Hydroarylations by cobalt-catalyzed C–H activation

• Rajagopal Santhoshkumar and
• Chien-Hong Cheng

Beilstein J. Org. Chem. 2018, 14, 2266–2288, doi:10.3762/bjoc.14.202

• pyridine as an additive (Scheme 6) [46]. Similarly, benzothiazoles also efficiently underwent hydroheteroarylation by using suitable ligands [47]. The reaction was successfully extended to indoles and benzimidazoles 7 bearing a removable 2-pyrimidyl (2-pym) directing group with alkynes at ambient

• ) for C–H functionalization [37]. The Co(III) catalyst was applied for the hydroarylation of alkynes with indoles 14 to form alkenes 15 with linear selectivity (Scheme 11) [53]. The reaction features a broad substrate scope including a variety of indoles, terminal and internal alkynes, mild reaction

• limited to terminal alkynes. Additionally, they applied this methodology to design a mitochondria-targeted imaging dye from electron-withdrawing formyl-substituted indoles and alkynes. Later, Maji’s group reported an N-tert-butyl amide-directed mono- and di-alkenylation reactions using a cobalt catalyst

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• identical nature of the substituents on the product. This severely limits its potential applications, and the usefulness of this protocol is likely limited to the creation of linkers or pendant groups. Benzo-fused five-membered heterocycles also find widespread use in medicinal chemistry, with indoles

• light (Scheme 21) [66]. However, benzofurans and, most importantly, indoles are also accessible through this cascade. The authors demonstrated the synthesis of an array of different, potentially drug-like compounds. The authors also showed the accessibility of their starting materials by synthesising

Hypervalent organoiodine compounds: from reagents to valuable building blocks in synthesis

• Gwendal Grelier,
• Benjamin Darses and
• Philippe Dauban

Beilstein J. Org. Chem. 2018, 14, 1508–1528, doi:10.3762/bjoc.14.128

• phenanthrenes 54 in moderate to good yields (Scheme 19) [59]. Indoles also are relevant substrates for the tandem arylation with cyclic diaryl-λ3-iodanes, allowing the preparation of dibenzocarbazoles 55 in moderate yields (Scheme 20) [60]. The reaction is catalyzed simply by Pd(OAc)2 in the absence of any

• indoles with diaryl-λ3-iodanes (Scheme 36) [75]. The reaction first involves the use of 20 mol % of CuI and 1.1 equivalents of di-tert-butylpyridine (dtbpy) to convert the indole to the C3–H arylated product. The released Ar–I building block, then, can be engaged in the subsequent step of N–H arylation by

• adding 30 mol % of dimethylethylenediamine (DMEDA) and potassium phosphate to the same pot. Symmetrical diaryl-λ3-iodanes afford the diarylated indoles 80 with yields ranging from 41% to 67%. More significantly, whereas non-symmetrical diaryl-λ3-iodanes based on electron poor/rich aryl moieties do not

Atom-economical group-transfer reactions with hypervalent iodine compounds

• Andreas Boelke,
• Peter Finkbeiner and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2018, 14, 1263–1280, doi:10.3762/bjoc.14.108

• with λ3-iodanes. These methods commonly exhibit good AE for (di)arylation procedures, since only small excesses of diaryliodonium salts are necessary. In an initial study, the selective diarylation of indoles 10 using symmetrical and unsymmetrical diaryliodonium salts 1 was demonstrated (Scheme 7) [32

• ]. A selective C–H arylation at C3 of the indole was realised under copper catalysis before the addition of a ligand and an inorganic base initiated the N-arylation with the in situ formed iodoarene. The desired diarylated indoles 11 are obtained with an AE of 46% (for R1 = R2 = H, Ar1 = Ar2 = Ph). The

• scope of this transformation is broad, only C2-substituted indoles show poor reactivity. Furthermore, this is a rare example for good chemoselectivities in atom-efficient reaction cascades even if unsymmetrical substituted diaryliodonium salts are applied. Based on this initial procedure, an impressive

Rhodium-catalyzed C–H functionalization of heteroarenes using indoleBX hypervalent iodine reagents

• Erwann Grenet,
• Ashis Das,
• Paola Caramenti and
• Jérôme Waser

Beilstein J. Org. Chem. 2018, 14, 1208–1214, doi:10.3762/bjoc.14.102

• regioselectivity for the C-6 position of bipyridinones and the C-8 position of quinoline N-oxides and tolerated a broad range of functionalities, such as halogens, ethers, or trifluoromethyl groups. Keywords: C–H activation; hypervalent iodine; indoleBX; indoles; pyridinones; rhodium catalysis; Introduction

• introduction of further heterocyclic rings, such as indoles, is particularly attractive. Most of the methods for indolylpyridinone synthesis involve a condensation cascade process to generate the pyridinone ring [4][5][6]. These methods usually require an electron-withdrawing group (nitrile, nitro, carbonyl

Mannich base-connected syntheses mediated by ortho-quinone methides

• Petra Barta,
• Ferenc Fülöp and
• István Szatmári

Beilstein J. Org. Chem. 2018, 14, 560–575, doi:10.3762/bjoc.14.43

• -1H-indole in the presence of lithium perchlorate as catalyst to afford the new 3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-ones and 3-substituted indoles. The process was then extended to isocyanides and new aminobenzofurans formed via [4 + 1] cycloaddition were isolated. Bharate et al. reported

• on its benzylic carbon atom. Rueping et al. recently performed reactions between aza-o-QMs in situ generated from α-substituted ortho-amino benzyl alcohols 48 and substituted indoles catalysed by N-triflylphosphoramides (NTPAs) [85]. (Scheme 6) The process provided new C-2 and C-3-functionalized

• indole polyheterocycles 49 and 50 in good yields with 90–99% ee. One of the latest publications around this topic has been reported by Deb et al. [86][87]. Various 2-(aminoalkyl)phenols or 1-(aminoalkyl)naphthols 51 were reacted with indoles under Brønsted acid catalysis resulting in 3-(α,α-diarylmethyl

Functionalization of N-arylglycine esters: electrocatalytic access to C–C bonds mediated by n-Bu₄NI

• Mi-Hai Luo,
• Yang-Ye Jiang,
• Kun Xu,
• Yong-Guo Liu,
• Bao-Guo Sun and
• Cheng-Chu Zeng

Beilstein J. Org. Chem. 2018, 14, 499–505, doi:10.3762/bjoc.14.35

• terminal oxidants [14]. The protocol was also extended to reactions with 2-alkylquinoline [15] and phenols [16] using O2 and di-tert-butyl peroxide (DTBP) as oxidant, respectively (Scheme 1). A CuCl-catalyzed oxidative cross coupling of glycine derivatives with indoles has been developed by Hou et al

One-pot sequential synthesis of tetrasubstituted thiophenes via sulfur ylide-like intermediates

• Jun Ki Kim,
• Hwan Jung Lim,
• Kyung Chae Jeong and
• Seong Jun Park

Beilstein J. Org. Chem. 2018, 14, 243–252, doi:10.3762/bjoc.14.16

• center and the substituents on the sulfur atom [10]. In general, these reagents are often applied in the preparation of simple small rings [13], such as epoxides [14][15][16][17][18], cyclopropanes [19][20][21][22], aziridines [23], indoles [24], pyrroles [24], and indolines [25]. In addition, other

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

• pharmaceutical applications [19]. During our studies on the reactions of nitroarenes with nucleophiles [20][21][22][23], particularly carbanions, we were interested in a direct transformation of the formed σH-adducts into heterocyclic systems – indoles [21][23] and quinolines [21][22]. Quinolines were formed

Progress in copper-catalyzed trifluoromethylation

• Guan-bao Li,
• Chao Zhang,
• Chun Song and
• Yu-dao Ma

Beilstein J. Org. Chem. 2018, 14, 155–181, doi:10.3762/bjoc.14.11

• conversion. Notably, electron-deficient pentafluorobenzene was highly reactive under these reaction conditions to afford octafluorotoluene in excellent yield, which provided a promising model for functionalizations of electron-deficient arenes. Furthermore, electron-rich indoles were applicable in these

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

• and aromatic thiols react under these conditions with aliphatic alkenes and styrenes. The direct C-3 sulfenylation of indoles with aryl thiols was reported by Guo, Chen and Fan, using Rose Bengal as organic photoredox catalyst and aerobic oxygen as oxidative species (Scheme 14) [44]. They propose that

• 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

• reaction conditions. In 2016, Wang and co-workers reported the thiocyanation reaction of indoles with TiO2/MoS2 nanocomposite as heterogeneous photoredox catalyst and molecular oxygen as terminal oxidant (Scheme 27) [62]. They propose that the efficiency of their reaction is due to a separation of

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

• -free and recyclable. A variety of heteroarenes, like pyrroles, oxazoles, furanes, thiophenes, indoles and pyrazines were successfully converted into the corresponding trifluoromethylated products in moderate to good yields (Scheme 27). Remarkably, a side chlorination reaction was observed during the

• indoles, except that the nature of the phosphine as well as the stoichiometry between CF3SO2Cl and PCy3 prevented the reduction of formed CF3SOCl and therefore allowed its direct reaction with the substrate (Scheme 38). 4 Chlorination Sparingly, CF3SO2Cl was employed as a chlorinating agent. The first

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• 49. Finally, oxidation of 49 by Cu(n + 1) and aromatisation afforded the oxindole and regenerated the copper catalyst (Scheme 25). The same indoles bearing a 2,2,2-trifluoroethyl side-chain were also obtained in reactions performed with CF3SO2Na and (NH4)2S2O8 as the oxidant in the presence of a

• metals found in Langlois’ reagent could be responsible for reaction initiation. The scope was evaluated on pyridines, pyrroles, indoles, pyrimidines, pyrazines, phthalazines, quinoxalines, deazapurine, thiadiazoles, uracils, xanthenes and pyrazolino-pyrimidines (Scheme 35). The combination of previous

A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic

• Marcus Baumann,
• Ian R. Baxendale and
• Fabien Deplante

Beilstein J. Org. Chem. 2017, 13, 2549–2560, doi:10.3762/bjoc.13.251

• chemistry; heterocycle; hydrogenation; indole; multistep; Introduction Indoles are amongst the most important bioactive heterocyclic structures being commonly encountered in the amino acid tryptophan (1), the related neurotransmitter serotonin (2) as well as numerous complex alkaloid natural products and

• pharmaceuticals [1][2][3][4]. Indoles also play a significant role as phytohormones that promote and regulate the growth and development of plants. Indeed, four of the five endogenously synthesised auxins produced by plants contain the indole motif (Figure 1, structures 3–7). As a consequence of their regulatory

• also deemed highly desirable to be able to produce material on demand using a flexible scale flow chemistry approach. Since the report of the first synthetic access to indoles by Fischer in 1835 more than a dozen further unique indole syntheses have been reported showcasing the importance of developing

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

• tetracyclic moieties are planar. The benzophosphole-fused indoles, such as phosphine oxide, phospholium salt, and borane complex, exhibited strong photoluminescence in dichloromethane (Φ = 67–75%). Keywords: benzophospholo[3,2-b]indole; DFT calculation; molecular structure; phosphole derivatives

• stretching vibration at 1188 cm−1 was observed. Figure 2 shows the X-ray crystal structures of the benzophospholo[3,2-b]indoles 3 and phosphine oxide 4. Selected bond lengths and angles are listed in Table 1. Figure 2 clearly shows that the tetracyclic skeletons are planar. The mean deviations are 0.022 Å

• ]indoles were evaluated using UV absorption and fluorescence spectroscopy in CH2Cl2. The spectra are shown in Figure 3, and the photophysical data are shown in Table 2. The functionalized phosphole derivatives 4–8 showed absorption maxima (λabs) at 299–307 nm and a broad absorption at ≈355 nm. In contrast

Conjugated nitrosoalkenes as Michael acceptors in carbon–carbon bond forming reactions: a review and perspective

• Yaroslav D. Boyko,
• Valentin S. Dorokhov,
• Alexey Yu. Sukhorukov and
• Sema L. Ioffe

Beilstein J. Org. Chem. 2017, 13, 2214–2234, doi:10.3762/bjoc.13.220

• unreactive under these conditions. Electron-rich aromatic heterocyclic compounds such as pyrroles and indoles enter reactions with nitrosoalkenes more smoothly [44][45][46][47][48][49][50][51][52][53][54][55]). The addition of nitrosoalkenes to pyrroles and indoles is a convenient and mild strategy for the

• -pot double addition of pyrroles (and indoles) to nitrosoalkenes derived from α,α’-dihalooximes 70 [60][61][62] (Scheme 25). The synthesis of bis-pyrroles 71 is carried out in water as the solvent. As pointed by the authors, heterogenous conditions can accelerate the rate of reaction compared to

• organic solvent phase. The described method of oximinoalkylation of the С-3 position of indoles has a great potential for the synthesis of pharmaceutically relevant compounds and natural products. Thus, de Lera and co-workers described the synthesis of indole-derived psammaplin A analogue 72, which

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

• example of a double Sonogashira reaction is shown [60]. Oxidative cross-dehydrogenative coupling Copper-catalyzed mechanochemical oxidative cross-dehydrogenative coupling (CDC) reactions [61][62][63][64][65][66] of tetrahydroisoquinolines with alkynes and indoles was reported by Su and co-workers (Scheme

• reacting catalyst. Su and co-workers reported an Fe(III)-catalyzed coupling of 3-benzyl indoles with molecules having active methylene group under solvent-free ball-mill in presence of silica gel as milling auxiliary. Using 10 mol % Fe(NO3)3·9H2O as catalyst and 1.0 equiv of DDQ afforded good yield of

• . They have also demonstrated a mechanochemical synthesis of 3-vinylindoles and β,β-diindolylpropionates by C–H activation. Substituted indoles and ethyl acrylates were reacted in presence of 10 mol % of Pd(OAc)2 and 1.2 equiv of MnO2 to afford highly substituted 3-vinylindoles using silica gel and

Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz–Fritsch–Bobbitt reaction with non-activated and moderately-activated systems

• Marco Mottinelli,
• Mathew P. Leese and
• Barry V. L. Potter

Beilstein J. Org. Chem. 2017, 13, 1871–1878, doi:10.3762/bjoc.13.182

• -substituted THIQs. Conditions: (a) 6 M HCl, rt. Formation of the 4-hydroxy and 4-methoxy-THIQs. Conditions: (a) 6 M HCl or 70% HClO4, rt (see Table 3). Competition between the formation of THIQs 10a,o,p and indoles 16a,o,p. Conditions: (a) 70% HClO4, rt. Competition between 6- and 7-membered ring formation

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

• proceeds via base-promoted propargyl–allenyl rearrangement followed by cyclization and allyl migration. Phosphine-substituted indoles can be synthesized by a similar strategy. Keywords: allyl migration; benzothiophene; indole; metal-free; propargyl-allenyl; Introduction Heterocycles are frequently found

• –57% yield. Besides methyl propargyl ethers, propargyl acetates were also tolerated under these conditions (2i–k). The presence of substituents on the aromatic ring, such as a methyl group or a chlorine atom, did not have much of an effect the reaction (2j,k). Indoles are also important heterocycles

• that are the key motif of many natural products and pharmaceuticals. Consequently, new and straightforward methods to access indoles are highly desirable [35][36]. We chose a propargyl phosphite rearrangement to achieve allenyl intermediates and aimed to synthetize indoles via allenyl phosphonates

Enzymatic synthesis of glycosides: from natural O- and N-glycosides to rare C- and S-glycosides

• Jihen Ati,
• Pierre Lafite and
• Richard Daniellou

Beilstein J. Org. Chem. 2017, 13, 1857–1865, doi:10.3762/bjoc.13.180

• retaining mechanism). In the case of O-GTs, the nucleophile is an alcohol or a phenol (carbohydrates, serine, threonine, …), whereas in N-GTs, the nature of the nitrogen-containing group is more diverse (amines, amides, guanidine or even indoles) [12]. S- and C-GTs follow a similar mechanism with the

Oxidative dehydrogenation of C–C and C–N bonds: A convenient approach to access diverse (dihydro)heteroaromatic compounds

• Santanu Hati,
• Ulrike Holzgrabe and
• Subhabrata Sen

Beilstein J. Org. Chem. 2017, 13, 1670–1692, doi:10.3762/bjoc.13.162

• electron-withdrawing substrates were favored in this case. A slight modification (5 mol % phd, 1 mol % ZnI2 and 1 mol % PPTS) of the existing procedure afforded indoles 62 from indolines 61. Bioinspired flavin mimics were also used as catalysts for oxidative dehydrogenation of dihydropyridines 63 and

• dehydrogenation of C–C and C–N bonds utilizing metal catalysts with synthetic oxidants. The first example is illustrated by transforming an indoline to an indole [91]. In general, indoles are one of the most popular moieties that are observed in a plethora of bioactive natural products and active pharmaceutical

• ingredients. Peng et al. reported a novel catalyst oxidant combo of ([Cu(MeCN)4]BF4) and tert-butylperoxy 2-ethylhexyl carbonate (TBPC) to generate the corresponding indoles 84 in excellent yields from indolines 83 (Scheme 30) [91]. The methodology was further utilized in the conversion of

A practical and efficient approach to imidazo[1,2-a]pyridine-fused isoquinolines through the post-GBB transformation strategy

• Taofeng Shao,
• Zhiming Gong,
• Tianyi Su,
• Wei Hao and
• Chao Che

Beilstein J. Org. Chem. 2017, 13, 817–824, doi:10.3762/bjoc.13.82

• ][30]. Although the Ugi-4CR generates linear α-acylamino-amides, a wide range of heterocycles are accessible through the combination with other transformations (post-transformation strategy) [31]. For example, the Ugi/Diels–Alder process leads to the formation of benzofurans and indoles [32] as well as

A new paradigm for designing ring construction strategies for green organic synthesis: implications for the discovery of multicomponent reactions to build molecules containing a single ring

• John Andraos

Beilstein J. Org. Chem. 2016, 12, 2420–2442, doi:10.3762/bjoc.12.236

• showed that benzimidazoles, Biginelli adducts, dihydropyridines, furans, pyrans, pyridinones, and thiophenes had a high representation of intrinsic greenness; whereas, a high proportion of MCRs producing chromene-4-ones, coumarins, indoles, and pyrazoles had low probabilities of achieving intrinsic

An effective one-pot access to polynuclear dispiroheterocyclic structures comprising pyrrolidinyloxindole and imidazothiazolotriazine moieties via a 1,3-dipolar cycloaddition strategy

• Alexei N. Izmest’ev,
• Galina A. Gazieva,
• Natalya V. Sigay,
• Sergei A. Serkov,
• Valentina A. Karnoukhova,
• Vadim V. Kachala,
• Alexander S. Shashkov,
• Igor E. Zanin,
• Angelina N. Kravchenko and
• Nina N. Makhova

Beilstein J. Org. Chem. 2016, 12, 2240–2249, doi:10.3762/bjoc.12.216

• regio- and diastereoselective one-pot method for the synthesis of new polynuclear dispiroheterocyclic systems with five stereogenic centers (dispiro[imidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-6,3′-pyrrolidine-2′,3′′-indoles]) comprising pyrrolidinyloxindole and imidazo[4,5-e]thiazolo[3,2-b]-1,2,4

• which the phenyl substituents are directed (anti-exo). Conclusion In summary, a simple, general, and efficient one-pot method for the construction of previously unknown substituted dispiro[imidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-6,3′-pyrrolidine-2′,3′′-indoles] was developed. This method is based

Microwave-assisted cyclizations promoted by polyphosphoric acid esters: a general method for 1-aryl-2-iminoazacycloalkanes

• Jimena E. Díaz,
• María C. Mollo and
• Liliana R. Orelli

Beilstein J. Org. Chem. 2016, 12, 2026–2031, doi:10.3762/bjoc.12.190

• ][26][27][28], indoles and 3,4-dihydroisoquinolines [23][29]. Microwave-assisted organic reactions proceed in general faster, with higher yields and more efficiently than those performed under conventional heating [30][31][32][33][34][35][36][37][38]. This technology has found interesting applications