Synthesis of diverse indole libraries on polystyrene resin – Scope and limitations of an organometallic reaction on solid supports

• Kerstin Knepper,
• Sylvia Vanderheiden and
• Stefan Bräse

Beilstein J. Org. Chem. 2012, 8, 1191–1199, doi:10.3762/bjoc.8.132

• limitations are presented. Keywords: chemical diversity; cross-coupling reactions; indole; Merrifield resin; Introduction Indoles are heterocyclic structures of unquestionable importance. It is well recognized that the indole moiety is a privileged structural motif found in numerous natural products, such

• indoles. Despite the interest in new indoles [3][4][5] and in particular for libraries of combinatorial compounds [2][6][7][8][9][10][11][12][13][14][15][16][17], there has only been one report for the application of the Bartoli reaction [18][19][20][21][22][23] on solid supports so far [24

• ]. Organometallic reactions on solid supports are always particularly challenging [25]. In the past, indoles were synthesized by using, for example, Fischer indole synthesis [26][27][28][29][30], Bartoli indole synthesis, Nenitzescu synthesis [31], Wittig indole synthesis [32], Madelung indole synthesis [33

Continuous-flow catalytic asymmetric hydrogenations: Reaction optimization using FTIR inline analysis

• Magnus Rueping,
• Teerawut Bootwicha and
• Erli Sugiono

Beilstein J. Org. Chem. 2012, 8, 300–307, doi:10.3762/bjoc.8.32

• Magnus Rueping Teerawut Bootwicha Erli Sugiono Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany 10.3762/bjoc.8.32 Abstract The asymmetric organocatalytic hydrogenation of benzoxazines, quinolines, quinoxalines and 3H-indoles in continuous-flow

• % Brønsted acid 1b, a flow rate of 0.1 mL min−1 and 60 min residence time (Table 5). To broaden the scope of the asymmetric hydrogenations in continuous flow further, the reduction of 3H-indoles 9 was studied (Table 6) [108]. Here the best reaction conditions turned out to be a temperature of 30 °C, a flow

• continuous-flow hydrogenations of benzoxazines, quinolines, quinoxalines and 3H-indoles. Following a real-time continuous-flow optimization, the corresponding products were obtained in good yields and with excellent enantioselectivities. By applying the FTIR inline monitoring, reaction parameters can be

Synthesis of oleophilic electron-rich phenylhydrazines

• Aleksandra Jankowiak and
• Piotr Kaszyński

Beilstein J. Org. Chem. 2012, 8, 275–282, doi:10.3762/bjoc.8.29

• : arylhydrazines; methodology; synthesis; Introduction Mono-arylhydrazines I are important intermediates in the synthesis of a number of heterocycles, including indoles [1] and some azoles (for example [2][3]), many of which exhibit biological activity and are used in drug development [4][5][6]. Arylhydrazines

A concise synthesis of 3-(1-alkenyl)isoindolin-1-ones and 5-(1-alkenyl)pyrrol-2-ones by the intermolecular coupling reactions of N-acyliminium ions with unactivated olefins

• Nianhong Lu,
• Lihong Wang,
• Zhanshan Li and
• Wei Zhang

Beilstein J. Org. Chem. 2012, 8, 192–200, doi:10.3762/bjoc.8.21

• terminal alkynes to give the doubly alkyl-substituted acetylenes [1][2][3]; the Brønsted acid and Lewis acid catalyzed coupling of alcohols with indoles to give the 3-alkyl-substituted indoles [4][5][6]; and the Brønsted acid and Lewis acid-catalyzed coupling of alcohols with 1,3-dicarbonyls to give the 2

Synthetic approaches to multifunctional indenes

• Neus Mesquida,
• Sara López-Pérez,
• Immaculada Dinarès and
• Ermitas Alcalde

Beilstein J. Org. Chem. 2011, 7, 1739–1744, doi:10.3762/bjoc.7.204

• approaches leading to these compounds lag behind those for heteroaromatic systems, e.g., indoles, being limited as it is by the scarce knowledge of indene chemistry in comparison with heterocyclic chemistry [3][17][18][19][20][21][22]. Moreover, chemical transformation by indenes, which could permit rapid

Equilibrium constants and protonation site for N-methylbenzenesulfonamides

• José A. Moreira,
• Ana M. Rosa da Costa,
• Luis García-Río and
• Márcia Pessêgo

Beilstein J. Org. Chem. 2011, 7, 1732–1738, doi:10.3762/bjoc.7.203

• Hammett’s methodology is only applicable to similar classes of compounds [18][19]. In reality, during the 1950’s, a variety of acidity constants for different kinds of bases, such as tertiary amines (H0’’’) [20], amides (Ha) [21], carbinoles (HR+) [22], and indoles (HI) [23], among others [19][24], were

Recent advances in direct C–H arylation: Methodology, selectivity and mechanism in oxazole series

• Cécile Verrier,
• Pierrik Lassalas,
• Laure Théveau,
• Guy Quéguiner,
• François Trécourt,
• Francis Marsais and
• Christophe Hoarau

Beilstein J. Org. Chem. 2011, 7, 1584–1601, doi:10.3762/bjoc.7.187

• the reactivity at the C2 position significantly. Tamagnan further reported the first example of Pd(0)/Cu(I)-catalyzed direct arylation of benzoxazole (Scheme 7) [41]. Interestingly, Bellina and Rossi reported the Pd(0)/Cu(I)-catalyzed direct arylation of indoles, imidazoles, oxazoles and thiazoles

Synthesis of fluoranthenes by hydroarylation of alkynes catalyzed by gold(I) or gallium trichloride

• Sergio Pascual,
• Christophe Bour,
• Paula de Mendoza and
• Antonio M. Echavarren

Beilstein J. Org. Chem. 2011, 7, 1520–1525, doi:10.3762/bjoc.7.178

• ][16][17][18][19][20][21]. In addition to gold, the intramolecular version of this reaction was also carried out with Ru(II) [22], Pt(II) [12][22][23], Pt(IV) [24], Ga(III) [25][26], and Hg(II) [27][28] as catalysts. Electron-rich indoles also react with alkynes in the presence of gold catalysts to

Access to pyrrolo-pyridines by gold-catalyzed hydroarylation of pyrroles tethered to terminal alkynes

• Elena Borsini,
• Gianluigi Broggini,
• Andrea Fasana,
• Chiara Baldassarri,
• Angelo M. Manzo and
• Alcide D. Perboni

Beilstein J. Org. Chem. 2011, 7, 1468–1474, doi:10.3762/bjoc.7.170

• -substituted alkynes have been demonstrated as efficient substrates for the construction of heteropolycyclic compounds. In particular, alkynyl indoles and pyrroles were successfully used to afford β-carbolines [16][17], pyrrolo-azepines [18], azepino-indoles and azocino-indoles [19] under mild conditions

Multistep flow synthesis of vinyl azides and their use in the copper-catalyzed Huisgen-type cycloaddition under inductive-heating conditions

• Lukas Kupracz,
• Jan Hartwig,
• Jens Wegner,
• Sascha Ceylan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2011, 7, 1441–1448, doi:10.3762/bjoc.7.168

• were also used in the Hemetsberger reaction, which yields indoles [8]. However, straightforward and safe methods for the preparation of vinyl azides are still scarce. In fact, in most cases the synthesis involves the generation of toxic and explosive azido intermediates. The most frequently used batch

Amines as key building blocks in Pd-assisted multicomponent processes

• Didier Bouyssi,
• Nuno Monteiro and
• Geneviève Balme

Beilstein J. Org. Chem. 2011, 7, 1387–1406, doi:10.3762/bjoc.7.163

• -step reaction with, first, a Sonogashira coupling of o-haloanilines with terminal alkynes, followed by a cyclization reaction of the resulting 2-alkynyaniline derivatives [26][27]. A strategy for the preparation of indoles through a three-component reaction consisted of generating the terminal alkyne

• -dihaloarene partner and the corresponding polysubstituted indoles were isolated in good yields as single regioisomers (Scheme 23). Based on this concept, Alper and coworkers reported the synthesis of isoindolin-1-one derivatives 53 through a four-component reaction starting from ortho-dihaloarenes and

• order to suppress the concurrent formation of 2-substituted indoles 60 by direct cyclization of o-alkynylaniline intermediates under the classical Sonogashira reaction conditions. Interestingly, aryl bromides were used as a third partner and may be added at the beginning of this one-pot reaction since

Functionalization of heterocyclic compounds using polyfunctional magnesium and zinc reagents

• Paul Knochel,
• Matthias A. Schade,
• Sebastian Bernhardt,
• Georg Manolikakes,
• Albrecht Metzger,
• Fabian M. Piller,
• Christoph J. Rohbogner and
• Marc Mosrin

Beilstein J. Org. Chem. 2011, 7, 1261–1277, doi:10.3762/bjoc.7.147

• yield, as well as the sPLA2 inhibitor 123, in a short reaction sequence (Scheme 19) [46]. Using TMPMgCl·LiCl (41), it is possible to prepare fully substituted indoles, such as 128 (Scheme 20) [47]. Thus, starting from the aniline 124, an ortho-directed chlorination with N-chlorosuccinimide at 90 °C

• magnesiation of the pyrimidine ring. Synthesis of a p38 kinase inhibitor 119 and of a sPLA2 inhibitor 123. Synthesis of highly substituted indoles of type 128. Efficient magnesiations of polyfunctional aromatics and heterocycles using TMP2Mg·2LiCl (129). Negishi cross-coupling in the presence of substrates

NMR studies of anion-induced conformational changes in diindolylureas and diindolylthioureas

• Damjan Makuc,
• Jennifer R. Hiscock,
• Mark E. Light,
• Philip A. Gale and
• Janez Plavec

Beilstein J. Org. Chem. 2011, 7, 1205–1214, doi:10.3762/bjoc.7.140

• extensively employed in synthetic anion receptors comprising groups such as amides, pyrroles, indoles, ureas and triazoles, as well as in ammonium, guanidinium and imidazolium moieties used as hydrogen bond donors [16][17][18][19][20][21][22][23]. Amongst neutral anion receptor systems, indole and related

• recently analyzed the conformational preferences of several 2,7-disubstituted indoles with amide substituents at C2 and urea substituents at C7, which showed preference for distinct conformations in the presence and in the absence of anions [33][34][35]. In addition, indole and urea groups were strongly

One-pot four-component synthesis of pyrimidyl and pyrazolyl substituted azulenes by glyoxylation–decarbonylative alkynylation–cyclocondensation sequences

• Charlotte F. Gers,
• Julia Rosellen,
• Eugen Merkul and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2011, 7, 1173–1181, doi:10.3762/bjoc.7.136

• glyoxylation of electron rich N-heterocycles, such as indoles and pyrroles, leads to the formation of glyoxylyl chlorides, which can be reacted without isolation by decarbonylative Sonogashira coupling to form the desired ynones. So far, only one example of the synthesis of azulenylynones has been described

• commercially available and inexpensive azulene derivative, and 1-hexyne (2b) as model substrates (Table 1) (for experimental details, see Supporting Information File 1). Initially, the optimized conditions for the glyoxylation–decarbonylative alkynylation of indoles were applied [47], except for the addition

Recent developments in gold-catalyzed cycloaddition reactions

• Fernando López and
• José L. Mascareñas

Beilstein J. Org. Chem. 2011, 7, 1075–1094, doi:10.3762/bjoc.7.124

• (VIII) that participate in (4 + 2) annulations with polarized alkenes such as indoles, carbonyls, imines or silyl enol ethers [45]. Thus, different types of 6-membered carbocycles and heterocycles were prepared in good yields and notable regioselectivities. An example of these annulations, using indoles

Recent advances in the gold-catalyzed additions to C–C multiple bonds

• He Huang,
• Yu Zhou and
• Hong Liu

Beilstein J. Org. Chem. 2011, 7, 897–936, doi:10.3762/bjoc.7.103

• catalytic amount of phosphite–gold(I) pre-catalyst and a silver additive. Notably, the addition is regioselective for the allene terminus, and generates (E)-allylation products 202. The direct C–H functionalization of indoles or pyrroles is an efficient method for the introduction of vinyl and aryl groups

• . A gold-catalyzed direct alkynylation of indole and pyrrole heterocycles 204 with a benziodoxolone-based hypervalent iodine reagent 203 has been developed [91]. The functional group tolerance was greatly increased when compared with direct alkynylation of indoles reported previously. Kar et al

• -activated alkene followed by a C–C bond cyclization reaction. The carbon, oxygen and nitrogen tethered 1,6-enynes react smoothly with methoxy substituted benzenes, indoles, pyrroles and furans as nucleophilic partners (Scheme 42). The cycloisomerization reactions of boronated enynes 233 was achieved with

Solvent- and ligand-induced switch of selectivity in gold(I)-catalyzed tandem reactions of 3-propargylindoles

• Estela Álvarez,
• Delia Miguel,
• Patricia García-García,
• Manuel A. Fernández-Rodríguez,
• Félix Rodríguez and
• Roberto Sanz

Beilstein J. Org. Chem. 2011, 7, 786–793, doi:10.3762/bjoc.7.89

• substituents at both the propargylic and terminal positions, was reversed by the proper choice of the catalyst and the reaction conditions. Thus, 3-(inden-2-yl)indoles, derived from an aura-Nazarov cyclization (instead of an aura-iso-Nazarov cyclization), were obtained in moderate to good yields from a variety

• of 3-propargylindoles. Keywords: catalysis; gold; indoles; Nazarov cyclizations; selectivity; Introduction Catalysis with gold complexes as carbophilic π-acids has become a highly developed area in the last decade [1][2][3][4][5][6][7]. In particular, 1,2-acyl migration reactions of propargylic

• nucleophilic nature of indoles [15], which are known to react with gold-activated alkynes or allenes [16][17], and by taking advantage of our reported methodology for the synthesis of 3-propargylindoles [18][19], we have shown that the indole nucleus is able to participate in gold-catalyzed 1,2-migration

Synthetic applications of gold-catalyzed ring expansions

• David Garayalde and
• Cristina Nevado

Beilstein J. Org. Chem. 2011, 7, 767–780, doi:10.3762/bjoc.7.87

• cyclization events [51]. 1-(1-Alkynyl)cyclopropyl ketones 56 proved to be versatile building blocks for this purpose and gave, in the presence of indoles 57 as dipolarophiles, tetracyclic furans 58 in excellent yields (Scheme 20, reaction 1). NHC carbenes are preferred as ancillary ligands on the metal center

One-pot gold-catalyzed synthesis of 3-silylethynyl indoles from unprotected o-alkynylanilines

• Jonathan P. Brand,
• Clara Chevalley and
• Jérôme Waser

Beilstein J. Org. Chem. 2011, 7, 565–569, doi:10.3762/bjoc.7.65

• -pot procedure with the Au(I)-catalyzed C3-selective direct alkynylation of indoles using the benziodoxolone reagent TIPS-EBX to give a mild, easy and straightforward entry to 2-substituted-3-alkynylindoles. The reaction can be applied to unprotected anilines, was tolerant to functional groups and easy

• to carry out (RT, and requires neither an inert atmosphere nor special solvents). Keywords: alkynylation; direct functionalization; gold; hypervalent iodine; indoles; Introduction Indoles are widespread in both natural products and synthetic drugs [1][2] and as a result, their synthesis and

• functionalization have been extensively studied [3][4]. Among the numerous syntheses of indoles, the cyclization of 2-alkynylanilines has the advantage that the resulting products, 2-substituted indoles, are easily functionalized by electrophilic aromatic substitution at position 3. Traditionally, this

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• to yield sunitinib (Scheme 8). Indoles The neuroamine transmitter serotonin contains an indole ring, so it is not surprising that indoles are a recurring theme in many drugs affecting central nervous system (CNS) function including antidepressants, antipsychotics, anxiolytics and antimigraine drugs

• carvedilol has an additional antioxidant mode of action. It has been proposed that the carbazole ring may be involved in scavenging oxygen radicals thereby accounting for reduced myocardial damage [41]. Since carbazoles are similar to indoles, analogous methods can be used for their synthesis. The key

Fluorometric recognition of both dihydrogen phosphate and iodide by a new flexible anthracene linked benzimidazolium-based receptor

• Kumaresh Ghosh and
• Debasis Kar

Beilstein J. Org. Chem. 2011, 7, 254–264, doi:10.3762/bjoc.7.34

• hydrogen bond donors and acceptors are of considerable importance. Among the different binding motifs for anions, the hydrogen bonding properties of NH groups in neutral amines [13], amides [14], ureas/thioureas [15][16], indoles [17][18][19] and pyrroles [20] as well as in guanidinium [21] and imidazolium

Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds

• Carolin Fischer and
• Burkhard Koenig

Beilstein J. Org. Chem. 2011, 7, 59–74, doi:10.3762/bjoc.7.10

• -labile functional groups are present. Electron-neutral and electron-poor aryl bromides are suitable substrates [17], and ortho-substituents on the aryl halide are tolerated. In contrast, electron-rich aryl bromides give only poor results. Recently, the modular synthesis of indoles by a palladium

• -catalysed cascade process provided an efficient entry to substituted indoles [25]. Although copper is less toxic and less expensive than palladium, the required harsh conditions, the limited range of suitable substrates and moderate yields prevented the use of Ullmann-type reaction from reaching its full

• resulted in good yields [4][26]. Copper-diamine-catalysed N-arylation facilitated the arylation of pyrroles, pyrazoles, indazoles, imidazoles, triazoles, benzimidazoles and indoles [27][28][29]. Besides aryl halides as the aryl donor, arylsiloxanes [30], arylstannanes [31], iodonium salts [32], aryl lead

Anion receptors containing thiazine-1,1-dioxide heterocycles as hydrogen bond donors

• Hong-Bo Wang,
• James A. Wisner and
• Michael C. Jennings

Beilstein J. Org. Chem. 2010, 6, No. 50, doi:10.3762/bjoc.6.50

• of nitrogen-based hydrogen bond donor groups such as amides [3][4], ureas [5], pyrroles/indoles/carbazoles [6][7] and sulfonamides [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] to complex the anionic targets in a topologically complementary fashion. Sulfonamides are an interesting

A review of new developments in the Friedel–Crafts alkylation – From green chemistry to asymmetric catalysis

• Magnus Rueping and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2010, 6, No. 6, doi:10.3762/bjoc.6.6

• of carbon- and heteroatom-centered nucleophiles were effectively applied resulting numerous diarylmethanes and 3-substituted indoles. Moreover, this method could be extended to the C-glycosylation of 1-hydroxysugars and the products 28 were obtained in high yields and with remarkable anomeric ratios

• . A gold(I)-catalyzed hydroarylation of indoles with styrenes as well as with aliphatic and cyclic alkenes was developed by Che et al. [64]. [AuCl(PPh3)]/AgOTf was the catalyst system of choice and the reaction was, depending on the substrate, performed under thermal or microwave-assisted conditions

• . The wide range of alkene substrates and the low catalyst amounts render this method a highly efficient and convenient synthesis of 3-functionalized indole derivatives (Scheme 19). An elegant PtCl2-catalyzed intramolecular alkylation of indoles with inactivated alkenes has been developed by Widenhoefer

Self-association of an indole based guanidinium-carboxylate-zwitterion: formation of stable dimers in solution and the solid state

• Carolin Rether,
• Wilhelm Sicking,
• Roland Boese and
• Carsten Schmuck

Beilstein J. Org. Chem. 2010, 6, No. 3, doi:10.3762/bjoc.6.3

• indoles is 3.636 Å. Furthermore, the “backside” of the out of plane twisted guanidinium cation also interacts with the carboxylate group one plane below (Figure 8). The corresponding hydrogen bond distances are 2.790 Å and 2.922 Å, respectively, and are therefore similar to the hydrogen bond distances