(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• substrate. Employing Lewis acid catalysis Deng and co-workers reported an alternative pathway to indole-derived BCHs. Polysubstituted BCHs were accessed by nucleophilic addition of the indole to the activated bicyclobutane followed by a Mannich cyclisation [81]. The synthesis of wide variety of tri- and

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes

• Julien Borrel and
• Jerome Waser

Beilstein J. Org. Chem. 2024, 20, 701–713, doi:10.3762/bjoc.20.64

• homopropargylic azide was formed using pyrrole 1e it could not be isolated due to its instability. No conversion was observed when the transformation was attempted directly on the indole scaffold 1f. Only a small amount of product was formed using styrene 1g bearing an extra α-phenyl substituent. A slightly

Production of non-natural 5-methylorsellinate-derived meroterpenoids in Aspergillus oryzae

• Jia Tang,
• Yixiang Zhang and
• Yudai Matsuda

Beilstein J. Org. Chem. 2024, 20, 638–644, doi:10.3762/bjoc.20.56

• pathway; their non-terpenoid portions can be polyketides, indole, or shikimate-derived compounds [1][2][3]. Their hybrid nature significantly contributes to their structural diversity and wide range of biological activities. Although meroterpenoids are found ubiquitously in nature, as both primary and

Chemical and biosynthetic potential of Penicillium shentong XL-F41

• Ran Zou,
• Xin Li,
• Xiaochen Chen,
• Yue-Wei Guo and
• Baofu Xu

Beilstein J. Org. Chem. 2024, 20, 597–606, doi:10.3762/bjoc.20.52

• investigations, accompanied by fermentation media optimization, of a newly isolated fungus, Penicillium shentong XL-F41, led to the isolation of twelve compounds. Among these are two novel indole terpene alkaloids, shentonins A and B (1 and 2), and a new fatty acid 3. Shentonin A (1) is distinguished by an

• activity against Candia albicans. Moreover, genome sequencing of Penicillium shentong XL-F41 uncovered abundant silent biosynthetic gene clusters, indicating the need for future efforts to activate these clusters and unlock the full chemical potential of the fungus. Keywords: genome analysis; indole

• ]. Recent studies have revealed that certain fungi are also prolific sources of indole alkaloids, which are among the largest classes of nitrogen-containing secondary metabolites. Characterized by at least one indole moiety and derived from tryptophan or tryptamine, indole alkaloids are known for their

Switchable molecular tweezers: design and applications

• Pablo Msellem,
• Maksym Dekthiarenko,
• Nihal Hadj Seyd and
• Guillaume Vives

Beilstein J. Org. Chem. 2024, 20, 504–539, doi:10.3762/bjoc.20.45

• a porphyrin carboxylate anion as the effector. This allowed the generation of photoinduced charge-separated states with extended lifetimes in a supramolecular triad [74]. Another switching unit controlled by an anion-binding stimulus is bis-indole, reported by Jang and co-workers (Figure 19a) [75

• ]. In the neutral state, the tweezers 34 adopt an anti-conformation because of steric hindrance between the N–H and the tert-butyl groups. Again, the N–H proton of the indole can bind to anions through hydrogen bonds and causes the system to adopt a cis-conformation, closing the tweezers. This closed

Pseudallenes A and B, new sulfur-containing ovalicin sesquiterpenoid derivatives with antimicrobial activity from the deep-sea cold seep sediment-derived fungus Pseudallescheria boydii CS-793

• Zhen Ying,
• Xiao-Ming Li,
• Sui-Qun Yang,
• Hong-Lei Li,
• Xin Li,
• Bin-Gui Wang and
• Ling-Hong Meng

Beilstein J. Org. Chem. 2024, 20, 470–478, doi:10.3762/bjoc.20.42

• -rich fluid emissions and unique sulfur oxidation–reduction reactions [1]. Due to the unique habitat, microorganisms surviving in the deep-sea cold seeps may serve as promising sources of secondary metabolites with functional and structural diversity [2]. In particular, two indole diketopiperazine

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

• -inflammatory, and even anticancer agents. Traditionally, the synthesis of BIMs has been achieved upon the acidic condensation of an aldehyde with indole, utilizing a variety of protic or Lewis acids. However, due to the increased environmental awareness of our society, the focus has shifted towards the

• reaction between aldehydes with indoles, while focusing on the more environmentally friendly methods developed over the years. Keywords: aldehyde; BIMs; Friedel–Crafts reaction; green chemistry; indole; Review Medicinal properties In recent years, diindolylmethane (DIM, 1) and its derivatives known as

• highest fungicidal activity [11]. Brønsted or Lewis acid catalysis – conventional synthetic methods The indole moiety is part of many natural products, agrochemicals, and pharmaceuticals. In medicinal chemistry, indole and its derivatives are considered important compounds, since they exhibit valuable

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• . Intramolecular radical addition into the radical cation of the furan ring would then form cation 50 before nucleophilic capture by H2O leads to product 45. In 2020, the Wang group reported the functionalization of enamides employing radicals derived from NHPI esters in combination with indole nucleophiles [57

• irradiation at 390 nm or through RuII-mediated EnT under blue light irradiation (456 nm). Following excitation, SET from the enamide to the active ester forms intermediate 53, which undergoes fragmentation and radical recombination to afford intermediate 54. At this stage, the indole nucleophile substitutes

Synthesis of π-conjugated polycyclic compounds by late-stage extrusion of chalcogen fragments

• Aissam Okba,
• Pablo Simón Marqués,
• Kyohei Matsuo,
• Naoki Aratani,
• Hiroko Yamada,
• Gwénaël Rapenne and
• Claire Kammerer

Beilstein J. Org. Chem. 2024, 20, 287–305, doi:10.3762/bjoc.20.30

• between carboranes and chalcogen-doped π-conjugated heterocycles, Yang and co-workers devised a two-step strategy for the synthesis of carborane-fused thiophene 43 (Scheme 11, bottom) [72]. Double lithiation of carboranyl indole 41 was followed by trapping with disulfur dichloride as chalcogen source to

Photochromic derivatives of indigo: historical overview of development, challenges and applications

• Gökhan Kaplan,
• Zeynel Seferoğlu and
• Daria V. Berdnikova

Beilstein J. Org. Chem. 2024, 20, 228–242, doi:10.3762/bjoc.20.23

• ]. After the determination of the molecular structure of indigo in 1883, various precursors such as isatin (1), cinnamic acid (2), 2-nitrobenzaldehyde (3), aniline (4), 2-aminobenzoic acid (5), phenylglycine (6), 1-(1H-indol-1-yl)ethan-1-one (7) and indole (8) have been used in the synthesis (Figure 1) [4

• using heme-containing oxygenases (cytochrome P450 monooxygenases, styrene/indole monooxygenases, flavin-containing monooxygenases, Baeyer–Villiger monooxygenases, etc.) or non-heme iron oxygenases (naphthalene dioxygenases, multicomponent phenol hydroxylases) [5][6][7][8]. The synthetic approaches

• , the resonance structures II and III with separated charges become predominant, while both benzene rings remain fully aromatic. The indigo dye contains two heterocyclic indole ring systems, which are connected through a double bond and have 22 π-electrons [16][17]. However, only 10 π-electrons are

Chiral phosphoric acid-catalyzed transfer hydrogenation of 3,3-difluoro-3H-indoles

• Yumei Wang,
• Guangzhu Wang,
• Yanping Zhu and
• Kaiwu Dong

Beilstein J. Org. Chem. 2024, 20, 205–211, doi:10.3762/bjoc.20.20

• great attention in organic synthesis. Various methods [9], including reductive hydrogenation [10][11], kinetic resolution [12][13][14], functionalization of indole [15], and de novo construction of chiral 2-substituted indolines, have been developed [16][17][18][19][20]. In recent years, the metal

• -catalyzed asymmetric hydrogenation of indoles to synthesize chiral indolines has been widely studied (Scheme 1a) [21][22]. Representative examples include Ir- or Ru-catalyzed asymmetric hydrogenation of 2,3,3-trisubstituted 3H-indole [23][24]. Generally, these methods employ precious metals and/or

• , synthesized in situ from a chiral boron phosphate complex with water, for asymmetric indole reduction (Scheme 1b) [30]. The mild reaction conditions, low catalyst loading, and high enantioselectivity rendered this transformation an attractive approach to synthesize optically active indolines. However, these

Visible-light-induced radical cascade cyclization: a catalyst-free synthetic approach to trifluoromethylated heterocycles

• Chuan Yang,
• Wei Shi,
• Jian Tian,
• Lin Guo,
• Yating Zhao and
• Wujiong Xia

Beilstein J. Org. Chem. 2024, 20, 118–124, doi:10.3762/bjoc.20.12

• radicals. This method allows the efficient synthesis of various indole derivatives without the need of photocatalysts or transition-metal catalysts. Mechanism experiments indicate that the process involves a radical chain process initiated by the homolysis of Umemoto's reagent. This straightforward method

• enables a rapid access to heterocycles containing a trifluoromethyl group. Keywords: cascade reaction; indole derivatives; photocatalysis; radical chain process; trifluoromethylation; Introduction Dihydropyrido[1,2-a]indolone (DHPI) skeletons are commonly found in natural products and pharmaceutical

• and at the same time improved cell membrane permeability. Therefore, it became a commonly used strategy to modify medicine candidates [22][23][24]. Based on these advantages, we envisioned a one-step synthesis of dihydropyrido[1,2-a]indolone skeletons utilizing an indole substrate and a

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

• pyrazole derivatives (including indazole), benzimidazole, 1,2,3-triazole, indole, carbazole, indoline, quinazoline, and isoquinoline. Nevertheless, many heterocyclic motifs still remain beyond the attention of researchers. For example, glutarimides that incorporate tetrazole and 1,2,4-triazole substituents

• , C–H insertion products 9 were also observed. Thus, when reacting with indole, the product of carbenoid attack at position 3 (9a) was isolated along with target compound 6a. Introduction of a carbomethoxy group into this position of indole leads to the exceptional formation of the N–H insertion

• the reaction mixture). The structure of the main reaction product 9i was confirmed by 2D HSQC NMR spectroscopy. To evaluate the influence of the catalyst on chemoselectivity of the reaction with indole (ratio 6a/9a) we have performed additional testing with Rh2(TFA)4 and Rh2(OAc)4, which differ from

Substituent-controlled construction of A₄B₂-hexaphyrins and A₃B-porphyrins: a mechanistic evaluation

• Seda Cinar,
• Dilek Isik Tasgin and
• Canan Unaleroglu

Beilstein J. Org. Chem. 2023, 19, 1832–1840, doi:10.3762/bjoc.19.135

• , heteroaryl-bearing tosylimines were also tested. The thiophene-substituted tosylimine 2j gave hexaphyrin 4j in 17% yield and porphyrin 3j in 10% yield, whereas the indole-bearing tosylimine gave only A3B-porphyrins but no A4B2-hexaphyrin (Table 1, entries 10 and 11). Signals of trace amounts of A2B2-type

Quinoxaline derivatives as attractive electron-transporting materials

• Zeeshan Abid,
• Liaqat Ali,
• Sughra Gulzar,
• Faiza Wahad,
• Raja Shahid Ashraf and
• Christian B. Nielsen

Beilstein J. Org. Chem. 2023, 19, 1694–1712, doi:10.3762/bjoc.19.124

• . explored the modulation of optoelectrochemical properties and thermal characteristics of pyridopyrazino[2,3-b]indole-based Qx46 series with varying substituents, i.e., bromine, chlorine, methyl and nitro group. Their study revealed inbuilt ICT and aggregation-induced emission (AIE) effects, forming

Decarboxylative 1,3-dipolar cycloaddition of amino acids for the synthesis of heterocyclic compounds

• Xiaofeng Zhang,
• Xiaoming Ma and
• Wei Zhang

Beilstein J. Org. Chem. 2023, 19, 1677–1693, doi:10.3762/bjoc.19.123

•  6) [75]. One-pot double annulations for the synthesis of tetrahydropyrrolothiazoles The unique tetrahydropyrrolothiazole and spiro[indole-tetrahydropyrrolothiazole] scaffolds are found in bioactive compounds such as those shown in Figure 7 [76][77]. Using cysteine as a key reactant, we developed a

N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• the HNO species, the pyrroline structure could oxidize and aromatize to the pyrrole ring 61 (Scheme 26). In 2021, Anbarasan and co-workers were able to obtain a diverse range of sulfenylated products 64 in a Co-catalyzed C2-sulfenylation and C2,C3-disulfenylation of indole derivatives with N

• reacted with thiosulfonates 70 and N-arylthiosuccinimides 1 as thiolating reagents. 1,2-Thiosulfonylethenes 71 were obtained via vicinal thiosulfonylation. However, in the case of 1,1-dithioethenes 69, germinal disulfenylation occurred. In addition, 1,2-difunctionalization of indole-derived 1,1

• -catalyzed C–H sulfenylation at the C2-position of protected and unprotected indoles 105 to form 2-thioindoles 106 (Scheme 44) [78]. The reaction initiated with TFA-promoted electrophilic addition of 1 to 105 towards C3-sulfenylated indole I, which was protonated by TFA, led to intermediate II. Then

Consecutive four-component synthesis of trisubstituted 3-iodoindoles by an alkynylation–cyclization–iodination–alkylation sequence

• Nadia Ledermann,
• Alae-Eddine Moubsit and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2023, 19, 1379–1385, doi:10.3762/bjoc.19.99

• generated by a consecutive four-component reaction starting from ortho-haloanilines, terminal alkynes, N-iodosuccinimide, and alkyl halides in yields of 11–69%. Initiated by a copper-free alkynylation, followed by a base-catalyzed cyclizive indole formation, electrophilic iodination, and finally

• electrophilic trapping of the intermediary indole anion with alkyl halides provides a concise one-pot synthesis of 3-iodoindoles. The latter are valuable substrates for Suzuki arylations, which are exemplified with the syntheses of four derivatives, some of them are blue emitters in solution and in the solid

• [9][10][11] and their preparation is an evergreen in organic synthesis [12][13][14][15]. Although the classical Fischer indole synthesis provides a very reliable and broadly applicable access to indole derivatives [16][17][18], striving for new indole syntheses is ongoing. In particular, metal

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

Aromatic C–H bond functionalization through organocatalyzed asymmetric intermolecular aza-Friedel–Crafts reaction: a recent update

• Anup Biswas

Beilstein J. Org. Chem. 2023, 19, 956–981, doi:10.3762/bjoc.19.72

• -functionalization of the indole (Scheme 2) [25]. In 2018, Lin and co-workers deployed pyrroles 9 in an aza-Friedel–Crafts reaction with trifluoromethyldihydrobenzoazepinoindoles 8 to achieve the aromatic electrophilic substitution at the C2 position of the pyrrole ring. A further extension of the scope of this

• process was achieved through the C3–H functionalization of indole derivatives 4. The nucleophile favors the attack at the imine carbon included in the seven-membered ring of compound 8 to generate an aza-quaternary stereocenter containing trifluoromethyl, pyrrole/indole, and benzoazepinoindole moieties

• . The products 16 were achieved with excellent enantioselectivites which were attributed to an attractive interaction between the indole ring and the anthracene substituent of the catalyst’s framework (Scheme 5) [29]. In 2018, Piersanti and co-workers developed a phosphoric acid-catalyzed cascade

Photoredox catalysis enabling decarboxylative radical cyclization of γ,γ-dimethylallyltryptophan (DMAT) derivatives: formal synthesis of 6,7-secoagroclavine

• Alessio Regni,
• Francesca Bartoccini and
• Giovanni Piersanti

Beilstein J. Org. Chem. 2023, 19, 918–927, doi:10.3762/bjoc.19.70

• selectively targeted by photoredox catalysis to enable unprecedented modification of the amino acid. In this context, it is worth mentioning that the single-electron oxidation of the indole moiety in tryptophan provides the radical cation, which enables selective C-radical generation at the weaker benzylic

• position via a sequential electron transfer–proton transfer (ET/PT) [52][53][54][55][56][57][58][59]. With our ongoing interest of establishing new methods for the asymmetric synthesis of nonproteinogenic tryptophan derivatives as well as their associated indole alkaloid natural products [60][61][62][63

• : 1) it functions as the central intermediate in the biosynthetic pathways leading to numerous prenylated indole alkaloids, such as ergot alkaloids in normal biosynthesis and clavicipitic acid in derailment biosynthesis [68][69][70][71]; and 2) the mechanism of the fundamental central C-ring formation

Facile access to 3-sulfonylquinolines via Knoevenagel condensation/aza-Wittig reaction cascade involving ortho-azidobenzaldehydes and β-ketosulfonamides and sulfones

• Ksenia Malkova,
• Andrey Bubyrev,
• Stanislav Kalinin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2023, 19, 800–807, doi:10.3762/bjoc.19.60

• substrate scope for the protocol proposed were found out during the course of the study. Indole- and pyrazole-based azidoaldehydes 1r and 1s failed to provide the desired compounds 5r and 5s (Scheme 4). The reaction stopped on the iminophosphorane formation and did not progress further likely due to

Strategies in the synthesis of dibenzo[b,f]heteropines

• David I. H. Maier,
• Barend C. B. Bezuidenhoudt and
• Charlene Marais

Beilstein J. Org. Chem. 2023, 19, 700–718, doi:10.3762/bjoc.19.51

•  8). 2.4 Ring expansion of N-arylindoles (41) The polyphosphoric acid (PPA)-catalysed rearrangement of N-arylindoles 41 was first reported by Tokmakov and Grandberg [48]. The reaction provided moderate yields with a simple 2 step linear sequence from indole 39. The reaction requires heating at

• -acridine methanol 37 (Scheme 8) and N-arylindoles 41 (Scheme 9). The authors reported an excellent two-step synthesis of substituted dibenzo[b,f]azepines 43 via commercially available substituted indole 39 precursors based on the method of Tokmakov and Grandberg [48]. N-Arylindoles 41 were successfully

Synthesis, structure, and properties of switchable cross-conjugated 1,4-diaryl-1,3-butadiynes based on 1,8-bis(dimethylamino)naphthalene

• Semyon V. Tsybulin,
• Ekaterina A. Filatova,
• Alexander F. Pozharskii,
• Valery A. Ozeryanskii and
• Anna V. Gulevskaya

Beilstein J. Org. Chem. 2023, 19, 674–686, doi:10.3762/bjoc.19.49

• of samples 5b, 5d, and 5e suitable for X-ray diffraction studies (Figure 3 and Figure 4). Crystals of compound 5c were grown up using CHCl3/EtOH solvent, and it was unexpectedly found that keeping this compound in the above system for a month leads to its partial heterocyclization to benzo[g]indole

• -terminated butadiyne 5 gradually underwent demethylation/acid-catalyzed heterocyclization involving one of the dimethylamino groups and the adjacent C≡C bond of the butadiyne linker, forming the corresponding benzo[g]indole derivative. Proton sponge-based 1,4-diaryl-1,3-butadiynes synthesized previously and

• of butadiyne 5c into benzo[g]indole 12. Possible ways of one- and two-electron oxidation of oligomers 5. Synthesis of 7-(arylethynyl)-2-iodo-DMAN 7. Some structural parameters of oligomers 5 and salt 11c (X-ray data). Summary of the UV–vis spectraa of monomers 6, oligomers 5 (in CHCl3), and salts 11

Direct C2–H alkylation of indoles driven by the photochemical activity of halogen-bonded complexes

• Martina Mamone,
• Giuseppe Gentile,
• Jacopo Dosso,
• Maurizio Prato and
• Giacomo Filippini

Beilstein J. Org. Chem. 2023, 19, 575–581, doi:10.3762/bjoc.19.42

• to yield the alkylated derivatives 3 (Figure 1b). Indoles play a crucial role in many natural and industrial processes. Therefore, the direct chemical manipulation of the indole system is a matter of paramount importance [24][25][26][27]. Moreover, the sulfonyl group is an extremely versatile

• observed that the addition of DABCO to the solution of 2a induced a bathochromic shift of the absorption spectrum towards the visible region, thus indicating the formation of an EDA complex between these chemical species. Importantly, we also confirmed that indole 1a and 2a do not form a photoactive EDA

• halogen-bonded EDA complex (Ia) between the sulfone 2a and DABCO (Figure 4). When irradiated, this photoactive aggregate led to the formation of reactive alkyl radicals (IIa), which may react with indole 1a eventually yielding the product 3a through a classical HAS pathway [31][32][33]. Then, we