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

• planning, interpreting results and developing new projects. In this regard, flow chemistry is the central motif of this automated approach. In contrast to batch mode, in flow chemistry the starting materials are continuously introduced into the flow reactor (e.g., a microreactor or a column) and the

• product is continuously eluted from the end of the flow reactor. This approach can be used from microscale to laboratory scale and even to production scale [4][5]. Some important advantages of flow chemistry are: Diffusion is clearly improved with regard to chemistry in batch (reagents and products), thus

• second flow reactor the Grignard was reacted with CO2 to obtain carboxylic acids (Figure 5). The whole process was monitored by on-line 1H NMR spectroscopy using a low field NMR instrument (Spinsolve-60 from Magritek). The reaction was analysed by in-line NMR and off-line with a standard NMR tube. In the

Diels–Alder reactions of myrcene using intensified continuous-flow reactors

• Christian H. Hornung,
• Miguel Á. Álvarez-Diéguez,
• Thomas M. Kohl and
• John Tsanaktsidis

Beilstein J. Org. Chem. 2017, 13, 120–126, doi:10.3762/bjoc.13.15

• different naturally occurring and synthetic dienophiles. The synthesis of the Diels–Alder adduct from myrcene and acrylic acid, containing surfactant properties, was scaled-up in a plate-type continuous-flow reactor with a volume of 105 mL to a throughput of 2.79 kg of the final product per day. This

• continuous flow [22][23]. Over the past years, Diels–Alder reactions of isoprene using laboratory-scale flow reactors were studied by different research groups [24][25]. A continuous-flow reactor can offer a range of benefits over batch processing, with the enhanced heat and mass transfer arguable being one

• R2/R4 tubular flow reactor to a reaction volume of typically 20 mL and then on a Chemtrix Plantrix® MR260 plate flow reactor to a reaction volume of typically 200 mL (see also experimental section). The results from these continuous-flow experiments are shown in Table 3. The 10-times scale-up in the

3D printed fluidics with embedded analytic functionality for automated reaction optimisation

• Andrew J. Capel,
• Andrew Wright,
• Matthew J. Harding,
• George W. Weaver,
• Yuqi Li,
• Russell A. Harris,
• Steve Edmondson,
• Ruth D. Goodridge and
• Steven D. R. Christie

Beilstein J. Org. Chem. 2017, 13, 111–119, doi:10.3762/bjoc.13.14

• flow reactor. Notable recent work in this area has been carried out by Cronin [14], Ley [15] and Jensen [16]. This research highlights the array of benefits that manufacturing fluidic devices via AM processes can bring, including the ability to produce multimaterial parts with complex microscale

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

• the reaction (the first few hours). Having demonstrated that the flow transformation is very fast we next explored reaction scale-up employing a bigger flow reactor (5 mL PTFE reactor, i.d. = 2.54 mm, l = 100 cm), in order to increase the productivity of the process. Using the same reaction set-up

• full conversion of the starting material no further purification was required. Continuous flow reduction of 4-nitrobenzophenone using a 0.5 mL PTFE flow reactor. Continuous flow reduction of aromatic nitro compounds. Continuous-flow reduction of aliphatic nitro compounds. Synthesis of 2-(4’-chlrophenyl

• )aniline (4) with a 5 mL flow reactor. Synthesis of intermediate 6, a direct precursor of the drug baclofen. Continuous-flow reduction of 1a and in-line extraction. Screening of reaction conditions. Scope of the reaction (see Scheme 2). Supporting Information Supporting Information File 488: General

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

• , due to the neutralisation of HCl – a byproduct – with triethylamine, and the need for effective heat removal imposes limitations on the batch scale-up of this step. It was envisaged that the efficient heat transfer properties of a high surface area tubular flow reactor would remove the need for

• . 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

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

• and acidic azo coupling conditions. Comparison of reaction conversion attained from two continuous flow reactor systems. Experimental domain. Experimental domain. Supporting Information Supporting Information File 442: Additional diagrams and NMR spectra. Acknowledgements We would like to thank the

A flow reactor setup for photochemistry of biphasic gas/liquid reactions

• Josef Schachtner,
• Patrick Bayer and
• Axel Jacobi von Wangelin

Beilstein J. Org. Chem. 2016, 12, 1798–1811, doi:10.3762/bjoc.12.170

• reproducible gas/liquid slug flow and the effective illumination by an appropriate light source. The optimized set of conditions enabled the shortening of reaction times by more than 99% with equal chemoselectivities. The modular home-made flow reactor can serve as a prototype model for the continuous

• several cases [39], our reactor shows higher versatility and tunability at a much lower price. In the following, we detail the technical specifications, step-by-step assembly, and lab-scale operation of an affordable, robust, and modular home-made flow reactor which shows great promise for general

• recent years, we therefore decided to develop our own home-made flow reactor for photooxidations of organic molecules but also envisaged its general applicability to other challenging processes with the ternary “reagent” combinations liquid/gas/light. With the objective of constructing a robust and

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

• amount of copper acetate was reduced to 0.1 equiv a drastic decrease in yield was observed indicating that the TOF of the catalyst prevented achievement of good yields within the time limits (residence time) of the flow reactor (entry 11, Table 1). A decrease in yield was also observed when the amount of

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

• via a reverse “tube-in-tube” flow reactor at elevated pressures to give yields of carboxylated products that are much higher than those obtained under normal batch conditions. Keywords: carbon monoxide; carbonylation of ortho-substituted substrates; flow chemistry; gases in flow; “tube-in-tube

• turnaround time is much longer. This makes the flow reactor more efficient in terms of processing time. Additionally, the added safety and potential benefits regarding scale up associated with the flow reactor makes this even more favourable. Having identified a set of reaction conditions for successful

• of X-ray structure; C) ball and stick representation of X-ray structure showing the tolyl group only; D) topside view of X-ray structure [18]. Reverse “tube-in-tube” reactor. Phosphine ligands used for the ortho-carbonylation reaction. X-ray structure of substrate 33. Comparison of plug flow reactor

Automated glycan assembly of a S. pneumoniae serotype 3 CPS antigen

• Markus W. Weishaupt,
• Stefan Matthies,
• Mattan Hurevich,
• Claney L. Pereira,
• Heung Sik Hahm and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2016, 12, 1440–1446, doi:10.3762/bjoc.12.139

• irradiation with UV light in a flow reactor [28] and analyzed by normal-phase HPLC (Figure 3). Trisaccharide 6 lacking one C2-benzoate ester protecting group was identified as the main product. The unexpected side reaction was attributed to the basicity of the Fmoc deprotection solution. In addition, two

Enabling technologies and green processes in cyclodextrin chemistry

• Giancarlo Cravotto,
• Marina Caporaso,
• Laszlo Jicsinszky and
• Katia Martina

Beilstein J. Org. Chem. 2016, 12, 278–294, doi:10.3762/bjoc.12.30

• miniaturized continuous flow reactor, also called microreactor, offers many advantages over conventional scale reactors, including considerable improved energy exploitation, increased reaction speed and yield, safety, reliability, scalability, on-site/on-demand production, etc., and a much finer degree of

Effective immobilisation of a metathesis catalyst bearing an ammonium-tagged NHC ligand on various solid supports

• Krzysztof Skowerski,
• Jacek Białecki,
• Stefan J. Czarnocki,
• Karolina Żukowska and
• Karol Grela

Beilstein J. Org. Chem. 2016, 12, 5–15, doi:10.3762/bjoc.12.2

• and circulating flow reactor, as well as in an industrial setup [30][31]. The concept was explored further, and a pyridinium-tagged complex deposited on modified silica gel was recently obtained by Kirschning, Mauduit et al., exhibiting much better activity and efficiency than 4 [32]. Specially

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

• , regulation of many parameters such as heat and mass transfer, mixing and residence times are much improved over related batch processes. Advantageously the flow reactor configuration can also be readily customised to meet the specific demands of the reaction and the continuous processing requirements. The

• DMF. This stream is then combined with a stream of ICl (21) to affect the 1,2-aryl migration in a heated flow reactor (1 min, 90 °C) followed by treatment of the stream with NaOH, 2-mercaptoethanol, MeOH and water in order to hydrolyse the intermediate methyl ester and quench residual ICl. After

• flow reactor simplifies the practical aspects of the transformation, however, extra precautions were required in order to address and remove any leftover methylamine that would pose a significant hazard during scaling up. The final arylation of 50 was intended to be performed as a SNAr reaction

Automated solid-phase synthesis of oligosaccharides containing sialic acids

• Chian-Hui Lai,
• Heung Sik Hahm,
• Chien-Fu Liang and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2015, 11, 617–621, doi:10.3762/bjoc.11.69

• equiv TfOH, NIS, DCM, −30 °C (5 min), −10 °C (25 min) for 9 and 10. Fmoc Deprotection: e) 3 × 20% NEt3 in DMF, 5 min. Photocleavage: f) UV irradiation using a continuous flow reactor, DCM, rt. Synthesis of 12 or 13: (1) 6, b, (2) e, (3) 4 or 5, a (4) f, 30% for four steps to yield 12, 40% for four steps

The Shono-type electroorganic oxidation of unfunctionalised amides. Carbon–carbon bond formation via electrogenerated N-acyliminium ions

• Alan M. Jones and
• Craig E. Banks

Beilstein J. Org. Chem. 2014, 10, 3056–3072, doi:10.3762/bjoc.10.323

• further advance to the micro-flow reactor strategy is to use a parallel laminar flow set-up (Figure 2 overviews such an experimental design) [38][39]. Due to the small size of the flow channel when two liquids are injected the liquid–liquid contact area will remain stable and laminar, where only contact

An integrated photocatalytic/enzymatic system for the reduction of CO₂ to methanol in bioglycerol–water

• Michele Aresta,
• Angela Dibenedetto,
• Tomasz Baran,
• Antonella Angelini,
• Przemysław Łabuz and
• Wojciech Macyk

Beilstein J. Org. Chem. 2014, 10, 2556–2565, doi:10.3762/bjoc.10.267

• enzymes FateDH, FaldDH, and ADH were encapsulated into silicate cages made from Ca alginate and tetraethoxysilanes (TEOS) and used at a controlled pH of 7. CO2 was admitted in a continuous flow reactor at such a rate to generate a 20% excess with respect to the stoichiometric amount required by 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

• -methoxynaphthalene (AMN) can be converted to hydroxynaproxen (HN), a precursor of naproxen (Scheme 13) [85][86]. Although yields up to 90% were obtained in a 1 L flow reactor, the switch to a 75 L system was accompanied by leaks and instrument problems resulting in a low yield (58%) and current efficiency (30%) [86

Continuous flow nitration in miniaturized devices

• Amol A. Kulkarni

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

• et al. [39] developed a simple and practical flow reactor to produce nitropyridine in an exothermic nitration reaction (ΔH ~ −167 kJ/mol). Their approach is suitable for large-scale productions of up to hundreds or thousands of kilograms of nitroaromatics, Typically nitropyridine is prepared in batch

• the flow reactor. Yu et al. [40] reported on the continuous flow process for the synthesis of 2,5-difluoronitrobenzene (43) via nitration of p-difluorobenzene (42) with a nitrating mixture composed of 2.0 equiv concentrated sulfuric acid and 1.1 equiv fuming nitric acid (Scheme 13). Two different

• nitration with the conventional batch method requires a cooling to temperatures between −50 to −20 °C, while the same reactions can be carried out in a microstructured flow reactor at 30 °C with a residence time of just 3 s. The outlet product composition contains both, the mononitro derivatives as well as

Continuous-flow Heck synthesis of 4-methoxybiphenyl and methyl 4-methoxycinnamate in supercritical carbon dioxide expanded solvent solutions

• Phei Li Lau,
• Ray W. K. Allen and
• Peter Styring

Beilstein J. Org. Chem. 2013, 9, 2886–2897, doi:10.3762/bjoc.9.325

• , 43500 Semenyih, Selangor Darul Shsan, Malaysia 10.3762/bjoc.9.325 Abstract The palladium metal catalysed Heck reaction of 4-iodoanisole with styrene or methyl acrylate has been studied in a continuous plug flow reactor (PFR) using supercritical carbon dioxide (scCO2) as the solvent, with THF and

• cost and product contamination [3]. Further efforts have focused on the development of heterogeneous catalysts or immobilised homogeneous catalysts, particularly for use in continuous flow reactor systems [3][4][5][6]. The yield and selectivity of Heck reactions are profoundly influenced by a number of

• -donating group relative to Pd, thereby eliminating the requirement of the phosphine ligand. The catalyst can also aid the reaction without requiring an inert atmosphere. In this paper we report the Heck reaction between 4-iodoanisole and either styrene or methyl acrylate in a continuous flow reactor. 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

• disproportionation to SF4 and explosive (Et2N)2SF2 when heating at over 90 °C [41][42][43]. Therefore, special care is required in handling a large quantity of DAST concerning the danger of the explosion under heating conditions. To solve these technical issues, the use of DAST in a continuous-flow reactor employing

• . Furthermore, efficient mixing becomes difficult when dealing with large quantities of insoluble CsF. They invented a packed-bed flow reactor, which allowed for easy handling of large quantities of insoluble CsF with efficient mixing (Scheme 5) [53]. As an alternative method for aromatic fluorination, Yoshida

• required to avoid rapid increase in temperature. The flow reactor systems with micromixer and microheat exchangers show efficacy of forming PFPMgBr (Scheme 11) [72]. In the well-controlled formation of PFPMgBr and the subsequent protonation, continuous running of the pilot plant-scale flow microreactor

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

• exceeding the standard boiling point at atmospheric pressure were required to avoid unwanted dimer formation unless low reaction concentrations (0.10 M) were used. A flow reactor is ideal for performing reactions well outside of normal operating conditions and we pushed forward seeking high temperature

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

• in a continuous-flow reactor using five different monosaccharides and one disaccharide. We showed that this flow set up provides excellent conversion rates with several substrates. All monosaccharides were shown to react under the same conditions with equivalent conversion rates, whereas the

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

• 3b overreacted with DIEA·HCl to afford 6, or 4 and 7 in the reaction mixture and that 5 and 8 were generated from the hydrolysis of these compounds under aqueous workup conditions. We decided to use a micro-flow reactor in order to suppress the overreaction [26][27] because the micro-flow technique

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

• reactants experiencing a (much) shorter residence time than the given (averaged) residence time based on the nominal flow rates. Under slug flow conditions, all reactants will see almost the same residence time due to reduced axial dispersion allowing the reactor to operate as an ideal plug flow reactor

• compared to the flow operation with the immobilized enzyme. For a residence time of 40 min the product yield is 34%. Thus, it is slightly higher than the best yield obtained for a flow reactor using the immobilized enzyme as packed bed. When comparing this result with the free enzyme reaction using a

One-step synthesis of pyridines and dihydropyridines in a continuous flow microwave reactor

• Mark C. Bagley,
• Vincenzo Fusillo,
• Robert L. Jenkins,
• M. Caterina Lubinu and
• Christopher Mason

Beilstein J. Org. Chem. 2013, 9, 1957–1968, doi:10.3762/bjoc.9.232

• Microwave Technology Ltd, 2 Middle Slade, Buckingham, MK18 1WA, UK 10.3762/bjoc.9.232 Abstract The Bohlmann–Rahtz pyridine synthesis and the Hantzsch dihydropyridine synthesis can be carried out in a microwave flow reactor or using a conductive heating flow platform for the continuous processing of

• . Strauss first demonstrated in 1994 that by combining microwave-heating technology with continuous flow processing, problems with the limited penetration depth of microwave irradiation and the physical restrictions of a standing wave cavity could be overcome [14]. A continuous flow reactor has the

• a selective heating element [21], or in a Pd-supported silica monolith flow reactor by Haswell et al. [22], using palladated Raschig rings in a PEEK [poly(ether ether ketone)] reactor by Kirschning et al. [23], in a de novo glass coiled flow cell by researchers at Boehringer Ingelheim [24] and with