Green chemistry

• Luigi Vaccaro

Beilstein J. Org. Chem. 2016, 12, 2763–2765, doi:10.3762/bjoc.12.273

• , including “Strategies in asymmetric catalysis” by Tehshik P. Yoon [6], “Organometallic chemistry” by Bernd F. Straub and Lutz H. Gade [7], “C–H functionalization/activation in organic synthesis” by Richmond Sarpong [8], “Bifunctional catalysis” by Darren J. Dixon [9], “Sustainable catalysis” by Nicholas J

C–H Functionalization/activation in organic synthesis

• Richmond Sarpong

Beilstein J. Org. Chem. 2016, 12, 2315–2316, doi:10.3762/bjoc.12.224

• Richmond Sarpong Department of Chemistry, University of California, Berkeley, 841A Latimer Hall, Berkeley, CA 94720, USA 10.3762/bjoc.12.224 Keywords: C–H activation; C–H functionalization; The last decade has seen an explosion in research reports in the area of C–H functionalization/activation

• therefore highly desirable to be able to take advantage of the myriad of C–H groups in organic molecules as functional handles for bond formation, and in some cases, bond-breaking processes. “Modern” C–H functionalization/activation can trace its roots to the “clarion call” by Bergman and co-workers [1] in

• C–H functionalization/activation reactions. The growth in popularity of C–H functionalization/activation in organic synthesis can be attributed to the desire to implement more sustainable methods for synthesis and to achieve novel reactivity and selectivity in building molecules. A lot of exciting

On the cause of low thermal stability of ethyl halodiazoacetates

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

Beilstein J. Org. Chem. 2016, 12, 1590–1597, doi:10.3762/bjoc.12.155

• organic chemists ever since Theodor Curtius synthesized ethyl diazoacetate (EDA, 1) for the first time in 1883 [1]. Even today, after more than a century of research, diazo compounds still play an important role in state-of-the-art organic chemistry in areas such as for example C–H functionalization [2

Palladium-catalyzed picolinamide-directed iodination of remote ortho-C−H bonds of arenes: Synthesis of tetrahydroquinolines

• William A. Nack,
• Xinmou Wang,
• Bo Wang,
• Gang He and
• Gong Chen

Beilstein J. Org. Chem. 2016, 12, 1243–1249, doi:10.3762/bjoc.12.119

• diverse substitution patterns from readily accessible starting materials. New synthetic strategy for THQs via PA-directed C−H functionalization. Preparation of iodo-substituted THQs via PA-directed C−H functionalization strategy. a) ArI (2 equiv), Pd(OAc)2 (10 mol %), (BnO)2PO2H (20 mol %), Ag2CO3 (1.5

• −H functionalization reactions starting from readily accessible aryl iodide and alkylamine precursors (Scheme 1) [8]. Alkylpicolinamides were first subjected to Pd-catalyzed γ-C(sp3)−H arylation with aryl iodides to form γ-arylpropylpicolinamides [9][10][11][12][13][14][15][16][17][18][19][20]. These

• many natural products and pharmaceutical agents [1][2]. Efficient and generally applicable methods for the synthesis of THQs with complex substitution patterns are still in great demand [3][4][5][6][7]. Recently, we reported a synthetic strategy for THQs based on picolinamide (PA)-directed sequential C

Synthesis of 2-oxindoles via 'transition-metal-free' intramolecular dehydrogenative coupling (IDC) of sp² C–H and sp³ C–H bonds

• Nivesh Kumar,
• Santanu Ghosh,
• Subhajit Bhunia and
• Alakesh Bisai

Beilstein J. Org. Chem. 2016, 12, 1153–1169, doi:10.3762/bjoc.12.111

• -arylamido esters with alkyl halides followed by a dehydrogenative coupling. Experimental evidences indicated toward a radical-mediated path for this reaction. Keywords: C−H functionalization; intramolecular dehydrogenative coupling (IDC); iodine; N-iodosuccinimide; oxidants; 2-oxindoles; Introduction The

• C−H functionalization is an attractive synthetic strategy used in organic synthesis for the development of atom- and step-economical routes [1][2][3][4][5][6][7][8][9][10]. In recent years it was witnessed a mushrooming growth in the number of reports in the literature owing to the efficiency of the

Synthesis of β-arylated alkylamides via Pd-catalyzed one-pot installation of a directing group and C(sp³)–H arylation

• Yunyun Liu,
• Yi Zhang,
• Xiaoji Cao and
• Jie-Ping Wan

Beilstein J. Org. Chem. 2016, 12, 1122–1126, doi:10.3762/bjoc.12.108

• ][27]. As a representative protocol for the synthesis of C–H elaborated alkyl/arylamides, the AQ-assisted C–H functionalization reactions have been broadly investigated and applied [28][29][30][31][32][33][34]. Since the prior preparation and purification of N-AQ amides have been required in all these

• functionalization chemistry [35][36][37][38][39][40], we have executed efforts to the AQ-assisted β-C–H functionalization reactions of alkylamides via activation of the C(sp3)–H bond, a classical protocol toward β-arylamide synthesis. While the known examples, including C(sp3)–H alkylation, arylation or oxygenation

• known syntheses, a domino process by which the AQ can be linked directly to the raw substrates to enable the subsequent arylation transformation in one pot would be highly favorable for enhancing step economy. Upon this assumption as well as our interest in both domino reactions and C–H

Iodine-mediated synthesis of 3-acylbenzothiadiazine 1,1-dioxides

• Long-Yi Xi,
• Ruo-Yi Zhang,
• Lei Shi,
• Shan-Yong Chen and
• Xiao-Qi Yu

Beilstein J. Org. Chem. 2016, 12, 1072–1078, doi:10.3762/bjoc.12.101

• -acylbenzothiadiazine 1,1-dioxides from 2-aminobenzenesulfonamides and acetophenones via iodine-mediated sp3 C–H functionalization. Results and Discussion We commenced our studies by heating acetophenone (1a), 2-aminobenzenesulfonamide (2a) and I2 in DMSO for 12 h. To our delight, the desired product was isolated in 60

Cationic Pd(II)-catalyzed C–H activation/cross-coupling reactions at room temperature: synthetic and mechanistic studies

• Takashi Nishikata,
• Alexander R. Abela,
• Shenlin Huang and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2016, 12, 1040–1064, doi:10.3762/bjoc.12.99

• intermediate, characterized by X-ray analysis. Roles of various additives in the stepwise process have also been studied. Keywords: arylation; cationic palladium; C–H functionalization; green chemistry; olefination; Introduction Transition metal-catalyzed, direct functionalization of aryl C–H bonds has made

• –H bonds. High temperatures are frequently required to realize aromatic C–H functionalization (>120 °C), increasing the potential for side reactions and functional group compatibility issues. Indeed, C–H activation transformations until recently have rarely proceeded at ambient temperature due to the

The synthesis of functionalized bridged polycycles via C–H bond insertion

• Jiun-Le Shih,
• Po-An Chen and
• Jeremy A. May

Beilstein J. Org. Chem. 2016, 12, 985–999, doi:10.3762/bjoc.12.97

• 53. A subsequent transannular C–H functionalization at the site of a weakly acidic proton then produces the bridged product 54. While an innovative transformation, it should be noted that a full equivalent of Wilkinson’s catalyst is needed as there is no catalytic turnover observed. Bridged

Enantioselective carbenoid insertion into C(sp³)–H bonds

• J. V. Santiago and
• A. H. L. Machado

Beilstein J. Org. Chem. 2016, 12, 882–902, doi:10.3762/bjoc.12.87

• into the C(sp3)–H bond catalyzed by a new bulky cyclopropylcarboxylate-based chiral dirhodium complex. 2,2,2-Trichloroethyl (TCE) aryldiazoacetates to improve the scope, regio- and enantioselective of the carbenoid insertion into primary C(sp3)–Hs bond by (R)-74. Sequential C–H functionalization

Recent advances in C(sp³)–H bond functionalization via metal–carbene insertions

• Bo Wang,
• Di Qiu,
• Yan Zhang and
• Jianbo Wang

Beilstein J. Org. Chem. 2016, 12, 796–804, doi:10.3762/bjoc.12.78

• the late-stage C–H functionalization of complex alkaloids and drug molecules (Scheme 3) [25]. C–H bond insertions at the allylic and benzylic positions Metal–carbene C–H insertion is also favored for allylic and benzylic sites. In 2014, Davies and co-workers reported an enantioselective C–H insertion

• and Etienne reported a perfluorinated F21-tris(pyrazoly)borate (F21-Tp) scorpionate ligand, which enhanced alkane C–H functionalization by carbene insertion with (F21-Tp)Cu and (F21-Tp)Ag catalysts (Figure 1) [38]. In particular, with silver catalyst remarkably low catalyst loading (ca. 0.5%), and

• (sp3)–H bonds. Rh(II)-catalyzed site-selective and enantioselective C–H functionalization of methyl ether. Late-stage C–H functionalization with Rh(II)-catalyzed carbene C(sp3)–H insertion. The Rh(II)-catalyzed selective carbene insertion into benzylic C–H bonds. The structure–selectivity relationship

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

• under mild conditions and could be applied to peptides containing other nucleophilic and aromatic amino acids, such as serine, phenylalanine or tyrosine. Keywords: alkynes; C–H functionalization; gold catalysis; hypervalent iodine; peptides; Introduction Alkynes have always been important building

• and unfolding, or protein engineering to install more accessible cysteines, are usually required. For these reasons, it is important to develop selective alkynylation methods in order to functionalize other amino acids. The direct C–H functionalization of aromatic compounds is an attractive method for

Opportunities and challenges for direct C–H functionalization of piperazines

• Zhishi Ye,
• Kristen E. Gettys and
• Mingji Dai

Beilstein J. Org. Chem. 2016, 12, 702–715, doi:10.3762/bjoc.12.70

• pharmaceuticals. Herein we summarize the current synthetic methods available to perform C–H functionalization on piperazines in order to lend structural diversity to this privileged drug scaffold. Multiple approaches such as those involving α-lithiation trapping, transition-metal-catalyzed α-C–H

• functionalizations, and photoredox catalysis are discussed. We also highlight the difficulties experienced when successful methods for α-C–H functionalization of acyclic amines and saturated mono-nitrogen heterocyclic compounds (such as piperidines and pyrrolidines) were applied to piperazine substrates. Keywords

• : α-lithiation; C–H functionalization; heterocycle; photoredox catalysis; piperazine; Introduction Piperazine is one of the most important saturated N-heterocycles frequently found in life-saving small-molecule pharmaceuticals [1]. In a recent statistical study done by Njardarson and co-workers

Copper catalysis in organic synthesis

• Sherry R. Chemler

Beilstein J. Org. Chem. 2015, 11, 2252–2253, doi:10.3762/bjoc.11.244

• field of copper-catalysis from 7 countries make up this Thematic Series, “Copper catalysis in organic synthesis”. Contributions include authoritative reviews on the latest developments in copper-catalyzed Click applications, C–N cross-coupling, C–H functionalization, trifluoromethylations, asymmetric

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