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

Recent advances in transition metal-catalyzed Csp²-monofluoro-, difluoro-, perfluoromethylation and trifluoromethylthiolation

• Grégory Landelle,
• Armen Panossian,
• Sergiy Pazenok,
• Jean-Pierre Vors and
• Frédéric R. Leroux

Beilstein J. Org. Chem. 2013, 9, 2476–2536, doi:10.3762/bjoc.9.287

Synthesis of homo- and heteromultivalent carbohydrate-functionalized oligo(amidoamines) using novel glyco-building blocks

• Felix Wojcik,
• Sinaida Lel,
• Alexander G. O’Brien,
• Peter H. Seeberger and
• Laura Hartmann

Beilstein J. Org. Chem. 2013, 9, 2395–2403, doi:10.3762/bjoc.9.276

• photoreactor was developed involving post functionalization of alkene presenting oligomers by thioglycosides [26]. The flow system allows for precise control over the reaction conditions, is easy to scale up and provides efficient irradiation of the samples by virtue of a sub-millimeter path length. Continuous

One-pot sequential synthesis of isocyanates and urea derivatives via a microwave-assisted Staudinger–aza-Wittig reaction

• Diego Carnaroglio,
• Katia Martina,
• Giovanni Palmisano,
• Andrea Penoni,
• Claudia Domini and
• Giancarlo Cravotto

Beilstein J. Org. Chem. 2013, 9, 2378–2386, doi:10.3762/bjoc.9.274

• been optimized under microwave irradiation and the scale-up experiment has been conducted under conventional conditions in a Parr reactor. The final compounds were isolated after simple filtration in almost quantitative overall yields which makes this procedure facile and rapid to execute. Keywords

• a one-pot, sequential synthesis of urea derivatives from alkyl bromides. With the aim to verify the feasibility of the method under conventional heating, the protocol was tested in a Parr reactor (90 mL) for an easier scale-up. Results and Discussion The Staudinger–aza-Wittig reaction is extremely

Micro-flow synthesis and structural analysis of sterically crowded diimine ligands with five aryl rings

• Shinichiro Fuse,
• Nobutake Tanabe,
• Akio Tannna,
• Yohei Konishi and
• Takashi Takahashi

Beilstein J. Org. Chem. 2013, 9, 2336–2343, doi:10.3762/bjoc.9.268

• crowded diimine ligands 3b and 3c were prepared in one step in good yields using a micro-flow technique. One of the advantages of using microreactors is the ease of scale-up. It should be possible to scale-up our developed process by either continuous running or by increasing the number of the

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

One-step synthesis of pyridines and dihydropyridines in a continuous flow microwave reactor

• Mark C. Bagley,
• Vincenzo Fusillo,
• Robert L. Jenkins,
• M. Caterina Lubinu and
• Christopher Mason

Beilstein J. Org. Chem. 2013, 9, 1957–1968, doi:10.3762/bjoc.9.232

• chemistry [1], colloidal science [2], natural product chemistry [3], medicinal chemistry [4][5][6], solid-phase peptide synthesis [7] and in the biosciences [8]. Despite the many advantages of this heating method, and the introduction of a wide range of instrumentation [1], the scale up of microwave

• -mediated reactions still poses a number of challenges, in particular as a result of a lack of uniform heating [9]. Scale-up using batch methodologies in open reaction vessels can give excellent yields but might not be appropriate for certain volatile or toxic reagents whereas continuous flow processing

• advantages for scale up, certainly in terms of process intensification or in combination with reagent and scavenger cartridges for multi-step synthesis [11], and is possible using conventionally heated micro- or mesofluidic flow devices [12][13], but is also feasible under microwave dielectric heating

Continuous flow photocyclization of stilbenes – scalable synthesis of functionalized phenanthrenes and helicenes

• Quentin Lefebvre,
• Marc Jentsch and
• Magnus Rueping

Beilstein J. Org. Chem. 2013, 9, 1883–1890, doi:10.3762/bjoc.9.221

• obtained along with its ribbon-like regioisomer 2r’ in a 1:1 ratio and 75% combined yield. In order to demonstrate the utility of the flow process we decided to scale up the synthesis of helical compound 2o. To our delight, we observed that the [5]helicene precursor 1o underwent photocyclization with

• substitution patterns are obtained in good to excellent yields. In addition our first attempts to scale up the flow photocyclization reactions were successful providing the opportunity for multi-gram syntheses. Flow-reactor setup used in the optimization study. Photocyclization of stilbene to phenanthrene

• . Photo-flow synthesis of [5]- and [6]helicenes. aFor experimental details see Supporting Information File 1. bReaction conditions: 1.1 equiv iodine, 20 equiv THF, UV-light, 2 h retention time. Scale up synthesis of the [5]helicene derivative 2o. Proof of principle and screening of reaction conditions

Topochemical control of the photodimerization of aromatic compounds by γ-cyclodextrin thioethers in aqueous solution

• Hai Ming Wang and
• Gerhard Wenz

Beilstein J. Org. Chem. 2013, 9, 1858–1866, doi:10.3762/bjoc.9.217

• photoproduct from aqueous solution by liquid/liquid extraction simplifies the scale up. Yields of photodimer based on the complex were nearly quantitative. The observed supramolecular catalysis was explained by the high pre-organization resulting from the tight packing of the two guests in the cavity, which

Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions

• Trevor A. Hamlin and
• Nicholas E. Leadbeater

Beilstein J. Org. Chem. 2013, 9, 1843–1852, doi:10.3762/bjoc.9.215

• increased experimental safety, easy scale-up and thorough mixing of reagents [3][4][5][6][7]. It is not surprising, therefore, that a wide range of synthetic chemistry transformations have been reported using this equipment [8][9]. When it comes to evaluating the outcome of reactions performed using flow

Integrating reaction and analysis: investigation of higher-order reactions by cryogenic trapping

• Skrollan Stockinger and
• Oliver Trapp

Beilstein J. Org. Chem. 2013, 9, 1837–1842, doi:10.3762/bjoc.9.214

• direct analytical information about a reaction is obtained, including the formation of by-products and eventually even the reaction kinetics [1][2][3][4]. This information is important to design efficient flow-through experiments and to scale-up a reaction in a continuous process [5][6][7][8][9], which

Ethyl diazoacetate synthesis in flow

• Mariëlle M. E. Delville,
• Jan C. M. van Hest and
• Floris P. J. T. Rutjes

Beilstein J. Org. Chem. 2013, 9, 1813–1818, doi:10.3762/bjoc.9.211

• conditions, a production yield of 20 g EDA day−1 was achieved using a microreactor with an internal volume of 100 μL. Straightforward scale-up or scale-out of microreactor technology renders this method viable for industrial application. Keywords: diazo compounds; diazotization; ethyl diazoacetate (EDA

• immediately used for either batch [13][15] or continuous-flow [16][17] follow-up reactions. Straightforward scale-up or scale-out of microreactor technology renders this method viable for industrial application. Results and Discussion Flow synthesis Ethyl diazoacetate (1) was synthesized from glycine ethyl