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

• stereoselective aldol reaction in DES. Aldol reaction under continuous flow conditions in DESs. ChCl-based eutectic mixtures used in the present work. DES screening for the proline-catalyzed in batch aldol reaction. Three different set-ups for the aldol reaction in continuo. In continuo aldol reactions of

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

• key α-thio-β-chloroacrylamide casade as a continuous flow reaction on a multi-gram scale is described, while the tuneable nature of the cascade, facilitated by continuous processing, is highlighted by selective generation of established intermediates and byproducts. Keywords: α-thio-β

• as an alternative solvent. As 1H NMR analysis indicated that the crude reaction product from batch tests (using methanol as solvent) consisted of 98% α-thioamide 2, the process was subsequently transferred to a continuous flow system (Scheme 5). A variety of temperatures (60–120 °C), bases (NaOMe

• , Table 1). After an improved stoichiometry of reagents had been established, lowering the residence time was investigated to facilitate efficient large scale synthesis by a continuous flow process. Ultimately, a residence time of 5 min at 120 °C, using a 0.25 M concentration of α-chloroacrylamide, was

Solvent-free synthesis of novel para-menthane-3,8-diol ester derivatives from citronellal using a polymer-supported scandium triflate catalyst

• Lubabalo Mafu,
• Ben Zeelie and
• Paul Watts

Beilstein J. Org. Chem. 2016, 12, 2046–2054, doi:10.3762/bjoc.12.193

• , the catalyst was reusable in the process without significant change towards the substrate conversion and product selectivity. Using the methodology described herein, further studies are currently underway within our laboratory to optimise the developed method in a continuous flow process. Experimental

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

• active compounds [11][12]. In 2009 the groups of Stevens and van der Eycken reported on the Chan–Lam reaction as a continuous flow protocol using copper(II) acetate (1.0 equiv), pyridine (2.0 equiv) and triethylamine (1.0 equiv) in dichloromethane [13]. Generally, when using anilines or phenols as the

• potentially an improvement on the use of stiochiometric copper(II) acetate in continuous flow, the use of TEMPO or tert-butyl peroxybenzoate as a co-oxidant introduces waste. Employing oxygen gas as an oxidant is preferred as it is cheap, renewable and environmentally benign. We therefore set out to develop a

• . 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

Dinuclear thiazolylidene copper complex as highly active catalyst for azid–alkyne cycloadditions

• Anne L. Schöffler,
• Ata Makarem,
• Frank Rominger and
• Bernd F. Straub

Beilstein J. Org. Chem. 2016, 12, 1566–1572, doi:10.3762/bjoc.12.151

• bioactive surfaces [8][14], imaging of biochemical processes [15], localization of bioactive compounds inside living cells [16], syntheses of small-molecule screening libraries [17], catenane and rotaxane syntheses [18], in reactions under continuous flow processing [19], polymer and surface science [20][21

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

• continuous flow hydroxy-carbonylation method. Flow carbonylation of 2-iodonaphtalene. Scale up synthesis of 2-chloro-4-fluorobenzoic acid (20). Optimisation for the carbonylation of ortho-substituted substrates in flow. Supporting Information Supporting Information File 427: Experimental part. Supporting

Supported bifunctional thioureas as recoverable and reusable catalysts for enantioselective nitro-Michael reactions

• José M. Andrés,
• Miriam Ceballos,
• Alicia Maestro,
• Isabel Sanz and
• Rafael Pedrosa

Beilstein J. Org. Chem. 2016, 12, 628–635, doi:10.3762/bjoc.12.61

• transformations [1][2][3][4][5]. In these processes one of the major problems is related to the recovering of the catalysts. The support of the small molecules on different materials has been proposed as a solution, including their use in continuous flow processes [6][7][8][9]. The most popular supports include

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

• that are operating in continuous flow mode [4][43][44]. Preparation of monosubstituted CD derivatives MW irradiation has been exploited in the synthesis of mono and persubstituted CDs. Several syntheses of CD derivatives have been successfully carried out under MW with higher yield, higher purity, and

• 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

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

• solutions of N,N-dialkyl-N-chloramines produced continuously will enable their use in tandem flow reactions with a range of nucleophilic substrates. Keywords: amine; biphasic; chloramine; chlorination; continuous flow chemistry; CSTR; static mixer; sodium hypochlorite; tube reactor; Introduction N

• -BuOCl in situ for chloramine formation, applying the methodology to a broad range of substrates in high yields [20]. Published literature on chloramine formation is limited to batch procedures, however, the use of continuous processes could offer significant advantages. Use of continuous flow reactors

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

• Marcus Baumann Ian R. Baxendale Department of Chemistry, Durham University, South Road, DH1 3LE Durham, United Kingdom 10.3762/bjoc.11.134 Abstract The implementation of continuous flow processing as a key enabling technology has transformed the way we conduct chemistry and has expanded our

• route was able to successfully deliver sufficient quantities of imatinib (23) and several of its analogues (~30–50 mg each) in high purity within one working day allowing subsequent testing of new derivatives. Although this approach was conducted as a fully integrated telescoped continuous flow sequence

• also been employed in the flow synthesis of a carprofen analogue [69] as well as in the regioselective bromination towards a rosuvastatin precursor [70] showcasing how continuous flow photochemistry is receiving a significant level of interest. This is not least because of the perceived green reagent

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

Photocatalytic nucleophilic addition of alcohols to styrenes in Markovnikov and anti-Markovnikov orientation

• Martin Weiser,
• Sergej Hermann,
• Alexander Penner and
• Hans-Achim Wagenknecht

Beilstein J. Org. Chem. 2015, 11, 568–575, doi:10.3762/bjoc.11.62

• chemistry has significant advantages over batch chemistry, such as easier temperature control, larger surface-to-volume ratio and more efficient photoirradiation. Two setups were used to transfer the reaction to continuous-flow systems. The first mesoflow reactor was equipped with four 250 mW high-power

3α,5α-Cyclocholestan-6β-yl ethers as donors of the cholesterol moiety for the electrochemical synthesis of cholesterol glycoconjugates

• Aneta M. Tomkiel,
• Adam Biedrzycki,
• Jolanta Płoszyńska,
• Dorota Naróg,
• Andrzej Sobkowiak and
• Jacek W. Morzycki

Beilstein J. Org. Chem. 2015, 11, 162–168, doi:10.3762/bjoc.11.16

• eliminate chloride ions that are formed by the reduction of dichloromethane. The solutions in both compartments were stirred during electrolysis and, additionally, a continuous flow of argon was applied in the anodic compartment. A platinum mesh was used as a cathode and a platinum plate (2 × 1.5 cm) was

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

Synthesis and immunological evaluation of protein conjugates of Neisseria meningitidis X capsular polysaccharide fragments

• Laura Morelli,
• Damiano Cancogni,
• Marta Tontini,
• Alberto Nilo,
• Sara Filippini,
• Paolo Costantino,
• Maria Rosaria Romano,
• Francesco Berti,
• Roberto Adamo and
• Luigi Lay

Beilstein J. Org. Chem. 2014, 10, 2367–2376, doi:10.3762/bjoc.10.247

• to 3 min, 46 mg of the α-H-phosphonate 7 were obtained in 0.5 h at higher isolated yield (76%) and purity than batch reaction. Based on the maximum volume of the syringes employed in our continuous-flow system (5 mL, see Supporting Information File 1), we can estimate that a production rate of 2.2 g

• /day would be achievable. To the best of our knowledge, this is the first example of the synthesis of glycosyl H-phosphonates using the continuous-flow MRT [30][31][32][33]. The occurrence of the H-phosphonate 7 was ascertained by a signal at 1.87 ppm in the 31P NMR, and the presence in the 1H NMR of

• fragments, based on the synthetic improvements and also the benefits of the continuous-flow microreactor technology herein described, is currently ongoing in our laboratory and it will be reported in due course. Besides the length of the carbohydrate haptens, the saccharide loading onto the protein is

A new charge-tagged proline-based organocatalyst for mechanistic studies using electrospray mass spectrometry

• J. Alexander Willms,
• Rita Beel,
• Martin L. Schmidt,
• Christian Mundt and
• Marianne Engeser

Beilstein J. Org. Chem. 2014, 10, 2027–2037, doi:10.3762/bjoc.10.211

• temporal evolution has been followed using a microreactor continuous-flow technique. Keywords: charge tag; electrospray; mass spectrometry; organocatalysis; proline; template; Introduction Electrospray ionization (ESI) mass spectrometry [1] has not only developed into a standard characterization method

• both reactions by ESIMS. These so-called continuous-flow experiments [5][20] allow the sampling of reaction times down to seconds. Solutions of the reagents are mixed in the first microreactor and diluted to concentrations suitable for ESIMS in the second microreactor. The reaction time between the

• (not reaction time) because analytes gradually accumulate in the system the longer their solutions are passed through. The extent of this effect depends on the height of the flow rate which necessarily has to be changed when observing a reaction process with the continuous-flow method. Nevertheless, we

Syntheses of fluorooxindole and 2-fluoro-2-arylacetic acid derivatives from diethyl 2-fluoromalonate ester

• Antal Harsanyi,
• Graham Sandford,
• Dmitri S. Yufit and
• Judith A.K. Howard

Beilstein J. Org. Chem. 2014, 10, 1213–1219, doi:10.3762/bjoc.10.119

• elemental fluorine for the key construction of the carbon–fluorine bond by complementary direct selective direct fluorination [41][42][43][44], continuous flow [45][46][47][48][49] and building block [50] strategies, in this paper, we describe nucleophilic aromatic substitution reactions of carbanions

Automated solid-phase peptide synthesis to obtain therapeutic peptides

• Veronika Mäde,
• Sylvia Els-Heindl and
• Annette G. Beck-Sickinger

Beilstein J. Org. Chem. 2014, 10, 1197–1212, doi:10.3762/bjoc.10.118

• a batch-wise or a continuous-flow modus. The decision for a peptide synthesizer has to be made according to the intended application and thus, the scale (necessary amounts), the type of chemistry (Fmoc or Boc-strategy) and the number of reaction tubes (plates or vessels). The decision should also be

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

• such as 4 are fully reduced. For maximum efficiency further hydrogenation procedures were carried out at the lower flow rate 0.1 mL min−1 and higher temperature 100 °C. In situ generation of the intermediate Performing an optimisation experiment in continuous flow – such as described in the previous

Continuous flow nitration in miniaturized devices

• Amol A. Kulkarni

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

• Amol A. Kulkarni Chem. Eng. & Proc. Dev. Division, CSIR-National Chemical Laboratory, Pune – 411 008, India, phone: +91-20-25902153 10.3762/bjoc.10.38 Abstract This review highlights the state of the art in the field of continuous flow nitration with miniaturized devices. Although nitration has

• presented herein and discussed in view of their advantages, limitations and applicability of the information towards scale-up. Selected recent patents that disclose scale-up methodologies for continuous flow nitration are also briefly reviewed. Keywords: continuous flow; flow chemistry; nitration; nitric

• more of these limitations are experienced in every batch operation it is necessary to check their feasibility for continuous flow processing. Such transformations from batch to flow have been carried out for a lot of reactions and many continuous nitration plants of commercial scale exist. However, the

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

• the reaction with methyl acrylate the reactor was scaled from a 1.0 mm to 3.9 mm internal diameter and the conversion and turnover frequency determined. The results show that the Heck reaction can be effectively performed in scCO2 under continuous flow conditions with a palladium metal, phosphine-free

• catalyst, but care must be taken when selecting the reaction temperature in order to ensure the appropriate isomer distribution is achieved. Higher reaction temperatures were found to enhance formation of the branched terminal alkene isomer as opposed to the linear trans-isomer. Keywords: continuous flow

• 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

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

• 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

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

• other value added structures that contain complex pyridines. The route terminates in a batch crystallization yielding high purity CAPIC. This outcome is expected to facilitate regulatory implementation of the overall process. Keywords: continuous; flow chemistry; HIV; Knoevenagel; nevirapine

A combined continuous microflow photochemistry and asymmetric organocatalysis approach for the enantioselective synthesis of tetrahydroquinolines

• Erli Sugiono and
• Magnus Rueping

Beilstein J. Org. Chem. 2013, 9, 2457–2462, doi:10.3762/bjoc.9.284

• Erli Sugiono Magnus Rueping Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany 10.3762/bjoc.9.284 Abstract A continuous-flow asymmetric organocatalytic photocyclization–transfer hydrogenation cascade reaction has been developed. The new protocol allows

• dihydropyridine as hydrogen source providing the desired products in good yields and with excellent enantioselectivities. Keywords: asymmetric transfer hydrogenation; binolphosphate; continuous-flow reactors; flow chemistry; microreactors; organocatalysis; photochemistry; Introduction Tetrahydroquinolines [1][2

• ][11][12][13][14][15][16][17]. In the past years, continuous-flow chemistry has received considerable attention and microstructured continuous-flow devices have emerged as useful devices for different chemical reactions [18][19][20][21][22]. Microreactor technology offers numerous practical advantages