One-pot synthesis of isosorbide from cellulose or lignocellulosic biomass: a challenge?

• Isaline Bonnin,
• Raphaël Mereau,
• Thierry Tassaing and
• Karine De Oliveira Vigier

Beilstein J. Org. Chem. 2020, 16, 1713–1721, doi:10.3762/bjoc.16.143

• this reaction under continuous flow using two catalytic beds. Finally, we emphasize that mechanistic insights on the catalytic conversion of biomass-derived platform molecules are required to make this value chain competitive with respect to the traditional synthesis of chemicals from fossil fuels. In

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

• Christopher G. Thomson Ai-Lan Lee Filipe Vilela Institute of Chemical Sciences, School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS Scotland, United Kingdom 10.3762/bjoc.16.125 Abstract The synergy between photocatalysis and continuous flow chemical reactors

• irradiation. Herein, we review some important developments of heterogeneous photocatalytic materials and their application in flow reactors for sustainable organic synthesis. Further, the application of continuous flow heterogeneous photocatalysis in environmental remediation is briefly discussed to present

• demonstrated the safe use of gaseous CF3I as a reagent for the continuous flow PRC trifluoromethylation of 5-membered heterocycles, such as N-methylpyrrole (1, Scheme 1), with a high conversion and selectivity for the monofunctionalised product 2 [62]. The system achieved full conversion for a variety of

An overview on disulfide-catalyzed and -cocatalyzed photoreactions

• Yeersen Patehebieke

Beilstein J. Org. Chem. 2020, 16, 1418–1435, doi:10.3762/bjoc.16.118

• -membered keto ester derivatives did not show any desired reaction. In combination with a continuous-flow strategy, this disulfide-catalyzed aerobic oxidation process can be scaled up to a gram-scale. A plausible mechanism of the reaction is shown in Scheme 11. The hydroxylation starts with the formation of

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

• batch-to-batch variability. Tubular reactors of solid reagents combined with solution-phase reagents enable the continuous-flow preparation of organomagnesium reagents. The use of stratified packed-bed columns of magnesium metal and lithium chloride for the synthesis of highly concentrated turbo

• lithium chloride separated with fiberglass for the turbo Grignard reagent synthesis. Steady-state concentration stability during the conversion of iPrCl in THF (56 mL, 2.2 M) into iPrMgCl·LiCl (50 mL, 1.91 M) using two perfluorinated disposable monocomponent tubular reactors. Continuous flow synthesis of

• TMPMgCl⋅LiCl with a stratified packed-bed column of activated magnesium and lithium chloride. Continuous flow synthesis of TMPMgCl⋅LiBr with a stratified packed-bed column of activated magnesium and lithium bromide. Continuous flow synthesis of t-AmylOMgCl⋅LiCl with a stratified packed-bed column of

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

• , Road, North Chicago, Illinois 60064, United States of America 10.3762/bjoc.16.111 Abstract The first example of photocatalytic trifluoromethoxylation of arenes and heteroarenes under continuous-flow conditions is described. Application of continuous-flow microreactor technology allowed to reduce the

• residence time up to 16 times in comparison to the batch procedure, while achieving similar or higher yields. In addition, the use of inorganic bases was demonstrated to increase the reaction yield under batch conditions. Keywords: C–H functionalization; continuous-flow; organic synthesis; photoredox

• photoredox protocols for the radical trifluoromethoxylation of unfunctionalized (hetero)arenes by using specifically designed CF3O radical-releasing agents (Scheme 1B). Following our long-standing interest in the development of continuous-flow approaches for C–H functionalization [18][26] and photochemical

Synthesis of esters of diaminotruxillic bis-amino acids by Pd-mediated photocycloaddition of analogs of the Kaede protein chromophore

• Esteban P. Urriolabeitia,
• Pablo Sánchez,
• Alexandra Pop,
• Cristian Silvestru,
• Eduardo Laga,
• Ana I. Jiménez and
• Carlos Cativiela

Beilstein J. Org. Chem. 2020, 16, 1111–1123, doi:10.3762/bjoc.16.98

• source and a Q-ToF mass analyzer. Acetonitrile and methanol were used as solvents. Samples were introduced at a continuous flow of 0.2 mL/min, and nitrogen served both as the nebulizer gas and the dry gas. Infrared spectra were recorded on a Spectrum 100 Perkin-Elmer FTIR spectrophotometer, with a

Recent applications of porphyrins as photocatalysts in organic synthesis: batch and continuous flow approaches

• Rodrigo Costa e Silva,
• Luely Oliveira da Silva,
• Aloisio de Andrade Bartolomeu,
• Timothy John Brocksom and
• Kleber Thiago de Oliveira

Beilstein J. Org. Chem. 2020, 16, 917–955, doi:10.3762/bjoc.16.83

• conjugated photosensitizers show increasing potential in photocatalysis since they combine both photo- and electrochemical properties which can substitute available metalloorganic photocatalysts. Batch and continuous-flow approaches are presented highlighting the relevance of enabling technologies for the

• ) [1][2][3]. This effect limits the penetration of photons to only a short distance into the reaction vessel, provoking increases of the reaction time, photocatalyst loading, byproducts, overheating and so on. Notably, the use of continuous-flow reactors for photochemical applications allows us to

• continuous-flow photochemistry a sustainable alternative approach being applied already by the chemical and pharmaceutical industries. Porphyrinoid is the term given for a class of organic compounds containing four pyrrole rings connected by four methylene bridges, and include porphyrin, chlorin

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

• centered on the combination of light with continuous flow reactors [1][2][3][4][5][6]. The reason for this increased interest is that continuous flow photochemical reactors can overcome various limitations that occur when the same reaction run in batch reactors [7]. For example, the flow reactor can

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

• Valerian Dragutan,
• Ileana Dragutan,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2020, 16, 738–755, doi:10.3762/bjoc.16.68

• peroxide bridge, has been subject of extensive scientific investigations during the last decade [53][54][55][56][57][58][59][60][61][62][63]. In this context, Seeberger and co-workers successfully developed an ingenious continuous-flow process for the hemisynthesis of pure artemisinin from

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

KOt-Bu-promoted selective ring-opening N-alkylation of 2-oxazolines to access 2-aminoethyl acetates and N-substituted thiazolidinones

• Qiao Lin,
• Shiling Zhang and
• Bin Li

Beilstein J. Org. Chem. 2020, 16, 492–501, doi:10.3762/bjoc.16.44

• synthesis of β-nitrate ester carboxamides using tert-butyl nitrite as the nitro source and oxygen as the oxidant through the ring opening of 2-oxazolines [9] (Scheme 1a). Kappe reported a two-step continuous-flow synthesis of N-(2-aminoethyl)acylamides through ring opening/hydrogenation of oxazolines with

Recent advances in photocatalyzed reactions using well-defined copper(I) complexes

• Mingbing Zhong,
• Xavier Pannecoucke,
• Philippe Jubault and
• Thomas Poisson

Beilstein J. Org. Chem. 2020, 16, 451–481, doi:10.3762/bjoc.16.42

• moderate to good yields. Notably, alkyl iodides were also suitable substrates. The methodology proved to be compatible with a broad range of functional groups. To demonstrate the synthetic utility of the process, the reaction was developed under continuous flow conditions to afford an easy and

• synthesized in 57% yield. Importantly, the reaction scale was increased to 1 g under continuous flow conditions. Then, the reaction was extended to the cyclization of a stilbene derivative into phenanthrene in a moderate 23% isolated yield. To explain the reaction pathway, the authors suggested an oxidative

• mechanism. One year later, 2013, Collins and co-workers extended this concept to the synthesis of carbazole derivatives under continuous flow conditions (Scheme 30) [44]. Using, the [Cu(I)(dmp)(xantphos)]BF4 catalyst, the oxidative cyclization of various triarylamines was carried out in the presence of I2

Synthesis of 3-alkenylindoles through regioselective C–H alkenylation of indoles by a ruthenium nanocatalyst

• Abhijit Paul,
• Debnath Chatterjee,
• Srirupa Banerjee and
• Somnath Yadav

Beilstein J. Org. Chem. 2020, 16, 140–148, doi:10.3762/bjoc.16.16

• ]. Noël and co-workers reported the C3–H olefination of indoles using Pd(OAc)2 as a catalyst and molecular oxygen as the oxidant under continuous flow conditions [29]. Jia et al. reported the synthesis of 3-alkenylindoles using Pd(OAc)2 as the catalyst and MnO2 as the oxidant under ball milling conditions

Functionalization of the imidazo[1,2-a]pyridine ring in α-phosphonoacrylates and α-phosphonopropionates via microwave-assisted Mizoroki–Heck reaction

• Damian Kusy,
• Agata Wojciechowska,
• Joanna Małolepsza and
• Katarzyna M. Błażewska

Beilstein J. Org. Chem. 2020, 16, 15–21, doi:10.3762/bjoc.16.3

• heterogeneous and homogeneous catalysts, as well as continuous-flow conditions [13][14][15]. Therefore, we tested microwave heating, a technique which is known for significant acceleration of the C–C coupling reaction [16]. We carried out the optimization studies using model substrates – compound 1a and benzyl

Progress in metathesis chemistry

• Karol Grela and
• Anna Kajetanowicz

Beilstein J. Org. Chem. 2019, 15, 2765–2766, doi:10.3762/bjoc.15.267

• pills are now truly user friendly. Olefin metathesis catalysts can work under homo- or heterogeneous conditions, as well as under continuous flow. The stability of Ru–methylidene species (an attribute important for a successful ethenolysis process) has been significantly improved. Importantly, we have

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

• explosive azide chemistry involved in a proposed Tamiflu route by taking advantage of the continuous-flow technology. The azide intermediates were safely synthesised in full conversions and >89% isolated yields. Keywords: azide chemistry; continuous flow synthesis; hazardous; safe; Tamiflu; Introduction

• ) (Scheme 1 and Figure 1). Continuous-flow synthesis offers the generation and consumption of dangerous intermediates in situ preventing their accumulation, thus it represents a potential solution for dealing with hazardous reaction intermediates and products [15]. Additionally, microreactors can handle

• exothermic reactions extremely well, due to the inherent high surface area to volume ratio and rapid heat dissipation [16] unlike the conventional batch process. Continuous-flow production may certainly enhance the green metrics of synthesis in several ways [17] and their work clearly demonstrated the

Chemical synthesis of the pentasaccharide repeating unit of the O-specific polysaccharide from Escherichia coli O132 in the form of its 2-aminoethyl glycoside

• Debasish Pal and
• Balaram Mukhopadhyay

Beilstein J. Org. Chem. 2019, 15, 2563–2568, doi:10.3762/bjoc.15.249

• -acetylation using NaOMe in MeOH followed by hydrogenolysis in a ThalesNano continuous flow hydrogenation assembly using a 10% Pd-C cartridge [29]. After three cycles of hydrogenation, formation of the target pentasaccharide 1 was evident from the mass spectrum (Scheme 4). Conclusion In conclusion, the

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

• Xiaowei Li,
• Xiaolin Shi,
• Xiangqian Li and
• Dayong Shi

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

• dehydrogenation process to afford the target product. Also in 2015, Li and co-workers [146] developed a mild and fast Cu(I/II)-catalyzed trifluoromethylation procedure to obtain 3-trifluoromethylcoumarins. The reaction was carried out with a CuCl/CF3SO2Na/TBHP system under continuous-flow conditions, affording

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

• polyfurfuryl alcohol-supported catalysts for applications in heterogeneous enamine catalysis. The utilization of the polymer-supported catalysts in both batch and continuous-flow organocatalytic procedures proved moderate catalytic efficacy and enantioselectivity, but excellent diastereoselectivity in the

• -supported chiral organocatalysts usually provides a much greener prospect for the synthesis of enantiomerically enriched building blocks [4][5][6]. Importantly, immobilized catalysts allow for both recyclability of the catalyst and the implementation of continuous-flow procedures, which usually encompass

• catalysts for applications in continuous-flow catalysis [8]. In an endeavor to develop a cheaper and renewable polymer-supported organocatalyst, herein we describe the multicomponent synthesis of furfuryl-containing prolyl pseudo-peptide catalysts and their subsequent utilization in the preparation of PFA

Design and synthesis of multivalent α-1,2-trimannose-linked bioerodible microparticles for applications in immune response studies of Leishmania major infection

• Chelsea L. Rintelmann,
• Tara Grinnage-Pulley,
• Kathleen Ross,
• Daniel E. K. Kabotso,
• Angela Toepp,
• Anne Cowell,
• Christine Petersen,
• Balaji Narasimhan and
• Nicola Pohl

Beilstein J. Org. Chem. 2019, 15, 623–632, doi:10.3762/bjoc.15.58

• , hydrogenolysis of the benzyl ethers under continuous flow (0.3–1 mL/min) and H2 pressure (30–60 bar) using an H-cube apparatus was found to be effective at removing the benzyl ethers, but arduously slow (>48 h) from the limited surface-mediated interactions with the Pd/C cartridge. By comparison, batch

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

• 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

• ]. 3D-printing, also known as additive manufacturing, is a process, where the object is created layer by layer directly from the computer-aided design (CAD) model. There are different technologies available for printing continuous flow reaction devices like fused deposition modeling (FDM) [13][14

Mechanistic studies of an L-proline-catalyzed pyridazine formation involving a Diels–Alder reaction with inverse electron demand

• Anne Schnell,
• J. Alexander Willms,
• S. Nozinovic and
• Marianne Engeser

Beilstein J. Org. Chem. 2019, 15, 30–43, doi:10.3762/bjoc.15.3

• ) in the reacting solution. In order to enhance the ESI response of putative reactive intermediates, the reaction was performed with the charge-tagged tetrazine 4∙Br (R2, Scheme 5). A continuous-flow setup [4][17][18] was used for fast sampling of the reaction R2 directly after its initiation. A

• substrate, L-proline, rt) ESIMS A 0.4 mmol/L stock solution of 4∙Br in dimethyl sulfoxide was prepared (stock solution ss1), as well as a 0.001 mmol/L stock solution of L-proline in dimethyl sulfoxide/acetone 1:1 (stock solution ss2). Continuous flow setup A continuous flow setup [4][17][18] was used for

• using a continuous-flow setup with a calculated reaction time of 86 s. The two insets show zooms into relevant parts of the spectrum. a) Reaction R2 after two hours (syringe setup). b) ESIMS monitoring of reaction R2. Signal intensities for substrate 4 and product 5 are depicted. ESI mass spectrum of

Photocatalyic Appel reaction enabled by copper-based complexes in continuous flow

• Clémentine Minozzi,
• Jean-Christophe Grenier-Petel,
• Shawn Parisien-Collette and
• Shawn K. Collins

Beilstein J. Org. Chem. 2018, 14, 2730–2736, doi:10.3762/bjoc.14.251

• anhydrides. The protocol was also amendable and optimized under continuous flow conditions. Keywords: Appel; continuous flow; copper; halides; photocatalysis; Introduction Synthetic photochemistry and photocatalysis continues to influence molecular synthesis [1][2][3][4]. In exploring photochemical

• transfer (PCET) reactions [22][23][24][25][26]. Herein, the evaluation of Cu(I)-complexes for photocatalytic Appel reactions and demonstration in continuous flow is described. Results and Discussion The first step in identifying a heteroleptic diamine/bisphosphine Cu(I)-based photocatalyst for the

• were then transferred to continuous flow (Table 2). Initially, an experimental set-up using a previously reported reactor for purple LEDs was selected for the reaction [30][31]. Following injection of the reaction mixture with a target residence time of 60 min, only traces of the desired bromide 2 were

The enzymes of microbial nicotine metabolism

• Paul F. Fitzpatrick

Beilstein J. Org. Chem. 2018, 14, 2295–2307, doi:10.3762/bjoc.14.204

• -hydroxynicotine in the active site is followed by hydrolysis of the oxidized amine in a second site to yield 6-hydroxypseudooxynicotine (Scheme 3) [15]. However, a recent analysis of the structure of the product of the LHNO reaction utilizing NMR and continuous-flow mass spectrometry established that the enzyme

A general and atom-efficient continuous-flow approach to prepare amines, amides and imines via reactive N-chloramines

• Katherine E. Jolley,
• Michael R. Chapman and
• A. John Blacker

Beilstein J. Org. Chem. 2018, 14, 2220–2228, doi:10.3762/bjoc.14.196

• Abstract Chloramines are an important class of reagents, providing a convenient source of chlorine or electrophilic nitrogen. However, the instability of these compounds is a problem which makes their isolation and handling difficult. To overcome these hazards, a continuous-flow approach is reported which

• afford amides. Primary and secondary imines were produced under continuous conditions from the reaction of N-chloramines with base, with one example subsequently reduced under asymmetric conditions to produce a chiral amine in 94% ee. Keywords: continuous flow; CSTR; N-chloramine; synthetic methods

• ; telescoping; Introduction N-Chloramines are versatile reagents, however, their availability is restricted by their stability, so useful would be in situ methods to produce and use them [1][2]. The continuous-flow methodology is useful in this context, enabling control over reaction exotherms and improved