Direct trifluoroethylation of carbonyl sulfoxonium ylides using hypervalent iodine compounds

• Radell Echemendía,
• Carlee A. Montgomery,
• Fabio Cuzzucoli,
• Antonio C. B. Burtoloso and
• Graham K. Murphy

Beilstein J. Org. Chem. 2024, 20, 3182–3190, doi:10.3762/bjoc.20.263

• the ethyl or ethoxy groups and therefore it is very attractive for applications in medicinal chemistry and related areas [10][11][12][13]. α-Carbonyl sulfoxonium ylides are well recognized as more stable and more easily handled surrogates of diazo compounds [14][15]. They have also emerged as

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

• ; Introduction The synthesis of molecules capable of mimicking the various secondary structures and key functions of proteins is a major challenge in medicinal chemistry, especially in the fields of protein–protein interactions [1][2]. Accordingly, the incorporation of heterocyclic amino acids into peptides

• is known about its β-analog (Figure 3), although β-amino acids have been shown to strongly modulate the structural, metabolic, and biological characteristics of peptides [13]. Finally, it is well known that fluorine is a very useful tool in medicinal chemistry as the incorporation of fluorinated

• has become an essential structural motif in medicinal chemistry due to its hydrogen-bond donor capacity, its lipophilic character, and as a bioisostere for alcohol, thiol, or amine groups [16][17][18][19]. Thus, the contribution of fluorinated compounds to pharmaceuticals has been crucial for more

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

• de Santiago de Compostela, 15782 Santiago de Compostela, Spain Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain Institute of Biomedicine of the University of Barcelona (IBUB), Av

• ; schizophrenia; Introduction Multicomponent reactions Due to efforts to develop new drug arsenals faster to overcome the difficulties of medicinal chemistry (multistage and highly wasteful processes), multicomponent reactions (MCRs) have emerged as a plausible solution. MCRs are convergent reactions in which

• /intramolecular Ullmann-type C–N coupling reactions. Azido-Ugi 4CR/cyclization (AU-4CR) strategy: The azido-Ugi four-component reaction (AU-4CR) is an elegant and atom economical approach for obtaining substituted tetrazoles, which are very relevant in medicinal chemistry [64]. When combined with suitable post

Controlled oligomerization of [1.1.1]propellane through radical polarity matching: selective synthesis of SF₅- and CF₃SF₄-containing [2]staffanes

• Jón Atiba Buldt,
• Wang-Yeuk Kong,
• Yannick Kraemer,
• Masiel M. Belsuzarri,
• Ansh Hiten Patel,
• James C. Fettinger,
• Dean J. Tantillo and
• Cody Ross Pitts

Beilstein J. Org. Chem. 2024, 20, 3134–3143, doi:10.3762/bjoc.20.259

• in the medicinal chemistry arena, in stark contrast to single BCP units over the past 12 years [20][21][22][23][24]. One plausible explanation for the paucity of applications of [n]staffanes in materials or biological settings is a synthetic accessibility issue. For instance, dimerization of

Advances in the use of metal-free tetrapyrrolic macrocycles as catalysts

• Mandeep K. Chahal

Beilstein J. Org. Chem. 2024, 20, 3085–3112, doi:10.3762/bjoc.20.257

• well as transition and rare-earth metals [32][33]. There are many comprehensive reviews covering these two areas along with the connection of these ligands to supramolecular and medicinal chemistry [34][35][36]. In addition, calix[4]pyrroles, due to the presence of four accessible inner NHs and well

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

• the application of this reagent as a central building block in the synthesis of hybrid systems via Ugi-azide reactions, including structures based on triazoles-tetrazoles [24][26][27], benzofuran-tetrazoles [23] and indolizines-tetrazoles [25], all of which have significant relevance in medicinal

• chemistry and optical science. A plausible reaction mechanism for the formation of the target molecules 18a–n via a high-order multicomponent reaction is shown in Scheme 3 and consists of two processes: an Ugi-azide reaction and a Pd/Cu-catalyzed heteroannulation reaction. The Ugi-azide reaction mechanism

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

• become sought-after functionalities, particularly following the multi-tone consumption in polymer production and success in medicinal chemistry. The selective introduction of a peroxide fragment at different positions on the target molecule is a priority in the modern reaction design. The pioneering

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

• controlled by such protein kinases. Therefore, the investigation of the influence of drugs on protein kinases plays an important role in current medicinal chemistry. Indigo naturalis is a traditional drug, derived from indigo plants, which has been used in China for centuries and also more recently against

• [12][13]. In addition, there are more and more applications in the field of medicinal chemistry, especially for the treatment of cancer [14][15]. In the course of the renewed interest in the chemistry of indigo, indirubin, and isoindigo in the field of cancer research, N-glycosides of these compounds

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

• compounds occupy a pivotal position in the arsenal of modern organic and medicinal chemistry due to their extensive spectrum of physiological activity [1]. Imidazo[1,2-a]pyrimidines represent one of the most promising classes of compounds within this group [2][3]. These small azoheterocyclic frameworks

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

• method to access structurally diverse chiral coumarin derivatives, which are of great interest in the fields of medicinal chemistry and synthetic organic chemistry (Scheme 22, 22a–y). Moreover, the utilization of 2-(1-ethoxyethylidene)malononitrile as a γ-nucleophile yielded the desired product 22z with

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

• [25][27] and for their known interest in medicinal chemistry. Towards this goal, N-phenylbenzoxazepine 5 was synthesized and subjected to the one-pot protocol within tert-butyl isocyanide and 3,5-dimethoxyaniline (Scheme 5). Unfortunately, the reaction mixture appeared very complex and the desired

Synthesis and cytotoxicity studies of novel N-arylbenzo[h]quinazolin-2-amines

• Battini Veeraiah,
• Kishore Ramineni,
• Dabbugoddu Brahmaiah,
• Nangunoori Sampath Kumar,
• Hélène Solhi,
• Rémy Le Guevel,
• Chada Raji Reddy,
• Frédéric Justaud and
• René Grée

Beilstein J. Org. Chem. 2024, 20, 2592–2598, doi:10.3762/bjoc.20.218

•  1), are recognized as a “privileged scaffold” in bioorganic and medicinal chemistry [1]. On the other hand, the 2-anilinoquinazolines have been less studied but our groups have developed recently the synthesis of new molecules of this family and discovered a compound (DB18) with a potent inhibition

• has not been used earlier, should offer attractive potentialities in bioorganic and medicinal chemistry. Extension of these studies are ongoing in our laboratories and corresponding results will be reported in due course. Experimental Chemical synthesis General information All reactions were performed

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

• significant potential for further industrial and medicinal chemistry applications (Scheme 5). Furthermore, Ackermann and coworkers described a straightforward C(sp3)–H amination of 1,3-diarylpropenes with sulfonamides via direct oxidation of allylic C(sp3)–H bonds [13]. During the reaction process, a radical

Photoredox-catalyzed intramolecular nucleophilic amidation of alkenes with β-lactams

• Valentina Giraldi,
• Giandomenico Magagnano,
• Daria Giacomini,
• Pier Giorgio Cozzi and
• Andrea Gualandi

Beilstein J. Org. Chem. 2024, 20, 2461–2468, doi:10.3762/bjoc.20.210

• -centered radicals, such as aminyl, amidyl, or iminyl radicals, N-heterocyclic amidyl radicals were largely underinvestigated despite their importance as intermediates or relevant N-heterocyclic products in medicinal chemistry [7][8][9][10]. Recently, photoredox catalysis has emerged as a novel area of

Synthesis, electrochemical properties, and antioxidant activity of sterically hindered catechols with 1,3,4-oxadiazole, 1,2,4-triazole, thiazole or pyridine fragments

• Daria A. Burmistrova,
• Andrey Galustyan,
• Nadezhda P. Pomortseva,
• Kristina D. Pashaeva,
• Maxim V. Arsenyev,
• Oleg P. Demidov,
• Mikhail A. Kiskin,
• Andrey I. Poddel’sky,
• Nadezhda T. Berberova and
• Ivan V. Smolyaninov

Beilstein J. Org. Chem. 2024, 20, 2378–2391, doi:10.3762/bjoc.20.202

• heteroatoms (nitrogen, sulfur, selenium, tellurium, etc.) as well as redox-active functional groups allows one to vary significantly the biological activity of such compounds. Heterocyclic molecular blocks are widely used in medicinal chemistry [12]. Thiazole, oxadiazole, triazole, imidazole, and other

• compounds leads to an increased lipophilicity and, as a result, facilitates the transfer of the molecule through cell membranes to the target site [22]. 1,2,4-Triazole derivatives also play a key role in medicinal chemistry, especially in the development of new antivirals [23][24] and antibacterial agents

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• ; rearrangement; Introduction Nitrogen-containing organic compounds (sometimes referred to as alkaloids due to their basic properties) are of critical importance in medicinal chemistry because of their unique binding properties to biomolecules [1]. Out of 55 drug candidates, approved by the FDA in 2023, 28 (51

• ][18][19][20][21][22][23], none have focused specifically on organocatalytic approaches, which are particularly important for medicinal chemistry due to their greener credentials. Given the wide range of organocatalytic methods for synthesising homoallylic amines developed in the past decade, it is

• practical potential of the methodology was illustrated by constructing the medicinal chemistry-relevant highly fused spiro compound 140 featuring 5 stereocentres (3 quaternary) in 99% ee and 76% overall yield from achiral 136 and racemic 137 in just 2 steps. Selected substrates were converted to the

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

• various diseases [17][18][19][20]. Therefore, due to their NO-releasing abilities, furoxan derivatives also demonstrate anticancer, antiplatelet, antiviral and antiparasitic properties [21][22][23][24][25][26][27][28][29][30][31][32]. Another valuable nitrogen heterocyclic scaffold in medicinal chemistry

Metal-free double azide addition to strained alkynes of an octadehydrodibenzo[12]annulene derivative with electron-withdrawing substituents

• Naoki Takeda,
• Shuichi Akasaka,
• Susumu Kawauchi and
• Tsuyoshi Michinobu

Beilstein J. Org. Chem. 2024, 20, 2234–2241, doi:10.3762/bjoc.20.191

• azide–alkyne cycloaddition; Introduction The strain-promoted azide–alkyne cycloaddition (SpAAC) is one of the most representative metal-free click chemistry reactions [1][2][3][4][5]. SpAAC has been mainly employed in bioconjugation in the fields of chemical biology and medicinal chemistry due to its

Heterocycle-guided synthesis of m-hetarylanilines via three-component benzannulation

• Andrey R. Galeev,
• Maksim V. Dmitriev,
• Alexander S. Novikov and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2024, 20, 2208–2216, doi:10.3762/bjoc.20.188

• the possible substitution patterns, meta-substituted anilines hold a special place. These compounds are difficult to access due to the inherent ortho-/para-directional reactivity of the amino group, at the same time they are widely used in medicinal chemistry, resulting in several marketed drugs

Finding the most potent compounds using active learning on molecular pairs

• Zachary Fralish and
• Daniel Reker

Beilstein J. Org. Chem. 2024, 20, 2152–2162, doi:10.3762/bjoc.20.185

• . Methods Datasets Datasets were obtained from Landrum et al. [23] which utilized their simulated medicinal chemistry project data (SIMPD) algorithm to curate and split 99 ChEMBL [24] Ki datasets with consistent values for target id, assay organism, assay category, and BioAssay Ontology (BAO) format into

• splits that were generated to mimic real-world medicinal chemistry project data sets [23] such that the external data simulates learning from historic data to predict undiscovered “future” compounds instead of simply being selected from a separate cluster based on chemical similarity (Supporting

• during medicinal chemistry projects. We believe that ActiveDelta and other pairwise approaches show particular promise for adaptive machine learning when training data hungry neural networks on limited data and can serve as accurate platforms to guide lead optimization and prioritization during drug

O,S,Se-containing Biginelli products based on cyclic β-ketosulfone and their postfunctionalization

• Kateryna V. Dil and
• Vitalii A. Palchykov

Beilstein J. Org. Chem. 2024, 20, 2143–2151, doi:10.3762/bjoc.20.184

• ) are the key methodology to access valuable heterocycles for medicinal chemistry projects. The classical Biginelli reaction (1893) is an acid-catalyzed, three-component reaction between an aldehyde, β-ketoester, and urea that produces 3,4-dihydropyrimidin-2(1H)-ones, also known as DHPMs (Scheme 1A

• compounds with anticancer, antihypertensive, antiinflammatory, antioxidant, antimicrobial, antifungal, antimalarial, antitubercular, antidiabetic, antifilarial, anti-Alzheimer, antiepileptics and other activities [1][2][3][4][5][6][7][8][9][10][11]. The concept of "privileged structures" in medicinal

• chemistry highlights derivatives capable of interacting with multiple receptors or enzymes, making them ideal candidates for drug discovery. Dihydropyrimidinones (DHPMs) and their derivatives are particularly noteworthy within this category. Accordingly, their synthesis is of significant interest for

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

• solution, as described in the experimental section. This information is provided in brackets. Review Synthesis of azacycles Nitrogen-containing heterocyclic compounds possess numerous applications in various domains such as materials science, agrochemistry and medicinal chemistry. Especially, 60% of all

Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations

• Pengcheng Lu,
• Luis Juarez,
• Paul A. Wiget,
• Weihe Zhang,
• Krishnan Raman and
• Pravin L. Kotian

Beilstein J. Org. Chem. 2024, 20, 1940–1954, doi:10.3762/bjoc.20.170

• pharmacophore in medicinal chemistry and the challenges in obtaining either N1- or N2-alkylated indazoles as the dominant regioisomer [30][34][35][36][37][38][39], we were interested in exploring the regioselectivity with methyl 5-bromo-1H-indazole-3-carboxylate (6, Figure 1) as a multifunctional model compound

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

• , while also holding a crucial function in many biological processes [8]. Non-canonical amino acids (NCAs) are widely used in medicinal chemistry [9]. Not surprisingly, they also find broad use as bifunctional building blocks (BBs) for DELs. In an early example, an 800-million-members DEL utilized Fmoc

• applicable to a broad range of substrates, however, it utilizes a catalyst that is not commercially available and small heteroaromatic rings are underrepresented in the scope. Recognizing the importance of small heteroaromatic rings and the amino acid motif in medicinal chemistry [30][31][32][33], and aiming

• underrepresented in the peer-reviewed literature in comparison to phenyl groups or their six-membered counterparts (e.g., pyridines, pyrimidines) [42]. Furthermore, the increasing importance of small heteroaromatic rings containing nitrogen, sulfur and/or oxygen in medicinal chemistry is well depicted by the list

Access to 2-oxoazetidine-3-carboxylic acid derivatives via thermal microwave-assisted Wolff rearrangement of 3-diazotetramic acids in the presence of nucleophiles

• Ivan Lyutin,
• Vasilisa Krivovicheva,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 1894–1899, doi:10.3762/bjoc.20.164

• (azetidin-2-one) scaffold to medicinal chemistry and drug design is self-evident. This four-membered heterocycle is a key fragment of many antibiotics [1], including penicillin and its analogues, as well as other pharmacologically important molecules [2]. Therefore, the search for new efficient and