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

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

• ][26][27]. A few examples of experimental set-ups of successfully demonstrated multistep flow synthesis encompassing various kinds of reactions from the literature are given in Table 1. Single step approaches were useful in terms of evaluating the concepts in continuous flow synthesis. However, since

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

• laboratories because of its ease of use, safety and control [3][4][5][6]. Continuous flow technologies are generally more effective than traditional batch processes with key advantages including intensified heat and mass transfer, inline reaction monitoring, higher mass throughput, safer control of hazardous

• developed a simple transition-metal-free continuous flow method for the reduction of aldehydes in aqueous media utilising sodium dithionite which does not generate or use molecular hydrogen. The process affords comparable yields to those obtained under batch conditions but in reduced reaction residence time

Cobalt–metalloid alloys for electrochemical oxidation of 5-hydroxymethylfurfural as an alternative anode reaction in lieu of oxygen evolution during water splitting

• Jonas Weidner,
• Stefan Barwe,
• Kirill Sliozberg,
• Stefan Piontek,
• Justus Masa,
• Ulf-Peter Apfel and
• Wolfgang Schuhmann

Beilstein J. Org. Chem. 2018, 14, 1436–1445, doi:10.3762/bjoc.14.121

• of the various cobalt–metalloid alloys supported on Ni RDE electrodes revealed CoB to be the most efficient HMF oxidation catalyst. Using a CoB modified Ni foam as anode material, and Ni foam as the cathode in a continuous flow reactor with an anion exchange membrane separating the anodic and

• of the activities of all investigated CoX-based catalysts (X = B, Si, P, As and Te) is highlighted in Table 1. HMF oxidation in a continuous flow reactor The surprisingly high HMF oxidation activity of CoB made it especially interesting to further study the product distribution and FDCA yield in a

Recent applications of chiral calixarenes in asymmetric catalysis

• Mustafa Durmaz,
• Erkan Halay and
• Selahattin Bozkurt

Beilstein J. Org. Chem. 2018, 14, 1389–1412, doi:10.3762/bjoc.14.117

• achieve reusable catalysts for batch and continuous-flow studies. Inherently chiral calix[4]arene-based phase-transfer catalysts. Calix[4]arene-amides used as phase-transfer catalysts. Proposed transition state model of asymmetric Henry reaction. Structure of inherently chiral oxazoline calix[4]arenes

[3 + 2]-Cycloaddition reaction of sydnones with alkynes

• Veronika Hladíková,
• Jiří Váňa and
• Jiří Hanusek

Beilstein J. Org. Chem. 2018, 14, 1317–1348, doi:10.3762/bjoc.14.113

• -carboxylate in good yield. Copper(II) acetate anchored on a modified silica gel can also serve as an efficient catalyst in batch reactor or if housed in stainless steel cartridges [127] in continuous-flow conditions (Table 10). Again, the 4-substituted pyrazole is preferentially formed. Conclusion Since its

Nanoreactors for green catalysis

• M. Teresa De Martino,
• Loai K. E. A. Abdelmohsen,
• Floris P. J. T. Rutjes and
• Jan C. M. van Hest

Beilstein J. Org. Chem. 2018, 14, 716–733, doi:10.3762/bjoc.14.61

• specific characteristics of nanoreactors should be employed more effectively. Physical protection and separation of catalytic species will allow the performance of multistep conversions in one-pot reactors. This would then enable continuous flow processing, as intermediate work-up steps and solvent

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

• described in the literature to alleviate the inactivation issue described above [9][10][11][12]. The continuous-flow microreactor technology has emerged as a safe and scalable way to approach oxidation reactions [13][14]. Due to its small dimensions, hazardous reactions can be easily controlled, owing to

• at elevated substrate concentrations may be an indication for a slight substrate inhibition. Performing these initial rate measurements in the presence of varying product concentrations showed a pronounced product inhibition (Supporting Information File 1, Figure S2, vide infra). Continuous-flow

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

• , University of Hull, Hull HU6 7RX, UK 10.3762/bjoc.14.52 Abstract Within the “compartmentalised smart factory” approach of the ONE-FLOW project the implementation of different catalysts in “compartments” provided by Pickering emulsions and their application in continuous flow is targeted. We present here the

• minimal leaching behaviour is demonstrated with various Suzuki–Miyaura cross-coupling reactions in batch as well as in continuous flow employing the so-called “plug & play reactor”. Finally, we demonstrate the use of these particles as the sole emulsifier of oil–water emulsions for a range of oils

• on the planned realisation of the integrated multistep continuous flow synthesis of valsartan and sacubitril within the frame of the ONE-FLOW project is given. The compounds are well known as APIs in a combination drug for the treatment of hypertension and chronic heart failure (Entresto®, Novartis

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

• 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

• facilitate the formation of 1, resulting in a comparable yield in less than 6 hours. Thus, we have integrated the continuous preparation of reaction with our new efficient continuous-flow synthesis of 12 with the final step by using a CSTR to accommodate the longer reaction time required to produce HCQ (1

Continuous multistep synthesis of 2-(azidomethyl)oxazoles

• Thaís A. Rossa,
• Nícolas S. Suveges,
• Marcus M. Sá,
• David Cantillo and
• C. Oliver Kappe

Beilstein J. Org. Chem. 2018, 14, 506–514, doi:10.3762/bjoc.14.36

• continuous-flow process. The general synthetic strategy involves a thermolysis of vinyl azides to generate azirines, which react with bromoacetyl bromide to provide 2-(bromomethyl)oxazoles. The latter compounds are versatile building blocks for nucleophilic displacement reactions as demonstrated by their

• subsequent treatment with NaN3 in aqueous medium to give azido oxazoles in good selectivity. Process integration enabled the synthesis of this useful moiety in short overall residence times (7 to 9 min) and in good overall yields. Keywords: azirines; continuous flow; heterocycles; oxazoles; process

• with unstable intermediates or reagents can be overcome with the use of continuous-flow chemistry. Continuous-flow processing has demonstrated to be an ideal tool for the development of uninterrupted multistep reactions [35][36][37]. The integration of several sequential steps can be readily achieved

Continuous-flow retro-Diels–Alder reaction: an efficient method for the preparation of pyrimidinone derivatives

• Imane Nekkaa,
• Márta Palkó,
• István M. Mándity and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2018, 14, 318–324, doi:10.3762/bjoc.14.20

• syntheses of various pyrimidinones as potentially bioactive products by means of the highly controlled continuous-flow retro-Diels–Alder reaction of condensed pyrimidinone derivatives are presented. Noteworthy, the use of this approach allowed us to rapidly screen a selection of conditions and quickly

• confirm the viability of preparing the desired pyrimidinones in short reaction times. Yields typically higher than those published earlier using conventional batch or microwave processes were achieved. Keywords: continuous-flow; desulfurisation; norbornene-fused heterocycles; pyrimidinones; retro-Diels

• –Alder reaction; Introduction The continuous-flow (CF) technology has gained significant importance in modern synthetic chemistry [1][2][3] and becomes a core technology in the pharmaceutical, agrochemical, and fine chemical industries [4][5]. The use of this technology opens a new door to a quick

Photocatalytic formation of carbon–sulfur bonds

• Alexander Wimmer and
• Burkhard König

Beilstein J. Org. Chem. 2018, 14, 54–83, doi:10.3762/bjoc.14.4

• -dicyanobenzene) as organic photoredox catalyst and [NiCl2·dme] as transition metal catalyst in a continuous flow set-up, high yields of the coupling products were obtained in short residence times (30 min). They propose, that photoexcited 4CzIPN* generates the thiyl radical, which adds to the [NiI] complex

Microfluidic radiosynthesis of [¹⁸F]FEMPT, a high affinity PET radiotracer for imaging serotonin receptors

• Thomas Lee Collier,
• Steven H. Liang,
• J. John Mann,
• Neil Vasdev and
• J. S. Dileep Kumar

Beilstein J. Org. Chem. 2017, 13, 2922–2927, doi:10.3762/bjoc.13.285

• Psychiatric Institute, New York, NY, USA 10.3762/bjoc.13.285 Abstract Continuous-flow microfluidics has shown increased applications in radiochemistry over the last decade, particularly for both pre-clinical and clinical production of fluorine-18 labeled radiotracers. The main advantages of microfluidics are

• continuous flow microfluidics for radiofluorination have shown higher yields, with less amount of reagents and shorter reaction times compared to traditional vessel-based techniques [12]. Microfluidic techniques also allow for cost-effective and rapid optimization of reaction parameters for new radiotracers

• as simultaneous reactions can be carried out. We have recently shown that continuous flow microfluidics is suitable for 18F-radiopharmaceutical production studies [13] and have applied this technique in human PET imaging studies [14]. Herein we present the microfluidic synthesis and evaluation of

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