Iodine-catalyzed electrophilic substitution of indoles: Synthesis of (un)symmetrical diindolylmethanes with a quaternary carbon center

• Thanigaimalai Pillaiyar,
• Masoud Sedaghati,
• Andhika B. Mahardhika,
• Lukas L. Wendt and
• Christa E. Müller

Beilstein J. Org. Chem. 2021, 17, 1464–1475, doi:10.3762/bjoc.17.102

• via an iodine-catalyzed coupling reaction of trifluoromethyl(indolyl)phenylmethanol with indole derivatives. This method has also been extended to the synthesis of pentafluoro-ethylated and heptafluoro-propylated DIMs in excellent yields. Selected compounds were evaluated in radioligand binding

• mol % to 5 mol % reduced the product formation (Table 1, entry 18). Having optimized the reaction conditions (I2, 10 mol %, 40 °C for 5 h in MeCN; entry 16, Table 1), we explored the scope of the reaction. At first, we employed differently substituted indole derivatives (Table 2). A large variety of

• phenyl ring of 1 was replaced by the heteroaryl moiety thiophene (1i), reacted efficiently with a series of indole derivatives (2a, 2d, 2h) providing yields of 82–90% (3v–x). We further extended this protocol to the preparation of unsymmetrical pentafluoroethylated and heptafluoropropylated DIM

Synthetic reactions driven by electron-donor–acceptor (EDA) complexes

• Zhonglie Yang,
• Yutong Liu,
• Kun Cao,
• Xiaobin Zhang,
• Hezhong Jiang and
• Jiahong Li

Beilstein J. Org. Chem. 2021, 17, 771–799, doi:10.3762/bjoc.17.67

• 22 can be afforded easily (Scheme 7). This procedure offers a novel cyclization method with bifunctionalization, causing a multicomponent reaction of vinylaniline, halide, and sulfonylate to give corresponding indole derivatives. Furthermore, a wide variety of applicable substrates and good

• indole derivatives 100 under blue-light irradiation (Scheme 35). Given the UV–vis spectra of the reaction mixture and its components, there was no evidence of the formation of a ternary EDA complex between Katritzky salt 99, 98, and morpholine. Moreover, the TDDFT calculation showed that electron

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

• generate CF3-substituted iminium ions able to promote Friedel–Crafts alkylations [110][111]. Ma et al. exploited this mode of activation in a Brønsted acid-catalyzed three-component asymmetric reaction [112]. Mixing hemiacetal 175, arylaniline 176, and indole derivatives 149 in the presence of a catalytic

When metal-catalyzed C–H functionalization meets visible-light photocatalysis

• Lucas Guillemard and
• Joanna Wencel-Delord

Beilstein J. Org. Chem. 2020, 16, 1754–1804, doi:10.3762/bjoc.16.147

• , thus rendering this methodology well suitable for the synthesis of a variety of indole derivatives. Subsequently, the panel of oxidative Heck coupling reactions via a photoredox catalytic system combined with C–H activation using Rh [74] or Ru [75] was extended by Rueping’s group. In 2014, Rueping

• applied to various C–H functionalization reactions [92][93]. In 2017, Noël, Van der Eycken and co-workers hence astutely combined the dual catalysis strategy with flow microreactor technology to achieve C2-acylation of indole derivatives with aldehydes (Figure 30) [94]. Both electron-rich and electron

• arylation with diazonium salts. The same year, Jana’s group independently reported an analogous approach allowing the C2-acylation of indole derivatives with aldehydes (Figure 32). The only difference in comparison with Noël and Van der Eycken’s procedure concerned the nature of the photocatalyst used for

Palladium-catalyzed regio- and stereoselective synthesis of aryl and 3-indolyl-substituted 4-methylene-3,4-dihydroisoquinolin-1(2H)-ones

• Valeria Nori,
• Antonio Arcadi,
• Armando Carlone,
• Fabio Marinelli and
• Marco Chiarini

Beilstein J. Org. Chem. 2020, 16, 1084–1091, doi:10.3762/bjoc.16.95

• -assisted cyclization and reductive elimination from the resulting σ-indolylpalladium complex C (Scheme 5). The reaction led to the stereoselective formation of indole derivatives 6ba–fc (aryl, heteroaryl and vinyl groups were allowed in substrates 5) in good to high yield. The stereochemistry of compounds

Copper-catalysed alkylation of heterocyclic acceptors with organometallic reagents

• Yafei Guo and
• Syuzanna R. Harutyunyan

Beilstein J. Org. Chem. 2020, 16, 1006–1021, doi:10.3762/bjoc.16.90

• , and Grignard reagents. Review Copper-catalysed C–C bond-forming reactions at the heterocycle The direct synthesis of chiral heterocyclic molecules from pyridine, quinolone, or indole derivatives is advantageous due to the abundance of such building blocks. Unfortunately, establishing catalytic

Reaction of indoles with aromatic fluoromethyl ketones: an efficient synthesis of trifluoromethyl(indolyl)phenylmethanols using K₂CO₃/n-Bu₄PBr in water

• Thanigaimalai Pillaiyar,
• Masoud Sedaghati and
• Gregor Schnakenburg

Beilstein J. Org. Chem. 2020, 16, 778–790, doi:10.3762/bjoc.16.71

• have been used as key precursors for the construction of complex indole derivatives that would be useful in pharmaceuticals as drugs and agrochemicals [2][3][4][5][6][7][8][9][10][11][12][13][14]. The simple (1H-indol-3-yl)methanol, a breakdown product of glucobrassicin, which can be found in

• broad substrate scope, functional group tolerance, and simple purification technique is highly desired. In our continuous effort of synthesizing indole derivatives [29][30][31], herein, we report an efficient synthesis of multiple halogen-substituted (1H-indol-3-yl)methanol derivatives in the presence

Cascade trifluoromethylthiolation and cyclization of N-[(3-aryl)propioloyl]indoles

• Ming-Xi Bi,
• Shuai Liu,
• Yangen Huang,
• Xiu-Hua Xu and
• Feng-Ling Qing

Beilstein J. Org. Chem. 2020, 16, 657–662, doi:10.3762/bjoc.16.62

• involved in these transformations. Keywords: cyclization; indole derivatives; oxidation; radical reaction; trifluoromethylthiolation; Introduction The trifluoromethylthio (SCF3) group could significantly improve the lipophilicity of organic molecules as shown by its high Hansch constant (π = 1.44 for

Architecture and synthesis of P,N-heterocyclic phosphine ligands

• Wisdom A. Munzeiwa,
• Bernard Omondi and
• Vincent O. Nyamori

Beilstein J. Org. Chem. 2020, 16, 362–383, doi:10.3762/bjoc.16.35

• methanesulfonyl chloride mediated cyclization of amide 97 and reaction with methyl iodide or methoxymethyl chloride afforded the N-substituted indole derivatives 99 (R = Me, MOM). The desired phosphinylated compounds 102 were obtained via three routes: The dicyclohexylphosphine derivatives 102a and b were only

Copper-promoted/copper-catalyzed trifluoromethylselenolation reactions

• Clément Ghiazza and
• Anis Tlili

Beilstein J. Org. Chem. 2020, 16, 305–316, doi:10.3762/bjoc.16.30

• heterocycle. This intermediate was then trifluoromethylselenylated by [(bpy)CuSeCF3]2. While benzofurans and benzothiophenes were prepared in moderate to good yields, only marginal yields were obtained with indole derivatives (up to 25%). Finally, the reactions could easily be scaled up to a gram scale. The

Copper-catalyzed enantioselective conjugate addition of organometallic reagents to challenging Michael acceptors

• Delphine Pichon,
• Jennifer Morvan,
• Christophe Crévisy and
• Marc Mauduit

Beilstein J. Org. Chem. 2020, 16, 212–232, doi:10.3762/bjoc.16.24

• enantioselective catalysis was reported by Evans and co-workers in 2005 [34]. The selected asymmetric transformation was the Friedel–Crafts 1,4-addition involving indole derivatives as nucleophiles, catalyzed by a scandium(III) triflate complex with chiral bis(oxazolinyl)pyridine ligands. As highlighted by Evans

Synthesis of 3-alkenylindoles through regioselective C–H alkenylation of indoles by a ruthenium nanocatalyst

• Abhijit Paul,
• Debnath Chatterjee,
• Srirupa Banerjee and
• Somnath Yadav

Beilstein J. Org. Chem. 2020, 16, 140–148, doi:10.3762/bjoc.16.16

• reaction was also carried out using [Ru(p-cymene)Cl2]2 as a homogeneous catalyst, but this also did not lead to the formation of the desired product. After establishing the optimum conditions for the reaction, we carried out the alkenylation of several indole derivatives 1 with different acrylates 2 under

Palladium-catalyzed synthesis and nucleotide pyrophosphatase inhibition of benzo[4,5]furo[3,2-b]indoles

• Hoang Huy Do,
• Saif Ullah,
• Alexander Villinger,
• Joanna Lecka,
• Jean Sévigny,
• Peter Ehlers,
• Jamshed Iqbal and
• Peter Langer

Beilstein J. Org. Chem. 2019, 15, 2830–2839, doi:10.3762/bjoc.15.276

• ten benzo[4,5]furo[3,2-b]indole derivatives based on regioselective Suzuki–Miyaura reaction of 2,3-dibromobenzofuran with 2-bromophenylboronic acid and subsequent cyclization. The difference between the work of Truong and our approach mainly lies in the synthesis of the cyclization precursor. The

Cyclopropanation–ring expansion of 3-chloroindoles with α-halodiazoacetates: novel synthesis of 4-quinolone-3-carboxylic acid and norfloxacin

• Sara Peeters,
• Linn Neerbye Berntsen,
• Pål Rongved and
• Tore Bonge-Hansen

Beilstein J. Org. Chem. 2019, 15, 2156–2160, doi:10.3762/bjoc.15.212

• of indole substituents on the yields of ethyl quinoline-3-carboxylates [15]. Green = good, orange = medium, red = poor. R = halogen, Me, MeO, NO2. Retrosynthetic outline for the synthesis of quinolone-3-carboxlates from indole derivatives. Synthesis of ethyl 4-quinolone-3-carboxylate (6) and proposed

Synthesis of benzo[d]imidazo[2,1-b]benzoselenoazoles: Cs₂CO₃-mediated cyclization of 1-(2-bromoaryl)benzimidazoles with selenium

• Mio Matsumura,
• Yuki Kitamura,
• Arisa Yamauchi,
• Yoshitaka Kanazawa,
• Yuki Murata,
• Tadashi Hyodo,
• Kentaro Yamaguchi and
• Shuji Yasuike

Beilstein J. Org. Chem. 2019, 15, 2029–2035, doi:10.3762/bjoc.15.199

• constructing tetracyclic aromatic heterocycles containing selenium. For example, the reaction of 2-(2-iodophenyl)indoles with selenium powder in the presence of CuO as catalyst resulted in benzoselenopheno[3,2-b]indole derivatives [14]. The reaction of 2-(2-haloaryl)imidazo[1,2-a]pyridines with selenium using

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• three-component reaction of 2-iodobenzamide 17, terminal alkyne 18 and pyrrole or indole derivatives 19. Palladium-catalysed three-component reaction of ethynylbenzamides 21, secondary amines 22 and CO (23). Proposed mechanism for the formation of methyleneisoindolinones 24. Copper-catalysed three

• quaternary centre [79]. The reaction takes places in water, even in the presence of air, and with nanodomain cuprous oxide as an inexpensive and reusable catalyst. The scope includes aryl, alkyl and carboxyl groups at 2- and 3-positions of the lactam ring. Pyrrole reacts across the 2-carbon while indole

• derivatives do it through the carbon at 3-position. Although a quaternary stereocentre is created in the process, no attempts to make this synthesis in a stereoselective fashion were reported. A tentative mechanism is proposed, based in a Sonogashira coupling of iodobenzamide 17 and copper acetylide, in a

Synthesis of indolo[1,2-c]quinazolines from 2-alkynylaniline derivatives through Pd-catalyzed indole formation/cyclization with N,N-dimethylformamide dimethyl acetal

• Antonio Arcadi,
• Sandro Cacchi,
• Giancarlo Fabrizi,
• Francesca Ghirga,
• Antonella Goggiamani,
• Antonia Iazzetti and
• Fabio Marinelli

Beilstein J. Org. Chem. 2018, 14, 2411–2417, doi:10.3762/bjoc.14.218

• -(o-aminophenyl)indole derivatives followed by further cyclization [19][20][21][22]. Our interest in this field led to the development of an original approach to 6-trifluoromethyl-12-aryl(vinyl)indolo[1,2-c]quinazolines 4 through sequential Pd-catalyzed reactions of bis(o-trifluoroacetamidophenyl

Anomeric modification of carbohydrates using the Mitsunobu reaction

• Julia Hain,
• Patrick Rollin,
• Werner Klaffke and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1619–1636, doi:10.3762/bjoc.14.138

• of indole derivatives were also approached by Zembower et al. employing 2,3,4,6-tetra-O-benzyl glucopyranose in a Mitsunobu reaction [92]. In the same period, Prudhomme’s group followed closely related approaches for the N-glycosylation of indolic structures. Various rebeccamycin analogues were

Transition-metal-free [3 + 3] annulation of indol-2-ylmethyl carbanions to nitroarenes. A novel synthesis of indolo[3,2-b]quinolines (quindolines)

• Michał Nowacki and
• Krzysztof Wojciechowski

Beilstein J. Org. Chem. 2018, 14, 194–202, doi:10.3762/bjoc.14.14

• -diacetylindoxyl [12] under basic conditions condensed with isatine to form quindoline-11-carboxylic acid easily transformed into quindoline (b) [12]. Another application of indole derivatives to the construction of quindoline starts with the reaction of 1-phenylsulfonylindole with 2-nitrobenzaldehyde (c) [13

• materials disappeared (TLC control) and we isolated indolophenanthridine 16 in 41% yield. Other nitroarenes under analogous reaction conditions gave condensed indole derivatives as summarized in Table 2. Better yields were obtained in the reactions of 1-(tert-butoxycarbonyl)indol-2-ylacetonitrile with

Photocatalytic formation of carbon–sulfur bonds

• Alexander Wimmer and
• Burkhard König

Beilstein J. Org. Chem. 2018, 14, 54–83, doi:10.3762/bjoc.14.4

• to heteroaromatic substrates like indoles would produce valuable synthetic intermediates. By applying Rose Bengal as organic photocatalyst and aerobic oxygen as terminal oxidant, they were able to functionalize a series of indole derivatives and also could show the applicability of the thiocyanation

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation and chlorination. Part 2: Use of CF₃SO₂Cl

• Hélène Chachignon,
• Hélène Guyon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2800–2818, doi:10.3762/bjoc.13.273

• , said reagent was used under reductive conditions in order to generate in situ the highly reactive CF3SCl, which could subsequently be trapped by nucleophiles. Indole derivatives proved to be appropriate substrates for this reaction, and a variety of them were selectively converted into their 3

• derivatives. Morevover, the scope could be extended to other substrates of interest, such as activated benzene derivatives and thiols. Similarly, Lu, Zhao and co-workers found out that excellent yields could also be achieved for indole derivatives when replacing PMe3 or (EtO)2P(O)H by cheap and stable

• of CF3SO2Cl and tricyclohexylphosphine, the trifluoromethylsulfinylation of various indole and pyrrole derivatives featuring diverse functional groups, as well as other azaarenes could be achieved in low to excellent yields (Scheme 38a). Generally, indole derivatives provided better results than

Synthesis and photophysical properties of novel benzophospholo[3,2-b]indole derivatives

• Mio Matsumura,
• Mizuki Yamada,
• Atsuya Muranaka,
• Misae Kanai,
• Naoki Kakusawa,
• Daisuke Hashizume,
• Masanobu Uchiyama and
• Shuji Yasuike

Beilstein J. Org. Chem. 2017, 13, 2304–2309, doi:10.3762/bjoc.13.226

• knowledge, the synthesis of benzophosphole-fused indole derivatives as tetracyclic heteroacenes has not been reported. In 2015, Lu et al. reported the synthesis of only one phosphole and indole-fused pentacyclic heteroacene [35]. Recently, we reported simple and efficient synthetic routes to benzothiophene

• -ray crystal analysis of benzophospholo[3,2-b]indoles showed that the nitrogen atoms are sp2 hybridized and the phosphorus atoms adopt pyramidal and tetrahedral geometry. A significant characteristic of the benzophosphole-fused indole derivatives is that the corresponding phosphine oxide, the

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• isolate up to 77% of differently substituted indole derivatives (Scheme 55). Advantages and limitations Over a couple of decades the area of mechanochemistry considered to be one of the best solvent-free synthetic methods. This area has become significantly interesting to chemists due to its benefits over

Synthesis of benzothiophene and indole derivatives through metal-free propargyl–allene rearrangement and allyl migration

• Jinzhong Yao,
• Yajie Xie,
• Lianpeng Zhang,
• Yujin Li and
• Hongwei Zhou

Beilstein J. Org. Chem. 2017, 13, 1866–1870, doi:10.3762/bjoc.13.181

• propargyl–allenyl rearrangement [17][18][19][20][21][22][23][24][25][26][27] and an allyl migration [32][33][34] (Scheme 1). In addition, phosphine-substituted indole derivatives could also be conveniently constructed by a similar strategy. This method not only avoids the use of transition metal catalysts

• allyl migration (Scheme 2). Phosphine-substituted indole derivatives were obtained in moderate yield (Figure 3, 4a–c). Conclusion In summary, we have developed an expedient route for the construction of benzothiophene and indole derivatives via propargyl–allene rearrangement and allyl migration. The

• reaction proceeded under mild conditions to produce useful benzothiophene and indole derivatives. Examples of biologically active benzothiophene derivatives. Synthesis of benzothiophenes. Reaction conditions: 1 (0.5 mmol), DBU (0.1 mmol), THF (2.0 mL), 50 °C, 12 h, under N2. Yields are isolated yields