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

Scope and limitations of a DMF bio-alternative within Sonogashira cross-coupling and Cacchi-type annulation

• Kirsty L. Wilson,
• Alan R. Kennedy,
• Jane Murray,
• Ben Greatrex,
• Craig Jamieson and
• Allan J. B. Watson

Beilstein J. Org. Chem. 2016, 12, 2005–2011, doi:10.3762/bjoc.12.187

• alternative to DMF, Cyrene. In addition, we have shown the capacity for extension of the utility of this new solvent towards enabling the cascade synthesis of functionalised indoles and benzofurans via a Cacchi-type annulation. Perhaps more importantly, we have documented some of the limitations of the use of

Rearrangements of organic peroxides and related processes

• Ivan A. Yaremenko,
• Vera A. Vil’,
• Dmitry V. Demchuk and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2016, 12, 1647–1748, doi:10.3762/bjoc.12.162

• synthesis of 2,3-disubstituted furans 210 (Scheme 60) [330]. The benzannulation of indoles 211 can be performed with γ-carbonyl tert-butyl peroxides 212 catalyzed by trifluoromethanesulfonic acid to give carbazoles 213. The key step of this approach is based on the acid-catalyzed rearrangement of tert-butyl

Synergistic chiral iminium and palladium catalysis: Highly regio- and enantioselective [3 + 2] annulation reaction of 2-vinylcyclopropanes with enals

• Haipan Zhu,
• Peile Du,
• Jianjun Li,
• Ziyang Liao,
• Guohua Liu,
• Hao Li and
• Wei Wang

Beilstein J. Org. Chem. 2016, 12, 1340–1347, doi:10.3762/bjoc.12.127

• the reaction with highly active dipolarophiles, such as electrophilic C=O [35], e.g., aldehydes [36][37][38], ketones [38][39], and imines [40], and nucleophilic enol ethers [38][41], enamides [42], and indoles [43]. Nonetheless, the reactions with the α,β-unsaturated aldehydes and ketones face

Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• for the synthesis of biologically active molecules, including natural products and drugs. The Reisman group has reported a Friedel–Crafts conjugate addition–enantioselective protonation for the synthesis of tryptophans 17 from 2-substituted indoles 14 and methyl 2-acetamidoacrylate (15) using

• enol ethers [20][21]. Electron-rich and neutral indoles were efficient substrates for the reaction; however, electron-poor indoles showed attenuated reactivity even when 1.6 equivalents of SnCl4 were employed (60–63% yield, 96:4 to 96.5:3.5 er). Indoles lacking substitution at the 2-position (R1 = H

• protonation of vinyl ketones. Using primary amine catalyst (S,S)-119, the authors were able to catalyze the Friedel–Crafts addition of indoles 117 to vinyl ketones 118 followed by enantioselective protonation (Scheme 27) [52]. During optimization it was found that addition of a weak acid, 2-naphthoic acid

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• group described the first chiral imidodiphosphoric acid-catalyzed enantioselective Friedel–Crafts reactions of indoles and pyrroles with 3-hydroxy-3-indolyloxindoles, giving the 3,3-diaryloxindoles in excellent yields (99% yield) and with excellent enantioselectivities (98% ee) at low catalyst loading

• the 3-position of indoles, while Shi et al. reported that they obtained regioisomers when 3-methylindoles were used (Scheme 49) [66], indicating that the 3-methyl group was important for the observed regioselectivity. Shi et al. established a chiral CPA-catalyzed asymmetric allylation of 3

• . Differently, treatment of 3-indolylmethanols with Nazarov reagents with TfOH in MeCN led to the generation of indoles through a cascade reaction in an (E/Z)-selective mode. These unusual reactions may serve as stereoselective and chemodivergent methods for accessing indole-containing scaffolds. Shi and co

A convenient route to symmetrically and unsymmetrically substituted 3,5-diaryl-2,4,6-trimethylpyridines via Suzuki–Miyaura cross-coupling reaction

• Dariusz Błachut,
• Joanna Szawkało and
• Zbigniew Czarnocki

Beilstein J. Org. Chem. 2016, 12, 835–845, doi:10.3762/bjoc.12.82

• teams in the construction of polyarylated benzenes [56], pyridines [57][58][59][60], thiophenes [61][62], quinoxalines [63], pyrazoles [64] pyrroles [65], pyrimidines [66][67], benzofuranes [68], imidazo[1,2-a]pyridines [69], diaryl/heteroaryl methanes [70], and indoles [71], bearing differently

Gold-catalyzed direct alkynylation of tryptophan in peptides using TIPS-EBX

• Gergely L. Tolnai,
• Jonathan P. Brand and
• Jerome Waser

Beilstein J. Org. Chem. 2016, 12, 745–749, doi:10.3762/bjoc.12.74

• the modification of biomolecules without the need for non-natural amino acids. However, the multiple functional groups present in biomolecules make such a process highly challenging. Based on our previous work on the alkynylation of indoles using TIPS-EBX (1a) and a gold catalysis [37][38], we

• wondered if this transformation could be extended to tryptophan-containing peptides. Even if the reaction gave C3-alkynylation for C3-unsubstituted indoles, we demonstrated that C2-alkynylation could be achieved on skatole (2a, Scheme 1B) [37]. Very recently, Hansen et al. indeed reported a modified

• . Conclusion In conclusion, our work combined with the results of Hansen and co-workers has demonstrated that the gold-catalyzed alkynylation of indoles could be extended to tryptophan in peptides. When considering the scarcity of methods allowing the modification of tryptophan under mild conditions without

Iridium/N-heterocyclic carbene-catalyzed C–H borylation of arenes by diisopropylaminoborane

• Mamoru Tobisu,
• Takuya Igarashi and
• Naoto Chatani

Beilstein J. Org. Chem. 2016, 12, 654–661, doi:10.3762/bjoc.12.65

• ) system. Results and Discussion On the basis of a superior reactivity of indoles in several C–H borylation reactions [7][8][9], we initially examined the borylation of indole 2 with aminoborane 1g using an iridium catalyst under forcing conditions (140 °C, 15 h). Although all the attempts to isolate an

• regioselectivity (99:1) (Table 1, entry 12). Having optimized the conditions, we next explored the scope of Ir/ICy-catalyzed borylation of heteroarene substrates using 1g (Table 2). Functionalized indoles, such as those containing methoxy, fluoro, bromo and chloro substituents, all underwent the borylation to form

• instability of 11-B during isolation (Table 2, entry 8). Our protocol was able to borylate non-benzofused five-membered heteroarenes. Pyrrole 12 was much less reactive than indoles, and required neat conditions to obtain a modest yield of the borylated product 12-B (Table 2, entry 9). Thiophene (13) afforded