Continuous-flow-enabled intensification in nitration processes: a review of technological developments and practical applications over the past decade

• Feng Zhou,
• Chuansong Duanmu,
• Yanxing Li,
• Jin Li,
• Haiqing Xu,
• Pan Wang and
• Kai Zhu

Beilstein J. Org. Chem. 2025, 21, 1678–1699, doi:10.3762/bjoc.21.132

• continuous-flow nitration technology – a process historically recognized as one of the most hazardous industrial operations – focusing on its technological advancements in process design, reaction kinetics characterization, and practical implementation over the past decade. Detailed discussions encompass

• /selectivity through optimized parameters (microwave energy, temperature, feed composition) [11]. Recent years have witnessed growing adoption of the continuous-flow technology in nitration processes across laboratory and industrial scales, driven by the reaction's classification as a highly hazardous chemical

• in nitration systems where minor deviations can lead to thermal runaway or hazardous by-product accumulation. Therefore, conducting long-term operational stability testing becomes imperative following the development of optimized continuous-flow nitration processes to validate industrial viability

Azobenzene protonation as a tool for temperature sensing

• Antti Siiskonen,
• Sami Vesamäki and
• Arri Priimagi

Beilstein J. Org. Chem. 2025, 21, 1528–1534, doi:10.3762/bjoc.21.115

• sensing becomes increasingly feasible. The aim is to create systems with tailored absorption wavelengths and spectral shifts, sensitivity, and well-defined operational ranges. While the experimental results are promising, the use of a hazardous, chlorinated solvent is a major limitation, highlighting the

Microwave-enhanced additive-free C–H amination of benzoxazoles catalysed by supported copper

• Andrei Paraschiv,
• Valentina Maruzzo,
• Filippo Pettazzi,
• Stefano Magliocco,
• Paolo Inaudi,
• Daria Brambilla,
• Gloria Berlier,
• Giancarlo Cravotto and
• Katia Martina

Beilstein J. Org. Chem. 2025, 21, 1462–1476, doi:10.3762/bjoc.21.108

• oxidant considerably impacts upon the sustainability of the process because it involves toxic reagents, generates hazardous by-products, increases the overall reaction cost and increases waste production [30][31][32]. In subsequent years, other base-catalysed protocols have been developed for the reaction

Recent advances in oxidative radical difunctionalization of N-arylacrylamides enabled by carbon radical reagents

• Jiangfei Chen,
• Yi-Lin Qu,
• Ming Yuan,
• Xiang-Mei Wu,
• Heng-Pei Jiang,
• Ying Fu and
• Shengrong Guo

Beilstein J. Org. Chem. 2025, 21, 1207–1271, doi:10.3762/bjoc.21.98

Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

• Betty A. Kustiana,
• Galuh Widiyarti and
• Teni Ernawati

Beilstein J. Org. Chem. 2025, 21, 1031–1086, doi:10.3762/bjoc.21.85

• % yields. Müller and co-workers (2019) reported the synthesis of 6-amino-5-carboxamidouracil derivatives 20 and 21, precursors for A2A antagonists, in good yields by using non-hazardous (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino(morpholino)carbenium hexafluorophosphate (COMU) as the coupling

Sequential two-step, one-pot microwave-assisted Urech synthesis of 5-monosubstituted hydantoins from L-amino acids in water

• Wei-Jin Chang,
• Sook Yee Liew,
• Thomas Kurz and
• Siow-Ping Tan

Beilstein J. Org. Chem. 2025, 21, 596–600, doi:10.3762/bjoc.21.46

• demonstrate that the process can be effectively scaled up, particularly in industries that prioritize sustainability and operational efficiency. In terms of green chemistry principles, this approach already meets several key goals, such as reducing the use of hazardous reagents and solvents, increasing

Photomechanochemistry: harnessing mechanical forces to enhance photochemical reactions

• Francesco Mele,
• Ana M. Constantin,
• Andrea Porcheddu,
• Raimondo Maggi,
• Giovanni Maestri,
• Nicola Della Ca’ and
• Luca Capaldo

Beilstein J. Org. Chem. 2025, 21, 458–472, doi:10.3762/bjoc.21.33

• exposure of the operator to potentially hazardous solid mixtures. A key technological challenge in this domain is to develop methods to effectively deliver photons to the reaction mixture. In 2017, Štrukil reported the first instance of a photochemical reaction conducted within a ball milling apparatus

Electrochemical synthesis of cyclic biaryl λ³-bromanes from 2,2’-dibromobiphenyls

• Andrejs Savkins and
• Igors Sokolovs

Beilstein J. Org. Chem. 2025, 21, 451–457, doi:10.3762/bjoc.21.32

• renders them particularly suitable for the generation of arynes for subsequent use in a wide range of synthetic applications. The common approach to generate cyclic biaryl λ3-bromanes is based on thermal decomposition of hazardous diazonium salts. Herein, we disclose a mild and straightforward approach to

Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• , secondary aliphatic or aromatic amines and thiols in the presence of catalytic Cu(OTf)2 (1 mol %) in aqueous media was proven to be a sustainable procedure to access thioaminals 5, avoiding high temperatures and/or hazardous reagents required by classical conditions (Scheme 4) [18]. The 1,2

Emerging trends in the optimization of organic synthesis through high-throughput tools and machine learning

• Pablo Quijano Velasco,
• Kedar Hippalgaonkar and
• Balamurugan Ramalingam

Beilstein J. Org. Chem. 2025, 21, 10–38, doi:10.3762/bjoc.21.3

• energy consumption and reduced use of hazardous materials, contributing to more sustainable chemical processes. Integrating ML algorithms to simultaneously optimize multiple parameters such as yield, purity, and cost within a closed-loop represents a significant advancement in process design. Furthermore

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

• [3]. These aspects are aligned with the goal of addressing concerns related to the generation of environmentally hazardous waste [4]. In addition, this type of reaction allows for the efficient discovery of low molecular weight compounds. As a result, most of these compounds are drug-like according

Tailored charge-neutral self-assembled L₂Zn₂ container for taming oxalate

• David Ocklenburg and
• David Van Craen

Beilstein J. Org. Chem. 2024, 20, 3007–3015, doi:10.3762/bjoc.20.250

• competitive anions. Our approach showcases that an adjustment of, e.g., the cavity size is a powerful lever to tame guests which are hazardous for metal-based cages or containers so that an undesired full or partial receptor disassembly is ruled out. Binding of oxalate occurs with a binding constant of log K

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• significant as it circumvents the use of costly and hazardous metals and ligands which are commercially not available. In order to obtain a variety of synthetically desirable tetrasubstituted α-aryl-α-fluoroacetoacetamides 7, Zaheer et al. disclosed a straightforward, metal-free technique for the α-arylation

• salt, subsequently leading to decarboxylative C–C coupling. Notably, this method achieves the incorporation of two fluorine atoms in the benzyl position without resorting to hazardous fluorination reagents, transition-metal catalysts, or organometallic compounds. The utility of this reaction is

Mechanochemical difluoromethylations of ketones

• Jinbo Ke,
• Pit van Bonn and
• Carsten Bolm

Beilstein J. Org. Chem. 2024, 20, 2799–2805, doi:10.3762/bjoc.20.235

• ; mechanochemistry; Introduction In recent years, mechanochemical organic synthesis has been advanced significantly, prompting organic chemists to reconsider the necessity of solvents in their reactions [1][2][3][4][5][6][7][8][9][10][11]. Eliminating hazardous solvents substantially reduces the ecological

Transition-metal-free decarbonylation–oxidation of 3-arylbenzofuran-2(3H)-ones: access to 2-hydroxybenzophenones

• Bhaskar B. Dhotare,
• Seema V. Kanojia,
• Chahna K. Sakhiya,
• Amey Wadawale and
• Dibakar Goswami

Beilstein J. Org. Chem. 2024, 20, 2655–2667, doi:10.3762/bjoc.20.223

• versatile method using decarbonylation of benzofuranone followed by oxidation, that produces only CO2 as a non-toxic side product, is considered less hazardous. Although decarboxylation of aldehydes, carboxylic acids, and ketones are well known, albeit using metal catalysts, decarboxylation methods for

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

• , 52074, Aachen, Germany 10.3762/bjoc.20.214 Abstract With the resurgence of electrosynthesis in organic chemistry, there is a significant increase in the number of routes available for late-stage functionalization (LSF) of drugs. Electrosynthetic methods, which obviate the need for hazardous chemical

Visible-light-mediated flow protocol for Achmatowicz rearrangement

• Joachyutharayalu Oja,
• Sanjeev Kumar and
• Srihari Pabbaraja

Beilstein J. Org. Chem. 2024, 20, 2493–2499, doi:10.3762/bjoc.20.213

• is accomplished. The combined steps include fast reaction (10 min), and post-synthetic work-up (extraction time 0.25 min and separation time 0.11 min) in safe environment with minimal human intervention and avoiding hazardous chemical exposure. The process utilizes nature abundant energy sources such

gem-Difluorination of carbon–carbon triple bonds using Brønsted acid/Bu₄NBF₄ or electrogenerated acid

• Mizuki Yamaguchi,
• Hiroki Shimao,
• Kengo Hamasaki,
• Keiji Nishiwaki,
• Shigenori Kashimura and
• Kouichi Matsumoto

Beilstein J. Org. Chem. 2024, 20, 2261–2269, doi:10.3762/bjoc.20.194

• gem-difluorination of alkynes (Figure 1, reaction 4) [38]. In 2020, the utility of 2,6-dichloropyridinium tetrafluoroborate was nicely demonstrated for the gem-difluorination by Liu and Wang (Figure 1, reaction 5) [39]. Although some procedures have been reported, the use of hazardous reagents such as

• not directly require the use of hazardous HF reagents and expensive metal catalysts. The simple combination of a Brønsted acid with Bu4NBF4 as the fluorine source as well as a simple electrolysis in Bu4NBF4/CH2Cl2 represent new routes to synthesize CF2-incorporated organic molecules from alkynes

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

• -metal-based transformations. However, their use is significantly hampered by their inherent instability and hazardous nature. Therefore, it is endlessly highly demanding to find a new mode of generation of diazo compounds from stable and safe precursors. The third part of this review is dedicated to

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

• the most employed approach for producing this family of substrates [12]. Despite its effectiveness, this approach requires hazardous cyanides and harsh conditions for the subsequent hydrolysis of the nitrile or the hydantoin. Additionally, it carries significant limitations in its scope, reducing its

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

• catalyst was tested only with 5-aminopyrazole 4, and no comparison with a “classic” GBB reaction can be made, the authors compared HEDP with other catalysts on the same substrates, demonstrating that HEDP in MeOH/water was superior for yields, mildness, and less hazardous conditions (Scheme 3). Longo et al

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

• 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

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

• past several decades [19][20][21][22]. The base-mediated solvent-free Cannizzaro reaction was achieved through various methods, such as by grinding reactants in mechanochemical approaches and/or solid-supported bases. Minimizing the use of hazardous solvents not only reduces environmental impact but

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

• recent photocatalysis methodologies in the field of C–O bond activation. As conventional techniques, such as Barton decarboxylation, create hazardous wastes, the use of alternative feedstocks, including alcohols and acids, has been encouraged to achieve sustainability. The recent advancements not only

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

• involves the hazardous chemicals NaN3, DIBAL-H, and CCl4 [25]. Moderhack described the synthesis of 1-substituted tetrazole-5-carbaldehyde through a Kröhnke reaction involving lengthy to access 5-chloromethyltetrazole and the well-known carcinogen p-nitrosodimethylaniline [27]. Also Ugi described the

• synthesis of 5-hydroxymethyltetrazoles through a Passerini reaction, however, in low yields, with very long reaction times, and using hazardous aluminum azide [30]. Clearly our novel access to this elusive substance class of 1-substituted tetrazole-5-carbaldehyde outperforms all hitherto described synthetic