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

Scalable synthesis of 5,11-diethynylated indeno[1,2-b]fluorene-6,12-diones and exploration of their solid state packing

• Bradley D. Rose,
• Peter J. Santa Maria,
• Aaron G. Fix,
• Chris L. Vonnegut,
• Lev N. Zakharov,
• Sean R. Parkin and
• Michael M. Haley

Beilstein J. Org. Chem. 2014, 10, 2122–2130, doi:10.3762/bjoc.10.219

• ) the formation of 10 was very sensitive to the reaction conditions and thus typically gave low yields (approx. 10%) upon scale-up; (2) the reaction must be run in very dilute solution to minimize the formation of larger cyclooligomers as well as polymer; (3) pure 10 in the solid state is reported to be

Synthesis of rigid p-terphenyl-linked carbohydrate mimetics

• Maja Kandziora and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 1749–1758, doi:10.3762/bjoc.10.182

• conditions providing diol 8 in excellent yield in multigram scale (up to 20 g). Attention should be paid to a possible reductive removal of the bromine substituent that can occur at higher temperature or longer reaction times as the resulting debrominated product is hard to remove from diol 8 by column

The chemoenzymatic synthesis of clofarabine and related 2′-deoxyfluoroarabinosyl nucleosides: the electronic and stereochemical factors determining substrate recognition by E. coli nucleoside phosphorylases

• Ilja V. Fateev,
• Konstantin V. Antonov,
• Irina D. Konstantinova,
• Tatyana I. Muravyova,
• Frank Seela,
• Roman S. Esipov,
• Anatoly I. Miroshnikov and
• Igor A. Mikhailopulo

Beilstein J. Org. Chem. 2014, 10, 1657–1669, doi:10.3762/bjoc.10.173

• to a high stability of the α-phosphate 12a under the studied reaction conditions. On the other hand, the extremely poor solubility of 2-chloroadenine in water (ca. 70 mg in 1.0 L at 50 °C) did not allow to scale up the synthesis, and based on an experiment on a milligram scale clofarabine was

Nonanebis(peroxoic acid): a stable peracid for oxidative bromination of aminoanthracene-9,10-dione

• Vilas Venunath Patil and
• Ganapati Subray Shankarling

Beilstein J. Org. Chem. 2014, 10, 921–928, doi:10.3762/bjoc.10.90

• with hexane/ethyl acetate (95:5) as an eluent to give purified product 2. Scale-up study The reaction of 1-aminoanthracene-9,10-dione with KBr in acetic acid and nonanebis(peroxoic acid) as an oxidant was scaled-up to 10 g to understand the functioning of the method on a larger scale. The reaction

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

• material wasted during start up and shutdown of the first step can be reduced. We anticipate that the potential to rapidly realise complex control sequences such as these will further broaden the scope for the use of flow chemistry reactors in both the research and scale-up environments. We hope that the

Preparation of new alkyne-modified ansamitocins by mutasynthesis

• Kirsten Harmrolfs,
• Lena Mancuso,
• Binia Drung,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2014, 10, 535–543, doi:10.3762/bjoc.10.49

• and MS experiments clearly showed common patterns for ansamitocins. Additionally, the isotopic pattern provided evidence for the incorporation of the bromo functionality (see Supporting Information File 1). However, yields for each of the four ansamitocins were too small for practical scale-up. To

• patterns and isotopic composition in the MS. Bromo-ansamitocin derivatives 22a, 22c and 22e were isolated after scale up to a 1000 mL culture broth. Structures, expected from HRMS analysis, were corroborated by NMR spectroscopy. Yields were determined to be in the low mg/L range or 0.01% yield based on

Direct and indirect single electron transfer (SET)-photochemical approaches for the preparation of novel phthalimide and naphthalimide-based lariat-type crown ethers

• Dae Won Cho,
• Patrick S. Mariano and
• Ung Chan Yoon

Beilstein J. Org. Chem. 2014, 10, 514–527, doi:10.3762/bjoc.10.47

• limited by scale up issues. However, several features of the currently described SET promoted excited state reactions make them suitable for applications in unique situations, especially when the processes require a high degree of temporal and spatial control. α-Heterolytic cleavage in ion radicals

Synthesis and stereochemical assignments of diastereomeric Ni(II) complexes of glycine Schiff base with (R)-2-(N-{2-[N-alkyl-N-(1-phenylethyl)amino]acetyl}amino)benzophenone; a case of configurationally stable stereogenic nitrogen

• Hiroki Moriwaki,
• Daniel Resch,
• Hengguang Li,
• Iwao Ojima,
• Ryosuke Takeda,
• José Luis Aceña and
• Vadim A. Soloshonok

Beilstein J. Org. Chem. 2014, 10, 442–448, doi:10.3762/bjoc.10.41

• commercial application of chiral complex 1 is rather limited. The major shortcomings of compound 1 are: problematic scale up of its synthesis, partial racemization of the N-(benzyl)proline moiety and undesirable stereochemical outcomes. To overcome these deficiencies we initiated a project aiming to design a

Continuous flow nitration in miniaturized devices

• Amol A. Kulkarni

Beilstein J. Org. Chem. 2014, 10, 405–424, doi:10.3762/bjoc.10.38

• presented herein and discussed in view of their advantages, limitations and applicability of the information towards scale-up. Selected recent patents that disclose scale-up methodologies for continuous flow nitration are also briefly reviewed. Keywords: continuous flow; flow chemistry; nitration; nitric

• an easy scale-up include: (i) an inadequate heat transfer area (20–100 m2/m3), (ii) an inhomogeneous system, mainly due to immiscible substrates and inefficient mixing, leading to mass transfer limitations, (iii) batch to batch variation in the degree of conversion, yield and selectivity, (iv

• features of this report are: (a) a thorough overview on continuous flow nitrations, (b) a discussion on general issues that have to be considered when conducting continuous nitrations, (c) how data from individual reactions are collected and analyzed in order to devise scale-up or numbering-up processes or

Practical synthesis of aryl-2-methyl-3-butyn-2-ols from aryl bromides via conventional and decarboxylative copper-free Sonogashira coupling reactions

• Andrea Caporale,
• Stefano Tartaggia,
• Andrea Castellin and
• Ottorino De Lucchi

Beilstein J. Org. Chem. 2014, 10, 384–393, doi:10.3762/bjoc.10.36

• generality of this protocol. It is also worth noting that these conditions are also highly practical and well suited to scale-up the reaction, since inexpensive 4 can be efficiently coupled with aryl bromides instead of iodides by using common solvents and ligands for the palladium catalyst. The copper-free

Synthesis of five- and six-membered cyclic organic peroxides: Key transformations into peroxide ring-retaining products

• Alexander O. Terent'ev,
• Dmitry A. Borisov,
• Vera A. Vil’ and
• Valery M. Dembitsky

Beilstein J. Org. Chem. 2014, 10, 34–114, doi:10.3762/bjoc.10.6

• on synthesis of cyclic peroxides. The indicated period of time is, on the whole, characterized by the development of new efficient and scale-up methods for the preparation of these cyclic compounds. It was shown that cyclic peroxides remain unchanged throughout the course of a wide range of

Continuous-flow Heck synthesis of 4-methoxybiphenyl and methyl 4-methoxycinnamate in supercritical carbon dioxide expanded solvent solutions

• Phei Li Lau,
• Ray W. K. Allen and
• Peter Styring

Beilstein J. Org. Chem. 2013, 9, 2886–2897, doi:10.3762/bjoc.9.325

• . It is clear that within experimental error that the TOFs in the two reactor configurations are essentially identical which is encouraging in terms of the ability to both scale up and scale out the reactions. The TOF is defined as the number of moles of substrate converted per mol of catalyst per unit

Flow microreactor synthesis in organo-fluorine chemistry

• Hideki Amii,
• Aiichiro Nagaki and
• Jun-ichi Yoshida

Beilstein J. Org. Chem. 2013, 9, 2793–2802, doi:10.3762/bjoc.9.314

• inert plastic flow tubes provided flexibility, scale-up production, and improved safety of operation. Using flow chemistry, the conversion of alcohols to fluorides was achieved by Seeberger and Ley, independently (Scheme 2) [44][45][46][47]. Usually, gem-difluorination of ketones by DAST is known to be

• , 3) improved product selectivity (yield and purity), 4) rapid removal of heat of reaction for increased process safety, 5) ease of scale-up from lab to plant scale, and so on. The reaction times are governed by the residence times (concerning path lengths and flow rates) inside flow microreactor

Multigramme synthesis and asymmetric dihydroxylation of a 4-fluorobut-2E-enoate

• James A. B. Laurenson,
• John A. Parkinson,
• Jonathan M. Percy,
• Giuseppe Rinaudo and
• Ricard Roig

Beilstein J. Org. Chem. 2013, 9, 2660–2668, doi:10.3762/bjoc.9.301

• acceptable level of purity (>95% by 1H NMR) and reproducibly on a large scale (up to ~200 mmol). These outcomes represent significant practical improvements on the published methods of preparation. The subsequent transformations were carried out on the n-propyl ester 25 for two reasons; firstly, the material