Reaction of indoles with aromatic fluoromethyl ketones: an efficient synthesis of trifluoromethyl(indolyl)phenylmethanols using K₂CO₃/n-Bu₄PBr in water

• Thanigaimalai Pillaiyar,
• Masoud Sedaghati and
• Gregor Schnakenburg

Beilstein J. Org. Chem. 2020, 16, 778–790, doi:10.3762/bjoc.16.71

• desired products were obtained in good to excellent yields without requiring a column chromatographic purification. The reusability of the catalytic system and large-scale synthesis of indolyl(phenyl)methanols, which would further transform into biological active indole-derived compounds, are further

• advantages of this protocol. Keywords: C–C-bond formation; C3-funtionalization of indole; diindolylmethane; Friedel–Crafts reaction; indole; indole-3-carbinol; large-scale synthesis; recyclability; Introduction (1H-Indol-3-yl)methanols have emerged as versatile pre-electrophiles for C–C functionalization

• the catalytic system and large-scale synthesis of products, which would further transform into biologically active indole-derived compounds, are further advantages of this protocol. Structures of trifluoromethylated compounds and their biological activities. Synthetic approaches toward

Safe and highly efficient adaptation of potentially explosive azide chemistry involved in the synthesis of Tamiflu using continuous-flow technology

• Cloudius R. Sagandira and
• Paul Watts

Beilstein J. Org. Chem. 2019, 15, 2577–2589, doi:10.3762/bjoc.15.251

• have been developed towards Tamiflu to date [1][2][3]. However, most of these synthetic approaches suffer from the use of potentially hazardous azide chemistry, thus raising safety concerns [4] and eventually ruled out for large scale synthesis in batch systems [1][2]. The importance and use of azide

• 1a is a potentially explosive compound because of its nitro and azide moieties [14] and its safety concerns need to be dealt with for large scale synthesis. Safety in this reaction was achieved by in situ formation and consumption in flow of the hazardous intermediates (azide 1a and isocyanate 1b

• large scale synthesis in batch systems on the basis of safety concerns poised by the use of the potentially explosive azide chemistry and other hazardous chemistry. Therefore, problems inherent in scale-up are effectively eliminated or reduced, making microreactor technology a viable tool in the

Thermal stability of N-heterocycle-stabilized iodanes – a systematic investigation

• Andreas Boelke,
• Yulia A. Vlasenko,
• Mekhman S. Yusubov,
• Boris J. Nachtsheim and
• Pavel S. Postnikov

Beilstein J. Org. Chem. 2019, 15, 2311–2318, doi:10.3762/bjoc.15.223

• with a significant higher reactivity. However, pyrazole 6 still shows a good reactivity in this model reaction with a concurrent outstanding thermal stability. If safety issues are a major concern, for example on a very large-scale synthesis, NHIs 6 or 12 should be the first choices. Except of 15 and 9

Efficient resolution of racemic crown-shaped cyclotriveratrylene derivatives and isolation and characterization of the intermediate saddle isomer

• Sven Götz,
• Andreas Schneider and
• Arne Lützen

Beilstein J. Org. Chem. 2019, 15, 1339–1346, doi:10.3762/bjoc.15.133

• elaborated derivatives [58][59] and the ease of a recently established large-scale synthesis reported by Rousseau and co-workers [60]. Hence, we decided to revisit this compound in order to improve the separation in terms of both better resolution of the enantiomeric bowl-shaped conformers and isolation of

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• the large-scale synthesis in pharmaceutical laboratories and industry. Nevertheless, among the multicomponent synthetic methods available for the preparation of isoindolinones II and 2-oxindoles III, only one is enantioselective, even though many of the reactions described in this review involve the

Polyaminoazide mixtures for the synthesis of pH-responsive calixarene nanosponges

• Antonella Di Vincenzo,
• Antonio Palumbo Piccionello,
• Alberto Spinella,
• Delia Chillura Martino,
• Marco Russo and
• Paolo Lo Meo

Beilstein J. Org. Chem. 2019, 15, 633–641, doi:10.3762/bjoc.15.59

• the 2:1:1 ratio expected on the grounds of numerical simulations. The separation of such a mixture would be unsuitable in view of a possible large-scale synthesis and application of the relevant nanosponge polymeric materials, because it should involve undesirable waste of time and materials. However

Asymmetric synthesis of a high added value chiral amine using immobilized ω-transaminases

• Antonella Petri,
• Valeria Colonna and
• Oreste Piccolo

Beilstein J. Org. Chem. 2019, 15, 60–66, doi:10.3762/bjoc.15.6

• configuration. Recent studies have favored the application of TAs at the industrial level, so it is not surprising that they are frequently found among the enzymes designed for the large-scale synthesis of chiral amines [2][4]. Moreover, immobilization of TAs has been developed in order to increase stability

The mechanochemical synthesis of quinazolin-4(3H)-ones by controlling the reactivity of IBX

• Md Toufique Alam,
• Saikat Maiti and
• Prasenjit Mal

Beilstein J. Org. Chem. 2018, 14, 2396–2403, doi:10.3762/bjoc.14.216

• aniline derivative with moderate reactivity. Therefore, we anticipate that the controlled reactivity of IBX under mechano-milling conditions led to successful reaction with 2-aminobenzamide. Finally, a large scale synthesis was performed to prove the synthetic utility of this methodology. By taking

• . aYields with respect to recovered aldehydes, for compound 3y, IBX was added after 1 h. Crystal structure of 3a (CCDC No. 1823611). Plausible mechanism for the quinazolin-4(3H)-ones synthesis using IBX. Large scale synthesis of 3a. Optimization of the reaction conditions.a Supporting Information

One hundred years of benzotropone chemistry

• Arif Dastan,
• Haydar Kilic and
• Nurullah Saracoglu

Beilstein J. Org. Chem. 2018, 14, 1120–1180, doi:10.3762/bjoc.14.98

• involves the condensation of o-phthalaldehyde (27) with diethyl 1,3-acetonedicarboxylate (28), followed by hydrolysis and decarboxylation steps [46][47] (Scheme 5). Similar syntheses were made by Cook’s [48] and Föhlisch’s [49] groups. Nevertheless, for performing large-scale synthesis, the cost of 27 make

Preparation of trinucleotide phosphoramidites as synthons for the synthesis of gene libraries

• Ruth Suchsland,
• Bettina Appel and
• Sabine Müller

Beilstein J. Org. Chem. 2018, 14, 397–406, doi:10.3762/bjoc.14.28

• this strategy the large scale synthesis (5 g) of 3'-unprotected trinucleotides proceeded with a total 75–90% yield [20]. Other strategies with potential for the solid-phase synthesis of protected trinucleotides might rely on a universal solid support, from which oligomers with free 3'-OH function are

• reductive conditions (disulfide cleavage or hydrogenation) or under mild basic conditions leaving all protecting groups at the trimer undamaged. In particular, soluble support strategies have great potential for an efficient large scale synthesis of fully protected trinucleotides. The essential feature here

Progress in copper-catalyzed trifluoromethylation

• Guan-bao Li,
• Chao Zhang,
• Chun Song and
• Yu-dao Ma

Beilstein J. Org. Chem. 2018, 14, 155–181, doi:10.3762/bjoc.14.11

• . Although this catalytic reaction worked efficiently, the trifluoromethyl source TESCF3 was expensive and relatively inaccessible, which made this process less economic, especially for large-scale synthesis. In 2014, Novák, Kotschy and co-workers [13] developed a new procedure with the relatively cheap and

• . Trifluoromethylation of aryl halides using trifluoroacetates as the trifluoromethyl source Reactions employing expensive electrophilic CF3 species such as Umemoto’s reagent or Togni’s reagent, were unpractical and limited on a large-scale synthesis. After comparison of the prices of different CF3 reagents, attention

Gram-scale preparation of negative-type liquid crystals with a CF₂CF₂-carbocycle unit via an improved short-step synthetic protocol

• Tatsuya Kumon,
• Shohei Hashishita,
• Takumi Kida,
• Shigeyuki Yamada,
• Takashi Ishihara and
• Tsutomu Konno

Beilstein J. Org. Chem. 2018, 14, 148–154, doi:10.3762/bjoc.14.10

• steps less than the previous method. In addition, the present synthetic protocol involves several standard organic transformations, such as hydrogenation and dehydration, which are advantageous for a large-scale synthesis of the target compounds. Thus, we attempted a detailed examination of the short

The synthesis of the 2,3-difluorobutan-1,4-diol diastereomers

• Robert Szpera,
• Nadia Kovalenko,
• Kalaiselvi Natarajan,
• Nina Paillard and
• Bruno Linclau

Beilstein J. Org. Chem. 2017, 13, 2883–2887, doi:10.3762/bjoc.13.280

• . While the use of Bu4NH2F3/KHF2 and TBAF/KHF2 achieves epoxide opening without acetonide rearrangement, the subsequent deoxyfluorination/deprotection sequence is low yielding (30%). Overall, the protocols provided will be of use for the large-scale synthesis of both syn- and anti-2,3-difluorobutan-1,4

Synthetic mRNA capping

• Fabian Muttach,
• Nils Muthmann and
• Andrea Rentmeister

Beilstein J. Org. Chem. 2017, 13, 2819–2832, doi:10.3762/bjoc.13.274

• release of the RNA. However, due to overall low coupling efficiencies and isolated yields (the compound was isolated in 20% overall yield after anion-exchange chromatography), this method was not used for large scale synthesis of capped RNA (Figure 6A). As the low reaction yields are mainly caused by the

• . A combination of chemical synthesis and enzymatic modification was also used by Thillier et al. for the large scale synthesis of capped RNA. Herein, to circumvent the problem of m7G instability, non-methylated capped RNAs were first synthesized using the phosphoramidite 2′-O-pivaloyloxymethyl method

Main group mechanochemistry

• Agota A. Gečiauskaitė and
• Felipe García

Beilstein J. Org. Chem. 2017, 13, 2068–2077, doi:10.3762/bjoc.13.204

• . In the field of organometallic chemistry, we highlight the large-scale synthesis of SrCp′2(OEt2) (Cp′ = C5Me4(n-Pr)) (1) [82], an ideal precursor for the chemical vapour deposition (CVD) of strontium-based semiconductors – a key material in memory devices [83]. Previously, this compound could only be

Synthesis of oligonucleotides on a soluble support

• Harri Lönnberg

Beilstein J. Org. Chem. 2017, 13, 1368–1387, doi:10.3762/bjoc.13.134

• used for the preparation of oligonucleotides from lab scale [3][22] to industrial synthesis up to kilogram scale [23]. In spite of the obvious success of this methodology, synthesis in solution phase has received continuous interest as an alternative for large-scale synthesis, and the recent advances

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

• rapid heating, its applicability for large-scale synthesis is yet unreported and may not be economical. For exothermic reactions, the heating unit should also be capable of cooling in case of some undesired events like a runaway reaction or an emergency shutdown. Most of the induction heating systems

Total synthesis of TMG-chitotriomycin based on an automated electrochemical assembly of a disaccharide building block

• Yuta Isoda,
• Norihiko Sasaki,
• Kei Kitamura,
• Shuji Takahashi,
• Sujit Manmode,
• Naoko Takeda-Okuda,
• Jun-ichi Tamura,
• Toshiki Nokami and
• Toshiyuki Itoh

Beilstein J. Org. Chem. 2017, 13, 919–924, doi:10.3762/bjoc.13.93

• structurally well-defined tetrasaccharide gave TMG-chitotriomycin after manipulations of the amino groups and global deprotection. Further investigations to improve the β-selectivity in the disaccharide synthesis and a large scale synthesis are in progress in our laboratory. Experimental General 1H and 13C NMR

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

• , Table 1). After an improved stoichiometry of reagents had been established, lowering the residence time was investigated to facilitate efficient large scale synthesis by a continuous flow process. Ultimately, a residence time of 5 min at 120 °C, using a 0.25 M concentration of α-chloroacrylamide, was

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

• devices. In summary, we have developed a simplified synthetic route to afford a range of MMs analogues of BTR. This simplified route has allowed large-scale synthesis of intermediate building blocks and of a multi-gram synthesis of the required MMs. Detailed structure–property studies have identified BQR

Potent triazine-based dehydrocondensing reagents substituted by an amido group

• Munetaka Kunishima,
• Daiki Kato,
• Nobu Kimura,
• Masanori Kitamura,
• Kohei Yamada and
• Kazuhito Hioki

Beilstein J. Org. Chem. 2016, 12, 1897–1903, doi:10.3762/bjoc.12.179

• superior to DMT-MM in terms of reactivity in dehydrocondensing reactions. Although DMT-MM is the appropriate reagent for dehydrocondensing reactions in large-scale synthesis, X have advantage for dehydrocondensing reactions in aprotic solvents such as THF, especially when low nucleophilic starting

Rearrangements of organic peroxides and related processes

• Ivan A. Yaremenko,
• Vera A. Vil’,
• Dmitry V. Demchuk and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2016, 12, 1647–1748, doi:10.3762/bjoc.12.162

• these methods, the Criegee rearrangement represents one key step and one example is presented in Scheme 48 [303]. A method for the large-scale synthesis of a trans-hydrindan derivatives 164, 165 related to vitamin D, based on the Criegee rearrangement of alkene 163 was realized (Scheme 49) [308

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

• diphenylcarbonate in DMF, have been prepared under MW irradiation (400 W) in 90 min. The optimized method was proven to be a unique opportunity for the large-scale synthesis of CD nanosponges in a high yield and uniform particle size distribution [78]. Ball mill One of the oldest, cheap, and efficient methods to

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

• , this method is fast and easy to implement, and it is suitable for large-scale synthesis (Scheme 1). Many isoindolinone skeletons show high biological potential as antihypertensives, anesthetics, etc. [66][67][68]. The useful hydrolyzed product rac-4a was obtained in 80% yield by treating rac-3a with

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

• -cyanoethyl-protected thiols as a means to further functionalise MPTTFs with thioethers and (ii) copper-mediated N-arylation of both MPTTFs and BPTTFs. Results and Discussion An improved large-scale synthesis of N-tosyl-(1,3)-dithiolo[4,5-c]pyrrole-2-one (6) The known compound 6 [4][25] is an important

• ) are versatile functional groups in many areas of chemistry. The large-scale synthesis of the key intermediate 6 improves the accessibility of these species and their derivatives. The related species 7 can be used to prepare further analogues. Compounds 6 and 7 can both be used to prepare BPTTFs and

• materials with applications in supramolecular chemistry, molecular electronics and as sensors. The sequential, reversible oxidation of TTF (1) to its stable radical cation (2) and dication (3) states. Structures and possible substitution positions of MPTTFs (4) and BPTTFs (5). Large-scale synthesis of 6