Tandem Cu-catalyzed ketenimine formation and intramolecular nucleophile capture: Synthesis of 1,2-dihydro-2-iminoquinolines from 1-(o-acetamidophenyl)propargyl alcohols

• Gadi Ranjith Kumar,
• Yalla Kiran Kumar,
• Ruchir Kant and
• Maddi Sridhar Reddy

Beilstein J. Org. Chem. 2014, 10, 1255–1260, doi:10.3762/bjoc.10.125

• compounds in moderate to good yields under mild reaction conditions. Keywords: alkyne; azide; cycloaddition; cyclization; quinoline; Introduction The synthesis of N-sulfonylketenimines via CuAAC (copper-catalyzed azide–alkyne cycloaddition) between terminal alkynes and sulfonyl azides has staged for a

Atherton–Todd reaction: mechanism, scope and applications

• Stéphanie S. Le Corre,
• Mathieu Berchel,
• Hélène Couthon-Gourvès,
• Jean-Pierre Haelters and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2014, 10, 1166–1196, doi:10.3762/bjoc.10.117

Staudinger ligation towards cyclodextrin dimers in aqueous/organic media. Synthesis, conformations and guest-encapsulation ability

• Malamatenia D. Manouilidou,
• Yannis G. Lazarou,
• Irene M. Mavridis and
• Konstantina Yannakopoulou

Beilstein J. Org. Chem. 2014, 10, 774–783, doi:10.3762/bjoc.10.73

• . These include the well-known copper-catalyzed azide–alkyne cyclization (CuAAC, “click” reaction) between an azido-CD derivative and an alkyne linker [19][22][23][24] [22], or vice versa, the metal catalyzed reactions between propargyl-CDs and aryl dihalides such as the Sonogashira and Glaser–Hay

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• ]. Multicomponent reactions towards amide isosteres often involve an Ugi reaction followed by a Click reaction, in which two of the Ugi-inputs either contain an alkyne or an azide moiety. A well-known example of the latter reaction is the Copper(I) catalyzed azide–alkyne cycloaddition (CuAAC) between acetylenes and

Preparation of new alkyne-modified ansamitocins by mutasynthesis

• Kirsten Harmrolfs,
• Lena Mancuso,
• Binia Drung,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2014, 10, 535–543, doi:10.3762/bjoc.10.49

• -ansamitocin derivative 6, folate-ansamitocin P-3 conjugate 7 and thiol 8. Strategies for introducing linker-based thiol groups to the aromatic moiety of ansamitocin P-3 for accessing tumor targeting conjugates (CuAAC; Cu-mediated azide–alkyne cycloaddition). Mutasynthetic transformation of aminobenzoic acid

Silver and gold-catalyzed multicomponent reactions

• Giorgio Abbiati and
• Elisabetta Rossi

Beilstein J. Org. Chem. 2014, 10, 481–513, doi:10.3762/bjoc.10.46

• between isoquinolinium-2-ylamide 43 and keteneimine 57 [79], silver salt plays the usual role of a π-philic catalyst, whereas ketene imine 57 is generated by a well-known procedure involving a copper(I)-catalyzed azide–alkyne [3 + 2] cycloaddition (CuAAC) giving rise to 5-cuprated triazole intermediate 56

Advancements in the mechanistic understanding of the copper-catalyzed azide–alkyne cycloaddition

• Regina Berg and
• Bernd F. Straub

Beilstein J. Org. Chem. 2013, 9, 2715–2750, doi:10.3762/bjoc.9.308

• Regina Berg Bernd F. Straub Organisch-Chemisches Institut, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany 10.3762/bjoc.9.308 Abstract The copper-catalyzed azide–alkyne cycloaddition (CuAAC) is one of the most broadly applicable and easy-to-handle

• reactions in the arsenal of organic chemistry. However, the mechanistic understanding of this reaction has lagged behind the plethora of its applications for a long time. As reagent mixtures of copper salts and additives are commonly used in CuAAC reactions, the structure of the catalytically active species

• itself has remained subject to speculation, which can be attributed to the multifaceted aggregation chemistry of copper(I) alkyne and acetylide complexes. Following an introductory section on common catalyst systems in CuAAC reactions, this review will highlight experimental and computational studies

Synthesis of homo- and heteromultivalent carbohydrate-functionalized oligo(amidoamines) using novel glyco-building blocks

• Felix Wojcik,
• Sinaida Lel,
• Alexander G. O’Brien,
• Peter H. Seeberger and
• Laura Hartmann

Beilstein J. Org. Chem. 2013, 9, 2395–2403, doi:10.3762/bjoc.9.276

• [20]. Carbohydrate conjugation was achieved by copper-catalyzed azide alkyne cycloaddtion (CuAAC) of carbohydrate ligands on alkyne presenting oligomers [21]. As an alternative conjugation approach to CuAAc, a very efficient thiol–ene coupling (TEC) [22][23][24][25] protocol in a continuous flow

Efficient continuous-flow synthesis of novel 1,2,3-triazole-substituted β-aminocyclohexanecarboxylic acid derivatives with gram-scale production

• Sándor B. Ötvös,
• Ádám Georgiádes,
• István M. Mándity,
• Lóránd Kiss and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2013, 9, 1508–1516, doi:10.3762/bjoc.9.172

• relatively short reaction time [18][19][20]. Recently, Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) has become the basis of the so-called click chemistry concept due to its wide applicability and efficiency. Over the past twenty years, alicyclic β-amino acids have attracted great interest among

• , including Cu2O, are formed on its surface [61], which can promote CuAAC. Thus, we utilized copper powder in a stainless steel column, which served as a catalyst bed later on. The catalyst bed was placed into a stainless steel block with a Peltier heating system, which could heat the column up to 100 °C. A

• setup is safe, even with unstable reactants such as azides (Figure 3). To maximize the CF triazole synthesis reaction rates, it appeared easiest to use high-temperature conditions initially. The application of elevated pressure in CuAAC is also beneficial, as it can promote the product formation in

End-labeled amino terminated monotelechelic glycopolymers generated by ROMP and Cu(I)-catalyzed azide–alkyne cycloaddition

• Ronald Okoth and
• Amit Basu

Beilstein J. Org. Chem. 2013, 9, 608–612, doi:10.3762/bjoc.9.66

• terminus. The molecular data for 7 obtained by MALDI was in agreement with that obtained from GPC and NMR analysis of polymer 6 (see Supporting Information File 1). Due to its high conversion and functional-group tolerance the copper(I)-promoted azide–alkyne click reaction (CuAAC) has become a powerful

• of the NHS esters had indeed been displaced. CuAAC between propargyl β-D-galactoside 10a [23] and azido polymer 9 was achieved in 10 minutes by a microwave-assisted protocol to give galactosyl polymer 11a. We also prepared the mannosylated glycopolymer 11b in a similar manner (see Supporting

• Information File 1). The progress of the CuAAC was assessed by monitoring the appearance of the triazole peak at 8.15 ppm in the 1H NMR spectra of 11a (Figure 1, middle spectrum). Furthermore, the IR spectra showed complete disappearance of the azide asymmetric stretch at 2100 cm−1 upon completion of the

Efficient synthesis of phenylene-ethynylene rods and their use as rigid spacers in divalent inhibitors

• Francesca Pertici,
• Norbert Varga,
• Arnoud van Duijn,
• Matias Rey-Carrizo,
• Anna Bernardi and
• Roland J. Pieters

Beilstein J. Org. Chem. 2013, 9, 215–222, doi:10.3762/bjoc.9.25

• to cover is ca. 26 Å, the best match in the phenylene-ethynylene series is the three-unit spacer 15. Just the spacer, without the aglycon linking moiety measures around 22 Å. Coupling of the galactose ligand and the flexible aglycon part should result in a promising compound. CuAAC of 15 with the

• their affinity for the target proteins, but can create solubility problems. Desilylation of 13 (TBAF, THF, Scheme 7) followed by in situ CuAAC with the pseudo-disaccharide 23 led to the divalent ligand 24, which was found to be fully soluble in water, at least up to millimolar concentrations. Compound

• still be further elongated, depending on the need of the project, thus enabling the preparation of long spacers with a well-defined number of monomeric units. The CuAAC of the three unit spacer 15 with a galactose ligand gave the divalent ligand 21 in good yield. After deprotection this compound was

Peptoids and polyamines going sweet: Modular synthesis of glycosylated peptoids and polyamines using click chemistry

• Daniel Fürniss,
• Timo Mack,
• Frank Hahn,
• Sidonie B. L. Vollrath,
• Katarzyna Koroniak,
• Ute Schepers and
• Stefan Bräse

Beilstein J. Org. Chem. 2013, 9, 56–63, doi:10.3762/bjoc.9.7

• conjugation methods such as the Staudinger ligation [1] or the copper-catalyzed alkyne azide cycloaddition (CuAAC) [2][3], a large number of versatile and functional bioconjugates are accessible for various applications in chemical biology [4]. To date, many therapeutically active molecules are synthetic

• functionalities. For peptoids, CuAAC has already been used successfully to introduce diverse side-chain functionalities directly during solid-phase synthesis of peptoids starting from both, azido- and alkyne-functionalized side chains [41][42]. In addition CuAAC has also been used in order to constrain peptoid

• secondary structures [43]. CuAAC reactions for the attachment of sugar residues to peptoid backbones have been reported for some cases [44][45]; however, a fully glycosylated structure is unknown (for glycodendrons see [46]). In this study, we describe the first solid-phase synthesis of glycosylated

Copper-catalyzed CuAAC/intramolecular C–H arylation sequence: Synthesis of annulated 1,2,3-triazoles

• Rajkumar Jeyachandran,
• Harish Kumar Potukuchi and
• Lutz Ackermann

Beilstein J. Org. Chem. 2012, 8, 1771–1777, doi:10.3762/bjoc.8.202

• -economical syntheses of annulated 1,2,3-triazoles were accomplished through copper-catalyzed intramolecular direct arylations in sustainable one-pot reactions. Thus, catalyzed cascade reactions involving [3 + 2]-azide–alkyne cycloadditions (CuAAC) and C–H bond functionalizations provided direct access to

• for direct arylations of 1,2,3-triazoles. Thus, we showed that intermolecular copper-catalyzed C–H bond functionalizations could be combined with the Huisgen [51] copper(I)-catalyzed [52][53] [3 + 2]-azide–alkyne cycloaddition (CuAAC)[54], while C–H bond arylations of 1,2,3-triazoles were previously

• consisting of copper(I)-catalyzed [3 + 2]-azide–alkyne cycloadditions (CuAAC) and intramolecular C–H bond arylations. Notably, the optimized copper catalyst accelerated two mechanistically distinct transformations, which set the stage for the formation of up to one C–C and three C–N bonds in a chemo- and

Antifreeze glycopeptide diastereomers

• Lilly Nagel,
• Carsten Budke,
• Axel Dreyer,
• Thomas Koop and
• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 1657–1667, doi:10.3762/bjoc.8.190

• proline replacements [5]. These peptides exhibit less antifreeze activity than monosaccharide-substituted AFGP analogues without proline residues. Peptoid glycoconjugates with carbohydrate moieties attached by CuI catalyzed azide-alkyne cycloaddition (CuAAC) were devoid of antifreeze activity [17

High-affinity multivalent wheat germ agglutinin ligands by one-pot click reaction

• Henning S. G. Beckmann,
• Heiko M. Möller and
• Valentin Wittmann

Beilstein J. Org. Chem. 2012, 8, 819–826, doi:10.3762/bjoc.8.91

• conveniently prepared by employing a one-pot procedure for Cu(II)-catalyzed diazo transfer and Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) starting from commercially available amines. These glycoclusters were probed for their binding potencies to the plant lectin wheat germ agglutinin (WGA) from

• explanation for the observed binding affinities. Results and Discussion Synthesis of glycoclusters The Cu(I)-catalyzed [49][50] Huisgen [3 + 2] cycloaddition [51] of azides and alkynes (CuAAC) is a frequently used method for the covalent attachment of carbohydrate epitopes to azide- or alkyne-presenting

• ) comprising different spacer geometries were selected. These amines were employed in the sequential one-pot procedure [48] for diazo transfer and CuAAC (Table 1). First, the Cu(II)-catalyzed diazo transfer was performed at ambient temperature until complete conversion of the amines to azides. Then, CuAAC was

Thiophene-based donor–acceptor co-oligomers by copper-catalyzed 1,3-dipolar cycloaddition

• Stefanie Potratz,
• Amaresh Mishra and
• Peter Bäuerle

Beilstein J. Org. Chem. 2012, 8, 683–692, doi:10.3762/bjoc.8.76

• high yield and purity. Click reactions generally involve a Cu(I)-catalyzed version of the Huisgen 1,3-dipolar cycloaddition of terminal acetylenes and azides (CuAAC), to regioselectively yield 1,4-disubstituted 1H-1,2,3-triazoles [11][12]. In the meanwhile, this type of click reaction has become very

Synthesis of heteroglycoclusters by using orthogonal chemoselective ligations

• Baptiste Thomas,
• Michele Fiore,
• Isabelle Bossu,
• Pascal Dumy and
• Olivier Renaudet

Beilstein J. Org. Chem. 2012, 8, 421–427, doi:10.3762/bjoc.8.47

• ligands [30] or vectors of hepatocytes [31]. As the second strategy, we have chosen the well-known copper(I)-catalyzed alkyne–azide cycloaddition (CuAAC) [32][33], which is intensively exploited for the conjugation of sugars to both molecular and biological systems [34][35]. Besides being fully compatible

• with carbohydrate and peptide chemistries, oximation and CuAAC reactions offer the advantage of being orthogonal [36][37], therefore allowing a controlled assembly process with a minimized risk of side reactions. The 2:2 series of heteroglycoclusters was prepared from the aminooxy [38][39][40] and

• observed by analytical HPLC. The excess of sugar was then quenched by the addition of acetone, and the resulting crude mixtures were used for CuAAC without further purification. The efficiency of CuAAC clearly depends on the experimental conditions [34][35]. The choice of the solvent and of the copper(I

A ferrocene redox-active triazolium macrocycle that binds and senses chloride

• Nicholas G. White and
• Paul D. Beer

Beilstein J. Org. Chem. 2012, 8, 246–252, doi:10.3762/bjoc.8.25

• that the redox-active macrocycle is capable of sensing chloride in CH3CN solution. Keywords: anion binding; C–H···anion interactions; electrochemistry; ferrocene; triazolium; Introduction The copper(I)-catalysed cycloaddition of alkynes and azides (CuAAC) [1][2] to give the 1,2,3-triazole group is

• investigate its anion binding and electrochemical-sensing properties. Results and Discussion Synthesis The CuAAC reaction of ferrocene bis(azide) 1 [12], with a large excess of 1,6-heptadiyne afforded 2 in 50% yield. An intramolecular Eglinton cyclisation reaction was used to prepare the ferrocene bis

Synthesis of 2-amino-3-arylpropan-1-ols and 1-(2,3-diaminopropyl)-1,2,3-triazoles and evaluation of their antimalarial activity

• Matthias D’hooghe,
• Stéphanie Vandekerckhove,
• Karen Mollet,
• Karel Vervisch,
• Stijn Dekeukeleire,
• Liesbeth Lehoucq,
• Carmen Lategan,
• Peter J. Smith,
• Kelly Chibale and
• Norbert De Kimpe

Beilstein J. Org. Chem. 2011, 7, 1745–1752, doi:10.3762/bjoc.7.205

• 1,2,3-triazole moiety instead. A powerful methodology towards the synthesis of functionalized 1,2,3-triazoles involves the Cu(I)-catalyzed azide-alkyne Huisgen cycloaddition (CuAAC) [33], which has gained major interest from the synthetic community due to its high efficiency and selectivity. Eligible

Continuous-flow enantioselective α-aminoxylation of aldehydes catalyzed by a polystyrene-immobilized hydroxyproline

• Xacobe C. Cambeiro,
• Rafael Martín-Rapún,
• Pedro O. Miranda,
• Sonia Sayalero,
• Esther Alza,
• Patricia Llanes and
• Miquel A. Pericàs

Beilstein J. Org. Chem. 2011, 7, 1486–1493, doi:10.3762/bjoc.7.172

• azides and alkynes (CuAAC) used as the immobilization strategy [44][45][46], led to improved efficiency, both in terms of catalytic activity and asymmetric induction, and different behaviour of the resulting materials in terms of hydrophilicity or hydrophobicity [47][48][49][50]. An even better

• aldehydes. Results and Discussion The preparation of the immobilized catalysts 1a and 1b was easily achieved by a modification of the reported procedure [41][42][43], with the tris(triazolyl)methyl copper complex 3 [76] as the catalyst for the CuAAC reaction between azidomethylpolystyrene, prepared from a

Multistep flow synthesis of vinyl azides and their use in the copper-catalyzed Huisgen-type cycloaddition under inductive-heating conditions

• Lukas Kupracz,
• Jan Hartwig,
• Jens Wegner,
• Sascha Ceylan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2011, 7, 1441–1448, doi:10.3762/bjoc.7.168

• -type cycloadditions The copper-catalyzed Huisgen-type cycloaddition (CuAAC) is a general and useful method for the synthesis of 1,4-disubstituted-1,2,3-triazoles and is based on the 1,3-dipolar cycloaddition of alkynes and azides [28]. Besides Cu(I) sources also Cu(0) sources, such as copper wire [29

• ] or copper-on-charcoal (Cu/C) [30], can serve as a catalytic source that promotes the CuAAC. Bogdan et al. combined this observation with flow technology by using a custom-made heated copper flow reactor [31]. We successfully implemented the CuAAC by inductively heating copper wire inside a flow

Synthesis of glycoconjugate fragments of mycobacterial phosphatidylinositol mannosides and lipomannan

• Benjamin Cao,
• Jonathan M. White and
• Spencer J. Williams

Beilstein J. Org. Chem. 2011, 7, 369–377, doi:10.3762/bjoc.7.47

• –alkyne cycloaddition (CuAAC) reaction [33][34]. Results and Discussion Since their introduction by Palcic and co-workers [35], hydrophobic alkyl glycosides have proven to be valuable derivatives for enzymatic assays, as their lipophilic nature allows easy product isolation by either reversed-phase

New amphiphilic glycopolymers by click functionalization of random copolymers – application to the colloidal stabilisation of polymer nanoparticles and their interaction with concanavalin A lectin

• Otman Otman,
• Paul Boullanger,
• Eric Drockenmuller and
• Thierry Hamaide

Beilstein J. Org. Chem. 2010, 6, No. 58, doi:10.3762/bjoc.6.58

• cycloaddition of azide and alkynes, CuAAC) constitutes another interesting approach. The versatile nature of this reaction has led to a tremendous amount of work, mainly due to the quantitative yields and the possibility of carrying out the synthesis in either organic solvents or water. Moreover, since various

• ), 26.00–26.07 (C-6, C-8), 18.57 (C-3). Coupling of azido functionalized carbohydrates by CuAAC The dry copolymer (100 mg, containing approximately 75 mg, 0.68 mmol of propargyl acrylate) and compound 4 (229 mg, 1.0 equiv vs propargyl acrylate) were dissolved in a 1:1 mixture of THF and water (4 mL) at