Electron-transfer-initiated benzoin- and Stetter-like reactions in packed-bed reactors for process intensification

• Anna Zaghi,
• Daniele Ragno,
• Graziano Di Carmine,
• Carmela De Risi,
• Olga Bortolini,
• Pier Paolo Giovannini,
• Giancarlo Fantin and
• Alessandro Massi

Beilstein J. Org. Chem. 2016, 12, 2719–2730, doi:10.3762/bjoc.12.268

• homogeneous NHCs [13][14]. On the other hand, heterogeneous catalysis in microstructured flow reactors represents a robust synthetic platform, with benefits over the corresponding batch processes such as catalyst stability, lower degradation of supports, and ease of scale-up with minimal changes to the

• -supported base. Together with the ease of product/promoter separation, an important benefit of the flow regime has been the significant long-term stability of the packing bed (ca. 5 five days on streams). Small-scale reactors have been described in this work; nevertheless, an easy scale-up of the disclosed

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

• . Flow chemistry has recently emerged as a powerful technology in synthetic chemistry [12] as it can reduce risks associated to the use of hazardous chemicals and favors reaction scale-up [13][14][15][16][17]. The possibility to efficiently perform nitro reduction in continuo would make the

• transformation safer and more appealing in view of an industrial application and a possible scale-up of the process [18][19][20]. Herein we report a very convenient, metal-free reduction of both aromatic and aliphatic nitro derivatives, including chiral compounds, to amines with HSiCl3 under continuous-flow

• the reaction (the first few hours). Having demonstrated that the flow transformation is very fast we next explored reaction scale-up employing a bigger flow reactor (5 mL PTFE reactor, i.d. = 2.54 mm, l = 100 cm), in order to increase the productivity of the process. Using the same reaction set-up

Development of a continuous process for α-thio-β-chloroacrylamide synthesis with enhanced control of a cascade transformation

• Olga C. Dennehy,
• Valérie M. Y. Cacheux,
• Benjamin J. Deadman,
• Denis Lynch,
• Stuart G. Collins,
• Humphrey A. Moynihan and
• Anita R. Maguire

Beilstein J. Org. Chem. 2016, 12, 2511–2522, doi:10.3762/bjoc.12.246

• into an oil bath at 90 °C (Scheme 2). While this route has consistently provided a robust means of generating the desired β-chloroacrylamides at scales of 1–10 g, it suffers from several disadvantages which impact on the ease of scale-up. The preparation of the α-chloroamide 1 is exothermic and

• requires significant external cooling, an undesirable feature for scale-up. The synthesis of the α-thioamide 2 involves prior generation of fresh sodium ethoxide from sodium metal. Furthermore, this α-thioamide protocol, at high pH, ordinarily does not go to completion, leaving unreacted starting material

• efficient rapid heating poses practical difficulties for scale-up and, furthermore, chromatographic separation is required to remove product impurities. The nature of the aforementioned difficulties outlined are, however, largely specific to the scale-up of batch chemistry. A continuous processing approach

Facile synthesis of indolo[3,2-a]carbazoles via Pd-catalyzed twofold oxidative cyclization

• Chao Yang,
• Kai Lin,
• Lan Huang,
• Wei-dong Pan and
• Sheng Liu

Beilstein J. Org. Chem. 2016, 12, 2490–2494, doi:10.3762/bjoc.12.243

• sequence to deliver 9-methoxycarbonyl indolo[3,2-a]carbazole derivatives. Previous literature aimed at providing rapid and efficient access to indolo[3,2-a]carbazoles, however, most of them have some disadvantages. Few methods were reported to be suitable for scale-up preparation and the introduction of

• material and the product may occur. To examine whether the desired transformation was suitable for scale-up, a gram-scale synthesis of 2a was also achieved (Table 1, entry 9). With the optimized conditions in hand, the generality and scope of the reaction were also examined (Scheme 3). A range of

Efficient mechanochemical synthesis of regioselective persubstituted cyclodextrins

• Laszlo Jicsinszky,
• Marina Caporaso,
• Katia Martina,
• Emanuela Calcio Gaudino and
• Giancarlo Cravotto

Beilstein J. Org. Chem. 2016, 12, 2364–2371, doi:10.3762/bjoc.12.230

• conditions nor the purifications were optimized in any terms the presented results can serve as starting point to develop more environmentally benign synthetic methods of important CD derivatives. The well-established engineering of HEBM reactions makes them easy to scale-up, while simplified work-up

• removal found in the small scale, as it becomes clear in the scale-up experiments (entries 4 and 11 in Table 1). Although the preparation of 6I-monoazido-6I-monodeoxy-β-CD [22] was very effective, the analogue reactions with per-6-substituted CDs (4a and 4b) were less efficient. Either the reaction did

• needed to get less deficit in the precipitates. Considerable losses during filtrations were found in the small-scale cases, which significantly reduced the yields because of the inevitably used diluted solutions. The ten-fold scale up (entry 28 in Table 1) further simplified the product isolation because

High performance p-type molecular electron donors for OPV applications via alkylthiophene catenation chromophore extension

• Paul B. Geraghty,
• Calvin Lee,
• Jegadesan Subbiah,
• Wallace W. H. Wong,
• James L. Banal,
• Mohammed A. Jameel,
• Trevor A. Smith and
• David J. Jones

Beilstein J. Org. Chem. 2016, 12, 2298–2314, doi:10.3762/bjoc.12.223

• active layer up to 310 nm thick. In this case fill-factors (FF) remain above 70%. However, OSC devices containing BTR are not stable to thermal annealing, a requirement for scale up using common printing processes, where temperatures >80 °C are required for drying or annealing of printed layers [15]. BTR

• has extremely interesting properties worth further study and leads to three key questions; Synthesis: Can we simplify the synthesis of BTR removing some chromatographic purification steps and use of toxic tin containing Stille condensation reactions? Scale-up: Can we develop a multi-gram synthesis

Economical and scalable synthesis of 6-amino-2-cyanobenzothiazole

• Jacob R. Hauser,
• Hester A. Beard,
• Mary E. Bayana,
• Katherine E. Jolley,
• Stuart L. Warriner and
• Robin S. Bon

Beilstein J. Org. Chem. 2016, 12, 2019–2025, doi:10.3762/bjoc.12.189

• ), which has an amine handle for straight-forward derivatisation. Here we present an economical and scalable synthesis of ACBT based on a cyanation catalysed by 1,4-diazabicyclo[2.2.2]octane (DABCO), and discuss its advantages for scale-up over previously reported routes. Keywords: ACBT; cyanation; 2

• variable yields (typically 30–50% in our hands). In addition, because DMSO can quickly penetrate the skin, working with KCN in DMSO requires substantial safety measures. Therefore, this route does not allow straightforward scale-up under laboratory conditions. Prescher and co-workers reported an

• . In view of scale-up of the DABCO-catalysed cyanation of 6, an alternative solvent (mixture) was sought in order to eliminate safety issues and work-up problems resulting from the use of DMSO. An initial attempt to run the reaction in water failed because of the low aqueous solubility of 6 – resulting

The in situ generation and reactive quench of diazonium compounds in the synthesis of azo compounds in microreactors

• Faith M. Akwi and
• Paul Watts

Beilstein J. Org. Chem. 2016, 12, 1987–2004, doi:10.3762/bjoc.12.186

• reaction conversions ranging between 66–91% were attained. Keywords: azo coupling; diazotization; microreactor; scale up; Introduction Going green, a familiar catch phrase in the chemical industry, in addition to environment protection laws have influenced and also triggered the development of cleaner

• investigative research involving the synthesis of two azo pigments (yellow and red pigments) in microreactors [24], demonstrated that scaling out in the microreactors provided better and more consistent quality of the pigments as compared to scale up in the batch vessels. Similarly, yellow pigment 12 (15) was

• reaction. In addition, industry always questions why reactions are done in micro structured reactors rather than simple tubular reactors. As such, we extended this investigation to study the optimized conditions obtained within the LTF microreactors within PTFE tubing (i.d. 1.5 mm) in order to scale up the

Catalytic Chan–Lam coupling using a ‘tube-in-tube’ reactor to deliver molecular oxygen as an oxidant

• Carl J. Mallia,
• Paul M. Burton,
• Alexander M. R. Smith,
• Gary C. Walter and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2016, 12, 1598–1607, doi:10.3762/bjoc.12.156

• characteristic NOESY signal encircled. Substrates that gave no products in flow. Comparison of early C–N and C–O coupling reactions. Scope of the catalytic Chan–Lam reaction in continuous flow. Syntheses of substrate 39. Scale-up procedure for 19. Optimisation of the Chan–Lam reaction in continuous flow

Flow carbonylation of sterically hindered ortho-substituted iodoarenes

• Carl J. Mallia,
• Gary C. Walter and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2016, 12, 1503–1511, doi:10.3762/bjoc.12.147

• smaller when larger volume flasks are used as in scale up procedures making the mass transfer even less efficient. In contrast, high interfacial areas can be achieved in flow reactors especially microchannel reactors (a = 3400–18000 m2 m−3) [30], which increases the mass transfer and thus helps solubilise

• turnaround time is much longer. This makes the flow reactor more efficient in terms of processing time. Additionally, the added safety and potential benefits regarding scale up associated with the flow reactor makes this even more favourable. Having identified a set of reaction conditions for successful

• of ortho-substituted substrates giving moderate to good yields. Comparison of 22 with 32 also showed that the steric encumbrance on the ortho position has an effect on the yield even when other electronic effects are in place such as those coming from the additional aromatic ring attached. A scale-up

Asymmetric α-amination of 3-substituted oxindoles using chiral bifunctional phosphine catalysts

• Qiao-Wen Jin,
• Zhuo Chai,
• You-Ming Huang,
• Gang Zou and
• Gang Zhao

Beilstein J. Org. Chem. 2016, 12, 725–731, doi:10.3762/bjoc.12.72

• -substituent was changed to an alkyl group (Table 3, entry 18). Subsequently, a scale-up experiment on 1.0 mmol scale of the reaction was examined, and the corresponding product could be obtained smoothly with a slightly reduced yield (70%) and ee (85%). The ee value of the product could be raised to 96% after

• spectra research in CD2Cl2. The mimetic activation mode of Mitsunobu reaction. Scale-up of the reaction and deprotection of the product. Proposed transition-state model. Catalyst screening. Optimization of conditions. Substrate scope. Supporting Information Supporting Information File 32: Experimental

Three new trixane glycosides obtained from the leaves of Jungia sellowii Less. using centrifugal partition chromatography

• Luíse Azevedo,
• Larissa Faqueti,
• Marina Kritsanida,
• Antonia Efstathiou,
• Despina Smirlis,
• Gilberto C. Franchi Jr,
• Grégory Genta-Jouve,
• Sylvie Michel,
• Louis P. Sandjo,
• Raphaël Grougnet and
• Maique W. Biavatti

Beilstein J. Org. Chem. 2016, 12, 674–683, doi:10.3762/bjoc.12.68

• technique for the investigation of polar extracts. Moreover, the commercial availability of industrial instruments enables scale-up to batch production for high-scale isolation. The CPC technique turned to be a versatile analytical tool leading to the purification and identification of new glycosylated

New synthetic strategies for xanthene-dye-appended cyclodextrins

• Milo Malanga,
• Andras Darcsi,
• Mihaly Balint,
• Gabor Benkovics,
• Tamas Sohajda and
• Szabolcs Beni

Beilstein J. Org. Chem. 2016, 12, 537–548, doi:10.3762/bjoc.12.53

• dyes and coupling agents, thus having clear potential for multigram scale-up. The mild, aqueous conditions, as well as the simplicity of the synthesis, make these reactions attractive tools for the preparation of fluorescent cyclodextrins connected through an amide bond. The obtained products were

Enabling technologies and green processes in cyclodextrin chemistry

• Giancarlo Cravotto,
• Marina Caporaso,
• Laszlo Jicsinszky and
• Katia Martina

Beilstein J. Org. Chem. 2016, 12, 278–294, doi:10.3762/bjoc.12.30

• technology can exploit a liquid milling medium. The preparation of CD and other complexes with the aid of ball milling is well-known [82][83]. In spite of an easy scale-up of this technology, some disadvantages might occur: metastable crystalline complexes can recrystallize to an equilibrium state upon

A quadruple cascade protocol for the one-pot synthesis of fully-substituted hexahydroisoindolinones from simple substrates

• Hong-Bo Zhang,
• Yong-Chun Luo,
• Xiu-Qin Hu,
• Yong-Min Liang and
• Peng-Fei Xu

Beilstein J. Org. Chem. 2016, 12, 253–259, doi:10.3762/bjoc.12.27

• [65]. However, substrates with aliphatic R1, R2 or R3 did not produce the desired products (Table 2, entries 21–26). This bifunctional catalysis cascade reaction was also amenable to scale-up. When the reaction was carried out on a 3 mmol scale, the desired product was obtained in 84% yield. Therefore

Catalytic asymmetric formal synthesis of beraprost

• Yusuke Kobayashi,
• Ryuta Kuramoto and
• Yoshiji Takemoto

Beilstein J. Org. Chem. 2015, 11, 2654–2660, doi:10.3762/bjoc.11.285

• improved to 85% ee while maintaining the high reactivity. Employing catalyst E we further investigated the reaction conditions and found that a scale-up synthesis can be performed using only 1 mol % of E with no loss of enantioselectivity, although gentle heating was required to ensure a high chemical

• exchange and subsequent addition to methyl 4-oxobutanoate was found to be the best method to introduce the C4 subunit with reproducibility in the case of scale-up synthesis. Deprotection of the resultant ester 23 followed by reduction of the benzylic OH group finally afforded the key intermediate 2

Continuous formation of N-chloro-N,N-dialkylamine solutions in well-mixed meso-scale flow reactors

• A. John Blacker and
• Katherine E. Jolley

Beilstein J. Org. Chem. 2015, 11, 2408–2417, doi:10.3762/bjoc.11.262

• phase separation into alternating organic–aqueous segmented flow; whilst meso-scale reactors are much better suited, and provide more accurate and reliable information for scale-up. Interaction of the reactants occurs only at the phase interface, so efficient mixing increases the surface area and

Efficient synthetic protocols for the preparation of common N-heterocyclic carbene precursors

• Morgan Hans,
• Jan Lorkowski,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2015, 11, 2318–2325, doi:10.3762/bjoc.11.252

• solvent and hinders scale up. Synthesis of 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride In most cases, experimental procedures leading to 1,3-dimesitylimidazolinium salts could be successfully extended to their 1,3-bis(2,6-diisopropylphenyl) counterparts without any adaptation. Thus, the three

• laboratories and do not require any particular skills from the experimenter. Furthermore, the detailed experimental procedures supplied in Supporting Information File 1 of this article are easy to scale up or down according to the particular needs for a given compound. Thus, we hope that they will be helpful

Investigation on the reactivity of α-azidochalcones with carboxylic acids: Formation of α-amido-1,3-diketones and highly substituted 2-(trifluoromethyl)oxazoles

• Kandasamy Rajaguru,
• Arumugam Mariappan,
• Rajendran Suresh,
• Periasamy Manivannan and
• Shanmugam Muthusubramanian

Beilstein J. Org. Chem. 2015, 11, 2021–2028, doi:10.3762/bjoc.11.219

• /ethyl acetate mixture (7:3) as the eluent. After the reaction was cooled to room temperature ice-cold water was added. The precipitate obtained was filtered, dried in vacuum and recrystallized from ethanol to afford 3. Representative scale-up example for the synthesis of 3e using the 80 mL vessel: In an

• completion of the reaction, the mass was treated with ice cold saturated solution of sodium bicarbonate and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated in vacuo to afford oxazole 8. Representative scale-up example for the synthesis

Dicarboxylic esters: Useful tools for the biocatalyzed synthesis of hybrid compounds and polymers

• Ivan Bassanini,
• Karl Hult and
• Sergio Riva

Beilstein J. Org. Chem. 2015, 11, 1583–1595, doi:10.3762/bjoc.11.174

• traditional polymerization methods [52]. Binns et al. summarized the attempts to scale up synthesis of polyesters by enzyme catalyzed polycondensation of adipic acid and hexane-1,6-diol in a very well-worth reading article [53]. They discussed the very slow progress in achieving high molecular weight polymers

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

• scale-up campaign were found to be related to safety, isolated purity and economics. The successful outcome of the above study can in part be ascribed to the use of a static mixing device which allowed for the selective and clean mono-deprotonation under scale-up conditions. This was in stark contrast

• chemistry is an increase in reproducibility this seems a rather negative trend. In 2012 researchers from AstraZeneca (Sweden) reported upon a scale-up campaign for their gastroesophageal reflux inhibitor programme. Specifically, flow chemical synthesis was used to efficiently and reliably provide sufficient

• worked well. As seen above, avoiding detrimental exotherms in scale up campaigns is a common reason for developing a continuous flow process. This approach is also demonstrated in the synthesis of the pyrrolotriazinone 73 via a exothermic oxidative rearrangement from 75, a key intermediate towards

Advances in the synthesis of functionalised pyrrolotetrathiafulvalenes

• Luke J. O’Driscoll,
• Sissel S. Andersen,
• Marta V. Solano,
• Dan Bendixen,
• Morten Jensen,
• Troels Duedal,
• Jess Lycoops,
• Cornelia van der Pol,
• Rebecca E. Sørensen,
• Karina R. Larsen,
• Kenneth Myntman,
• Christian Henriksen,
• Stinne W. Hansen and
• Jan O. Jeppesen

Beilstein J. Org. Chem. 2015, 11, 1112–1122, doi:10.3762/bjoc.11.125

• sodium borohydride and lithium bromide to 40 g scale, obtaining diol 11 with only a small reduction in yield (77% vs 85% at 15 g scale [33]). Compound 11 is then treated with phosphorus tribromide to afford dibromide 12. The scale up of this reaction to 36 g scale also results in a lower, but still

Aspergiloid I, an unprecedented spirolactone norditerpenoid from the plant-derived endophytic fungus Aspergillus sp. YXf3

• Zhi Kai Guo,
• Rong Wang,
• Wei Huang,
• Xiao Nian Li,
• Rong Jiang,
• Ren Xiang Tan and
• Hui Ming Ge

Beilstein J. Org. Chem. 2014, 10, 2677–2682, doi:10.3762/bjoc.10.282

• perform more biological assays for this unusual norditerpenoid, further scale-up isolation is in progress. Experimental General experimental procedures The melting point was measured on a Beijing Taike X-5 stage apparatus and reported without correction. The optical rotation was recorded using a Rudolph

Electrocarboxylation: towards sustainable and efficient synthesis of valuable carboxylic acids

• Roman Matthessen,
• Jan Fransaer,
• Koen Binnemans and
• Dirk E. De Vos

Beilstein J. Org. Chem. 2014, 10, 2484–2500, doi:10.3762/bjoc.10.260

• ]. Besides carbonyl compounds, imines have also shown value as substrates for electrocarboxylation, namely in the synthesis of non-natural amino acids [102][103][104][105][106][107][108]. A semi-industrial setup was designed for the electrocarboxylation of benzalaniline (Scheme 14). Scale up was done in a

Synthesis and immunological evaluation of protein conjugates of Neisseria meningitidis X capsular polysaccharide fragments

• Laura Morelli,
• Damiano Cancogni,
• Marta Tontini,
• Alberto Nilo,
• Sara Filippini,
• Paolo Costantino,
• Maria Rosaria Romano,
• Francesco Berti,
• Roberto Adamo and
• Luigi Lay

Beilstein J. Org. Chem. 2014, 10, 2367–2376, doi:10.3762/bjoc.10.247

• approaches are improved safety characteristics, enhanced rates of heat and mass transfer, simplicity and robustness in scale-up and easiness in handling the instrumentation [30][31][32][33]. For the synthesis of compound 7, two distinct solutions containing the hemiacetal 6 in pyridine and