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

• polyfunctionalized biaryls, using a flow microreactor, has been recently reported by Yoshida [54]. Using the integrated microflow system reported in Scheme 8, arylboronic esters were prepared by a lithiation/borylation sequence, and used in a Suzuki–Miyaura coupling in a monolithic reactor. A remarkable aspect of

• the process was the use of an integrated supported monolithic Pd(0) catalyst that allowed to perform cross-coupling reactions in continuous flow mode (Scheme 8). This integrated microflow system allow to handle the borylation of aryl halides (Ar1X), and the subsequent Suzuki–Miyaura coupling using

• microreactor system. Control of anionic Fries rearrangement reactions by using submillisecond residence time. (Adapted with permission [43], copyright 2016 American Association for the Advancement of Science). Flow microreactor system for lithiation, borylation, Suzuki–Miyaura coupling and selected examples of

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

• large scale use of tin reagents we required the key bis-borylated benzodithiophene (BDT) core 13, which was synthesised from the known BDT core 12 using iridium catalyzed borylation via CH-activation. The bis-borylated product was isolated by precipitation on addition of isopropanol (IPA), and an

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

• our one-pot bromine-lithium-exchange-borylation-Suzuki (BLEBS) sequence [78], employing an excess of 3,7-dibromo-10-hexyl-10H-phenothiazine (3) [45] as a coupling component in the Suzuki step (Scheme 1). With three bromo-substituted (oligo)phenothiazines 1 in hand the consecutive pseudo five-component

• oligophenothiazines 3 (calculated with the B3LYP functional in vacuo and the 6-311G(d,p) basis set). One-pot bromine-lithium-exchange-borylation-Suzuki (BLEBS) synthesis of 7-bromo-substituted phenothiazines 1b and 1c with 3,7-dibromo-10-hexyl-10H-phenothiazine (2). Pseudo five-component Sonogashira-Glaser

Practical synthetic strategies towards lipophilic 6-iodotetrahydroquinolines and -dihydroquinolines

• David R. Chisholm,
• Garr-Layy Zhou,
• Ehmke Pohl,
• Roy Valentine and
• Andrew Whiting

Beilstein J. Org. Chem. 2016, 12, 1851–1862, doi:10.3762/bjoc.12.174

• 21 and 22 using typical Miyaura borylation conditions (Scheme 10) [32]. Both were highly crystalline compounds, and comparison of the two crystal structures (Figure 4) highlighted the more planar structure of 30 as a result of the enamine function, as predicted by ab initio methods in Figure 2

• route for the synthesis of 20a. Synthesis of THQ 21 and DHQ 22 using borane·dimethyl sulphide complex or DIBAL, respectively. Postulated mechanism for the formation of 22 using DIBAL. Miyaura borylation of 21 and 22 to give crystalline boronic esters 29 and 30. Temperature and solvent effects from the

Iridium/N-heterocyclic carbene-catalyzed C–H borylation of arenes by diisopropylaminoborane

• Mamoru Tobisu,
• Takuya Igarashi and
• Naoto Chatani

Beilstein J. Org. Chem. 2016, 12, 654–661, doi:10.3762/bjoc.12.65

• C–H borylation of arenes has been widely used in organic synthesis because it allows the introduction of a versatile boron functionality directly onto simple, unfunctionalized arenes. We report herein the use of diisopropylaminoborane as a boron source in C–H borylation of arenes. An iridium(I

• ) complex with 1,3-dicyclohexylimidazol-2-ylidene is found to efficiently catalyze the borylation of arenes and heteroarenes. The resulting aminoborylated products can be converted to the corresponding boronic acid derivatives simply by treatment with suitable diols or diamines. Keywords: boronic acid; C–H

• borylation; iridium; N-heterocyclic carbene; Introduction Catalytic C–H borylation of arenes has become an essential tool in organic synthesis [1]. The eminent features of this methodology include 1) no directing group is needed, allowing the direct functionalization of simple arenes; 2) the

Carbon–carbon bond cleavage for Cu-mediated aromatic trifluoromethylations and pentafluoroethylations

• Tsuyuka Sugiishi,
• Hideki Amii,
• Kohsuke Aikawa and
• Koichi Mikami

Beilstein J. Org. Chem. 2015, 11, 2661–2670, doi:10.3762/bjoc.11.286

• . and Buchwald et al. used the Ruppert–Prakash reagent (CF3–SiMe3) directly as a CF3− source [46][47]. From CF3–SiMe3, Hartwig et al. developed a new combination of Ir-catalyzed C–H borylation and oxidative cross-coupling using [(phen)CF3Cu] [48]. Grushin et al. utilized fluoroform for the preparation

Chiral Cu(II)-catalyzed enantioselective β-borylation of α,β-unsaturated nitriles in water

• Lei Zhu,
• Taku Kitanosono,
• Pengyu Xu and
• Shū Kobayashi

Beilstein J. Org. Chem. 2015, 11, 2007–2011, doi:10.3762/bjoc.11.217

• -unsaturated nitriles in water. The catalyst system, which consisted of Cu(OAc)2 and a chiral 2,2′-bipyridine ligand, enabled β-borylation and chiral induction in water. Subsequent protonation, which was accelerated in aqueous medium, led to high activity of this asymmetric catalysis. Both solid and liquid

• reactions, which exhibit extremely high TOF values, can be performed easily without requiring the preparation of an array of chiral ligands [1][16][17][18][19]. Rapid protonation in water subsequent to β-borylation would liberate the desired adducts almost instantaneously. In addition to the synthetic

• -borylation of α,β-unsaturated nitriles in water [1][19]. Herein, we describe the Cu(II)-catalyzed asymmetric boron conjugate addition of α,β-unsaturated nitriles in water. Results and Discussion At the outset, an aqueous solution of a chiral Cu(II) complex was formed by vigorous stirring of Cu(OAc)2 with

Pyridine-promoted dediazoniation of aryldiazonium tetrafluoroborates: Application to the synthesis of SF₅-substituted phenylboronic esters and iodobenzenes

• George Iakobson,
• Junyi Du,
• Alexandra M. Z. Slawin and
• Petr Beier

Beilstein J. Org. Chem. 2015, 11, 1494–1502, doi:10.3762/bjoc.11.162

• )phenylboronic esters, iodo(pentafluorosulfanyl)benzenes and (pentafluorosulfanyl)benzene is shown. Keywords: borylation; diazonium salts; iodination; pyridine; sulfur pentafluorides; Introduction Pentafluorosulfanyl-containing compounds have been known for more than half a century [1][2][3][4]; however, for a

• ][58], Lewis acid catalyzed electrophilic borylations of electron-rich arenes [59][60][61][62], and Sandmeyer-type borylation of arylamines or diazonium salts with B2pin2 [63][64][65][66][67], B2(OH)4 [68] or R2N-BH2 [69]. Several attempts were made to synthesize the SF5-phenylboronates. Patent

• C–H borylation of several 1-substituted-3-(pentafluorosulfanyl)benzenes and applied the products of borylation to the Pd-catalyzed Suzuki–Miyaura reaction with aryl bromides or iodides. However, the reaction is limited to borylations in position five of 1-substituted-3-(pentafluorosulfanyl)benzenes

Selected synthetic strategies to cyclophanes

• Sambasivarao Kotha,
• Mukesh E. Shirbhate and
• Gopalkrushna T. Waghule

Beilstein J. Org. Chem. 2015, 11, 1274–1331, doi:10.3762/bjoc.11.142

• a key step. The L,L-cyclodi(iodotryrosin) (131) was subjected to a benzylation reaction to give the protected compound 132 (76%). A one-pot Pd-catalyzed borylation and Suzuki–Miyaura coupling was employed to generate the cross-coupling product 134 (42%). Finally, deprotection of 134 was carried out

Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

• Katherine M. Byrd

Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60

• )diboron to various α,β-unsaturated carbonyl compounds [121]. Use of bisboronic acid and tetrakis(dimethylamino)diboron provides boron sources that are more atom economical than B2pin2. Scheme 11 shows an example of the asymmetric 1,4-borylation where the authors used an α,β-unsaturated amide as the

On the mechanism of photocatalytic reactions with eosin Y

• Michal Majek,
• Fabiana Filace and
• Axel Jacobi von Wangelin

Beilstein J. Org. Chem. 2014, 10, 981–989, doi:10.3762/bjoc.10.97

• the visible part of the spectrum (Figure 3) [30]. At the UV–vis edge (400 nm), the absorbance of the system is still more than 0.1 which translates into 21% of all light being absorbed at this wavelength. When we performed the borylation reaction according to the literature report [21] but without the

• addition of the photocatalyst eosin Y, 54% yield of the borylation product were obtained by direct photolysis (Scheme 4). These observations are in full accord with a report of direct reaction of thermally generated aryl cations (from arenediazonium salts) with bispinacolato diboron to give the

• -catalyzed substitutions with arene diazonium salts. Acid–base behaviour of eosin Y. Eosin Y-catalyzed and dye-free photolytic borylation. Eosin Y-catalyzed and dye-free reactions with ethyl propiolate. Quantum yield determinations of selected visible-light-driven aromatic substitutions. Supporting

Clean and fast cross-coupling of aryl halides in one-pot

• Valerica Pandarus,
• Geneviève Gingras,
• François Béland,
• Rosaria Ciriminna and
• Mario Pagliaro

Beilstein J. Org. Chem. 2014, 10, 897–901, doi:10.3762/bjoc.10.87

• Unsymmetrically coupled biaryls are synthesized in high yield starting from different aryl bromides and bis(pinacolato)diboron by carrying out the Miyaura borylation reaction followed by the Suzuki–Miyaura reaction in the same reaction pot over 1–2 mol % SiliaCat DPP-Pd. The SiliaCat DPP-Pd catalyst is air-stable

• and the method does not require the use of inert conditions. The use of non-toxic isopropanol or 2-butanol as reaction solvent further adds to the environmental benefits of this new green synthetic methodology. Keywords: borylation; SiliaCat; Suzuki–Miyaura; cross-coupling; one-pot; Findings

• ]. Of direct relevance to this research report, Giroux and co-workers reported the homogeneously palladium-catalyzed one-pot borylation/Suzuki coupling reactions already in 1997 [7]. Yet, it remains desirable to efficiently heterogenize palladium catalytic species used in cross-coupling reactions with

Towards allosteric receptors – synthesis of β-cyclodextrin-functionalised 2,2’-bipyridines and their metal complexes

• Christopher Kremer,
• Gregor Schnakenburg and
• Arne Lützen

Beilstein J. Org. Chem. 2014, 10, 814–824, doi:10.3762/bjoc.10.77

• 1,3-dimethoxybenzene via lithiation and borylation [39] afforded 22 in very good yield [40][41][42]. 22 forms the 1:1 complex [Cu(22)([H3CCN)2]BF4 upon coordination to copper(I) ions. Zinc(II) ions were found to form the dimeric complex [Zn(22)2](OTf)2 with an excess of 22 if no other ligand is

Group-assisted purification (GAP) chemistry for the synthesis of Velcade via asymmetric borylation of N-phosphinylimines

• Jian-bo Xie,
• Jian Luo,
• Timothy R. Winn,
• David B. Cordes and
• Guigen Li

Beilstein J. Org. Chem. 2014, 10, 746–751, doi:10.3762/bjoc.10.69

• Abstract A new approach to the anticancer drug Velcade was developed by performing asymmetric borylation of an imine anchored with a chiral N-phosphinyl auxiliary. Throughout the 7-step synthesis, especially in the imine’s synthesis and in the asymmetric borylation reactions, operations and work-up were

• conducted in simple and easy ways without any column chromatographic purification, which defines the GAP (group-assisted purification) chemistry concept. It was found that the optically pure isomer (dr > 99:1) can be readily obtained by washing the crude mixture of the asymmetric borylation reaction with

• hexane; the chiral N-phosphinyl auxiliary can be easily recovered after deprotection is finished. Several other N-phosphinylimines were also investigated for the asymmetric borylation reaction. The absolute configuration of the borylation product was confirmed by single crystal X-ray diffraction analysis

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

• of a one-pot, two-stage reaction, with Ir-catalyzed borylation of an aromatic sp2-C–H bond, followed by a copper-mediated or -catalyzed perfluoroalkylation of the resulting arylboronic ester intermediate. Since the work by J. F. Hartwig et al. uses stoichiometric amounts of ex situ-prepared Cu-Rf

• interest of this reaction resides in the fact that the Ir-catalyzed borylation with bis(pinacolato)diboron is highly influenced by the steric bulk of the arene, and therefore leads to regioselective functionalization of the substrate. Arenes and heteroarenes, variously substituted, could undergo 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

Metal–ligand multiple bonds as frustrated Lewis pairs for C–H functionalization

• Matthew T. Whited

Beilstein J. Org. Chem. 2012, 8, 1554–1563, doi:10.3762/bjoc.8.177

• Ir(I) center followed by hydride migration [64][79][80]. The well-developed C–H borylation chemistry of Hartwig and others provides an indication that cooperation may be operative to some extent in the activation of C–H bonds at metal boryls [81][82][83][84], though the exact mechanism of C–H

Sonogashira–Hagihara reactions of halogenated glycals

• Dennis C. Koester and
• Daniel B. Werz

Beilstein J. Org. Chem. 2012, 8, 675–682, doi:10.3762/bjoc.8.75

• functionalization allowed for the mild and selective borylation of unfunctionalized glycals. Starting from persilylated glycals Ishikawa and Miyaura applied an Ir-catalyzed C–H-functionalization with B2pin2 to obtain 1-borylated glycals, such as 3, in excellent yields and selectivity. They elegantly demonstrated

Directed aromatic functionalization in natural-product synthesis: Fredericamycin A, nothapodytine B, and topopyrones B and D

• Charles Dylan Turner and
• Marco A. Ciufolini

Beilstein J. Org. Chem. 2011, 7, 1475–1485, doi:10.3762/bjoc.7.171

• by DAF technology [31]. The starting point for the assembly of an appropriate variant of 4 was diethylamide 6 (Scheme 2), which underwent smooth Beak–Snieckus-type ortho-deprotonation [32][33][34][35] with the sec-BuLi–TMEDA complex and consequent borylation in high yield. Oxidation of the ensuing 7

Bromine–lithium exchange: An efficient tool in the modular construction of biaryl ligands

• Laurence Bonnafoux,
• Frédéric R. Leroux and
• Françoise Colobert

Beilstein J. Org. Chem. 2011, 7, 1278–1287, doi:10.3762/bjoc.7.148

• -Dimethylamino-2',6-dibromobiphenyl (1c) was obtained in an overall yield of 79% in 3 steps (Scheme 1). To introduce the methoxy group, 2,2',6-tribromobiphenyl (1a) was successively subjected to lithiation, borylation with fluorodimethoxyborane·diethyl ether, followed by oxidation with hydrogen peroxide and O

One-pot four-component synthesis of pyrimidyl and pyrazolyl substituted azulenes by glyoxylation–decarbonylative alkynylation–cyclocondensation sequences

• Charlotte F. Gers,
• Julia Rosellen,
• Eugen Merkul and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2011, 7, 1173–1181, doi:10.3762/bjoc.7.136

• , azulenes must be functionalized, either by halogenation or borylation, and some of these derivatives were found to be quite unstable [45][46]. To the best of our knowledge, no diversity-oriented multicomponent syntheses of azulenyl heterocycles have been reported so far. Here, we report the development of

Convenient methods for preparing π-conjugated linkers as building blocks for modular chemistry

• Jiří Kulhánek,
• Filip Bureš and
• Miroslav Ludwig

Beilstein J. Org. Chem. 2009, 5, No. 11, doi:10.3762/bjoc.5.11

• the Horner–Wadsworth–Emmons reaction described above. These substituted 4-bromostilbenes could be most effectively converted to target pinacol esters 5a–c via borylation (Scheme 1, Method C) utilizing bis(pinacolato)diboron (pin2B2) [39] in a mixed solvent system DMSO/dioxane ensuring good solubility

• . It should be noted here that 5a–c were also accessible via the routine sequence showed for Method B. On the contrary, borylation of 4-bromobiphenyls with pin2B2 (Method C) yielded only traces of 4a–c. Linear phenylethynylphenyl π-linkers 6a–c were gained by a Sonogashira cross-coupling between the

• . Overall 12 extended π-linkers have been easily synthesized (8 of them are new compounds) utilizing procedures such as a lithiation/reaction with triisopropyl borate/esterification with pinacol, Mizoroki–Heck coupling with vinylboronate pinacol ester, borylation with bis(pinacolato)diboron or Sonogashira