Controlled synthesis of poly(3-hexylthiophene) in continuous flow

• Helga Seyler,
• Jegadesan Subbiah,
• David J. Jones,
• Andrew B. Holmes and
• Wallace W. H. Wong

Beilstein J. Org. Chem. 2013, 9, 1492–1500, doi:10.3762/bjoc.9.170

• optimization of large area devices is costly and often impossible to achieve. Continuous-flow synthesis enables straight-forward scale-up of materials compared to conventional batch reactions. In this study, poly(3-hexylthiophene), P3HT, was synthesized in a bench-top continuous-flow reactor. Precise control

• -flow synthesis methods offer several advantages over traditional batch methods [14][15][16][17][18]. The scale-up of reactions is not only straightforward in continuous processing, but there are also benefits in high reaction reproducibility through accurate parameter control, superior heating and

• comparable performance to both commercial and batch-synthesized samples. This study paves the way for the continuous-flow synthesis of other polymers using the KCTP method. With efficient synthesis of polymers possible in a benchtop flow reactor, scale-up of such materials will become straight forward

C–C Bond formation catalyzed by natural gelatin and collagen proteins

• Dennis Kühbeck,
• Basab Bijayi Dhar,
• Eva-Maria Schön,
• Carlos Cativiela,
• Vicente Gotor-Fernández and
• David Díaz Díaz

Beilstein J. Org. Chem. 2013, 9, 1111–1118, doi:10.3762/bjoc.9.123

• influence product yield and kinetics, affording the nitroaldol products in both aqueous and organic media under mild conditions. Significantly, the scale-up of the process between 4-nitrobenzaldehyde and nitromethane is successfully achieved at 1 g scale and in good yield. A comparative kinetic study with

• organic media under mild conditions, affording the nitroaldol product in variable yields depending on the aldehyde and nitroalkane nature. Moreover, the scale-up of the process between 4-nitrobenzaldehyde and nitromethane could also be achieved on a 1 g scale and in good yield. A comparative kinetics

From bead to flask: Synthesis of a complex β-amido-amide for probe-development studies

• Kevin S. Martin,
• Cristian Soldi,
• Kellan N. Candee,
• Hiromi I. Wettersten,
• Robert H. Weiss and
• Jared T. Shaw

Beilstein J. Org. Chem. 2013, 9, 260–264, doi:10.3762/bjoc.9.31

• compounds related to LLW62 was developed on Rink resin as part of a “one-bead, one-compound” combinatorial approach for on-bead screening purposes. The current synthesis is carried out in solution and is amenable to scale-up for follow-up studies on LLW62 and investigations of related structures. The key

Peptoids and polyamines going sweet: Modular synthesis of glycosylated peptoids and polyamines using click chemistry

• Daniel Fürniss,
• Timo Mack,
• Frank Hahn,
• Sidonie B. L. Vollrath,
• Katarzyna Koroniak,
• Ute Schepers and
• Stefan Bräse

Beilstein J. Org. Chem. 2013, 9, 56–63, doi:10.3762/bjoc.9.7

• azide during the scale-up of the reaction but this caused a decrease of the overall reaction yields. In all cases, the test reactions were performed starting from D-glucosamine hydrochloride as a model compound for the synthesis of 1,3,4,6-tetra-O-acetyl-N-azidoacetyl-D-glucosamine (Ac4GlcNAz = 1

Flow photochemistry: Old light through new windows

• Jonathan P. Knowles,
• Luke D. Elliott and
• Kevin I. Booker-Milburn

Beilstein J. Org. Chem. 2012, 8, 2025–2052, doi:10.3762/bjoc.8.229

• , in the lab it is often very difficult to scale up above a few grams in a classic immersion-well reactor (see below). It is perhaps then not surprising that synthetic chemists, as potential first-time users, avoid this medium. This in turn leads to the more fundamental problem: synthetic chemists do

• temperature gave high enantioselectivity. The low productivity of the 100 µL microreactor led the reaction to be transferred to an FEP macroflow reactor for further scale-up, which led to hugely increased productivity. This does, however, demonstrate the utility of microreactors for initial screening of

• reaction conditions prior to scale-up [54]. Later work demonstrated that the reaction could be extended to a number of aldehydes with good yields and high to excellent ee’s [55]. Photocatalysis in microreactors can also be applied to gas-phase reactions. For instance, the titanium dioxide photocatalysed

Efficient electroorganic synthesis of 2,3,6,7,10,11-hexahydroxytriphenylene derivatives

• Carolin Regenbrecht and
• Siegfried R. Waldvogel

Beilstein J. Org. Chem. 2012, 8, 1721–1724, doi:10.3762/bjoc.8.196

• density allows a scale-up of this electroorganic synthesis. Cyclic voltammetry Cyclic voltammetry studies show that triphenylene ketal 2a gets more easily oxidized at lower potentials than subunit 1a (Figure 1). The first reversible process at Eox = 1.22 V corresponds to the oxidation of 2a to a radical

Continuous-flow catalytic asymmetric hydrogenations: Reaction optimization using FTIR inline analysis

• Magnus Rueping,
• Teerawut Bootwicha and
• Erli Sugiono

Beilstein J. Org. Chem. 2012, 8, 300–307, doi:10.3762/bjoc.8.32

• pursued. Microreactor technology offers numerous advantages, including precise control of reaction variables, enhanced mixing quality, improved operational safety, reduced reagent consumption and ready scale-up of chemical processes. Due to the high surface-area-to-volume ratios of microstructured

A general and facile one-pot process of isothiocyanates from amines under aqueous conditions

• Nan Sun,
• Bin Li,
• Jianping Shao,
• Weimin Mo,
• Baoxiang Hu,
• Zhenlu Shen and
• Xinquan Hu

Beilstein J. Org. Chem. 2012, 8, 61–70, doi:10.3762/bjoc.8.6

• particularly for highly electron-deficient substrates. This novel and economical method is suitable for scale-up activities. Keywords: aqueous conditions; cyanuric acid; isothiocyanates; one-pot process; organic synthesis; primary amines; Introduction Isothiocyanates are a class of heteroallenic compounds

• . Moreover, to evaluate the procedure for the potential scaling-up capability, we used aniline as test substrate to scale up the synthesis in 1.0 mol scale. It became clear that the desired phenyl isothiocyanate could be conveniently isolated via vacuum distillation (Table 2, entry 9). This experiment

• wide range of primary alkyl and arylamines into their corresponding isothiocyanates in excellent yields and provides promise for further scale-up activities. Morevover, this method is advantageous over many other methods for the synthesis of highly electron-deficient aromatic isothiocyanates

Recent advances in direct C–H arylation: Methodology, selectivity and mechanism in oxazole series

• Cécile Verrier,
• Pierrik Lassalas,
• Laure Théveau,
• Guy Quéguiner,
• François Trécourt,
• Francis Marsais and
• Christophe Hoarau

Beilstein J. Org. Chem. 2011, 7, 1584–1601, doi:10.3762/bjoc.7.187

• direct arylation of oxazole was further improved for scale-up (Scheme 2) [34]. The C2-magnesation of oxazole was first performed with lithium tributylmagnesate at room temperature, and rapid evolution of the C2-magnesated oxazole to a ring-open isonitrile tautomer was evidenced by 1H NMR spectroscopy

Continuous-flow enantioselective α-aminoxylation of aldehydes catalyzed by a polystyrene-immobilized hydroxyproline

• Xacobe C. Cambeiro,
• Rafael Martín-Rapún,
• Pedro O. Miranda,
• Sonia Sayalero,
• Esther Alza,
• Patricia Llanes and
• Miquel A. Pericàs

Beilstein J. Org. Chem. 2011, 7, 1486–1493, doi:10.3762/bjoc.7.172

• ][58][59][60][61][62][63][64][65][66]. It offers as its main advantages facile automation and excellent heat and mass transfer, rendering the scale-up of a process a trivial task, in contrast with the obstacles always met in the scale-up of batch processes [67][68][69][70][71]. The combination of flow

Efficient syntheses of 25,26-dihydrodictyostatin and 25,26-dihydro-6-epi-dictyostatin, two potent new microtubule-stabilizing agents

• María Jiménez,
• Wei Zhu,
• Andreas Vogt,
• Billy W. Day and
• Dennis P. Curran

Beilstein J. Org. Chem. 2011, 7, 1372–1378, doi:10.3762/bjoc.7.161

• place. The synthesis of each fragment is amenable to scale-up and takes ten steps or less. Ten more steps are needed from the start of fragment coupling to the end of the synthesis, providing the target compounds in about 7–8% overall yield. The intramolecular NHK reaction was successful for the

• minor isomer along with about 75% of the target isomer. The subsequent testing data identify 25,26-dihydrodictyostatin and 25,26-dihydro-6-epi-dictyostatin as candidates for scale-up synthesis and further preclinical development. Structures of dictyostatin and selected analogs varying at C6, C16, and

• dictyostatin SAR. Phillips [25], Ramachandran [26] and Gennari [27] have also developed efficient synthetic routes to the natural product or fully functionalized analogs. Based on the biological profile of over 30 analogs of dictyostatin synthesized in Pittsburgh, we selected 6-epi-dictyostatin (1b) for scale

Triple-channel microreactor for biphasic gas–liquid reactions: Photosensitized oxygenations

• Ram Awatar Maurya,
• Chan Pil Park and
• Dong-Pyo Kim

Beilstein J. Org. Chem. 2011, 7, 1158–1163, doi:10.3762/bjoc.7.134

• interfacial area between the gas and liquid phases is quite small and the ratio of the interfacial area to the volume further decreases with the volume of the reaction mixture. Thus, in scale-up batch reactors the rate of reaction is significantly decreased due to the considerably reduced interfacial-area-to

• (Table 2). To compare the productivity for scale-up synthesis, the space–time yield of the triple-channel microreactor and that of the round bottom flask was calculated at various times during the course of the reaction. The space–time yield data reveals that triple-channel microreactors are quite

Scaling up of continuous-flow, microwave-assisted, organic reactions by varying the size of Pd-functionalized catalytic monoliths

• Ping He,
• Stephen J. Haswell,
• Paul D. I. Fletcher,
• Stephen M. Kelly and
• Andrew Mansfield

Beilstein J. Org. Chem. 2011, 7, 1150–1157, doi:10.3762/bjoc.7.133

• to scale up the rate of product formation without a loss in the intrinsic reaction performance, by using a continuous-flow, microwave-assisted, Pd-supported silica-monolith reactor. The Pd-monolith-3.2 and Pd-monolith-6.4 (both with the same length of 3 cm) were used to perform the model reaction (1

• conversion. This methodology was also used to test Suzuki–Miyaura reactions with a variety of substrates, as shown in Table 3. It can be seen that this scale-up strategy also works very well, with the amount of product obtained with the Pd-monolith-6.4 being four times greater than that obtained with the Pd

• length monolith, the scale-up method as used here, offers the advantage that the pressure drop required to produce a certain flow rate decreases with increasing diameter. However, as microwave penetration is necessary to obtain reliable heating characteristics, there will come a point at which the

Evaluation of a commercial packed bed flow hydrogenator for reaction screening, optimization, and synthesis

• Marian C. Bryan,
• David Wernick,
• Christopher D. Hein,
• James V. Petersen,
• John W. Eschelbach and
• Elizabeth M. Doherty

Beilstein J. Org. Chem. 2011, 7, 1141–1149, doi:10.3762/bjoc.7.132

• H-Cube® and the effect of that dispersion on the reaction outcome [15]. As a result of that study, we generated a predictive correlation between non-steady state and continuous flow scale-up conditions for simple reductions. In this report, using the reduction of styrene to ethylbenzene over 10% Pd

Unusual behavior in the reactivity of 5-substituted-1H-tetrazoles in a resistively heated microreactor

• Bernhard Gutmann,
• Toma N. Glasnov,
• Tahseen Razzaq,
• Walter Goessler,
• Dominique M. Roberge and
• C. Oliver Kappe

Beilstein J. Org. Chem. 2011, 7, 503–517, doi:10.3762/bjoc.7.59

• reaction mixture in a sealed vessel to temperatures far above the boiling point of the solvent under atmospheric conditions. Since batch microwave chemistry is inherently difficult to scale up to production quantities [14][15][16], translating high-speed, high-temperature microwave chemistry to scalable

• toxic but also highly explosive, a scale-up of this batch protocol is clearly not possible. A key advantage of using microreactors compared to conventional batch reactors is the ability to process potentially hazardous compounds or reagents safely [1][2][3][4][5][6][7][8][9][29][30][31][32]. In a

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• significantly lower yields. Another obvious drawback of the initially described route [65] when considering scale up, is the number of sequential steps in the synthesis (8 steps, 21% overall yield) (Scheme 43). Hence an improved synthesis was sought [66]. This revised route utilised a palladium-mediated

Studies on Pd/NiFe₂O₄ catalyzed ligand-free Suzuki reaction in aqueous phase: synthesis of biaryls, terphenyls and polyaryls

• Sanjay R. Borhade and
• Suresh B. Waghmode

Beilstein J. Org. Chem. 2011, 7, 310–319, doi:10.3762/bjoc.7.41

• solvents such as water to make the scale up procedure economical and viable for industrial applications [33][34][35][36][37]. This has led to the use of water soluble ligands, additives and reusable heterogeneous supported Pd catalysts [38][39]. However, the limited availability of water soluble aryl

Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds

• Carolin Fischer and
• Burkhard Koenig

Beilstein J. Org. Chem. 2011, 7, 59–74, doi:10.3762/bjoc.7.10

• ]. Industrial scale-up of these methods has already been applied on the 100 kg scale for arylpiperazines and different diarylamines [21]. In addition, Nolan et al. and Organ et al. have reported Pd-N-heterocyclic carbene (NHC)-catalysed Buchwald–Hartwig amination protocols that provide access to a range of

• dehalogenated by-product to 4% (Scheme 4). The beneficial effect of added water may be due to better dissolution of K3PO4. Scale-up to gram amounts was possible without any significant decrease in yield. The reaction failed with both copper-mediated Ullmann-type reactions and heterogeneous palladium catalysis

• (Scheme 13). The method benefits from controlled regiochemistry and is applicable to various aliphatic and aromatic amines 58. Although the reaction scope was limited to 1-bromo-2-iodobenzenes 59, scale-up to multigram quantities was possible [65]. A key intermediate 64 of imatinib 61, a standard anti

Development of dynamic kinetic resolution on large scale for (±)-1-phenylethylamine

• Lisa K. Thalén and
• Jan-E. Bäckvall

Beilstein J. Org. Chem. 2010, 6, 823–829, doi:10.3762/bjoc.6.97

• screening.a Scale up of dynamic kinetic resolution.a Acknowledgements Financial support from the European FP7 network INTENANT (“Integrated synthesis and purification of single enantiomers”) is gratefully acknowledged. Christine Rösch (née Hoben) is gratefully acknowledged for her contribution to some of the

New amphiphilic glycopolymers by click functionalization of random copolymers – application to the colloidal stabilisation of polymer nanoparticles and their interaction with concanavalin A lectin

• Otman Otman,
• Paul Boullanger,
• Eric Drockenmuller and
• Thierry Hamaide

Beilstein J. Org. Chem. 2010, 6, No. 58, doi:10.3762/bjoc.6.58

• enough to allow scale-up. Thus, we elected to use the simplest carbohydrates, i.e., those which are easy to prepare and easy to handle, e.g., the peracetylated monosaccharide 1 [16]. Although other derivatives, such as the 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetimidoyl mannose might give rise to better

• glycosylation yields, the scale-up of these reactions was shown to be difficult. As a spacer, we chose triethylene glycol. The reaction of 1 with 8-azido-3,6-dioxaoctyloctan-1-ol (prepared in several steps from triethylene glycol) [17] was found to be unsatisfactory since the by-products formed in the reaction

Synthesis of bis(3-{[2-(allyloxy)ethoxy]methyl}-2,4,6-trimethylbenzoyl)(phenyl)phosphine oxide – a tailor-made photoinitiator for dental adhesives

• Norbert Moszner,
• Iris Lamparth,
• Jörg Angermann,
• Urs Karl Fischer,
• Frank Zeuner,
• Thorsten Bock,
• Robert Liska and
• Volker Rheinberger

Beilstein J. Org. Chem. 2010, 6, No. 26, doi:10.3762/bjoc.6.26

• phosphine. These were found to be 3:5, 4:1 or 8:1 by HPLC. Only temperatures higher than 60 °C ensure a fast and complete oxidation of the bisacylphosphine. Finally, different batches of WBAPO were investigated by LC-MS during the scale-up of the synthesis. The results show that a side-chain extended WBAPO

Acid- mediated reactions under microfluidic conditions: A new strategy for practical synthesis of biofunctional natural products

• Katsunori Tanaka and
• Koichi Fukase

Beilstein J. Org. Chem. 2009, 5, No. 40, doi:10.3762/bjoc.5.40

• ; microfluidic reactions can offer a direct and practical route to the desired compounds without the usual scale-up problems associated with mixing efficiency and the temperature control. They can therefore be regarded as one of the new strategies for the practical synthesis, or in favorable cases, the

• reactive sialyl donors having C-5 cyclic imides (Table 1), especially N-phthalimide 1a, by virtue of the “fixed-dipole moment effects” (α-only, 92% on 50 mg scale) [41]. The scale-up in a batch process, however, significantly decreased the yield and selectivity. Thus, a 100 mg scale reaction of 1a gave

Continuous flow based catch and release protocol for the synthesis of α-ketoesters

• Alessandro Palmieri,
• Steven V. Ley,
• Anastasios Polyzos,
• Mark Ladlow and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2009, 5, No. 23, doi:10.3762/bjoc.5.23

• –20 mL/min, and can be configured for multistep or parallel operation. Exiting products can be collected as aliquots using an automated fraction collector for reaction optimisation or as a bulk sample for scale-up. In addition, product purification can be achieved as part of the overall flow process

Asymmetric reactions in continuous flow

• Xiao Yin Mak,
• Paola Laurino and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2009, 5, No. 19, doi:10.3762/bjoc.5.19

• alternatives to the traditional ‘round-bottomed flask’ concept, which is still typically widely used for most chemical reactions [1][2][3][4][5][6][7][8]. Many advantages have been attributed to the use of flow devices, such as improved heat and mass transfer as well as mixing, and also easier scale-up and

• conditions, reliable and consistent stereoselectivities as well as yields can be maintained; scale-up and rapid screening is also facilitated. While many notable examples of asymmetric synthesis using continuous flow technology have been reported, it is certain that many more applications will be developed

A biphasic oxidation of alcohols to aldehydes and ketones using a simplified packed- bed microreactor

• Andrew Bogdan and
• D. Tyler McQuade

Beilstein J. Org. Chem. 2009, 5, No. 17, doi:10.3762/bjoc.5.17

• higher degree of safety [1][2][3][4][5][6][7][8][9][10][11][12]. Alcohol oxidations are well suited for microreactors due to high by-product formation, catalyst contamination and safety concerns often associated with scale-up in batch reactors [13]. Recent developments in microreactor technology and

• run continuously and sampled periodically to monitor its activity. As seen in Figure 3, the activity of the catalyst bed remained high even after hours of use. Furthermore, the work-up of this simplified oxidation scale-up comprised only of phase separation followed by concentration, yielding a white