One-pot functionalisation of N-substituted tetrahydroisoquinolines by photooxidation and tunable organometallic trapping of iminium intermediates

• Joshua P. Barham,
• Matthew P. John and
• John A. Murphy

Beilstein J. Org. Chem. 2014, 10, 2981–2988, doi:10.3762/bjoc.10.316

• construct THIQs using green technologies, in mild conditions and with high atom efficiencies. Catalytic oxidative functionalisation of the C–H bond α- to the amine function is one such methodology. Iminium salts generated in this way can be intercepted by a nucleophile in a one-pot reaction (Scheme 1

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

• -arylation. The following conventional cross-coupling or directed C–H arylation resulted in substituted phenanthridines. Homolytic aromatic substitution (HAS) by an aryl radical was used for the construction of biaryl motifs as alternative to transition metal-catalysed C–H bond arylation. That approach was

Palladium-catalyzed 2,5-diheteroarylation of 2,5-dibromothiophene derivatives

• Fatma Belkessam,
• Aidene Mohand,
• Jean-François Soulé,
• Abdelhamid Elias and
• Henri Doucet

Beilstein J. Org. Chem. 2014, 10, 2912–2919, doi:10.3762/bjoc.10.309

• -diheteroarylated thiophenes bearing two different heteroaryl units. Keywords: aryl halides; catalysis; C–H bond activation; direct arylation; heteroarenes; palladium; Introduction 2,2':5',2"-Terthiophene (or 2,5-di(2-thienyl)thiophene) (Figure 1) and many of its derivatives are important structures due to their

• ][9][10][11][12][13][14][15][16]. However, an organometallic derivative must be prepared to perform such reactions. In 1990, Ohta and co-workers reported the Pd-catalyzed direct arylation of heteroaromatics using aryl halides as coupling partners via a C–H bond activation [17][18]. Since then Pd

Hindered aryl bromides for regioselective palladium-catalysed direct arylation at less favourable C5-carbon of 3-substituted thiophenes

• Rongwei Jin,
• Charles Beromeo Bheeter and
• Henri Doucet

Beilstein J. Org. Chem. 2014, 10, 1239–1245, doi:10.3762/bjoc.10.123

• desired 5-arylation products in moderate to good yields using only 0.5 mol % of a phosphine-free and air-stable palladium catalyst. Then, from these 5-arylthiophenes, a second palladium-catalysed C–H bond functionalization at C2 of the thiophene ring allows the synthesis of 2,5-diarylthiophenes with two

• different aryl units. Keywords: aryl bromides; atom economy; C–H bond activation; palladium; regioselectivity; thiophenes; Introduction As thiophenes bearing aryl substituents are known to be present in several bioactive molecules and are used as precursors of materials, the regioselective introduction of

• aryls on thiophenes is an important research area in organic synthesis. The coupling of thiophene derivatives with aryl halides via a C–H bond activation/functionalisation [1][2][3][4][5][6][7][8][9][10][11][12] provides an environmentally attractive and cost-effective procedure for the preparation of a

Synthesis of ethoxy dibenzooxaphosphorin oxides through palladium-catalyzed C(sp²)–H activation/C–O formation

• Seohyun Shin,
• Dongjin Kang,
• Woo Hyung Jeon and
• Phil Ho Lee

Beilstein J. Org. Chem. 2014, 10, 1220–1227, doi:10.3762/bjoc.10.120

• the ortho-position of 2-(phenyl)phenylphosphonic acid monoethyl ester is not involved in the rate-limiting step and the C–H bond metallation is reversible. To elucidate the mechanism of the present reaction, the reaction was conducted with a stoichiometric amount of Pd(OAc)2 and without the oxidant

Theoretical studies on the intramolecular cyclization of 2,4,6-t-Bu₃C₆H₂P=C: and effects of conjugation between the P=C and aromatic moieties

• Masaaki Yoshifuji and
• Shigekazu Ito

Beilstein J. Org. Chem. 2014, 10, 1032–1036, doi:10.3762/bjoc.10.103

• -optimized structure of the transition state (TS), and Figure 2 shows the energy profile of the cyclization process. Considerable elongation of the C–H bond of the corresponding methyl group has been characterized, whereas the P=C length was found comparable to that in 1 (vide infra). The optimized

Silver and gold-catalyzed multicomponent reactions

• Giorgio Abbiati and
• Elisabetta Rossi

Beilstein J. Org. Chem. 2014, 10, 481–513, doi:10.3762/bjoc.10.46

• silver-catalyzed approach, involving the activation of the C–H bond of alkyne by an Au(I) species. For the AuBr3-catalyzed reaction, the authors argued that Au(I) could be generated in situ by a reduction of Au(III) from the alkyne. Starting from this seminal work, many other gold catalysts, including

• -copper catalytic system for the oxidation of aliphatic C–H bonds [70]. Thus, oxidation of the aliphatic C–H bond, alpha to the reacting amine 50, resulted in the formation of nucleophilic enamine 51, which is able to react with the isoquinolinium-2-ylamide 43, thereby affording a tricyclic intermediate

Substrate dependent reaction channels of the Wolff–Kishner reduction reaction: A theoretical study

• Shinichi Yamabe,
• Guixiang Zeng,
• Wei Guan and
• Shigeyoshi Sakaki

Beilstein J. Org. Chem. 2014, 10, 259–270, doi:10.3762/bjoc.10.21

• , H2N–NH2 and OH−(H2O)7. Here, ketones are acetone and acetophenone. While routes of the ketone → hydrazone → diimine are similar, those from the diimines are different. From the isopropyl diimine, the N2 extrusion and the C–H bond formation takes place concomitantly. The concomitance leads to the

[²H₂₆]-1-epi-Cubenol, a completely deuterated natural product from Streptomyces griseus

• Christian A. Citron and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2013, 9, 2841–2845, doi:10.3762/bjoc.9.319

• deduced from the mass spectrum. Due to the significantly shorter C–D bond compared to a C–H bond resulting in a lower polarisability and weaker interaction of the deuterated analyte with the stationary phase deuterated compounds can be gas chromatographically separated from their non-labelled counterparts

Advancements in the mechanistic understanding of the copper-catalyzed azide–alkyne cycloaddition

• Regina Berg and
• Bernd F. Straub

Beilstein J. Org. Chem. 2013, 9, 2715–2750, doi:10.3762/bjoc.9.308

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

• ) followed by oxidative coupling of the formed alkylgold moiety with the ortho C–H bond of the tethered phenyl group. Compound 137 was finally obtained via reductive elimination of intermediate 141 (Scheme 34). The formal [3 + 2] annulation between the aniline moiety and the C–C double bond constitutes the

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

• demonstrated recently by D. Bouyssi, O. Baudoin and coworkers, copper proved also able to catalyze the introduction of a CF3 group at the “imino” C–H bond of N,N-disubstituted (het)arylhydrazones [85]. Here again, a simple system consisting of Togni’s reagent and 10 mol % of copper(I) chloride could

• and catalytic experiments and came to the conclusion that the reaction most probably proceeded via a trifluoromethylcopper(I) species, which would activate the C–H bond of the substrate and then be oxidized to a copper(III) complex, finally releasing the trifluoromethylated product by reductive

• of a one-pot, two-stage reaction, with Ir-catalyzed borylation of an aromatic sp2-C–H bond, followed by a copper-mediated or -catalyzed perfluoroalkylation of the resulting arylboronic ester intermediate. Since the work by J. F. Hartwig et al. uses stoichiometric amounts of ex situ-prepared Cu-Rf

Elucidation of the regio- and chemoselectivity of enzymatic allylic oxidations with Pleurotus sapidus – conversion of selected spirocyclic terpenoids and computational analysis

• Verena Weidmann,
• Mathias Schaffrath,
• Holger Zorn,
• Julia Rehbein and
• Wolfgang Maison

Beilstein J. Org. Chem. 2013, 9, 2233–2241, doi:10.3762/bjoc.9.262

• ether subunit may be rationalized by the particularly low BDH298 for the corresponding C–H bond compared to the other allylic C–H bonds (Table 2). Carbon-centered radicals adjacent to an oxygen atom are commonly known to be stabilized as they benefit from inductive effects as well as from orbital

• as well as in the model system 11B-R3 helps to stabilize the radical further, mainly by hyperconjugation. In total, both substituent effects result in a rather low C–H bond-dissociation enthalpy of 79.5 kcal/mol at CBS-QB3 level of theory (74.9 kcal/mol B3LYP/6-31+G**, Table 2). Compared to the other

Structure of 1,5-benzodiazepinones in the solid state and in solution: Effect of the fluorination in the six-membered ring

• Marta Pérez-Torralba,
• Rosa M. Claramunt,
• M. Ángeles García,
• Concepción López,
• M. Carmen Torralba,
• M. Rosario Torres,
• Ibon Alkorta and
• José Elguero

Beilstein J. Org. Chem. 2013, 9, 2156–2167, doi:10.3762/bjoc.9.253

• 4b. The introduction of an N-methyl group, derivatives 2b, 4b and 6b, fold the seven-membered ring with a concomitant destabilization of these tautomers. The tautomerism between a and b implies the breaking/formation of a C–H bond. This is similar to the case of acetylacetone (diketo and ketoenol

An investigation of the observed, but counter-intuitive, stereoselectivity noted during chiral amine synthesis via N-chiral-ketimines

• Thomas C. Nugent,
• Richard Vaughan Williams,
• Andrei Dragan,
• Alejandro Alvarado Méndez and
• Andrei V. Iosub

Beilstein J. Org. Chem. 2013, 9, 2103–2112, doi:10.3762/bjoc.9.247

• convincingly understood to be controlled by the phenyl group of the auxiliary (Figure 1 and Scheme 1) [36][37][39][40][41][42][43][44][45][46][47][48][49][50][51]. Thus the N-phenylethyl fragment of PEA adopts a single low-energy conformation about the nitrogen-benzylic carbon bond wherein the benzylic C–H

• bond is co-planar with the imine double bond and pointing toward, not away from, the imine carbonyl substituent as depicted in Figure 1 [52][53]. Accepting that facial control is enforced by the phenyl group, it is apparent from inspection of Figure 1 that reduction of the cis-imine will proceed

An easy direct arylation of 5-pyrazolones

• Hao Gong,
• Yiwen Yang,
• Zechao Wang and
• Chunxiang Kuang

Beilstein J. Org. Chem. 2013, 9, 2033–2039, doi:10.3762/bjoc.9.240

• Education, Shanghai 200092, China 10.3762/bjoc.9.240 Abstract A mild, efficient and catalytic ligand-free method for the direct arylation of 5-pyrazolones by Pd-catalyzed C–H bond activation is reported. The process smoothly proceeds and yields are moderate to excellent. Keywords: arylation; aryl halide

• ; C–H bond activation; Pd(OAc)2; pyrazolone; Introduction 5-Pyrazolones are attracting considerable research interest because of their unique chemical properties and their structures that facilitate their application as biological and pharmaceutical intermediates and products [1][2][3]. Over the

• have been described [15]. In this paper, we report a convenient and catalytic ligand-free synthesis of a series of 4-aryl-5-pyrazolones 3 from 5-pyrazolones 1 and aryl halides 2 (Scheme 1). The direct arylation of 5-pyrazolones by Pd-catalyzed C–H bond activation was utilized. Results and Discussion We

Synthesis of enantiomerically pure (2S,3S)-5,5,5-trifluoroisoleucine and (2R,3S)-5,5,5-trifluoro-allo-isoleucine

• Holger Erdbrink,
• Elisabeth K. Nyakatura,
• Susanne Huhmann,
• Ulla I. M. Gerling,
• Dieter Lentz,
• Beate Koksch and
• Constantin Czekelius

Beilstein J. Org. Chem. 2013, 9, 2009–2014, doi:10.3762/bjoc.9.236

• polarized than the C–H bond, and electrostatic interactions of the fluorinated group with the solvent are energetically more favored. As a consequence, fluoroalkyl side chains possess two seemingly contrary physicochemical properties, hydrophobicity and polarity, and the combination of both leaves

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

• converted to iminium ion 4 by another one-electron oxidation. The acidifying effect of one-electron oxidation on the α-C–H bond remains debatable [56][57][58][59][60]. The rate for deprotonation of amine radical cation 2 has been measured experimentally by several groups, and a broad range has been obtained

• (Scheme 26) [93]. Functionalization of the sp3 C–H bond α to the nitrogen atom in tetrahydroquinolines and indolines via iminium ions is challenging because the corresponding iminium ions are enolizable and thus tend to tautomerize to enamines [94][95] and/or aromatize [96][97]. The authors adopted a

AgOTf-catalyzed one-pot reactions of 2-alkynylbenzaldoximes with α,β-unsaturated carbonyl compounds

• Qiuping Ding,
• Dan Wang,
• Puying Luo,
• Meiling Liu,
• Shouzhi Pu and
• Liyun Zhou

Beilstein J. Org. Chem. 2013, 9, 1949–1956, doi:10.3762/bjoc.9.231

• -alkenylated isoquinoline 4 was synthesized via a Pd-mediated C–H bond activation approach in a one-pot reaction. The intermediate isoquinoline N-oxide A was produced in situ from 2-alkynylbenzaldoximes and reacted with the α,β-unsaturated carbonyl compound 2e to yield 1-alkenylated isoquinoline 4 (Scheme 3

• . Procedure for the synthesis of 1-alkenylated isoquinoline 4 by a Pd-mediated C–H bond activation approach: A solution of 2-alkynylbenzaldoxime 1a (0.3 mmol) and AgOTf (0.015 mmol, 5 mol %) in CH2Cl2 (2 mL) was stirred at rt for 2 h. Then, the solvent was removed under reduced pressure. Subsequently, a

Gold-catalyzed cyclization of allenyl acetal derivatives

• Dhananjayan Vasu,
• Samir Kundlik Pawar and
• Rai-Shung Liu

Beilstein J. Org. Chem. 2013, 9, 1751–1756, doi:10.3762/bjoc.9.202

• , and assignable to other products including 4g and 4h. The reaction worked well with substrates bearing a different trisubstituted allenes, giving the desired cyclopentenone 4g and 4h in 82–83% yields. The preceding cyclization is mechanistically interesting because it involves a cleavage of the C–H

• bond of the acetal group. We prepared d1-1a bearing a deuterium (>98%, Scheme 2, reaction 1) at its acetal group. The resulting product d1-4a has almost one full deuterium (X = 0.98 D) at one of the methylene protons according to DEPT 13C NMR analysis. In the presence of added D2O, undeuterated 1a gave

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

• aliphatic alkenes using tert-butyl nitrite (t-BuONO) and oxygen [21]. In this reaction, three positions including an unreactive sp3 C–H bond are functionalized in alkenes to produce nitrated γ-lactols in one step. For instance, treatment of alkene 1 with 5 equivalents of t-BuONO in a dried solvent under an

• nitrate ester 24 was detected in the reaction of 14. This implies that the 1,5-hydrogen shift on the methine site is not so fast (entry 10). Typically, in the radical hydrogen abstraction, a methine C–H bond is more reactive than methyl and methylene sites, whereas it might be difficult for substrates

A³-Coupling catalyzed by robust Au nanoparticles covalently bonded to HS-functionalized cellulose nanocrystalline films

• Jian-Lin Huang,
• Derek G. Gray and
• Chao-Jun Li

Beilstein J. Org. Chem. 2013, 9, 1388–1396, doi:10.3762/bjoc.9.155

• ). The Au@HS-CNC (4.4 mol %) decomposed at above 250 °C under an inert atmosphere, making them an attractive catalyst for catalytic reactions. The FT-IR spectra of CNC, HS-CNC and Au@HS-CNC (4.4 mol %) (Figure 4) showed absorbance bands around 2920 cm−1 due to the stretching vibration of the C–H bond in

True and masked three-coordinate T-shaped platinum(II) intermediates

• Manuel A. Ortuño,
• Salvador Conejero and
• Agustí Lledós

Beilstein J. Org. Chem. 2013, 9, 1352–1382, doi:10.3762/bjoc.9.153

• . Moreover, recent experimental and theoretical reports are analyzed, which suggest the involvement of such intermediates in reaction mechanisms, particularly C–H bond-activation processes. Keywords: C–H bond activation; intermediate; platinum(II); reactive intermediates; three-coordinate; T-shaped; Review

• of olefins into M–H bonds, electrophilic attack at Pt–C bonds, and ligand cycloplatination [2]. Likewise, related Pd(II) complexes [3][4] are relevant in cross-coupling reactions and C–H bond-activation processes. The accessibility of three-coordinate Pd(II) species have been recently discussed [5

• complexes in solution will be discussed. Finally, participation of three-coordinate Pt(II) intermediates in reactions, mainly C–H bond-activation processes and ligand exchanges, will be analyzed. A thorough review on the bonding and stereochemistry of three-coordinate transition-metal compounds was

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

• -pot procedure, the isolated yields of 3p–3r were moderate (45–52% yields) (Table 3, entries 1–3). The oxygenation of the adamantyl C–H bond was especially sluggish, giving the desired 1,4-diol 3s in only 23% yield (Table 3, entry 4). Similarly, in these reactions, the formation of reduced alcohols 5

• could be envisioned that this aerobic C–H bond oxygenation could be combined with the present remote C–H oxygenation with hydroperoxides, presumably resulting in direct formation of 1,4-dioxygenated compounds from nonoxygenated alkanes (Scheme 6). With this hypothesis, alkane 10 bearing a dibenzylic

• tertiary C–H bond (marked in green) was treated with the catalytic system of CuCl-1,10-phen (20 mol %) with NHPI in benzene/MeCN solvent under an O2 atmosphere (1 atm) (Scheme 7). The reaction with 20 mol % of NHPI proceeded as expected at 50 °C to afford a mixture of lactol 2i and 1,4-diols 3i in 29% and

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

• phenanthridine 17 was obtained as a side product. Compound 17 is presumably generated through the PhI(OAc)2-mediated oxidation of the benzylic C–H bond to form a phenanthridinium intermediate 18, which then undergoes a removal of the PA group. Encouraged by these observations, we proceeded to explore whether the

• , forming 17 in excellent yield. We believe that PhI(OAc)2 serves as the oxidant for the initial Pd-catalyzed intramolecular C–H amination step, in which a PdII/IV catalytic manifold might be operative. Cu(OAc)2 is responsible for the subsequent oxidation of the benzylic C–H bond of dihydrophenanthridine

• 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