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

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

Transition-metal-catalyzed C–H bond activation as a sustainable strategy for the synthesis of fluorinated molecules: an overview

• Louis Monsigny,
• Floriane Doche and
• Tatiana Besset

Beilstein J. Org. Chem. 2023, 19, 448–473, doi:10.3762/bjoc.19.35

• (24a–f, 82–87% yields). The substitution of the indole at the C3-position did not impact the reaction and the product 24g was obtained in 91% yield. Substituted pyridines and pyrimidine (24h and 24i) were also used as directing groups (7 examples, up to 86% yield). This methodology was extended to the

Group 13 exchange and transborylation in catalysis

• Dominic R. Willcox and
• Stephen P. Thomas

Beilstein J. Org. Chem. 2023, 19, 325–348, doi:10.3762/bjoc.19.28

• -coordinated heterocycle 21. Hydride transfer from the BH3-amide 22 to HBpin regenerated the borohydride catalyst 19, and gave a neutral aminoborane 23, which then underwent B‒N/B‒H transborylation with HBpin to give the N‒Bpin dihydropyridine 24 and BH3 (Scheme 6). The mechanism of stoichiometric indole

• reduction with Me2S·BH3 was investigated by Fontaine, and applied to a catalytic variant using HBpin as the turnover reagent (Scheme 7) [70]. Computational analysis showed two plausible, cooperative catalytic cycles: 1) hydroboration of indole 25 with BH3 to give a H2B-N-indoline 26, which then underwent B

1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

• Bram Ryckaert,
• Ellen Demeyere,
• Frederick Degroote,
• Hilde Janssens and
• Johan M. Winne

Beilstein J. Org. Chem. 2023, 19, 115–132, doi:10.3762/bjoc.19.12

• equivalent of a simple allyl cation in (3 + 2) cycloadditions. More recently, our group was able to extend the scope of dihydrodithiin-mediated cycloadditions to indole substrates [30]. Indoles are formal styrene analogs, with very different electronic properties and reactivity profiles, and initially gave

• . This protonation effectively prevents any possible side reactions of the dearomatized products with electrophiles. A remarkably wide substrate scope was observed for this dearomative indole cyclopentannulation reaction, as demonstrated by the smooth ring expansion of the natural alkaloid drug yohimbine

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• reduction steps allowed the total synthesis of GB13 (8), himgaline (126), and GB22 (125) in only one third of the number of steps of prior syntheses (Scheme 10). Concise syntheses of eburnane alkaloids (Qin 2018) [68][69]: Eburnane indole alkaloids comprise a highly diverse class of natural products mainly

• discoveries, namely a photoredox-catalytic nitrogen-centered radical cascade [72], which has resulted in the impressive collective total synthesis of 33 alkaloids of three different classes of indole natural products (please see the inset of Scheme 11 for concise representation). Specifically, this included

• reduction of the amide using Wilkinson’s catalyst provided diastereoisomeric indole 131. Careful manipulation of the nitrile and alcohol side chains allowed selective cyclizations to the nitrogen atom of the indole core to conclude the total syntheses of 132–134. Samarium diiodide-mediated reductive

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• from the indoline to B(C6F5)3. The resultant iminium ion is deprotonated by a second indoline molecule with the formation of an ammonium ion and the final indole. The ammonium ion reacts with a HB(C6F5)3 anion with the release of a H2 molecule and the regeneration of B(C6F5)3 for the next catalytic

Design, synthesis, and evaluation of chiral thiophosphorus acids as organocatalysts

• Karen R. Winters and
• Jean-Luc Montchamp

Beilstein J. Org. Chem. 2022, 18, 1471–1478, doi:10.3762/bjoc.18.154

• influence of the substituent position in the CPAs (Figure 3). In the BINOL-derived CPA, the R-substituent and the phosphorus atom are separated by three bonds. In the indole-based CPAs 1 and 2, the distance is reduced to two bonds, whereas in CPA 3 it is three bonds, and in 4 it is just one bond. Both 3 and

• enantioselective catalyst. On the other hand, their successful completions attest to the inexpensive and scalable requirements we had set. Indole scaffolds The synthesis of racemic tryptophol CPA 1 is shown in Scheme 2. Commercially available tryptophol (5, 225 $/mol) was N-arylated into 6 via copper-catalyzed

• prepare chiral thiophosphorus acids have been described [41][42][43]. Once equipped with our new methods [38], the synthesis of indole-derived 2 was undertaken (Scheme 3). Known 3-allylindole (10) [44] was obtained from indole uneventfully. Intermediate 11 was furnished in moderate yield via our palladium

Vicinal ketoesters – key intermediates in the total synthesis of natural products

• Marc Paul Beller and
• Ulrich Koert

Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129

• Koert et al. in the racemic synthesis of the bisindole alkaloid (rac)-cladoniamide G (103, Scheme 17) [33]. The synthesis started with benzaldehyde 97 and indole 99 which were converted to the indole building blocks 98 and 100, respectively. These were connected to bisindole 101, which reacted with

Synthesis of tryptophan-dehydrobutyrine diketopiperazine and biological activity of hangtaimycin and its co-metabolites

• Houchao Xu,
• Anne Wochele,
• Minghe Luo,
• Gregor Schnakenburg,
• Yuhui Sun,
• Heike Brötz-Oesterhelt and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 1159–1165, doi:10.3762/bjoc.18.120

• step using milder conditions (Scheme 3). The newly developed synthesis started from 7 that was Boc-protected at the indole to yield 11. Removal of the benzyl group by catalytic hydrogenation to 12 was followed by coupling with benzyloxycarbonyl (Cbz) and methoxymethyl (MOM)-protected threonine to give