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

Copper-catalyzed multicomponent reactions for the efficient synthesis of diverse spirotetrahydrocarbazoles

• Shao-Cong Zhan,
• Ren-Jie Fang,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 796–808, doi:10.3762/bjoc.18.80

• results indicate the in situ generation of both indole-based ortho-quinodimethanes (o-QDMs) as active dienes and cyclic dienophiles are the key intermediates in these reactions. Moreover, this protocol exhibited good functional group tolerance, broad substrate scope and facile scalability. It would

Synthesis of α-(perfluoroalkylsulfonyl)propiophenones: a new set of reagents for the light-mediated perfluoroalkylation of aromatics

• Durbis J. Castillo-Pazos,
• Juan D. Lasso and
• Chao-Jun Li

Beilstein J. Org. Chem. 2022, 18, 788–795, doi:10.3762/bjoc.18.79

• developed a robust synthetic methodology for α-(perfluoroalkylsulfonyl)propiophenones, envisioned as new members of photocleavable perfluoroalkylating reagents. In this work, we have demonstrated their scalability and applicability in the metal-, catalyst- and additive-free, redox- and pH-neutral

Continuous flow synthesis of azobenzenes via Baeyer–Mills reaction

• Jan H. Griwatz,
• Anne Kunz and
• Hermann A. Wegner

Beilstein J. Org. Chem. 2022, 18, 781–787, doi:10.3762/bjoc.18.78

• used Baeyer–Mills coupling reaction was adopted to a continuous flow setup. The versatility was demonstrated with a scope of 20 substances and the scalability of this method exemplified by the synthesis of >70 g of an azobenzene derivative applied in molecular solar thermal storage (MOST) systems

• usually gives similar or improved yields and eliminates the shortcomings in scalability. For the applications of ABs as molecular materials often larger amounts are required, for example, as active compounds in molecular solar thermal energy storage (MOST) systems. Therefore, we utilized the set-up for

Synthesis of odorants in flow and their applications in perfumery

• Merlin Kleoff,
• Paul Kiler and
• Philipp Heretsch

Beilstein J. Org. Chem. 2022, 18, 754–768, doi:10.3762/bjoc.18.76

• of flow chemistry for photoreactions and reactions with gases providing shorter reaction times and improved scalability [44]. Woody odorants Woody odorants are widely used, especially in masculine perfumes. Some woody essential oils like cedarwood are relatively inexpensive, however, sandalwood oil

New synthesis of a late-stage tetracyclic key intermediate of lumateperone

• Mátyás Milen,
• Bálint Nyulasi,
• Tamás Nagy,
• Gyula Simig and
• Balázs Volk

Beilstein J. Org. Chem. 2022, 18, 653–659, doi:10.3762/bjoc.18.66

• a Fischer indole synthesis. The inexpensive starting material, the efficient synthetic steps, and the avoidance of the borane-based reduction step provide a reasonable potential for scalability. Keywords: drug substance; indole synthesis; key intermediate; protecting group; telescoping

Shift of the reaction equilibrium at high pressure in the continuous synthesis of neuraminic acid

• Jannis A. Reich,
• Miriam Aßmann,
• Kristin Hölting,
• Paul Bubenheim,
• Jürgen Kuballa and
• Andreas Liese

Beilstein J. Org. Chem. 2022, 18, 567–579, doi:10.3762/bjoc.18.59

• recycling steps, and were characterized regarding the reaction kinetics (initial rate) and scalability (different lab scales) in a batch reactor. The reaction kinetics were studied in a continuous flow reactor. A high-pressure circular reactor (up to 130 MPa) was applied for the investigation of changes in

Flow synthesis of oxadiazoles coupled with sequential in-line extraction and chromatography

• Kian Donnelly and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 232–239, doi:10.3762/bjoc.18.27

• poly-heterocyclic compound 2m in low yield (Scheme 4). Having investigated the substrate scope in continuous flow mode, we then moved to probe the scalability of the reaction. A primary advantage of carrying out a reaction in continuous flow is the ease of which it can subsequently be scaled-up

Solvent-free synthesis of enantioenriched β-silyl nitroalkanes under organocatalytic conditions

• Akhil K. Dubey and
• Raghunath Chowdhury

Beilstein J. Org. Chem. 2021, 17, 2642–2649, doi:10.3762/bjoc.17.177

• was found to adopt “(S)” configuration which was unambiguously established by single crystal X-ray diffraction analysis (Figure 1) [45]. To prove the scalability of this synthetic method, we examined the synthesis of 3c and ent-3d in a 1 mmol scale (Scheme 5). The products 3c and ent-3d were isolated

Cryogels: recent applications in 3D-bioprinting, injectable cryogels, drug delivery, and wound healing

• Luke O. Jones,
• Leah Williams,
• Tasmin Boam,
• Martin Kalmet,
• Chidubem Oguike and
• Fiona L. Hatton

Beilstein J. Org. Chem. 2021, 17, 2553–2569, doi:10.3762/bjoc.17.171

• physically crosslinked PVA cryogels show even greater mechanical strength than their chemically crosslinked counterparts [23]. Therefore, it is achievable to obtain similar properties with physical crosslinking, yet the matter of reproducibility and scalability remains an issue. To assess the mechanical

A novel methodology for the efficient synthesis of 3-monohalooxindoles by acidolysis of 3-phosphate-substituted oxindoles with haloid acids

• Li Liu,
• Yue Li,
• Tiao Huang,
• Dulin Kong and
• Mingshu Wu

Beilstein J. Org. Chem. 2021, 17, 2321–2328, doi:10.3762/bjoc.17.150

• -substituted oxindole intermediates and SN1 reactions with haloid acids. This new procedure features mild reaction conditions, simple operation, good yield, readily available and inexpensive starting materials, and gram-scalability. Keywords: acidolysis; haloid acids; isatin; 3-monohalooxindole; 3-phosphate

Facile and innovative catalytic protocol for intramolecular Friedel–Crafts cyclization of Morita–Baylis–Hillman adducts: Synergistic combination of chiral (salen)chromium(III)/BF₃·OEt₂ catalysis

• Karthikeyan Soundararajan,
• Helen Ratna Monica Jeyarajan,
• Raju Subimol Kamarajapurathu and
• Karthik Krishna Kumar Ayyanoth

Beilstein J. Org. Chem. 2021, 17, 2186–2193, doi:10.3762/bjoc.17.140

• the dialkoxy and ortho-halide- substituted MBH adducts. Thereby alternative synthetic routes should be accessed to overcome the harsh reaction conditions, structural requirements and scalability issues intrinsically associated with the literature reported procedures. Hence chiral catalysts could

Progress and challenges in the synthesis of sequence controlled polysaccharides

• Giulio Fittolani,
• Theodore Tyrikos-Ergas,
• Denisa Vargová,
• Manishkumar A. Chaube and
• Martina Delbianco

Beilstein J. Org. Chem. 2021, 17, 1981–2025, doi:10.3762/bjoc.17.129

• considerably reduced the time needed for the stereoselective synthesis of linear α(1–6)-mannans (ranging from 5mer to 20mer) [275]. The biggest advantage of this approach is the easy scalability, up to a gram scale. However, this strategy is limited to one type of linkage (i.e., only α(1–6) linkages) and does

Iodine-catalyzed electrophilic substitution of indoles: Synthesis of (un)symmetrical diindolylmethanes with a quaternary carbon center

• Thanigaimalai Pillaiyar,
• Masoud Sedaghati,
• Andhika B. Mahardhika,
• Lukas L. Wendt and
• Christa E. Müller

Beilstein J. Org. Chem. 2021, 17, 1464–1475, doi:10.3762/bjoc.17.102

• , and scalability to obtain gram amounts for biological studies. Selected compounds were found to display affinity for cannabinoid receptors, which are promising drug targets for the treatment of inflammatory and neurodegenerative diseases. Keywords: alkylation of indole; anti-inflammatory; binding

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• temperature and pressure range access, the potential for in-line purification, monitoring and telescoping, linear scalability and more efficient mixing. These applications are very attractive for a synthetic chemist in all settings, especially considering the current ever-increasing industrial pressure to

• , difficulty in maintaining the reaction temperature and the occurrence of greater amounts of acetone and aldehyde self-condensation/polymerisation. By adopting a flow protocol and using a Comet X-01 micromixer (with linear scalability), more efficient mixing was attained and less aldehyde self-condensation

• for a marked reduction in reaction times (20 min vs 40 h) via improved mixing, and the ability to conduct the experiment at higher temperature without detrimental results. They also confirmed the easy scalability of the process from a 1 to 4 mL reactor without loss of selectivity and efficiency. The