High-speed vibration-milling-promoted synthesis of symmetrical frameworks containing two or three pyrrole units

• Marco Leonardi,
• Mercedes Villacampa and
• J. Carlos Menéndez

Beilstein J. Org. Chem. 2017, 13, 1957–1962, doi:10.3762/bjoc.13.190

• proved to be useful include the protease of the human immunodeficiency virus HIV [1], cellular prion protein, PrPc [2], and the transient receptor potential melastatin 8 (TRPM8) channel receptor [3]. The synthesis of these symmetrical molecules normally relies on multistep sequences. Due to the special

One-pot multistep mechanochemical synthesis of fluorinated pyrazolones

• Joseph L. Howard,
• William Nicholson,
• Yerbol Sagatov and
• Duncan L. Browne

Beilstein J. Org. Chem. 2017, 13, 1950–1956, doi:10.3762/bjoc.13.189

• solvent-based processes. Herein, we describe a methodical process to run one solventless reaction directly into another through multistep mechanochemistry, effectively amplifying the solvent savings. The approach has to consider the solid form of the materials and compatibility of any auxiliary used. This

• ; mechanochemistry; multistep; solid-state synthesis; Introduction Mechanochemical methods are emerging as an alternative approach to traditional solvent-based reactions for chemical synthesis. Under mechanochemical conditions reactions are performed between neat reagents and do not require a solvent. Processing

• an up to date tool for synthesis is to gain a better insight into the ability to run multistep procedures. One-pot multistep procedures are particularly efficient, in that the same reaction vessel is used for each step, additional reagents are simply added to the reaction mixture at each stage with

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• ]. b) Multistep and multicomponent synthesis of Re-complexes [176]. c) Mechano-synthesis of NHC-Au complex [177]. Mechanochemical activation of C–H bond of unsymmetrical azobenzene [178]. Mechanochemical synthesis of organometallic pincer complex [179]. Mechanochemical synthesis of tris(allyl)aluminum

Development of a method for the synthesis of 2,4,5-trisubstituted oxazoles composed of carboxylic acid, amino acid, and boronic acid

• Kohei Yamada,
• Naoto Kamimura and
• Munetaka Kunishima

Beilstein J. Org. Chem. 2017, 13, 1478–1485, doi:10.3762/bjoc.13.146

• materials, such as α-haloketones and primary amides [8], alkynes and nitriles [9], amines and α,β-unsaturated carbonyl compounds [10], etc. [11] have been reported. However, these reactions are often conducted under harsh reaction conditions and multistep syntheses of the starting materials are needed. ii

• ) The functionalization method: various regioselective metalations and subsequent functionalizations of the oxazole core skeleton using Cu [12], Pd [13], Mg [14], Zn [14], etc. [15] have been developed. This linear synthetic approach inevitably requires multistep processes and often needs

One-pot synthesis of block-copolyrotaxanes through controlled rotaxa-polymerization

• Jessica Hilschmann,
• Gerhard Wenz and
• Gergely Kali

Beilstein J. Org. Chem. 2017, 13, 1310–1315, doi:10.3762/bjoc.13.127

• polyrotaxanes was already investigated in the fields of biomedicine, as drug [22] or gene [23] delivery vehicles, or in materials sciences, as slide ring gels [6]. Polyrotaxanes are mostly synthesized by a threading approach [2], a multistep method starting from pre-synthesized (co)polymers. Due to the

• dethreading already takes place. This multistep reaction methodology hinders the large-scale production and broad application of these materials. Recently our group has developed a method for a simple and environmentally friendly synthesis of polyrotaxanes. This, so called rotaxa-polymerization, is an aqueous

Strategies toward protecting group-free glycosylation through selective activation of the anomeric center

• A. Michael Downey and
• Michal Hocek

Beilstein J. Org. Chem. 2017, 13, 1239–1279, doi:10.3762/bjoc.13.123

• ]. On the other hand, the disadvantage is the need to synthesize NDP-sugars as substrates for the GT which is typically a multistep laborious process. Another particularly interesting application of glycosyltransferases is the chemoenzymatic synthesis of nucleosides. This is an incredibly powerful tool

• SN2-like reaction (Scheme 9). The most unfortunate drawbacks of the procedure include the need for a large excess of the alcohol acceptor and the multistep synthesis of the galactosyl donor. The synthesis of the monoprotected activated galactosyl donor requires the use of protecting groups, however

• furanosides. These may find application as enzyme substrates and possibly as inhibitors in several bacterial diseases, as well as in solid-phase-oligosaccharide synthesis, as shown. However, the main drawback is still the multistep synthesis of these anomeric activating donors. 3.2 Self-activation of the

An eco-compatible strategy for the diversity-oriented synthesis of macrocycles exploiting carbohydrate-derived building blocks

• Sushil K. Maurya and
• Rohit Rana

Beilstein J. Org. Chem. 2017, 13, 1106–1118, doi:10.3762/bjoc.13.110

• synthesis of sugar-embedded glycoconjugates [52][53]. Further, the linear syntheses of macrocycles based on multistep protocols are not cost-effective and the development of efficient, sustainable, greener and economical methods is highly desired. Synthetic methods to produce a diverse collection of

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

• The implementation of automation in the multistep flow synthesis is essential for transforming laboratory-scale chemistry into a reliable industrial process. In this review, we briefly introduce the role of automation based on its application in synthesis viz. auto sampling and inline monitoring

• , optimization and process control. Subsequently, we have critically reviewed a few multistep flow synthesis and suggested a possible control strategy to be implemented so that it helps to reliably transfer the laboratory-scale synthesis strategy to a pilot scale at its optimum conditions. Due to the vast

• literature in multistep synthesis, we have classified the literature and have identified the case studies based on few criteria viz. type of reaction, heating methods, processes involving in-line separation units, telescopic synthesis, processes involving in-line quenching and process with the smallest time

DMAP-assisted sulfonylation as an efficient step for the methylation of primary amine motifs on solid support

• Johnny N. Naoum,
• Koushik Chandra,
• Dorit Shemesh,
• R. Benny Gerber,
• Chaim Gilon and
• Mattan Hurevich

Beilstein J. Org. Chem. 2017, 13, 806–816, doi:10.3762/bjoc.13.81

• 10.3762/bjoc.13.81 Abstract Several multistep strategies were developed to ensure single methylation of amines on solid support. These strategies rely on the introduction of the o-NBS protecting/activating group as a key step. We found that the state-of-the-art strategies fail for the methylation of

Energy down converting organic fluorophore functionalized mesoporous silica hybrids for monolith-coated light emitting diodes

• Markus Börgardts and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2017, 13, 768–778, doi:10.3762/bjoc.13.76

• coated LEDs. Supporting Information Supporting Information File 192: Multistep synthetic procedures, spectroscopic and analytical data of the precursors 9 and 10, and the syntheses of the dye-functionalized MCM-41 hybrid materials 8@MCM, 9@MCM, and 10@MCM as well as the determined dye loadings of the

Transition-metal-catalyzed synthesis of phenols and aryl thiols

• Yajun Liu,
• Shasha Liu and
• Yan Xiao

Beilstein J. Org. Chem. 2017, 13, 589–611, doi:10.3762/bjoc.13.58

• , classic methods for the synthesis of phenols included the sulfonation of benzene [11], the Dakin reaction [12][13] and the Sandmeyer-type reaction [14]. These methods are useful for the preparation of various phenols, however, they suffer from several drawbacks such as multistep syntheses, toxic solvents

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

• Flavio Fanelli,
• Giovanna Parisi,
• Leonardo Degennaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2017, 13, 520–542, doi:10.3762/bjoc.13.51

• the potential of microreactor technology and flow chemistry in sustainable synthesis, recent outstanding “proof of concepts” will be described. Kobayashi and co-workers reported a multistep continuous-flow synthesis of a drug target via heterogeneous catalysis. The developed process not requiring any

• produce enantioenriched materials were employed. It is worth mentioning that this work represents a very nice example on the use of chiral catalysis in a multistep flow synthesis of a drug target on gram scale. The multistep synthesis of (S)-rolipram reported in Scheme 23 begins from a benzaldehyde

• very compact in size [1.0 m × 0.7 m × 1.8 m, (W × L × H)], and low-weighing (about 100 kg) and was able to perform complex multistep synthesis, work-up procedures as well as purification operations such as crystallization. This platform was also equipped with devices for real-time monitoring and final

Highly reactive, liquid diacrylamides via synergistic combination of spatially arranged curing moieties

• Maximilian Maier,
• Magnus S. Schmidt,
• Markus Ringwald and
• Christoph P. Fik

Beilstein J. Org. Chem. 2017, 13, 372–383, doi:10.3762/bjoc.13.40

• synthesis of 12 and other similar derivatives through a multistep reaction with the final step comprising the treatment of N,N'-dipropylperhydropyridazine-3,6-dione with a borane solution in THF [31]. Considering the high reactivity of 7 and the assumption, that the allylic double bond to the halide is

A chemoselective and continuous synthesis of m-sulfamoylbenzamide analogues

• Arno Verlee,
• Thomas Heugebaert,
• Tom van der Meer,
• Pavel I. Kerchev,
• Frank Van Breusegem and
• Christian V. Stevens

Beilstein J. Org. Chem. 2017, 13, 303–312, doi:10.3762/bjoc.13.33

• one single step. Furthermore, acid chlorides show a high reactivity [21] making m-(chlorosulfonyl)benzoyl chloride an ideal starting material as was shown by Yang et al. [18]. By transferring this reaction to a multistep flow set-up, we envisioned an improved chemoselectivity. This phenomenon is not

Continuous-flow synthesis of highly functionalized imidazo-oxadiazoles facilitated by microfluidic extraction

• Ananda Herath and
• Nicholas D. P. Cosford

Beilstein J. Org. Chem. 2017, 13, 239–246, doi:10.3762/bjoc.13.26

• -oxadiazoles starting from carboxylic acids is reported. This process was applied to the multistep synthesis of imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazoles, using a three reactor, multistep continuous-flow system without isolation of intermediates. This continuous-flow method was successfully combined with a

• describe the utilization of liquid–liquid microextraction to facilitate a complex, multistep flow synthesis process. Our research in the field of flow synthesis has focused on developing continuous-flow chemistry methods to access complex, drug-like molecules from readily available precursors without

• sphingosine-1-phosphate 1 (S1P1) receptor agonists [25][26][27] and metabotropic glutamate subtype 5 (mGlu5) receptor negative allosteric modulators (NAMs) [25][28][29][30]. Most synthetic efforts toward the preparation of these heterocyclic systems utilize a multistep, in-flask approach as illustrated by the

Orthogonal protection of saccharide polyols through solvent-free one-pot sequences based on regioselective silylations

• Serena Traboni,
• Emiliano Bedini and
• Alfonso Iadonisi

Beilstein J. Org. Chem. 2016, 12, 2748–2756, doi:10.3762/bjoc.12.271

• represents a typical issue in organic synthesis in the elaboration of highly functionalized molecules such as carbohydrates, and lengthy multistep procedures are often needed to this aim [1][2]. Silyl groups are widely applied in organic chemistry in orthogonal protection strategies owing to their stability

Tunable microwave-assisted method for the solvent-free and catalyst-free peracetylation of natural products

• Manuela Oliverio,
• Paola Costanzo,
• Monica Nardi,
• Carla Calandruccio,
• Raffaele Salerno and
• Antonio Procopio

Beilstein J. Org. Chem. 2016, 12, 2222–2233, doi:10.3762/bjoc.12.214

• , phenols and amino groups is a classical protection method in multistep syntheses as well as a transient chemical modification to improve the bioavailaibility and bioactivity of hydrophilic drugs and natural polyols [1][2][3][4][5][6][7][8][9]. Several in vitro and in vivo studies on peracetylated

Thiophene-forming one-pot synthesis of three thienyl-bridged oligophenothiazines and their electronic properties

• Dominik Urselmann,
• Konstantin Deilhof,
• Bernhard Mayer and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2016, 12, 2055–2064, doi:10.3762/bjoc.12.194

• intramolecular electronic coupling of (oligo)phenothiazines [45][64] and the low torsional displacement from a coplanar arrangement of both redox moieties of the dumbbells might represent conjugatively linked nanometer-scaled novel multistep redox active oligomers. As part of our concept to develop novel

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

• multistep synthesis of cannabinergic lactones from dimethylheptylresorcinol. Two regioisomeric cannabinergic lactones were obtained, one of which possessed pronounced affinity towards the CB1 receptor and lower affinities for mCB2 and hCB2 receptors [228]. Oxidation with H2O2–acid systems: With in situ

• [280][281][282] as the catalyst. The obtained asymmetric oxidation products can be used in the multistep synthesis of new biologically active compounds. Possible mechanisms for the asymmetric oxidation of 3-substituted cyclobutanone 96a with H2O2 catalyzed by chiral phosphoric acid are presented in

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

• multistep process (Scheme 9). After elongation by the iterative type I fatty acid synthase MmpB, redox transformations and a dehydration on the MacpE-bound substrate 58 finally lead to pseudomonic acid A (61) with a 3,4-dihydroxy-2,5-disubstituted pyran ring. The reason for the elaborate oxidation–reduction

3,6-Carbazole vs 2,7-carbazole: A comparative study of hole-transporting polymeric materials for inorganic–organic hybrid perovskite solar cells

• Wei Li,
• Munechika Otsuka,
• Takehito Kato,
• Yang Wang,
• Takehiko Mori and
• Tsuyoshi Michinobu

Beilstein J. Org. Chem. 2016, 12, 1401–1409, doi:10.3762/bjoc.12.134

• as its complicated multistep synthesis, low hole mobility in its pristine form, and expensive fabrication costs of the PSCs due to the sublimable small molecule. Accordingly, solution-processable hole-transporting polymers with simple structures have also been pursued as HTMs in the PSCs. Common p

Synthesis of highly functionalized 2,2'-bipyridines by cyclocondensation of β-ketoenamides – scope and limitations

• Paul Hommes and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2016, 12, 1170–1177, doi:10.3762/bjoc.12.112

• compound 10 no full conversion to the desired star-shaped compound was observed under the applied reaction conditions (SiCl4, EtOH) [60][61], very likely due to the insolubility of the intermediates involved in this multistep process. The chloro-substituted 2,2´-bipyridine derivative 5g – available due to

A convenient route to symmetrically and unsymmetrically substituted 3,5-diaryl-2,4,6-trimethylpyridines via Suzuki–Miyaura cross-coupling reaction

• Dariusz Błachut,
• Joanna Szawkało and
• Zbigniew Czarnocki

Beilstein J. Org. Chem. 2016, 12, 835–845, doi:10.3762/bjoc.12.82

• simple approach is tedious and time consuming; however the proper choice of conditions allows obtaining satisfactory yields of the unsymmetrically substituted diaryls in most cases. The first step of such multistep processes requires fine tuning of the reaction conditions to maximize the yields of the

Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic–ribosome complex supervised by experiment and electronic structure methods

• Jörg Grunenberg and
• Giuseppe Licari

Beilstein J. Org. Chem. 2016, 12, 415–428, doi:10.3762/bjoc.12.45

• single modern computing node) allows for a screening of tens of candidates per day in production mode. Our multistep strategy relies on the reproduction of 1) experimentally known ribosome–drug complex geometries, 2) experimentally known ribosome–drug complex affinities 3) the known enantioselectivity of

Self and directed assembly: people and molecules

• Tony D. James

Beilstein J. Org. Chem. 2016, 12, 391–405, doi:10.3762/bjoc.12.42

• of Victoria, I knew very little about Japan and almost-nothing about the Japanese Language. (Karate had taught me to count from 1 to 10). Having just finished a project with a lot of multistep synthesis, I was immediately drawn to projects as part of the boronic acid research group. The boronic acid