Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

• Flavio Fanelli,
• Giovanna Parisi,
• Leonardo Degennaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2017, 13, 520–542, doi:10.3762/bjoc.13.51

• telescoped homocatalysis procedure consisting of a three-step sequence (metalation, zincation and Negishi cross-coupling) which furnishes an easy access to a variety of functionalized 2-fluorobiaryl and heteroaryl products (Scheme 9) [59]. This strategy is rightfully considered green because it guarantees

Direct arylation catalysis with chloro[8-(dimesitylboryl)quinoline-κN]copper(I)

• Sem Raj Tamang and
• James D. Hoefelmeyer

Beilstein J. Org. Chem. 2016, 12, 2757–2762, doi:10.3762/bjoc.12.272

• -enediol in situ as an electron donor [62]. While the SET mechanism has drawn much interest, our observation of large rate enhancement upon addition of the preformed catalyst 2 may be better described with a metalation–deprotonation step followed by oxidative addition/reductive elimination (Scheme 2) [63

• ]. Thus, t-BuO− substitutes the halogen ligand on 2, followed by deprotonation–metalation of benzene, followed by oxidative addition of the arylhalide, and finally reductive elimination of the biaryl. The molecule 2 may be uniquely suited for this pathway. The electron-rich Cu(I) in the (L-Z)Cu(OR

• ) intermediate may be well-stabilized by boron as a Z-type ligand, and the mesityl groups surrounding boron may favor the association of arenes for the deprotonation–metalation and the oxidative addition steps. Wang et al. proposed concerted metalation–deprotonation via a sigma bond metathesis involving a cyclic

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

• transformations. Three approaches (Figure 1) have generally been employed to enhance the reactivity and promote the key metalation/C–H bond cleavage step: (1) tuning of the reaction conditions through inclusion of various additives such as metal salts [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18

• [72][73][74][75][76][77][78][79]. Literature studies have suggested that certain anionic ligands on palladium, such as acetate or carbonate, may assist C–H bond cleavage by acting as internal bases as part of a concerted metalation–deprotonation (CMD) pathway, particularly in the case of less electron

• bond cleavage, most notably the concerted metalation-deprotection (CMD) or electrophilic palladation pathways (Scheme 1) [221][222][223][224]. Although control experiments had previously indicated the importance of conditions involving cationic palladium for achieving overall reaction conversion, our

A modular approach to neutral P,N-ligands: synthesis and coordination chemistry

• Vladislav Vasilenko,
• Torsten Roth,
• Clemens K. Blasius,
• Sebastian N. Intorp,
• Hubert Wadepohl and
• Lutz H. Gade

Beilstein J. Org. Chem. 2016, 12, 846–853, doi:10.3762/bjoc.12.83

• was removed under reduced pressure and the residue was taken up in 300 mL of toluene. The mixture was then filtered through a plug of Celite© and the solvent was evaporated in vacuo yielding the desired product which was used without further purification in the subsequent metalation steps. For

Base metal-catalyzed benzylic oxidation of (aryl)(heteroaryl)methanes with molecular oxygen

• Hans Sterckx,
• Johan De Houwer,
• Carl Mensch,
• Wouter Herrebout,
• Kourosch Abbaspour Tehrani and
• Bert U. W. Maes

Beilstein J. Org. Chem. 2016, 12, 144–153, doi:10.3762/bjoc.12.16

• ) delivered the corresponding ketone 6f, albeit in a poor yield of 40%, thus supporting the metalation hypothesis. The regioisomer of diazine 5f, 3-benzyl-6-methylpyridazine (5g), could be smoothly oxidized to the corresponding ketone in 81% yield. It is worth mentioning that in 5f as well as 5g no additional

Pyridylidene ligand facilitates gold-catalyzed oxidative C–H arylation of heterocycles

• Kazuhiro Hata,
• Hideto Ito,
• Yasutomo Segawa and
• Kenichiro Itami

Beilstein J. Org. Chem. 2015, 11, 2737–2746, doi:10.3762/bjoc.11.295

• electrophilic metalation of heteroarene 1 with C with concurrent generation of an acid (HX) produces diarylated gold(III) species D. Finally, the reductive elimination from D releases the coupling product 3 along with the regeneration of gold(I) species A. The side reaction leading to the homocoupling product

• calculations on the oxidation process of the AuCl(ligand) to AuCl3(ligand) also clarified the advantage of the PyC ligand over IPr by 3.6 kcal mol–1 (see Supporting Information File 1 for details). While it still remains unclear how the PyC ligand affects the transmetalation, C–H metalation and reductive

Rhodium, iridium and nickel complexes with a 1,3,5-triphenylbenzene tris-MIC ligand. Study of the electronic properties and catalytic activities

• Carmen Mejuto,
• Beatriz Royo,
• Gregorio Guisado-Barrios and
• Eduardo Peris

Beilstein J. Org. Chem. 2015, 11, 2584–2590, doi:10.3762/bjoc.11.278

• rotation about the C–C sigma bonds of the ligand, and the Ccarbene–Ni bond. The 13C NMR spectrum showed the distinctive signal due to the metalation of the carbene carbon at 151.4 ppm, which is in the same region of the previously reported [NiCpCl(MIC)] complex (148 ppm) [49]. The trimetallic nature of the

Pyridinoacridine alkaloids of marine origin: NMR and MS spectral data, synthesis, biosynthesis and biological activity

• Louis P. Sandjo,
• Victor Kuete and
• Maique W. Biavatti

Beilstein J. Org. Chem. 2015, 11, 1667–1699, doi:10.3762/bjoc.11.183

• protocol previously reported for a similar ketone prepared from pyridine and N,N-dimethylbenzamide [69]. The first sequence of the route was the metalation of pyridine subsequently using BuLi-LiDMAE, then treating pyridyllithium formed with N,N-dimethylbenzamide. The ketone was recovered with 80% within 2

Pd(OAc)₂-catalyzed dehydrogenative C–H activation: An expedient synthesis of uracil-annulated β-carbolinones

• Biplab Mondal,
• Somjit Hazra,
• Tarun K. Panda and
• Brindaban Roy

Beilstein J. Org. Chem. 2015, 11, 1360–1366, doi:10.3762/bjoc.11.146

• mechanistic pathway that commence with electrophilic metalation at the indole C3 postion. The nucleophilicity of indole at C3 is well known [58] and a similar kind of electrophilic reaction leads to the intermediate A (Scheme 3). We believe this intermediate then undergoes a σ-bond metathesis reaction to form

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• several research groups reported on specific flow transformations that enabled a new synthesis of these known pharmaceuticals. Examples of these early endeavours include the syntheses of efaproxiral (1) and rimonabant (2) using a AlMe3-mediated direct amidation in flow [40], an improved metalation step in

Discrete multiporphyrin pseudorotaxane assemblies from di- and tetravalent porphyrin building blocks

• Mirko Lohse,
• Larissa K. S. von Krbek,
• Sebastian Radunz,
• Suresh Moorthy,
• Christoph A. Schalley and
• Stefan Hecht

Beilstein J. Org. Chem. 2015, 11, 748–762, doi:10.3762/bjoc.11.85

• obtained through the condensation of aldehyde 3 with mesityldipyrromethane (6) followed by metalation of the intermediately formed free base porphyrin 7 to give its respective zinc complex 2. In the next step, axle precursor 8 was synthesized by reductive amination of 4-bromobenzaldehyde (9) and

• using 20 and pyrrole (4) following the Lindsey protocol [77] for A4 porphyrins gives the desired tetravalent porphyrin host as the free base 21, which is subsequently converted into the desired product C4 by metalation using zinc(II) acetate. Host C2 was synthesized according to the above-mentioned

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

Triazol-substituted titanocenes by strain-driven 1,3-dipolar cycloadditions

• Andreas Gansäuer,
• Andreas Okkel,
• Lukas Schwach,
• Laura Wagner,
• Anja Selig and
• Aram Prokop

Beilstein J. Org. Chem. 2014, 10, 1630–1637, doi:10.3762/bjoc.10.169

• access as yet unexplored functional titanocenes. This is most easily achieved with modular, efficient, and general strategies for the synthesis of these complexes. Classical approaches with metalation at the end of the sequence usually do not meet these requirements. This is because introduction of

• functional groups is difficult due to the nucleophilicity of the cyclopentadienyl anions before metalation and the electrophilicity of titanium after metalation [21][22]. We have devised a conceptually different approach addressing these issues. It relies on the use of carboxylate-containing titanocene

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• work was carried out in the groups of Castedo [110] and Couture [111][112]. A beautiful application of a directed ortho-metalation (DoM) strategy was reported in the synthesis of piperolactam C (131) by Snieckus (Scheme 16) [113]. Treatment of 129 with base afforded aminophenanthrene 130 via a remote

• lateral metalation–cyclization sequence. Metalation of 130 with excess n-butyllithium followed by carbonation then yielded piperolactam C (131). In 2008, Heo and coworkers reported the synthesis of several aristolactams employing a one-pot cross-coupling/aldol condensation cascade reaction (Scheme 17) [91

Polar reactions of acyclic conjugated bisallenes

• Reiner Stamm and
• Henning Hopf

Beilstein J. Org. Chem. 2013, 9, 36–48, doi:10.3762/bjoc.9.5

• transformations. Keywords: β-lactams; conjugated bisallenes; cyclopentenones; epoxidation; halogen addition; hydrohalogenation; ionic additions; metalation; Introduction Whereas the use of hexa-1,2,4,5-tetraene (1) and its derivatives in pericyclic reactions is well documented [2][3][4][5][6], relatively little

• is known about the behavior of noncyclic, conjugated bisallenes in ionic or polar reactions, whether these involve metalation processes, the addition of halogens and hydrogen halides, or oxidation reactions, to name but a few. To fill this gap we initiated a research program, hoping also that polar

• discoloration sets in, and in neat form it withstands polymerization for about a week in the deep freezer. The protocols for making these two derivatives from readily available starting materials are straightforward and high-yielding. Results and Discussion Reactions of 2/4 with electrophiles Metalation of 2

The chemistry of bisallenes

• Henning Hopf and
• Georgios Markopoulos

Beilstein J. Org. Chem. 2012, 8, 1936–1998, doi:10.3762/bjoc.8.225

• . Metalation of 27 with n-butyllithium provided the allenyllithium reagent 28 next, which was subsequently converted into the organozinc reagent 29. In a Negishi-type coupling of this intermediate with either the bromoallene 30 or its deuterated version 27 the two target compounds were obtained in the final

• ), they are also known for conjugated bisallenes. We also would like to include metalation reactions in this chapter, namely the reactions we have already briefly referred to above (see Sections 1.1 and 1.2). Another example encountered earlier is the transformation recorded in Scheme 25, where silver and

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

• effect of Cu(OAc)2 and AgOAc as oxidant, a determinant role on the selectivity of direct C–H to C–H cross-coupling reactions was played by the acidity of the medium, as shown by reactions carried out in the presence of AcOH [58][59]. Based on experimental and computational data, a concerted metalation

Aldol elaboration of 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridin-4-ones, masked precursors to acylpyridones

• Raymond C. F. Jones,
• Abdul K. Choudhury,
• James N. Iley,
• Mark E. Light,
• Georgia Loizou and
• Terence A. Pillainayagam

Beilstein J. Org. Chem. 2012, 8, 308–312, doi:10.3762/bjoc.8.33

• condensation to give new 3-alkenyl-4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-4-ones, which are masked forms related to the acylpyridone natural products. Keywords: aldol reaction; fused-ring systems; heterocycles; isoxazole; metalation; pyridone; Introduction The 3-acyl-4-hydroxypyridin-2-one moiety 1

• tetrahydroisoxazolopyridone 6 was to use the direct deprotonation strategy employed with the corresponding dehydro derivative 4 [16]. It is well-precedented that 3,5-disubstituted isoxazoles undergo lateral deprotonation–metalation preferentially at the C-5 substituent [17][18] (isoxazole numbering), which corresponds to the

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

• in this article. Methodologies, selectivity, mechanism and future aspects are presented. Keywords: ate complex; catalytic direct arylation; mechanism; oxazole; selectivity; transition-metal catalysis; Introduction Deprotonative metalation of aromatics is widely used as a powerful method for

• ], manganate ((Me3SiCH2)2Mn(TMP)Li·TMEDA) [3][8], cuprates (MeCu(TMP)(CN)Li2, (TMP)2CuLi) [9][10] and cadmium amides ((TMP)3CdLi) [11][12], for regio- and/or chemoselective deprotonative metalation of aromatics, producing arylmetal intermediates under smooth reaction conditions that are directly suitable for

• electrophilic reactions as well as transition-metal-catalyzed cross-coupling reactions. By contrast, the methodology for transition-metal-catalyzed direct arylation [13][14][15][16][17][18] is based upon the use of various catalytic metalation processes, such as electrophilic metalation, oxidative addition

Directed ortho,ortho'-dimetalation of hydrobenzoin: Rapid access to hydrobenzoin derivatives useful for asymmetric synthesis

• Inhee Cho,
• Labros Meimetis,
• Lee Belding,
• Michael J. Katz,
• Travis Dudding and
• Robert Britton

Beilstein J. Org. Chem. 2011, 7, 1315–1322, doi:10.3762/bjoc.7.154

• .7.154 Abstract A variety of ortho,ortho'-disubstituted hydrobenzoin derivatives are readily accessible through a directed ortho,ortho'-dimetalation strategy in which the alcohol functions in hydrobenzoin are deprotonated by n-BuLi and the resulting lithium benzyl alkoxides serve as directed metalation

• groups. The optimization and scope of this reaction are discussed, and the utility of this process is demonstrated in the one-pot preparation of a number of chiral diols as well as a short synthesis of the chiral ligand Vivol. Keywords: chiral diol; directed ortho-metalation; hydrobenzoin; Introduction

• ] through a directed ortho,ortho'-dimetalation strategy in which the alcohol functions in hydrobenzoin are deprotonated by n-BuLi and the resulting lithium benzyl alkoxides serve as directed metalation groups (DMGs) [24][25][26][27][28] and facilitate formation of the tetralithio intermediate 8. Herein, we

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

• . Experimental details are given for the most important reactions in the Supporting Information File 1 of this article. Keywords: cross-coupling; heterocycles; insertion; metalation; organomagnesium; organozinc; Introduction The functionalization of heterocyclic scaffolds is an important task in current

• aryl or heteroaryl halides; the metalation of aryl or heteroaryl derivatives with TMP2Zn·2MgCl2·2LiCl. These three methods, developed recently in our laboratories, provide access to numerous heterocyclic zinc reagents (Scheme 1). 1.1 The direct insertion of zinc in the presence of LiCl Although the

• TMPMgCl·LiCl (41) can be performed. The strongly electron-withdrawing properties of the chloro-substituent favor a metalation at position 5. After the addition of pivaldehyde, the subsequent addition of a second equivalent of TMPMgCl·LiCl (41; −30 °C, 1.5 h) allows now a magnesiation in position 3. Quenching

Combined directed ortho-zincation and palladium-catalyzed strategies: Synthesis of 4,n-dimethoxy-substituted benzo[b]furans

• Verónica Guilarte,
• M. Pilar Castroviejo,
• Estela Álvarez and
• Roberto Sanz

Beilstein J. Org. Chem. 2011, 7, 1255–1260, doi:10.3762/bjoc.7.146

• took place regioselectively and, after treatment with iodine, afforded the corresponding 3-halo-2-iodoanisole derivatives 4 in good yields (Table 1). It is interesting to note that substrates 3c and 3d bearing the two methoxy groups in a meta relationship selectively undergo metalation at the position

Use of mixed Li/K metal TMP amide (LiNK chemistry) for the synthesis of [2.2]metacyclophanes

• Marco Blangetti,
• Patricia Fleming and
• Donal F. O'Shea

Beilstein J. Org. Chem. 2011, 7, 1249–1254, doi:10.3762/bjoc.7.145

• substituted m-xylenes is described. The strategy employs a selective benzylic metalation and oxidative C–C bond formation for both synthetic operations. Regioselective benzylic metalation is achieved using the BuLi, KOt-Bu, TMP(H) (2,2,6,6-tetramethylpiperidine) combination (LiNK metalation conditions) and

• oxidative coupling with 1,2-dibromoethane. The synthetic ease of this approach compares favourably with previously reported methods and allows for ready access to potentially useful planar chiral derivatives. Keywords: benzylic metalation; LiNK chemistry; [2.2]metacyclophane; oxidative coupling; planar

• chirality; Introduction While direct metalation reactions are an essential contribution to the repertoire of modern synthetic methods, an underlying and often underestimated challenge remains in the achievement of predictable selective metalations of substrates that offer several potential sites of

Selectivity in C-alkylation of dianions of protected 6-methyluridine

• Ngoc Hoa Nguyen,
• Christophe Len,
• Anne-Sophie Castanet and
• Jacques Mortier

Beilstein J. Org. Chem. 2011, 7, 1228–1233, doi:10.3762/bjoc.7.143

• organolithiums [14], and indeed, 7 failed to react, in our experiments, with 4-bromo-but-1-ene to give 9. We then turned our attention to the metalation of the 5'-O-TBDMS protected nucleoside 10 (Figure 2). Treatment with LDA (5 equiv) in THF at −70 °C followed by addition of D2O provided 12 in 82% yield

• then embarked on a detailed investigation of the lithiation/alkylation of 6-methyluridine 2, varying the base, metalation temperature, and exposure times (Scheme 3). We were concerned with the question of relative acidity of the methyl (C7) and the C5 centers that can compete through 18A or 18B [34][35

• the assignment of the proton–proton correlations of H7 and the allylic methylene groups. Metalation with s-BuLi/TMEDA complex was less efficient although the reaction did not lead to degradation products (entry 6). Ring/internal lithiations of uridine derivatives with s-BuLi/TMEDA are usually

Directed aromatic functionalization

• Victor Snieckus

Beilstein J. Org. Chem. 2011, 7, 1215–1218, doi:10.3762/bjoc.7.141

• since the independent discoveries by Gilman and Wittig, the directed ortho metalation (DoM) reaction has trickled into the armamentarium of the synthetic chemist (but not significantly into textbooks [8][14]), as a general and rational strategy for the construction of polysubstituted aromatics and

• Roberto Sanz; a hint of the potential of meta metalation by mixed metal/amide bases is posited by Robert Mulvey; and the application of such base combinations for the ready construction of planar chiral metacyclophanes is delightfully revealed by Donal O’Shea; striking evidence of the power of aryl metal