Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

• Hui Yu and
• Feng Xu

Beilstein J. Org. Chem. 2023, 19, 1259–1288, doi:10.3762/bjoc.19.94

• application of this method still limited by sustainability, safety, and cost factors. Therefore, further development to shorten the reaction time, improve the reaction efficiency, and reduce energy consumption in an environmentally friendly, practical, and safe method for CDC will be a continuous process [131

Modern flow chemistry – prospect and advantage

• Philipp Heretsch

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

• mesylate, diazomethane was an inevitable necessity. By moving the generation of this toxic and explosive reagent into a continuous process with manageable amounts present at any given point and continuously stripping the chemical with a stream of nitrogen, safety protocols could be met [10]. Among the

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

• continuous process could be established by oxidation with molecular oxygen introduced into the reaction stream via a tube-in-tube membrane reactor, a process which should be very attractive for industrial applications, as oxygen or air act as cheap and environmentally friendly oxidants [82]. An interesting

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

• quenched aldol outlet stream was directed into a cooled receiver vessel, to which trifluoroacetic anhydride (TFAA) was simultaneously added, creating a net semi-continuous process. Subsequent ammonia-mediated cyclisation of the resultant diene followed by alkylation with the chlorotriazolinone 48 yielded

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

• indicated that a slight excess of 1.8 equiv was needed to ensure the full and rapid conversion of the isocyanate intermediate into the desired Cbz-carbamate product 3. A Vapourtec E-series flow platform was used to operate this continuous process as depicted in Scheme 1. In order to rapidly create a small

Novel solid-phase strategy for the synthesis of ligand-targeted fluorescent-labelled chelating peptide conjugates as a theranostic tool for cancer

• Sagnik Sengupta,
• Mena Asha Krishnan,
• Premansh Dudhe,
• Ramesh B. Reddy,
• Bishnubasu Giri,
• Sudeshna Chattopadhyay and
• Venkatesh Chelvam

Beilstein J. Org. Chem. 2018, 14, 2665–2679, doi:10.3762/bjoc.14.244

• successfully designed and demonstrated a novel continuous process for assembling targeting ligands, peptidic spacers, fluorescent tags and a chelating core for the attachment of cytotoxic molecules, radiotracers, nanomaterials in a standard Fmoc solid-phase peptide synthesis in high yield and purity. The

• ligand for biomarkers, a fluorescent tag and a chelating moiety for tethering cargo in a continuous process using solid-phase peptide synthesis is poorly developed. Traditional solid-phase peptide synthesis methods for preparation of bioconstructs employ orthogonally protected functional moieties present

• segment [38] without fluorescent tag using Wang resin that is cleaved in strongly acidic conditions. Contrary to the aforementioned drawbacks, the present manuscript elicits a novel synthetic strategy for building new bioconstructs with several components in a continuous process without isolation of any

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

• (reaction/drying/crystallization/adsorption/desorption), solubility data (extraction/crystallization), etc. This approach is useful for testing proof of the concept for a continuous process of various drugs which are in clinical trials. However, this approach may not be feasible for pilot or production

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

• the selective reduction of aldehydes in the presence of ketones and has been demonstrated as a continuous process. Keywords: aldehyde reduction; flow chemistry; selective reduction; sodium dithionite; Introduction Flow chemistry and continuous processing has been acknowledged by the American

• , Figure 4). Demonstration of a continuous process Finally, we were interested in converting the approach to a continuously run process, however, a concern at this stage was the formation of the aforementioned precipitate and although this was negligible at 110 °C, we felt it could potentially lead to

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

• synthesis of the antimalarial drug hydroxychloroquine (HCQ). Key improvements in the new process include the elimination of protecting groups with an overall yield improvement of 52% over the current commercial process. The continuous process employs a combination of packed bed reactors with continuous

• of 68% for compound 12. With an optimized continuous process for producing the key intermediate 12 in-hand the reaction conditions for the conversion of 12 to HCQ (1) were examined. In the commercial process this step is carried out in batch under neat reactant conditions and requires a relatively

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

• fully continuous process are described in detail. Results and Discussion Thermolysis of the vinyl azide and oxazole formation. Batch optimization The reaction conditions for the thermolysis of the vinyl azide and the subsequent ring expansion of the intermediate azirine to form the oxazole ring were

A chemoselective and continuous synthesis of m-sulfamoylbenzamide analogues

• Arno Verlee,
• Thomas Heugebaert,
• Tom van der Meer,
• Pavel I. Kerchev,
• Frank Van Breusegem and
• Christian V. Stevens

Beilstein J. Org. Chem. 2017, 13, 303–312, doi:10.3762/bjoc.13.33

• potential of a chemoselective synthesis as a continuous process. As bench mark, aniline and azepane were used as first and second reagent, respectively. After addition of the first reactant and completion of the reaction (followed by TLC) the second reactant was added. The chemoselectivity was determined by

• -sulfamoylbenzamide analogues a) Continuous process with primary amines as F1: Triethylamine and a primary amine (F1) were dissolved in acetonitrile (c = 40 mM), m-chlorosulfonylbenzoyl chloride (F2) was dissolved in the same solvent in a separate volumetric flask (c = 40 mM). A third solution was prepared with

• was purified by either preparative thin-layer chromatography or by recrystallization. b) Continuous process with secondary amines as F1: Triethylamine and a secundary amine (F1) were dissolved in acetonitrile (c = 5 mM), m-chlorosulfonylbenzoyl chloride (F2) was dissolved in acetonitrile in a second

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

• isolation of intermediates. We have shown that the “telescoping” of multiple synthetic steps into a single continuous process provides an efficient method for the production of heterocyclic compound libraries in sufficient quantities for biological screening in high-throughput assay formats as well as

• readily available starting materials in a single continuous process [7]. We now report an efficient continuous-flow procedure for the synthesis of 1,2,4-oxadiazoles directly from arylnitriles and carboxylic acid derivatives. We further demonstrate the incorporation of this procedure into a continuous

• ]pyridin-2-yl-1,2,4-oxadiazoles, a scaffold with activity as S1P1 agonists, are prepared directly from commercially available building blocks in a single continuous process without isolating intermediates. As noted previously, the standard in-flask (batch) synthesis of these compounds involves multiple

Extrusion – back to the future: Using an established technique to reform automated chemical synthesis

• Deborah E. Crawford

Beilstein J. Org. Chem. 2017, 13, 65–75, doi:10.3762/bjoc.13.9

• pyrophoric reagent, such as s-BuLi, is involved is quite remarkable, and it is carried out as a continuous process and not on a small scale. This suggests that solvent-free extrusion can be on par with continuous flow technology, allowing a wider range of hazardous reagents to be used continuously and on

Towards the development of continuous, organocatalytic, and stereoselective reactions in deep eutectic solvents

• Davide Brenna,
• Elisabetta Massolo,
• Alessandra Puglisi,
• Sergio Rossi,
• Giuseppe Celentano,
• Maurizio Benaglia and
• Vito Capriati

Beilstein J. Org. Chem. 2016, 12, 2620–2626, doi:10.3762/bjoc.12.258

• . Keywords: continuous process; DES; organocatalysis; proline; stereoselective aldol reaction; Introduction The aldol reaction is a powerful synthetic tool to create new C–C bonds [1]. It offers several possibilities to control the stereochemical outcome of the process and to afford stereochemically defined

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

• a reaction scale-up, followed by an in-line extraction in order to obtain a full continuous process with no need for intermediate operations (Scheme 6). A syringe pump equipped with two SGE gas tight 25 mL syringes was used to feed the reagents into a 5 mL PTFE reactor through a T-junction (syringe

Development of a continuous process for α-thio-β-chloroacrylamide synthesis with enhanced control of a cascade transformation

• Olga C. Dennehy,
• Valérie M. Y. Cacheux,
• Benjamin J. Deadman,
• Denis Lynch,
• Stuart G. Collins,
• Humphrey A. Moynihan and
• Anita R. Maguire

Beilstein J. Org. Chem. 2016, 12, 2511–2522, doi:10.3762/bjoc.12.246

• Department of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Cork, Ireland 10.3762/bjoc.12.246 Abstract A continuous process strategy has been developed for the preparation of α-thio-β

• process scales caused us to consider alternative ‘greener’ solvent systems [27]. A screen of alternative solvents in batch test reactions revealed that, while the amide formation was tolerant to most solvents, rapid precipitation of triethylamine hydrochloride would be problematic in a continuous process

• . Indeed, trial runs of a continuous process in ethyl acetate resulted in immediate blockage of the flow reactor at the point of reagent mixing. To prevent blockages due to salt formation we investigated replacements for triethylamine that would produce a more soluble HCl salt. Diisopropylethylamine (DIPEA

Continuous formation of N-chloro-N,N-dialkylamine solutions in well-mixed meso-scale flow reactors

• A. John Blacker and
• Katherine E. Jolley

Beilstein J. Org. Chem. 2015, 11, 2408–2417, doi:10.3762/bjoc.11.262

• phase require longer reaction times, provided by the CSTR, to compensate for low mass transfer rates in the biphasic system. The green metrics of the reaction have been assessed and compared to existing procedures and have shown the continuous process is improved over previous procedures. The organic

• of the continuous process for chloramine formation described in this publication, the metrics of the reaction were assessed and compared with existing literature procedures [35]. The results are summarised in Table 3. The yields of the continuous N-chloramine process were high, and comparable to

• achieved for most. The green metrics of the reaction have been assessed and compared to existing procedures for chloramine formation, and have shown the continuous process is improved over previous procedures. Work to expand the scope of N-chloramines, and their subsequent use in flow reactions with

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• distributions and excellent heat and mass transfer. Consequently, long batch processes (including crystallisations, fermentations, polymerisations or waste water treatments) can be translated into a continuous process. In an early example such COBRs were applied to the flow synthesis of aspirin showcasing the

• step approach towards ibuprofen (16) using microreactor technology [48]. A fully continuous process was aspired to, in which only final purification was to be performed off-line at the end of the sequence. Each of the individual steps were first optimised in flow being mindful of the reagents used in

• synthesis of ibuprofen in only ten minutes residence time albeit in a yield of only 51% equating to a productivity of 9 mg/min. Although this work nicely demonstrates the feasibility of constructing a continuous process it is mainly an academic proof of principle based upon an important well known molecule

Highly selective generation of vanillin by anodic degradation of lignin: a combined approach of electrochemistry and product isolation by adsorption

• Dominik Schmitt,
• Carolin Regenbrecht,
• Marius Hartmer,
• Florian Stecker and
• Siegfried R. Waldvogel

Beilstein J. Org. Chem. 2015, 11, 473–480, doi:10.3762/bjoc.11.53

• avoids acidification of the solution and no precipitation occurs. The performance and applicability of this process was investigated by ten identical electrochemical degradation reactions followed by adsorption of the resulting solutions in a continuous process on the same column. After adsorption the

Electrocarboxylation: towards sustainable and efficient synthesis of valuable carboxylic acids

• Roman Matthessen,
• Jan Fransaer,
• Koen Binnemans and
• Dirk E. De Vos

Beilstein J. Org. Chem. 2014, 10, 2484–2500, doi:10.3762/bjoc.10.260

• , the gradual consumption of the anode material is a major drawback for industrial applications. Not only is it rather expensive to consume such large amounts of metal; it also strongly hinders the implementation of a continuous process. Additionally, in order to obtain the free acids, an acid

• during the reaction. But more importantly, in contrast to the use of a dissolving anode, this method allows a more efficient implementation of a continuous process. The first reports on electrocarboxylation date back to the early 1960s with a patent of Loveland, demonstrating the dicarboxylation of 1,3

• implementation in a continuous process. The anodic oxidation of formate generates one CO2 molecule and one proton, giving a controlled supply of protons to the cathode (Scheme 8). Conducting the electrocarboxylation with tetraethylammonium oxalate, without formate salts, increases the amount of C6 compared to C5

Visible light photoredox-catalyzed deoxygenation of alcohols

• Daniel Rackl,
• Viktor Kais,
• Peter Kreitmeier and
• Oliver Reiser

Beilstein J. Org. Chem. 2014, 10, 2157–2165, doi:10.3762/bjoc.10.223

• (trifluoromethyl)benzoic acid can be recycled and reactivated under redox neutral conditions, and moreover, the in situ activation of alcohols with this auxiliary is possible we envision that an overall continuous process could be developed for the deoxygenation of alcohols by this protocol. That ultimately only

Copolymerization and terpolymerization of carbon dioxide/propylene oxide/phthalic anhydride using a (salen)Co(III) complex tethering four quaternary ammonium salts

• Jong Yeob Jeon,
• Seong Chan Eo,
• Jobi Kodiyan Varghese and
• Bun Yeoul Lee

Beilstein J. Org. Chem. 2014, 10, 1787–1795, doi:10.3762/bjoc.10.187

• ]. The highly efficient catalyst (1 in Scheme 1) showed a high turnover frequency (TOF, 16,000 h−1), high molecular weight (Mn, up to 300,000), and good selectivity (>99%). These promising performances motivated to construct a continuous-process pilot plant in industry [13]. Currently, many hurdles in

Integration of enabling methods for the automated flow preparation of piperazine-2-carboxamide

• Richard J. Ingham,
• Claudio Battilocchio,
• Joel M. Hawkins and
• Steven V. Ley

Beilstein J. Org. Chem. 2014, 10, 641–652, doi:10.3762/bjoc.10.56

• , which is responsible for the hydration activity of the metal oxide. Consequently, the use of water-miscible solvents is preferred in order to have a continuous process instead of a plug flow protocol using water-immiscible solvents. Under the optimised conditions, a solution of nitrile 3 in ethanol/H2O

• meant that the flow rates did not necessarily have to be matched, resulting in a semi-continuous process. Using the two different flow rates and having the hydrolysis step stop automatically when the reservoir filled up led to a total running time of about 10 hours (Figure 14). However, we can imagine

Continuous flow nitration in miniaturized devices

• Amol A. Kulkarni

Beilstein J. Org. Chem. 2014, 10, 405–424, doi:10.3762/bjoc.10.38

• per man-hour and per square foot of floor space. Furthermore, the mixed acid can be avoided. The raw material costs are also lower due to a virtually quantitative conversion. However, the major disadvantages of the continuous process are associated with the comparatively higher costs of the reactor

Investigating the continuous synthesis of a nicotinonitrile precursor to nevirapine

• Ashley R. Longstreet,
• Suzanne M. Opalka,
• Brian S. Campbell,
• B. Frank Gupton and
• D. Tyler McQuade

Beilstein J. Org. Chem. 2013, 9, 2570–2578, doi:10.3762/bjoc.9.292

• treating 4 with DMF-DMA in the presence of acetic anhydride, and ultimately 2-bromo-4-methylnicotinonitrile (6b) is produced after 5 is treated with HBr in acetic acid. Transferring the batch synthesis into a semi-continuous process requires one to consider solvent exchanges and byproducts that might

• of normal process windows [45]. Attempts to increase the reaction concentration beyond 1.0 M led to reactor clogging due to the limited of solubility of 5. We proceeded to develop a continuous process by coupling the enamine step with the Knoevenagel condensation (Scheme 4). To achieve this, we

• a completely continuous process provides the opportunity to advance process chemistry/technology, a new process can often require significant investment for regulatory validation. We wish to implement our technology as quickly as feasible and to do so we want to avoid potential regulatory problems