Recent advances in copper-catalyzed C–H bond amidation

• Jie-Ping Wan and
• Yanfeng Jing

Beilstein J. Org. Chem. 2015, 11, 2209–2222, doi:10.3762/bjoc.11.240

• aerobic conditions. Upon systematic screening, the 2-phenyloxazole structure was found as an excellent DG to enable the ortho-C–H functionalization of amide 42 to provide products 43. Under the assistance of this novel DG, this catalytic method exhibited exceptionally broad tolerance to the C–H

• activation of alkyne C–H bonds were also implemented. In 2008, Stahl et al. [73] reported the first copper-catalyzed alkyne amidation via the oxidation with molecular oxygen. The synthetic protocol exhibited excellent tolerance to the C–H functionalization by reacting not only with lactams, but also with

• functionalization with nitrogen nucleophiles, including amides, sulfonamides and primary arylamines. In addition, the oxazole-based DG could be easily deprotected to provide the corresponding benzoic acid 44 by heating in EtOH in the presence of KOH (Scheme 13). As another easily available N-containing aromatic

C–H bond halogenation catalyzed or mediated by copper: an overview

• Wenyan Hao and
• Yunyun Liu

Beilstein J. Org. Chem. 2015, 11, 2132–2144, doi:10.3762/bjoc.11.230

• , harsh reaction conditions and/or restricted product diversity remain as challenges for these methods. The transition metal-catalyzed C–H functionalization has recently gained considerable attention in the preparation of numerous organic molecules [12][13][14][15][16][17][18]. In this context

• alkenes via C–H cleavage is much less known in literature. In 2014, Yu and co-workers [66] reported the cascade synthesis of functionalized pyrrolones 66 via the dual C–H functionalization of α-alkenoylketene N,S-acetals 65. The construction of the products involved the oxidative alkene C–H amination and

• . CuI-mediated synthesis of iododibenzo[b,d]furans via C–H functionalization. Cu-Mn spinel oxide-catalyzed phenol and heteroarene halogenation. Copper-catalyzed halogenations of 2-amino-1,3thiazoles. Copper-mediated chlorination and bromination of indolizines. Copper-catalyzed three-component synthesis

Synthesis of quinoline-3-carboxylates by a Rh(II)-catalyzed cyclopropanation-ring expansion reaction of indoles with halodiazoacetates

• Magnus Mortén,
• Martin Hennum and
• Tore Bonge-Hansen

Beilstein J. Org. Chem. 2015, 11, 1944–1949, doi:10.3762/bjoc.11.210

• transition metal-catalyzed C–H functionalization by diazo compounds [5][6][7][8]. The reactions of indoles with electrophilic metal-bound carbenes, or carbenoids, generated from diazo compounds, takes place under mild reaction conditions. The reaction has been studied for the three principle classes of

The facile construction of the phthalazin-1(2H)-one scaffold via copper-mediated C–H(sp²)/C–H(sp) coupling under mild conditions

• Wei Zhu,
• Bao Wang,
• Shengbin Zhou and
• Hong Liu

Beilstein J. Org. Chem. 2015, 11, 1624–1631, doi:10.3762/bjoc.11.177

• the viewpoint of practicality and feasibility, increasing attention was paid to develop cheap and easily available transition metals, such as copper, to realize direct C–H functionalization [17]. Miura and Yu successfully demonstrated a novel protocol for the direct C–H/C–H coupling with combinations

• recovered in good yield. Based on previous works [22][23][25], a copper(II)-mediated C–H functionalization pathway is proposed in Scheme 5. A base-promoted cupration of the relatively acidic C–H of ethynylbenzene provides ethynylcopper intermediate M1. The following bidentate chelation with 1a yields

Eosin Y-catalyzed visible-light-mediated aerobic oxidative cyclization of N,N-dimethylanilines with maleimides

• Zhongwei Liang,
• Song Xu,
• Wenyan Tian and
• Ronghua Zhang

Beilstein J. Org. Chem. 2015, 11, 425–430, doi:10.3762/bjoc.11.48

• as a photocatalyst has been developed. The metal-free protocol involves aerobic oxidative cyclization via sp3 C–H bond functionalization process to afford good yields in a one-pot procedure under mild conditions. Keywords: aerobic oxidative cyclization; C–H functionalization; Eosin Y; photoredox

Cross-dehydrogenative coupling for the intermolecular C–O bond formation

• Igor B. Krylov,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2015, 11, 92–146, doi:10.3762/bjoc.11.13

• ; C–H functionalization; C–O bond formation; cross-dehydrogenative coupling; oxidative cross-coupling; Introduction The development of methods for the cross-dehydrogenative coupling (CDC; or oxidative cross coupling) is an important field of modern organic chemistry. These terms commonly refer to

Sequential decarboxylative azide–alkyne cycloaddition and dehydrogenative coupling reactions: one-pot synthesis of polycyclic fused triazoles

• Kuppusamy Bharathimohan,
• Thanasekaran Ponpandian,
• A. Jafar Ahamed and
• Nattamai Bhuvanesh

Beilstein J. Org. Chem. 2014, 10, 3031–3037, doi:10.3762/bjoc.10.321

• followed by C–H functionalization (Scheme 1). Specifically, they demonstrated a C–H functionalization of an indole nucleus with 5-iodo-1,2,3-triazoles. In the present study, we replaced the 5-iodo-1,2,3-triazoles with 5H-1,2,3-triazoles with intramolecular sp2 C–H/C–H cross coupling reaction. To the best

• , Cu(OAc)2, benzoquinone and O2 among others. In the present study, we have chosen a Cu2+ salt because it can be used as an oxidant and as a pre-catalyst for the C–H functionalization and the decarboxylative CuAAC reaction, respectively. 1-(2-Azidophenyl)-1H-benzo[d]imidazole (1a) and phenylpropiolic

Come-back of phenanthridine and phenanthridinium derivatives in the 21st century

• Lidija-Marija Tumir,
• Marijana Radić Stojković and
• Ivo Piantanida

Beilstein J. Org. Chem. 2014, 10, 2930–2954, doi:10.3762/bjoc.10.312

• ] (Scheme 11). This synthesis published by Pearson et al. was based on palladium-catalysed picolinamide-directed sequential C–H functionalization reactions, while readily available benzylamine and aryl iodide were used as precursors. In the first step the Pd-catalyzed reaction yielded a biaryl compound. The

Exploration of C–H and N–H-bond functionalization towards 1-(1,2-diarylindol-3-yl)tetrahydroisoquinolines

• Michael Ghobrial,
• Marko D. Mihovilovic and
• Michael Schnürch

Beilstein J. Org. Chem. 2014, 10, 2186–2199, doi:10.3762/bjoc.10.226

• –Hartwig coupling; C–C coupling; C–H functionalization; iron catalysis; regioselective arylation; Introduction 1,2,3,4-Tetrahydroisoquinolines (THIQs) are common substructures in natural products [1]. The structural motif of 1-(indol-3-yl)-THIQ is also found in compounds with biological activity, for

• well established via a series of transformations. The direct arylation via C–H functionalization represents a very efficient approach in this regard [24][25][26][27][28][29][30][31] with methods available to either decorate position 2 or 3 regioselectively [32][33][34][35][36][37][38][39][40][41][42

Organophosphorus chemistry

• Paul R. Hanson

Beilstein J. Org. Chem. 2014, 10, 2087–2088, doi:10.3762/bjoc.10.217

• their use as recyclable heterogeneous reagents, the Atherton–Todd reaction, cyclic phosphonium ionic liquids with distinct properties, photo-removable phosphate protecting groups, new methods of C–H functionalization using phosphoryl-related directing groups, the exciting chemistry of substituted

P(O)R₂-directed Pd-catalyzed C–H functionalization of biaryl derivatives to synthesize chiral phosphorous ligands

• Rong-Bin Hu,
• Hong-Li Wang,
• Hong-Yu Zhang,
• Heng Zhang,
• Yan-Na Ma and
• Shang-dong Yang

Beilstein J. Org. Chem. 2014, 10, 2071–2076, doi:10.3762/bjoc.10.215

• ]. Despite the progress in this area, only limited development has been accomplished through metal-catalyzed C–H activation to build C–P bonds [17][18]. As an alternative, we disclosed a novel protocol of palladium-catalyzed C–H functionalization by using the P(O)R2 moiety as a new directing group to

• using palladium-catalyzed C–H functionalization. Results and Discussion To obtain the axially chiral phosphorus compounds, we first synthesized the special chiral-bridged atropisomeric monophosphorus ligand L-1 through an eight-step reaction sequence starting from 1,3-dimethoxybenzene. According to the

• good optical rotation. Those results showed that the products of C–H functionalization were maintained with high enantioselectivities when the substrates were optically pure, even when these reactions were carried out in air atmosphere and at high temperature. Herein, we provided a method to synthesize

C–H-Functionalization logic guides the synthesis of a carbacyclopamine analog

• Sebastian Rabe,
• Johann Moschner,
• Marina Bantzi,
• Philipp Heretsch and
• Athanassios Giannis

Beilstein J. Org. Chem. 2014, 10, 1564–1569, doi:10.3762/bjoc.10.161

• States 10.3762/bjoc.10.161 Abstract The chemical synthesis of carbacyclopamine analog 2, a cyclopamine analog with an all-carbon E-ring, is reported. The use of C–H-functionalization logic and further metal-catalyzed transformations allows for a concise entry to this new class of acid-stable cyclopamine

• analogs. Keywords: cyclopamine; C–H-functionalization; hedgehog signaling pathway; natural products; steroidal alkaloids; Introduction The isolation of cyclopamine (1, Figure 1) nearly 50 years ago followed by the determination of its biological target and pharmacological profile has drawn considerable

• reporter and a constitutive Renilla luciferase reporter [18]. The analog was tested in a concentration range from 0.01 μM to 100 μM but showed no activity (data not shown). Conclusion We have reported the synthesis of a new, acid stable cyclopamine analog. The implementation of C–H-functionalization logic

New developments in gold-catalyzed manipulation of inactivated alkenes

• Michel Chiarucci and
• Marco Bandini

Beilstein J. Org. Chem. 2013, 9, 2586–2614, doi:10.3762/bjoc.9.294

• first example of C–H functionalization by alkylgold intermediates. The optimized conditions required the use of the electrophilic complex [(p-CF3Ph)3PAuNTf2] and 30 equivalents of water, in order to increase the solubility of Selectfluor in THF. Heteroarylation of alkenes with arylboronic acids under

Recent advances in transition metal-catalyzed Csp²-monofluoro-, difluoro-, perfluoromethylation and trifluoromethylthiolation

• Grégory Landelle,
• Armen Panossian,
• Sergiy Pazenok,
• Jean-Pierre Vors and
• Frédéric R. Leroux

Beilstein J. Org. Chem. 2013, 9, 2476–2536, doi:10.3762/bjoc.9.287

• type and reaction mechanism. One can identify two major approaches, trifluoromethylation via cross-coupling reactions or the more recent C–H functionalization. 3.1 Palladium catalysis 3.1.1 Trifluoromethylation of Csp2–X bonds (X = halogen or sulfonate) by means of a nucleophilic CF3-source. The first

Cyclopamine analogs bearing exocyclic methylenes are highly potent and acid-stable inhibitors of hedgehog signaling

• Johann Moschner,
• Anna Chentsova,
• Nicole Eilert,
• Irene Rovardi,
• Philipp Heretsch and
• Athanassios Giannis

Beilstein J. Org. Chem. 2013, 9, 2328–2335, doi:10.3762/bjoc.9.267

• hampered by its low metabolic stability (decomposition at pH < 3) [31] and rather moderate potency (IC50 ~ 5 µM). We previously reported the first chemical synthesis of cyclopamine (1) starting from dehydroepiandrosterone and utilizing the C–H-functionalization logic and a biomimetic skeleton rearrangement

Gold(I)-catalyzed hydroarylation reaction of aryl (3-iodoprop-2-yn-1-yl) ethers: synthesis of 3-iodo-2H-chromene derivatives

• Pablo Morán-Poladura,
• Eduardo Rubio and
• José M. González

Beilstein J. Org. Chem. 2013, 9, 2120–2128, doi:10.3762/bjoc.9.249

• other hand, migratory cycloisomerization are important processes in contemporary catalysis [41]. In this context, our group is interested in C–H functionalization reactions of arenes involving propargylic derivatives [42]. Furthermore, the influence of different gold(I) catalysts over the outcome of the

The chemistry of amine radical cations produced by visible light photoredox catalysis

• Jie Hu,
• Jiang Wang,
• Theresa H. Nguyen and
• Nan Zheng

Beilstein J. Org. Chem. 2013, 9, 1977–2001, doi:10.3762/bjoc.9.234

• provides an indirect approach for α-C–H functionalization of N-aryltetrahydroquinolines and N-arylindolines. Based on the feasibility of oxidation of aromatic amines as well as reduction of di-tert-butyl azodicarboxylate (110) by the photoexcited Ir(III) complex [98][99], the authors favored a mechanism

Zinc–gold cooperative catalysis for the direct alkynylation of benzofurans

• Yifan Li and
• Jérôme Waser

Beilstein J. Org. Chem. 2013, 9, 1763–1767, doi:10.3762/bjoc.9.204

• allowing the direct and regioselective C–H functionalization of benzofurans [12]. In this context, the introduction of an alkyne would be particularly useful, as acetylenes are important building blocks in synthetic chemistry, chemical biology and materials science [13]. Nevertheless, to the best of our

Iron-catalyzed decarboxylative alkenylation of cycloalkanes with arylvinyl carboxylic acids via a radical process

• Jincan Zhao,
• Hong Fang,
• Jianlin Han and
• Yi Pan

Beilstein J. Org. Chem. 2013, 9, 1718–1723, doi:10.3762/bjoc.9.197

• excellent stereoselectivity, and only trans-isomers are obtained. Keywords: alkenylation; cycloalkanes; decarboxylative; Fe(acac)3; free radical; sp3 C–H bonds; Introduction Direct C–H functionalization has become one of the most useful and attractive tools in organic chemistry because it can construct

• carbon–carbon or carbon–heteroatom bonds in a highly atom economical manner [1][2][3][4][5][6][7][8]. Among all these C–H functionalization methods, the direct C(sp3)–H functionalization attracts particular attention due to its low reactivity and challenging activation [9][10][11]. In previous studies

Aerobic radical multifunctionalization of alkenes using tert-butyl nitrite and water

• Daisuke Hirose and
• Tsuyoshi Taniguchi

Beilstein J. Org. Chem. 2013, 9, 1713–1717, doi:10.3762/bjoc.9.196

• 10.3762/bjoc.9.196 Abstract Water induces a change in the product of radical multifunctionalization reactions of aliphatic alkenes involving an sp3 C–H functionalization by an 1,5-hydrogen shift using tert-butyl nitrite and molecular oxygen. The reaction without water, reported previously, gives nitrated

• reactivity. Addition reactions of radical species to multiple bonds in the presence of appropriate trapping reagents give double functionalized compounds [10][11]. In addition, a radical methodology is a powerful tool for sp3 C–H functionalization [12][13][14][15][16]. It is frequently achieved by

• the current work has shown that this old methodology still has a large potential. The development of other direct C–H functionalization reactions based on radical chemistry is currently on-going together with further optimization of the presented reaction in our laboratory. The effect of water in

Copper-catalyzed aerobic aliphatic C–H oxygenation with hydroperoxides

• Pei Chui Too,
• Ya Lin Tnay and
• Shunsuke Chiba

Beilstein J. Org. Chem. 2013, 9, 1217–1225, doi:10.3762/bjoc.9.138

• oxidative sp3 C–H functionalization with predictable chemo- and regioselectivity [1][2][3][4]. To achieve this goal, we have recently utilized 1,5-H-radical shift [5][6] with iminyl radical species (N-radicals) generated under Cu-catalyzed aerobic reaction conditions, in which the resulting carbon-centered

• tertiary C–H bonds, respectively (Scheme 1b) [8][9]. Stimulated by these remote sp3 C–H oxidation reactions using the nitrogen-centered radicals derived from amidines and ketimines, we became interested to utilize oxygen-centered radicals (O-radicals) for the sp3 C–H functionalization. In this context, we

Synthesis of phenanthridines via palladium-catalyzed picolinamide-directed sequential C–H functionalization

• Ryan Pearson,
• Shuyu Zhang,
• Gang He,
• Nicola Edwards and
• Gong Chen

Beilstein J. Org. Chem. 2013, 9, 891–899, doi:10.3762/bjoc.9.102

• States of America 10.3762/bjoc.9.102 Abstract We report a new synthesis of phenanthridines based on palladium-catalyzed picolinamide-directed sequential C–H functionalization reactions starting from readily available benzylamine and aryl iodide precursors. Under the catalysis of Pd(OAc)2, the ortho-C–H

• position of these dihydrophenanthridines could be further oxidized with Cu(OAc)2, removing the picolinamide group and providing phenathridine products. The cyclization and oxidation could be carried out in a single step and afford phenathridines in moderate to good yields. Keywords: C–H functionalization

• sequential palladium-catalyzed picolinamide (PA)-directed C–H functionalization reactions beginning from easily accessible PA-protected benzylamine and aryl iodide precursors. Results and Discussion New synthetic strategy for phenanthridine compounds. The picolinamide (PA) group has been shown to be an

Complete σ* intramolecular aromatic hydroxylation mechanism through O₂ activation by a Schiff base macrocyclic dicopper(I) complex

• Albert Poater and
• Miquel Solà

Beilstein J. Org. Chem. 2013, 9, 585–593, doi:10.3762/bjoc.9.63

• and C–O bond formation, followed finally by a proton transfer to an alpha aromatic carbon that immediately yields the product [CuII2(bsH2m-O)(μ-OH)]2+. Keywords: aromatic hydroxylation; C–H bond activation; C–H functionalization; copper; DFT calculations; mechanism; Schiff base; Introduction Bearing

N-Heterocyclic carbene–palladium catalysts for the direct arylation of pyrrole derivatives with aryl chlorides

• Ismail Özdemir,
• Nevin Gürbüz,
• Nazan Kaloğlu,
• Öznur Doğan,
• Murat Kaloğlu,
• Christian Bruneau and
• Henri Doucet

Beilstein J. Org. Chem. 2013, 9, 303–312, doi:10.3762/bjoc.9.35

• with heteroarenes. Keywords: aryl chlorides; atom-economy; C–H bond activation; C–H functionalization; carbenes; palladium; pyrroles; Introduction N-Heterocyclic carbenes (NHC) have emerged as an important class of ligands in the development of homogeneous catalysis [1][2][3][4][5][6][7][8][9]. Such

Alkyne hydroarylation with Au N-heterocyclic carbene catalysts

• Cristina Tubaro,
• Marco Baron,
• Andrea Biffis and
• Marino Basato

Beilstein J. Org. Chem. 2013, 9, 246–253, doi:10.3762/bjoc.9.29

• selectivity compared to the previously published complex AuCl(PPh3). Preliminary results on intramolecular hydroarylations using this catalytic system indicate, however, that alkyne hydration by traces of water may become a serious competing reaction. Keywords: alkyne; C–H functionalization; cyclisation