Formaldehyde surrogates in multicomponent reactions

• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Bernhard Westermann

Beilstein J. Org. Chem. 2025, 21, 564–595, doi:10.3762/bjoc.21.45

• esters of indazoles 26. In all these multicomponent reactions DMSO was applied to install a C1-bridge between two structural units that already have a heterocycle moiety incorporated. Dihalomethanes Dihalomethanes are good solvents for several organic syntheses. Their low boiling points and polar non

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

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

• . documented the synthesis of 1H-indazoles 9 via the electrooxidative cyclization of (hetero)aromatic ketones-derived N-phenylhydrazones 8 (Scheme 3) [38]. In contrast with the above-mentioned works, the electrolysis was carried out in an undivided cell under galvanostatic conditions. High yields were obtained

• applications in industry. Synthesis of triazolopyridinium salts [34][35][36]. Synthesis of pyrazoles [37]. Synthesis of indazoles from ketone-derived hydrazones [38]. Intramolecular C(sp2)–H functionalization of aldehyde-derived N-(2-pyridinyl)hydrazones for the synthesis of 1,2,4-triazolo[4,3-a]pyridines [39

Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations

• Pengcheng Lu,
• Luis Juarez,
• Paul A. Wiget,
• Weihe Zhang,
• Krishnan Raman and
• Pravin L. Kotian

Beilstein J. Org. Chem. 2024, 20, 1940–1954, doi:10.3762/bjoc.20.170

• compounds 6, 18, and 21 via natural bond orbital (NBO) analyses which further support the suggested reaction pathways. Keywords: DFT; indazole; indazole substitution; mechanism; N1-substituted indazole; N2-substituted indazole; regioselectivity; Introduction Indazoles constitute an important class of

• wide range of pharmacological activities, such as anti-inflammatory, anti-arrhythmic, antitumor, antifungal, antibacterial, and anti-HIV activities [7][8][9][10][11][12][13]. For example, two N1-substituted bioactive indazoles are found in Figure 1, danicopan (1), a complement factor D inhibitor for

• treatment of renal cell carcinoma, and Takeda’s MCHR1 antagonist 4 further exemplify indazole’s biological importance. Generally, direct alkylation of 1H-indazoles leads to a mixture of N1- and N2-substituted products [17][18][19][20]. Procedures that selectively produce either N1- or N2-substituted

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• unaffected by the presence of light (see pages 5 and 6 in Supporting Information File 1). In the case of indazoles, increased reaction rates were observed in the presence of light, but the overall yield was the same for the dark and irradiated experiments. Although these reactions are typically complete

• , showing that N-protection is not mandatory for this transformation. 3-Bromo- and 3-chloroindazoles offered moderate yields (39% and 48% for 2p and 2q, respectively), while 5-substituted 2r was isolated with 82% yield. In contrast to pyrazoles and indazoles, benzimidazoles and imidazoles required the

• , no reaction was observed with indazoles and furans using the first two conditions, requiring the formation of the ketoesters 4j and 4r first, followed by the functional group interconversion (FGI) with NH2OH·HCl (Scheme 6, blue and green sections). The Riley oxidation of the furanyl derivative 2j

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

• and efficiency in various XH insertion reactions [27][28][29]. In many cases (e.g., indoles, indazoles, benzotriazoles, tetrazoles, Scheme 3) the reaction progressed expeditiously (as indicated by gas evolution upon adding diazo reagent to the mixture of NH-substrate and catalyst) and was completed in

Recent advancements in iodide/phosphine-mediated photoredox radical reactions

• Tinglan Liu,
• Yu Zhou,
• Junhong Tang and
• Chengming Wang

Beilstein J. Org. Chem. 2023, 19, 1785–1803, doi:10.3762/bjoc.19.131

• functionalized coumarin derivatives and related nitrogen-containing heterocycles, opening up exciting possibilities for their diverse applications in other fields. Similarly, the regioselective photodecarboxylative C–H alkylation of 2H-indazoles and azauracils using NaI/PPh3 as mediators and redox esters 3 was

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

Synthesis and reactivity of azole-based iodazinium salts

• Thomas J. Kuczmera,
• Annalena Dietz,
• Andreas Boelke and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2023, 19, 317–324, doi:10.3762/bjoc.19.27

• . Next, the iodonium center was stabilized through an additional N-coordination via ortho-pyrazole substitution, giving the iodonium salts 5ba and 5bb in 88% and 50% yield. When replacing imidazoles by indazoles the oxidation was not as efficient giving the products 5bc and 5bd with only 24% and 44

Synthesis of N-phenyl- and N-thiazolyl-1H-indazoles by copper-catalyzed intramolecular N-arylation of ortho-chlorinated arylhydrazones

• Yara Cristina Marchioro Barbosa,
• Guilherme Caneppele Paveglio,
• Claudio Martin Pereira de Pereira,
• Sidnei Moura,
• Cristiane Storck Schwalm,
• Gleison Antonio Casagrande and
• Lucas Pizzuti

Beilstein J. Org. Chem. 2022, 18, 1079–1087, doi:10.3762/bjoc.18.110

• de Caxias do Sul, 95070-560, Caxias do Sul-RS, Brazil 10.3762/bjoc.18.110 Abstract The broad application of 1H-indazoles has prompted the development of several approaches for the synthesis of such compounds, including metal-free, palladium-, or copper-promoted intramolecular N-arylation of in situ

• available and less expensive than brominated analogs. Seeking to cover a lack in the literature, this work reports a convenient protocol for the synthesis of N-phenyl- and N-thiazolyl-1H-indazoles by copper-catalyzed intramolecular N-arylation of o-chlorinated arylhydrazones. Therefore, a series of seven N

• . All products were fully characterized by HRMS as well as 1H and 13C NMR spectroscopy. Thus, this approach is valuable for promoting the synthesis of N-phenyl-1H-indazoles in a higher yield than that reported in the literature using copper catalysis and the same substrates. This study also prompted the

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

• Ryan M. Alam and
• John J. Keating

Beilstein J. Org. Chem. 2021, 17, 1939–1951, doi:10.3762/bjoc.17.127

• alkylindazoles. Initial screening of various conditions revealed that the combination of sodium hydride (NaH) in tetrahydrofuran (THF) (in the presence of an alkyl bromide), represented a promising system for N-1 selective indazole alkylation. For example, among fourteen C-3 substituted indazoles examined, we

• observed > 99% N-1 regioselectivity for 3-carboxymethyl, 3-tert-butyl, 3-COMe, and 3-carboxamide indazoles. Further extension of this optimized (NaH in THF) protocol to various C-3, -4, -5, -6, and -7 substituted indazoles has highlighted the impact of steric and electronic effects on N-1/N-2 regioisomeric

• distribution. For example, employing C-7 NO2 or CO2Me substituted indazoles conferred excellent N-2 regioselectivity (≥ 96%). Importantly, we show that this optimized N-alkylation procedure tolerates a wide structural variety of alkylating reagents, including primary alkyl halide and secondary alkyl tosylate

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

Azidophosphonium salt-directed chemoselective synthesis of (E)/(Z)-cinnamyl-1H-triazoles and regiospecific access to bromomethylcoumarins from Morita–Baylis–Hillman adducts

• Soundararajan Karthikeyan,
• Radha Krishnan Shobana,
• Kamarajapurathu Raju Subimol,
• J. Helen Ratna Monica and
• Ayyanoth Karthik Krishna Kumar

Beilstein J. Org. Chem. 2020, 16, 1579–1587, doi:10.3762/bjoc.16.130

• transformations employed quaternary phosphonium salts as favourable catalysts [36]. Their synthetic utility was not only confined to catalysis, but they were also used as intermediates for the synthesis of 1H-indazoles [37], as promoters for stereoselective rearrangements [38], and as temporary protectors of O,P

Thermal stability of N-heterocycle-stabilized iodanes – a systematic investigation

• Andreas Boelke,
• Yulia A. Vlasenko,
• Mekhman S. Yusubov,
• Boris J. Nachtsheim and
• Pavel S. Postnikov

Beilstein J. Org. Chem. 2019, 15, 2311–2318, doi:10.3762/bjoc.15.223

• thermal stability of pyrazoles and indazoles (6–8) in direct comparison to triazoles (2–5) is very likely connected with the lower C/N ratio. Benzimidazoles 9–11 showed increased ΔHdec values (58.5–76.4 kJ/mol) in comparison with pyrazoles 6–8. Broad decomposition peaks (up to 14 °C peak width – see

Formation of an unexpected 3,3-diphenyl-3H-indazole through a facile intramolecular [2 + 3] cycloaddition of the diazo intermediate

• Andrew T. King,
• Hugh G. Hiscocks,
• Lidia Matesic,
• Mohan Bhadbhade,
• Roger Bishop and
• Alison T. Ung

Beilstein J. Org. Chem. 2019, 15, 1347–1354, doi:10.3762/bjoc.15.134

• unfamiliarity, the C–H···H–C contacts illustrated in Figure 6 are similarly attractive in nature. Proposed mechanism for the formation of 8 Indazoles are well-recognised for their important biological activities. They are known to be used as building blocks in drug development. A review by Gaikwad et al

• . describes reliable routes to particularly fused aromatic 1H and 3H-indazoles [24]. The common synthetic routes for the formation of cyclic 1H-indazoles are diazotisation of corresponding o-alkylanilines [25] and nitrosation of the N-acetyl derivatives of 2-alkylanilines (Jacobson modification) [26][27][28

• ]. More recently, the formation of cyclic 3,3-disubstituted 3H-indazoles was reported to form mainly through the [2 + 3] cycloaddition of diazo compounds with arynes under mild reaction conditions [29][30][31]. However, none of these contained a 2-diphenylmethyl (benzhydryl) aniline system, as found in

Azologization of serotonin 5-HT₃ receptor antagonists

• Karin Rustler,
• Galyna Maleeva,
• Piotr Bregestovski and
• Burkhard König

Beilstein J. Org. Chem. 2019, 15, 780–788, doi:10.3762/bjoc.15.74

• developed [26]. Since then the development of 5-HT3R antagonists progressed. The first-generation antagonists are structurally categorized in three major classes: (I) carbazole derivatives (e.g., ondansetron), (II) indazoles (e.g., granisetron), and (III) indoles (e.g., dolasetron) [26][30]. Generally, 5

[3 + 2]-Cycloaddition reaction of sydnones with alkynes

• Veronika Hladíková,
• Jiří Váňa and
• Jiří Hanusek

Beilstein J. Org. Chem. 2018, 14, 1317–1348, doi:10.3762/bjoc.14.113

• this synthetic approach for the synthesis of polysubstituted 1,2-diazoles (pyrazoles, indazoles). However, until 2013 when Taran’s group introduced the regioselective Cu(I)-phenanthroline catalysis [3] this method was of limited value due to the harsh reaction conditions and sometimes also due to low

• of substituted 1,3,4-tri- or 1,3,4,5-tetrasubstituted pyrazoles [1][2][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] or indazoles. Dimethyl acetylenedicarboxylate (DMAD, R3 = COOMe) or its analogues (diethyl; R3

• from 2-aminobenzoic acid [48], from symmetrically substituted 2-trimethylsilylphenyl triflates [49][50][51][52] or from 2-(trimethylsilyl)phenyl trimethylsilyl ethers [53] react with sydnones in MeCN or THF giving 2-substituted 2H-indazoles in good to excellent yields (40–99%) at room temperature

Bromide-assisted chemoselective Heck reaction of 3-bromoindazoles under high-speed ball-milling conditions: synthesis of axitinib

• Jingbo Yu,
• Zikun Hong,
• Xinjie Yang,
• Yu Jiang,
• Zhijiang Jiang and
• Weike Su

Beilstein J. Org. Chem. 2018, 14, 786–795, doi:10.3762/bjoc.14.66

• highly efficient route for the synthesis of axitinib. Keywords: axitinib; ball-milling; dehalogenation; Heck reaction; indazoles; Introduction The palladium-catalyzed vinylation of alkenes in the presence of a base, known as the Heck reaction (Mizoroki–Heck reaction), is one of the most important

• the investigation of the scope and limitations of the developed method with respect to a broad range of indazoles and olefins (Scheme 5). Pleasingly, neutral, electron-rich and electron-poor indazoles were perfectly tolerated in this reaction, affording the corresponding target product 3ba–ka in high

• -selectivity under 700 rpm, giving 6-bromo-substituted product 3da in 94% yield. Indazoles with N-Me, THP and Bn groups afforded good to excellent yields in the coupling reaction with n-butyl acrylate. However, the N-Boc substrate readily underwent removal of the protecting group [65], and resulted in the

Multicomponent synthesis of spiropyrrolidine analogues derived from vinylindole/indazole by a 1,3-dipolar cycloaddition reaction

• Manjunatha Narayanarao,
• Lokesh Koodlur,
• Vijayakumar G. Revanasiddappa,
• Subramanya Gopal and
• Susmita Kamila

Beilstein J. Org. Chem. 2016, 12, 2893–2897, doi:10.3762/bjoc.12.288

• -alkylindole and indazole derivatives 2 that can be obtained from 5-bromoindoles/indazoles (1). The latter compounds were synthesized according to procedures described in the literature [18][19][20]. The regioisomers of N-alkylated 5-bromoindazoles were isolated by column chromatography using a hexane–ethyl

• in yields ranging from 60 to 93% (Table 1, entries 1–11). Unfortunately the product 7 with X–R = NCOCH3, Y = N could not be synthesized due to low amounts of the required regioisomer of the N-acylated indazole. In both cases of vinylic indole and indazoles, we have shown that the cyclic adducts were

Dimerisation, rhodium complex formation and rearrangements of N-heterocyclic carbenes of indazoles

• Zong Guan,
• Jan C. Namyslo,
• Martin H. H. Drafz,
• Martin Nieger and
• Andreas Schmidt

Beilstein J. Org. Chem. 2014, 10, 832–840, doi:10.3762/bjoc.10.79

• . Virtasen aukio 1), FIN-00014 University of Helsinki, Finland 10.3762/bjoc.10.79 Abstract Deprotonation of indazolium salts at low temperatures gives N-heterocyclic carbenes of indazoles (indazol-3-ylidenes) which can be trapped as rhodium complexes (X-ray analysis). In the absence of Rh, the indazol-3

• . Keywords: E/Z isomerism; indazol-3-ylidene; mesomeric betaine; pyrazole; quinazoline; Rh complex; Introduction As a result of their biochemical and pharmacological significance, there has been a considerably growing interest in indazoles in recent years, which is reflected in several book chapters and

Microwave-assisted synthesis of 5,6-dihydroindolo[1,2-a]quinoxaline derivatives through copper-catalyzed intramolecular N-arylation

• Fei Zhao,
• Lei Zhang,
• Hailong Liu,
• Shengbin Zhou and
• Hong Liu

Beilstein J. Org. Chem. 2013, 9, 2463–2469, doi:10.3762/bjoc.9.285

• , the copper-catalyzed N-arylation has been extensively utilized for C–N coupling, especially for the arylation of N-containing heterocycles such as indoles, imidazoles, indazoles, pyrroles, pyrazoles and triazoles [25][26][27][28] to construct more fused heterocycles. In recent years, several

ML212: A small-molecule probe for investigating fluconazole resistance mechanisms in Candida albicans

• Willmen Youngsaye,
• Cathy L. Hartland,
• Barbara J. Morgan,
• Amal Ting,
• Partha P. Nag,
• Benjamin Vincent,
• Carrie A. Mosher,
• Joshua A. Bittker,
• Sivaraman Dandapani,
• Michelle Palmer,
• Luke Whitesell,
• Susan Lindquist,
• Stuart L. Schreiber and
• Benito Munoz

Beilstein J. Org. Chem. 2013, 9, 1501–1507, doi:10.3762/bjoc.9.171

• Two different routes were adopted to access the various functionalized indazoles required to evaluate the SAR associated with hit compound 1 (Scheme 1). The robust Suzuki–Miyaura reaction was selected for the preparation of analogues bearing substituents around the central indazole core. This approach

• also permitted rapid replacement of the phenyl ring at C3 with functionalized phenyl rings and alternative heterocycles. Preliminary attempts to couple substituted 3-iodoindazoles 4 failed to produce isolable amounts of the desired product directly. Subsequently, the indazoles were protected as their

Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds

• Carolin Fischer and
• Burkhard Koenig

Beilstein J. Org. Chem. 2011, 7, 59–74, doi:10.3762/bjoc.7.10

• resulted in good yields [4][26]. Copper-diamine-catalysed N-arylation facilitated the arylation of pyrroles, pyrazoles, indazoles, imidazoles, triazoles, benzimidazoles and indoles [27][28][29]. Besides aryl halides as the aryl donor, arylsiloxanes [30], arylstannanes [31], iodonium salts [32], aryl lead