A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• temperatures, fragrance ingredients/intermediates make ideal candidates for continuous-flow manufacturing. This review highlights the potential crossover between a multibillion dollar industry and the flourishing sub-field of flow chemistry evolving within the discipline of organic synthesis. This is

• published in the chemical and engineering literature which would constitute a known solution or inspiration for commonly encountered procedures in the manufacture of fragrance and flavour chemicals. Keywords: flavours and fragrances; flow chemistry; process chemistry; synthesis; Introduction The fragrance

• activity within the field today (Figure 2). Flow chemistry Batch-based synthetic methods have enabled a wide variety of transformations to be performed at industrial scales, however, the implementation of flow-based protocols often lends itself to the creation of superior synthetic systems. Improved

Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives

• Alexander Leslie,
• Thomas S. Moody,
• Megan Smyth,
• Scott Wharry and
• Marcus Baumann

Beilstein J. Org. Chem. 2021, 17, 379–384, doi:10.3762/bjoc.17.33

• flow chemistry is by now a mature field with chemists in both academia and industry regularly reporting on the multitude of benefits arising from exploiting reactor miniaturization [1][2][3][4][5]. The steady increase of applications highlighting improved syntheses is thereby paralleled by a growing

• appreciation of pitfalls and challenges [6][7] as well as solutions for their rectification that result from increasing knowledge and experience [8]. Pleasingly, recent years have also witnessed the expansion of flow chemistry in university curricula [9] although considerable efforts are still needed to

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

• reaction conditions were also applied to this reaction (Scheme 15). The reagents were premixed in THF at room temperature and injected into a heated reactor fitted with a back pressure regulator to allow operation at temperatures that exceeded the boiling point of the solvent. In this flow chemistry setup

A sustainable strategy for the straightforward preparation of 2H-azirines and highly functionalized NH-aziridines from vinyl azides using a single solvent flow-batch approach

• Michael Andresini,
• Leonardo Degannaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2021, 17, 203–209, doi:10.3762/bjoc.17.20

• Michael Andresini Leonardo Degannaro Renzo Luisi Flow Chemistry and Microreactor Technology FLAME-Lab, Department of Pharmacy – Drug Sciences, University of Bari “A. Moro”, Via E. Orabona 4, Bari, 70125, Italy 10.3762/bjoc.17.20 Abstract The reported flow-batch approach enables the easy

• and potentially automatable method for the synthesis of interesting strained compounds. Keywords: aziridines; 2H-azirines; flow chemistry; green chemistry; organolithium compounds; Introduction Since their conception in the early 1990s, Green Chemistry Principles (GCP) have been applied with

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

• path length of l = 17.7 mm at which distance (from the surface) 90% of the light is absorbed. Flow chemistry provides an elegant means for scaling photochemical reactions [211][212][213][214], primarily due to the shorter path lengths for light transmission provided by flowing the reaction mixture

When metal-catalyzed C–H functionalization meets visible-light photocatalysis

• Lucas Guillemard and
• Joanna Wencel-Delord

Beilstein J. Org. Chem. 2020, 16, 1754–1804, doi:10.3762/bjoc.16.147

• of both substrates bearing various functional groups, thus furnishing more than 30 acylated products in moderate to good yields. As the molecular oxygen was the terminal oxidant, the typical high loading of an external oxidant could be avoided. Flow chemistry is an important technology for

• photochemical reactions due to the inherent lack of scalability issues as a consequence of the Beer–Lambert law of absorption. Consequently, continuous-flow chemistry represents one of the few ways in which pharmaceutically relevant quantities of compounds can be synthesized through photoinduced transformations

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• described, including the use of metals other than cobalt (such as rhodium, iridium, titanium, ruthenium, nickel, and palladium), or the use of CO surrogates such as aldehydes, alcohols and formates. Recently, its utility in flow chemistry has also been described [42]. Intramolecular Pauson–Khand reactions

Heterogeneous photocatalysis in flow chemical reactors

• Christopher G. Thomson,
• Ai-Lan Lee and
• Filipe Vilela

Beilstein J. Org. Chem. 2020, 16, 1495–1549, doi:10.3762/bjoc.16.125

• some interesting reactor designs that could be implemented to enhance organic synthesis. Keywords: air purification; flow chemistry; heterogeneous photoredox catalysis; organic synthesis; reactor design; water purification; Review 1 Introduction 1.1 Scope of the review This review aims to be of

• interest to synthetic organic chemists who are considering applying heterogeneous photocatalysis (HPC) and flow chemistry in their research, and especially those who are already involved in one of the two areas. Many independent reviews have focused on individual types of HPCat materials [1][2][3][4][5][6

• is no review dedicated to this important and developing research area. Within the introduction, we cover the importance of the field and some important historical developments of photocatalysis (Section 1.2). We also discuss the synergy between flow chemistry and HPCats that allows chemists and

Disposable cartridge concept for the on-demand synthesis of turbo Grignards, Knochel–Hauser amides, and magnesium alkoxides

• Mateo Berton,
• Kevin Sheehan,
• Andrea Adamo and
• D. Tyler McQuade

Beilstein J. Org. Chem. 2020, 16, 1343–1356, doi:10.3762/bjoc.16.115

• ; Introduction Flow chemistry has facilitated: (1) new applications of high-energy or otherwise unsafe chemistry [1][2], enabled by a controlled/rapid heat removal and generation and the immediate use of unstable species [3][4]; (2) flash chemistry, where rapid mixing can outcompete unimolecular side reactions

• quantitative organic chloride conversion. Challenges: Metal surface activation, organomagnesium solubility, formation of a black side product, performance, and degradation over time. System setup: A commercial flow chemistry system [50] equipped with a temperature-controlled glass manifold reactor [51] was

• used (Figure S1, Supporting Information File 1). We have found that both glass and PFA columns with similar dimensions can be used. To reduce the costs, the flow chemistry system can be replaced by syringe or HPLC pumps, and the reactor heating can be accomplished using standard heating tools (water

Photocatalytic trifluoromethoxylation of arenes and heteroarenes in continuous-flow

• Alexander V. Nyuchev,
• Ting Wan,
• Borja Cendón,
• Carlo Sambiagio,
• Job J. C. Struijs,
• Michelle Ho,
• Moisés Gulías,
• Ying Wang and
• Timothy Noël

Beilstein J. Org. Chem. 2020, 16, 1305–1312, doi:10.3762/bjoc.16.111

• Alexander V. Nyuchev Ting Wan Borja Cendon Carlo Sambiagio Job J. C. Struijs Michelle Ho Moises Gulias Ying Wang Timothy Noel Micro Flow Chemistry and Synthetic Methodology, Department of Chemical Engineering and Chemistry, Eindhoven University of Technology, Het Kranenveld, Bldg 14 − Helix, 5600

A method to determine the correct photocatalyst concentration for photooxidation reactions conducted in continuous flow reactors

• Clemens R. Horn and
• Sylvain Gremetz

Beilstein J. Org. Chem. 2020, 16, 871–879, doi:10.3762/bjoc.16.78

• maxima close to the absorption maximum of each catalyst. Keywords: catalyst concentration; channel height; flow chemistry; photooxidation; Introduction The renaissance of photochemistry that occurred over the last decade has been described as “old light through new windows”, and much of this work

Photocatalytic deaminative benzylation and alkylation of tetrahydroisoquinolines with N-alkylpyrydinium salts

• David Schönbauer,
• Carlo Sambiagio,
• Timothy Noël and
• Michael Schnürch

Beilstein J. Org. Chem. 2020, 16, 809–817, doi:10.3762/bjoc.16.74

• David Schonbauer Carlo Sambiagio Timothy Noel Michael Schnurch Institute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9/163, 1060 Vienna, Austria Department of Chemical Engineering and Chemistry, Micro Flow Chemistry and Synthetic Methodology, Eindhoven University of Technology, Den

Synthesis of disparlure and monachalure enantiomers from 2,3-butanediacetals

• Adam Drop,
• Hubert Wojtasek and
• Bożena Frąckowiak-Wojtasek

Beilstein J. Org. Chem. 2020, 16, 616–620, doi:10.3762/bjoc.16.57

• -2,3-Disubstituted butanediacetal derivatives of dimethyl tartrates 9–11 can be converted to cis-isomers 12–14 (Scheme 2) [32]. Compound 12 can be obtained from trans-dimethyl ester 9 in a two-step procedure either following a traditional way or using continuous flow chemistry [32][33][34]. The

Visible-light-induced addition of carboxymethanide to styrene from monochloroacetic acid

• Kaj M. van Vliet,
• Nicole S. van Leeuwen,
• Albert M. Brouwer and
• Bas de Bruin

Beilstein J. Org. Chem. 2020, 16, 398–408, doi:10.3762/bjoc.16.38

• under the applied reaction conditions. The photoredox activation of monochloroacetic acid leads to the formation of precipitate during the reaction (see Figure 4), again indicating catalyst precipitation/deactivation. Works in the group of Noël and others have revealed that flow chemistry can increase

Safe and highly efficient adaptation of potentially explosive azide chemistry involved in the synthesis of Tamiflu using continuous-flow technology

• Cloudius R. Sagandira and
• Paul Watts

Beilstein J. Org. Chem. 2019, 15, 2577–2589, doi:10.3762/bjoc.15.251

• ’ strategy, which is exclusive to flow chemistry technology. In this strategy, reagents are passed through a heated zone under high temperature at very fast flow rates allowing for rapid reaction completion and is out of the heated zone before significant byproduct is formed [25]. NaN3 is the cheapest and

Ugi reaction-derived prolyl peptide catalysts grafted on the renewable polymer polyfurfuryl alcohol for applications in heterogeneous enamine catalysis

• Alexander F. de la Torre,
• Gabriel S. Scatena,
• Oscar Valdés,
• Daniel G. Rivera and
• Márcio W. Paixão

Beilstein J. Org. Chem. 2019, 15, 1210–1216, doi:10.3762/bjoc.15.118

• asymmetric Michael addition of n-butanal to β-nitrostyrene that was used as a model reaction. This work supports the potential of multicomponent reactions towards the assembly of catalysts and their simultaneous functionalization for immobilization. Keywords: flow chemistry; heterogeneous catalysis

• packing amount (wtot) was also determined by pycnometry. Porosity (εtot) of 0.67 is an optimal value for this material, which is according to the accepted values. One of the most important features of a microreactor for continuous-flow chemistry is the residence time (τ) which is known as the time in

The LANCA three-component reaction to highly substituted β-ketoenamides – versatile intermediates for the synthesis of functionalized pyridine, pyrimidine, oxazole and quinoxaline derivatives

• Tilman Lechel,
• Roopender Kumar,
• Mrinal K. Bera,
• Reinhold Zimmer and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2019, 15, 655–678, doi:10.3762/bjoc.15.61

• materials [24][25]. They can smoothly be prepared in multigram scale and recently a flow chemistry approach on the use of lithiated methoxyallene was published [26]. For the case, that substituents R3 are strongly electron withdrawing the relatively electrophilic amido carbonyl group of the β-ketoenamides

Low-budget 3D-printed equipment for continuous flow reactions

• Jochen M. Neumaier,
• Amiera Madani,
• Thomas Klein and
• Thomas Ziegler

Beilstein J. Org. Chem. 2019, 15, 558–566, doi:10.3762/bjoc.15.50

• in flow chemistry. We developed a rack of four syringe pumps controlled by one Arduino computer, which can be manufactured with a commonly available 3D printer and readily available parts. Also, we printed various flow reactor cells, which are fully customizable for each individual reaction. With

• this equipment we performed some multistep glycosylation reactions, where multiple 3D-printed flow reactors were used in series. Keywords: continuous flow; 3D printing; glycosylation; microreactor; multistep; Introduction The use of flow chemistry in comparison to batch chemistry shows great benefits

• flow [2][3][4]. One use of such multiple step reactions is, for instance, the on-demand production of pharmaceuticals using compact, reconfigurable continuous flow systems [5]. The combination of flow chemistry with 3D-printed reactors is also a growing terrain in the last years [6][7][8][9][10][11][12

Microfluidic light-driven synthesis of tetracyclic molecular architectures

• Javier Mateos,
• Nicholas Meneghini,
• Marcella Bonchio,
• Nadia Marino,
• Tommaso Carofiglio,
• Xavier Companyó and
• Luca Dell’Amico

Beilstein J. Org. Chem. 2018, 14, 2418–2424, doi:10.3762/bjoc.14.219

• molecules. Keywords: [4 + 2] photoenol; cycloaddition; flow chemistry; microfluidic photoreactor; photoredox catalysis; synthetic photochemistry; Introduction In recent years synthetic photochemistry has become highly sophisticated [1]. The opportunity of using renewable energy sources to transform and

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• reaction specifically investigated the dimerization of thiols. Some of the experiments carried out by the group were in a flow chemistry set up, exemplifying the scalability of the procedure. In addition, the oxidant that achieves the transformation is molecular oxygen, making this a very sustainable route

• an organophotocatalytic version of the Ugi reaction. These procedures were undertaken in a flow chemistry set-up, using irradiation by green LEDs and Rose Bengal as the photocatalyst (Scheme 13) [56]. The scope of the reaction is fairly broad, especially considering the method was developed in a flow

• chemistry set-up, which requires a large amount of optimisation itself. A range of nucleophiles including nitroalkanes, cyanides, malonates and phosphonates are used to modify different N-aryltetrahydroisoquinolines. These products have the potential for quite a range of subsequent reactions for elaboration

Assessing the possibilities of designing a unified multistep continuous flow synthesis platform

• Mrityunjay K. Sharma,
• Roopashri B. Acharya,
• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2018, 14, 1917–1936, doi:10.3762/bjoc.14.166

• ’, in reality, such an envisaged system would be much more complex than these examples. Keywords: automation; continuous flow synthesis; cybernetics; multistep flow synthesis; unified platforms; Review Introduction Flow chemistry is now seen as a reliable approach for the synthesis of simple organic

• ]. Flow chemistry gains its benefits from excellent heat and mass transfer rates and rapid mixing which is not possible in the case of conventional synthesis modes [21]. In general, the continuous flow synthesis aims at conducting the reactions at intrinsic kinetics. This helps to have reactors having

• of flow chemistry which is not an easy task. The utilization of the same approach for the synthesis of a wide range of products is very challenging since each product in the chemical synthesis involves different synthesis procedures, different conditions, different phases and different isolation

Mild and selective reduction of aldehydes utilising sodium dithionite under flow conditions

• Nicole C. Neyt and
• Darren L. Riley

Beilstein J. Org. Chem. 2018, 14, 1529–1536, doi:10.3762/bjoc.14.129

• the selective reduction of aldehydes in the presence of ketones and has been demonstrated as a continuous process. Keywords: aldehyde reduction; flow chemistry; selective reduction; sodium dithionite; Introduction Flow chemistry and continuous processing has been acknowledged by the American

• Chemical Society (ACS), the Green Chemistry Institute (GCI) and several global pharmaceutical companies as one of the primary areas for research and development for chemical manufacturing [1][2][3][4]. For the past decade flow chemistry and the application of flow devices has been gaining acceptance in

Biocatalytic synthesis of the Green Note trans-2-hexenal in a continuous-flow microreactor

• Morten M. C. H. van Schie,
• Tiago Pedroso de Almeida,
• Gabriele Laudadio,
• Florian Tieves,
• Elena Fernández-Fueyo,
• Timothy Noël,
• Isabel W. C. E. Arends and
• Frank Hollmann

Beilstein J. Org. Chem. 2018, 14, 697–703, doi:10.3762/bjoc.14.58

• Engineering and Chemistry, Micro Flow Chemistry & Process Technology, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands Centro de Investigaciones Biológicas, CSIC, Madrid, Spain 10.3762/bjoc.14.58 Abstract The biocatalytic preparation of trans-hex-2-enal from trans-hex-2

• ; alcohol oxidation; aldehyde; flow chemistry; Introduction trans-2-Hexenal is well-known as a major component of the Green Notes of fruits and vegetables such as apples, strawberries, cherries and more. It is widely used in the flavour and fragrance industry as fresh flavour ingredient in foods and

• induced by the segmented flow regime. This flow pattern guarantees an enhanced contact between the two phases and provides a uniform gas concentration in the liquid segment. Therefore, it is not very astonishing that also the biocatalysis community is showing interest in flow chemistry. Several

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

• . Keywords: compartmentalisation; heterogeneous catalysis; multistep flow chemistry; palladium; Pickering emulsions; Introduction Palladium (Pd) catalysis has been established as a key component in the toolbox of organic chemists. Reactions that are catalysed by palladium benefit from the remarkable

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

• starting materials and reagents, simplifying the synthetic route in terms of reducing the total number of steps as well as reducing the cost and improving the efficiency of individual steps. Flow chemistry methodologies have been increasingly investigated in recent years in the pharmaceutical industry for

• batch processes. HCQ (1) is currently produced via the batch method shown in Scheme 1. Therefore, continuous-flow chemistry approaches to synthesizing HCQ (1) offer a great potential to maximize the efficiency, and thus significantly reduces the overall manufacturing costs of this important medicine

• to limited solubility of ammonia in THF. H2/Raney-nickel reductions are often carried out in alcoholic media where much higher concentrations of ammonia are achievable but would require a solvent exchange. There are many reports of continuous-flow chemistry methods for reductive amination of ketones