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

Biomimetic molecular design tools that learn, evolve, and adapt

• David A Winkler

Beilstein J. Org. Chem. 2017, 13, 1288–1302, doi:10.3762/bjoc.13.125

• generation of improved materials. Early progress in this area has been made – for example, a closed loop flow synthesis method has been developed that automatically optimizes the yield and selectivity of the products [49]. Use of evolutionary and machine learning in silico methods as well as robotic

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

• The implementation of automation in the multistep flow synthesis is essential for transforming laboratory-scale chemistry into a reliable industrial process. In this review, we briefly introduce the role of automation based on its application in synthesis viz. auto sampling and inline monitoring

• , optimization and process control. Subsequently, we have critically reviewed a few multistep flow synthesis and suggested a possible control strategy to be implemented so that it helps to reliably transfer the laboratory-scale synthesis strategy to a pilot scale at its optimum conditions. Due to the vast

• scale of operation. This classification will cover the broader range in the multistep synthesis literature. Keywords: automation; control strategy; flow chemistry; in-line monitoring; multistep synthesis optimization; Introduction Multistep flow synthesis In the recent time the concept of flow

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

• produce enantioenriched materials were employed. It is worth mentioning that this work represents a very nice example on the use of chiral catalysis in a multistep flow synthesis of a drug target on gram scale. The multistep synthesis of (S)-rolipram reported in Scheme 23 begins from a benzaldehyde

• 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

NMR reaction monitoring in flow synthesis

• M. Victoria Gomez and
• Antonio de la Hoz

Beilstein J. Org. Chem. 2017, 13, 285–300, doi:10.3762/bjoc.13.31

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

• describe the utilization of liquid–liquid microextraction to facilitate a complex, multistep flow synthesis process. Our research in the field of flow synthesis has focused on developing continuous-flow chemistry methods to access complex, drug-like molecules from readily available precursors without

• follow-up confirmatory studies. We previously reported a method for the preparation of 1,2,4-oxadiazoles in an uninterrupted continuous-flow sequence using arylnitriles and acyl chloride precursors [9]. We also reported the flow synthesis of highly functionalized imidazo[1,2-a]heteroaryl derivatives from

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

• synthetically relevant intermediates (precursors of baclofen and boscalid). Keywords: chemoselectivity; continuous processes; flow synthesis; nitro reduction; trichlorosilane; Introduction The reduction of nitro compounds to amines is a fundamental transformation in organic synthesis. The nitration of

• 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

Flow carbonylation of sterically hindered ortho-substituted iodoarenes

• Carl J. Mallia,
• Gary C. Walter and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2016, 12, 1503–1511, doi:10.3762/bjoc.12.147

• Carl J. Mallia Gary C. Walter Ian R. Baxendale Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, United Kingdom Syngenta CP R&D Chemistry, Jealott's Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom 10.3762/bjoc.12.147 Abstract The flow

• synthesis of ortho-substituted carboxylic acids, using carbon monoxide gas, has been studied for a number of substrates. The optimised conditions make use of a simple catalyst system compromising of triphenylphosphine as the ligand and palladium acetate as the pre-catalyst. Carbon monoxide was introduced

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

• A. John Blacker Katherine E. Jolley Institute of Process Research and Development, School of Chemistry and School of Chemical and Process Engineering, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, Leeds, UK 10.3762/bjoc.11.262 Abstract The continuous flow synthesis of a range of organic

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

• : continuous processing; flow synthesis; in-line analysis; manufacture; pharmaceuticals; scalability; Introduction The last 20 years have witnessed a true renaissance in the way synthetic chemistry is performed due to the implementation of various enabling technologies allowing the modern synthesis chemist to

• the scaled synthesis of NBI-75043 (3) [41], a continuous dehydration process to deliver over 5 kg of dehydropristane 4, a precursor of the immunoactivating agent pristane [42] or the flow synthesis of hydroxamic acids by a procedure that was also applied to the preparation of suberoylanilide

• 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

Continuous flow nitration in miniaturized devices

• Amol A. Kulkarni

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

• initial development and demonstration of the continuous flow synthesis using miniaturized devices or microreactors took place in academia and research institutions. The benefits of the approach are particularly evident for highly exothermic reactions and for reactions involving unstable intermediates

• -dimethyl-4-nitropyrazole (31) and 3-ethyl-4-nitropyrazole (32) were obtained with nitrating mixture and were expected to show detonating properties under severe confinement (Scheme 9). This flow synthesis did not allow the pressure inside the reactor to undergo rapid variations in a short time, thereby

• step to isolate the product. However, since the large-scale synthesis of nitropyrazoles is not a safe reaction under batch conditions, the continuous flow synthesis is the process of choice. Henke and Winterbauer [46] reported a corrosion resistant microreactor built up of PTFE and tantalum for the

Flow microreactor synthesis in organo-fluorine chemistry

• Hideki Amii,
• Aiichiro Nagaki and
• Jun-ichi Yoshida

Beilstein J. Org. Chem. 2013, 9, 2793–2802, doi:10.3762/bjoc.9.314

• fluorine chemistry. Meanwhile, flow microreactor synthesis, the use of microfluidic devices, has emerged as a new method for producing chemical substances with high efficiency [11][12][13]. Now, the introduction of continuous-flow synthesis technique to laboratory synthesis represents a highly useful and

• conducted in one flow by adding the reagents at different places in continuous-flow synthesis [18][19][20][21][22][23][24][25]. This review deals with the successful examples on synthesis and reactions of fluorine-containing molecules by the use of flow microreactor systems. Useful applications using flow

• [18F]-radiolabeled molecular imaging probes. Flow microreactor synthesis of dipeptides. Flow synthesis involving SNAr reactions. Flow synthesis of fluoroquinolone antibiotics. Highly controlled formation of PFPMgBr. Selective flow synthesis of photochromic diarylethenes. Flow microreactor system for

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

• concept flow synthesis of the key intermediate used to produce the bromo derivative of the CAPIC precursor, 2-bromo-4-methylnicotinonitrile (6b). The synthesis telescopes three steps using substantially less expensive starting materials. Flow or continuous chemistry is alternative to batch chemistry where

Synthesis of homo- and heteromultivalent carbohydrate-functionalized oligo(amidoamines) using novel glyco-building blocks

• Felix Wojcik,
• Sinaida Lel,
• Alexander G. O’Brien,
• Peter H. Seeberger and
• Laura Hartmann

Beilstein J. Org. Chem. 2013, 9, 2395–2403, doi:10.3762/bjoc.9.276

• heteromultivalent glycosylation patterns by combining building blocks presenting different mono- and disaccharides. Keywords: continuous flow; flow chemistry: flow synthesis; glycoligands; multivalency; photochemistry; solid-phase synthesis; thiol–ene; thioglycosides; Introduction Multivalent carbohydrate ligand

Micro-flow synthesis and structural analysis of sterically crowded diimine ligands with five aryl rings

• Shinichiro Fuse,
• Nobutake Tanabe,
• Akio Tannna,
• Yohei Konishi and
• Takashi Takahashi

Beilstein J. Org. Chem. 2013, 9, 2336–2343, doi:10.3762/bjoc.9.268

• detailed structural study. Herein, we report an efficient micro-flow synthesis and structural analysis of sterically crowded 1,2,3,4,5-pentaaryl-1,3,5-triazapenta-1,4-diene ligands 3b and 3c, and their use in the copolymerization of ethylene and polar monomers. According to the previous report, 1,2,3,4,5

• . The reaction mixture was concentrated in vacuo. The residue was used for the next reaction without further purification. General procedure for micro-flow synthesis of 1,2,3,4,5-pentaaryl-1,3,5-triazapenta-1,4-dienes 3b and 3c: A T-shape mixer and reaction tube were immersed in a water bath (20 °C

• crowded, and neutral chelating diimine ligands. Micro-flow synthesis of the ligands 3b and 3c. ORTEP drawing of 3b. Thermal ellipsoids are set at 35% probability level. Hydrogen atoms are omitted for clarity. Selected bond lengths [Å] and angles [°] are as follows: C(1)–N(1) 1.273(4), C(1)–N(2) 1.420(4

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

Flow synthesis of phenylserine using threonine aldolase immobilized on Eupergit support

• Jagdish D. Tibhe,
• Hui Fu,
• Timothy Noël,
• Qi Wang,
• Jan Meuldijk and
• Volker Hessel

Beilstein J. Org. Chem. 2013, 9, 2168–2179, doi:10.3762/bjoc.9.254

• flow synthesis of phenylserine was developed, and the effects of temperature and residence time were studied in particular. Calculations of the Damköhler number revealed that no mass transfer limitations are given in the micro-interstices of the packed bed. The yield does not exceed 40% and can be

• rationalized by the natural equilibrium as well as product inhibition which was experimentally proven. The flow synthesis with the immobilized enzyme was compared with the corresponding transformation conducted with the free enzyme. The product yield was further improved by operating under slug flow conditions

• support. In continuation of our previous work [48], this paper includes further investigation of the thermal stability of TA on Eupergit by a so-called direct and indirect method. Also, a flow synthesis of Eupergit-immobilized TA in a packed bed microreactor was established and compared to the use of free