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

• /bjoc.20.162 Abstract The Groebke–Blackburn–Bienaymé (GBB) three-component reaction, discovered in 1998, is a very efficient strategy to assemble imidazo[1,2-a]-heterocycles starting from amidines, aldehydes and isocyanides. This review aims to exhaustively describe innovative aspects of this reaction

• 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

Hetero-polycyclic aromatic systems: A data-driven investigation of structure–property relationships

• Sabyasachi Chakraborty,
• Eduardo Mayo Yanes and
• Renana Gershoni-Poranne

Beilstein J. Org. Chem. 2024, 20, 1817–1830, doi:10.3762/bjoc.20.160

• heteroatoms boron, nitrogen, oxygen, and sulfur and ranging in size from four-membered to six-membered rings. Compared to the parent polycyclic aromatic hydrocarbons (PAHs), PASs containing heterocycles offer greater structural diversity as well as a much broader range of optoelectronic properties. Such

• constructing the COMPAS-2 dataset, we opted to maintain equal percentages of the different types of heterocycles (~10% of each type). This was done to avoid biasing the construction of molecules towards specific motifs. However, because there are multiple types of B-containing and N-containing heterocycles

• of building block affects the properties, and whether these effects are due solely to the presence of the heteroatoms or to the aromatic nature of heterocycles are among the questions we aim to answer in the subsequent sections. Influence of global structural features In this section, we investigate

Discovery of antimicrobial peptides clostrisin and cellulosin from Clostridium: insights into their structures, co-localized biosynthetic gene clusters, and antibiotic activity

• Moisés Alejandro Alejo Hernandez,
• Katia Pamela Villavicencio Sánchez,
• Rosendo Sánchez Morales,
• Karla Georgina Hernández-Magro Gil,
• David Silverio Moreno-Gutiérrez,
• Eddie Guillermo Sanchez-Rueda,
• Yanet Teresa-Cruz,
• Brian Choi,
• Armando Hernández Garcia,
• Alba Romero-Rodríguez,
• Oscar Juárez,
• Siseth Martínez-Caballero,
• Mario Figueroa and
• Corina-Diana Ceapă

Beilstein J. Org. Chem. 2024, 20, 1800–1816, doi:10.3762/bjoc.20.159

• two larger heterocycles (of seven and nine amino acids) in this sequence region, whilst most lanthipeptides only form small ones (up to five) or none at all. As for the second part of the alignment, where most lanthipeptides form various heterocycles, cellulosin shares a very similar profile to

• liquenicidin VK21, and as the experimental results confirm, despite the in silico predictions, clostrisin does not form heterocycles. These differences in primary and secondary structure could be responsible for the divergent biological activities we encountered. In silico characterization of the post

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles

• Javier Gómez-Ayuso,
• Pablo Pertejo,
• Tomás Hermosilla,
• Israel Carreira-Barral,
• Roberto Quesada and
• María García-Valverde

Beilstein J. Org. Chem. 2024, 20, 1758–1766, doi:10.3762/bjoc.20.154

• Javier Gomez-Ayuso Pablo Pertejo Tomas Hermosilla Israel Carreira-Barral Roberto Quesada Maria Garcia-Valverde Departamento de Química, Universidad de Burgos, Burgos 09001, Spain 10.3762/bjoc.20.154 Abstract Piperazines and diazepines are examples of nitrogen heterocycles present in many marketed

• hurdles. Here, we have demonstrated the possibility of using the combination of arylglyoxals and carboxylic acids tethered to nonprotected deactivated amines as a powerful strategy for the synthesis of complex fused heterocycles. The limited nucleophilic character of the amino group of the anthranilic

• strategies to easily generate multiple fused nitrogen heterocycles including benzodiazepinone and piperazinone cores. Keywords: arylglyoxals; deactivated amines; nitrogen heterocycles; Ugi reaction; Introduction Nitrogen heterocycles such as piperazines or diazepines represent important systems in the

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

• , spanning the period from 2000 to 2023, for the preparation of spiro heterocyclic steroids. The compounds surveyed encompass four-, five-, six-, and seven-membered heterocycles appended to various positions of steroidal backbones, with spirocycles containing oxygen, nitrogen, and sulfur atoms being

• predominant. The outlined synthetic procedures emphasize the pivotal steps for constructing the heterocycles, often accompanied by a detailed account of the overall synthesis pathway. The review encompasses innovative compounds, including bis-steroids linked by a spiro heterocycle and steroids conjugated to

• 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

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

• )iodane is proposed as the reactive intermediate. Keywords: alcohol oxidation; hypervalent iodine; N-heterocycles; Introduction The oxidation of alcohols to aldehydes and ketones is an essential transformation in organic chemistry [1][2]. Generating aldehydes is particularly challenging as they are

Ring opening of photogenerated azetidinols as a strategy for the synthesis of aminodioxolanes

• Henning Maag,
• Daniel J. Lemcke and
• Johannes M. Wahl

Beilstein J. Org. Chem. 2024, 20, 1671–1676, doi:10.3762/bjoc.20.148

• success. Being conscious about the challenges associated with intermolecular ring openings at four-membered heterocycles, we considered an in situ tethering approach, which has proved an attractive alternative in our recent study on oxetane-ring openings [31]. Therefore, electron-deficient ketone 7 was

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

• represents the molecule. Finally, to mirror the dataset by Roszak et al. [3], we also incorporate 43 heterocycles without experimental pKa values from Shen et al., leaving us with a dataset of 775 compounds [11]. This dataset will be used to calculate QM pKa values using our QM workflow described in the next

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

• showed biological activity according to the ChEMBL database. Keywords: fused rings; heterocycles; imidazoles; isonitrile; multicomponent reactions; Introduction Multicomponent reactions are widely recognized as a powerful source of biologically active compounds, in particular, for drug discovery

• reaction is a three-component condensation of an α-amino heterocycle (e.g., 2-aminopyridine) 1, an aldehyde 2, and an isonitrile 3 providing the corresponding fused imidazoles (e.g., imidazo[1,2-a]pyridines) of general formula 4 (Scheme 1) [18][19][20][21]. Imidazo[1,2-a]pyridines and related heterocycles

• demonstrating poor performance. Using the resulting sets of amino heterocycles 1{22–485}, aldehydes 2{4–867}, and isonitriles 3{4–78}, 892 library members 4{22–485,4–867,4–78} were deliberately selected and subjected to the parallel synthesis using the Sc(OTf)3-based protocol. As a result, 790 library members

Electrocatalytic hydrogenation of cyanoarenes, nitroarenes, quinolines, and pyridines under mild conditions with a proton-exchange membrane reactor

• Koichi Mitsudo,
• Atsushi Osaki,
• Haruka Inoue,
• Eisuke Sato,
• Naoki Shida,
• Mahito Atobe and
• Seiji Suga

Beilstein J. Org. Chem. 2024, 20, 1560–1571, doi:10.3762/bjoc.20.139

• cyanoarenes is a straightforward and powerful method for the synthesis of primary amines [5], and the reduction of nitroarenes is useful for the synthesis of aniline derivatives [6][7][8][9][10][11]. Nitrogen-containing aliphatic heterocycles, such as piperidines and tetrahydroquinolines, are key motifs in

• pharmaceuticals, and the reductive syntheses of these heterocycles from pyridines and quinolines have been well studied [12]. Although these transformations have been studied intensively, such reductive reactions usually require harsh reaction conditions such as high reaction temperatures and high pressure of

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

• propagation methods, noting the importance of high purity reagents and the presence of O2. Radical fluorination of hetereobenzylic C(sp3)–H bonds was demonstrated by Van Humbeck and co-workers in 2018, who enabled the fluorination of aza-heterocycles at the benzylic position using Selectfluor (Figure 20) [61

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

• yields (up to 97%) and high enantioselectivities (up to 98.5% ee) under mild reaction conditions. In addition, this protocol was further expanded to synthesize highly enantioenriched hybrid molecules bearing biologically relevant heterocycles. Keywords: α,β-unsaturated ketones; iminium catalysis

• ; 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

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

• pyrazoles to give the corresponding thiocyanated pyrazoles (Scheme 1d) [50]. However, to our knowledge, there are only few reports on the electrophilic selenocyanation of heterocycles [51][52][53] including the biologically important pyrazoles. In this regard, it should be highly desirable to develop an

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

• intermediates through selective FeCl3-catalyzed intramolecular N-annulation. Keywords: α-aminoacetals; fused-ring systems; heterocyclic hemiaminals; heterocyclic N,O-aminals; multicomponent reactions; Introduction N-Fused heterocycles are ubiquitous within crucial molecules, including biologically active

• natural products, pharmaceuticals, and functional materials (Figure 1) [1][2][3]. It has been assessed that almost one-third of the best-selling therapeutics contains fused heterocyclic structures [4]. Among the N-heterocycles, imidazopyrazine structures [5][6], derived from amalgamation of privileged

• to afford, by a chemospecific Lewis acid-catalyzed ring-closure protocol, valuable heterocyclic N,O-aminals (Scheme 1). Results and Discussion Since the direct functionalization of N-heterocycles offers an attractive entry to important molecular targets that might otherwise require lengthy synthetic

Hypervalent iodine-catalyzed amide and alkene coupling enabled by lithium salt activation

• Akanksha Chhikara,
• Fan Wu,
• Navdeep Kaur,
• Prabagar Baskaran,
• Alex M. Nguyen,
• Zhichang Yin,
• Anthony H. Pham and
• Wei Li

Beilstein J. Org. Chem. 2024, 20, 1405–1411, doi:10.3762/bjoc.20.122

• Conversion of Chemical Feedstock to O- and N-Containing Heterocycles”. Funding We thank the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R15GM139156 for supporting this work. We thank the University of Toledo for an internal seed grant from the Summer

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

• strategies to explore access to triazole–pyrazole hybrids. Triazole–pyrazole hybrids, particularly non-fused heterocycles of this class, have not been investigated systematically. Selected known derivatives (Figure 1, 1–4) inhibit the serine-threonine kinase ERK3 [12] or the cholera-causing bacterium Vibrio

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

• intramolecular synthetic strategies. Immense applications in the synthesis of hydroxy acids and esters, heterocycles, fused carbocycles, natural products, and others with broad substrate scope have raised profound interest from methodological and synthetic standpoints. The ongoing development of reagents

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

• in a satisfactory yield. Various hydrocinnamic acids having electron-donating and electron-withdrawing substituents provided the targeted products 3a–c in good yield. Heterocycles containing carboxylic acids also provided the products 3d–g in moderate to good yield. Aliphatic carboxylic acids, under

Synthesis of 1,2,3-triazoles containing an allomaltol moiety from substituted pyrano[2,3-d]isoxazolones via base-promoted Boulton–Katritzky rearrangement

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

Beilstein J. Org. Chem. 2024, 20, 1334–1340, doi:10.3762/bjoc.20.117

• a valuable recyclization of various systems containing an N–O bond in the ring. This approach is a powerful synthetic tool allowing to obtain diverse types of nitrogen-containing five-membered heterocycles [1][2]. Among the wide variety of recyclizations of this class the processes with

• participation of hydrazones attract special attention. This reaction is a general method for the preparation of 1,2,3-triazoles bearing various substituents at position 2. Wherein, depending on the type of starting heterocycles various functional derivatives are formed. So, the well-known Boulton–Katritzky

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1256–1269, doi:10.3762/bjoc.20.108

• of the substituent located at carbon C3 of the chromone moiety and also on the type of nucleophile employed. Keywords: cyclizations; 1,3-dicarbonyl compounds; domino reactions; heterocycles; regioselectivity; silyl enol ethers; Introduction Domino reactions (also called cascade or tandem reactions

• phosphoranes were less studied in my group. Chromones are oxygen heterocycles which are of pharmacological interest and represent versatile synthetic building blocks which can undergo various types of domino reactions [24][25][26][27][28]. In 2001, Nehad N. R. Saleh in my group developed a new synthesis of

Synthesis and optical properties of bis- and tris-alkynyl-2-trifluoromethylquinolines

• Stefan Jopp,
• Franziska Spruner von Mertz,
• Peter Ehlers,
• Alexander Villinger and
• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1246–1255, doi:10.3762/bjoc.20.107

• steady state absorption and fluorescence spectroscopy which give insights of the influence of the substitution pattern and of the type of substituents on the optical properties. Keywords: alkynes; catalysis; fluorescence; heterocycles; palladium; Introduction Quinoline is a well-known core structure

• ][23], dyes, preservatives and as ligands in complex chemistry [24][25][26][27]. In the context of our interest in the application of cross-coupling reactions to polyhalogenated heterocycles [28][29][30][31], we studied Sonogashira reactions of brominated 2-trifluoromethylquinolines. The optical

Bismuth(III) triflate: an economical and environmentally friendly catalyst for the Nazarov reaction

• Manoel T. Rodrigues Jr.,
• Aline S. B. de Oliveira,
• Ralph C. Gomes,
• Amanda Soares Hirata,
• Lucas A. Zeoly,
• Hugo Santos,
• João Arantes,
• Catarina Sofia Mateus Reis-Silva,
• João Agostinho Machado-Neto,
• Leticia Veras Costa-Lotufo and
• Fernando Coelho

Beilstein J. Org. Chem. 2024, 20, 1167–1178, doi:10.3762/bjoc.20.99

• 3-aryl-1-indanones) in good to excellent yield. The reaction did not require additives and was insensitive to both air and moisture. Preliminary biological evaluation of some indanones showed a promising profile against some human cancer line cells. Keywords: bismuth; catalysis; heterocycles

Manganese-catalyzed C–C and C–N bond formation with alcohols via borrowing hydrogen or hydrogen auto-transfer

• Mohd Farhan Ansari,
• Atul Kumar Maurya,
• Abhishek Kumar and
• Saravanakumar Elangovan

Beilstein J. Org. Chem. 2024, 20, 1111–1166, doi:10.3762/bjoc.20.98

• control studies with Hg and TEMPO indicated that the reactions were homogeneous and did not proceed through a radical pathway. Synthesis of heterocycles via C–C and C–N bond formation In 2016, Beller and co-workers reported an intramolecular cyclization using 2-(2-aminophenyl)ethanol for the synthesis of

Mild and efficient synthesis and base-promoted rearrangement of novel isoxazolo[4,5-b]pyridines

• Vladislav V. Nikol’skiy,
• Mikhail E. Minyaev,
• Maxim A. Bastrakov and
• Alexey M. Starosotnikov

Beilstein J. Org. Chem. 2024, 20, 1069–1075, doi:10.3762/bjoc.20.94

• ]triazol-4-yl)pyridines was observed. Keywords: aromatic nitro compounds; Boulton–Katritzky rearrangement; isoxazolo[4,5-b]pyridines; nucleophilic substitution; 1,2,3-triazoles; Introduction Nitrogen heterocycles represent a very important class of organic compounds that has found application in various

Novel analogues of a nonnucleoside SARS-CoV-2 RdRp inhibitor as potential antivirotics

• Luca Julianna Tóth,
• Kateřina Krejčová,
• Milan Dejmek,
• Eva Žilecká,
• Blanka Klepetářová,
• Lenka Poštová Slavětínská,
• Evžen Bouřa and
• Radim Nencka

Beilstein J. Org. Chem. 2024, 20, 1029–1036, doi:10.3762/bjoc.20.91

• designed based on the work reported by Potts et al. [29] and is described in Scheme 3. The 2-bromo-2-phenylacetyl chloride, necessary for the first step of the synthesis, was prepared from readily available phenylacetic acid [30][31]. The reaction with the 5-membered heterocycles 21 and 26, respectively