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

• acid derivatives in a simple and efficient continuous-flow procedure is reported. The 1,3-dipolar cycloaddition reactions were performed with copper powder as a readily accessible Cu(I) source. Initially, high reaction rates were achieved under high-pressure/high-temperature conditions. Subsequently

• applications in numerous other areas of modern chemical sciences, such as bioconjugation [13], supramolecular chemistry, [14] and polymer sciences [15]. Probably the most useful and powerful procedure for the synthesis of 1,2,3-triazoles is the Huisgen 1,3-dipolar cycloaddition of organic azides with

Dipolar addition to cyclic vinyl sulfones leading to dual conformation tricycles

• Steven S. Y. Wong,
• Michael G. Brant,
• Christopher Barr,
• Allen G. Oliver and
• Jeremy E. Wulff

Beilstein J. Org. Chem. 2013, 9, 1419–1425, doi:10.3762/bjoc.9.159

• -broadening in the NMR spectra was found to depend on the presence of substitution next to the inverting nitrogen center. Keywords: DFT calculations; dipolar addition; fluxional behavior; sulfones; VT NMR; Introduction The 1,3-dipolar cycloaddition [1][2][3] represents a powerful methodology for the

Microwave-assisted three-component domino reaction: Synthesis of indolodiazepinotriazoles

• Rajesh K. Arigela,
• Sudhir K. Sharma,
• Brijesh Kumar and
• Bijoy Kundu

Beilstein J. Org. Chem. 2013, 9, 401–405, doi:10.3762/bjoc.9.41

• Abstract A microwave-assisted three-component protocol involving N-1 alkylation of 2-alkynylindoles with epichlorohydrin, ring opening of the epoxide with sodium azide, and an intramolecular Huisgen azide–internal alkyne 1,3-dipolar cycloaddition domino sequence has been described. The efficacy of the

• methodology has been demonstrated by treating various 2-alkynylindoles (aromatic/aliphatic) with epichlorohydrin and sodium azide furnishing annulated tetracyclic indolodiazepinotriazoles in satisfactory yields. Keywords: 2-alkynylindoles; azides; 1,3-dipolar cycloaddition; domino reaction

• ; indolodiazepinotriazoles; Introduction The intermolecular Huisgen azide–alkyne 1,3-dipolar cycloaddition reaction [1][2][3][4][5][6] for the synthesis of 1,2,3-triazoles in both aqueous [7][8][9][10] and organic solvents under either metal-catalyzed [11][12][13] or metal-free conditions [14][15][16] has received

Towards a biocompatible artificial lung: Covalent functionalization of poly(4-methylpent-1-ene) (TPX) with cRGD pentapeptide

• Lena Möller,
• Christian Hess,
• Jiří Paleček,
• Yi Su,
• Axel Haverich,
• Andreas Kirschning and
• Gerald Dräger

Beilstein J. Org. Chem. 2013, 9, 270–277, doi:10.3762/bjoc.9.33

• alternatively pursued a copper-free approach that relied on the oxanorbornadiene strategy of Rutjes [24][25][26][27][28]. This type of specific conjugation most likely proceeds by a 1,3-dipolar cycloaddition/retro-Diels–Alder cascade. By incubating oxanorbornadiene functionalized membranes 7b with cRGD

• ). Absorption maxima of fluorescein were located at 457 nm and 481 nm, which can be ascribed to the presence of two isomeric forms (lacton versus carboxylate) of fluorescein [31]. These measurements clearly revealed the successful covalent functionalization of TPX with fluorescein by 1,3-dipolar cycloaddition

• ) of the TPX membrane with an increased factor for the absorption intensity of about 65 compared to 8c. This remarkable result may be rationalized if one assumes that copper is not ideally distributed during the course of the 1,3-dipolar cycloaddition reaction, as the presence of the heterogeneous TPX

Asymmetric synthesis of γ-chloro-α,β-diamino- and β,γ-aziridino-α-aminoacylpyrrolidines and -piperidines via stereoselective Mannich-type additions of N-(diphenylmethylene)glycinamides across α-chloro-N-sulfinylimines

• Gert Callebaut,
• Sven Mangelinckx,
• Pieter Van der Veken,
• Karl W. Törnroos,
• Koen Augustyns and
• Norbert De Kimpe

Beilstein J. Org. Chem. 2012, 8, 2124–2131, doi:10.3762/bjoc.8.239

• , comparable non-halogenated trans-imidazolidines were already synthesized by 1,3-dipolar cycloaddition of N-benzylidene glycine ester enolates across N-sulfinylaldimines in the presence of a Lewis acid [43]. The trans-stereochemistry of imidazolidine 12b was ensured by the vicinal coupling constant 3JH4-H5

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

• Rutjes [68] as well as Sharpless [69] elegantly devised alternative approaches exploiting 1-haloalkynes [70], we became interested in exploring a single [71][72][73] inexpensive copper catalyst for one-pot reaction sequences comprising a 1,3-dipolar cycloaddition along with an intramolecular C–H bond

• sequential synthesis of 1,4-dihydrochromeno[3,4-d][1,2,3]triazole (4b, Scheme 2). We were delighted to observe that the desired reaction sequence consisting of a copper-catalyzed 1,3-dipolar cycloaddition and an intramolecular C–H bond arylation converted alkyne 1a to the desired product 4b with high

Parallel solid-phase synthesis of diaryltriazoles

• Matthias Wrobel,
• Jeffrey Aubé and
• Burkhard König

Beilstein J. Org. Chem. 2012, 8, 1027–1036, doi:10.3762/bjoc.8.115

• – Huisgen 1,3-dipolar cycloaddition of solid-phase-immobilized azides with terminal alkynes by copper(I) catalysis: An azide-functionalized Wang resin 7 or 9 (1 equiv) was preswollen in dimethylformamide (1.5 mL/100 mg resin) for 2 h at room temperature. The copper(I) catalyst was prepared in situ by using

• steps with water, dimethylformamide, methanol and dichloromethane (each solvent 3 × 2 mL/100 mg resin) were carried out. GP 3 – Huisgen 1,3-dipolar cycloaddition of solid-phase-immobilized azides with terminal or internal alkynes by ruthenium(II) catalysis: The azide functionalized Wang resin (1 equiv

Parallel and four-step synthesis of natural-product-inspired scaffolds through modular assembly and divergent cyclization

• Hiroki Oguri,
• Haruki Mizoguchi,
• Hideaki Oikawa,
• Aki Ishiyama,
• Masato Iwatsuki,
• Kazuhiko Otoguro and
• Satoshi Ōmura

Beilstein J. Org. Chem. 2012, 8, 930–940, doi:10.3762/bjoc.8.105

• (Scheme 3). According to the previously reported protocol [22], Ugi reaction employing allylamine (31) and stepwise installation of a diazoimide group provided 35 in good yield. Upon treatment of 35 with Rh2(OAc)4 in benzene under reflux, 1,3-dipolar cycloaddition of the ylide intermediate with the

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

Aryl nitrile oxide cycloaddition reactions in the presence of pinacol boronic acid ester

• Sarah L. Harding,
• Sebastian M. Marcuccio and
• G. Paul Savage

Beilstein J. Org. Chem. 2012, 8, 606–612, doi:10.3762/bjoc.8.67

• bonds, and 1,3-dipolar cycloaddition reactions to construct five-membered heterocycles are both powerful tools for assembling organic molecules. Used in combination, these tools offer great flexibility for strategies such as diversity-oriented synthesis [1], solution-phase combinatorial libraries [2

• convenient substrate would be the arylboronate nitrile oxide 1, which would undergo 1,3-dipolar cycloaddition to give isoxazolines 2. This latter compound could in turn be coupled with heterocycles or aryl groups to give insecticidal [5] derivatives of type 3 (Scheme 1). The utility of arylboronic acids and

• pinacolyl boronate esters have the advantage of being stable, readily handled compounds. The Huisgen 1,3-dipolar cycloaddition reaction is a powerful and versatile method for constructing five-membered heterocycles [12][13][14]. Nitrile oxide 1,3-dipoles react with carbon–carbon dipolarophiles, such as

Intramolecular carbenoid ylide forming reactions of 2-diazo-3-keto-4-phthalimidocarboxylic esters derived from methionine and cysteine

• Marc Enßle,
• Stefan Buck,
• Roland Werz and
• Gerhard Maas

Beilstein J. Org. Chem. 2012, 8, 433–440, doi:10.3762/bjoc.8.49

• rise to an annelated bicyclic substructure. In contrast, in our case as well as in [29], the olefinic dipolarophile is found as a substituent at a remote ring position of the cyclic carbonyl ylide, such that the intramolecular 1,3-dipolar cycloaddition generates a bridged oxabicyclo[3.2.1]octane

Synthesis of highly functionalized β-aminocyclopentanecarboxylate stereoisomers by reductive ring opening reaction of isoxazolines

• Melinda Nonn,
• Loránd Kiss,
• Reijo Sillanpää and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2012, 8, 100–106, doi:10.3762/bjoc.8.10

• , University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary 10.3762/bjoc.8.10 Abstract A rapid and simple procedure was devised for the synthesis of multifunctionalized cyclic β-amino esters and γ-amino alcohols via the 1,3-dipolar cycloaddition of nitrile oxides to β-aminocyclopentenecarboxylates. The

Photochemical and thermal intramolecular 1,3-dipolar cycloaddition reactions of new o-stilbene-methylene-3-sydnones and their synthesis

• Kristina Butković,
• Željko Marinić,
• Krešimir Molčanov,
• Biserka Kojić-Prodić and
• Marija Šindler-Kulyk

Beilstein J. Org. Chem. 2011, 7, 1663–1670, doi:10.3762/bjoc.7.196

• hybrids of a number of mesomeric ionic structures (Figure 1). One of the most characteristic reactions of sydnones is the intermolecular 1,3-dipolar cycloaddition. In the presence of acetylenic or ethylenic dipolarophiles, sydnones undergo cycloaddition reactions, which can be induced thermally [4][6][7

• such a system, where two chromophores, stilbene and sydnone, are divided by a methylene bridge, an intramolecular 1,3-dipolar cycloaddition and the formation of diverse polycyclic compounds could be expected. Herein we describe, for the first time, the synthesis of cis- and trans-3-(stilbenylmethyl

• , giving cycloadducts 11 or 12, respectively. We also performed the thermal intramolecular reactions with the starting compounds 3a and 3b. Theoretically the intramolecular 1,3-dipolar cycloaddition of the sydnone moiety, acting as a masked azomethine dipole, and the double bond of the stilbene moiety

Efficient synthesis of 1,3-diaryl-4-halo-1H-pyrazoles from 3-arylsydnones and 2-aryl-1,1-dihalo-1-alkenes

• Yiwen Yang,
• Chunxiang Kuang,
• Hui Jin,
• Qing Yang and
• Zhongkui Zhang

Beilstein J. Org. Chem. 2011, 7, 1656–1662, doi:10.3762/bjoc.7.195

• based on the condensation of hydrazines with 1,3-dicarbonyl compounds or their equivalents. However, the 1,3-dipolar cycloaddition offers a more convenient synthetic route. Sydnones are easily accessible aromatic compounds and versatile synthetic intermediates. They can be used as unusual, alternative

• stirred in the dark in a sealed tube maintained at 140 °C in an oil bath. After 16 h, the product 3a was isolated in 72% yield. The effects of different bases, molar ratios of 1a to 2a, solvents, and temperatures on the formation of 3a were investigated. The optimization of the 1,3-dipolar cycloaddition

• elimination of a hydrogen halide from 2-aryl-1,1-dihalo-1-alkenes 2 with Cs2CO3 as a base [36]. Then, haloalkyne reacts with 3-arylsydnone 1 in a 1,3-dipolar cycloaddition reaction. Finally, CO2 is lost [18][34] and pyrazole 3 is generated. Subsequently, the arylation reaction of pyrazoles 3 with iodobenzene

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

Recent developments in gold-catalyzed cycloaddition reactions

• Fernando López and
• José L. Mascareñas

Beilstein J. Org. Chem. 2011, 7, 1075–1094, doi:10.3762/bjoc.7.124

• -catalyzed synthesis of polycyclic, fully substituted furans from 1-(1-alkynyl)cyclopropyl ketones [45]. Gold-catalyzed 1,3-dipolar cycloaddition of 2-(1-alkynyl)-2-alken-1-ones with nitrones [47]. Enantioselective 1,3-dipolar cycloaddition of 2-(1-alkynyl)-2-alken-1-ones with nitrones [48]. Gold-catalyzed

• 1,3-dipolar cycloaddition of 2-(1-alkynyl)-2-alken-1-ones with α,β-unsaturated imines [49]. Gold-catalyzed (4 + 3) cycloadditions of 1-(1-alkynyl)oxiranyl ketones [50]. (3 + 2) Cycloaddition of gold-containing azomethine ylides [52]. Gold-catalyzed generation and reaction of azomethine ylides [53

Chiral gold(I) vs chiral silver complexes as catalysts for the enantioselective synthesis of the second generation GSK-hepatitis C virus inhibitor

• María Martín-Rodríguez,
• Carmen Nájera,
• José M. Sansano,
• Abel de Cózar and
• Fernando P. Cossío

Beilstein J. Org. Chem. 2011, 7, 988–996, doi:10.3762/bjoc.7.111

• , Apdo. 1072, E-20018 San Sebastián, Spain 10.3762/bjoc.7.111 Abstract The synthesis of a GSK 2nd generation inhibitor of the hepatitis C virus, by enantioselective 1,3-dipolar cycloaddition between a leucine derived iminoester and tert-butyl acrylate, was studied. The comparison between silver(I) and

• origin of the enantioselectivity of the chiral gold(I) catalyst was justified according to DFT calculations, the stabilizing coulombic interaction between the nitrogen atom of the thiazole moiety and one of the gold atoms being crucial. Keywords: BINAP; 1,3-dipolar cycloaddition; gold; HCV

• synthesis of the endo-pyrrolidine core of 5 is the key step for the preparation of these antiviral agents, and can be efficiently achieved by a 1,3-dipolar cycloaddition (1,3-DC) between the corresponding azomethine ylide and an alkyl acrylate [14][15][16][17][18] (Scheme 1). The first synthesis of racemic

High chemoselectivity in the phenol synthesis

• Matthias Rudolph,
• Melissa Q. McCreery,
• Wolfgang Frey and
• A. Stephen K. Hashmi

Beilstein J. Org. Chem. 2011, 7, 794–801, doi:10.3762/bjoc.7.90

• intermediates A or B. Apart from intermolecular trapping [26][27][28][29][30][31][32][33], intramolecular trapping of such carbenoids has also been reported [34]. One option would be to offer a competing carbonyl group, to produce a carbonyl ylide, which could then undergo a 1,3-dipolar cycloaddition [35]. The

• b). The latter would form intermediate H, which could then either afford product 17 via intramolecular 1,3-dipolar cycloaddition with the olefin, or could form the diene 19 by proton migration. The synthesis of 16 was only possible by a 9-step sequence (Scheme 8). The starting point was a Claisen

Synthetic applications of gold-catalyzed ring expansions

• David Garayalde and
• Cristina Nevado

Beilstein J. Org. Chem. 2011, 7, 767–780, doi:10.3762/bjoc.7.87

• formation of the 1,4-furan dipole (Scheme 21). In fact, a resonance structure of 60 can be envisaged entailing a gold–carbene and a carbonyl ylide 63. Upon 1,3-dipolar cycloaddition with the alkoxy vinyl ether, bridged bicycle 64 is formed. 1,2-Alkyl migration and bridge opening produces a spiro cation 66

Advances in synthetic approach to and antifungal activity of triazoles

• Kumari Shalini,
• Nitin Kumar,
• Sushma Drabu and
• Pramod Kumar Sharma

Beilstein J. Org. Chem. 2011, 7, 668–677, doi:10.3762/bjoc.7.79

• which an azide and an alkyne undergo a 1,3-dipolar cycloaddition reaction in the presence of a catalyst such as copper (Scheme 1) or ruthemium (Scheme 2) [27]. Some new synthetic methods for 1,2,3-triazoles are given below (Scheme 3, Scheme 4) [28][29]. Structure activity relationships have revealed

• occupies the most important place in the treatment of fungal diseases. The triazole derivatives noted below were synthesized by various groups and show antifungal activity. Novel 1,2,3-triazole-linked with β-lactam–bile acid conjugates were prepared via 1,3-dipolar cycloaddition reactions of azido β

• ]. Holla et al. synthesized triazole derivatives by the 1,3-dipolar cycloaddition reaction of 4-azido-8-trifluoromethylquinoline with ethyl acetoacetate and acetylacetone, respectively, and tested for antifungal activity against Candida albicans. Among the various synthesized compounds, 1-(1-(8

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• pyrazole [74]. However, preparation of the alkyne intermediates involves a number of steps and often requires extensive column chromatography, which makes it an unattractive method for synthesis on a larger scale (Scheme 48). A novel 1,3-dipolar cycloaddition between a nitrile imide 244 and an

Rh-Catalyzed rearrangement of vinylcyclopropane to 1,3-diene units attached to N-heterocycles

• Franca M. Cordero,
• Carolina Vurchio,
• Stefano Cicchi,
• Armin de Meijere and
• Alberto Brandi

Beilstein J. Org. Chem. 2011, 7, 298–303, doi:10.3762/bjoc.7.39

• domino 1,3-dipolar cycloaddition/thermal rearrangement sequence, were converted by Wittig methylenation to the corresponding vinylcyclopropanes (VCPs), which underwent rearrangement to 1,3-dienes in the presence of the Wilkinson Rh(I) complex under microwave heating. The previously unexplored Rh(I

• shift in the cyclopropanated 1,6-diradical intermediate, which in this case is probably facilitated by the enhanced mobility of the benzylic hydrogen and by the formation of the conjugationally stabilized imine 9 [11]. The 1,3-dipolar cycloaddition/thermal rearrangement domino reaction of BCP (2) with

• (Scheme 6). Conclusion Azaheterocycles 14, 15 and 17 containing a spiro-annelated VCP moiety have been synthesized starting from cyclic nitrones and BCP by a three-step two-pot sequence consisting of a 1,3-dipolar cycloaddition, thermal rearrangement and Wittig methylenation. These compounds in the

Calix[4]arene-click-cyclodextrin and supramolecular structures with watersoluble NIPAAM-copolymers bearing adamantyl units: “Rings on ring on chain”

• Bernd Garska,
• Monir Tabatabai and
• Helmut Ritter

Beilstein J. Org. Chem. 2010, 6, 784–788, doi:10.3762/bjoc.6.83

• -cyclodextrin combi-receptor (4) was synthesized via copper-catalyzed Huisgen 1,3-dipolar cycloaddition. Investigations of the interactions with an adamantyl moiety containing copolymer have been carried out, showing the existence of a supramolecular structure. Due to deprotonation of the calixarene moieties at

Addition of lithiated enol ethers to nitrones and subsequent Lewis acid induced cyclizations to enantiopure 3,6-dihydro-2H-pyrans – an approach to carbohydrate mimetics

• Fabian Pfrengle and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2010, 6, No. 75, doi:10.3762/bjoc.6.75

• further diversification of our pyran derivatives, e.g., by 1,3-dipolar cycloaddition leading to isoxazole derivatives [22] or, by addition of nucleophiles to this electrophilic unit [9]. Compounds 8 and 21 proved to be excellent precursors for the stereoselective preparation of enantiopure aminopyrans

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

• surface of the nanoparticles Results and Discussion Synthesis and characterization of the polymer surfactants Besides well-known functionalization of anhydride-based copolymers, the grafting of carbohydrate moieties on a polymer backbone by Huisgen [2 + 3] cycloaddition (CuI-catalyzed 1,3-dipolar

• 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