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

• were explored, using a total volume of 4.5 mL reaction mixture, and the screening results can be readily translated to continuous flow synthesis. The application of segmented flow or microslug reactors was demonstrated in the decarboxylative arylation cross-coupling reaction promoted by catalysts and

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

• significance and practical value for process optimization. Results and Discussion In this section, we perform kinetic modeling for the continuous flow synthesis of NIO from IO and mixed acid (Scheme 1). The reaction was then optimized by kinetic modeling. Prescreening experiments The solubility of IO in H2SO4

Honeycomb reactor: a promising device for streamlining aerobic oxidation under continuous-flow conditions

• Masahiro Hosoya,
• Yusuke Saito and
• Yousuke Horiuchi

Beilstein J. Org. Chem. 2023, 19, 752–763, doi:10.3762/bjoc.19.55

• from operators or the equipment can have disastrous consequences. Because the large headspace of batch reactor aggravates these safety risks, the use of O2 in batch manufacturing is very limited [14]. Recently, continuous flow synthesis has recently been studied as a way to mitigate the safety risks

• ], and its screening results can be transferred to obtain a wide variety of benzaldehydes from benzyl alcohols. The screening was conducted under batch conditions. Toward its application to continuous-flow synthesis, we considered the description of the reaction mixture as well as the reaction rate

Continuous flow synthesis of 6-monoamino-6-monodeoxy-β-cyclodextrin

• János Máté Orosz,
• Dóra Ujj,
• Petr Kasal,
• Gábor Benkovics and
• Erika Bálint

Beilstein J. Org. Chem. 2023, 19, 294–302, doi:10.3762/bjoc.19.25

• Reddy et al. [48] is worth mentioning, who used metallic indium and ammonium chloride for the reduction of N3-β-CD. Continuous flow synthesis of 6A-O-(p-toluenesulfonyl)-β-CD (2) According to the literature, most of the tosylations of CDs took place under heterogeneous conditions. However, small solid

• similar conversions were achieved in over 2 hours. The flow tosylation was also investigated using acetonitrile instead of THF, however, a much lower conversion was observed (Table 1, entry 4). Continuous flow synthesis of 6A-azido-6A-deoxy-β-CD (3) After the tosylation step was successful in flow, next

• time was greatly reduced to only 10 minutes. Continuous flow synthesis of 6A-amino-6A-deoxy-β-CD (4) In the last step of the flow synthesis, the reduction of the N3-β-CD (3) was investigated in an H-Cube Pro® flow hydrogenating reactor containing a 10% Pd/C pre-packed cartridge (Scheme 3). Generally, a

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

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

• uptake of continuous flow synthesis can also be seen in the development of less frequently exploited extraction technologies. This is the case for a multi-jet oscillating disc reactor (MJOD) [64], where a continuous flow iodination reaction was coupled with a telescoped continuous flow work-up section

• continuous flow synthesis focus on palladium [85], cobalt [86], or copper (particularly useful for the widely used CuAAc) [87]. Nevertheless, the use of metal scavengers in large scale applications is limited as often discussed [88]. The use of a homogeneous scavenger as part of batch-based offline

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

• report a continuous flow synthesis of non-symmetric AB compounds via the Baeyer–Mills reaction, which allows to obtain large quantities of products from different substrates in a fast and efficient manner. Results and Discussion For optimization of the Baeyer–Mills coupling in continuous flow the

• a nitro-substituent. Moreover, some further cases of ortho-substituted anilines were unsuccessful, for which steric effects could serve as an explanation (see Supporting Information File 1 for details). In comparison with published batch syntheses, the herein reported continuous flow synthesis

• the proposed mechanism, which involves nucleophilic attack of the aniline on the nitrosobenzene derivatives in acidic or basic media (Scheme 1) [18][19][20][21]. However, in order to use azobenzenes as functional materials, access to a large-scale process is necessary. In this context continuous flow

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• nanostructured particles (MagSilicaTM) and packed bed reactor embedded in inductor (right); B. heating profile of different materials exposed to an electromagnetic field. Heating profiles of MagSilicaTM, MnFe2O4, BayferroxTM, and iron powder. Continuous flow synthesis of isopulegol (2) from citronellal (1). Dry

• . Inductively heated continuous flow protocol for the synthesis of Iso E Super (88) [91][92]. Three-step continuous flow synthesis of macrocycles 89 and 90 with musk-like olfactoric properties. Acknowledgements We thank Dr. J. Panten (Symrise AG, Holzminden, Germany) and Dr. H. Herzog (EVONIK Degussa GmbH

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

Heterogeneous photocatalysis in flow chemical reactors

• Christopher G. Thomson,
• Ai-Lan Lee and
• Filipe Vilela

Beilstein J. Org. Chem. 2020, 16, 1495–1549, doi:10.3762/bjoc.16.125

Disposable cartridge concept for the on-demand synthesis of turbo Grignards, Knochel–Hauser amides, and magnesium alkoxides

• Mateo Berton,
• Kevin Sheehan,
• Andrea Adamo and
• D. Tyler McQuade

Beilstein J. Org. Chem. 2020, 16, 1343–1356, doi:10.3762/bjoc.16.115

• lithium chloride separated with fiberglass for the turbo Grignard reagent synthesis. Steady-state concentration stability during the conversion of iPrCl in THF (56 mL, 2.2 M) into iPrMgCl·LiCl (50 mL, 1.91 M) using two perfluorinated disposable monocomponent tubular reactors. Continuous flow synthesis of

• TMPMgCl⋅LiCl with a stratified packed-bed column of activated magnesium and lithium chloride. Continuous flow synthesis of TMPMgCl⋅LiBr with a stratified packed-bed column of activated magnesium and lithium bromide. Continuous flow synthesis of t-AmylOMgCl⋅LiCl with a stratified packed-bed column of

KOt-Bu-promoted selective ring-opening N-alkylation of 2-oxazolines to access 2-aminoethyl acetates and N-substituted thiazolidinones

• Qiao Lin,
• Shiling Zhang and
• Bin Li

Beilstein J. Org. Chem. 2020, 16, 492–501, doi:10.3762/bjoc.16.44

• synthesis of β-nitrate ester carboxamides using tert-butyl nitrite as the nitro source and oxygen as the oxidant through the ring opening of 2-oxazolines [9] (Scheme 1a). Kappe reported a two-step continuous-flow synthesis of N-(2-aminoethyl)acylamides through ring opening/hydrogenation of oxazolines with

Safe and highly efficient adaptation of potentially explosive azide chemistry involved in the synthesis of Tamiflu using continuous-flow technology

• Cloudius R. Sagandira and
• Paul Watts

Beilstein J. Org. Chem. 2019, 15, 2577–2589, doi:10.3762/bjoc.15.251

• explosive azide chemistry involved in a proposed Tamiflu route by taking advantage of the continuous-flow technology. The azide intermediates were safely synthesised in full conversions and >89% isolated yields. Keywords: azide chemistry; continuous flow synthesis; hazardous; safe; Tamiflu; Introduction

• ) (Scheme 1 and Figure 1). Continuous-flow synthesis offers the generation and consumption of dangerous intermediates in situ preventing their accumulation, thus it represents a potential solution for dealing with hazardous reaction intermediates and products [15]. Additionally, microreactors can handle

• ; the first step in the synthesis of Tamiflu [18]. Results and Discussion Continuous-flow synthesis of ethyl (3S,4R,5R)-3-azido-4,5-bis(methanesulfonyloxy)cycohex-1-enecarboxylate (5). Mesyl shikimate azidation is a pivotal step in our proposed Tamiflu route. Mesyl shikimate 4 in the presence of a

Low-budget 3D-printed equipment for continuous flow reactions

• Jochen M. Neumaier,
• Amiera Madani,
• Thomas Klein and
• Thomas Ziegler

Beilstein J. Org. Chem. 2019, 15, 558–566, doi:10.3762/bjoc.15.50

• channels, which shows a width of ≈200 μm. CAD drawing of two CSTR with three (a) and two inlets (b) with in-printed screw nuts 1/4’’ – 28 thread for flat bottom fittings. a) Unassembled parts used for one syringe pump. b) Assembled pump with controller. a) Schematic diagram for the continuous-flow

• synthesis of acetobromo-α-D-glucose 2. b) Photograph of a typical setting for continuous flow reaction. Preparation of acetobromo-α-D-glucose 2. Flow Koenigs–Knorr reaction to methyl glycoside 3 with silver triflate. Preparation of glycosyl donor 5. Two-step glycosylation reactions starting from pyranose 3

Assessing the possibilities of designing a unified multistep continuous flow synthesis platform

• Mrityunjay K. Sharma,
• Roopashri B. Acharya,
• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2018, 14, 1917–1936, doi:10.3762/bjoc.14.166

• ’, in reality, such an envisaged system would be much more complex than these examples. Keywords: automation; continuous flow synthesis; cybernetics; multistep flow synthesis; unified platforms; Review Introduction Flow chemistry is now seen as a reliable approach for the synthesis of simple organic

• ]. Flow chemistry gains its benefits from excellent heat and mass transfer rates and rapid mixing which is not possible in the case of conventional synthesis modes [21]. In general, the continuous flow synthesis aims at conducting the reactions at intrinsic kinetics. This helps to have reactors having

• ][26][27]. A few examples of experimental set-ups of successfully demonstrated multistep flow synthesis encompassing various kinds of reactions from the literature are given in Table 1. Single step approaches were useful in terms of evaluating the concepts in continuous flow synthesis. However, since

Heterogeneous Pd catalysts as emulsifiers in Pickering emulsions for integrated multistep synthesis in flow chemistry

• Katharina Hiebler,
• Georg J. Lichtenegger,
• Manuel C. Maier,
• Eun Sung Park,
• Renie Gonzales-Groom,
• Bernard P. Binks and
• Heidrun Gruber-Woelfler

Beilstein J. Org. Chem. 2018, 14, 648–658, doi:10.3762/bjoc.14.52

• on the planned realisation of the integrated multistep continuous flow synthesis of valsartan and sacubitril within the frame of the ONE-FLOW project is given. The compounds are well known as APIs in a combination drug for the treatment of hypertension and chronic heart failure (Entresto®, Novartis

High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

• Eric Yu,
• Hari P. R. Mangunuru,
• Nakul S. Telang,
• Caleb J. Kong,
• Jenson Verghese,
• Stanley E. Gilliland III,
• Saeed Ahmad,
• Raymond N. Dominey and
• B. Frank Gupton

Beilstein J. Org. Chem. 2018, 14, 583–592, doi:10.3762/bjoc.14.45

• facilitate the formation of 1, resulting in a comparable yield in less than 6 hours. Thus, we have integrated the continuous preparation of reaction with our new efficient continuous-flow synthesis of 12 with the final step by using a CSTR to accommodate the longer reaction time required to produce HCQ (1

Continuous multistep synthesis of 2-(azidomethyl)oxazoles

• Thaís A. Rossa,
• Nícolas S. Suveges,
• Marcus M. Sá,
• David Cantillo and
• C. Oliver Kappe

Beilstein J. Org. Chem. 2018, 14, 506–514, doi:10.3762/bjoc.14.36

• continuous-flow synthesis of 2-(azidomethyl)oxazoles 7. Side products generated during the reaction of azirine 2a with bromoacyl bromide at room temperature. Batch optimization of the thermolysis of vinyl azide 1a.a Optimization of the reaction conditions for the generation of oxazole 6a from azirine 2a.a

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

• . also facilitate continuous separation and significantly reduce the time for process development. Recent reviews on multistep synthesis clearly highlight the potential application of multistep syntheses in fine and pharmaceutical industries [5][31][32]. However, while continuous-flow synthesis helps to

• options which are critical to the implementation of a process. Case studies Till date, there are more than 80 excellent publications that use continuous-flow synthesis of high-value molecules where the synthesis involves two and more stages. While choosing the representative case studies we have applied

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

• Flavio Fanelli,
• Giovanna Parisi,
• Leonardo Degennaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2017, 13, 520–542, doi:10.3762/bjoc.13.51

• the potential of microreactor technology and flow chemistry in sustainable synthesis, recent outstanding “proof of concepts” will be described. Kobayashi and co-workers reported a multistep continuous-flow synthesis of a drug target via heterogeneous catalysis. The developed process not requiring any

• pharmaceutical manufacturing, has been recently reported by Jensen and his research team. The research team set up a compact and reconfigurable manufacturing platform for the continuous-flow synthesis and formulation of active pharmaceutical ingredients (APIs) [92]. The “mini” plant (reported in Figure 3) was

Continuous-flow synthesis of highly functionalized imidazo-oxadiazoles facilitated by microfluidic extraction

• Ananda Herath and
• Nicholas D. P. Cosford

Beilstein J. Org. Chem. 2017, 13, 239–246, doi:10.3762/bjoc.13.26

• Ananda Herath Nicholas D. P. Cosford Cancer Metabolism & Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA 10.3762/bjoc.13.26 Abstract A versatile continuous-flow synthesis of highly functionalized 1,2,4

• developed methodology, our next goal was to incorporate a carboxylic acid synthesis step into the flow process. As noted above, we previously reported the continuous-flow synthesis of imidazo[1,2-a]pyridine-2-carboxylic acids in a single, uninterrupted process directly from readily available starting

• flash chromatography (SiO2) to afford the desired product (CombiFlash® Rf, 12 g flash column). The solvent gradient was 90% hexane to 50% ethyl acetate over 15 min at a flow rate of 15 mL/min. General procedure for the continuous flow synthesis of imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazoles (Table 3

The digital code driven autonomous synthesis of ibuprofen automated in a 3D-printer-based robot

• Philip J. Kitson,
• Stefan Glatzel and
• Leroy Cronin

Beilstein J. Org. Chem. 2016, 12, 2776–2783, doi:10.3762/bjoc.12.276

• continuous-flow synthesis of ibuprofen. The reaction was designed specifically such that the byproducts and excess reagents of each step were compatible with the subsequent transformations, eliminating the need for isolation and purification of intermediate products. This approach suited the development of

Continuous-flow synthesis of primary amines: Metal-free reduction of aliphatic and aromatic nitro derivatives with trichlorosilane

• Riccardo Porta,
• Alessandra Puglisi,
• Giacomo Colombo,
• Sergio Rossi and
• Maurizio Benaglia

Beilstein J. Org. Chem. 2016, 12, 2614–2619, doi:10.3762/bjoc.12.257

• conditions, but the presence of noble metal catalysts, packed into disposable cartridges, suffers from functional group compatibility and catalyst poisoning during time. In 2012 Kappe’s research group reported the microwave-assisted continuous-flow synthesis of anilines from nitroarenes using hydrazine as

The in situ generation and reactive quench of diazonium compounds in the synthesis of azo compounds in microreactors

• Faith M. Akwi and
• Paul Watts

Beilstein J. Org. Chem. 2016, 12, 1987–2004, doi:10.3762/bjoc.12.186

• Faith M. Akwi Paul Watts Nelson Mandela Metropolitan University, University Way, Port Elizabeth, 6031, South Africa 10.3762/bjoc.12.186 Abstract In this paper, a micro-fluidic optimized process for the continuous flow synthesis of azo compounds is presented. The continuous flow synthesis of Sudan

• documented in literature [26][27][28][29][30], the ease of reaction parameter optimization in the synthesis of azo compounds in microreactors is highlighted. In this study, the continuous flow synthesis of Sudan II azo dye (19, Scheme 6) constituting of the diazotization of 2,4-dimethylaniline (16) and its

• microreactor technology offers to organic syntheses such as this one by performing both reaction steps in continuous flow reactors. Continuous flow synthesis of Sudan II azo dye in LTF-MS microreactors Having determined the reaction parameters that affect the azo coupling reaction in the synthesis of Sudan II

Catalytic Chan–Lam coupling using a ‘tube-in-tube’ reactor to deliver molecular oxygen as an oxidant

• Carl J. Mallia,
• Paul M. Burton,
• Alexander M. R. Smith,
• Gary C. Walter and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2016, 12, 1598–1607, doi:10.3762/bjoc.12.156

• . Comparison of 1H NMR spectra of non-purified (top) and QP-DMA purified (bottom) continuous flow synthesis of compound 20. NOESY NMR spectrum for 30 with the characteristic NOESY signal encircled. NOESY NMR spectrum for 33 with the characteristic NOESY signal encircled. NOESY NMR spectrum for 35 with the