Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• other hand, 4-(α-tetrasubstituted)alkyl-1,2,3-triazoles 45 can be obtained by a two-step reaction of cyclohexanone, amines, silylacetylene, and aryl or alkyl azides in the presence of copper(II) catalysts (Scheme 34) [53]. In a first step, there is the formation of a propargylamine derivative XLIII

• isoxazole-linked imidazo[1,2-a]azines 35. Synthesis of 2,3-dihydro-1,2,4-triazoles 36. Synthesis of naphthopyrans 37. Synthesis of benzo[g]chromene derivatives 38. Synthesis of naphthalene annulated 2-aminothiazoles 39, piperazinyl-thiazoloquinolines 40 and thiazolocoumarins 41. Synthesis of furo[3,4-b

• ]pyrazolo[4,3-f]quinolinones 42. Synthesis of spiroindoline-3,4’-pyrano[3,2-b]pyran-4-ones 43. Synthesis of N-(α-alkoxy)alkyl-1,2,3-triazoles 44. Synthesis of 4-(α-tetrasubstituted)alkyl-1,2,3-triazoles 45. Funding This work has been supported by Università degli Studi dell’Insubria and Università degli

Germanyl triazoles as a platform for CuAAC diversification and chemoselective orthogonal cross-coupling

• John M. Halford-McGuff,
• Thomas M. Richardson,
• Aidan P. McKay,
• Frederik Peschke,
• Glenn A. Burley and
• Allan J. B. Watson

Beilstein J. Org. Chem. 2024, 20, 3198–3204, doi:10.3762/bjoc.20.265

• 10.3762/bjoc.20.265 Abstract We report the synthesis of germanyl triazoles formed via a copper-catalysed azide–alkyne cycloaddition (CuAAC) of germanyl alkynes. The reaction is often high yielding, functional group tolerant, and compatible with complex molecules. The installation of the Ge moiety enables

• towards the synthesis of germanyl triazoles. These reagents are generally compatible but seem to be less reactive than other classes of alkyne. The germanyl alkyne CuAAC is applicable to functional group-rich molecules, opening opportunities for downstream diversification by chemoselective

• ) Functionalisation of germylated triazoles. Isolated yields unless stated. (i) Pd(PPh3)4 (10 mol %), 2-bromothiazole (1.2 equiv), KCl (3.0 equiv), PhMe/EtOH 4:1, N2, 100 °C, 16 h. NMR yield in parentheses. (ii) Pd2(dba)3 (2.5 mol %), iodobenzene (1.5 equiv), AgBF4 (1.5 equiv), DMF, N2, 80 °C, 16 h. (iii) NBS (2.0

Synthesis of the 1,5-disubstituted tetrazole-methanesulfonylindole hybrid system via high-order multicomponent reaction

• Cesia M. Aguilar-Morales,
• América A. Frías-López,
• Nadia V. Emilio-Velázquez,
• Alejandro Islas-Jácome,
• Angelica Judith Granados-López,
• Jorge Gustavo Araujo-Huitrado,
• Yamilé López-Hernández,
• Hiram Hernández-López,
• Luis Chacón-García,
• Jesús Adrián López and
• Carlos J. Cortés-García

Beilstein J. Org. Chem. 2024, 20, 3077–3084, doi:10.3762/bjoc.20.256

• the application of this reagent as a central building block in the synthesis of hybrid systems via Ugi-azide reactions, including structures based on triazoles-tetrazoles [24][26][27], benzofuran-tetrazoles [23] and indolizines-tetrazoles [25], all of which have significant relevance in medicinal

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• auxiliary enhanced the arylation yields. Hypervalent iodonium salts are also useful to achieve the N-arylation of azoles. Prakash and co-workers applied iodonium salts 48 in the presence of a base to obtain regioselectively the N2-arylated products of 1,2,3-triazoles via ligand exchange followed by

• reductive elimination in exceptional yields (Scheme 20) [71]. Although screening studies indicated the possibility of achieving the N-arylation at both, the N1- and N2-positions of the triazoles, N2-arylation was predominantly observed. It was incredible to achieve splendid regioselectivity without the

• usage of directing groups and any metal catalyst. Also, the electronic nature of a substituent at the C4 position of the starting triazole did not negatively impact the regioselectivity. Further, C4 and C5 disubstituted triazoles also produced the N2-arylated product. Remarkably, this is the only

Synthesis and antimycotic activity of new derivatives of imidazo[1,2-a]pyrimidines

• Dmitriy Yu. Vandyshev,
• Daria A. Mangusheva,
• Khidmet S. Shikhaliev,
• Kirill A. Scherbakov,
• Oleg N. Burov,
• Alexander D. Zagrebaev,
• Tatiana N. Khmelevskaya,
• Alexey S. Trenin and
• Fedor I. Zubkov

Beilstein J. Org. Chem. 2024, 20, 2806–2817, doi:10.3762/bjoc.20.236

• -spectrum antifungal agents. Among the many drugs and hits, the azole-based systems (including triazoles and imidazoles) are of particular importance in this context. Their mechanism of action is the inhibition of the activity of the enzyme lanosterol 14α-demethylase (CYP51), which is encoded by the CYP51

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• Sonogashira cyclization sequence from (triisopropylsilyl)butadiyne (118). Subsequent immediate desilylation and Click reaction with organoazides lead to 4-pyrazolyl-1,2,3-triazoles 119 (Scheme 42) [139]. Notably, in some examples, it was even possible to synthesize the organoazides in situ from alkyl halides

• and cesium azide for the synthesis of compounds 120. The choice of the hydrazine substituent represents a limitation, as no aromatic substituents are tolerated in the strategy due to the reduced reactivity. However, due to the building blocks’ simplicity, various 4-pyrazolyl-1,2,3-triazoles are

Harnessing the versatility of hydrazones through electrosynthetic oxidative transformations

• Aurélie Claraz

Beilstein J. Org. Chem. 2024, 20, 1988–2004, doi:10.3762/bjoc.20.175

• 2018, Yuan and Yang developed a multicomponent synthesis of 1-aryl and 1,5-disubstitued 1,2,4-triazoles using tetrabutylammonium iodide as electromeditor [49]. 1-Methylene-2-arylhydrazine 52 was in situ generated through the condensation of paraformaldehyde 51 with arylhydrazines 50, while the

• atom abstraction by iodide radical and deprotonation. Inspired by these works, Li and Gu et al. proposed the electrosynthesis of 1,3,5-trisubstituted 1,2,4-triazoles from preformed aldehyde-derived N-arylhydrazones 60, aldehydes 61 and ammonium acetate. Herein, the authors suggested the electromediated

• oxidation of N-arylhydrazone by electrogenerated iodide radical (Scheme 11) [50]. In parallel, the group of Yuan achieved the electrosynthesis of 1,3,5-trisubstituted 1,2,4-triazoles 67 from arylhydrazines 64, aldehydes 65 and primary amines 66. Iodine-mediated electrooxidation of in situ-generated aldehyde

2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space

• Carlos Nieto,
• Alejandro Manchado,
• Ángel García-González,
• David Díez and
• Narciso M. Garrido

Beilstein J. Org. Chem. 2024, 20, 1880–1893, doi:10.3762/bjoc.20.163

• originally synthesized by Palazzo et al. [76] and several other derivatives were developed based on ethylamine-chain homologation [77]. Triazoles: Hall and co-workers [78] developed 1,2,3-triazolyl analogues 111 of ʟ-histidine for ʟ-type amino acid transporter 1 (LAT1) activity, a sodium-independent membrane

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

Synthesis of substituted triazole–pyrazole hybrids using triazenylpyrazole precursors

• Simone Gräßle,
• Laura Holzhauer,
• Nicolai Wippert,
• Olaf Fuhr,
• Martin Nieger,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2024, 20, 1396–1404, doi:10.3762/bjoc.20.121

• ][2]. We are interested in feasible strategies to synthesize nitrogen-rich heterocyclic scaffolds that can extend the currently available libraries with new drug-like molecules. Our past work on pyrazoles [3][4][5][6] and triazoles [7][8][9][10][11] motivated us to search for suitable and versatile

• -mediated reaction with alkyl halides [21]. So far, the literature-reported methods are most often limited to N-unsubstituted pyrazoles or triazoles and pyrazoles being fused to a second (hetero)cycle; the synthesis of promising multi-substituted structures such as 1 has not yet been described

Synthesis of 1,2,3-triazoles containing an allomaltol moiety from substituted pyrano[2,3-d]isoxazolones via base-promoted Boulton–Katritzky rearrangement

• Constantine V. Milyutin,
• Andrey N. Komogortsev and
• Boris V. Lichitsky

Beilstein J. Org. Chem. 2024, 20, 1334–1340, doi:10.3762/bjoc.20.117

• ]isoxazolone derivatives with various hydrazines was studied. It was shown that the considered process includes formation of corresponding hydrazones followed by Boulton–Katritzky rearrangement. As a result, the general method for the synthesis of substituted 1,2,3-triazoles bearing an allomaltol fragment was

• types of aforementioned structures were proved by X-ray analysis. Keywords: allomaltol; Boulton–Katritzky rearrangement; hydrazones; pyrano[2,3-d]isoxazolones; recyclization; 1,2,3-triazoles; Introduction The Boulton–Katritzky rearrangement (BKR) also known as mononuclear heterocyclic rearrangement is

• participation of hydrazones attract special attention. This reaction is a general method for the preparation of 1,2,3-triazoles bearing various substituents at position 2. Wherein, depending on the type of starting heterocycles various functional derivatives are formed. So, the well-known Boulton–Katritzky

Mild and efficient synthesis and base-promoted rearrangement of novel isoxazolo[4,5-b]pyridines

• Vladislav V. Nikol’skiy,
• Mikhail E. Minyaev,
• Maxim A. Bastrakov and
• Alexey M. Starosotnikov

Beilstein J. Org. Chem. 2024, 20, 1069–1075, doi:10.3762/bjoc.20.94

• ]triazol-4-yl)pyridines was observed. Keywords: aromatic nitro compounds; Boulton–Katritzky rearrangement; isoxazolo[4,5-b]pyridines; nucleophilic substitution; 1,2,3-triazoles; Introduction Nitrogen heterocycles represent a very important class of organic compounds that has found application in various

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

• properties of the triazoles thus obtained [9][10][11][12]. It should be noted that the synthesis of amidines containing other heterocycles in addition to 1,2,3-triazole in the molecule has not been described in the literature. In this regard, it is of interest to develop an effective method for the synthesis

• of the substituents in azides 2 was observed. We assume the higher yield of pyrimidine containing triazoles 3a–k by their lower solubility in 1,4-dioxane compared with the solubility of azole containing compounds 3l–s in both 1,4-dioxane and ethanol. With regard to the scope of diaminoacrylonitriles

• the structure of the prepared compounds. To explain the outcome of the tandem reaction of 3,3-diaminoacrylonitriles to heterocyclic azides, a tentative mechanism for the formation of 1,2,3-triazoles 3 from acrylonitriles 1 and azides 2 is shown in Scheme 3. Firstly, treatment with a base, leads to

N-Boc-α-diazo glutarimide as efficient reagent for assembling N-heterocycle-glutarimide diads via Rh(II)-catalyzed N–H insertion reaction

• Grigory Kantin,
• Pavel Golubev,
• Alexander Sapegin,
• Alexander Bunev and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2023, 19, 1841–1848, doi:10.3762/bjoc.19.136

• the preparation of modified glutarimides with a wide range of aromatic and aliphatic NH-heterocycles under mild conditions in moderate to high yields. It is shown that electron-rich substrates tend to give C–H insertion products. The N-modification of tetrazoles and 1,2,4-triazoles using a

Trifluoromethylated hydrazones and acylhydrazones as potent nitrogen-containing fluorinated building blocks

• Zhang Dongxu

Beilstein J. Org. Chem. 2023, 19, 1741–1754, doi:10.3762/bjoc.19.127

• trifluoromethylated 1,2,4-triazoles were synthesized with excellent regioselectivities in [3 + 2] cycloaddition reactions of trifluoromethylated hydrazonoyl chlorides with imidates, amidine and 1H-benzo[d]imidazole-2-thiols, all of which were individually reported by Wang, Deng and Cai, respectively [77][78][79

Morpholine-mediated defluorinative cycloaddition of gem-difluoroalkenes and organic azides

• Tzu-Yu Huang,
• Mario Djugovski,
• Sweta Adhikari,
• Destinee L. Manning and
• Sudeshna Roy

Beilstein J. Org. Chem. 2023, 19, 1545–1554, doi:10.3762/bjoc.19.111

• gem-difluoroalkenes with organic azides in morpholine as a solvent to construct fully decorated morpholine-substituted 1,2,3-triazoles. Mechanistic studies revealed the formation of an addition–elimination intermediate of morpholine and gem-difluoroalkenes prior to the triazolization reaction via two

• plausible pathways. Attractive elements include the regioselective and straightforward direct synthesis of fully substituted 1,2,3-triazoles, which are otherwise difficult to access, from readily available starting materials. Keywords: [3 + 2] cycloaddition; defluorination; fully decorated 1,2,3-triazoles

• -trisubstituted-1,2,3-triazoles, with a pendant morpholine at the C-4 position are formed with complete regiocontrol via β-fluoride elimination in an SNV-like transformation (Figure 1C). 1,2,3-Triazoles are a privileged scaffold in medicinal chemistry with a myriad of pharmacological activities against cancer [11

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

• nucleophilic substitutions employing sodium azide and organic substrates with potential leaving groups have been reported. The resulting organic azides were trapped in situ by a suitable alkyne to give the 1,2,3-triazoles [26][27][28][29][30][31][32][33][34][35][36]. Fairly recent review articles summarize

• was also discussed in a review article [57] dealing with the various types of bis(1,2,3-triazoles). Since we were not interested in compounds such as 4 we did not further investigate details in order to optimize this process. Instead, we looked at the one-pot nucleophilic substitution to generate

• led to the expected bis(1,2,3-triazoles) 20 or 21 in moderate or very good yield (Scheme 6). We cannot decide whether the lower yields in this series are caused by the unprotected hydroxy group of precursor 19 or the corresponding products. Although we did not isolate the conceivable mono-adducts we

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

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

• , which also improves safety issues as it traps toxic and explosive reactive intermediates (Scheme 7) [76]. Additional studies include a 3-step reaction to form triazoles in good yields [77], and the synthesis of the bisoxazole natural product siphonazole A using immobilized species [78]. The use of real

A novel bis-triazole scaffold accessed via two tandem [3 + 2] cycloaddition events including an uncatalyzed, room temperature azide–alkyne click reaction

• Ksenia Malkova,
• Andrey Bubyrev,
• Vasilisa Krivovicheva,
• Dmitry Dar’in,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1636–1641, doi:10.3762/bjoc.18.175

• proceeded further, in uncatalyzed fashion at room temperature and yielded, after intramolecular azide–alkyne click reaction novel, structurally intriguing bistriazoles. Keywords: α-acetyl-α-diazomethane sulfonamide; intramolecular click reaction; uncatalyzed; room temperature; 1,2,3-triazoles

• ; Introduction 1,2,3-Triazoles are well-established heterocycles in drug discovery [1] and are even considered pharmacophores (i.e., structural motifs defining the compound’s biological activity profile) on their own [2]. Therefore, synthetic methods allowing to construct a 1,2,3-triazole heterocycle are a

• valuable part of the drug discovery chemistry toolbox. For the same reason, development of new methods [3] to either build 1,2,3-triazoles de novo and/or incorporate them into polycyclic scaffolds is a worthy undertaking which can help discover biological activity associated with hitherto unattainable

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

• diversity of metal complexes incorporating 1,2,3-triazoles as ligands have been reported [16][17][18]. Triazole ligands with N-heterocycles such as Pyta (4-(2-pyridyl)-1,2,3-triazole) and related structures were employed to obtain novel metal complexes as catalysts [19][20] and imaging probes [21], as well

• desired product 16 whereas addition of zinc powder seems to have different effects depending on the derivative (see Supporting Information File 1). We could then show that the conversion of tetrazoles to both triazoles and imidazoles can occur together in the same molecule. When bis(tetrazolo)[1,5-a:5',1

Synthesis of novel alkynyl imidazopyridinyl selenides: copper-catalyzed tandem selenation of selenium with 2-arylimidazo[1,2-a]pyridines and terminal alkynes

• Mio Matsumura,
• Kaho Tsukada,
• Kiwa Sugimoto,
• Yuki Murata and
• Shuji Yasuike

Beilstein J. Org. Chem. 2022, 18, 863–871, doi:10.3762/bjoc.18.87

• -triazoles [33]. Based on these findings, we examined the reaction of Cu-mediated AAC. The reaction of 4aa with benzyl azide in the presence of one equivalent of CuI and pentamethyldiethylenetriamine (PMDETA) in THF at 60 °C gave the desired 5-selanyl-1,2,3-triazole 8 in 72% yield. This reaction yielded a

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• coupled with in situ generation of the azide from the corresponding bromide. The 1,2,3-triazoles are formed in up to 99% yield and in less than 10 minutes residence time, which includes azide formation prior to the cycloaddition step. Interestingly, this process could not be successfully repeated under

1,2-Naphthoquinone-4-sulfonic acid salts in organic synthesis

• Ruan Carlos B. Ribeiro,
• Patricia G. Ferreira,
• Amanda de A. Borges,
• Luana da S. M. Forezi,
• Fernando de Carvalho da Silva and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 53–69, doi:10.3762/bjoc.18.5

• involving the addition of arylamines to β-NQS 18 followed by N-alkynylation and then Cu(I)-catalyzed heterocyclization with tosyl azide in toluene at room temperature, leading to triazoles 50c–k in moderate to excellent yields (Scheme 14). The research group that most explored the formation of heterocycles

• -naphthoquinones. Synthesis of 4-semicarbazide-1,2-naphthoquinone. Reactions of 4-azido-1,2-naphthoquinone. Derivatives of 1,2-naphthoquinones obtained from β-NQS. Oximes as well as 4-amino- and 4-phenoxy-1,2-naphthoquinone as potential anti-inflammatory agents. Synthesis of triazoles from β-NQS. Synthesis of

Ligand-dependent stereoselective Suzuki–Miyaura cross-coupling reactions of β-enamido triflates

• Tomáš Chvojka,
• Athanasios Markos,
• Svatava Voltrová,
• Radek Pohl and
• Petr Beier

Beilstein J. Org. Chem. 2021, 17, 2657–2662, doi:10.3762/bjoc.17.179

• isomerization of N-allyl amides [20], but still possess drawbacks, especially for stereoselective synthesis of tri- and tetrasubstituted enamides. Recently, we have reported a triflic acid-mediated reaction of N-fluoroalkyl-1,2,3-triazoles leading to (Z)-β-enamido triflates [21] and Lewis acid-mediated reaction

• to (Z)-β-enamido fluorides [22] and halovinyl imidoyl halides [23]. In addition, Li and co-workers extended the scope of accessible (Z)-β-enamido triflates by denitrogenative reaction of N1-H-1,2,3-triazoles in the presence of acyl halides and sodium triflate [24]. These enamido triflates and halides