Versatile synthesis of end-reactive polyrotaxanes applicable to fabrication of supramolecular biomaterials

• Atsushi Tamura,
• Asato Tonegawa,
• Yoshinori Arisaka and
• Nobuhiko Yui

Beilstein J. Org. Chem. 2016, 12, 2883–2892, doi:10.3762/bjoc.12.287

• modified with dibenzylcyclooctyne (DBCO)-conjugated fluorescent molecules via a copper-free click reaction; this fluorescently labeled PRX was utilized for intracellular fluorescence imaging. The method of synthesizing end-reactive PRXs described herein is simple and versatile for the design of diverse

• (Supporting Information File 1, Figure S2). These results clearly demonstrate the successful synthesis of PRXs with well-defined terminal structures. Reactivity of terminal azide groups in PRXs with alkynes via copper-catalyzed click reaction The reactivity of the terminal azide groups of 4a and 4b with

• alkynes via the copper-catalyzed click reaction was examined. In this experiment, p-(tert-butyl)phenylacetylene was utilized as the model alkyne. One equivalent of p-(tert-butyl)phenylacetylene was allowed to react with the terminal azide groups of the PRXs in the presence of CuSO4 and sodium ascorbate

Synthesis of three-dimensional porous hyper-crosslinked polymers via thiol–yne reaction

• Mathias Lang,
• Alexandra Schade and
• Stefan Bräse

Beilstein J. Org. Chem. 2016, 12, 2570–2576, doi:10.3762/bjoc.12.252

• tetraphenylmethane-based networks by another click reaction, the thiol–yne reaction [14][15][16][17][18][19]. This reaction type has been known for several decades and relived a renaissance in the past decade, especially in material sciences [20][21][22][23][24][25][26][27][28][29][30][31][32], due to its mild, and

Synthesis, dynamic NMR characterization and XRD studies of novel N,N’-substituted piperazines for bioorthogonal labeling

• Constantin Mamat,
• Marc Pretze,
• Matthew Gott and
• Martin Köckerling

Beilstein J. Org. Chem. 2016, 12, 2478–2489, doi:10.3762/bjoc.12.242

• applicability of these compounds as possible 18F-building blocks, two biomolecules were modified and chosen for conjugation either using the Huisgen-click reaction or the traceless Staudinger ligation. Keywords: building blocks; coalescence; dynamic NMR; labeling; Staudinger ligation; Introduction The

• to demonstrate the Cu-catalyzed azide–alkyne click reaction (Huisgen 1,3-dipolar cycloaddition) and the traceless Staudinger ligation, a proof of concept study was performed for the site-selective labeling of a pharmacologically active peptide and a small organic compound. These compounds provide the

• , 3a,b were alkylated with 4-tosylbutyne to give compounds 4a,b in high yields of 84% and 82%, respectively. These compounds are applicable in the classical Cu-catalyzed Huisgen-click reaction with azide-functionalized, biologically active molecules. Additionally, 3a,b were reacted with 3-azidopropyl

Dinuclear thiazolylidene copper complex as highly active catalyst for azid–alkyne cycloadditions

• Anne L. Schöffler,
• Ata Makarem,
• Frank Rominger and
• Bernd F. Straub

Beilstein J. Org. Chem. 2016, 12, 1566–1572, doi:10.3762/bjoc.12.151

• ). Disfavored mononuclear pathway and favored dinuclear pathway in the CuAAC click reaction, according to the mechanistic proposal of reference [37]. R, R’ = alkyl, aryl, silyl, carbonyl groups; L = NHC; L’ = NHC or solvent; L’’ = solvent, acetylide, carboxylate, halide. Synthesis of dinuclear copper complex 2

Beta-hydroxyphosphonate ribonucleoside analogues derived from 4-substituted-1,2,3-triazoles as IMP/GMP mimics: synthesis and biological evaluation

• Tai Nguyen Van,
• Audrey Hospital,
• Corinne Lionne,
• Lars P. Jordheim,
• Charles Dumontet,
• Christian Périgaud,
• Laurent Chaloin and
• Suzanne Peyrottes

Beilstein J. Org. Chem. 2016, 12, 1476–1486, doi:10.3762/bjoc.12.144

• sugar, and finally with Met53 and Lys292 for the phosphonate group, within the IMP-nucleotide binding site of cN-II. Experimental General procedure A for click reaction: The azido-sugar 2 (1 equiv) was dissolved in dry THF (45 mL/mmol) and the required alkyne derivative (5.4 equiv

• ). The organic layer was dried over MgSO4, filtered and the solvent removed. Purification of the crude material on column chromatography on silica gel (CH2Cl2/EtOAc) afforded the desired product. General procedure B for click reaction: The azido-sugar 2 (1 equiv) was dissolved in acetonitrile (25 mL/mmol

• H2O twice and once with an aqueous solution of EDTA (1%, m/v). The organic layer was dried over with MgSO4, filtered and the solvent was removed. Purification of the crude material on column chromatography on silica gel (CH2Cl2/EtOAc) afforded the desired product. General procedure C for click

From N-vinylpyrrolidone anions to modified paraffin-like oligomers via double alkylation with 1,8-dibromooctane: access to covalent networks and oligomeric amines for dye attachment

• Daniela Obels,
• Melanie Lievenbrück and
• Helmut Ritter

Beilstein J. Org. Chem. 2016, 12, 1395–1400, doi:10.3762/bjoc.12.133

• poly(ethylene glycol) side chains. Keywords: double alkylation; modified N-vinylpyrrolidone; oligomeric anthraquinone dye; paraffin-like oligomer; radical thiol-ene click reaction; Introduction Poly(N-vinylpyrrolidone) (PVP) is established in daily life due to its high water solubility and

• bonds of 2a were subjected to further modification through a thiol–ene [40][41][42] click reaction with 2-aminoethanethiol hydrochloride yielding oligomer 4 (Scheme 2). Subsequently, the reactivity of the primary amino groups in 4 was proven by the attachment of 1,4-difluoro-9,10-anthraquinone (DFA

• -dibromooctane can easily be conducted through a one-pot synthesis. Swellable networks can be obtained by radical copolymerization of 2a with N-VP. Furthermore, the conversion of the double bonds through thiol–ene click reaction with 2-aminoethanethiol hydrochloride leads to paraffinic oligomers 4 bearing

Application of Cu(I)-catalyzed azide–alkyne cycloaddition for the design and synthesis of sequence specific probes targeting double-stranded DNA

• Svetlana V. Vasilyeva,
• Vyacheslav V. Filichev and
• Alexandre S. Boutorine

Beilstein J. Org. Chem. 2016, 12, 1348–1360, doi:10.3762/bjoc.12.128

• 14 (conjugate 25). The “click” reaction proceeded smoothly with complete conversion of the starting TFO at room temperature and the formation of only one product (see 20% denaturing PAGE, Figure 13). In case of bifunctional TFO 16 the bis-polyamide product is mainly formed (Figure 13B, line 6, f

Superstructures with cyclodextrins: chemistry and applications III

• Gerhard Wenz and
• Eric Monflier

Beilstein J. Org. Chem. 2016, 12, 937–938, doi:10.3762/bjoc.12.91

• has been achieved in the synthesis of CD polyrotaxanes. The one-pot and one-step polyrotaxane synthesis of β-CDs was performed in aqueous solution by employing a click reaction [7] as well as by radical copolymerization [8]. Slide-ring gels, synthesized by the group of K. Ito through the crosslinking

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

• -assisted click cluster synthesis. An example of the MW-promoted ‘cooperative’ click reaction of azido-CDs has recently been reported and offers useful synthetic insights into a specific labelling strategy [54]. The aforementioned reaction afforded a new series of antimicrobial γ-CD derivatives that

• strongly disrupt bacterial membranes, and a series of persubstituted γ-CD derivatives bearing polyamino groups (77% yield) [55]. MW-promoted Cu-catalyzed click reaction for the preparation of second generation CD derivatives and hybrid structures The MW-promoted CuAAC between CD monoazides and acetylenic

Recent advances in metathesis-derived polymers containing transition metals in the side chain

• Ileana Dragutan,
• Valerian Dragutan,
• Bogdan C. Simionescu,
• Albert Demonceau and
• Helmut Fischer

Beilstein J. Org. Chem. 2015, 11, 2747–2762, doi:10.3762/bjoc.11.296

• triazolyl unit was first attached to the η4-cyclopentadiene CpCo(I) complex by click reaction of the corresponding alkyne precursor and then the triazolyl-Co scaffold was incorporated into the norbornene monomer 9 by conventional esterification. It is important to note that the cyclopentadienyl-cobalt-1,3

Selectively fluorinated cyclohexane building blocks: Derivatives of carbonylated all-cis-3-phenyl-1,2,4,5-tetrafluorocyclohexane

• Mohammed Salah Ayoup,
• David B. Cordes,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2015, 11, 2671–2676, doi:10.3762/bjoc.11.287

• illustrated in Scheme 4 [17]. Reduction of benzyl azide 21 to generate amine 27 as its hydrochloride salt was achieved by a Staudinger reduction in good yield [18]. Azide 21 was also amenable to a ‘click’ reaction, in this case with the acetylenic protected amino acid 24 [19]. This gave the 1,2,3-triazol

Exploring architectures displaying multimeric presentations of a trihydroxypiperidine iminosugar

• Camilla Matassini,
• Stefania Mirabella,
• Andrea Goti,
• Inmaculada Robina,
• Antonio J. Moreno-Vargas and
• Francesca Cardona

Beilstein J. Org. Chem. 2015, 11, 2631–2640, doi:10.3762/bjoc.11.282

• ). The low yield observed for the click reaction of the deprotected azido derivative 10 can be ascribed to the tricky purification of 11 that was recovered from silica gel only by eluting with 33% NH4OH due to its high basicity (see Experimental section). For this reason we decided to change the strategy

• by performing the click reaction on the protected azido derivative 4, analogously to what reported with the tetravalent scaffold 5. Reaction of 4 (9 equiv) with the nonavalent alkyne scaffold 6 gave compound 12 in excellent 92% yield (Scheme 5). After treatment in acidic methanol at room temperature

Synthesis of bi- and bis-1,2,3-triazoles by copper-catalyzed Huisgen cycloaddition: A family of valuable products by click chemistry

• Zhan-Jiang Zheng,
• Ding Wang,
• Zheng Xu and
• Li-Wen Xu

Beilstein J. Org. Chem. 2015, 11, 2557–2576, doi:10.3762/bjoc.11.276

• with different or same azides that require the deprotection of the second reactive site to liberate another alkyne moiety. In 2007, Monkowius et al. reported that the 4,4'-bitriazoles 3 could be synthesized by the two-fold click reaction between 1,3-butadiyne and substituted organic azides [17], and

• (OAc)2·H2O (0.2 equiv). After the in situ deprotection with TBAF, followed by the CuI-catalyzed click reaction with another azide in THF in the presence of 1.2 equiv of 1,1,4,7,7-pentamethyldiethylenetriamine, the unsymmetrically 4,4'-bitriazoles 6 are obtained in good yield (52–86%, Scheme 3). Simpson

Copper catalysis in organic synthesis

• Sherry R. Chemler

Beilstein J. Org. Chem. 2015, 11, 2252–2253, doi:10.3762/bjoc.11.244

• . Some of the most highly cited papers of all time on this topic are reviews on conjugate addition, cross-coupling, and [3 + 2] “Click” reaction applied to bioconjugation. The growth in copper-catalyzed organic reactions may be driven by a couple of factors. First, copper chemistry is incredibly diverse

• synthesis, amide bond formation and photochemical Click reaction development. I am grateful to the contributors and the reviewers who participated in the production of this Thematic Series. It is clear from the impact copper catalysis has had on organic synthesis that copper should be considered a first

Easy access to heterobimetallic complexes for medical imaging applications via microwave-enhanced cycloaddition

• Nicolas Desbois,
• Sandrine Pacquelet,
• Adrien Dubois,
• Clément Michelin and
• Claude P. Gros

Beilstein J. Org. Chem. 2015, 11, 2202–2208, doi:10.3762/bjoc.11.239

• and alkyne derivatives to further interconnect by microwave-assisted click reaction. Azidocorroles/porphyrins Azidocorrole 1 [9] was obtained by the condensation of the corresponding meso-mesityl-substituted dipyrromethane with 4-azidobenzaldehyde in the presence of a catalytic amount of

• radiolabeled imaging agents with increasing frequency [7][32]. A methodology for the click reaction of azidocorrole or porphyrin has been recently developed in our laboratory [28][33]. We thus used similar conditions. The reactions were carried out in DMF, using excess of the alkyne derivative in the presence

• Nicolas Desbois Sandrine Pacquelet Adrien Dubois Clement Michelin Claude P. Gros Université de Bourgogne Franche-Comté, ICMUB (UMR CNRS 6302), 9 Avenue Alain Savary, BP 47870, 21078 Dijon Cedex, France 10.3762/bjoc.11.239 Abstract The Cu(I)-catalysed Huisgen cycloaddition, known as “click

Synthesis and spectroscopic properties of β-triazoloporphyrin–xanthone dyads

• Dileep Kumar Singh and
• Mahendra Nath

Beilstein J. Org. Chem. 2015, 11, 1434–1440, doi:10.3762/bjoc.11.155

• ) were synthesized in good yields by the “click reaction” of 3,6-diethynylxanthen-9-one (11) with copper and zinc azidoporphyrins, respectively. Further, the free-base diporphyrins 12b and 13b were obtained in 81% and 84% yields, respectively after the treatment of 12a with conc. H2SO4 at 0 °C and 13a

Synthesis of alpha-tetrasubstituted triazoles by copper-catalyzed silyl deprotection/azide cycloaddition

• Zachary L. Palchak,
• Paula T. Nguyen and
• Catharine H. Larsen

Beilstein J. Org. Chem. 2015, 11, 1425–1433, doi:10.3762/bjoc.11.154

• -deprotection with azide–alkyne cycloaddition, producing hindered triazoles in 6 hours. This tandem reaction was optimal with a copper(II) triflate and sodium ascorbate (NaAsc) as a mild reductant. The outcome that copper(II) triflate provides the highest yields for the one-pot deprotection/click reaction was

Synthesis of γ-hydroxypropyl P-chirogenic (±)-phosphorus oxide derivatives by regioselective ring-opening of oxaphospholane 2-oxide precursors

• Iris Binyamin,
• Shoval Meidan-Shani and
• Nissan Ashkenazi

Beilstein J. Org. Chem. 2015, 11, 1332–1339, doi:10.3762/bjoc.11.143

• ., after the "click" reaction) [61]. Conclusion In this work, we demonstrated the generality and the versatility of oxaphospholanes such as 4 and 5 to serve as precursors for the synthesis of γ-hydroxypropyl (±)-phosphinates and phosphine oxides, respectively, using Grignard reactions. Noteworthy is the

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

• (Scheme 51). [3 + 2] Cycloaddition (1,3-dipolar cycloaddition/click reaction): In 2010, Raghunathan and co-workers [185] have synthesized a C2-symmetric triazolophane by a copper(I)-catalyzed azide-alkyne cycloaddition, involving a click reaction. The dipropargyl fluorenyl derivative 299 was prepared from

Synthesis of novel N-cyclopentenyl-lactams using the Aubé reaction

• Madhuri V. Shinde,
• Rohini S. Ople,
• Ekta Sangtani,
• Rajesh Gonnade and
• D. Srinivasa Reddy

Beilstein J. Org. Chem. 2015, 11, 1060–1067, doi:10.3762/bjoc.11.119

• literature and the data were compared with that reported [34]. The structure of the minor diastereomer (±)-4’ was assigned based on 2D NMR correlations. Secondly, the azido alcohol (±)-3 was subjected to a click reaction with phenylacetylene under standard conditions and the resulting two compounds, (±)-5

Synthesis of carbohydrate-scaffolded thymine glycoconjugates to organize multivalency

• Anna K. Ciuk and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2015, 11, 668–674, doi:10.3762/bjoc.11.75

• )-catalyzed click reaction [21][22]. Before, the acid-labile isopropylidene protecting group was removed using 10% TFA in dichloromethane leading to mannoside 4, and then the azide function in 4 was converted in a Staudinger reduction [23] with simultaneous Boc-protection giving rise to mannoside 5 in high

• for eventual immobilisation of the final thymine glycoconjugate on a surface or for conjugation to another multivalent compound. For the click reaction of 5 with the thymine derivative 6, copper sulfate and sodium ascorbate were used. The conjugation product 7 was obtained in 71% yield and showed good

• (Scheme 2). Staudinger reduction of the azide group and Boc-protection in the same pot gave 9 and subsequent click reaction with the thymine derivative 6 the isopropylidene-protected dimeric thymine glycoconjugate 10 in good yield. This could be alkylated employing the bromoethyl mannoside 11 [11] in an

Functionalized branched EDOT-terthiophene copolymer films by electropolymerization and post-polymerization “click”-reactions

• Miriam Goll,
• Adrian Ruff,
• Erna Muks,
• Felix Goerigk,
• Beatrice Omiecienski,
• Ines Ruff,
• Rafael C. González-Cano,
• Juan T. Lopez Navarrete,
• M. Carmen Ruiz Delgado and
• Sabine Ludwigs

Beilstein J. Org. Chem. 2015, 11, 335–347, doi:10.3762/bjoc.11.39

• and alkynes (“click”-reaction) is a commonly used reaction in post-polymerization processes [39][40]. In the case of the azidomethyl-modified EDOT (EDOT-N3) building block different approaches of modifying the corresponding polymer PEDOT-N3 have been conducted so far, including the modification of

• during the polymerization process. In a next step we further transferred the copolymerization approach to the azidomethyl-substituted EDOT-N3 monomer which allows for the straightforward modification with various alkynes by Cu(I)-catalyzed 1,3-dipolar cycloaddition (“click”-reaction) [57]. For the

Articulated rods – a novel class of molecular rods based on oligospiroketals (OSK)

• Pablo Wessig,
• Roswitha Merkel and
• Peter Müller

Beilstein J. Org. Chem. 2015, 11, 74–84, doi:10.3762/bjoc.11.11

• defined a 1,2,3-triazole containing linkage between two piperidine rings as the flexible joint F, which should be easily accessible by copper-catalyzed cycloaddition between an azide G and a terminal alkyne H (CuAAC, “Click” reaction) [16]. Primary alcohols I serve as “protected” azides accessible by

Conjugates of methylated cyclodextrin derivatives and hydroxyethyl starch (HES): Synthesis, cytotoxicity and inclusion of anaesthetic actives

• Lisa Markenstein,
• Antje Appelt-Menzel,
• Marco Metzger and
• Gerhard Wenz

Beilstein J. Org. Chem. 2014, 10, 3087–3096, doi:10.3762/bjoc.10.325

• ] and its Cu+-catalyzed version, called click reaction [31][32], is of special interest because this coupling proceeds rapidly and specific in aqueous media and tolerates many functional groups. Mono-6-azido-6-deoxy-β-CD was already coupled by the click reaction to propargylated dextrane by Nielsen et

• propargyl ether leading to a highly water soluble polymer 3 with DSHES(propargyl) = 0.55. Coupling of the CD azides 1a and 1b to the propargylated HES was performed by Cu+-catalyzed [2 + 3] cycloaddition, the so-called click reaction, leading to the corresponding triazol groups (Scheme 3). The standard

• polymer backbone by the click-reaction is a very efficient way to synthesise polymeric hosts with both low toxicity and excellent binding potential. The conjugate of DIMEB and HES 5a is regarded as a good candidate for oral or parenteral delivery of hydrophobic drugs. Experimental Complexation of

Synthesis of divalent ligands of β-thio- and β-N-galactopyranosides and related lactosides and their evaluation as substrates and inhibitors of Trypanosoma cruzi trans-sialidase

• María Emilia Cano,
• Rosalía Agusti,
• Alejandro J. Cagnoni,
• María Florencia Tesoriero,
• José Kovensky,
• María Laura Uhrig and
• Rosa M. de Lederkremer

Beilstein J. Org. Chem. 2014, 10, 3073–3086, doi:10.3762/bjoc.10.324

• infection process. Experimental The synthetic general methods are described in the Supporting Information File 1. Synthesis of compounds 10, 12, 15, 17, 20 and 22. General procedure for the click reaction [43][44]. The corresponding azido-saccharides 9 or 14 [34] (0.20 mmol) and N-linked glycosides 3 or 6