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

Rh(III)-catalyzed directed C–H bond amidation of ferrocenes with isocyanates

• Satoshi Takebayashi,
• Tsubasa Shizuno,
• Takashi Otani and
• Takanori Shibata

Beilstein J. Org. Chem. 2012, 8, 1844–1848, doi:10.3762/bjoc.8.212

• ] catalyzed the C–H bond amidation of ferrocenes possessing directing groups with isocyanates in the presence of 2 equiv/Rh of HBF4·OEt2. A variety of disubstituted ferrocenes were prepared in high yields, or excellent diastereoselectivities. Keywords: amidation; C–H activation; C–H functionalization

Copper-catalyzed CuAAC/intramolecular C–H arylation sequence: Synthesis of annulated 1,2,3-triazoles

• Rajkumar Jeyachandran,
• Harish Kumar Potukuchi and
• Lutz Ackermann

Beilstein J. Org. Chem. 2012, 8, 1771–1777, doi:10.3762/bjoc.8.202

• fully substituted 1,2,3-triazoles with excellent chemo- and regioselectivities. Likewise, the optimized catalytic system proved applicable to the direct preparation of 1,2-diarylated azoles through a one-pot C–H/N–H arylation reaction. Keywords: cascade reaction; C–H functionalization; copper

Palladium-catalyzed dual C–H or N–H functionalization of unfunctionalized indole derivatives with alkenes and arenes

• Gianluigi Broggini,
• Egle M. Beccalli,
• Andrea Fasana and
• Silvia Gazzola

Beilstein J. Org. Chem. 2012, 8, 1730–1746, doi:10.3762/bjoc.8.198

• . Keywords: alkenylation; arylation; C–H functionalization; indoles; N–H functionalization; Pd catalysis; Introduction The development of mild and selective reactions for the direct conversion of carbon–hydrogen bonds into carbon–carbon and carbon–heteroatom bonds is a challenging goal in organic chemistry

• of C–H functionalization on unactivated substrates typically occur with electrophilic Pd(II) catalysts and require an oxidizing agent in order to make possible the reoxidation of the Pd(0) species, generated in the final elimination step, for a new catalytic cycle [12][13][14][15]. The well

• providing conditions to access asymmetric biaryl compounds by dual C–H functionalization [55]. In 2007, Fagnou and co-workers combined, in a single catalytic cycle, the reactivity of electron-deficient palladium(II) complexes with electron-rich arenes (through an electrophilic C–H activation mechanism) and

Extending the utility of [Pd(NHC)(cinnamyl)Cl] precatalysts: Direct arylation of heterocycles

• Anthony R. Martin,
• Anthony Chartoire,
• Alexandra M. Z. Slawin and
• Steven P. Nolan

Beilstein J. Org. Chem. 2012, 8, 1637–1643, doi:10.3762/bjoc.8.187

• investigated. Among four different precatalysts, [Pd(SIPr)(cinnamyl)Cl] proved to be the most efficient promoter of the reaction. The C–H functionalization of sulfur- or nitrogen-containing heterocycles has been achieved at low catalyst loadings. These catalyst charges range from 0.1 to 0.01 mol % palladium

• . Keywords: C–H functionalization; direct arylation; heterocycles; N-heterocyclic carbenes; palladium; Introduction As a powerful addition to the classic palladium cross-coupling reactions, C–H bond functionalization has become a growing field of research over the last few years. The ubiquity of C–H bonds

• observed in 3. With complexes 1–4 in hand, their catalytic activity towards the direct arylation of heteroaromatic compounds was evaluated. For this purpose, the arylation of benzothiophene (6) with 4-bromotoluene (7) was selected as a benchmark reaction (Table 2). This C–H functionalization, initially

Synthesis of conformationally restricted glutamate and glutamine derivatives from carbonylation of orthopalladated phenylglycine derivatives

• Esteban P. Urriolabeitia,
• Eduardo Laga and
• Carlos Cativiela

Beilstein J. Org. Chem. 2012, 8, 1569–1575, doi:10.3762/bjoc.8.179

• results, however, in the formation of the cyclic isoindolinone or the open 2-carboxyphenylglycine methyl esters, with the reaction outcome being driven by the choice of the solvent. Keywords: C–H functionalization; carbonylation; glutamic acid; glutamide; palladium; phenylglycine; Introduction The

Arylglycine-derivative synthesis via oxidative sp³ C–H functionalization of α-amino esters

• Zhanwei Xu,
• Xiaoqiang Yu,
• Xiujuan Feng and
• Ming Bao

Beilstein J. Org. Chem. 2012, 8, 1564–1568, doi:10.3762/bjoc.8.178

• phenols with α-amino esters proceeded smoothly in the presence of meta-chloroperoxybenzoic acid as an oxidant under ambient conditions, to produce arylglycine derivatives in satisfactory yields. Keywords: α-amino ester; arylglycine; C–H functionalization; oxidation; synthesis; Findings Arylglycine

• -(disubstituted amino)acetates with naphthols and phenols. The proposed coupling reaction proceeded smoothly in the presence of mCPBA as an oxidant under ambient conditions to provide arylglycine derivatives in satisfactory yields. Synthesis of arylglycine derivatives. Oxidative sp3 C–H functionalization of α

Metal–ligand multiple bonds as frustrated Lewis pairs for C–H functionalization

• Matthew T. Whited

Beilstein J. Org. Chem. 2012, 8, 1554–1563, doi:10.3762/bjoc.8.177

• demonstrate that the resultant reactivity may be a powerful tool for the functionalization of C–H and E–H bonds. Keywords: ambiphilic reactivity; C–H activation; C–H functionalization; frustrated Lewis pair; metal carbene; multiple bond; Introduction Orbital cooperation has long been recognized as an

• high oxidation states that are attached to π-basic ligands (i.e., Mδ+═Eδ−), and (2) late transition metals in low oxidation states attached to π-acidic ligands (i.e., Mδ−═Eδ+). The reactivity engendered by such a bonding situation can in some cases be quite useful in C–H functionalization schemes that

• processes in catalysis, in which only a few specialized systems have been reported to accomplish catalytic C–H functionalization [47][48][49]. In fact, the bond-breaking process across metal–ligand multiple bonds is closely related to σ-bond metathesis [43], highlighting the potential of Mδ+═Eδ− FLPs to

C–H Functionalization

• Huw M. L. Davies

Beilstein J. Org. Chem. 2012, 8, 1552–1553, doi:10.3762/bjoc.8.176

• Huw M. L. Davies Department of Chemistry, Emory University, 440 Atwood Hall, 1515 Dickey Drive, Atlanta GA 30322, USA 10.3762/bjoc.8.176 Keywords: C–H Functionalization; C–H Functionalization has the potential to become a paradigm-shifting strategy for organic synthesis. Over the last decade

• , the field has experienced explosive growth and a large variety of new C–H functionalization methodologies have been developed. In particular, regioselective functionalization of sp2 C–H bonds has become a broadly flexible approach for the synthesis of complex aromatic carbocycles and heterocycles. In

• can become broadly applicable. Metal-bound carbenes, nitrenes and oxo species have been particularly effective at stereoselective sp3 C–H functionalization. However, considerable advances still need to be made to enhance the selectivity and to increase the range of functionality that can be introduced

C2-Alkylation of N-pyrimidylindole with vinylsilane via cobalt-catalyzed C–H bond activation

• Zhenhua Ding and
• Naohiko Yoshikai

Beilstein J. Org. Chem. 2012, 8, 1536–1542, doi:10.3762/bjoc.8.174

• indoles in moderate to good yields. Keywords: alkylation; C–H functionalization; cobalt; indole; vinylsilane; Introduction The indole ring ubiquitously occurs in biologically active natural and unnatural compounds [1][2][3]. Consequently, there has been a strong demand for catalytic methods allowing

Sonogashira–Hagihara reactions of halogenated glycals

• Dennis C. Koester and
• Daniel B. Werz

Beilstein J. Org. Chem. 2012, 8, 675–682, doi:10.3762/bjoc.8.75

• functionalization allowed for the mild and selective borylation of unfunctionalized glycals. Starting from persilylated glycals Ishikawa and Miyaura applied an Ir-catalyzed C–H-functionalization with B2pin2 to obtain 1-borylated glycals, such as 3, in excellent yields and selectivity. They elegantly demonstrated

• co-workers utilized 1-stannylated glycals of type 1 in a Stille cross-coupling for the synthesis of aryl-C-glycosides such as 2 (R = Ar) [14][15]. To generate these 1-substituted glycals a prefunctionalization of the pseudoanomeric carbon is mandatory. Recent advances in the field of C–H