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

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

• as solvent system to get the product in 2 h excluding work-up procedure. However, safety concerns, long reaction time, downstream process in a time and labor-efficient manner and scalability of the product still arose and thus prompted us to initiate a flow process that could overcome the above

Homogeneous continuous flow nitration of O-methylisouronium sulfate and its optimization by kinetic modeling

• Jiapeng Guo,
• Weike Su and
• An Su

Beilstein J. Org. Chem. 2024, 20, 2408–2420, doi:10.3762/bjoc.20.205

• continuous flow device. The highly exothermic nature of nitration makes the conversion from batch to continuous flow significantly safer. Additionally, the optimization model demonstrates excellent scalability and can accurately predict reaction conversions, with errors not exceeding 4%, for residence times

Diastereoselective synthesis of highly substituted cyclohexanones and tetrahydrochromene-4-ones via conjugate addition of curcumins to arylidenemalonates

• Deepa Nair,
• Abhishek Tiwari,
• Banamali Laha and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2024, 20, 2016–2023, doi:10.3762/bjoc.20.177

• KOH using TBAB as a suitable phase transfer catalyst in a biphasic medium at room temperature. The scalability of the reaction has also been demonstrated. Our future efforts will involve performing an asymmetric version of this reaction using chiral phase-transfer catalysts and the results will be

Transition-metal-catalyst-free electroreductive alkene hydroarylation with aryl halides under visible-light irradiation

• Kosuke Yamamoto,
• Kazuhisa Arita,
• Masami Kuriyama and
• Osamu Onomura

Beilstein J. Org. Chem. 2024, 20, 1327–1333, doi:10.3762/bjoc.20.116

• smoothly to afford 3kd and 3ki in 85% and 73% yields, respectively. In order to demonstrate the scalability of this transformation, a gram-scale reaction was performed (Scheme 3a). The hydroarylation of 2a with 1a was successfully carried out in a simple glass beaker under the standard reaction conditions

Synthesis and physical properties of tunable aryl alkyl ionic liquids based on 1-aryl-4,5-dimethylimidazolium cations

• Stefan Fritsch and
• Thomas Strassner

Beilstein J. Org. Chem. 2024, 20, 1278–1285, doi:10.3762/bjoc.20.110

• scalability [38][39][40][41][42]. The substituted imidazoles 1–9 were synthesized using a condensation reaction between the corresponding aniline and diacetyl monoxime (Scheme 1), since the condensation using diacetyl was not successful for electron-poor aniline derivatives. This reaction leads to the

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

• scalability of the two-step one-pot reaction protocol, we performed the synthesis of tetracyclic tetrazolo-pyrazino[2,1-a]isoquinolin-6(5H)-one 6c in gram quantity from 10 mmol of 1a which led to the formation of product 6c in a satisfactory yield 77% (Scheme 6). The products 6 and 8 were characterized by 1H

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

Synthesis of spiropyridazine-benzosultams by the [4 + 2] annulation reaction of 3-substituted benzoisothiazole 1,1-dioxides with 1,2-diaza-1,3-dienes

• Wenqing Hao,
• Long Wang,
• Jinlei Zhang,
• Dawei Teng and
• Guorui Cao

Beilstein J. Org. Chem. 2024, 20, 280–286, doi:10.3762/bjoc.20.29

• employed in the reaction. However, the yield of the corresponding product 3ba was obviously lower than 3aa and 3ca generated from dienophiles bearing linear alkyl groups (Scheme 2, 3ba vs 3aa and 3ca). A gram-scale reaction was subsequently conducted to investigate the scalability of the experiment. The

Quinoxaline derivatives as attractive electron-transporting materials

• Zeeshan Abid,
• Liaqat Ali,
• Sughra Gulzar,
• Faiza Wahad,
• Raja Shahid Ashraf and
• Christian B. Nielsen

Beilstein J. Org. Chem. 2023, 19, 1694–1712, doi:10.3762/bjoc.19.124

• should focus on understanding degradation mechanisms, developing effective device encapsulation strategies, and ensuring environmental compatibility to guarantee sustained performance and viability in commercial applications. Additionally, scalability and cost-effective manufacturing processes are key

Selective and scalable oxygenation of heteroatoms using the elements of nature: air, water, and light

• Damiano Diprima,
• Hannes Gemoets,
• Stefano Bonciolini and
• Koen Van Aken

Beilstein J. Org. Chem. 2023, 19, 1146–1154, doi:10.3762/bjoc.19.82

• flow using the HANU flow reactor, indicating scalability and improving safety. Keywords: catalyst-free; flow chemistry; oxygen; photochemistry; sustainable oxidation; Introduction Oxidation reactions are widely used in the chemical industry, but are often problematic due to challenges with

• running the process in continuous flow [5][6][7][8]. Moreover, flow reactors that provide intense mixing can overcome the gas–liquid mass transfer limitations typical of batch reactions and improve productivity. Several studies have demonstrated the scalability and safety of such methods for the oxidation

• protocol demonstrates excellent scalability, as we have successfully transferred it to the HANU flow reactor. This flow photoreactor is designed for multi-phase reactions (solid–liquid, gas–liquid) [30][31][32], and allows for seamless scale-up to production scale. Finally, by the use of specific “easy to

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

• feedstocks, and scalability up to gram scales in continuous flow. This review provides comparisons between the two techniques (multi-photon photoredox catalysis and PEC) to help the reader to fully understand their similarities, differences and potential applications and to therefore choose which method is

• first efforts in this direction [32][33]. Finally, both techniques are amenable to large-scale synthesis and ideally integrated with state-of-the-art reactor technology platforms, such as continuous flow reactors and high throughput screening plates. Various examples of scalability will be highlighted

Copper-catalyzed N-arylation of amines with aryliodonium ylides in water

• Kasturi U. Nabar,
• Bhalchandra M. Bhanage and
• Sudam G. Dawande

Beilstein J. Org. Chem. 2023, 19, 1008–1014, doi:10.3762/bjoc.19.76

• development since the pioneering work by Ullmann [13] and Goldberg [14]. Despite the significant advances, the main limitations are the harsh reaction conditions such as high temperatures, pressure, and unsustainability which limits their scalability for industrial applications. Further, palladium-catalyzed

Sulfate radical anion-induced benzylic oxidation of N-(arylsulfonyl)benzylamines to N-arylsulfonylimines

• Joydev K. Laha,
• Pankaj Gupta and
• Amitava Hazra

Beilstein J. Org. Chem. 2023, 19, 771–777, doi:10.3762/bjoc.19.57

• with ortho-substituted anilines is also reported. The key features of the protocol include the use of a green oxidant, a short reaction time (30 min), chromatography-free isolation, scalability, and economical, delivering N-arylsulfonylimines in excellent yields of up to 96%. While the oxidation of N

• position gave benzophenone in 80% yield with a trace of N-benzenesulfonylketimine 2m under the optimized reaction conditions. Likewise, N-(arylsulfonyl)benzylamine 1n having a methyl group present at the benzylic position gave product 2n only in a trace quantity. To demonstrate further the scalability of

• -substituted anilines. The key features including the use of a green oxidant, a short reaction time, chromatography-free isolation, and scalability mark a distinction from the contemporary methods. Although we propose a dual role for SO4·− involving both hydrogen atom abstraction (HAT) and single electron

Total synthesis: an enabling science

• Bastien Nay

Beilstein J. Org. Chem. 2023, 19, 474–476, doi:10.3762/bjoc.19.36

• constantly needed to improve methods and strategy, keeping in mind the difficulty of performing transformations on highly functionalized compounds, the total synthesis of complex natural products is indeed mature in terms of efficiency, practicality, economy, and scalability. In short, it has become an

Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles

• Bilge Banu Yagci,
• Selin Ezgi Donmez,
• Onur Şahin and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2023, 19, 66–77, doi:10.3762/bjoc.19.6

• -lactam heterocycles 19 in up to 76% yield and with good to high diastereoselectivities (4.3:1 to 16:1). We have demonstrated the scalability of the reaction with a gram-scale example. The relative stereochemistry of the α-methylene-γ-lactam products 19 has been determined via the single-crystal X-ray

• , were obtained as single diastereomers. In order to assess the scalability of the aza-Nazarov cyclization, we investigated the synthesis of the previously unreported lactam 7c via the reaction between imine 5b and acyl chloride 6b on a gram scale (Scheme 2). Acyl chloride 6b was prepared in four steps

Modern flow chemistry – prospect and advantage

• Philipp Heretsch

Beilstein J. Org. Chem. 2023, 19, 33–35, doi:10.3762/bjoc.19.3

• stage in the last decades [1]. Originating from the petrochemical industry, where it enabled high productivity and scalability even for the most standard processes of heating, cracking, and refining of crude oil to bulk chemicals [2], it has since entered the production of pharmaceuticals and other fine

• chemicals. This has again led to improved scalability, higher purity of products, and eventually decreased manufacturing costs. From the undisputed role of continuous flow chemistry for process chemists, the advent of this technology in academic research laboratories, especially for method development and

• scalability, and higher sustainability are the most prevalent ones. To provide examples and explanation for these claims, “flash chemistry”, a term coined by late Yoshida [4] for reactions at the diffusion limit, i.e., reactions completed within milliseconds with proper mixing, showcases the fast heat- and

Two-step continuous-flow synthesis of 6-membered cyclic iodonium salts via anodic oxidation

• Julian Spils,
• Thomas Wirth and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2023, 19, 27–32, doi:10.3762/bjoc.19.2

• continuous-flow procedure for the generation of six-membered diaryliodonium salts. The accompanying scalability and atom economy are significant improvements to existing batch methods. Benzyl acetates are submitted to this two-step procedure as highly available and cheap starting materials. An acid-catalyzed

• alcohols as a solvent [37][38]. Therefore, we attempt to transfer our already established one-pot procedure towards CDIS 1 into a multi-step electrochemical flow process, improving reaction times, atom economy, and scalability (Scheme 1C). Results and Discussion We initially investigated the second step of

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• for biological screening. The era of scalability [2] in total synthesis prompts researchers in this field to make use of more direct retrosynthetic disconnections with the aid of “radical” retrosynthetic analysis, as the advancement in the area now allows to harness one-electron power in a highly

• disconnections. As radical disconnections are gaining ground, more sophisticated retrosyntheses of natural products are unlocked, enriching thus their synthetic scalability [6][7]. A direct comparison of a classic vs a radical approach highlights the complementarity and, more often than not, the superiority of

Inline purification in continuous flow synthesis – opportunities and challenges

• Jorge García-Lacuna and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182

• and mass transfer, improved safety and scalability as well as the potential of reaction telescoping and automation [1][2]. Consequently, researchers from academia and the fine chemical industry have established flow technology as a complementary and oftentimes superior approach to traditional batch

• optimization as well as a set of pumps and several membranes are required, and scalability is often limited. In this context, Kappe and co-workers achieved the effective synthesis of methyl oximino acetoacetate using a multistage separation platform, including inline monitoring as depicted in Scheme 2 [51

• regarding scalability. The first issue is largely a problem for academic researchers where the cost to perform a traditional gravity separation is far lower than the price of these commercial membranes. The latter is a problem for industrial applications, as fouling and related issues may arise for

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• include their synthetic availability, wide opportunities for rational structure design, generally lower toxicity, air and water stability, metal-free nature, and the scalability of their production and use. These features have made organocatalysis a prospering area and an even more promising methodology

Heterogeneous metallaphotoredox catalysis in a continuous-flow packed-bed reactor

• Wei-Hsin Hsu,
• Susanne Reischauer,
• Peter H. Seeberger,
• Bartholomäus Pieber and
• Dario Cambié

Beilstein J. Org. Chem. 2022, 18, 1123–1130, doi:10.3762/bjoc.18.115

• synthesis [3]. The adoption of flow chemistry ensured short photon path lengths and overcame issues related to scalability and productivity caused by the limited light penetration in large batch reactors (Lambert–Beer law), thereby making photocatalysis a promising option for industrially relevant processes

Electrochemical formal homocoupling of sec-alcohols

• Kosuke Yamamoto,
• Kazuhisa Arita,
• Masashi Shiota,
• Masami Kuriyama and
• Osamu Onomura

Beilstein J. Org. Chem. 2022, 18, 1062–1069, doi:10.3762/bjoc.18.108

• -coupling reaction of two different benzyl alcohols (Scheme 3). Pleasingly, the reaction using a 1:1 mixture of 1a and 1f under the standard reaction conditions provided the cross-coupling product 2af (dr = 94:6) together with the homocoupling products 2a and 2f. To demonstrate the scalability of the

Automated grindstone chemistry: a simple and facile way for PEG-assisted stoichiometry-controlled halogenation of phenols and anilines using N-halosuccinimides

• Dharmendra Das,
• Akhil A. Bhosle,
• Amrita Chatterjee and
• Mainak Banerjee

Beilstein J. Org. Chem. 2022, 18, 999–1008, doi:10.3762/bjoc.18.100

• , reproducibility, and scalability. An alternative and efficient way of grinding is the use of automation instead of manual intervention. Notably, an industrial-scale synthesis is possible by the suitable choice of a large automated grindstone apparatus. However, there are only limited examples of the use of

• offer the versatility in obtaining mono-, di-, or trihalo derivatives as per the requirement within a very short time, which is a sheer advantage of this mechanochemical method. A further study of mechanochemical decarboxylative aromatic halogenations is underway in our laboratory. The scalability of

Morita–Baylis–Hillman reaction of 3-formyl-9H-pyrido[3,4-b]indoles and fluorescence studies of the products

• Nisha Devi and
• Virender Singh

Beilstein J. Org. Chem. 2022, 18, 926–934, doi:10.3762/bjoc.18.92

• methodology is decorated with several advantages like scalability and selectivity. Additionally, no column chromatographic purification was required at any stage and each step was high yielding. After the synthesis of starting materials, the Morita–Baylis–Hillman reaction was explored for C-3