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

• outline which structural motifs are included in this work and which ones are discarded (Scheme 1). In detail, this review encompasses bioactive compounds which satisfy: flexible, open chain-substituted 5/6-membered heteroaromatic scaffolds with decorations, condensed heteroaromatic or polycyclic systems

• specific heteroaromatic subsection indicates no biologically relevant data has been reported up to date. Review 2‑Heteroarylethylamine scaffolds of biological importance Six-membered heteroaromatic rings Pyridines: IL4I1, interleukin-4 induced gene 1, encodes ʟ-phenylalanine oxidase IL4I1 present in the

• observed for this family of tetrazole scaffolds. Conclusion The present review focuses on an examination of the expanded 2-phenethylamine chemical space, highlighting heteroaromatic structures with reported pharmacological profiles. The close inspection of each of the phenyl and other heteroaryl ring

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• achieved during the last five years, and classifies them into five categories: synthetic methods, building blocks, scaffolds, biological activities and physical properties. Keywords: Groebke–Blackburn–Bienaymé reaction; multicomponent reactions; heterocycles; imidazo[1,2-a]pyridines; isocyanides

• on biological activities or photophysical properties (i.e., fluorescence) of GBB adducts. Another advantage is that, by replacing the amidine component (classically 2-aminopyridines) with other heterocycles, different scaffolds are obtained, and this is extremely efficient in diversity-oriented

• synthesis (DOS) where a single methodology should generate diverse scaffolds. This comprehensive review focuses on all these aspects, and has been divided into five chapters, describing, respectively: a) efforts to develop new and milder reaction conditions; b) the use of new building blocks; c) the

Synthesis and characterization of 1,2,3,4-naphthalene and anthracene diimides

• Adam D. Bass,
• Daniela Castellanos,
• Xavier A. Calicdan and
• Dennis D. Cao

Beilstein J. Org. Chem. 2024, 20, 1767–1772, doi:10.3762/bjoc.20.155

• Adam D. Bass Daniela Castellanos Xavier A. Calicdan Dennis D. Cao Chemistry Department, Macalester College, 1600 Grand Avenue, Saint Paul, Minnesota 55105, United States 10.3762/bjoc.20.155 Abstract We report the synthesis and characterization of naphthalene and anthracene scaffolds end-capped by

• described isomers and expand the toolbox of electron-deficient aromatic compounds available to organic materials chemists. Keywords: electron acceptors; organic materials; polycyclic aromatic hydrocarbons; Introduction Aromatic diimides are ubiquitous molecular scaffolds that have served as the basis for

• -) derivatization of aromatic scaffolds because it can be exploited to stabilize the longer (hetero)acenes. In contrast to cata-benzannulation, cata-imide-annulation does not perturb aromaticity patterns and further introduces inductive stabilization of frontier MO levels, which has enabled the production of n-type

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

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• using an enzyme or at what stage in a synthesis the enzyme is employed: 1) regio- and stereoselective late-stage functionalization of core scaffolds, 2) in situ generation of highly reactive intermediates, and 3) the one-step construction of macrocyclic or fused multicyclic scaffolds via regio- and

• comprehensive understanding of the chemo-enzymatic synthetic approach, we refer the reader to recent excellent reviews that provide multiple perspectives on the topic [1][2][3][4][5][6][7][8][9][10]. Review Late-stage oxidative transformations of natural product scaffolds: cotylenol and brassicicenes Chemo

• -enzymatic synthesis, featuring the late-stage enzymatic oxidation of chemically synthesized intricate scaffolds are attracting increasing attention. A collaboration between Stoltz and Arnold led to the pioneering accomplishment in the total synthesis of nigelladine A by exploiting P450 enzymes engineered

Generation of multimillion chemical space based on the parallel Groebke–Blackburn–Bienaymé reaction

• Evgen V. Govor,
• Vasyl Naumchyk,
• Ihor Nestorak,
• Dmytro S. Radchenko,
• Dmytro Dudenko,
• Yurii S. Moroz,
• Olexiy D. Kachkovsky and
• Oleksandr O. Grygorenko

Beilstein J. Org. Chem. 2024, 20, 1604–1613, doi:10.3762/bjoc.20.143

• , extended Bemis–Murcko scaffolds were generated by cutting off the side chains of the molecules and retaining ring systems and linkers between them. After removal of duplicates, Tanimoto similarity coefficients were calculated for each pair of the molecules in the compared databases (T = 1 and 0 for similar

• space were found in the ChEMBL database, and some of them had high potency against various biological targets. Marketed drugs comprising imidazo[1,2-a]azine scaffolds. Yields of library members 4 synthesized using both Sc(OTf)3 and TsOH as the catalysts. Amino heterocycles 1{1–27} demonstrating poor

• yellow. Distribution of maximal values among pairwise-calculated Tanimoto similarities T (MFP2 fingerprints [46]) of extended Bemis–Murcko scaffolds for the generated chemical space members (5.60 Mln. scaffolds) to the extended Bemis–Murcko scaffolds of A) ChEMBL compounds (v. 33); B) PubChem compounds

Supramolecular assemblies of amphiphilic donor–acceptor Stenhouse adducts as macroscopic soft scaffolds

• Ka-Lung Hung,
• Leong-Hung Cheung,
• Yikun Ren,
• Ming-Hin Chau,
• Yan-Yi Lam,
• Takashi Kajitani and
• Franco King-Chi Leung

Beilstein J. Org. Chem. 2024, 20, 1590–1603, doi:10.3762/bjoc.20.142

• revealed by X-ray diffraction analysis. Upon visible-light irradiation, significant transformations of the DA geometry enabled transformations of the supramolecular assemblies on a microscopic scale, subsequently disassembling macroscopic soft scaffolds of DAs. The current work shows promising use for the

• fabrication of visible-light-controlled macroscopic scaffolds, offering the next generation of biomedical materials with visible-light-controlled microenvironments and future soft-robotic systems. Keywords: donor–acceptor Stenhouse adduct; photoresponsive molecular amphiphile; supramolecular transformation

• are available. UV-light-driven supramolecular transformations on a macroscopic length scale were pioneered by Leung and Feringa [42][43]. Besides, we recently reported the first indigo amphiphiles in fabrication of macroscopic soft scaffolds with photoshrinking properties as a smart functional cell

Mining raw plant transcriptomic data for new cyclopeptide alkaloids

• Draco Kriger,
• Michael A. Pasquale,
• Brigitte G. Ampolini and
• Jonathan R. Chekan

Beilstein J. Org. Chem. 2024, 20, 1548–1559, doi:10.3762/bjoc.20.138

• ]. These RiPP natural products encompass a wide range of structural scaffolds including cyclopeptide alkaloids that contain a phenolic ether-linkage and the lyciumin-type peptides that are composed of a crosslink between the Trp-indole-N and the carbon in another amino acid side chain or peptide backbone

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

• fascinating but at the same time challenging. Pyrazoles [4][5][6][7], benzofurans [34], and indoles [35][36] are popular scaffolds as they are prevalent in many bioactive molecules. Compounds bearing both pyrazole and indole moieties or pyrazole and benzofuran moieties (Figure 1) are highly attractive since

Towards an asymmetric β-selective addition of azlactones to allenoates

• Behzad Nasiri,
• Ghaffar Pasdar,
• Paul Zebrowski,
• Katharina Röser,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1504–1509, doi:10.3762/bjoc.20.134

• . Spirobiindane-based salts C emerged as promising alternative for quaternary ammonium salt scaffolds recently [40][41] and were also the catalysts of choice in our recently developed β-selective allenoate addition of isoxazolidinones 2 (compare with Scheme 1B [18]). Unfortunately, these catalysts were found to

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

• readily converted into a myriad of functional groups including carbonyls, amines, imines, and a variety of heterocyclic scaffolds with well-established procedures [4][5][6][7][8][9]. In particular, tertiary nitriles are common structural motifs in many bioactive compounds and are widely used as

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

• Abstract A new class of heterocyclic N,O-aminal and hemiaminal scaffolds was successfully obtained by means of a three-component reaction (3-CR) of 1,2-diaza-1,3-dienes (DDs), α-aminoacetals and iso(thio)cyanates. These stable imine surrogates are generated from key-substituted (thio)hydantoin

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

• ][2]. We are interested in feasible strategies to synthesize nitrogen-rich heterocyclic scaffolds that can extend the currently available libraries with new drug-like molecules. Our past work on pyrazoles [3][4][5][6] and triazoles [7][8][9][10][11] motivated us to search for suitable and versatile

Synthetic applications of the Cannizzaro reaction

• Bhaskar Chatterjee,
• Dhananjoy Mondal and
• Smritilekha Bera

Beilstein J. Org. Chem. 2024, 20, 1376–1395, doi:10.3762/bjoc.20.120

• scaffolds Burroughs et al. developed an intramolecular Cannizzaro-based cascade synthesis for the construction of 8-membered cycloocta-2,5-dienones [91]. The initial formation of the organolithium species 82 formed by acetylide addition to the ortho-substituted bromoaldehyde 81, was subjected to halogen

Generation of alkyl and acyl radicals by visible-light photoredox catalysis: direct activation of C–O bonds in organic transformations

• Mithu Roy,
• Bitan Sardar,
• Itu Mallick and
• Dipankar Srimani

Beilstein J. Org. Chem. 2024, 20, 1348–1375, doi:10.3762/bjoc.20.119

• the SET transfer process of PPh3 and quenching of photoexcited *[Ir(dF(CF3)ppy)2(bpy)]PF6 by PPh3. Fluorinated organic compounds are widely used in pharmaceuticals and pesticides. Therefore, it is crucial to diversify organic scaffolds by addition of fluorinated groups or by defluorination. In 2020

Computation-guided scaffold exploration of 2E,6E-1,10-trans/cis-eunicellanes

• Zining Li,
• Sana Jindani,
• Volga Kojasoy,
• Teresa Ortega,
• Erin M. Marshall,
• Khalil A. Abboud,
• Sandra Loesgen,
• Dean J. Tantillo and
• Jeffrey D. Rudolf

Beilstein J. Org. Chem. 2024, 20, 1320–1326, doi:10.3762/bjoc.20.115

• recent discovery of the aridacins, which transforms a 2E-cis-eunicellane into a 6/7/5-tricyclic diterpene via a cytochrome P450 [12]. Coincidentally, these reactive skeletons also provide chemists the ability to access synthetically challenging scaffolds with simple electrophilic cyclizations. With

Phenotellurazine redox catalysts: elements of design for radical cross-dehydrogenative coupling reactions

• Alina Paffen,
• Christopher Cremer and
• Frederic W. Patureau

Beilstein J. Org. Chem. 2024, 20, 1292–1297, doi:10.3762/bjoc.20.112

• , which exploit the redox flexibility of tellurium, especially in the context of phenotellurazine scaffolds. Notably, we showed that phenotellurazine PTeZ1 could significantly catalyze the cross-dehydrogenative phenothiazination of phenols bearing challenging electron-withdrawing substituents under a

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids

• Carolina S. Marques,
• Aday González-Bakker and
• José M. Padrón

Beilstein J. Org. Chem. 2024, 20, 1213–1220, doi:10.3762/bjoc.20.104

• chemists regarding process formation of new bonds and synthesis of new scaffolds. In drug discovery and development, medicinal chemists struggle everyday towards the creation of new synthetic methods, driven by the increasing complexity of the molecules and taking into consideration economic and social

• . Generally, the biological results point out the relevance of these isatin hybrids as privileged scaffolds for the development of new therapeutically relevant substances. Conclusion Two new families of α-acetamide carboxamide oxindole and isatin hybrids were synthesized efficiently using the sustainable and

Cofactor-independent C–C bond cleavage reactions catalyzed by the AlpJ family of oxygenases in atypical angucycline biosynthesis

• Jinmin Gao,
• Liyuan Li,
• Shijie Shen,
• Guomin Ai,
• Bin Wang,
• Fang Guo,
• Tongjian Yang,
• Hui Han,
• Zhengren Xu,
• Guohui Pan and
• Keqiang Fan

Beilstein J. Org. Chem. 2024, 20, 1198–1206, doi:10.3762/bjoc.20.102

• scaffolds (Scheme 1) [1][2][8][9][10][11][12][13][14]. Noteworthy is the prerequisite for FADH2/FMNH2, provided by E. coli Fre or flavin reductases in corresponding biosynthetic pathways, to facilitate these oxidation reactions. Experimental data support that 1 was firstly oxidized to a lactone intermediate

Structure–property relationships in dicyanopyrazinoquinoxalines and their hydrogen-bonding-capable dihydropyrazinoquinoxalinedione derivatives

• Tural N. Akhmedov,
• Ajeet Kumar,
• Daken J. Starkenburg,
• Kyle J. Chesney,
• Khalil A. Abboud,
• Novruz G. Akhmedov,
• Jiangeng Xue and
• Ronald K. Castellano

Beilstein J. Org. Chem. 2024, 20, 1037–1052, doi:10.3762/bjoc.20.92

• and charge injection/extraction processes [7]. The additional merits of H-bonding designs in organic optoelectronic materials include higher thermal stability, synergistic stabilizing effects with π-stacking interactions, etc. [8]. Acenes and N-heteroacenes are two prominent π-conjugated scaffolds for

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• indoles Metal-catalyzed cyclocarbonylative coupling reaction of indoles to 6H-isoindolo[2,1-a]indol-6-one scaffolds Substituted 6H-isoindolo[2,1-a]indol-6-ones are important structural components of many naturally occurring and pharmacologically active compounds [45][46][47][48][49][50][51]. They are also

• alcohols were used as the nucleophiles (Scheme 32). About three years later, the same group developed a simple and efficient method to access CO-linked heterocyclic scaffolds by a Pd-catalyzed carbonylative cyclization of alkene–indole derivatives with 2-alkynylanilines and 2-alkynylphenols, in the

• functionalize indole scaffolds. We have seen different approaches in which high catalyst efficiencies, mild conditions and the use of low-toxic chemicals as CO source, that do not require the use of autoclaves, have been successfully applied. Furthermore, in some cases, “green” oxidants such as air were used

Enhancing structural diversity of terpenoids by multisubstrate terpene synthases

• Min Li and
• Hui Tao

Beilstein J. Org. Chem. 2024, 20, 959–972, doi:10.3762/bjoc.20.86

• introducing a GPP C2-methyltransferase from Pseudanabaena limnetica to yeast together with an engineered C11-specific TS, 40 C11 terpene scaffolds were produced, which significantly increased the chemical space of terpenoids [54]. More recently, the GPP C6-methyltransferase BezA was discovered in Streptomyces

• ), hammershoyl diphosphate (111), and ancheryl diphosphate (112) (Figure 8c). Subsequently, terpentetriene synthase from Kitasatospora griseola (Cyc2) and kolavelool synthase from Herpetosiphon aurantiacus (HaKS) were identified as capable of converting these building blocks into C16 scaffolds, whereas other

Innovative synthesis of drug-like molecules using tetrazole as core building blocks

• Jingyao Li,
• Ajay L. Chandgude,
• Qiang Zheng and
• Alexander Dömling

Beilstein J. Org. Chem. 2024, 20, 950–958, doi:10.3762/bjoc.20.85

• . It aims to meet the growing demand for tetrazole-based compound libraries and novel scaffolds, which are challenging to synthesize through other methods. Keywords: building blocks; green chemistry; multicomponent reaction; Passerini tetrazole reaction; tetrazole; Ugi reaction; Introduction The

• the high synthetic value, significant efforts have been devoted to developing methods for the preparation of the tetrazole scaffolds, in particular recently through multicomponent reactions (MCRs) and mostly Ugi and Passerini reactions [7][8][9]. Traditionally, due to its charged nature the tetrazole

• moiety is introduced in a late-stage-modification approach, mostly from nitriles or isocyanides (Figure 1b) [13]. On the other hand, accessing diverse tetrazole scaffolds from MCRs, typically involves first de novo construction of the tetrazole scaffold and subsequent post-modifications (Figure 1c) [14

One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline

• Jiawei Niu,
• Yuhui Wang,
• Shenghu Yan,
• Yue Zhang,
• Xiaoming Ma,
• Qiang Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2024, 20, 912–920, doi:10.3762/bjoc.20.81

• reaction for the synthesis of tetrazolyl-1,2,3,4-tetrahydroisoquinoline scaffolds 6 and 8 (Scheme 3). The first step is the Ugi-azide reaction of a 2-bromobenzoaldehyde 1, allylamine hydrochloride (2), azidotrimethylsilane (TMSN3, 3), and an isocyanide 4 affording tetrazoles 5. If ethyl isocyanoacetate is

• compound 6d (left) [CCDC: 2164364] and 8c (right) [CCDC: 2321622]. The Ugi and Ugi-azide reactions. Ugi-azide and post-condensation reactions for the synthesis of various heterocyclic scaffolds. One-pot synthesis of tetrazolyl-1,2,3,4-tetrahydroisoquinoline. One-pot synthesis of tetrazolo-pyrazino[2,1-a

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• development of these important bioisosteres. We will highlight both the synthetic routes used to access the proposed bioisosteric scaffolds, as well as any subsequent derivatization thereof which help expand their utility. Our aim is to provide an overview of the types of scaffold that can be prepared with

• isosteres and bioisosteres. Scaffolds suggested for the replacement of ortho- or meta-benzenes shall be defined as a geometrical isostere if they exhibit similar geometric properties to the parent compound. A scaffold shall be defined as a bioisostere only if both its geometrical properties and its

• biological activity are similar to the parent compound. For simplicity, geometric isosteres will be simply referred to as isosteres. More densely substituted scaffolds will be briefly discussed at the end of the review. Geometrical equivalence between disubstituted benzenes and scaffolds will be quantified