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

• Periklis X. Kolagkis Eirini M. Galathri Christoforos G. Kokotos Laboratory of Organic Chemistry, Department of Organic Chemistry, National and Kapodistrian University of Athens, Athens, 15771, Greece 10.3762/bjoc.20.36 Abstract The synthesis of indoles and their derivatives, more specifically bis

• 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

• pharmaceutical and biological activities. Among indole derivatives, bis(indolyl)methanes (BIMs) are profoundly interesting, due to their wide range of pharmaceutical properties. The most common approach involves the electrophilic substitution of various aldehydes and ketones by indoles, utilizing either protic

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

• synthesis of optically active difluoro-substituted indoline derivatives starting from the corresponding 3H-indoles by chiral phosphoric acid-catalyzed transfer hydrogenation was developed. Using Hantzsch ester as the hydrogen source under mild reaction conditions, the target products can be obtained with

• -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

• relatively strict reaction conditions (up to 150 bar H2). In 2022, Liu’s group reported an asymmetric hydrogenation of 3H-indoles catalyzed by a chiral Mn complex, which showed good yield and enantioselectivity [25]. In addition to metal catalysis for the enantioselective reduction, asymmetric

Perspectives on push–pull chromophores derived from click-type [2 + 2] cycloaddition–retroelectrocyclization reactions of electron-rich alkynes and electron-deficient alkenes

• Michio Yamada

Beilstein J. Org. Chem. 2024, 20, 125–154, doi:10.3762/bjoc.20.13

• ][42][43][44][45][46], azulenes and their homologous compounds [32][47][48][49][50][51][52][53][54][55][56][57][58], boron dipyrromethenes (BODIPYs) [41][59][60][61], porphyrins [62][63][64], chlorophylls [65][66], triazenes [67][68], ynamides [69][70][71], arylynamines [72], indoles [73], and γ

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

• of the substrates bearing substituents at the C5 position on the indole skeleton reacted well, furnishing the products in moderate to good yields from 53–79% (3e–i) except the 5-CHO-substituted substrate which afforded product 3j in 28% yield. Indoles with substituents at the C7 position of the

Photoinduced in situ generation of DNA-targeting ligands: DNA-binding and DNA-photodamaging properties of benzo[c]quinolizinium ions

• Julika Schlosser,
• Olga Fedorova,
• Yuri Fedorov and
• Heiko Ihmels

Beilstein J. Org. Chem. 2024, 20, 101–117, doi:10.3762/bjoc.20.11

• [7], quinoxalines [8], naphthalimides [9], phenanthridines [10], cyanines [11], or indoles [12], as well as metal-organic complexes [13], and several others [1][2][4]. In this context, benzoquinolizinium derivatives and resembling polycyclic azoniahetarenes are an established class of DNA-binding

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

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

• is noteworthy that the use of diphenyl disulfide as a sulfenylating agent was not effective in this protocol. N-(Aryl/alkylthio)phthalimide as an efficient sulfenylating reagent could also react with indoles to produce 3-thioindoles in the presence of 0.5 mol % of MgBr2, as a Lewis acid [68

• -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

• acid organocatalysts were evaluated for sulfenylation on C3, or C2 position of N-heterocycles 115, including indoles, peptides, pyrrole, and 1-methyl-1H-pyrrolo[2,3-b]pyridine. The authors hypothesized a mechanism for the activation of N-sulfanylsuccinimides 1 or 14 by conjugate Lewis base Brønsted

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

• state, in good yield. Keywords: alkynylation; catalysis; cyclization; indoles; iodination; multicomponent reactions; Introduction Indoles and their derived substitution patterns are omnipresent heterocyclic structural motifs in nature [1], many natural products [2][3], drugs [4][5][6][7][8], and dyes

• -catalyzed processes for accessing indoles have become attractive alternatives over the past decades [19][20][21][22][23][24]. Besides Larock's indole synthesis employing alkyne anellation [25] and Cacchi's cyclization of ortho-alkynylanilines [20][22] catalytic syntheses of indoles from alkynes have become

• increasingly interesting [26][27]. In addition, as one-pot processes with a huge exploratory potential and diversity-oriented character, syntheses of indoles by multicomponent reactions have aroused considerable interest [28][29][30]. As part of our program to develop heterocycle syntheses based upon

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

• Hui Yu and
• Feng Xu

Beilstein J. Org. Chem. 2023, 19, 1259–1288, doi:10.3762/bjoc.19.94

• form cationic intermediate C and Fe(II) through a single electron transfer (SET) process. Subsequent abstraction of a proton from species C by a basic tert-butoxy anion generated from DTBP affords the product. Li et al. reported Fe-catalyzed CDC reactions of C(sp2)–H bonds of indoles and C(sp3)–H bonds

• catalyst. The authors demonstrated that the introduction of the two indoles occurs in two distinct steps, a radical process and a Friedel–Crafts alkylation reaction. Coumarin and flavonoid derivatives are very valuable precursors in drug synthesis. In 2015, Ge et al. developed the regioselective and atom

• indoles with 1,4-dioxane C(sp3)–H bonds via Ni(II) catalysis (Scheme 35) [100]. The selectivity of the reaction is determined by the catalyst used, which provides an efficient strategy for the selective construction of cyclic ethers containing heteroaromatic structures. Huang et al. reported a highly

Exploring the role of halogen bonding in iodonium ylides: insights into unexpected reactivity and reaction control

• Carlee A. Montgomery and
• Graham K. Murphy

Beilstein J. Org. Chem. 2023, 19, 1171–1190, doi:10.3762/bjoc.19.86

• 44, from which reductive elimination of iodobenzene would generate 40. In 2021, Sen and Gremaud disclosed a blue LED-mediated formal C–H insertion reaction between iodonium ylides (e.g., 31) and pyrroles (e.g., 45), indoles and furans, producing malonate-substituted heterocycles 46 (Scheme 9) [126

Copper-catalyzed N-arylation of amines with aryliodonium ylides in water

• Kasturi U. Nabar,
• Bhalchandra M. Bhanage and
• Sudam G. Dawande

Beilstein J. Org. Chem. 2023, 19, 1008–1014, doi:10.3762/bjoc.19.76

• generation of carbene as a reactive intermediate [36][37]. Also, spirocyclic iodonium ylides have been used for radiolabeling techniques [38]. In 2013, Shibata’s research group reported a novel trifluoromethanesulfonyl iodonium ylide for trifluoromethylthiolation of enamines, indoles, and ketoesters

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

• aza-Friedel–Crafts process between indoles 4 and cyclic N-sulfonyl ketimines 5. The authors employed the BINOL-based chiral phosphoric acid P2 bearing two imidazoline moieties at the ortho-positions as the catalyst which activates both reactants through H-bonding where the NH group of the nucleophile

• than with indoles (Scheme 3) [26]. In 2018, Kim and co-workers developed an aza-Friedel–Crafts protocol involving pyrroles 9 as the π-nucleophile in combination with cyclic N-sulfimines 12. The chiral phosphoric acid P4 was used to catalyze the introduction of a pyrrole-substituted aza-quaternary

• for the functionalization of the C3–H bond in indoles 9 in the presence of BINOL-derived chiral phosphoric acid P6 as the catalytic agent. They utilized trifluoromethyl ester-substituted N-unprotected imine 15 as the potential electrophile to install an aza-quaternary stereocenter in the C3 position

Clauson–Kaas pyrrole synthesis using diverse catalysts: a transition from conventional to greener approach

• Dileep Kumar Singh and
• Rajesh Kumar

Beilstein J. Org. Chem. 2023, 19, 928–955, doi:10.3762/bjoc.19.71

• solvent at 100 °C (Scheme 6). Finally, compounds 13 were used to prepare various arylpyrrolo- and pyrazolopyrrolizinones for diverse biological activity. In 2007, Török and co-workers [60] reported a convenient one-pot synthesis of N-sulfonyl-substituted pyrroles, indoles, and carbazole via a modified

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

• -dimethylallyltryptophan (DMAT) derivatives containing unactivated alkene moieties has been developed, providing green and efficient access to various six-, seven-, and eight-membered ring 3,4-fused tricyclic indoles. This type of cyclization, which was hitherto very difficult to comprehend in ergot biosynthesis and to

• in CH2Cl2 at room temperature using our integrated photoreactor enabled efficient cyclization to give a decarboxylated compound with the correct mass (m/z 426.2) after 16 h. While we were delighted to find that the proposed radical–radical coupling in the synthesis of extracyclic fused indoles was

• functionalized 3,4-fused tricyclic indoles with medium-sized rings (seven and eight), which have been largely neglected in previous studies, can be synthesized by this new protocol. Notably, the reaction has been successfully applied in the formal synthesis of (±)-6,7-secoagroclavine, a key intermediate for a

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

• )malonates 24. Ring expansion via C–H functionalisation. The synthesis of fluorinated 5H-dibenzo[b,f]azepine 38 from isatin (32). The synthesis of substituted dibenzo[b,f]azepines 43 from indoles 39. Retrosynthetic pathways to dibenzo[b,f]azepines via Buchwald–Hartwig amination. Synthesis of dibenzo[b,f

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

• and Technology Alliance (BRTA), Paseo de Miramón 194, 20014, Donostia San Sebastián, Spain Basque Fdn Sci, Ikerbasque, 48013 Bilbao, Spain 10.3762/bjoc.19.42 Abstract A light-driven metal-free protocol for the synthesis of sulfone-containing indoles under mild conditions is reported. Specifically

• ). Mechanistic investigations are reported. These studies provide convincing evidences for the photochemical formation of reactive open-shell species. Keywords: alkylation; EDA complex; halogens; indoles; photochemistry; Findings Direct replacement of carbon–hydrogen (C–H) bonds with new carbon–carbon (C–C

• to photochemically generate electrophilic radicals that can drive the functionalization of suitable electron-rich substrates [23]. Exploiting this strategy, here we report a novel metal-free methodology for the direct homolytic aromatic substitution (HAS) reaction of indoles 1 with α-iodosulfones 2

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

• derivatives 85. The reaction was amenable for both electron-rich and deficient indoles. When the reaction was attempted on electron-deficient oxabicyclic alkene derivatives, it was observed the reaction did not undergo dehydration to give the 2-naphthyl product, rather the ring-opened 1,2-hydroxy adduct. When

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

• , the group of Li disclosed the Cp*Rh(III)-catalyzed regioselective trifluoromethylthiolation of N-substituted indoles with (substituted) pyridines or pyrimidine as the directing groups (Scheme 10) [123]. The selective trifluoromethylthiolation of indoles at the C2 position was achieved in the presence

• of N-(trifluoromethylthio)saccharine (VI, Shen’s reagent) as both oxidant and electrophilic source (18 examples, up to 91% yield). Indoles bearing various electron-donating and electron-withdrawing groups as well as halogens at the C5-position and at the C6-position were functionalized in high yields

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

• ‒H borylation, with an initial B‒Y/B‒H transborylation activating the precatalyst [62][63][64][65]. Zhang showed that benzoic acid decomposed HBpin to BH3 in situ to catalyse the C2‒H borylation of indoles (Scheme 4b) [66][67]. Gellrich reported the bis(pentafluorophenyl)borane-catalysed dimerisation

• . Alkoxide-promoted hydroboration of heterocycles and the proposed mechanism. Borane-catalysed reduction of indoles and the proposed mechanism. H-B-9-BBN-catalysed hydrocyanation of enones and the proposed mechanism. Borane-catalysed hydroboration of nitriles and the proposed mechanism. Myrtanylborane

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

• very poor results with dihydrodithiinmethanol, with incomplete conversion to complex mixtures of diverse addition products. However, we found that the reactions of allyl alcohol 90 with indoles become very reliable and quite general when a large excess of a very strong Brønsted acid is used (Scheme 15a

• ][91][92][93][94][95][96][97][98][99][100]. Cycloadditions of 1,4-dithiane-fused allyl cations derived from dihydrodithiin-methanol 90 [101][102][103][104][105][106][107]. Dearomative [3 + 2] cycloadditions of unprotected indoles with 1,4-dithiane-fused allyl alcohol 90 [30]. Comparison of reactivity

Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles

• Bilge Banu Yagci,
• Selin Ezgi Donmez,
• Onur Şahin and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2023, 19, 66–77, doi:10.3762/bjoc.19.6

• syntheses of C-aryl luotonins and vasicinones (Scheme 1c) [23][24]. Moreover, an aza-Nazarov cyclization was utilized for the construction of a variety of heterocyclic frameworks such as aminopyrroles [25][26], N-hydroxyoxindoles [27], indolizines [28], pyrido[1,2-a]indoles [29][30], indoles [31][32], and

Electrochemical Friedel–Crafts-type amidomethylation of arenes by a novel electrochemical oxidation system using a quasi-divided cell and trialkylammonium tetrafluoroborate

• Hisanori Senboku,
• Mizuki Hayama and
• Hidetoshi Matsuno

Beilstein J. Org. Chem. 2022, 18, 1040–1046, doi:10.3762/bjoc.18.105

• 1,3,5-trimethoxybenzene or indoles in DMA containing 0.1 M iPr2NHEtBF4 using an undivided cell equipped with a Pt plate cathode and a Pt wire anode (a quasi-divided cell) resulted in selective formation of N-acyliminium ions of DMA at the anode, which reacted with arenes to give the corresponding

• -trimethoxybenzene and indoles (this work in Scheme 1). To the best of our knowledge, this is the first example of the use of trialkylammonium salts, such as iPr2NHEtBF4, in electroorganic synthesis, especially with the electrochemical oxidation system as a supporting electrolyte as well as a proton source for the

• with diamidomethylation products, and it was difficult to analyze them exactly. Although N-acetylindole was also ineffective, several indoles were found to be applicable to the present amidomethylation reaction and the results are summarized in Scheme 2. When N-methylindole (4a) was electrolyzed using

Morita–Baylis–Hillman reaction of 3-formyl-9H-pyrido[3,4-b]indoles and fluorescence studies of the products

• Nisha Devi and
• Virender Singh

Beilstein J. Org. Chem. 2022, 18, 926–934, doi:10.3762/bjoc.18.92

• . Additionally, the scope of the reaction was further extended and the effect of substituents at the N-9 position on the reactivity of 3-formyl-1-aryl-9H-pyrido[3,4-b]indoles was also investigated. Furthermore, fluorescence properties of these β-carboline conjugates were also studied and they were found to

Copper-catalyzed multicomponent reactions for the efficient synthesis of diverse spirotetrahydrocarbazoles

• Shao-Cong Zhan,
• Ren-Jie Fang,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 796–808, doi:10.3762/bjoc.18.80

• ][11][12][13][14][15]. Among many well-designed strategies for the synthesis of tetrahydrocarbazoles, the direct assembly of the tetrahydrocyclohexenyl ring with readily available functionalized indoles as precursors has proven to be one of the most efficient synthetic protocols [16][17][18][19][20][21

• indoles without electron-withdrawing activating groups could be employed in the Levy reaction, which will greatly develop the potential synthetic applications of the Levy-type reaction. Herein, we wish to report a Levy-type reaction by using readily available 2-methylindole to replace ethyl indole-2

• ring were all transformed smoothly into the corresponding desired products 6a–g with good to excellent yields. Though 3,3'-(p-tolylmethylene)bisindoles have been previously prepared by acid-catalyzed reaction of aromatic aldehydes and various indoles. Here we also provided an alternative synthetic

Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

• Jonali Das and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2022, 18, 293–302, doi:10.3762/bjoc.18.33

• approaches toward such compounds have been developed. Among these, cyclization and annulation of 3,5-unsubstituted, 4-substituted indoles involving an electrophilic aromatic substitution (SEAr) as the ring closure are particularly attractive, because they avoid the use of 3,4- or 4,5-difunctionalized indoles

• as starting materials. However, since 3,5-unsubstituted, 4-substituted indoles have two potential ring-closure sites (indole C3 and C5 positions), such reactions in principle can furnish either or both of the indole 3,4- and 4,5-fused ring systems. This Commentary will briefly highlight the issue by

• summarizing recent relevant literature reports. Keywords: annulation; cyclization; fused indoles; regioselectivity; SEAr; Introduction Over the decades, countless cyclization and annulation reactions of substituted arenes/heteroarenes involving an electrophilic aromatic substitution (SEAr) reaction as the