Consecutive hydrazino-Ugi-azide reactions: synthesis of acylhydrazines bearing 1,5-disubstituted tetrazoles

• Angélica de Fátima S. Barreto,
• Veronica Alves dos Santos and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2017, 13, 2596–2602, doi:10.3762/bjoc.13.256

• -amide bond. Furthermore, they can be used to pre-organize the amide bonds of peptides [9]. Most methods for the synthesis of tetrazoles have limitations that include multistep syntheses of starting materials and/or the use of expensive reagents. The most commonly used synthesis of 1,5-disubstituted

A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic

• Marcus Baumann,
• Ian R. Baxendale and
• Fabien Deplante

Beilstein J. Org. Chem. 2017, 13, 2549–2560, doi:10.3762/bjoc.13.251

• chemistry; heterocycle; hydrogenation; indole; multistep; Introduction Indoles are amongst the most important bioactive heterocyclic structures being commonly encountered in the amino acid tryptophan (1), the related neurotransmitter serotonin (2) as well as numerous complex alkaloid natural products and

• precursors in a multistep sequence prior to indole ring formation [7]. In order to address these potential shortcomings we set out to develop a benign process relying on inexpensive substrates and non-toxic reagents that would rapidly deliver the desired indole in a readily scalable and continuous fashion

Exploring mechanochemistry to turn organic bio-relevant molecules into metal-organic frameworks: a short review

• Vânia André,
• Sílvia Quaresma,
• João Luís Ferreira da Silva and
• M. Teresa Duarte

Beilstein J. Org. Chem. 2017, 13, 2416–2427, doi:10.3762/bjoc.13.239

• bioactive molecules is achieved by degradation of the framework, ii) no multistep synthesis is required as the molecules are part of the matrix itself, iii) synergetic effects between the active molecule and the metal may be explored, and iv) co-delivery of drugs is possible if a porous network is built

Synthesis, effect of substituents on the regiochemistry and equilibrium studies of tetrazolo[1,5-a]pyrimidine/2-azidopyrimidines

• Elisandra Scapin,
• Paulo R. S. Salbego,
• Caroline R. Bender,
• Alexandre R. Meyer,
• Anderson B. Pagliari,
• Tainára Orlando,
• Geórgia C. Zimmer,
• Clarissa P. Frizzo,
• Helio G. Bonacorso,
• Nilo Zanatta and
• Marcos A. P. Martins

Beilstein J. Org. Chem. 2017, 13, 2396–2407, doi:10.3762/bjoc.13.237

• formed from 5-aminotetrazole, such as 1,3-binucleophile synthons, have not been sufficiently discussed [17]. Today, several existing methods are known to have several disadvantages, including long reaction time, the use of harmful solvents, and multistep synthesis [18][19]. Moreover, researchers in the

Dialkyl dicyanofumarates and dicyanomaleates as versatile building blocks for synthetic organic chemistry and mechanistic studies

• Grzegorz Mlostoń and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2017, 13, 2235–2251, doi:10.3762/bjoc.13.221

• dicyanofumarates and maleates as highly functionalized electron-deficient dipolarophiles, dienophiles and Michael acceptors is summarized. The importance for the studies on reaction mechanisms of cycloadditions is demonstrated. Multistep reactions with 1,2-diamines and β-aminoalcohols leading to diverse five- and

• exploration in mechanistic studies of their reactions. Similar to TCNE, these compounds are also attractive Michael acceptors with numerous applications for multistep reactions leading to heterocyclic products. The chemistry of E-1 and Z-1 has not been reviewed, and the goal of the present survey is to

• dimethyl 2,3-bis(hydroxyiminomethyl)fumarate with (CF3CO)2O in dioxane in the presence of pyridine at 0–10 °C [13]. The starting material was prepared in a multistep reaction from methyl β-nitropropanoate. An efficient method for the preparation of E-1b comprises the multistep reaction of dialkylselenonium

Main group mechanochemistry

• Agota A. Gečiauskaitė and
• Felipe García

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

• methods (see Scheme 3).· Also noteworthy is the multistep solvent-free mechanochemical route to indium(III) complexes featuring aryl bis(imino)acenaphthene (Ar-BIAN) ligands [84]. Ar-BIAN ligands are versatile π-acceptors and have been widely employed for catalysis. These ligands are typically synthesised

• completion. A rare example of a one-pot multistep ball milling reaction is the case of an electron-rich aniline derivative that produced 4 in good yield without the need for ligand isolation. Previously reported examples typically employ “preformed” ligands and metal complexes [68][86], raising the

• orthogonality of multistep mechanochemical synthesis and widening its applicability. A significant example of the transformative potential of mechanochemistry is its ability to produce metal complexes directly from bulk metal or metal oxides [66]. Within this context, the LAG synthesis of germanes (GeR4

Intramolecular glycosylation

• Xiao G. Jia and
• Alexei V. Demchenko

Beilstein J. Org. Chem. 2017, 13, 2028–2048, doi:10.3762/bjoc.13.201

• has also made these methodologies more attractive for use in more complicated multistep syntheses. Despite the advancements made, there are still no definitive rules on why small changes may affect the stereochemical outcomes so dramatically. There is a greater need to study the underlying concepts

Solvent-free and room temperature synthesis of 3-arylquinolines from different anilines and styrene oxide in the presence of Al₂O₃/MeSO₃H

• Hashem Sharghi,
• Mahdi Aberi,
• Mohsen Khataminejad and
• Pezhman Shiri

Beilstein J. Org. Chem. 2017, 13, 1977–1981, doi:10.3762/bjoc.13.193

• ]. Transition metal-catalyzed processes [5][6][7][8] and metal-free paths [9][10][11] are two general approaches for the synthesis of this type of compounds. However, the existing methods suffer from complicated multistep processes, limited availability of substrates, toxic organic solvents, long reaction times

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