Switchable pathways of multicomponent heterocyclizations of 5-amino-1,2,4-triazoles with salicylaldehydes and pyruvic acid

• Yana I. Sakhno,
• Oleksander V. Buravov,
• Kostyantyn Yu. Yurkov,
• Anastasia Yu. Andryushchenko,
• Svitlana V. Shishkina and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2025, 21, 2030–2035, doi:10.3762/bjoc.21.158

• depending on the conditions, can either be limited to a Biginelli condensation with the formation of hydroxytetrahydropyrimidines or proceed with further post-cyclization to form oxygen-bridged triazolobenzoxadiazocine derivatives. Furthermore, a multicomponent synthesis of oxygen-bridged pyrimidine systems

α-Ketoglutaric acid in Ugi reactions and Ugi/aza-Wittig tandem reactions

• Vladyslav O. Honcharov,
• Yana I. Sakhno,
• Olena H. Shvets,
• Vyacheslav E. Saraev,
• Svitlana V. Shishkina,
• Tetyana V. Shcherbakova and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2025, 21, 2021–2029, doi:10.3762/bjoc.21.157

• library of bis- and tetraamides was synthesized by the Ugi reaction with α-ketoglutaric acid, tert-butyl isocyanide, aromatic aldehydes, and aromatic amines. When o-azidoanilines were used, azidated peptidomimetics were obtained, the post-cyclization of which by the aza-Wittig reaction yielded a series of

• ], antibacterial [8][14][15], and anticancer [16][17] activities. The use of the Ugi reaction followed by post-cyclization is an effective strategy that yields diverse heterocycle-containing peptidomimetics and requires a minimal number of steps [18]. For example, Mazur et al. [19] developed an efficient method

• in 33–93% yields (Scheme 3; Table 3). According to the literature [31][53], this reaction proceeds through the formation of an iminophosphorane intermediate (Scheme 3), the product of a Staudinger reaction, which, however, was not isolated because it easily undergoes intramolecular cyclization on a

Measuring the stereogenic remoteness in non-central chirality: a stereocontrol connectivity index for asymmetric reactions

• Ivan Keng Wee On,
• Yu Kun Choo,
• Sambhav Baid and
• Ye Zhu

Beilstein J. Org. Chem. 2025, 21, 1995–2006, doi:10.3762/bjoc.21.155

• are assigned following the 3-step procedure for all types of strategies including cyclization, biaryl coupling, and desymmetrization, irrespective of the chemical identity of the newly established chiral axis including C–C [10][11] (Scheme 3C and 3D), C–N [12] (Scheme 3B), N–N [13] (Scheme 3A), and C

• same procedure as in Scheme 5C. In analogy to Scheme 5B, the direct cyclization forging the planar chirality [24] in Scheme 6B is regarded as [31 10], in which two stereogenic arenes are proximate and the two distal arenes are considered diastereomeric. The desymmetrization cross-coupling of cavitands

Aryl iodane-induced cascade arylation–1,2-silyl shift–heterocyclization of propargylsilanes under copper catalysis

• Rasma Kroņkalne,
• Rūdolfs Beļaunieks,
• Armands Sebris,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2025, 21, 1984–1994, doi:10.3762/bjoc.21.154

• likely formed via the allylic cation intermediate Int-1 (Scheme 2), from where on two competing mechanistic pathways are possible. Deprotonation of the β-H and reductive elimination affords diene 10. Alternatively, an intramolecular cyclization leads to silylindenes 11. We were interested to see whether

• techniques, indicating that the observed arylation–cyclization cascade reaction is highly stereospecific. With this result in hand, we performed copper catalyst screening (Table 3). We observed that CuCl and the CuOTf benzene complex gave similarly good yields (82–84% by NMR, Table 3, entries 2 and 4), while

• propargylsilane 7d halogenation–cyclization cascade and Suzuki–Miyaura cross-coupling in the second step [22]. Thus, we have developed a faster and palladium-free route towards tetrahydrofurans 8. The latter can still be modified further through silicon–halide exchange followed by cross-coupling chemistry as

Asymmetric total synthesis of tricyclic prostaglandin D2 metabolite methyl ester via oxidative radical cyclization

• Miao Xiao,
• Liuyang Pu,
• Qiaoli Shang,
• Lei Zhu and
• Jun Huang

Beilstein J. Org. Chem. 2025, 21, 1964–1972, doi:10.3762/bjoc.21.152

• available has prevented its practical use, and synthesis methods for tricyclic-PGDM methyl ester are required. Based on the utilization of oxidative radical cyclization for the stereoselective construction of the cyclopentanol subunit with three consecutive stereocenters, we describe an asymmetric total

• synthesis of tricyclic-PGDM methyl ester in 9 steps and 8% overall yield. Keywords: asymmetric total synthesis; oxidative radical cyclization; tricyclic prostaglandin D2 metabolite methyl ester; Introduction Prostaglandins (PGs), a family of hormone-like lipid compounds, are ubiquitous natural products

• total synthesis of 4 and is required to explore alternative synthetic strategies for PGs and analogues [17]. Biosynthetically, 4 is proposed to arise via a 5-exo-trig biogenetic radical-mediated cyclization (Scheme 1C) [18][19]. Over the past five decades, the Snider oxidative radical reaction has been

Enantioselective desymmetrization strategy of prochiral 1,3-diols in natural product synthesis

• Lihua Wei,
• Rui Yang,
• Zhifeng Shi and
• Zhiqiang Ma

Beilstein J. Org. Chem. 2025, 21, 1932–1963, doi:10.3762/bjoc.21.151

• JohnPhos (6) induced cyclization, yielding bicyclic compound 7 with a 7-membered heterocycle. Final deprotection of the methoxymethyl (MOM) group in 7 afforded (+)-heliannuol D (8). Having successfully applied PPL-catalyzed acetylation to the synthesis of (+)-heliannuol D, the Shishido group subsequently

• intramolecular cyclization of 16 generated benzofuran 17 in 83% yield. After protecting the phenolic hydroxy group of 17, cross-metathesis (CM) with allylic alcohol 18 catalyzed by 13 furnished intermediate 19. Desilylation of 19 produced heliannuol G (20) and heliannuol H (21), with the structure of 21

• 62% ee. A two-step conversion of 34 gave diol 35, which underwent Prins/Friedel–Crafts tandem cyclization to construct tetracyclic compound 36. Final deprotection delivered (+)-brazilin (37). Candida antarctica lipase (CAL) CAL is a type of lipase originating from the yeast Candida antarctica and

Synthesis of N-doped chiral macrocycles by regioselective palladium-catalyzed arylation

• Shuhai Qiu and
• Junzhi Liu

Beilstein J. Org. Chem. 2025, 21, 1917–1923, doi:10.3762/bjoc.21.149

• ; inherent chirality; N-doped macrocycle; nonplanarity; regioselective cyclization; Introduction Chiral macrocycles have attracted significant research interest owing to their diverse applications in enantioselective recognition [1][2], catalysis [3][4], and circularly polarized luminescence [5][6

• . Interestingly, for the cyclization of 3b, only compound MC3 was obtained in 85% yield, which is probably attributed to larger steric hindrance deriving from bis(trifluoromethyl)phenyl groups. These macrocycles show good solubility in common solvents, and their chemical structures have been unambiguously

Stereoselective electrochemical intramolecular imino-pinacol reaction: a straightforward entry to enantiopure piperazines

• Margherita Gazzotti,
• Fabrizio Medici,
• Valerio Chiroli,
• Laura Raimondi,
• Sergio Rossi and
• Maurizio Benaglia

Beilstein J. Org. Chem. 2025, 21, 1897–1908, doi:10.3762/bjoc.21.147

• , and a ceramic diaphragm [44]. This method was found to be effective for synthesizing trans-2,3-diarylpiperazines through the intramolecular reductive coupling of 1,2-diimines and seven- and eight-membered heterocycles which were obtained in moderate to good yields via the cyclization of 1,3- and 1,4

• electrochemical cyclization process. In contrast, more complex and extended heterocyclic electronrich π-systems such as compound 2j was obtained in 35% yield only, presumably as a result of electronic factors affecting the efficiency of the initial radical formation [47]. To further extend the scope of this

Chiral phosphoric acid-catalyzed asymmetric synthesis of helically chiral, planarly chiral and inherently chiral molecules

• Wei Liu and
• Xiaoyu Yang

Beilstein J. Org. Chem. 2025, 21, 1864–1889, doi:10.3762/bjoc.21.145

• CPA-catalyzed cyclization of INT-E through the dual hydrogen bonding activation transition state TS-1 afforded the eight-membered heterocycle INT-F with a stereogenic center. Through the elimination of aniline 73, the saddle-shaped dibenzo[1,5]diazocine 72 was produced via a central-to-inherent

Fe-catalyzed efficient synthesis of 2,4- and 4-substituted quinolines via C(sp²)–C(sp²) bond scission of styrenes

• Prafull A. Jagtap,
• Manish M. Petkar,
• Vaishnavi R. Sawant and
• Bhalchandra M. Bhanage

Beilstein J. Org. Chem. 2025, 21, 1799–1807, doi:10.3762/bjoc.21.142

• cycloaddition, tandem annulation, intramolecular cyclization, and cross-coupling reactions are commonly employed under thermal conditions, utilizing metal catalysts based on Pd, Ru, Au, Cu, and Fe to access a wide array of substituted quinoline frameworks [29][30][31][32][33][34][35][36][37][38]. Conversely, in

• cleavage as well as inadequate Lewis acid activation of N-methylaniline (1a′), which hinders its further cyclization into the final product 3a′. The reaction, when conducted in the absence of a catalyst, failed to proceed, thereby highlighting the crucial role of catalytic activation in facilitating the

• formation of intermediates III and III′. Subsequent electrophilic cyclization/C–H annulation of the aromatic amine, followed by aromatization, afford intermediates V and V′. The oxidative dehydrogenation of intermediates V and V′ then results in the formation of products 3a and 3a′ and the regeneration of

Synthesis of chiral cyclohexane-linked bisimidazolines

• Changmeng Xi,
• Qingshan Sun and
• Jiaxi Xu

Beilstein J. Org. Chem. 2025, 21, 1786–1790, doi:10.3762/bjoc.21.140

• , condensation of N-sulfonylated 1,2-diphenylethane-1,2-diamines and cyclohexane-1,2-dicarboxylic acid, and the final cyclization with the in situ generated Hendrickson reagent. Keywords: bisimidazoline; cyclohexane; cyclohexane-1,2-dicarboxylic acid; 1,2-diphenylethane-1,2-diamine; Introduction Chiral

• cyclized product 5e in a low yield of 30% due to its poor nucleophilicity. However, 1,2-cyclohexane-1,2-dicarboxamide 4f with two very strong electron-poor trifluoromethyl groups did not undergo cyclization due to its very poor nucleophilicity. The results are collected in Table 1. Following the similar

• )-N1,N2-bis((1R,2R)-2-(tert-butoxycarbonyl)-1,2-diphenylethyl)cyclohexane-1,2-dicarboxamide (4h) in 65% yield through the reaction with (1S,2S)-cyclohexane-1,2-dicarboxylic acid (3). However, compound 4h did not undergo cyclization possibly due to weak nucleophilicity and steric hindrance of the Boc

Research progress on calixarene/pillararene-based controlled drug release systems

• Liu-Huan Yi,
• Jian Qin,
• Si-Ran Lu,
• Liu-Pan Yang,
• Li-Li Wang and
• Huan Yao

Beilstein J. Org. Chem. 2025, 21, 1757–1785, doi:10.3762/bjoc.21.139

• modifiable ring positions, and many PA derivatives with different functional groups can be obtained through the cyclization reaction of 1,4-dialkoxybenzene monomers or post-synthetic modification reactions [74]. PAs possess a unique internal cavity characterized by an electron-rich and hydrophobic

Preparation of a furfural-derived enantioenriched vinyloxazoline building block and exploring its reactivity

• Madara Darzina,
• Anna Lielpetere and
• Aigars Jirgensons

Beilstein J. Org. Chem. 2025, 21, 1737–1741, doi:10.3762/bjoc.21.136

• . Cleavage of the N-Alloc group leading to a mixture of isomers cis-S-5 and trans-S-5. Cleavage of the N-Alloc group with PdCl2(S-BINAP) leading to trans-S-5 and trans-R-5. Cyclization of amides trans-S-5 and trans-R-5 to oxazolines S-6 and R-6. aza-Diels–Alder reaction of vinyloxazoline S-6 with TsNCO. The

3,3'-Linked BINOL macrocycles: optimized synthesis of crown ethers featuring one or two BINOL units

• Somayyeh Kheirjou,
• Jan Riebe,
• Maike Thiele,
• Christoph Wölper and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2025, 21, 1719–1729, doi:10.3762/bjoc.21.134

• this is too short to result in a mono-BINOL macrocycle. The corresponding BINOL-based dichlorides Me/H/iPr-62 could be obtained in good yields (59/78/76%) and further reacted with the diols Me/H/iPr-2 in the presence of Cs2CO3 (CH3CN, 80 °C). This cyclization yielded the symmetrically tetrasubstitued

Catalytic asymmetric reactions of isocyanides for constructing non-central chirality

• Jia-Yu Liao

Beilstein J. Org. Chem. 2025, 21, 1648–1660, doi:10.3762/bjoc.21.129

• cycloamidation of N-alkyl-2-isocyanobenzamides 5 with 2,6-disubstituted aryl iodides 6 (Scheme 2a) [28]. Through a coupling–cyclization reaction sequence, axially chiral 2-arylquinazolinones 7 were synthesized in 35–93% yield with 71–95% ee. Interestingly, by using N-(2,4-dimethoxyphenyl)-2-isocyanobenzamide (8

• cyclization of functionalized phenyl isocyanides, guided by DFT calculations (Scheme 2b) [29]. Three types of isocyanides (10–12) were evaluated in reactions with aryl iodides, affording indole-fused N-heteroaryl scaffolds 13–15, featuring either a C–C or C–N stereogenic axis, in moderate-to-high yields with

• double C(sp2)–H imidoylative cyclization with aryl iodides, furnishing symmetrical pyrido[6]helicenes 23 or furan-incorporating pyrido[7]helicenes 24 with stable helical chirality, respectively. Furthermore, pre-cyclized monoisocyanides, such as 25a and 25b, were identified as another class of suitable

Photocatalysis and photochemistry in organic synthesis

• Timothy Noël and
• Bartholomäus Pieber

Beilstein J. Org. Chem. 2025, 21, 1645–1647, doi:10.3762/bjoc.21.128

• , and flow chemistry are being harnessed to push the limits of light-driven reactions [36]. Terada and colleagues show in this thematic issue how flow chemistry is used to significantly improve the yield of a π-Lewis acidic metal-catalyzed cyclization–radical addition sequence [37]. Recently, chemists

Transition-state aromaticity and its relationship with reactivity in pericyclic reactions

• Israel Fernández

Beilstein J. Org. Chem. 2025, 21, 1613–1626, doi:10.3762/bjoc.21.125

• Cope rearrangements [20]. More recently, Alabugin and co-workers reported that the gold(I)-catalyzed propargyl rearrangement depicted in Scheme 1b also follows a concerted oxonia Claisen pathway (via an aromatic TS) rather than through a higher barrier 6-endo-dig cyclization [21], which provides

• corresponding transition states is comparable). Thermal cycloisomerization of 1,3-hexadien-5-ynes (Hopf cyclization) Since the original report by Hopf and Musso in 1969 [80], the thermal cycloisomerization reactions of 1,3-haxedien-5-ynes have been widely applied to the synthesis of aromatic six-membered rings

• [81]. From a mechanistic point of view, this process involves the initial formation of a bent-allene intermediate, which leads to the final reaction product via hydrogen shifts (Scheme 2) [82]. The so-called Bergman cyclization of cis-3-hexene-1,5-diynes [83][84], which is suggested to proceed through

Synthesis of optically active folded cyclic dimers and trimers

• Ena Kumamoto,
• Kana Ogawa,
• Kazunori Okamoto and
• Yasuhiro Morisaki

Beilstein J. Org. Chem. 2025, 21, 1603–1612, doi:10.3762/bjoc.21.124

• ]paracyclophanes via Wurtz-type intramolecular cyclization [3]. [2.2]Paracyclophane has a molecular structure in which two benzene rings are stacked face-to-face with ethylene chains at the para positions. Various studies have been conducted on their reactivities and physical properties derived from their unique

3-Aryl-2H-azirines as annulation reagents in the Ni(II)-catalyzed synthesis of 1H-benzo[4,5]thieno[3,2-b]pyrroles

• Julia I. Pavlenko,
• Pavel A. Sakharov,
• Anastasiya V. Agafonova,
• Derenik A. Isadzhanyan,
• Alexander F. Khlebnikov and
• Mikhail S. Novikov

Beilstein J. Org. Chem. 2025, 21, 1595–1602, doi:10.3762/bjoc.21.123

• to the azirine C=N bond, followed by cyclization and the aziridine ring opening into the [3 + 2] cycloaddition product 5 (Scheme 3). It is noteworthy that the annulation proceeds via the azirine N‒C3 bond cleavage. Elimination of the methoxycarbonyl group most likely occurs under the action of

Heterologous biosynthesis of cotylenol and concise synthesis of fusicoccane diterpenoids

• Ye Yuan,
• Zhenhua Guan,
• Xue-Jie Zhang,
• Nanyu Yao,
• Wenling Yuan,
• Yonghui Zhang,
• Ying Ye and
• Zheng Xiang

Beilstein J. Org. Chem. 2025, 21, 1489–1495, doi:10.3762/bjoc.21.111

• Nozaki–Hiyama–Kishi reaction and a one-pot Prins cyclization/transannular hydride transfer to construct the 5-8-5 tricyclic scaffold. Enzymatic oxidations were used to install the hydroxy group at the C-3 position. Ten fusicoccanes were synthesized in 8–13 steps each. Despite these efforts, a strategy

• enzymatic terpene cyclization and chemical synthesis [30][31][32][33]. Briefly, the carbon scaffolds are forged by terpene cyclases, followed by concise chemical transformations to yield the desired natural products. Here, we describe heterologous biosynthesis of cotylenol by engineering the biosynthetic

• ). Results and Discussion Fusicoccanes feature a characteristic dicyclopenta[a,d]cyclooctane (5-8-5) ring system that is biosynthesized from geranylgeranyl pyrophosphate (GGPP) via class I terpene cyclization (Figure 2a). To date, two fusicoccadiene synthases have been identified by the analysis of the

Advances in nitrogen-containing helicenes: synthesis, chiroptical properties, and optoelectronic applications

• Meng Qiu,
• Jing Du,
• Nai-Te Yao,
• Xin-Yue Wang and
• Han-Yuan Gong

Beilstein J. Org. Chem. 2025, 21, 1422–1453, doi:10.3762/bjoc.21.106

• chiroptical retention upon nitrogen incorporation. Qian’s group developed a series of azahelicenes 15a–d through Bischler–Napieralski cyclization [28]. Notably, compound 15b displayed a high interconversion barrier of 36.0 kcal mol−1, enabling enantiomeric resolution. All compounds exhibited visible-range

• double aza-oxa[7]helicene via oxidative coupling followed by dehydrative cyclization [85]. The resulting meso-isomer (P,M)-71 emerged as the major product, exhibiting dual emission bands at 415 and 440 nm and solvent-independent absorption at 407 nm. Expanding the structural diversity, the group

• developed a two-pot synthesis of unsymmetrical hetero[7]helicenes 72a–g in 2023 [86], employing p-benzoquinone and N-aryl-2-naphthylamines through acid-promoted cyclization followed by electrochemical domino reactions. This method produced six compounds with yields ranging from 33–45%, all featuring

Reactions of acryl thioamides with iminoiodinanes as a one-step synthesis of N-sulfonyl-2,3-dihydro-1,2-thiazoles

• Vladimir G. Ilkin,
• Pavel S. Silaichev,
• Valeriy O. Filimonov,
• Tetyana V. Beryozkina,
• Margarita D. Likhacheva,
• Pavel A. Slepukhin,
• Wim Dehaen and
• Vasiliy A. Bakulev

Beilstein J. Org. Chem. 2025, 21, 1397–1403, doi:10.3762/bjoc.21.104

• ]. 2,5-Dihydro-1,2-thiazoles were synthesized by oxidative cyclization of N-arylamides of 3-(alkylamino)prop-2-enethiocarboxylic acids with iodine (Scheme 1А) [16]. 2,3-Dihydro-1,2-thiazoles were first synthesized in 1997 by the reaction of 2,2-dimethyl-N-alkylsulfonyl-N-benzylaminoacetonitrile with

High-pressure activation for the solvent- and catalyst-free syntheses of heterocycles, pharmaceuticals and esters

• Kelsey Plasse,
• Valerie Wright,
• Guoshu Xie,
• R. Bernadett Vlocskó,
• Alexander Lazarev and
• Béla Török

Beilstein J. Org. Chem. 2025, 21, 1374–1387, doi:10.3762/bjoc.21.102

• -products. A computational study accompanies the experimental data to interpret the outcome of the reactions. Keywords: acetaminophen; acetylsalicylic acid; benzimidazoles; catalyst-free synthesis; cyclization; esters; high hydrostatic pressure; pyrazoles; Introduction Non-traditional activation methods

• ][33][34][35], especially in the realm of high pressure chemistry [36][37], in the present work we demonstrate a variety of new, catalyst- and additional solvent-free applications of HHP to develop green synthesis methods. Here, we describe several cyclization reactions for the preparation of a variety

• appears to be applicable for other substrates as well, although the yields were lower, which is mainly due to the decomposition of the products (Scheme 1). HHP-assisted cyclization of chalcones with hydrazines for the synthesis of pyrazoles The cyclization of 1,3-bifunctional compounds, such chalcones

Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

• , and 6-endo cyclization pathways – this may be attributed to precoordination of the Cu(I) catalyst to the alkoxide, which facilitates oxidative addition into the C–Br bond and results in the formation of a favorable five-membered Cu-containing intermediate [48]. Ten years later, while developing the

Recent advances and future challenges in the bottom-up synthesis of azulene-embedded nanographenes

• Bartłomiej Pigulski

Beilstein J. Org. Chem. 2025, 21, 1272–1305, doi:10.3762/bjoc.21.99

• [52]. With the appropriate choice of substrates, this approach can also be used for the synthesis of π-extended azulenes. For example, Tobe and co-workers conducted the intramolecular cyclization of 1,4,5,8-tetrakis(mesitylethynyl)naphthalene 50 using I2 in CH2Cl2 (Scheme 8) [53]. In the reaction

• methoxide or morpholine, giving the corresponding substitution products 131 and 132 in 60% and 74%, respectively. Very recently, during revision of this work, Aratani and co-workers reported the use of this strategy in the synthesis of two azulene-embedded isomers of perylene monoimide [88]. Cyclization of

• alkenes: A bismuth-catalysed cyclization of alkenes has been demonstrated as an efficient synthetic tool for the creation of benzenoid PAHs [89]. Murai and co-workers applied this approach to the synthesis of azulene-embedded nanographenes (Scheme 18) [90]. Vinyl ethers 133a–d were cyclized using Bi(OTf)3