The photodecarboxylative addition of carboxylates to phthalimides as a key-step in the synthesis of biologically active 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones

• Ommid Anamimoghadam,
• Saira Mumtaz,
• Anke Nietsch,
• Gaetano Saya,
• Cherie A. Motti,
• Jun Wang,
• Peter C. Junk,
• Ashfaq Mahmood Qureshi and
• Michael Oelgemöller

Beilstein J. Org. Chem. 2017, 13, 2833–2841, doi:10.3762/bjoc.13.275

• ]. Selected transformations have been furthermore realized on large multigram scales [25][34][35] and in continuous-flow mode [36][37][38][39][40]. The photodecarboxylation procedure was subsequently applied to the synthesis of 2-dialkylaminoalkyl-3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones. The

• in the synthesis of 2-dialkylaminoalkyl-3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones, among these the potent local anesthetics AL-12, AL-12A and AL-5 (in their neutral forms). The simple procedures make this three-step process attractive for in-series continuous flow applications [40][66][67

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation and chlorination. Part 2: Use of CF₃SO₂Cl

• Hélène Chachignon,
• Hélène Guyon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2800–2818, doi:10.3762/bjoc.13.273

• pathway that involved Ru(II)/Ru(III) metallic species (Scheme 1). The trifluoromethylation of silyl enol ethers can also be adressed in a continuous-flow procedure. To do so, the appropriate ketones were transformed in situ into the corresponding silyl enol ethers, which were then reacted with CF3SO2Cl in

• silyl enol ethers. Continuous flow trifluoromethylation of ketones under photoredox catalysis. Trifluoromethylation of enol acetates. Photoredox-catalysed tandem trifluoromethylation/cyclisation of N-arylacrylamides: a route to trifluoromethylated oxindole derivatives. Tandem trifluoromethylation

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• anhydride and dimethyl maleate were hydrotrifluoromethylated with CF3SO2Na in the presence of 4,4’-dimethoxybenzophenone as photosensitiser under near-UV irradiation (350 nm) and hexafluoroisopropanol (HFIP) as a proton donor (Scheme 20) [40]. The reactions were performed in batch and under continuous flow

• trifluoromethylation with CF3SO2Na are highly efficient, the original Langlois’ conditions were nevertheless applied to a series of heteroarenes. Li and co-workers reported the synthesis of 3-trifluoromethylcoumarins 64 by Cu(I)-catalysed trifluoromethylation with CF3SO2Na and t-BuOOH in a continuous-flow reactor [61

• ]. After optimisation of the reaction conditions in batch, the optimal reaction conditions were established in a continuous-flow reactor at a flow rate of 100 µL min−1 at 60 °C for 40 min. The substrate scope was evaluated on 11 coumarins and showed that both electron-rich and electron-deficient functional

Grip on complexity in chemical reaction networks

• Albert S. Y. Wong and
• Wilhelm T. S. Huck

Beilstein J. Org. Chem. 2017, 13, 1486–1497, doi:10.3762/bjoc.13.147

• the negative feedback loop. The network displays complex behavior in an open system. In contrast to earlier examples, we used a continuous flow of the reactants (Tg, Ap, and Pro-I) to create out-of-equilibrium conditions (Figure 5c) [95]. A poly(dimethylsiloxane) (PDMS)-based microfluidic continuous

Photocatalyzed synthesis of isochromanones and isobenzofuranones under batch and flow conditions

• Manuel Anselmo,
• Lisa Moni,
• Hossny Ismail,
• Davide Comoretto,
• Renata Riva and
• Andrea Basso

Beilstein J. Org. Chem. 2017, 13, 1456–1462, doi:10.3762/bjoc.13.143

• decomposed during 13C NMR analysis). The interest of both academia and industry in flow chemistry has recently increased. In particular, photochemical reactions performed under continuous flow have been proven particularly effective [6], as the reduced size of the reaction channels allows for a more

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

• . also facilitate continuous separation and significantly reduce the time for process development. Recent reviews on multistep synthesis clearly highlight the potential application of multistep syntheses in fine and pharmaceutical industries [5][31][32]. However, while continuous-flow synthesis helps to

• options which are critical to the implementation of a process. Case studies Till date, there are more than 80 excellent publications that use continuous-flow synthesis of high-value molecules where the synthesis involves two and more stages. While choosing the representative case studies we have applied

• maintain continuous flow or an efficient arrangement of continuous activation of the bed like a simulated moving bed chromatographic reactor (SMB). Alternatively, one can also charge the azide resin as a suspended mass in the flow to avoid this complexity to some extent and to have a filter to keep the

Continuous-flow processes for the catalytic partial hydrogenation reaction of alkynes

• Carmen Moreno-Marrodan,
• Francesca Liguori and
• Pierluigi Barbaro

Beilstein J. Org. Chem. 2017, 13, 734–754, doi:10.3762/bjoc.13.73

• to alkenes is a process of high importance in the manufacture of several market chemicals. The present paper shortly reviews the heterogeneous catalytic systems engineered for this reaction under continuous flow and in the liquid phase. The main contributions appeared in the literature from 1997 up

• hydrogenation reaction of alkynes is thus of utmost importance [14][15]. Compared to batch setups, considerable process intensification [16][17] to this regard can be provided by continuous-flow operations either in terms of safety, purification, waste emission, durability, reproducibility, automation, energy

• and space consumption [18][19]. Particularly, continuous-flow catalysis may enhance the performance of a given catalyst while reducing the number of processing steps [20][21], which may result in a significant contribution to the reduction of the high E-factor (kg waste generated/kg product) usually

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

• chemistry could play an important role in the development of green and sustainable synthetic processes. In this review, some recent relevant examples in the field of flash chemistry, catalysis, hazardous chemistry and continuous flow processing are described. Selected examples highlight the role that flow

• ]. Contribution of continuous-flow metal-, organo-, and photocatalysis in green chemistry The development of continuous-flow catalysis is appealing because it combines the advantages of a catalytic reaction with the benefits of flow microreactors. Under homogeneous conditions a soluble catalyst, which flows

• through the reactor together with the reactants, is employed. At the end of the process, a separation step would be required in order to remove the catalyst and byproducts. On the other hand, heterogeneous catalysis is widely used in the synthesis of bulk and fine chemicals. In a continuous-flow process

Continuous N-alkylation reactions of amino alcohols using γ-Al₂O₃ and supercritical CO₂: unexpected formation of cyclic ureas and urethanes by reaction with CO₂

• Emilia S. Streng,
• Darren S. Lee,
• Michael W. George and
• Martyn Poliakoff

Beilstein J. Org. Chem. 2017, 13, 329–337, doi:10.3762/bjoc.13.36

• could be synthesised by incorporation of CO2 from the supercritical solvent into the product. Keywords: continuous flow; heterocycle; N-alkylation; self-optimisation; supercritical CO2; Introduction N-alkylated amines are an important motif present in a range of pharmaceutically and industrially

• (scCO2) have mainly been focused on continuous flow systems and the etherification of alcohols, where alcohols are activated by heterogeneous catalysts [31][32][33][34][35][36][37][38]. We have usually employed γ-alumina as the catalyst, as this is a simple, readily available and environmentally benign

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

• known for their bioactivity, a chemoselective procedure has been developed starting from m-(chlorosulfonyl)benzoyl chloride. Although a chemoselective process in batch was already reported, a continuous-flow process reveals an increased selectivity at higher temperatures and without catalysts. In total

• synthesis, delivering stock solutions suitable for initial testing at the outlet of the reactor. Results and Discussion Development of a continuous-flow process Although a continuous-flow process shows many advantages compared to batch reactions, there are some difficulties which should be overcome or be

• batch or continuous flow. This is not surprising since a similar result is reported for the reaction of amines with sulfonyl chlorides [34]. Triethylamine was added as base for the capture of hydrogen chloride which is produced during the reaction. Nonetheless, the precipitation of anilinium salts and

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

• (photochemistry, electrochemistry, microwave, ultrasound, etc.) [6][7][8][9]. In this regard, in a recent paper a compact reconfigurable flow system was described for the continuous flow production of pharmaceuticals. The system comprised different types of preparation, reaction and elaboration modules that could

• low field NMR instruments have been introduced in flow chemistry to overcome these limitations, with the advantage of lower cost and better integration with the continuous flow platform since the whole system can be set up in a fume hood. The main drawback of these systems is the lower resolution and

• proportional to its diameter. For a volume-limited sample, the signal is maximized when the coil is scale-down to enclose this volume sample. Although these probes show several advantages, as for instance are the coupling into continuous flow systems and its integration in compact magnets due to their lower

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

• -oxadiazoles starting from carboxylic acids is reported. This process was applied to the multistep synthesis of imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazoles, using a three reactor, multistep continuous-flow system without isolation of intermediates. This continuous-flow method was successfully combined with a

• been used successfully in some cases [1][2][3][4][5][6]. However, this approach has a number of drawbacks, primarily because of mutual interference between various reactive components. Recently, continuous-flow chemistry has emerged as a powerful technique in organic synthesis. This is in part due to

Self-optimisation and model-based design of experiments for developing a C–H activation flow process

• Alexander Echtermeyer,
• Yehia Amar,
• Jacek Zakrzewski and
• Alexei Lapkin

Beilstein J. Org. Chem. 2017, 13, 150–163, doi:10.3762/bjoc.13.18

• this is the complexity of chemistry and the duration of time required for the development of good mechanistic models. A game changer in this area is the recently emerged field of automated continuous-flow experiments driven by algorithms for sequential design of experiments (DoE), which significantly

• , guided by D-optimal design. In a different approach, transient data from continuous-flow experiments were used to identify parameters of a known mechanistic scheme to discriminate between several alternative model structures and to identify model parameters, but no specific design of experiments method

• algorithm would learn the response surface as fast as it was the case for its previous application. A framework of closed-loop or self-optimisation combining smart DoE algorithms, process analytics, chemoinformatics and automated reactor systems. Schematics of the automated continuous-flow system used for

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 approach provides a facile alternative scale-up route to conventional batch processing, and it helps to intensify the synthesis protocol by applying higher reaction temperatures and shorter reaction times. Keywords: continuous processing; flow chemistry; renewable feedstock; surfactant

• of compact continuous-flow reactors has begun to transform the way chemical synthesis is conducted in research laboratories and small manufacturing over the past few years [14][15][16][17][18][19][20][21]. In several applications, where reaction times are short and heat management is important

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

• solvents and reagents, making it ideally suited to continuous flow chemistry. The part was again tested using the semicarbazide preparation previously outlined (Scheme 1), and automated through the Chemstation software. For this optimisation an 1100 series binary pump module was used to pump the two

• of using 3D printing to produce microfluidic devices using AM techniques such as stereolithography (SL) [11], polymer jetting and fused deposition modelling (FDM) [12][13]. There is therefore considerable interest in the optimisation of chemical systems using this type of multifunctional continuous

• 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

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

• continuous flow chemistry is typically very narrow of several millimetres. Furthermore, the kneading segments can be positioned at angles of 30o, 60o and 90o relative to each other, with the latter angle providing the greatest kneading (and shear). The kneading section can be quite hostile as it involves not

• 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

• point to react with polystyrene in a second reaction (Scheme 2) [16]. This is an example of telescoping which is considered to be very advantageous in continuous flow technology for example. As a result of being able to carry out polymerisation and post polymerisation functionalisation by TSE, different

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

Electron-transfer-initiated benzoin- and Stetter-like reactions in packed-bed reactors for process intensification

• Anna Zaghi,
• Daniele Ragno,
• Graziano Di Carmine,
• Carmela De Risi,
• Olga Bortolini,
• Pier Paolo Giovannini,
• Giancarlo Fantin and
• Alessandro Massi

Beilstein J. Org. Chem. 2016, 12, 2719–2730, doi:10.3762/bjoc.12.268

• heterogeneous continuous-flow procedure for the polarity reversal of aromatic α-diketones is presented. Propaedeutic batch experiments have been initially performed to select the optimal supported base capable to initiate the two electron-transfer process from the carbamoyl anion of the N,N-dimethylformamide

• chemical and pharmaceutical industries facilitating the automation of the production processes with reduced costs and improved safety and sustainability [18][19][20][21]. Very recently, Monbaliu and co-workers described a convenient continuous-flow setup for the generation of common free NHCs under

• umpolung catalysis (Figure 1). Significantly, the current investigation on the heterogeneous continuous-flow version of the α-diketone activation process resulted in the fabrication of fixed-bed reactors with elevated stability, allowing their operation for about five days with maintenance of productivity

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

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

• performed for the first time under continuous-flow conditions. Aromatic as well as aliphatic nitro derivatives were converted to the corresponding primary amines in high yields and very short reaction times with no need for purification. The methodology was also extended to the synthesis of two

• transformation safer and more appealing in view of an industrial application and a possible scale-up of the process [18][19][20]. Herein we report a very convenient, metal-free reduction of both aromatic and aliphatic nitro derivatives, including chiral compounds, to amines with HSiCl3 under continuous-flow

• conditions. Typically, the transformation of nitro compounds to amines under continuous-flow conditions is performed through the metal-catalyzed hydrogenation [21][22][23] with ThalesNano H-Cube®, which exploits H2 generated in situ by water electrolysis [24]. The procedure involves relatively mild reaction

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