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

• all of these authors confirmed, after analyzing the position of the deuterium atoms in the final compound, that the methylene unit incorporated into the heterocycle came from DMSO. In the case of pyrazole synthesis, Guo et al. proposed a three-component cascade reaction of enaminones, hydrazines, and

• using formaldehyde in only minor yields. This can be explained in terms of the regiospecificity of the reaction: when DMSO is used as the C1 synthon, two different ways of transferring the CH group at different positions in the pyrazole ring (12 and 12’) are allowed. However, this cannot be accomplished

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

• the molecule. In this regard we performed the acylation of starting compound 8o using pivaloyl chloride. The process was carried out with 3-fold excess of the aforementioned reagent at reflux in MeCN for 3 h. As a result, product 13 bearing two acyl fragments at oxygen atoms of pyranone and pyrazole

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

• between 4-alkylidene-5-aminopyrazoles and alkyl trifluoropyruvates leading to highly functionalized tertiary alcohols bearing a trifluoromethyl group and a pyrazole ring is presented. The corresponding trifluoromethyl alcohols are obtained in moderate to good yields (up to 80%) and high

• -butyl group is present in the C-3 position of the pyrazole as in the case of substrate 2e, the reaction did not take place, likely due to a considerable increase in steric hindrance. We also attempted to synthesize 4-(alkenyl)-5-aminopyrazoles using an acyclic ketone, such as acetone, but unfortunately

• the double bond to the carbonyl in a relative re-si approach, generating intermediate I, which undergoes a tautomerization to recover the aromatic pyrazole ring. The increased yield observed in some cases with SQ-1 may be attributed to the formation of additional hydrogen bonds that enhance

Unprecedented visible light-initiated topochemical [2 + 2] cycloaddition in a functionalized bimane dye

• Metodej Dvoracek,
• Brendan Twamley,
• Mathias O. Senge and
• Mikhail A. Filatov

Beilstein J. Org. Chem. 2025, 21, 500–509, doi:10.3762/bjoc.21.37

• , School of Chemistry, Trinity College Dublin, The University of Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin D02 R590, Ireland 10.3762/bjoc.21.37 Abstract Bimanes, a class of molecules based on the 1H,7H-pyrazolo[1,2-a]pyrazole-1,7-dione scaffold, were first introduced by

• E. M. Kosower in 1978. In this study, we report the topochemical cycloaddition of diethyl 2,6-dichloro-1,7-dioxo-1H,7H-pyrazolo[1,2-a]pyrazole-3,5-dicarboxylate (Cl2B), initiated by visible light. Crystal structure analysis confirmed that the reactive double bonds are parallel and coplanar, in line

• development of a novel scaffold for topochemically active monomers. Bimanes Bimanes, a class of bicyclic compounds first synthesized by Kosower and Pazhenchevsky in 1978 [16], are based on a 1H,7H-pyrazolo[1,2-a]pyrazole-1,7-dione scaffold. The general structure of a bimane is depicted in Figure 1a. The term

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

• Barcelona, Spain 10.3762/bjoc.21.29 Abstract A new series of o-carborane-fused pyrazoles has been recently successfully synthesized. This fusion was expected to create a hybrid 3D/2D aromatic system, combining the 3D aromaticity of o-carborane with the 2D aromaticity of pyrazole. However, while the boron

• the n + 1 MOs of the carborane prevents significant electronic delocalization between the two fused components. This contrasts with the fusion of pyrazole and benzene to form indazole, where both rings maintain their 2D aromaticity. Our findings demonstrate that the peripheral σ-aromaticity of

• of aromaticity. Therefore, relying solely on NICS can be misleading, and other computational indicators, along with experimental or structural data, should be used to accurately assess aromaticity. Keywords: 3D aromaticity; carborane; density functional theory; NICS ambiguity; pyrazole

Synthesis, characterization, antimicrobial, cytotoxic and carbonic anhydrase inhibition activities of multifunctional pyrazolo-1,2-benzothiazine acetamides

• Ayesha Saeed,
• Shahana Ehsan,
• Muhammad Zia-ur-Rehman,
• Erin M. Marshall,
• Sandra Loesgen,
• Abdus Saleem,
• Simone Giovannuzzi and
• Claudiu T. Supuran

Beilstein J. Org. Chem. 2025, 21, 348–357, doi:10.3762/bjoc.21.25

• are synthesized by incorporation of benzothiazine, pyrazole, and amide moieties in a new scaffold to create multifunctional derivatives of pyrazolo-1,2-benzothiazine. The presented compounds have been synthesized and analyzed using spectroscopic and spectrometric techniques including FTIR, HRMS, 1H

• [4]. Notable previous efforts include the synthesis of benzothiazine scaffolds connected to other heterocyclic moieties such as piperazine [5], triazole [6][7], hydantoin [8], and pyrazole moieties [9][10]. Very few examples of pyrazolobenzothiazines presenting an amide moiety are published. This

• work covers the synthesis of synergistic scaffolds containing biologically active 1,2-benzothiazine, pyrazole, and amide moieties. 1,2-Benzothiazines are chemically gifted drug candidates. Since one of the very first synthesis in 1956 [11], these scaffolds have proved themselves as versatile and

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

• , Ankara 06800, Türkiye 10.3762/bjoc.20.273 Abstract Acenaphthylene-fused heteroarenes with a variety of five- and six-membered heterocycles such as thiophene, furan, benzofuran, pyrazole, pyridine and pyrimidine were synthesized via an efficient Pd-catalyzed reaction cascade in good to high yields (45–90

• methodology was further examined with (1-methyl-1H-pyrazole-5-yl)boronic acid pinacol ester as the pyrazole ring is one of the most frequently occurring aromatic nitrogen heterocycles among the pharmaceuticals approved by the U.S. FDA between 2013 and 2023 according to a recently-reported analysis [53]. With

• the use of this boronic ester, acenaphthylene-fused pyrazole product 15d was isolated in 80% yield (Table 2, entry 3). Importantly, the use of 1,8-dibromo-4,5-dimethoxynaphthalene (14) with the same boronic ester afforded dimethoxy-substituted acenaphthylene-fused pyrazole 15e in good yield (73

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

• improved biological activities. Employing this approach, Kushwaha et al. [34] synthesized a series of compounds containing benzofuran, tetrazole, and pyrazole within a single structure (Scheme 2). Benzofurans and tetrazole pharmacophores have demonstrated potential anti-Alzheimer activity by inhibiting

• AChE, while pyrazole scaffolds possess the ability to reduce the tau and β-amyloid dual aggregation. Benzofuran-pyrazole aldehydes were employed in the Ugi azide reaction to give the desired hybrids. From the screened compounds, 2a, 2b, 2c, 2d, 2e, and 2f demonstrated notable efficacy in regulating the

• of best derivatives obtained by Hasaninejad et al. [49]. Best DRD2 compounds synthesized using a multicomponent strategy. Oxoindole-β-lactam core produced in a U4C-3CR. Ugi-azide synthesis of benzofuran, pyrazole and tetrazole hybrids. Four-component Ugi reaction for the synthesis of novel

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 reactions; pyrazole; Introduction Pyrazoles and 1,2-diazoles [1] have received considerable interest in the past years. Although they are rarely found in nature [2], their spectrum of biological activity is remarkably broad, leading to numerous applications in pharmaceutical chemistry [3][4

• ][5][6]. For instance, pyrazoles serve as monoamine oxidase A and B inhibitors [7] and as COX-II inhibitors [8], making them valuable analgesics [9]. Furthermore, several blockbuster drugs, such as VIAGRA® [10], Celecoxib® [11], and Rimonabant [12], contain pyrazole cores. In addition, extensive

• concatenation of organic elementary steps in a one-pot fashion. Many reviews on general syntheses of pyrazoles have been published [25][26][27][28][29][30][31][32][33][34][35][36][37][38], as well as a few dedicated reviews on MCR synthesis of pyrazole derivatives [39][40][41]. In sensu stricto, multicomponent

Understanding X-ray-induced isomerisation in photoswitchable surfactant assemblies

• Beatrice E. Jones,
• Camille Blayo,
• Jake L. Greenfield,
• Matthew J. Fuchter,
• Nathan Cowieson and
• Rachel C. Evans

Beilstein J. Org. Chem. 2024, 20, 2005–2015, doi:10.3762/bjoc.20.176

• replaced by a pyrazole, which improves several aspects of their performance, including quantitative photoswitching between isomers and significantly enhanced thermal stability of the Z isomer [13][14][15]. This has led to recent reports on the integration of AAPs into surfactants to form systems with

Harnessing the versatility of hydrazones through electrosynthetic oxidative transformations

• Aurélie Claraz

Beilstein J. Org. Chem. 2024, 20, 1988–2004, doi:10.3762/bjoc.20.175

• conducted in a divided cell under potentiostatic conditions at 1.2–1.65 V vs SCE in acetonitrile. In 1976, the same group reported the anodic cyclization of chalcone-derived N-phenylhydrazone 3 to pyrazole 4 in a divided cell at constant current (Scheme 2) [37]. The obtained poor yield was explained by the

• iodonium through a two-electron process. Subsequent reaction with the hydrazone and deprotonation formed the N-iodo hydrazone intermediate 80, triggering the reaction with the amine 78 through cationic species 81. Final cyclization delivered the desired pyrazole 79 (Scheme 15) [60]. The group of D. Tang

• 2022, the group of Huang employed aromatic azoles 118 as additional suitable nucleophilic partners for C(sp2)–H functionalization of aldehyde-derived N,N-disubstituted hydrazones 117. A wide range of aldehyde-derived hydrazones reacted smoothly with various azoles including pyrazole derivatives

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

• results, thiazole 2b, benzothiazole 2i and benzimidazole 2t react very well with sodium nitrite in an acidic environment (Scheme 6, red section). Among the various subclasses of compounds, pyrazole 2l exhibited a high reactivity using t-BuONO and EtONa in ethanol (Scheme 6, red section). On the other hand

2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space

• Carlos Nieto,
• Alejandro Manchado,
• Ángel García-González,
• David Díez and
• Narciso M. Garrido

Beilstein J. Org. Chem. 2024, 20, 1880–1893, doi:10.3762/bjoc.20.163

• importance and applications of ring-modified histidines, Sharma et al. [66] reviewed the design, synthesis, and medicinal chemistry of these motifs covering antimicrobial, antiplasmodial, CNS and anticancer applications among others. Pyrazoles: Betazole (95) is a pyrazole-like histamine analogue with H2

Oxidation of benzylic alcohols to carbonyls using N-heterocyclic stabilized λ³-iodanes

• Thomas J. Kuczmera,
• Pim Puylaert and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2024, 20, 1677–1683, doi:10.3762/bjoc.20.149

• mild oxidation of primary and secondary benzylic alcohols to aldehydes and ketones as an alternative to λ5-iodanes. Results and Discussion Initially, we investigated a variety of pyrazole-, triazole-, and oxazole-substituted hydroxy-NHIs previously developed by our group [25]. However, none of them

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• ]. Furthermore, alternative alkyl groups such as ethyl, propargyl, allyl, benzyl, and nitrobenzyl groups can be transferred [31][138][139][140][141][142]. Such alkylation strategies have been successfully applied to small molecules such as coumarin [141], anthranilate [21], and pyrazole [24], as well as larger

pKalculator: A pK_a predictor for C–H bonds

• Rasmus M. Borup,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2024, 20, 1614–1622, doi:10.3762/bjoc.20.144

• pKa values. In the case of compound 3, most chemists would expect the pKa of pyrazole C–H sites to be considerably lower than those on the benzene ring, suggesting that factors other than pKa determine the site of borylation for this compound. In the case of compound 5, the most likely explanation is

Primary amine-catalyzed enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones

• Pooja Goyal,
• Akhil K. Dubey,
• Raghunath Chowdhury and
• Amey Wadawale

Beilstein J. Org. Chem. 2024, 20, 1518–1526, doi:10.3762/bjoc.20.136

• 10.3762/bjoc.20.136 Abstract The enantioselective 1,4-addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones catalyzed by a cinchona alkaloid-derived primary amine–Brønsted acid composite is reported. Both enantiomers of the anticipated pyrazole derivatives were obtained in good to excellent

• ; organocatalysis; pyrazoles; Introduction N-Heterocycles are attractive molecules owing to their extensive applications in small-molecule drugs, natural products, and agrochemical products [1][2][3]. Among the N-heterocycles, pyrazole is an important structural scaffold, found in several marketed drugs and

• structurally diverse pyrazole derivatives [4][5][6][7][10][11][12]. 4-Unsubstituted pyrazolin-5-ones are well known precursors for the construction of optically active structurally diverse pyrazoles [10][11][12]. In this context, the organocatalyzed asymmetric Michael addition of 4-unsubstituted pyrazolin-5

Synthesis of 4-functionalized pyrazoles via oxidative thio- or selenocyanation mediated by PhICl₂ and NH₄SCN/KSeCN

• Jialiang Wu,
• Haofeng Shi,
• Xuemin Li,
• Jiaxin He,
• Chen Zhang,
• Fengxia Sun and
• Yunfei Du

Beilstein J. Org. Chem. 2024, 20, 1453–1461, doi:10.3762/bjoc.20.128

• oxidant. This metal-free approach was postulated to involve the in situ generation of reactive thio/selenocyanogen chloride (Cl–SCN/SeCN) from the reaction of PhICl2 and NH4SCN/KSeCN, followed by an electrophilic thio/selenocyanation of the pyrazole skeleton. Keywords: PhICl2; pyrazoles; selenocyanation

• and bone diseases), dimetilan (III, Figure 1) (demonstrating excellent insecticidal effects) [13][14][15] all possess a pyrazole framework in their respective chemical structure. Considering the pharmaceutical significance of pyrazole compounds, there has been growing interest in the development of

• efficient strategies for accessing functionalized pyrazole derivatives. Thio/selenocyano groups are widely existing in the core structural motifs of various natural products and pharmaceutical agents [16][17][18][19][20]. Many S/SeCN-containing bioactive small molecules have been proved to possess wide

Synthesis of substituted triazole–pyrazole hybrids using triazenylpyrazole precursors

• Simone Gräßle,
• Laura Holzhauer,
• Nicolai Wippert,
• Olaf Fuhr,
• Martin Nieger,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2024, 20, 1396–1404, doi:10.3762/bjoc.20.121

• of Technology, Kaiserstraße 12, 76131 Karlsruhe, Germany 10.3762/bjoc.20.121 Abstract A synthesis route to access triazole–pyrazole hybrids via triazenylpyrazoles was developed. Contrary to existing methods, this route allows the facile N-functionalization of the pyrazole before the attachment of

• the triazole unit via a copper-catalyzed azide–alkyne cycloaddition. The developed methodology was used to synthesize a library of over fifty new multi-substituted pyrazole–triazole hybrids. We also demonstrate a one-pot strategy that renders the isolation of potentially hazardous azides obsolete. In

• addition, the compatibility of the method with solid-phase synthesis is shown exemplarily. Keywords: azide; click reaction; CuAAC; pyrazole; triazene; triazole; Introduction Nitrogen-containing heterocycles are central scaffolds in medicinal chemistry and are incorporated in most small-molecule drugs [1

Three-component N-alkenylation of azoles with alkynes and iodine(III) electrophile: synthesis of multisubstituted N-vinylazoles

• Jun Kikuchi,
• Roi Nakajima and
• Naohiko Yoshikai

Beilstein J. Org. Chem. 2024, 20, 891–897, doi:10.3762/bjoc.20.79

• between various azoles and internal alkynes is mediated by benziodoxole triflate as the electrophile in a trans-fashion, affording azole-bearing vinylbenziodoxoles in moderate to good yields. The tolerable azole nuclei include pyrazole, indazole, 1,2,3-triazole, benzotriazole, and tetrazole. The iodanyl

• catalysis encompassed various azoles such as pyrazole, indazole, and (benzo)triazole, exhibiting high Z-selectivity. In addition, Cao et al. reported a gold-catalyzed addition of 5-substituted tetrazoles to terminal alkynes [11]. Analogous hydroazolation reactions of alkynes have also been achieved under

• reaction of azoles with alkynes and iodine(III) electrophile, benziodoxole triflate (BXT, 1; Scheme 1c). Displaying exclusive trans-selectivity, the reaction tolerates a broad range of azoles, including pyrazole, 1,2,3-triazole, tetrazole, indazole, and benzotriazole, with internal alkynes as coupling

N-Boc-α-diazo glutarimide as efficient reagent for assembling N-heterocycle-glutarimide diads via Rh(II)-catalyzed N–H insertion reaction

• Grigory Kantin,
• Pavel Golubev,
• Alexander Sapegin,
• Alexander Bunev and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2023, 19, 1841–1848, doi:10.3762/bjoc.19.136

• pyrazole derivatives (including indazole), benzimidazole, 1,2,3-triazole, indole, carbazole, indoline, quinazoline, and isoquinoline. Nevertheless, many heterocyclic motifs still remain beyond the attention of researchers. For example, glutarimides that incorporate tetrazole and 1,2,4-triazole substituents

• decrease in the yield of the target compound 6h. The structures of the obtained regioisomers 6g and 6h were confirmed by the NOESY spectra, in which cross-peaks between the protons of the glutarimide ring and the singlet of the proton of the pyrazole cycle are observed. Reactions with benzotriazoles are

Trifluoromethylated hydrazones and acylhydrazones as potent nitrogen-containing fluorinated building blocks

• Zhang Dongxu

Beilstein J. Org. Chem. 2023, 19, 1741–1754, doi:10.3762/bjoc.19.127

• as fluorinated building blocks for the synthesis of difluoromethylated pyrazole derivatives by such [3 + 2] cycloaddition reactions [73][84][85] (Scheme 13). These studies therefore emphasize that fluoromethylated nitrile imines are versatile building blocks for [3 + 2] and [3 + 3] cycloaddition

Unprecedented synthesis of a 14-membered hexaazamacrocycle

• Anastasia A. Fesenko and
• Anatoly D. Shutalev

Beilstein J. Org. Chem. 2023, 19, 1728–1740, doi:10.3762/bjoc.19.126

• Anastasia A. Fesenko Anatoly D. Shutalev N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Ave., 119991 Moscow, Russian Federation 10.3762/bjoc.19.126 Abstract The transformation of 3-[(ethoxymethylene)amino]-1-methyl-1H-pyrazole-4-carbonitrile into the 14

• and therefore more conformationally rigid compounds. Previously, the unintentional preparation of two polyunsaturated 1,2,4,8,9,11-hexaazamacrocycles fused with two benzene or two pyrazole rings has been reported [39][40]. In particular, Dolzhenko et al. attempted to reproduce the synthesis of 4-imino

• -2-methyl-2,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-amine described by Baraldi et al. [41] using the reaction of 3-[(ethoxymethylene)amino]-1-methyl-1H-pyrazole-4-carbonitrile with excess hydrazine hydrate in EtOH under reflux. However, a pyrazole-fused 1,2,4,8,9,11-hexaazamacrocycle was unexpectedly

Cyanothioacetamides as a synthetic platform for the synthesis of aminopyrazole derivatives

• Valeriy O. Filimonov,
• Alexandra I. Topchiy,
• Vladimir G. Ilkin,
• Tetyana V. Beryozkina and
• Vasiliy A. Bakulev

Beilstein J. Org. Chem. 2023, 19, 1191–1197, doi:10.3762/bjoc.19.87

• pyrazoles has been thus synthesized. The structure of the reaction products was studied using NMR spectroscopy and mass spectrometry and confirmed by X-ray diffraction analysis. Keywords: aminopyrazoles; 2-cyanothioacetamides; enamines; hydrazines; Introduction Compounds containing a pyrazole cycle

• biologically active substances containing amide groups [14]. The presence of a pyrazole core and a thioamide group within the hybrid molecules that we are planning to obtain, allows us to expect both an increase in their activity and the emergence of other types of biological activity, and also high synthetic

•  1D). Results and Discussion Considering that the construction of the pyrazole cycle can be carried out by the interaction of hydrazine with 1,3-bielectrophilic reagents, we paid attention to the structure of 2-cyanothioacetamides 1 and 3-amino-2-cyanoprop-2-enethioamides 2 [22] which combine in one

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81