Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review

• Fabio Tonin and
• Isabel W. C. E. Arends

Beilstein J. Org. Chem. 2018, 14, 470–483, doi:10.3762/bjoc.14.33

• production step. Particular attention is placed on the precursors availability as well as the substrate loading in the process. Potential new routes and recent developments are discussed, in particular on the employment of flow-reactors. The latter technology allows to develop processes with shorter reaction

• rapid reaction [44]. In this field, flow reactors offer benefits in terms of mass and heat transfer, both enhanced by the geometry of the reactor. Furthermore, the possibility to have a continuous production and to easily perform multiple modular reactions, leads to the improved scalability of these

• process. Several examples are reported in literature about substrate or product inhibition of HSDHs. Protein engineering could help to solve or lowering the effect of these issues, leading to the optimization of the biocatalyst for industrial applications. In addition, the use of flow-reactors can be

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

• shows oscillations in Tr activity (with experimental conditions in inset). Adapted with permission from [94], copyright 2015 Nature Publishing Group. Functions obtained by linking multiple network modules in microfluidic flow reactors (depicted as CSTR 1 and 2). In each case, the oscillating catalyst

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

• demonstrated the use of automation for integrating batch and flow reactors on a single platform [46]. Their process also involved extraction and distillation operations. III) Automation for control: The third and the most important purpose of automation is to control the process variables like temperature

• volatile or the process stream is a two-phase mixture. Recently, Movsisyan et al. have reviewed the application of flow reactors for hazardous reactions [1]. Although the flow reactors allow such reactions to be carried in a safer manner controlling such reactors at production scale could be challenging

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

• 7 was successfully achieved in the past using batch Pd catalysts (0.15–5% wt), with typical 7a yields in the range of 60–70% [147][148]. More recently, a number of catalytic flow reactors were also described for this process. Best yields (94–100%) were achieved using either 16% CeO2@TiO2 (100%) [119

• scope An explanation for efficiency differences observed in catalytic flow reactors in relation to the molecular structure and/or substituent groups of alkynes substrates is not apparent due to a number of reasons. For example, although a higher selectivity in partial hydrogenation was reported for 1

• , respectively, has been explored with a variety of catalytic flow reactors. While direct comparison in terms of substrate conversion is prevented by non-uniformity of reaction conditions, the dearth of a common trend emerges in terms of selectivity at the same level of conversion. An overall picture of

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

• 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

• , intensified continuous processes inside tubular or plate-type flow reactors can successfully replace batch methodologies classically carried out in stirred glass vessels. We have demonstrated the benefits of this superior heat management in previous work looking at exothermic radical polymerizations in

• 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

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

• laboratory equipment, but also to manufacture functional chemical and thermally compatible reactors with embedded functionality. Conclusion AM has been shown to be a highly versatile manufacturing process for the production of multifunctional bespoke flow reactors. This allows conceptual parts to be realised

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

• homogeneous NHCs [13][14]. On the other hand, heterogeneous catalysis in microstructured flow reactors represents a robust synthetic platform, with benefits over the corresponding batch processes such as catalyst stability, lower degradation of supports, and ease of scale-up with minimal changes to the

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

• batch made continuous processing an attractive alternative for scale-up due to its capacity for excellent temperature control. Efficient heat transfer due to the high surface, low volume geometry of tubular flow reactors makes it possible to achieve extremely rapid temperature transitions. It was

• coiled tube reactor at 120 °C. The high surface area–volume ratio of tubular flow reactors is ideal for such rapid temperature transitions. It was noted that a relatively short residence time of only 20 min could be used, with a longer time of 50 min offering only a modest improvement on the reaction

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

• 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

• azo dye, an attempt to perform both reaction steps involved in this synthesis in continuous flow reactors was thus made. This was achieved in LTF-MS reactors with the aid of statistical modeling where the continuous flow synthesis of Sudan II azo dye was optimized and used a model reaction. Based on

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

• due to the inherent properties of micro/flow reactors: high mass-transfer rates [8], spatial separation of reagent addition and mixing, high reagent dispersion, high energy efficiency, improved irradiation [9][10][11], ease of upscaling, low hazard potential and multidimensional parameter control [7

• alkylbenzenes [48] and [2 + 2]-cycloadditions with ethylene [49]. Results and Discussion Microreactor parts and setup When studying the numerous literature reports of applications of flow reactors to organic synthesis it became obvious that there are no simple and quick technical solutions to such endeavours

• processes (e.g., N-alkyl maleimides, ε = ~700 M−1 cm−1) [62] lead to more efficient light penetration in batch reactions and therefore only show a limited benefit of using flow reactors for such purposes. On the other hand, a 1 mM solution of methylene blue exhibits total absorption (>99.9%) at 0.35 mm

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

• ”; Introduction Carbonylation reactions have received a great deal of attention both in batch as well as in flow (using plug/annular flow reactors [1][2][3][4][5] or “tube-in-tube” reactors [6][7][8][9][10]) and generally produce the desired products in good yields [11][12][13][14]. This is not the case though

• efficient mixing along with high heat and mass transfer that are achieved through the use of small dimensioned channels such as those found in flow reactors, allow for the use of a wider range of reaction conditions which are otherwise difficult or impossible to achieve. The interfacial mixing area is also

• smaller when larger volume flasks are used as in scale up procedures making the mass transfer even less efficient. In contrast, high interfacial areas can be achieved in flow reactors especially microchannel reactors (a = 3400–18000 m2 m−3) [30], which increases the mass transfer and thus helps solubilise

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

• -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

• selected syntheses using micro or meso-scaled flow reactors will be exemplified for key transformations and process control. It is hoped that the reader will gain an appreciation of the innovative technology and transformational nature that flow chemistry can leverage to an overall process. Keywords

• a sample loop). In addition both of these pumping solutions require homogeneous solutions where particulates or precipitates (slurries) are extremely detrimental. These shortcomings obviously impact the performance of flow reactors when attempting reaction scale-up, especially when precise and

Continuous flow nitration in miniaturized devices

• Amol A. Kulkarni

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

• be elaborated in section 3. In this review, we analyze recent studies on continuous flow nitration using miniaturized flow reactors. We provide a guideline that helps to quickly decide under which conditions it is worthwhile to conduct continuous flow nitration from a practical point of view. Key

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

• flow reactions All reactions were performed in 300 or 100 cm stainless steel tubular plug flow reactors (PFRs) of 1 mm internal diameter. A larger diameter (3.9 mm) PFR was also used as a comparison in one example (Figure 2). Initial studies used flow rates commensurate with the concentration used in

• the autoclave reactor. Residence time in the continuous flow reactors The volume of the unpacked 1 mm diameter reactors in the styrene and methyl acrylate reactions were 2.36 and 0.79 mL respectively. The reactors containing catalyst with packing were found to have a porosity of 0.80, so neglecting

• using the instrument software. ICP–AE analysis gave the concentration of palladium metal on the silica gel support as 0.02 g or 0.189 mmol Pd/g. This was later diluted with Chromopac for use in the flow reactors at a ratio of 1:3 catalyst/packing. Stirred autoclave reactions The autoclave reaction set

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

• using microreactor systems. Use of DAST in continuous-flow reactors. Flow microreactor synthesis of fluorinated epoxides. Highly controlled isomerization of gem-difluoroalkenes. Flow system for catalytic aromatic fluorination. Continuous-flow reactor for electrophilic aromatic fluorination. Examples of

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

• reactions are performed by passing reagents through devices containing small-dimensional channels as opposed to using batch reactors [15][16][17]. Flow reactors are particularly advantageous in multistep syntheses where telescoping steps avoids isolation of dangerous and/or unstable intermediates and

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

• 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

Ethyl diazoacetate synthesis in flow

• Mariëlle M. E. Delville,
• Jan C. M. van Hest and
• Floris P. J. T. Rutjes

Beilstein J. Org. Chem. 2013, 9, 1813–1818, doi:10.3762/bjoc.9.211

• ][7][8]. While the synthesis of diazomethane has been extensively explored in batch [9] and in continuous-flow reactors [10][11], EDA is synthesized via different routes in batch [12][13], but relatively little is known about continuous-flow approaches [14]. Considering the importance of EDA in a wide

The application of a monolithic triphenylphosphine reagent for conducting Ramirez gem-dibromoolefination reactions in flow

• Kimberley A. Roper,
• Malcolm B. Berry and
• Steven V. Ley

Beilstein J. Org. Chem. 2013, 9, 1781–1790, doi:10.3762/bjoc.9.207

• or facilitates direct isolation of pure compounds from flow reactors, removing the need for labour-intensive manual operations [8][9][10][11][12][13]. Reagents are typically supported on low-crosslinked gel-type or macroporous beads; however, these are characterised by poor mass transfer properties

[3 + 2]-Cycloadditions of nitrile ylides after photoactivation of vinyl azides under flow conditions

• Stephan Cludius-Brandt,
• Lukas Kupracz and
• Andreas Kirschning

Beilstein J. Org. Chem. 2013, 9, 1745–1750, doi:10.3762/bjoc.9.201

• from the corresponding vinyl azide. Keywords: azirines; cycloaddition; flow chemistry; flow reactors; inductive heating; nitrile ylides; photochemistry; vinyl azides; Introduction Recently, photochemistry has seen a renaissance despite the fact that under batch conditions specialized reaction vessels

• refer to [6][7][8][9][10][11][12][13][14][15]. Recently, the Seeberger group has published a flow protocol on the photochemical degradation of aryl azides and the subsequent formation of 3H-azepinones [16]. With the emergence of continuous processes involving miniaturized flow reactors in organic

• -chemistry laboratories, photochemistry has found a wider interest in the chemical community [17][18]. Particularly large-scale photochemical syntheses can simply be achieved by numbering-up miniaturized flow reactors in a parallel set-up. Uniform irradiation can be guaranteed when the penetration depth of

Chemistry in flow systems III

• Andreas Kirschning

Beilstein J. Org. Chem. 2013, 9, 1696–1697, doi:10.3762/bjoc.9.193

• chemical synthesis in the laboratory from a classical batch approach to continuous processes by using micro- and miniaturized flow reactors. In the past two decades this technology has seen a dramatic increase of visibility. Considering an analyses of the accompanied developments in flow synthesis one has

The rapid generation of isothiocyanates in flow

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 1613–1619, doi:10.3762/bjoc.9.184

• still seen and there normally remains the requirement for time consuming purifications such as column chromatography in order to isolate pure products. Immobilised reagents have shown great promise as enabling technologies when incorporated in flow reactors to aid in the processing, work-up and

Simple and rapid hydrogenation of p-nitrophenol with aqueous formic acid in catalytic flow reactors

• Rahat Javaid,
• Shin-ichiro Kawasaki,
• Akira Suzuki and
• Toshishige M. Suzuki

Beilstein J. Org. Chem. 2013, 9, 1156–1163, doi:10.3762/bjoc.9.129

• XPS analysis confirmed complete oxidation of the Pd surface to PdO, as presented in our previous study [13]. Hydrogenation of p-nitrophenol in the catalytic flow reactors The experimental setup of our flow reaction system is simple, as depicted in Figure 2, where a reactor tube loop was immersed in a

Aqueous reductive amination using a dendritic metal catalyst in a dialysis bag

• Jorgen S. Willemsen,
• Jan C. M. van Hest and
• Floris P. J. T. Rutjes

Beilstein J. Org. Chem. 2013, 9, 960–965, doi:10.3762/bjoc.9.110

• utilized for purification purposes after the reaction [22] and in continuous-flow reactors during the reaction [23]. Dendritic catalysts have also been applied while enclosed in commercially available dialysis bags [24][25][26]. The latter examples, however, were conducted in organic, environmentally