Continuous flow synthesis of 6-monoamino-6-monodeoxy-β-cyclodextrin

• János Máté Orosz,
• Dóra Ujj,
• Petr Kasal,
• Gábor Benkovics and
• Erika Bálint

Beilstein J. Org. Chem. 2023, 19, 294–302, doi:10.3762/bjoc.19.25

• reduction steps were compatible to be coupled in one flow system obtaining 6-monoamino-6-monodeoxy-β-cyclodextrin in a high yield. Our flow method developed is safer and faster than the batch approaches. Keywords: azidation; continuous flow; β-cyclodextrin; H-cube; 6-monoamino-6-monodeoxy-β-cyclodextrin

• , these two drawbacks are not a problem for large-scale flow synthesis when using an H-Cube system with an incorporated electrolytic cell producing H2 in situ from ultrapure water [47]. The Pd/C catalyst is placed in a stainless steel cartridge, so it is not necessary to separate it from the solution

• time was greatly reduced to only 10 minutes. Continuous flow synthesis of 6A-amino-6A-deoxy-β-CD (4) In the last step of the flow synthesis, the reduction of the N3-β-CD (3) was investigated in an H-Cube Pro® flow hydrogenating reactor containing a 10% Pd/C pre-packed cartridge (Scheme 3). Generally, a

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

• authors screened several other 3D printed reactors evaluating materials (PTFE, PLA or Nylon), volumes (1 or 10 mL), and channel shape (circular, square, or rectangular). The process was then merged with a hydrogenation step using the H-Cube® apparatus (Pd/C, 30 °C, 15 bar) for the continuous preparation

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

A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic

• Marcus Baumann,
• Ian R. Baxendale and
• Fabien Deplante

Beilstein J. Org. Chem. 2017, 13, 2549–2560, doi:10.3762/bjoc.13.251

• contained 0.4 M product 11 which was further diluted with EtOH to furnish a 0.2 M stock solution for use in the next reductive cyclisation step. The reduction was performed using a ThalesNano H-cube system [20][21] operating in full hydrogen mode with a 10 mol % Pd/C catalyst cartridge. At a flow rate of

• process limiting step (Scheme 7). However, several options including commercially available larger scale flow apparatus for performing such flow hydrogenations are available (i.e., H-Cube Mid [38], FlowCAT [39]) [40][41]. However, as intermediate 12 was shown to be a highly stable structure, in practice

• -carboxylate (12) [23]: A 0.2 M solution of compound 11 in a 1:1 mixture of EtOAc/EtOH with 10 mol % AcOH was passed through a ThalesNano H-cube at 1.3 mL/min containing a 10 mol % Pd/C heated at 50 °C and pressurised at 15 bar. The solvent was removed under reduced pressure and the residue triturated with 9

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

• need of repetitive work, which can be transformed to an automated synthesis platform (viz. vapourtec, H-cube, etc.). It is always possible to develop customized automation platforms that suit for specific synthesis and building such avenues using well-established programming tools like Lab View is

• -supported phosphine (20 equiv) as the trapping agent. The imine is further hydrogenated at 25 °C and 20 bar pressure by using an H-cube reactor with 10% Pd/C as a catalyst [72]. Trifluoroacetylation of the amine intermediate is then carried out in a chip reactor with trifluoroacetic anhydride (in DCM) as a

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

• (4.3:1), using the Lindlar catalyst packed into a commercial H-Cube® apparatus under mild hydrogenation conditions (298 K, 10 bar H2, Table 1, entry 21). 1,1-Diphenyl-2-propyn-1-ol High yields of alkene 6a were obtained by partial hydrogenation of 1,1-diphenyl-2-propyn-1-ol (6) using the monolithic Pd

Continuous-flow synthesis of primary amines: Metal-free reduction of aliphatic and aromatic nitro derivatives with trichlorosilane

• Riccardo Porta,
• Alessandra Puglisi,
• Giacomo Colombo,
• Sergio Rossi and
• Maurizio Benaglia

Beilstein J. Org. Chem. 2016, 12, 2614–2619, doi:10.3762/bjoc.12.257

• conditions. Typically, the transformation of nitro compounds to amines under continuous-flow conditions is performed through the metal-catalyzed hydrogenation [21][22][23] with ThalesNano H-Cube®, which exploits H2 generated in situ by water electrolysis [24]. The procedure involves relatively mild reaction

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

• allowing safe and efficient use of gaseous reagents as well as more effective ways of quickly transitioning between very low and very high temperatures that are key for streamlining modern flow synthesis routes. Although the widely used H-Cube system had provided a popular solution for safe and convenient

Integration of enabling methods for the automated flow preparation of piperazine-2-carboxamide

• Richard J. Ingham,
• Claudio Battilocchio,
• Joel M. Hawkins and
• Steven V. Ley

Beilstein J. Org. Chem. 2014, 10, 641–652, doi:10.3762/bjoc.10.56

• purity as determined by elemental analysis (>98%). Pyrazine ring reduction An initial investigation showed that this aromatic carboxamide could be efficiently reduced using an H-Cube® reactor [27][28]. There has been recent interest in the use of automation to optimise reaction conditions [29][30][31

• ], and thus we hoped to use a linear programming method [32][33] in a similar way to iteratively improve the hydrogenation settings. This turned out to be impractical for two reasons: the flow rate, dead volume, and stabilisation time required for the H-Cube to reach steady state meant that each

• , we decided to use an automated system to perform these experiments in order to reduce the amount of operator’s time that is required. Combining the control of a Knauer HPLC pump, the H-Cube® reactor and a multi-position valve (V2) (Figure 8, Figure 9) we could perform up to nine reactions in a row. A

Flow synthesis of a versatile fructosamine mimic and quenching studies of a fructose transport probe

• Matthew B. Plutschack,
• D. Tyler McQuade,
• Giulio Valenti and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2013, 9, 2022–2027, doi:10.3762/bjoc.9.238

• byproducts from a water soluble product. Thus, we obtained crude 2 by simple work up: neutralization, concentration, precipitation of salts using tetrahydrofuran, filtration, concentration and dissolution in 10:1 ethanol/acetic acid. This solution was converted to amine 3 using an H-Cube (commercially

• of compound 3 because the throughput drops down to only 2-fold enhancement relative to batch. We predict that this throughput could be significantly improved if the wider range of catalysts were screened. The fructose analog probe NBDM was then produced by combining the concentrated output from the H

• -Cube in saturated sodium bicarbonate (0.4 M) with a 0.4 M solution of NBD-Cl. This step can be conducted in flow as well as in batch with no significant difference in yield or productivity. The low yield (20–30%) of NBDM may be the result of competitive reactivity between the NBD-Cl and the hydroxy

Efficient continuous-flow synthesis of novel 1,2,3-triazole-substituted β-aminocyclohexanecarboxylic acid derivatives with gram-scale production

• Sándor B. Ötvös,
• Ádám Georgiádes,
• István M. Mándity,
• Lóránd Kiss and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2013, 9, 1508–1516, doi:10.3762/bjoc.9.172

• soaking in solutions of trace-metal-grade nitric acid and hydrochloric acid (Suprapur, Merck), followed by rinsing with copious amounts of doubly deionized water. General procedure for the CF reactions An H-Cube® system was used as a CF reactor in the “no H2” mode. For the CF reactions, the catalyst bed

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

• the ThalesNano H-Cube®, a commercial packed bed flow hydrogenator, was evaluated in the context of small scale reaction screening and optimization. A model reaction, the reduction of styrene to ethylbenzene through a 10% Pd/C catalyst bed, was used to examine performance at various pressure settings

• run-to-run reproducibility of the H-Cube® reactor for screening and reaction optimization is discussed. Keywords: catalyst leaching; CatCart®; H-Cube®; packed bed flow hydrogenation; Introduction The potential advantages of heterogeneous catalytic flow hydrogenation over traditional batch reactor

• a convenient bench-top hydrogen flow reactor, the H-Cube®, designed for smaller-scale use in academic and drug discovery labs [6]. The reactor features a built-in hydrogen generator that functions by the electrolysis of water. Disposable pre-packed catalyst cartridges (CatCart®) are also available

Fused bicyclic piperidines and dihydropyridines by dearomatising cyclisation of the enolates of nicotinyl-substituted esters and ketones

• Heloise Brice,
• Jonathan Clayden and
• Stuart D. Hamilton

Beilstein J. Org. Chem. 2010, 6, No. 22, doi:10.3762/bjoc.6.22

• obtained by the use of an H-cube flow hydrogenation apparatus at 40 bar and 30 °C. Unfortunately, again the lack of crystallinity and the large number of overlapping signals in the 1H NMR spectrum frustrated an unequivocal assignment of the stereochemistry. However, hydrogenation of related fused