Regioselective quinazoline C2 modifications through the azide–tetrazole tautomeric equilibrium

• Dāgs Dāvis Līpiņš,
• Andris Jeminejs,
• Una Ušacka,
• Anatoly Mishnev,
• Māris Turks and
• Irina Novosjolova

Beilstein J. Org. Chem. 2024, 20, 675–683, doi:10.3762/bjoc.20.61

• a 4 M HCl solution in iPrOH, forming the respective hydrochlorides of terazosin [29][30] and prazosin [31][32] (Scheme 10). In addition, we explored some other reactions of the azido group, and derivatives 17 were used in CuAAC and Staudinger reactions, yielding products 20 and 21 (Scheme 11). For

• CuAAC reactions no conversion towards the desired triazolyl product 20 was observed in systems such as CuSO4·5H2O/sodium ascorbate/t-BuOH/H2O, CuSO4·5H2O/sodium ascorbate/THF/H2O, CuI/DIPEA/DCM. Instead, triazolyl derivatives 20 were synthesized using [Cu(MeCN)4]PF6/TBTA (tris(benzyltriazolylmethyl

Cycloaddition reactions of heterocyclic azides with 2-cyanoacetamidines as a new route to C,N-diheteroarylcarbamidines

• Pavel S. Silaichev,
• Tetyana V. Beryozkina,
• Vsevolod V. Melekhin,
• Valeriy O. Filimonov,
• Andrey N. Maslivets,
• Vladimir G. Ilkin,
• Wim Dehaen and
• Vasiliy A. Bakulev

Beilstein J. Org. Chem. 2024, 20, 17–24, doi:10.3762/bjoc.20.3

• synthesis of various nitrogen-containing heterocyclic compounds and have a variety of biological activities [1][2][3][4]. After the discovery of click chemistry [5][6] involving the CuAAC method of 1,2,3-triazole synthesis [7][8], there has been great interest of studing the chemical and biological

Aldiminium and 1,2,3-triazolium dithiocarboxylate zwitterions derived from cyclic (alkyl)(amino) and mesoionic carbenes

• Nedra Touj,
• François Mazars,
• Guillermo Zaragoza and
• Lionel Delaude

Beilstein J. Org. Chem. 2023, 19, 1947–1956, doi:10.3762/bjoc.19.145

• -disubstituted-1,2,3-triazole derivatives is readily achieved via the copper(I)-catalyzed [3 + 2] cycloaddition of an azide and a terminal alkyne (CuAAC) [63][64][65]. A further alkylation of the N3 position with an alkyl halide is an equally straightforward procedure that ultimately affords a large assortment

• ). The active catalytic species for the CuAAC reaction were generated by reducing copper(II) sulfate with sodium ascorbate according to literature procedures [66][67]. 2-Azido-1,3,5-trimethylbenzene (mesityl azide) was easily synthesized in a distinct, preliminary step through the Sandmeyer reaction of

Active-metal template clipping synthesis of novel [2]rotaxanes

• Cătălin C. Anghel,
• Teodor A. Cucuiet,
• Niculina D. Hădade and
• Ion Grosu

Beilstein J. Org. Chem. 2023, 19, 1776–1784, doi:10.3762/bjoc.19.130

• of the final [2]rotaxanes by active template copper(I)-catalyzed alkyne–azide cycloaddition (CuAAC) as key step of the synthesis. HRMS and NMR experiments have been performed to confirm the formation of the interlocked structures. Keywords: active-metal template; clipping; copper(I)-catalyzed alkyne

• primary alkyl bromides [36] and cooper(I)-catalyzed alkyne–azide cycloaddition (CuAAC) click chemistry [37]. In all these cases a templated metal ion–macrocycle complex is used to catalyze the rotaxane formation by connecting two components of the dumbbell-shaped molecule (Figure 1a). In this context, we

• molecule which catalyzes the macrocyclization reaction around the axle (Figure 1b). Results and Discussion In order to access the target [2]rotaxanes we made use of the CuAAC reaction, performed in the presence of a copper(I) N-heterocyclic carbene, a very stable and efficient class of catalysts used in

Selectivity control towards CO versus H₂ for photo-driven CO₂ reduction with a novel Co(II) catalyst

• Lisa-Lou Gracia,
• Philip Henkel,
• Olaf Fuhr and
• Claudia Bizzarri

Beilstein J. Org. Chem. 2023, 19, 1766–1775, doi:10.3762/bjoc.19.129

• complex obtainable via a straightforward synthesis, with improved solubility, concerning our previous Co(II) complexes [21]. Thus, the new Co(II) complex bears two 1-benzyl-4-(quinolin-2-yl)-1H-1,2,3-triazole (BzQuTr) units, that were obtained through a copper-catalyzed alkyne–azide cycloaddition (CuAAC

One-pot nucleophilic substitution–double click reactions of biazides leading to functionalized bis(1,2,3-triazole) derivatives

• Hans-Ulrich Reissig and
• Fei Yu

Beilstein J. Org. Chem. 2023, 19, 1399–1407, doi:10.3762/bjoc.19.101

• discovery of the copper-catalyzed alkyne azide (3 + 2) cycloaddition (CuAAC) [3][4], has dramatically changed the approaches to many problems in chemistry, supramolecular chemistry, materials science, biological chemistry and related fields (selected reviews: [5][6][7][8][9][10][11][12][13][14][15

• ]). Mechanistic aspects of the CuAAC have been studied in detail [16][17]. Whereas the traditional 1,3-dipolar cycloaddition (Huisgen reaction) [18][19][20] of azides and alkynes requires often – but not always – relatively harsh conditions and proceeds with moderate regioselectivity only [21], the copper

• situ are possible [23]. Later, examples were published showing that these methods are also compatible with the conditions of CuAAC. The earliest case was probably published by Fokin et al. [24][25], one of the inventors of the original copper-catalyzed (3 + 2) cycloaddition. Many examples of

CuAAC-inspired synthesis of 1,2,3-triazole-bridged porphyrin conjugates: an overview

• Dileep Kumar Singh

Beilstein J. Org. Chem. 2023, 19, 349–379, doi:10.3762/bjoc.19.29

• -dipolar cycloaddition reaction between an azide and a terminal alkyne, also popular as "click reaction" or CuAAC reaction. Moreover, the 1,2,3-triazole ring also serves as a spacer and an electron transfer bridge between the porphyrin and the attached chromophores. In order to provide a critical overview

• of the synthesis and properties of various porphyrin-triazole hybrids, this review will discuss some of the key reactions involved in the preparation of triazole-linked porphyrin conjugates. Keywords: azide–alkyne; click chemistry; CuAAC; 1,3-dipolar cycloaddition; porphyrin; 1,2,3-triazole

• includes a brief synthetic procedure with reaction conditions, product yields, and photophysical and other properties of the end products. Review Overview of CuAAC click reactions on porphyrins The CuAAC-inspired click reaction is particularly useful for the coupling of two different moieties comprising

Inline purification in continuous flow synthesis – opportunities and challenges

• Jorge García-Lacuna and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182

• -butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine on polystyrene) which is valuable for reaction scale-ups [75] is used. Alternatively, a CuAAc (copper-catalyzed azide–alkyne cycloaddition) reaction has been demonstrated where the copper catalyst is supported on an Amberlist A-21 resin

• continuous flow synthesis focus on palladium [85], cobalt [86], or copper (particularly useful for the widely used CuAAc) [87]. Nevertheless, the use of metal scavengers in large scale applications is limited as often discussed [88]. The use of a homogeneous scavenger as part of batch-based offline

Preparation of β-cyclodextrin-based dimers with selectively methylated rims and their use for solubilization of tetracene

• Konstantin Lebedinskiy,
• Volodymyr Lobaz and
• Jindřich Jindřich

Beilstein J. Org. Chem. 2022, 18, 1596–1606, doi:10.3762/bjoc.18.170

• silyl groups. Both other reagents used for the cleavage in CD chemistry (TBAF and BF3.Et2O) yielded byproducts that unnecessarily complicated the purification. The CuAAC "click reaction" in CD chemistry is also a well-known approach, allowing coupling reactions of azido-containing CDs with different

• desymmetrization of the molecule caused by a partial and reversible self-inclusion of the triazole moiety into the CD cavity, as was previously studied in detail for the CD dimers prepared by CuAAC reaction [15]. Although such self-inclusion was not prominent for dimers based on the short propargyl ether linker

Scope of tetrazolo[1,5-a]quinoxalines in CuAAC reactions for the synthesis of triazoloquinoxalines, imidazoloquinoxalines, and rhenium complexes thereof

• Laura Holzhauer,
• Chloé Liagre,
• Olaf Fuhr,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2022, 18, 1088–1099, doi:10.3762/bjoc.18.111

• , Germany 10.3762/bjoc.18.111 Abstract The conversion of tetrazolo[1,5-a]quinoxalines to 1,2,3-triazoloquinoxalines and triazoloimidazoquinoxalines under typical conditions of a CuAAC reaction has been investigated. Derivatives of the novel compound class of triazoloimidazoquinoxalines (TIQ) and rhenium(I

• investigated and the denitrogenative annulation towards imidazoloquinoxalines could be observed as a competing reaction depending on the alkyne concentration and the substitutions at the quinoxaline. Keywords: click reaction; CuAAC; denitrogenative annulation; imidazole; metal complexes; quinoxaline

• nitrogen-enriched quinoxaline-based structures. Literature-known procedures for such a quinoxaline modification starting from tetrazolo[1,5-a]quinoxalines 1 are the synthesis of 1,2,3-triazoloquinoxalines 3 via copper-catalyzed azide–alkyne cycloaddition (CuAAC) [10] and the synthesis of imidazo[1,2-a

Heteroleptic metallosupramolecular aggregates/complexation for supramolecular catalysis

• Prodip Howlader and
• Michael Schmittel

Beilstein J. Org. Chem. 2022, 18, 597–630, doi:10.3762/bjoc.18.62

• computations [110]. Once the second click reaction has occurred, the rotaxane is liberated under release of strain in the catalyst if there was a distance mismatch. For cases with a close match of distances, product inhibition reduced the yield. Due to the high relevance of the CuAAC approach [111] for the

Synthesis of a new water-soluble hexacarboxylated tribenzotriquinacene derivative and its competitive host–guest interaction for drug delivery

• Man-Ping Li,
• Nan Yang and
• Wen-Rong Xu

Beilstein J. Org. Chem. 2022, 18, 539–548, doi:10.3762/bjoc.18.56

• synthesized starting from the known TBTQ-based hexakis(propargyl ether) 1 [29] (Scheme 1a). Through the CuAAC reaction with ethyl azidoacetate under Cu(I) catalysis, the TBTQ-based hexakis(ethyl acetate) compound 2 was obtained in 73% yield. Subsequent hydrolysis with sodium hydroxide followed by

Anomeric 1,2,3-triazole-linked sialic acid derivatives show selective inhibition towards a bacterial neuraminidase over a trypanosome trans-sialidase

• Peterson de Andrade,
• Sanaz Ahmadipour and
• Robert A. Field

Beilstein J. Org. Chem. 2022, 18, 208–216, doi:10.3762/bjoc.18.24

• sialic acid derivatives in good yields and high purity via copper-catalysed azide–alkyne cycloaddition (CuAAC, click chemistry) and evaluated their activity towards TcTS and neuraminidase. Surprisingly, the compounds showed practically no TcTS inhibition, whereas ca. 70% inhibition was observed for

• (CuAAC, click chemistry), from α-azidosialic acid 1 and commercially available terminal alkynes (Figure 2B), and assessed their inhibitory activity towards TcTS and bacterial neuraminidase. Results and Discussion Synthesis of sialic acid derivatives A small series of anomeric 1,2,3-triazole-linked sialic

• acid derivatives was synthesised as outlined in Figure 2B. Emulating our previous work with anomeric azide CuAAC click chemistry [17][22][23][24], the well-known α-azidosialic acid 1 [25] was synthesised from N-acetylneuraminic acid in four steps [26] in good overall yield (55%). The assignment of the

Exfoliated black phosphorous-mediated CuAAC chemistry for organic and macromolecular synthesis under white LED and near-IR irradiation

• Azra Kocaarslan,
• Zafer Eroglu,
• Önder Metin and
• Yusuf Yagci

Beilstein J. Org. Chem. 2021, 17, 2477–2487, doi:10.3762/bjoc.17.164

• , Turkey King Abdulaziz University, Faculty of Science, Chemistry Department, 21589 Jeddah, Saudi Arabia 10.3762/bjoc.17.164 Abstract The development of long-wavelength photoinduced copper-catalyzed azide–alkyne click (CuAAC) reaction routes is attractive for organic and polymer chemistry. In this study

• , we present a novel synthetic methodology for the photoinduced CuAAC reaction utilizing exfoliated two-dimensional (2D) few-layer black phosphorus nanosheets (BPNs) as photocatalysts under white LED and near-IR (NIR) light irradiation. Upon irradiation, BPNs generated excited electrons and holes on

• its conduction (CB) and valence band (VB), respectively. The excited electrons thus formed were then transferred to the CuII ions to produce active CuI catalysts. The ability of BPNs to initiate the CuAAC reaction was investigated by studying the reaction between various low molar mass alkyne and

(Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia

• Luiz Claudio Ferreira Pimentel,
• Lucas Villas Boas Hoelz,
• Henayle Fernandes Canzian,
• Frederico Silva Castelo Branco,
• Andressa Paula de Oliveira,
• Vinicius Rangel Campos,
• Floriano Paes Silva Júnior,
• Rafael Ferreira Dantas,
• Jackson Antônio Lamounier Camargos Resende,
• Anna Claudia Cunha,
• Nubia Boechat and
• Mônica Macedo Bastos

Beilstein J. Org. Chem. 2021, 17, 2260–2269, doi:10.3762/bjoc.17.144

• cycloaddition reactions via the copper-catalyzed 1,3-dipolar cycloaddition reaction (CuAAC) of the azides 5 and 9 with suitably functionalized acetylenes 6a–j, using sodium ascorbate and copper sulfate in ACN/H2O 2:1 under microwave irradiation were carried out to obtain the 1,4-regioisomers of the final

A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• -catalyzed azide–alkyne cycloaddition (CuAAC) for the synthesis of 1,4-disubstituted 1,2,3-triazole derivatives was initially discovered by the groups of Meldal and Sharpless. Then, Ru-catalyzed azide–alkyne cycloaddition (RuAAC), affording selectively 1,5-disubstituted 1,2,3-triazoles, was introduced [38

• corresponding product under the standard conditions, denoting that the reaction did not include the sequence of CuAAC followed by C–H activation. According to these facts, the reaction mechanism may be as below. First, the copper(I)-substituted acetylide 78 was generated via the reaction of the copper source

• disulfide (97) was reported by Xu et al. The reaction has been achieved using a catalytic amount of CuI, LiOt-Bu, and 4 Å molecular sieves in THF as solvent at 40 °C under N2 atmosphere for 12 h and proceeds via a multicomponent CuAAC/persulfuration sequence. The strategy features a wide substrate scope

Double-headed nucleosides: Synthesis and applications

• Vineet Verma,
• Jyotirmoy Maity,
• Vipin K. Maikhuri,
• Ritika Sharma,
• Himal K. Ganguly and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2021, 17, 1392–1439, doi:10.3762/bjoc.17.98

• the nucleophilic opening of O-2,2′-anhydrouridine [44]. The azido nucleoside 12 was reacted with N6-benzoyl-N9-propargyladenine (13a) and N1-propargylthymine (13b) via a CuAAC reaction where the triazole-containing linker connected the additional thymine or adenine to the 2′-position of 2

• -ethynylpyrene (40) under copper-catalyzed alkyne–azide cycloaddition (CuAAC) reaction conditions to yield the double-headed nucleoside 41 (Scheme 10) [23]. The double-headed nucleoside 41 was phosphitylated and then incorporated into oligonucleotides and was found to form highly stable DNA duplexes and three

• nucleosides were further reacted with propargylated nucleobases through a copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction followed by treatment with methanolic ammonia to give the C-3′-substituted double-headed ribofuranonucleosides 46a–c and 50a–e (Scheme 11) [36]. The double-headed nucleosides

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

1,2,3-Triazoles as leaving groups: S_NAr reactions of 2,6-bistriazolylpurines with O- and C-nucleophiles

• Dace Cīrule,
• Irina Novosjolova,
• Ērika Bizdēna and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 410–419, doi:10.3762/bjoc.17.37

• (CuAAC) reaction provides the target product IV (Scheme 1, pathway A) [59][60][61]. Pathway B is designed on the basis of our group investigations on the synthesis of 2,6-bistriazolylpurine derivatives and their application in reactions with N-, S- and P-nucleophiles making use of regioselective SNAr

• reactions at C(6) (V→VI→IV, Scheme 1) [11][14][62][63][77][78]. The main advantage of pathway B is a straightforward access to 2,6-diazidopurines V and 2,6-bistriazolylpurines VI due to excellent nucleophilic properties of the azide ion and well-established CuAAC reaction. Pathway B also avoids performing

• -bistriazolylpurine derivatives 2a–c were obtained in the synthetic procedures developed by us before [11][14][67]. The CuAAC reaction was performed between diazide derivatives 1a and 1b and phenylacetylene or methyl propiolate (Scheme 2). SNAr reactions between bistriazolylpurine derivatives and O-nucleophiles were

1,2,3-Triazoles as leaving groups in S_NAr–Arbuzov reactions: synthesis of C6-phosphonated purine derivatives

• Kārlis-Ēriks Kriķis,
• Irina Novosjolova,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 193–202, doi:10.3762/bjoc.17.19

• chlorine at the purine C2 position by azide, and 3) copper-catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC) with different alkynes. Pathway B included: 1) the two-step synthesis of 2,6-bistriazolylpurine derivatives 6 from 2,6-dichloropurine derivative 1 [22] and 2) the SNAr–Arbuzov reaction with

• crude reaction mixtures revealed the presence of the products 7a and 8a (Scheme 3). When the latter mixture was submitted to CuAAC with phenylacetylene (CuI/Et3N/AcOH/EtOH (or DCM), CuSO4∙5H2O/sodium ascorbate/EtOH (or DMF)), no triazole formation at the purine C2 position was observed. We briefly tried

• reaction of the Cl atom at the C2 position of purine with an excess of NaN3, and after chromatographic isolation. We obtained the pure azido-substituted phosphonate monoesters 9a and 9b in 28 and 23% yield, respectively (Scheme 4). The products 9a and 9b were further submitted to CuAAC reactions, but the

Changed reactivity of secondary hydroxy groups in C8-modified adenosine – lessons learned from silylation

• Jennifer Frommer and
• Sabine Müller

Beilstein J. Org. Chem. 2020, 16, 2854–2861, doi:10.3762/bjoc.16.234

• cycloaddition (CuAAC) became very popular [16]. A variant of this, the strain-promoted alkyne–azide cycloaddition (SPAAC) even offers the possibility of in cell application, as applies also to the inverse electron-demand Diels–Alder reaction (IEDDA) [17][18]. In vitro, often a combination of orthogonal methods

• is desired, in order to introduce two or even more functionalities in a specific manner. For example, in earlier work we have used amine-NHS coupling reactions in combination with CuAAC to prepare double labeled RNA molecules for FRET analysis [19]. The conjugation of, sometimes rather large

Easy access to a carbohydrate-based template for stimuli-responsive surfactants

• Thomas Holmstrøm,
• Daniel Raydan and
• Christian Marcus Pedersen

Beilstein J. Org. Chem. 2020, 16, 2788–2794, doi:10.3762/bjoc.16.229

• commercially available levoglucosan. It was shown that the building block could undergo alkylations under strongly basic conditions. The building block with azido groups could furthermore take part in CuAAC reactions, generating derivatives with ester or carboxylic acid functionalities. In addition, the

• ]. Furthermore, starting from the azide 8, it was possible to achieve ester functionalities by a CuAAC reaction [23][24] in the presence of the two different alkynes 14 and 15, giving rise to the diester derivative 12 and the tetraester derivative 13 (Scheme 2). Subsequently, the esters could be hydrolyzed by

• group has earlier been used as metal chelator [25]. At this stage, it was possible to separate both anomers of the diazide 18 using flash column chromatography. The pure α-anomer was then subjected to a CuAAC reaction using 1-heptyne and, in only two steps, the new surfactant 19 could be prepared from

Water-soluble host–guest complexes between fullerenes and a sugar-functionalized tribenzotriquinacene assembling to microspheres

• Si-Yuan Liu,
• Xin-Rui Wang,
• Man-Ping Li,
• Wen-Rong Xu and
• Dietmar Kuck

Beilstein J. Org. Chem. 2020, 16, 2551–2561, doi:10.3762/bjoc.16.207

• 31% yield. The subsequent CuAAC reaction with 1-azido-2,3,4,6-tetraacetylglucose, which was prepared according to the reported method [39], in the presence of Cu(I) as the catalyst afforded the acetyl-protected, sugar-functionalized derivative TBTQ-(OAcG)6 in 50% yield. As expected, compound TBTQ

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

• cycloadditions with model alkynes. Besides two ortho- and para-bromo-substituted benzaldehydes, the azide functionalization of a fluorene-based structure will be presented. The copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) of the so-synthesized azide-functionalized bromocarbaldehydes with terminal

• oxazoline 24, oxazolidine 27 cyclized already during the reaction, caused by the increased basicity of the ring nitrogen. CuAAC reactions of bromocarbaldehydes We further investigated the reactivity of azide-functionalized bromocarbaldehydes 3, 4, and 5 in copper(I)-catalyzed azide–alkyne cycloaddition

• reactions (CuAAC). For this, we treated the azide-functionalized luminophores with alkynes exhibiting different degrees of steric demand, including 1-decyne (29), phenylacetylene (30), 1-ethynyladamantane (31) and 1,3-di-tert-butyl-5-ethynylbenzene (32, see Scheme 5). All triazoles 33–44, based on the

A systematic review on silica-, carbon-, and magnetic materials-supported copper species as efficient heterogeneous nanocatalysts in “click” reactions

• Pezhman Shiri and
• Jasem Aboonajmi

Beilstein J. Org. Chem. 2020, 16, 551–586, doi:10.3762/bjoc.16.52

• reaction proceeds under mild conditions, is effective, efficient, and requires no column purification in many cases. The Cu alkyne–azide cycloaddition (CuAAC) version also gives only 1,2,3-triazole products substituted at the 1- and 4-positions in an aqueous medium even at room temperature and requires no

• of product separation, catalyst recovery, simplifying the production process, and cleaner operation conditions [18][19][20]. Thus far, several heterogeneous catalysts have been explored for CuAAC and RuAAC processes. The catalytic activities of heterogeneous copper catalysts as novel catalysts are

• applications that focused on the title catalysts in CuAAC reactions. Review Copper anchored on functionalized silica materials: efficient and recyclable catalysts for CuAAC reactions In recent years, silica or silicon dioxide nanomaterials have received much attention from researchers and industry and have