. The

• yields and enantiomeric purities. The reaction was initiated by the formation of acylazolium intermediate Int-24 that underwent a 1,6-addition with the enol form of the carbonyl substrate to give Int-25. Cyclization was realized via an intramolecular aldol reaction to Int-26 (Scheme 15). Ye and co

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

• [30][31][32]. We herein report the palladium-catalyzed intramolecular C–H arylation of several pyridine and non-pyridine amides to afford multiply fused heterocyclic compounds. Results and Discussion First, we started with the synthesis of the cyclization precursors 1a–c that was carried out by the

• with the case of 1a. The reactivity toward the palladium-catalyzed cyclization was thus shown as 3 ≈ 1a >> 1b > 1c. The related trend was also observed in the reaction of phenanthroline monoamide 5a and diamide 5b. The reaction of 5a afforded the cyclized product in 51% yield, which contrasted with our

• previous result for the cyclization of 5b to afford the doubly cyclized product 6b (reported yield: 85% [23]), suggesting that the superior reactivity was found for bifunctional bisamides compared to monoamides. It was also found that the reaction also is applicable to a carbocyclic amide derivative. When

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• enables the synthesis of structurally distinct cyclic derivatives which are difficult to access by other methodologies, using an efficient and atom-economical path from simple precursors. In recent years several asymmetric catalytic cyclization strategies have been accomplished for the construction of N

• -heterocycles using various catalytic systems such as chiral metal catalysts, chiral Lewis acids or chiral organocatalysts. This review presents an overview of the recent advances in enantioselective cyclization reactions of 1-azadienes catalyzed by non-covalent organocatalysts. Keywords: α,β-unsaturated

• imines; asymmetric organocatalysis; cyclization; N-heterocycles; inverse electron demand aza-Diels–Alder reaction; Introduction Nitrogen-containing heterocycles are abundant scaffolds present in natural products, biologically active compounds, pharmaceuticals, synthetic agrochemicals, and functional

Synthesis of 2H-azirine-2,2-dicarboxylic acids and their derivatives

• Anastasiya V. Agafonova,
• Mikhail S. Novikov and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2024, 20, 3191–3197, doi:10.3762/bjoc.20.264

• complex, which facilitates the cleavage of the N–O bond and subsequent 1,3-cyclization, ultimately leading to the formation of 2H-azirine. Therefore, the isomerization of isoxazole 1j was carried out at a higher temperature, 82 °C, but after hydrolysis of the reaction mixture, instead of the expected

• azirine dicarboxylic acid 6j, oxazole-4-carboxylic acid 9 was isolated. Apparently, azirine 2j underwent ring opening at higher temperature to nitrile ylide 7, which after cyclization and hydrolysis gave acid 9 (Scheme 3) (cf., e.g. [23]). Next, given that the preparation of 2H-azirine-2-carboxamides from

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

• ,anti. Then, hydrazones 3 were reacted with zinc and methyl 2-(bromomethyl)acrylate (4). This aza-Barbier reaction was performed in a biphasic medium (THF/aqueous solution of saturated NH4Cl) to avoid the formation of the α-methylene-γ-lactam obtained by intramolecular cyclization of the zinc amide on

• not the enamine. As for the hydrazones 3e and 3f, we assumed that the hydrazones 6e and 6f were obtained as a mixture of conformers, E,syn and E,anti (Scheme 4). Surprisingly, the ratio of each conformer differs for hydrazones 6e (ratio 77:23) and 6f (ratio 52:48). The last cyclization step was based

• on an intramolecular Michael addition carried out in DMF and catalyzed by 10% of potassium carbonate. As previously observed [37], under these conditions, the 5-endo-trig cyclization was selective and the lactam resulting from the 5-exo-trig cyclization was not observed. Furthermore, in the case of

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• synthesizing diverse scaffolds [6]. Furthermore, the Ugi reaction exhibits versatility in forming both fused and unfused heterocyclic compounds, involving 4-, 5-, 6-, and 7-membered rings [17]. This capability is exploited by various approaches, including the Ugi–Deprotection–Cyclization strategy (UDC) and

• post-modification reactions. Examples of these reactions include the Ugi/Dieckmann reactions, Ugi/Robinson–Gabriel reactions, Ugi/Buchwald–Hartwig reactions, Ugi reaction followed by a catalytic aza-Wittig cyclization, Ugi reaction followed by SNAr strategy, Ugi/Heck reactions, Ugi/Huisgen

• cycloaddition, and Ugi reactions followed by Mitsunobu cyclization, among other strategies (Figure 2) [16]. Central nervous system diseases Central nervous system (CNS) diseases are the main cause of disability and the second cause of mortality worldwide, indeed, according to the 2019 World Health Organization

Synthesis of the 1,5-disubstituted tetrazole-methanesulfonylindole hybrid system via high-order multicomponent reaction

• Cesia M. Aguilar-Morales,
• América A. Frías-López,
• Nadia V. Emilio-Velázquez,
• Alejandro Islas-Jácome,
• Angelica Judith Granados-López,
• Jorge Gustavo Araujo-Huitrado,
• Yamilé López-Hernández,
• Hiram Hernández-López,
• Luis Chacón-García,
• Jesús Adrián López and
• Carlos J. Cortés-García

Beilstein J. Org. Chem. 2024, 20, 3077–3084, doi:10.3762/bjoc.20.256

• -indole system 10, in a two-step reaction: Ugi-azide followed by a cyclization reaction catalyzed by AuCl3, in good to high yields [21]. In 2019, Salahi et al. synthesized the series of tetrazole-indoles 15 via an Ugi-azide reaction in moderate to high yields [22]. It is noteworthy that none of the

• to obtain the 1,5-disubstituted tetrazole-alkyne 19 is well-documented and hence, it is not herein described in detail [1][26][31]. Thus, based on Pal and co-workers’ proposal [32][33], the second process involves two catalytic cycles: 1) a Sonogashira coupling, and 2) a 5-endo-dig cyclization. The

• , an intramolecular cyclization takes place, facilitated by CuI. This step involves a 5-endo-dig cyclization, where the negatively nitrogen atom of the sulfonamide 25 attacks intramolecularly to yield the intermediate 26. The final product is formed when iodide is regenerated as CuI, allowing it to re

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

C–H Trifluoromethylthiolation of aldehyde hydrazones

• Victor Levet,
• Balu Ramesh,
• Congyang Wang and
• Tatiana Besset

Beilstein J. Org. Chem. 2024, 20, 2883–2890, doi:10.3762/bjoc.20.242

• cyclization of aryl hydrazones with aryl isothiocyanates promoted by elemental sulfur [70]. In the course of their studies for the thiocyanation of ketene dithioacetals, Yang, Wang and co-workers developed an electrochemical oxidization-based synthetic strategy to circumvent the need for external oxidants. In

Synthesis of pyrrole-fused dibenzoxazepine/dibenzothiazepine/triazolobenzodiazepine derivatives via isocyanide-based multicomponent reactions

• Marzieh Norouzi,
• Mohammad Taghi Nazeri,
• Ahmad Shaabani and
• Behrouz Notash

Beilstein J. Org. Chem. 2024, 20, 2870–2882, doi:10.3762/bjoc.20.241

• electrophilic sites simultaneously in their structure, these zwitterions are able to participate in various cyclization processes, especially for the synthesis of pyrroles [37][38][39][40]. For example, Li et al. developed a one-pot four-component reaction (4-CR) of malononitrile, aldehydes, and isocyanides

• ) [42][43]. Another I-MCR for forming pyrroles is the in situ formation reaction of the zwitterion III, known as Huisgens 1,4-dipole. The latter is formed by the reaction of imines with acetylenedicarboxylates and can be trapped by an isocyanide through a [4 + 1] cyclization reaction to synthesize

• pyrroles. In our recent studies, we prepared pyrrole-fused dibenzoxazepines via an Ugi reaction. Here, the reaction of benzoxazepine imine and acetylenedicarboxylate leads to the Huisgens 1,4-dipole zwitterion in situ, which is trapped by an isocyanide through the cyclization process (Scheme 1c) [44][45

N-Glycosides of indigo, indirubin, and isoindigo: blue, red, and yellow sugars and their cancerostatic activity

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 2840–2869, doi:10.3762/bjoc.20.240

• precursors. The base-mediated reaction of 5-chloroanthranilic acid (8a) with chloroacetic acid afforded 8b (Scheme 5) [20]. Acetylation and base-mediated cyclization gave indoxyl 9a which was transformed to indigo 1c by oxidative dimerization. Benzylation finally afforded 1d. 4,6-Benzylidenation of ᴅ

• cyclization of 4e with oxalyl chloride afforded yellow isatin-N-glycoside 16a as an anomeric mixture from which the pure α- and β-anomer could be separated by chromatography. Likewise, isatin-N-glycosides 16b–f were prepared which were all isolated (except from rhamnoside 16b) as the pure β-anomers. The

• low activity was observed for oxime β-17f which is surprising, as good activities were previously reported for indirubin oximes as compared to other non-glycosylated indirubins. As mentioned above, the synthesis of acceptor-substituted isatin-N-glycosides by Lewis acid-mediated cyclization of the

Synthesis of tricarbonylated propargylamine and conversion to 2,5-disubstituted oxazole-4-carboxylates

• Kento Iwai,
• Akari Hikasa,
• Kotaro Yoshioka,
• Shinki Tani,
• Kazuto Umezu and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2024, 20, 2827–2833, doi:10.3762/bjoc.20.238

• reacts with butyllithium, ring closure occurs between the ethynyl and carbamoyl groups, yielding 2,5-disubstituted oxazole-4-carboxylates. This cyclization also occurs when the propargylamine is heated with ammonium acetate, resulting in double activation. Keywords: acid amide; diethyl mesoxalate; N

• , entries 6–8). When N-propanoyl derivative 4e was used, cyclization proceeded similarly, yielding the corresponding oxazole 5e (Table 3, entry 9). When the reaction was quenched with deuterium oxide instead of acetic acid, monodeuterated oxazole 5a-d1 was obtained (Scheme 2). Based on these experimental

• mechanism, as illustrated in Scheme 3b [13][14], we cannot negate this mechanism because the reaction media and bases were different. PCPA 4a was heated in the presence of methanesulfonic acid to undergo 6-endo-dig cyclization. However, hydration predominantly occurred, converting the ethynyl group to a

Synthesis and antimycotic activity of new derivatives of imidazo[1,2-a]pyrimidines

• Dmitriy Yu. Vandyshev,
• Daria A. Mangusheva,
• Khidmet S. Shikhaliev,
• Kirill A. Scherbakov,
• Oleg N. Burov,
• Alexander D. Zagrebaev,
• Tatiana N. Khmelevskaya,
• Alexey S. Trenin and
• Fedor I. Zubkov

Beilstein J. Org. Chem. 2024, 20, 2806–2817, doi:10.3762/bjoc.20.236

• intramolecular cyclization were observed (Table 1, entries 3 and 4). The best results were obtained when isopropyl alcohol was used, which furnished yields of the final product 4а up to 89% within 1 h (entry 9 in Table 1). In the case of methanol and ethanol, the maximum conversion was also observed during the

• 6a, which undergoes subsequent cyclization steps more favorably, leading to the formation of the target product 4a (∆G = −3.02 kcal/mol). This suggests that the first step of intermediate formation is the critical one. It is also noteworthy that the Michael addition via intermediate 6a is an

Copper-catalyzed yne-allylic substitutions: concept and recent developments

• Shuang Yang and
• Xinqiang Fang

Beilstein J. Org. Chem. 2024, 20, 2739–2775, doi:10.3762/bjoc.20.232

• , they also achieved the construction of C–N axis chirality through remote substitution/cyclization/1,5-H shift process (Scheme 26). The control experiments confirmed that the reaction requires the joint participation of copper and terminal alkyne, and the radical-capture experiment also ruled out a

• yne-allylic cation intermediate, followed by an intramolecular cyclization. The disparity in reactivity could stem from the chelation between acyclic 1,3-dicarbonyl enolates and the copper catalyst, enhancing γ-position attack in an intramolecular manner. Conversely, Meldrum's acid's rigid cyclic

• structure precludes stable copper-carbonyl interaction, favoring attack from a less hindered site. Later, Qi and Xu et al. [75] achieved highly enantioselective copper-catalyzed [4 + 1] cyclization of yne-allylic esters and cyclic 1,3-dicarbonyls, achieving remote stereoselective control through copper

Synthesis of spiroindolenines through a one-pot multistep process mediated by visible light

• Francesco Gambuti,
• Jacopo Pizzorno,
• Chiara Lambruschini,
• Renata Riva and
• Lisa Moni

Beilstein J. Org. Chem. 2024, 20, 2722–2731, doi:10.3762/bjoc.20.230

• cyclization of the indole derivatives is the most popular (Scheme 1a). For instance, the efficient synthesis of spiro[indoline-3,2′-pyrrolidines] [8][9][10] or spiro-isoxazoles [11] through different dearomatization processes has been reported. Recently, Ramana and Dothe have proposed an elegant gold

• –N bond oxidation to generate α-iminoamidines and then a final cyclization takes place (Scheme 2a). Although the synthetic procedure allowed the preparation of highly substituted complex structures under mild reaction conditions and on gram scale, it suffers from a limited structural diversity. Since

• , our plan provides: the oxidation of N-aryltetrahydroisoquinolines (N-Ar-THIQs) generating in situ the iminium ions 1, the 3C Ugi-type reaction of an electron-rich aniline, an isocyanide and 1; the subsequent oxidation of the Ugi-type product 2; and the final cyclization to give the spiro[indole-THIQs

Synthesis of benzo[f]quinazoline-1,3(2H,4H)-diones

• Ruben Manuel Figueira de Abreu,
• Peter Ehlers and
• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 2708–2719, doi:10.3762/bjoc.20.228

• was studied by UV–vis and fluorescence spectroscopy. Keywords: cross-coupling; cyclization; heterocycles; palladium; Introduction Nucleobases contain the coded information and give DNA and RNA their typical structure. As a nucleobase, uracil is involved in numerous vital processes and is therefore a

5th International Symposium on Synthesis and Catalysis (ISySyCat2023)

• Anthony J. Burke and
• Elisabete P. Carreiro

Beilstein J. Org. Chem. 2024, 20, 2704–2707, doi:10.3762/bjoc.20.227

• carbene (NHC) framework from polysubstituted aminoimidazo[5,1-b]oxazol-6-ium salts, which demonstrated strong catalytic activity in gold-catalyzed alkyne hydration and arylative cyclization reactions [14]. The synthesis of this new carbene involved the use of a novel nitrenoid reagent that was

Base-promoted cascade recyclization of allomaltol derivatives containing an amide fragment into substituted 3-(1-hydroxyethylidene)tetronic acids

• Andrey N. Komogortsev,
• Constantine V. Milyutin and
• Boris V. Lichitsky

Beilstein J. Org. Chem. 2024, 20, 2585–2591, doi:10.3762/bjoc.20.217

• deprotonates to the anion B under action of DBU. Subsequent intramolecular cyclization at the double bond of pyranone fragment leads to the formation of spiro compound C. Next, opening of the dihydropyranone ring results in pyrrolidin-2-one D which further transformed to the salt of 3-acyltetronic acid E