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

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 in medicinal chemistry, as it can be employed as a rational to expand bioactive chemical space to tackle lead optimization issues like lack of potency, efficacy, and selectivity or pharmacokinetic/dynamic issues. One of the most important building blocks (in the sense of participating in a vast

• area of chemical space of biological importance) in medicinal chemistry is the 2-phenethyl moiety, a key component of diverse drug-like entities. Although the core 2-phenethylamine structure has been recognized by the drug discovery community, little attention has been given to the various ring-based

• examples, which will be a valuable repository of phenyl, heteroaryl, and other replacement units of high value to the drug discovery community. Keywords: bioisosteres; 2-heteroarylethylamines; medicinal chemistry; 2-phenethylamine; scaffold hopping; Introduction One of the major hit-2-lead exploration

A facile three-component route to powerful 5-aryldeazaalloxazine photocatalysts

• Ivana Weisheitelová,
• Radek Cibulka,
• Marek Sikorski and
• Tetiana Pavlovska

Beilstein J. Org. Chem. 2024, 20, 1831–1838, doi:10.3762/bjoc.20.161

• of applications in medicinal chemistry, chemosensors, polymers and catalysis [1][2][3][4][5][6][7][8]. Among them, flavins (Fl) are essential redox-active natural compounds that act as enzyme cofactors in numerous biochemical processes [9]. Structurally related to flavins are isomeric alloxazines

Synthesis of polycyclic aromatic quinones by continuous flow electrochemical oxidation: anodic methoxylation of polycyclic aromatic phenols (PAPs)

• Hiwot M. Tiruye,
• Solon Economopoulos and
• Kåre B. Jørgensen

Beilstein J. Org. Chem. 2024, 20, 1746–1757, doi:10.3762/bjoc.20.153

• properties make them privileged structures in medicinal chemistry [2]. Benzoquinone and naphthoquinone can exist as ortho-quinone and para-quinone, with the latter considered more stable [5]. Additionally, p- and o-quinones are formed in metabolism of drugs [6] as well as polycyclic aromatic hydrocarbons

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• the future design of more potent and selective drugs. Keywords: biological activity; drug development; heterocycle; spiro steroid; synthetic transformations; Introduction Small-ring heterocycles constitute valuable scaffolds in medicinal chemistry for generating biologically active derivatives

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

• ] and experimentally validated their approach using six pharmaceutical intermediates from medicinal chemistry programs. In the article, they state that ”Iridium catalysts ligated by bipyridine ligands catalyze the borylation of the aryl C–H bonds that are most acidic and least sterically hindered…”[45

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• -oxidation and decomposition to improve the reaction efficiency overall. Conclusion The fluorination of benzylic C(sp3)–H bonds provides rapid access to an important functional group used in medicinal chemistry to control the pharmacokinetic profile of drug candidates. Historical and recent research efforts

Electrophotochemical metal-catalyzed synthesis of alkylnitriles from simple aliphatic carboxylic acids

• Yukang Wang,
• Yan Yao and
• Niankai Fu

Beilstein J. Org. Chem. 2024, 20, 1497–1503, doi:10.3762/bjoc.20.133

• functional group compatibility and is applicable to alkyl acids with all substitution pattern. Due to the wide utility of alkylnitriles, we expect this method to be widely adopted within the synthetic and medicinal chemistry communities. The present work also demonstrated electrophotochemical transition

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

• thioethers [27]. Likewise, selenocyanates can be used as versatile precursors for the synthesis of a variety of selenium-containing compounds [28][29][30][31][32]. As the S/SeCN-containing organic compounds play an important role in organic and medicinal chemistry, organic chemists have devoted a great deal

Challenge N- versus O-six-membered annulation: FeCl₃-catalyzed synthesis of heterocyclic N,O-aminals

• Giacomo Mari,
• Lucia De Crescentini,
• Gianfranco Favi,
• Fabio Mantellini,
• Diego Olivieri and
• Stefania Santeusanio

Beilstein J. Org. Chem. 2024, 20, 1412–1420, doi:10.3762/bjoc.20.123

• imidazole and pyrazine pharmacophores, are well represented in the area of medicinal chemistry since they possess pharmacological properties as mammalian target of rapamycin (mTOR) inhibitors [7], adenosine triphosphate (ATP) competitive inhibitors of the insuline-like growth factor 1 (IGF-1) receptor

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

• 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

Rhodium-catalyzed homo-coupling reaction of aryl Grignard reagents and its application for the synthesis of an integrin inhibitor

• Kazuyuki Sato,
• Satoki Teranishi,
• Atsushi Sakaue,
• Yukiko Karuo,
• Atsushi Tarui,
• Kentaro Kawai,
• Hiroyuki Takeda,
• Tatsuo Kinashi and
• Masaaki Omote

Beilstein J. Org. Chem. 2024, 20, 1341–1347, doi:10.3762/bjoc.20.118

• -bromoethyl)arenes or styrenes in this reaction. Unfortunately, we have not clarified the reason why a cross-coupling reaction did not proceed. At this stage, we speculate that the elimination rate of ethylene and reductive elimination rate of 3 might be fast in this reaction. Medicinal chemistry application

Oxidative hydrolysis of aliphatic bromoalkenes: scope study and reactivity insights

• Amol P. Jadhav and
• Claude Y. Legault

Beilstein J. Org. Chem. 2024, 20, 1286–1291, doi:10.3762/bjoc.20.111

• bromoalkenes as substrates delivering dialkyl α-bromoketones which are highly sought-after synthons in heterocycle synthesis and medicinal chemistry, thus overcoming the limitations of previous methods. The reaction accommodates sterically hindered bromoalkenes as substrates, leading to the corresponding α