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

The role of silver additives in gold-mediated C–H functionalisation

• Scott R. Patrick,
• Ine I. F. Boogaerts,
• Sylvain Gaillard,
• Alexandra M. Z. Slawin and
• Steven P. Nolan

Beilstein J. Org. Chem. 2011, 7, 892–896, doi:10.3762/bjoc.7.102

• gold in homogeneous catalysis is an area where fascinating advances have been realised in the last few years [1][2][3][4]. One of these discoveries has focused on the possibility of using gold in metalation reactions [5][6][7][8] directly leading to organogold complexes. The further use of organogold

• complexes bearing N-heterocyclic carbenes (NHC) [9][10] as supporting ligands has enabled the isolation of a “golden synthon”, [Au(OH)(IPr)] 1 (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene), that is able to participate in metalation reactions with aromatic C–H bonds (Scheme 1) [11]. The reactivity

• (Scheme 2) [16]. The observation of a high kinetic isotope effect is suggestive of a concerted metalation–deprotonation mechanism, as first suggested for Pd(II) complexes, in which a pivalate ligand behaves as a proton acceptor via a six-membered transition state [17]. However, addition via a transient Au

Au(I)/Au(III)-catalyzed Sonogashira-type reactions of functionalized terminal alkynes with arylboronic acids under mild conditions

• Deyun Qian and
• Junliang Zhang

Beilstein J. Org. Chem. 2011, 7, 808–812, doi:10.3762/bjoc.7.92

• cationic gold(I) species A is oxidized by Selectfluor® to give a gold(III) species B [26][27][28][29][30][31][32][36]. With the aid of base, the reaction between B and alkyne affords intermediate C. The weak Au–F bond and the strong B–F bond drive the trans-metalation to produce intermediate D [29][36][37

Syntheses and properties of thienyl-substituted dithienophenazines

• Annemarie Meyer,
• Eva Sigmund,
• Friedhelm Luppertz,
• Gregor Schnakenburg,
• Immanuel Gadaczek,
• Thomas Bredow,
• Stefan-S. Jester and
• Sigurd Höger

Beilstein J. Org. Chem. 2010, 6, 1180–1187, doi:10.3762/bjoc.6.135

• prepared first 3,3’-thenil (2) by metalation of 3-bromothiophene and reaction with dimethyl oxalate [19]. Subsequent oxidative intramolecular thiophene-thiophene coupling [20] with FeCl3 yielded 3 as a dark red (nearly black) solid. Bromination of 3 with bromine in acetic acid/chloroform gave 4 in nearly

Molecular recognition of organic ammonium ions in solution using synthetic receptors

• Andreas Späth and
• Burkhard König

Beilstein J. Org. Chem. 2010, 6, No. 32, doi:10.3762/bjoc.6.32

A short and efficient synthesis of valsartan via a Negishi reaction

• Samir Ghosh,
• A. Sanjeev Kumar and
• G. N. Mehta

Beilstein J. Org. Chem. 2010, 6, No. 27, doi:10.3762/bjoc.6.27

• Samir Ghosh A. Sanjeev Kumar G. N. Mehta Applied Chemistry Department, S.V. National Institute of Technology, Surat-395 007, India 10.3762/bjoc.6.27 Abstract An efficient synthesis of the angiotensin-II inhibitor valsartan (Diovan®) is presented. Directed ortho-metalation of 5-phenyl-1-trityl-1H

• -pentanoyl-L-valinate (5) [9] in 70% yield. Ortho-metalation of 5-phenyl-1-trityl-1H-tetrazole (6) [10] with n-butyllithium at 25 °C followed by treatment with zinc chloride at −20 °C gave the desired organozinc chloride compound. Coupling of the latter with aryl bromide 5 in presence of a catalytic amount

Trifluoromethyl ethers – synthesis and properties of an unusual substituent

• Frédéric R. Leroux,
• Baptiste Manteau,
• Jean-Pierre Vors and
• Sergiy Pazenok

Beilstein J. Org. Chem. 2008, 4, No. 13, doi:10.3762/bjoc.4.13

• reacts with sec-butyllithium in the presence of N,N,N',N'-tetramethylethylenediamine ("TMEDA") smoothly under hydrogen/metal permutation ("metalation") as shown in Scheme 13 [72]. 4-Trifluoromethoxybiphenyl can be metalated using the Schlosser superbase LIC-KOR made by combining butyllithium (LIC) with

• , as in fluoro(trifluoromethoxy)benzenes, the fluorine-adjacent positions are always metalated (Scheme 16) [75]. The OCF3 group reveals a powerful π-polarization as it acidifies not only the ortho but also the meta and para positions strongly. Therefore, metalation of 2- and 4-(trifluoromethoxy)anisole

• metalation with tert-butyllithium, followed by carboxylation (Scheme 20) [71]. When the amino function is protected instead of a BOC group by a silyl group, 3-trifluoromethoxy-N-(trimethylsilyl)aniline is metalated in position 2. However, 3- and 4-trifluoromethoxy-N,N-bis(trimethylsilyl)aniline are metalated

Total syntheses of oxygenated brazanquinones via regioselective homologous anionic Fries rearrangement of benzylic O-carbamates

• Glaucia Barbosa Candido Alves Slana,
• Mariângela Soares de Azevedo,
• Rosângela Sabattini Capella Lopes,
• Cláudio Cerqueira Lopes and
• Jari Nobrega Cardoso

Beilstein J. Org. Chem. 2006, 2, No. 1, doi:10.1186/1860-5397-2-1

• Metalation (DoM) strategy, [17] offer a mild and regioselective complement to classical Friedel-Crafts approaches for the rational construction of polysubstituted aromatics, biaryls, and several classes of heterocycles (Figure 1). In 1993, Gawley showed that O-benzylcarbamates in the presence of directed

• metalation groups (DMGs) undergo competitive anionic [1,2] and [1,4] Wittig – carbamoyl rearrangements (paths a and b) [18][19] orientated by the groups R and DMGs (Figure 1). Conceptual combination of path b and the well established tandem DoM route to anthraquinones and heteroanthraquinones [20] led to the

• undergoes an intramolecular anionic Fries rearrangement to intermediate 4, that was isolated in our previous results. [12] Snieckus reported the remote metalation and cyclization of diethyl N-methyl-O-tolylanthranilamide to N-methyl dibenzazepinone [24][25][26] developing a new regiospecific construction of