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

• hydrostatic pressure (HHP) was found to be an efficient activation method in several catalyst- and solvent-free reactions and has found application for the syntheses of heterocycles and the preparation of active pharmaceutical ingredients (APIs) via acylation and acid- and solvent-free esterification. The

• of important heterocycles, the synthesis of well-known APIs, such as acetaminophen and acetylsalicylic acid, a variety of esterification reactions and the successful scale up (up to 100 g scale) of the Paal–Knorr reaction. The use of HHP appears to provide several advantages, for example, resulting

• . Water is used as a pressure transmitting medium that has relatively low compressibility, readily available, and non-toxic. Results and Discussion HHP-assisted synthesis of 1,3-dihydrobenzimidazoles Heterocycles are extremely versatile compounds and are used as building blocks for fine chemicals and

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

• stable isosteric replacements for gem-dimethyl and carbonyl groups. This work reviews possible synthetic strategies towards these strained heterocycles, covering both de novo constructions of the 4-membered ring as well as derivatisations of oxetane building blocks, then reactivity of oxetanes in terms

• –2021, Kuduk and co-workers published three different tandem, one-pot methodologies towards complex polycyclic heterocycles [100][101][102]. All of them are two-step reactions consisting of an intermolecular coupling followed by an intramolecular, base-induced oxetane opening (Scheme 48). The first one

• reaction is assumed to proceed via an initial SN1 substitution of the tertiary alcohol followed by intramolecular opening of the oxetane ring. The authors further demonstrated the wide scope of this methodology by preparing spirocyclic and fused bicyclic dioxanes as well as sulphur-containing heterocycles

Recent advances in amidyl radical-mediated photocatalytic direct intermolecular hydrogen atom transfer

• Hao-Sen Wang,
• Lin Li,
• Xin Chen,
• Jian-Li Wu,
• Kai Sun,
• Xiao-Lan Chen,
• Ling-Bo Qu and
• Bing Yu

Beilstein J. Org. Chem. 2025, 21, 1306–1323, doi:10.3762/bjoc.21.100

• require electrophilic heterocycles. These limitations hinder the broader application of such systems. Alexanian’s group modified amidyl radical precursors by incorporating halogen atoms, transforming them into bifunctional reagents. The HAT component of amidyl radical precursors was facilitated by amidyl

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

• and co-workers demonstrated that also BN heterocycles can be obtained using similar types of precursors (Scheme 23) [107]. Compound 179 was reacted with PhBCl2 to yield BN heterocycle 180 in 78% yield. Compound 180 exhibits high sensitivity for the visual detection of fluoride ions and undergoes an

Recent advances in oxidative radical difunctionalization of N-arylacrylamides enabled by carbon radical reagents

• Jiangfei Chen,
• Yi-Lin Qu,
• Ming Yuan,
• Xiang-Mei Wu,
• Heng-Pei Jiang,
• Ying Fu and
• Shengrong Guo

Beilstein J. Org. Chem. 2025, 21, 1207–1271, doi:10.3762/bjoc.21.98

• difunctionalization of N-arylacrylamides has emerged as a powerful strategy for the construction of diverse nitrogen-containing heterocycles, particularly oxindoles and related scaffolds. This review provides a comprehensive summary of recent advances in oxidative radical difunctionalization of N-arylacrylamides with

Salen–scandium(III) complex-catalyzed asymmetric (3 + 2) annulation of aziridines and aldehydes

• Linqiang Wang and
• Jiaxi Xu

Beilstein J. Org. Chem. 2025, 21, 1087–1094, doi:10.3762/bjoc.21.86

• -containing five-membered saturated heterocycles. They are not only useful building blocks for the synthesis of biologically active compounds [1], for example, side-chain precursor of paclitaxel [2], but also widely exist in some pharmaceuticals [3][4], such as antibacterial agents of Gram-positive organisms

Synthesis of pyrrolo[3,2-d]pyrimidine-2,4(3H)-diones by domino C–N coupling/hydroamination reactions

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

Beilstein J. Org. Chem. 2025, 21, 1010–1017, doi:10.3762/bjoc.21.82

• . Keywords: alkynes; catalysis; cyclizations; domino reactions; heterocycles; Introduction Pyrimidines and purines are one of the most important heterocyclic compounds with prevalent biological functions. Both are found in nucleosides and their corresponding polymeric DNA and RNA, and hence are vital for

Recent total synthesis of natural products leveraging a strategy of enamide cyclization

• Chun-Yu Mi,
• Jia-Yuan Zhai and
• Xiao-Ming Zhang

Beilstein J. Org. Chem. 2025, 21, 999–1009, doi:10.3762/bjoc.21.81

• cyclization modes that provide entries to various N-heterocycles, some of which serve as key structural motifs in natural alkaloids. This review highlights recent advancements in enamide-based cyclization reactions, including enamide–alkyne cycloisomerization, [3 + 2] annulation, and polycyclization, with a

• principles, tandem reactions or annulations can be designed to efficiently access N-heterocycles. As the enamides are also easily accessible via condensations, applications of these nitrogen-containing building blocks in the synthesis of N-heterocycles are synthetically straightforward. When applied properly

• . Cyclization/isomerization – collective total synthesis of fawcettimine-type alkaloids The bicyclic decahydroquinoline enamide motif can serve as a versatile precursor to access different types of tricyclic N-heterocycles. As demonstrated in the above work from She’s group, the aza-Prins cyclization renders

Study of tribenzo[b,d,f]azepine as donor in D–A photocatalysts

• Katy Medrano-Uribe,
• Jorge Humbrías-Martín and
• Luca Dell’Amico

Beilstein J. Org. Chem. 2025, 21, 935–944, doi:10.3762/bjoc.21.76

• behavior is supported by the DFT studies, which suggested a better spatial separation between the HOMO and LUMO. As expected, the HOMO–LUMO energy gap followed a trend that is dependent on the electron-donating capacity of the nitrogen heterocycles and amine present in compounds 5e (2.9 eV), 5d (3.5 eV

Silver(I) triflate-catalyzed post-Ugi synthesis of pyrazolodiazepines

• Muhammad Hasan,
• Anatoly A. Peshkov,
• Syed Anis Ali Shah,
• Andrey Belyaev,
• Chang-Keun Lim,
• Shunyi Wang and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2025, 21, 915–925, doi:10.3762/bjoc.21.74

• isocyanides, followed by a silver(I) triflate-catalyzed intramolecular heteroannulation of the resulting pyrazole-tethered propargylamides occurring in a 7-endo-dig fashion. The approach is scalable and tolerates a diverse range of substitution patterns. Keywords: heterocycles; post-MCR transformations

• ; pyrazolodiazepines; silver catalysis; Ugi reaction; Introduction Synthetic chemists are continuously involved in the development of methodologies for accessing new heterocyclic scaffolds that resemble naturally occurring products and biologically active molecules [1][2]. Nitrogen heterocycles draw particular

• synthetic methods to access diazepines fused with other nitrogen-containing heterocycles towards their broader exploration in high-throughput screening for identifying new drug candidates. Traditional synthetic methods for producing medium-ring nitrogen-containing heterocycles often involve complex

4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Luc Van Meervelt,
• Do Thi Thao and
• Nguyen Minh Thong

Beilstein J. Org. Chem. 2025, 21, 817–829, doi:10.3762/bjoc.21.65

• , Vietnam Academy of Science and Technology (VAST), Hanoi 10072, Vietnam 10.3762/bjoc.21.65 Abstract Pyrrolidine-2,3-diones are important intermediates in the synthesis of numerous nitrogen-containing heterocycles which possess a broad spectrum of biological and pharmacological activities. In this article

Synthesis and photoinduced switching properties of C₇-heteroatom containing push–pull norbornadiene derivatives

• Daniel Krappmann and
• Andreas Hirsch

Beilstein J. Org. Chem. 2025, 21, 807–816, doi:10.3762/bjoc.21.64

• catalytic back-conversion studies. Keywords: heterocycles; molecular solar thermal systems; norbornadiene; photochemistry; quadricyclane; Introduction In recent decades, the demand for renewable energy has increased tremendously [1]. A promising alternative to fossil fuels is the utilization of so-called

Regioselective formal hydrocyanation of allenes: synthesis of β,γ-unsaturated nitriles with α-all-carbon quaternary centers

• Seeun Lim,
• Teresa Kim and
• Yunmi Lee

Beilstein J. Org. Chem. 2025, 21, 800–806, doi:10.3762/bjoc.21.63

• are important intermediates in organic syntheses because of the versatility of the cyano group, which can be readily transformed into a wide range of functional groups, including amides, carboxylic acids, amines, aldehydes, ketones, and N-heterocycles [6][7][8]. However, the synthesis of all-carbon

New advances in asymmetric organocatalysis II

• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 766–769, doi:10.3762/bjoc.21.60

• organocatalytic cycloaddition reactions of unsaturated imines. A broad variety of activation modes, as well as catalyst structures, was covered and found to be useful in affording a diverse array of chiral N-heterocycles [27]. In my group, we recently became interested in atroposelective catalytic syntheses

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

• amine (e.g., a fluorinated analogue of the antidepressant drug, citalopram 93 [160]). We now turn our attention to cyclic amines. Fluorine has been shown to be capable of modifing the conformations of a variety of N-heterocycles, ranging in size from four- to eight-membered rings [48][161][162][163]. In

Entry to 2-aminoprolines via electrochemical decarboxylative amidation of N‑acetylamino malonic acid monoesters

• Olesja Koleda,
• Janis Sadauskis,
• Darja Antonenko,
• Edvards Janis Treijs,
• Raivis Davis Steberis and
• Edgars Suna

Beilstein J. Org. Chem. 2025, 21, 630–638, doi:10.3762/bjoc.21.50

• facilitated the cyclization, and the 6-membered heterocycles 6h,i could be obtained in 27% and 18% yield, respectively. In addition to sulfonamides, carbamates such as N-Boc and benzamide are also suitable as nucleophiles for the anodic decarboxylation/cyclization reaction. However, the corresponding 2

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

• concerns and improved reaction control can be addressed, paving the way for more efficient and sustainable synthetic methodologies. Keywords: cascade reactions; formaldehyde surrogates; green chemistry; heterocycles; multicomponent reactions; Introduction Organic chemistry is a mature discipline that has

• the MCR product is possible thus increasing the versatility of these reactions in terms of structural diversity and molecular complexity. In this context, a wide variety of heterocycles and macrocycles as important biological scaffolds have been synthesized [6]. One of the most important components

• the cyclization process producing various highly diverse nitrogen-containing heterocycles, which are valuable scaffolds in medicinal chemistry [46]. Synthesis of non-aromatic heterocycles As stated above, DMSO can also hydrolytically decompose to formaldehyde. There are many examples of reactions in

Study of the interaction of 2H-furo[3,2-b]pyran-2-ones with nitrogen-containing nucleophiles

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

Beilstein J. Org. Chem. 2025, 21, 556–563, doi:10.3762/bjoc.21.44

• ][9]. Wherein, the wide variety of easily available starting butenolides and amines allows one to create a huge array of practically useful products. At the same time, the application of hydrazine derivatives expands the range of formed heterocycles. So, along with the aforementioned N-substituted

Vinylogous functionalization of 4-alkylidene-5-aminopyrazoles with methyl trifluoropyruvates

• Judit Hostalet-Romero,
• Laura Carceller-Ferrer,
• Gonzalo Blay,
• Amparo Sanz-Marco,
• José R. Pedro and
• Carlos Vila

Beilstein J. Org. Chem. 2025, 21, 533–540, doi:10.3762/bjoc.21.41

• diastereoselectivity (up to 7:1). Keywords: alcohols; diastereoselectivity; nitrogen heterocycles; pyrazoles; vinylogous reaction; Introduction Vinylogy refers to the transmission of electronic effects through a conjugated π-system, enabling the extension of a functional group's nucleophilic or electrophilic

• biologically active compounds, particularly antibacterial and antifungal agents [13][14]. This class of functionalized nitrogen heterocycles is notable for its synthetic versatility, because it shows different nucleophilic positions, making regioselectivity a synthetic challenge. Numerous studies have reported

Synthesis of electrophile-tethered preQ₁ analogs for covalent attachment to preQ₁ RNA

• Laurin Flemmich and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 483–489, doi:10.3762/bjoc.21.35

• novel compound DPQ1. Keywords: deazapurines; heterocycles; pyrrolopyrimidines; queuosine; riboswitches; ribozymes; RNA alkylation; RNA labelling; Introduction Pre-queuosine 1 (preQ1) is a biosynthetic precursor of the hypermodified nucleoside queuosine (Q) that is found in the wobble position of

New tandem Ugi/intramolecular Diels–Alder reaction based on vinylfuran and 1,3-butadienylfuran derivatives

• Yuriy I. Horak,
• Roman Z. Lytvyn,
• Andrii R. Vakhula,
• Yuriy V. Homza,
• Nazariy T. Pokhodylo and
• Mykola D. Obushak

Beilstein J. Org. Chem. 2025, 21, 444–450, doi:10.3762/bjoc.21.31

• and step-economy, making them promising for future commercial applications. Partly hydrogenated isoindoles and their derivatives exhibit broad biological activities and are considered privileged motifs in medicinal chemistry [20][21]. These compounds, when condensed with aromatics or heterocycles

Unraveling aromaticity: the dual worlds of pyrazole, pyrazoline, and 3D carborane

• Zahra Noori,
• Miquel Solà,
• Clara Viñas,
• Francesc Teixidor and
• Jordi Poater

Beilstein J. Org. Chem. 2025, 21, 412–420, doi:10.3762/bjoc.21.29

• ], offering enhanced properties and efficacy [28][30][33][34][35]. Therefore, the advancement of simple, efficient methodologies for synthesizing o-carborane-fused heterocycles is critically needed. However, the limited number of synthetic strategies for carborane functionalization [36] continues to constrain

• , whereas the boron cage is aromatic, the heterocyclic ring is clearly non-aromatic, with MCI that amount to 0.002, 0.000 and 0.003 a.u., respectively (Figure 4). At difference, based on NICS, these heterocycles should be considered aromatic (−8.5, −7.1, and −8.3 ppm, respectively). However, we have

• neighboring cycles exhibit high or very high NICS values. For a more reliable evaluation, it is important to also consider structural factors and additional indicators like the multicenter index (MCI) [54][55][56][57]. Thus, from now on, we will evaluate the aromaticity of heterocycles solely using the

Synthesis, structure, ionochromic and cytotoxic properties of new 2-(indolin-2-yl)-1,3-tropolones

• Yurii A. Sayapin,
• Eugeny A. Gusakov,
• Inna O. Tupaeva,
• Alexander D. Dubonosov,
• Igor V. Dorogan,
• Valery V. Tkachev,
• Anna S. Goncharova,
• Gennady V. Shilov,
• Natalia S. Kuznetsova,
• Svetlana Y. Filippova,
• Tatyana A. Krasnikova,
• Yanis A. Boumber,
• Alexey Y. Maksimov,
• Sergey M. Aldoshin and
• Vladimir I. Minkin

Beilstein J. Org. Chem. 2025, 21, 358–368, doi:10.3762/bjoc.21.26

• ; Introduction 1,2-Benzoquinones represent unique building blocks for various classes of heterocyclic systems. Their structure depends on the reactivity of the initial heterocycles and 1,2-benzoquinones, as well as on the reaction conditions. In the series of 2-methylquinolines [1], 2-methylquinoxalines [2], 2

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

• significant attention for their unique photophysical characteristics and versatility in NIR-driven reactions [51]. Cyanins consist of nitrogen-containing heterocycles connected by a polymethin chain [52][53], whose synthesis and modifications have been widely explored [54][55][56]. Such compounds exhibit

Heteroannulations of cyanoacetamide-based MCR scaffolds utilizing formamide

• Marios Zingiridis,
• Danae Papachristodoulou,
• Despoina Menegaki,
• Konstantinos G. Froudas and
• Constantinos G. Neochoritis

Beilstein J. Org. Chem. 2025, 21, 217–225, doi:10.3762/bjoc.21.13

• structure was obtained, revealing certain geometrical features. Keywords: 2-amino-substituted heterocycles; cyanoacetamide; Gewald reaction; multicomponent reaction (MCR); pyrimidine; Introduction The term “net-zero carbon” is becoming increasingly common as we consider a future marked by a rising global

• (hetero)aromatic, bulky and linear amines with different substitution patterns. The compounds 2–4 were purified by recrystallization and employed as such (Scheme 2). To our great delight, the heterocycles 2–4 could successfully be subjected to refluxing formamide under neat conditions, instantly yielding

• anthranilic acid and B) access to heteroannulated pyrimidones by MCRs of suitably substituted heterocycles and formamide as C1 source. Access to the key building blocks 2–4 by employing three different nonisocyanide-based MCRs. Diversity and complexity were the essential features of our library of starting