Clickable azide-functionalized bromoarylaldehydes – synthesis and photophysical characterization

• Dominik Göbel,
• Marius Friedrich,
• Enno Lork and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2020, 16, 1683–1692, doi:10.3762/bjoc.16.139

• . Condensation with 2-amino-2-methylpropan-1-ol and oxidation with NBS yielded oxazoline 6 in a good yield. Directed ortho-metalation utilizing TMPMgCl·LiCl under mild conditions and subsequent smooth formylation with DMF afforded benzaldehyde 7 (see Scheme 2). Due to rapid decomposition of 7 under ambient and

• of the ortho-bromine substituent was again accomplished by metalation using TMPMgCl·LiCl and subsequent reaction with 1,2-dibromotetrachloroethane to afford 11 in 76% yield. A second bromination at the benzylic position provided the dibrominated derivative 12 in 66% yield. The substitution reaction

• -carbaldehyde 16 in excellent yield over three steps. Conversion to the 2-aryloxazoline 17 was accomplished in 92% yield using the same method as described for the synthesis of 6 and 10. ortho-Metalation with TMPMgCl·LiCl [70] and conversion of the magnesiated species with DMF to carbaldehyde 18 was followed by

Facile synthesis of 7-alkyl-1,2,3,4-tetrahydro-1,8-naphthyridines as arginine mimetics using a Horner–Wadsworth–Emmons-based approach

• Rhys A. Lippa,
• John A. Murphy and
• Tim N. Barrett

Beilstein J. Org. Chem. 2020, 16, 1617–1626, doi:10.3762/bjoc.16.134

• cores for these compounds in high yields (63–83% over 3 steps) with no need for chromatography. Key to this transformation is the phosphoramidate protecting group, which is stable to metalation steps. Keywords: arginine; Horner–Wadsworth–Emmons; integrin; phosphoramidate; tetrahydronaphthyridine

• tetrahydronaphthyridine in THF at this temperature. The use of iPrMgCl, a strong but room temperature-stable base, gave the highest conversion to phosphoramidate 13. Further investigation into the use of iPrMgCl revealed that a quantitative conversion was achieved at ambient temperature with a metalation time of <1

Towards triptycene functionalization and triptycene-linked porphyrin arrays

• Gemma M. Locke,
• Keith J. Flanagan and
• Mathias O. Senge

Beilstein J. Org. Chem. 2020, 16, 763–777, doi:10.3762/bjoc.16.70

• as before. After silica gel column chromatography, a dark purple solid of 16 was isolated in 8% yield. The unsymmetrically substituted triptycene 12 was utilized for several other cross-coupling reactions, including one with the dibrominated porphyrin 17c which was prepared via metalation of 17b and

Room-temperature Pd/Ag direct arylation enabled by a radical pathway

• Amy L. Mayhugh and
• Christine K. Luscombe

Beilstein J. Org. Chem. 2020, 16, 384–390, doi:10.3762/bjoc.16.36

• proposed mechanisms for direct arylation (Scheme 2). Amongst these mechanisms, the most widely accepted is the concerted metalation–deprotonation (CMD) pathway [21]. Within the indole direct-arylation literature, however, there remains much discussion of an electrophilic metalation mechanism, with the

Architecture and synthesis of P,N-heterocyclic phosphine ligands

• Wisdom A. Munzeiwa,
• Bernard Omondi and
• Vincent O. Nyamori

Beilstein J. Org. Chem. 2020, 16, 362–383, doi:10.3762/bjoc.16.35

• where the metalated organohalogen compound is reacted with the halogen phosphine. Alternatively, the metal phosphide can be reacted with an organohalogen compound leading to the desired product. The most commonly used trans-metalation reagents are Grignard [54] or organolithium reagents [55] and other

• suitable bases. The metalation reaction is prone to side reactions when carried out at higher temperatures and as such, the reaction must be carried out below 0 °C. For example, pyridyllithium derivatives as intermediates can be subjected to deprotonation, substrate addition and pyridine formation due to

• nucleophiles compared to organometallic or metal phosphides generated through metalation processes. Hayashi et al. [66] used tris(trimethylsilyl)phosphine to control the nucleophilic substitution in the preparation of P,N-(phosphino)triazine ligands (Scheme 5). It was shown that the use of other nucleophiles

Potent hemithioindigo-based antimitotics photocontrol the microtubule cytoskeleton in cellulo

• Alexander Sailer,
• Franziska Ermer,
• Yvonne Kraus,
• Rebekkah Bingham,
• Ferdinand H. Lutter,
• Julia Ahlfeld and
• Oliver Thorn-Seshold

Beilstein J. Org. Chem. 2020, 16, 125–134, doi:10.3762/bjoc.16.14

• , lithium diisopropylamide (LDA)-mediated cyclisation of 2-(methylthio)benzamides, which were obtained by directed ortho-metalation of the respective benzamides followed by quenching with dimethyl disulfide [27] (Supporting Information File 1, Scheme S1). In general, we found the LDA-mediated cyclisation

Functionalization of 4-bromobenzo[c][2,7]naphthyridine via regioselective direct ring metalation. A novel approach to analogues of pyridoacridine alkaloids

• Benedikt C. Melzer,
• Alois Plodek and
• Franz Bracher

Beilstein J. Org. Chem. 2019, 15, 2304–2310, doi:10.3762/bjoc.15.222

• metalation at C-5 with TMPMgCl∙LiCl at −40 °C. Quenching with various electrophiles gives a broad range of 5-substituted products, which are building blocks for the synthesis of heterocyclic natural products and analogues thereof. In combination with a Parham-type cyclization a novel approach to pyrido[4,3,2

• -mn]acridones has been worked out. Keywords: alkaloids; cyclization; metalation; naphthyridine; pyridoacridine; Introduction Polycyclic aromatic alkaloids are a unique class of natural products with a broad pattern of biological activities. One of the most prominent classes are the so-called

• 4,5-disubstituted benzo[c][2,7]naphthyridines utilizing ortho-directed ring metalation/biaryl cross-coupling strategies [9]. 4-Chlorobenzo[c][2,7]naphthyridine (9a) was conveniently converted into other 4-substituted benzo[c][2,7]naphthyridines by substitution reactions with nucleophiles (alcoholates

1,2,3-Triazolium macrocycles in supramolecular chemistry

• Mastaneh Safarnejad Shad,
• Pulikkal Veettil Santhini and
• Wim Dehaen

Beilstein J. Org. Chem. 2019, 15, 2142–2155, doi:10.3762/bjoc.15.211

• triazole containing dialdehyde and binaphthyl with dipyrromethene, followed by zinc metalation and subsequent reaction with MeI resulted in the synthesis of the two-component catalytic system 16 (Figure 13). Here, the cooperative effect of nucleophilic triazolium moieties, their counter ion near the

Attempted synthesis of a meta-metalated calix[4]arene

• Christopher D. Jurisch and
• Gareth E. Arnott

Beilstein J. Org. Chem. 2019, 15, 1996–2002, doi:10.3762/bjoc.15.195

• , followed by metalation of the triazolium salt 4 with silver oxide, which was immediately transmetalated with [RuCl2(p-cymene)]2. In our hands, purification using Albrecht’s trituration method was unsuccessful, however, neutral alumina column chromatography produced the desired model ruthenium metallocycle

• quantitative yield. In the final step towards a mesoionic calix[4]arene metallocycle, the synthesis was unfortunately not as trivial or as successful as we had hoped. The metalation reaction, using the methods described by Albrecht and co-workers [19], were repeated a number of times. In all cases the problem

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

Borylation and rearrangement of alkynyloxiranes: a stereospecific route to substituted α-enynes

• Ruben Pomar Fuentespina,
• José Angel Garcia de la Cruz,
• Gabriel Durin,
• Victor Mamane,
• Jean-Marc Weibel and
• Patrick Pale

Beilstein J. Org. Chem. 2019, 15, 1416–1424, doi:10.3762/bjoc.15.141

• Shimizu [6][7], and our experience on the metalation of alkynyloxiranes and reactivity studies of the so-formed alkynyloxirane anions [12][13], we explored the reaction of such anions with various boron derivatives in order to produce stereodefined α-enynes after Matteson-type rearrangement [14] and

• challenge in organic chemistry. Results and Discussion Reaction set up First we selected the simple 2-ethynyl-3-dimethyloxirane 1a to probe the feasibility of the reaction. In order to avoid unwanted reactions upon metalation [23], the ethynyl group was silylated and a bulky silyl group was installed to

• occurred upon oxygen-directed metalation. The resulting oxiranyllithium probably exists as a dimer in solution, as it has been nicely evidenced by structural characterization and NMR studies of the lithiated o-trifluoromethylstyrene oxide [37]. Such dimerization obviously stabilizes the oxiranyllithium

Extending mechanochemical porphyrin synthesis to bulkier aromatics: tetramesitylporphyrin

• Qiwen Su and
• Tamara D. Hamilton

Beilstein J. Org. Chem. 2019, 15, 1149–1153, doi:10.3762/bjoc.15.111

• mechanochemical synthesis is carried out at room temperature with no added solvent during the condensation step, simplifying and reducing the environmental impact for the synthesis of this important class of molecules. Notably, James et al. have reported the simple and clean mechanochemical metalation of

Design, synthesis and spectroscopic properties of crown ether-capped dibenzotetraaza[14]annulenes

• Krzysztof M. Zwoliński and
• Julita Eilmes

Beilstein J. Org. Chem. 2019, 15, 617–622, doi:10.3762/bjoc.15.57

• satisfactory 26–28% isolated yields and fully characterized based on HR-ESIMS, FTIR-ATR, 1H and 13C NMR spectroscopy and elemental analysis. These novel receptors are expected to bind both the transition, alkali and alkaline-earth metals, and also, after DBTAA subunit metalation the whole ion pairs. The

Synthesis and biological activity of methylated derivatives of the Pseudomonas metabolites HHQ, HQNO and PQS

• Sven Thierbach,
• Max Wienhold,
• Susanne Fetzner and
• Ulrich Hennecke

Beilstein J. Org. Chem. 2019, 15, 187–193, doi:10.3762/bjoc.15.18

• PQS such as formylation followed by oxidation failed when applied to OMe-HHQ (3). Alternatively, ortho-metalation next to the methoxy group of OMe-HHQ (3) followed by borylation/oxidation was investigated. Several trials using different lithium bases failed and only small amounts of oxidation products

• in the benzylic position could be observed. Instead of direct ortho-metalation, a strategy based on halogen–lithium exchange proved to be more suitable. To this end, HHQ (1) was converted into 3I-HHQ (8) following a literature procedure [21]. 3I-HHQ (8) was then methylated using the MeI/K2CO3

Hydroarylations by cobalt-catalyzed C–H activation

• Rajagopal Santhoshkumar and
• Chien-Hong Cheng

Beilstein J. Org. Chem. 2018, 14, 2266–2288, doi:10.3762/bjoc.14.202

• conditions and inexpensive catalyst. The reaction proceeds through an amide-assisted C–H metalation followed by alkyne insertion and protonation [54]. The reaction also acknowledged that the Co(III) species possess unique nucleophilic reactivity compared with the Rh(III) species for the annulation reaction

Cobalt-catalyzed peri-selective alkoxylation of 1-naphthylamine derivatives

• Jiao-Na Han,
• Cong Du,
• Xinju Zhu,
• Zheng-Long Wang,
• Yue Zhu,
• Zhao-Yang Chu,
• Jun-Long Niu and
• Mao-Ping Song

Beilstein J. Org. Chem. 2018, 14, 2090–2097, doi:10.3762/bjoc.14.183

• calculations (DFT) [30][31], the C–H activation most possibly proceeded via a single-electron transfer (SET) path compared to a concerted metalation-deprotonation (CMD) path. Followed by an intermolecular SET process, the cation-radical intermediate A was generated, which coordinates with a CoIII species to

Cobalt-catalyzed C–H cyanations: Insights into the reaction mechanism and the role of London dispersion

• Eric Detmar,
• Valentin Müller,
• Daniel Zell,
• Lutz Ackermann and
• Martin Breugst

Beilstein J. Org. Chem. 2018, 14, 1537–1545, doi:10.3762/bjoc.14.130

• experimental data indicated a reversible C–H metalation, which led to the suggested catalytic cycle of Scheme 2 [30]. As computational investigations also allow the study of intermediates that are too unstable to be observed under the experimental conditions, we have analyzed the underlying reaction mechanism

• agreement with the experimental findings: The calculated high barriers match the prolonged reaction times and high temperature required in the experimental studies and the reversible C–H metalation [30]. Influence of London dispersion In recent years, London dispersion, the attractive part of the van-der

Hyper-reticulated calixarene polymers: a new example of entirely synthetic nanosponge materials

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

Beilstein J. Org. Chem. 2018, 14, 1498–1507, doi:10.3762/bjoc.14.127

• acquired on a FEG-SEM FEI versa 3D microscope. The acceleration voltage was 10 kV. Tiny amounts of powdered samples were dispersed in ethanol. Two drops were deposited on the stub and let evaporating. Micrographs were directly acquired without metalation. DSC determinations were performed on a DSC Q200

Polysubstituted ferrocenes as tunable redox mediators

• Sven D. Waniek,
• Jan Klett,
• Christoph Förster and
• Katja Heinze

Beilstein J. Org. Chem. 2018, 14, 1004–1015, doi:10.3762/bjoc.14.86

• application as redox mediator (Scheme 2) [55][56]. Ferrocenyl esters 1–4 are synthetically accessible via the acids of 1 [45][46], 2 [57], 3 and 4 [54] in a direct selective metalation of ferrocene [54][57][58][59][60], quenching with carbon dioxide, followed by esterification [45][46][47][48][54]. The 1,1

Aminomethylation/hydrogenolysis as an alternative to direct methylation of metalated isoquinolines – a novel total synthesis of the alkaloid 7-hydroxy-6-methoxy-1-methylisoquinoline

• Benedikt C. Melzer,
• Jan G. Felber and
• Franz Bracher

Beilstein J. Org. Chem. 2018, 14, 130–134, doi:10.3762/bjoc.14.8

• products and in drug development and hence, effective synthetic approaches are required. Here we present a novel method for the introduction of a methyl group at C1 of isoquinolines. This is exemplified by a new total synthesis of the alkaloid 7-hydroxy-6-methoxy-1-methylisoquinoline. Direct metalation of

• , after quaternization with iodomethane, is easily converted into the desired 1-methylisoquinoline by hydrogenolysis of both the benzylamine and benzyl ether groups. Keywords: alkaloid; aminomethylation; hydrogenolysis; isoquinoline; metalation; methylation; Introduction The isoquinoline ring system has

• methods have been published over the decades for the construction of highly substituted isoquinolines [4]. Alternatively, subsequent functionalization of isoquinolines is feasible, e.g., via Pd-catalyzed C–H functionalization [5] or regioselective direct ring metalation (at C1) [6][7][8]. General aspects

Reactivity of bromoselenophenes in palladium-catalyzed direct arylations

• Aymen Skhiri,
• Ridha Ben Salem,
• Jean-François Soulé and
• Henri Doucet

Beilstein J. Org. Chem. 2017, 13, 2862–2868, doi:10.3762/bjoc.13.278

• Scheme 5 can be proposed. The first step is probably the oxidative addition of the 2-bromoselenophene to Pd(0) to afford the Pd(II) intermediate A. Then, after elimination of KBr with KOAc, a concerted metalation–deprotonation pathway involving an heteroarene gives B. Reductive elimination affords the 2

Ring-size-selective construction of fluorine-containing carbocycles via intramolecular iodoarylation of 1,1-difluoro-1-alkenes

• Takeshi Fujita,
• Ryo Kinoshita,
• Tsuyoshi Takanohashi,
• Naoto Suzuki and
• Junji Ichikawa

Beilstein J. Org. Chem. 2017, 13, 2682–2689, doi:10.3762/bjoc.13.266

• β-selective metalation or protonation of difluoroalkenes generates α-fluorocarbocations, which were stabilized by the resonance effect of fluorine substituents. In the course of our studies on the cationic cyclization of 1,1-difluoro-1-alkenes, we undertook an investigation of their iodine-mediated

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

A novel approach to oxoisoaporphine alkaloids via regioselective metalation of alkoxy isoquinolines

• Benedikt C. Melzer and
• Franz Bracher

Beilstein J. Org. Chem. 2017, 13, 1564–1571, doi:10.3762/bjoc.13.156

• Benedikt C. Melzer Franz Bracher Department für Pharmazie - Zentrum für Pharmaforschung, Ludwig-Maximilians Universität München, Butenandtstr. 5-13, D-81377 Munich, Germany 10.3762/bjoc.13.156 Abstract Oxoisoaporphine alkaloids are conveniently prepared via direct ring metalation of alkoxy

• oxoisoaporphine type. The yield of the cyclization step strongly depends on the electrophilic properties of ring B. An alternative cyclization protocol via directed remote metalation of ester and amide intermediates was investigated thoroughly, but found to be not feasible. Two of the alkaloids showed strong

• cytotoxicity against the HL-60 tumor cell line. Keywords: directed ortho/remote metalation; Eaton’s reagent; isoquinolines; Suzuki cross-coupling; Introduction Benzylisoquinoline alkaloids represent a very large group of plant secondary metabolites, which includes about 2,500 known structures. Besides simple

Direct catalytic arylation of heteroarenes with meso-bromophenyl-substituted porphyrins

• Alexei N. Kiselev,
• Olga K. Grigorova,
• Alexei D. Averin,
• Sergei A. Syrbu,
• Oskar I. Koifman and
• Irina P. Beletskaya

Beilstein J. Org. Chem. 2017, 13, 1524–1532, doi:10.3762/bjoc.13.152

• isocyanide Pd complex followed by the ring closure [32]; on the other hand, the arylation of benzothiophene in the presence of Pd(OAc)2/PCy3*HBF4/PivOH proceeds in accordance with the concerted metalation–deprotonation mechanism [33][34]. We also investigated the reaction of zinc meso-(3-bromophenyl