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

• equiv at 80°C, the reaction time was significantly prolonged, which is not suitable for the flow synthesis (Table 2, entry 7). Based on these findings, entry 6 was considered to be the optimal reaction conditions, and the application to flow synthesis using the honeycomb reactor was tried under these

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

• -toluenesulfonyl)-β-CD, 6A-azido-6A-deoxy-β-CD, and 6A-amino-6A-deoxy-β-CD to see how compatible batch methods are with flow synthesis, and then our main aim was to develop continuous flow approaches for the preparation of the mentioned CD derivatives. Results and Discussion Batch synthesis of 6A-O-(p

• , these two drawbacks are not a problem for large-scale flow synthesis when using an H-Cube system with an incorporated electrolytic cell producing H2 in situ from ultrapure water [47]. The Pd/C catalyst is placed in a stainless steel cartridge, so it is not necessary to separate it from the solution

• 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

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

• chemistry tools developed in academia. Keywords: flow synthesis; inline purification; process development; reaction telescoping; scale-up; Introduction Continuous flow chemistry is a mature and widely applied platform technology that exploits intrinsic advantages over batch processing such as better heat

• 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

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

• . Overall, the lack of catalyst separation and the possibility of combining the reactor with in-line analytical feedback enables the flow synthesis of C–S and C–O coupled products in a simple, versatile and amenable to automation way. Different approaches to heterogeneous photochemistry in flow. a) Serial

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

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

• cyclohexanone in flow. Synthesis of macrocyclic olefine 60 by ring-closing metathesis of diene 58 in a continuously stirred tank reactor (CSTR). Synthesis of macrocycles 65 and 66 by ring-closing metathesis of dienes 62 or 63, respectively, in a tube-in-tube reactor removing the formed ethylene. Z-Selective

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

• multistep flow synthesis of Iloperidone (80) accompanied with a “catch and release” purification protocol. Continuous two-step flow process consisting of Grignard reaction followed by water elimination being the last steps of a multistep flow synthesis of the hydrochloride salt of amitryptiline 84

• . 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

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

• an integrated quenching and extraction step. Lastly, the use of an automated in-line chromatography system was exploited to realise a powerful flow platform for the generation of the heterocyclic targets. Keywords: chromatography; flow synthesis; in-line purification; oxadiazole; reaction

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

• monitoring features such as pressure sensors that can both detect, assess, and if necessary, invoke emergency venting or diversion of material to auxiliary depressurisation stages, often without needing a full reactor shut down. There are numerous examples within the literature in which a flow synthesis has

Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives

• Alexander Leslie,
• Thomas S. Moody,
• Megan Smyth,
• Scott Wharry and
• Marcus Baumann

Beilstein J. Org. Chem. 2021, 17, 379–384, doi:10.3762/bjoc.17.33

• species. This strategy thus highlights the applicability of this work towards the creation of important chemical building blocks for the pharmaceutical and speciality chemical industries. Keywords: biocatalysis; CALB; Curtius rearrangement; flow synthesis; reaction telescoping; Introduction Continuous

• provide future chemists with hands-on experience in modern synthesis technologies. Apart from increased safety and scalability, reaction telescoping is one of the most attractive features of flow synthesis allowing for streamlined routes to minimize the need for the isolation and handling of potentially

A sustainable strategy for the straightforward preparation of 2H-azirines and highly functionalized NH-aziridines from vinyl azides using a single solvent flow-batch approach

• Michael Andresini,
• Leonardo Degannaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2021, 17, 203–209, doi:10.3762/bjoc.17.20

• -azirines. Flow synthesis of 2H-azirines from vinyl azides. aThe solution of vinyl azide was re-introduced twice into the flow system to achieve full conversion. Mixed flow-batch approach for the preparation of functionalized NH-aziridines from vinyl azides. Thermally induced cyclization of 1-(1-azidovinyl

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

• the homogeneous photocatalyst. The flow synthesis also prevented the formation of a chlorinated byproduct identified on the batch resins as an intermediate, and purification could be applied to wash out reactants from the first step of the one-pot synthesis, a potentially useful synthetic advantage of

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

• 411008, India 10.3762/bjoc.14.166 Abstract The multistep flow synthesis of complex molecules has gained momentum over the last few years. A wide range of reaction types and conditions have been integrated seamlessly on a single platform including in-line separation as well as monitoring. Beyond merely

• getting considered as ‘flow version’ of conventional ‘one-pot synthesis’, multistep flow synthesis has become the next generation tool for creating libraries of new molecules. Here we give a more ‘engineering’ look at the possibility of developing a ‘unified multistep flow synthesis platform’. A detailed

• ’, 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

Mild and selective reduction of aldehydes utilising sodium dithionite under flow conditions

• Nicole C. Neyt and
• Darren L. Riley

Beilstein J. Org. Chem. 2018, 14, 1529–1536, doi:10.3762/bjoc.14.129

• Nicole C. Neyt Darren L. Riley Department of Chemistry, University of Pretoria, Pretoria 0002, South Africa 10.3762/bjoc.14.129 Abstract We recently reported a novel hybrid batch–flow synthesis of the antipsychotic drug clozapine in which the reduction of a nitroaryl group is described under flow

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

Continuous-flow retro-Diels–Alder reaction: an efficient method for the preparation of pyrimidinone derivatives

• Imane Nekkaa,
• Márta Palkó,
• István M. Mándity and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2018, 14, 318–324, doi:10.3762/bjoc.14.20

• requiring harsh conditions in batch methods. A simple, efficient and scalable production was implemented with a short processing time, which might open up new horizons for a potential CF industrial synthesis of heterocycles. Schematic outline of the continuous-flow reactor. Flow synthesis for the

Microfluidic radiosynthesis of [¹⁸F]FEMPT, a high affinity PET radiotracer for imaging serotonin receptors

• Thomas Lee Collier,
• Steven H. Liang,
• J. John Mann,
• Neil Vasdev and
• J. S. Dileep Kumar

Beilstein J. Org. Chem. 2017, 13, 2922–2927, doi:10.3762/bjoc.13.285

• microfluidic flow synthesis of [18F]fluoroethyltosylate (10) and [18F]FEMPT (7). Kis of FEMPT for receptors and transporters. Selected reaction conditions for two-step continuous-flow radiosynthesis. Supporting Information Supporting Information File 408: Experimental part.

A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic

• Marcus Baumann,
• Ian R. Baxendale and
• Fabien Deplante

Beilstein J. Org. Chem. 2017, 13, 2549–2560, doi:10.3762/bjoc.13.251

• for the synthesis intermediate 11. Stepwise reduction of intermediate 11 under hydrogenation conditions. * Indicates potential tautomeric structure. Species in parentheses are proposed transient intermediates. Flow sequence for the construction of product 8. Assembled process for flow synthesis of