Aminomethylation/hydrogenolysis as an alternative to direct methylation of metalated isoquinolines – a novel total synthesis of the alkaloid 7-hydroxy-6-methoxy-1-methylisoquinoline

• Benedikt C. Melzer,
• Jan G. Felber and
• Franz Bracher

Beilstein J. Org. Chem. 2018, 14, 130–134, doi:10.3762/bjoc.14.8

• of the direct methylation of electron-deficient N-heterocycles have been reviewed [9]. In a project aimed at the synthesis of tri- and tetracylic alkaloids containing the isoquinoline scaffold, we were interested in isoquinoline building blocks which bear a methyl group at C1, since this group should

Solvent-free copper-catalyzed click chemistry for the synthesis of N-heterocyclic hybrids based on quinoline and 1,2,3-triazole

• Martina Tireli,
• Silvija Maračić,
• Stipe Lukin,
• Marina Juribašić Kulcsár,
• Dijana Žilić,
• Mario Cetina,
• Ivan Halasz,
• Silvana Raić-Malić and
• Krunoslav Užarević

Beilstein J. Org. Chem. 2017, 13, 2352–2363, doi:10.3762/bjoc.13.232

• synthesis of 5–8 Based on the recently obtained 1,2,3-triazole-appended N-heterocycles, as promising lead compounds with efficient and selective cytostatic activities [8][9], our research groups share an interest in derivatization of target compounds by a triazole bridge [33]. Quinoline is an important

Preparation of imidazo[1,2-a]-N-heterocyclic derivatives with gem-difluorinated side chains

• Layal Hariss,
• Kamal Bou Hadir,
• Mirvat El-Masri,
• Thierry Roisnel,
• René Grée and
• Ali Hachem

Beilstein J. Org. Chem. 2017, 13, 2115–2121, doi:10.3762/bjoc.13.208

• , Lebanon Université de Rennes 1, Institut des Sciences Chimiques de Rennes, CNRS UMR 6226, Avenue du Général Leclerc, 35042 Rennes Cedex, France 10.3762/bjoc.13.208 Abstract Using an aerobic oxidative coupling, different new imidazo[1,2-a]-N-heterocycles with gem-difluroroalkyl side chains have been

• coupling reactions as well as nucleophilic substitutions have been performed successfully in order to increase the molecular diversity. Keywords: aerobic oxidative coupling; imidazo[1,2-a]-N-heterocycles; gem-difluoroalkyl derivatives; propargylic fluorides; Introduction Nitrogen-containing heterocyclic

• fluorinated propargylic derivatives [21]. Thus, taking into account the known biological properties of the imidazo-fused N-heterocycles, we became interested in the preparation of new derivatives of this type possessing gem-difluorinated side chains as indicated in Figure 1. Such new fluorinated heterocycles

Pd(OAc)₂/Ph₃P-catalyzed dimerization of isoprene and synthesis of monoterpenic heterocycles

• Dominik Kellner,
• Maximilian Weger,
• Andrea Gini and
• Olga García Mancheño

Beilstein J. Org. Chem. 2017, 13, 1807–1815, doi:10.3762/bjoc.13.175

• - and N-heterocycles The different dimers of isoprene can be transformed into a large number of derivatives such as terpene-alcohols or ethers [38]. Moreover, some isoprene dimers have been submitted to Diels–Alder reactions with olefins such as maleic acid anhydride or methacrolein to form products

• isoprene. Functionalization of the isoprene-dimer 2-TT to substituted O- and N-heterocycles. Optimization of the dimerization reaction of isoprene.a Supporting Information Supporting Information File 244: 1H NMR and 13C NMR spectra collection of the products and GC–FID analysis of the isoprene dimer’s

Oxidative dehydrogenation of C–C and C–N bonds: A convenient approach to access diverse (dihydro)heteroaromatic compounds

• Santanu Hati,
• Ulrike Holzgrabe and
• Subhabrata Sen

Beilstein J. Org. Chem. 2017, 13, 1670–1692, doi:10.3762/bjoc.13.162

• ]. Encouraged by these results a variety of functionalized N-heterocycles were oxidatively dehydrogenated with IBX, to afford their aromatic counterpart. For example imidazoles 11, dihydroisoquinoline 12, pyridine 13, and pyrrole 14 were obtained from their corresponding heterocyclic precursors 7–10 in

• dehydrogenation of N-heterocycles [31][32][33][34]. IBX-mediated room temperature one-pot condensation–oxidative dehydrogenation of o-aminobenzylamines. Anhydrous cerium chloride-catalyzed, IBX-mediated oxidative dehydrogenation of various heterocycles at room temperature. Oxidative dehydrogenation of

N-Propargylamines: versatile building blocks in the construction of thiazole cores

• S. Arshadi,
• E. Vessally,
• L. Edjlali,
• R. Hosseinzadeh-Khanmiri and
• E. Ghorbani-Kalhor

Beilstein J. Org. Chem. 2017, 13, 625–638, doi:10.3762/bjoc.13.61

• biologically important compounds. Keywords: 6-endo-dig cyclization; 5-exo-dig cyclization; N-heterocycles; N-propargylamines; thiazoles; Introduction Thiazoles are an important class of azole compounds that have attracted considerable attention due to the fact that they exhibit a wide variety of

• patterns. It is well known that they can undergo a number of cyclization reactions to produce various N-heterocycles and complex natural products. In this context we recently reviewed their role in the syntheses of pyrrole [65], pyridine [66], quinoline [67], pyrazine [68], 1,4-oxazepane, and 1,4-diazepane

Effect of the ortho-hydroxy group of salicylaldehyde in the A³ coupling reaction: A metal-catalyst-free synthesis of propargylamine

• Sujit Ghosh,
• Kinkar Biswas,
• Suchandra Bhattacharya,
• Pranab Ghosh and
• Basudeb Basu

Beilstein J. Org. Chem. 2017, 13, 552–557, doi:10.3762/bjoc.13.53

• interest of synthetic and medicinal chemists. Synthesis of various propargylamines from various salicylaldehydes under metal-catalyst-free conditions. Representative examples of bioactive compounds bearing a propargylamine moiety and synthesis of various N-heterocycles from propargylamine-containing

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

• of nitrogen-containing moieties, such as amides [86][87], N-heterocycles [88][89], imines [90][91], pyridine N-oxide [92], amines [93][94], as well as a variety of others [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• cyclization, giving the tricyclic N-heterocyclic core. Very recently, Shi and co-workers reported the chiral phosphoric acid (CPA, cat. 31)-catalyzed asymmetric dearomatization reactions of tryptamines with 3-indolyl-3-hydroxyoxindoles, affording the indole-containing tricyclic N-heterocycles in a highly

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

• efforts to better comprehend the scope of this catalytic system, especially on features concerning the BARF salt effect [43][44] and electronic effects on the aromatic rings of the chiral ligands [45]. In 2014, Maguire at al reported the syntheses of N-heterocycles by the enantioselective insertion of

• . Cyclopropanation/Insertion rhodium carbenoid reactions into C(sp3)–H reported by Pavlyuk and coworkers. Syntheses of N-heterocycles by RCM reported by Pavlyuk and coworkers. Acknowledgements We thank the Brazilian National Research Council (CNPq, Gran Nos. 477418/2013-9), the Brazilian Coordination for the

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

• : 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

• , piperazine ranks among the top three N-heterocycles along with pyridine and piperidine in the U.S. FDA-approved pharmaceuticals [2]. Due to its broad utilization, piperazine has been considered as a privileged scaffold in drug discovery to combat various human diseases (Figure 1). For example, Imatinib (also

• , path b). Although there have been major advancements made in the field of direct sp3 C–H bond activation and functionalization adjacent to nitrogen in saturated N-heterocycles and acyclic amines [25][26][27], C–H functionalization of piperazines has been a daunting challenge. In comparison to the well

Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

• Katherine M. Byrd

Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60

• been discussed. Gandelman and Jacobsen reported the first asymmetric 1,4-addition of various N-heterocycles to α,β-unsaturated imides [246]. This reaction represented a novel approach to synthesizing functionalized chiral N-heterocycles, which are studied in areas such as material science [247][248

• studies as the basis for the development of the 1,4-addition of N-heterocycles to α,β-unsaturated imides. They applied both substituted and unsubstituted purines, benzotriazole, and 5-substituted tetrazoles as nucleophiles to this reaction, which resulted in moderate to excellent yields and excellent

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

• yields (up to 95%, Scheme 4). McBurney et al. prepared various N-heterocycles, using oxime carbonates as excellent precursors for the photoinduced generation of iminyl radicals, whereby at standard photolysis conditions, 3-substituted 6-methylphenanthridines were obtained in good to quantitative yields

Preparation of neuroprotective condensed 1,4-benzoxazepines by regio- and diastereoselective domino Knoevenagel–[1,5]-hydride shift cyclization reaction

• László Tóth,
• Yan Fu,
• Hai Yan Zhang,
• Attila Mándi,
• Katalin E. Kövér,
• Tünde-Zita Illyés,
• Attila Kiss-Szikszai,
• Balázs Balogh,
• Tibor Kurtán,
• Sándor Antus and
• Péter Mátyus

Beilstein J. Org. Chem. 2014, 10, 2594–2602, doi:10.3762/bjoc.10.272

• Chemistry, University of Debrecen, H-4010 Debrecen, Hungary Porfirin Ltd., Mikszáth K. u. 7. III/3, 4032 Debrecen, Hungary 10.3762/bjoc.10.272 Abstract Condensed O,N-heterocycles containing tetrahydro-1,4-benzoxazepine and tetrahydroquinoline moieties were prepared by a regio- and diastereoselective domino

• preparation of condensed O,N-heterocycles with the 1,2,8,9-tetrahydro-7bH-quinolino[1,2-d][1,4]benzoxazepine skeleton, the neuroprotective activities of which were tested against hydrogen peroxide (H2O2), Alzheimer's amyloid β-peptide fragment Aβ25–35 and oxygen–glucose deprivation (OGD)-induced neurotoxicity

• derivative afforded three condensed O,N-heterocycles containing tetrahydro-1,4-benzoxazepine and tetrahydroquinoline moieties. trans-Diastereoselectivity of the cyclizations was determined by the correlation of 3JH,H coupling constants with the geometry of the computed conformers, while (2R,15aR) absolute

Facile synthesis of 1H-imidazo[1,2-b]pyrazoles via a sequential one-pot synthetic approach

• András Demjén,
• Márió Gyuris,
• János Wölfling,
• László G. Puskás and
• Iván Kanizsai

Beilstein J. Org. Chem. 2014, 10, 2338–2344, doi:10.3762/bjoc.10.243

• -imidazo[1,2-b]pyrazole; isocyanide; multicomponent reaction; N-heterocycles; Introduction For the relatively rapid design and construction of a diverse, large pharmacophore library, the basic concepts of diversity-oriented synthesis and isocyanide-based multicomponent reactions, such as the Ugi four

• diversity arising from the pyrazole starting material. As far as we are aware, a one-pot two-step process involving the in situ formation of the desired amino-substituted N-heterocycles such as C4 functionalized 5-aminopyrazoles, followed by GBB-3CR has not been described to date. On the other hand, 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

• in recent years [67][68][69]. Especially one of these protocols drew our attention: The group of C. Bolm reported a facile, iron-catalyzed protocol for N-arylation of various N-heterocycles including one example on indole (phenylation in 60% yield), employing aryliodides, N,N'-dimethylethylenediamine

Copper–phenanthroline catalysts for regioselective synthesis of pyrrolo[3′,4′:3,4]pyrrolo[1,2-a]furoquinolines/phenanthrolines and of pyrrolo[1,2-a]phenanthrolines under mild conditions

• Rupankar Paira,
• Tarique Anwar,
• Maitreyee Banerjee,
• Yogesh P. Bharitkar,
• Shyamal Mondal,
• Sandip Kundu,
• Abhijit Hazra,
• Prakas R. Maulik and
• Nirup B. Mondal

Beilstein J. Org. Chem. 2014, 10, 692–700, doi:10.3762/bjoc.10.62

• the above catalytic system. To the best of our knowledge, this is the first report of the application of this catalyst for the regioselective 1,3-dipolar cycloaddition reaction, involving azomethine ylides derived from structurally complex quinoline-based N-heterocycles. Results and Discussion Our

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

• new key intermediates encompass the structural motif C=N+–N−, a very useful framework for further functionalizations. Wu and co-workers widely used preformed N’-(2-alkynylbenzylidene)hydrazides 42 in two component reactions involving 43 as an intermediate for the construction of N-heterocycles

The Flögel-three-component reaction with dicarboxylic acids – an approach to bis(β-alkoxy-β-ketoenamides) for the synthesis of complex pyridine and pyrimidine derivatives

• Mrinal K. Bera,
• Moisés Domínguez,
• Paul Hommes and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 394–404, doi:10.3762/bjoc.10.37

• powerful tools for the assembly of small-molecule libraries [1][2]. MCRs leading to functionalized N-heterocycles [3][4][5][6][7] have long been known before the general concept of MCRs was introduced, e.g. the Hantzsch dihydropyridine synthesis [8] or the Biginelli reaction [9] leading to

Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• Xiang-Guo Hu Luke Hunter School of Chemistry, The University of New South Wales, Sydney NSW 2052, Australia 10.3762/bjoc.9.306 Abstract The stereoselective incorporation of fluorine atoms into N-heterocycles can lead to dramatic changes in the molecules’ physical and chemical properties. These

• changes can be rationally exploited for the benefit of diverse fields such as medicinal chemistry and organocatalysis. This brief review will examine some of the effects that fluorine substitution can have in N-heterocycles, including changes to the molecules’ stability, their conformational behaviour

• , their hydrogen bonding ability, and their basicity. Finally, some methods for the synthesis of stereoselectively fluorinated N-heterocycles will also be reviewed. Keywords: conformation; fluorine; N-heterocycles; iminosugars; medicinal chemistry; organo-fluorine; Review 1. Introduction A cursory

[3 + 2]-Cycloadditions of nitrile ylides after photoactivation of vinyl azides under flow conditions

• Stephan Cludius-Brandt,
• Lukas Kupracz and
• Andreas Kirschning

Beilstein J. Org. Chem. 2013, 9, 1745–1750, doi:10.3762/bjoc.9.201

• to perform many transformations that are hardly possible under thermal conditions. This includes photocatalytic reactions that have seen an immense interest lately [1]. Nitrile ylides 3 are 1,3-dipoles that have served for the preparation of different five-membered N-heterocycles in 1,3-dipolar

• further generalization of this flow protocol along with telescoping it with vinyl azide formation. Formation of azirines 2 from vinyl azides 1, photoinduced ring-opening to the nitrile ylides 3, and 1,3-dipolar cycloaddition to the pentacyclic N-heterocycles 5. Solid-phase assisted synthesis of vinyl

Establishing the concept of aza-[3 + 3] annulations using enones as a key expansion of this unified strategy in alkaloid synthesis

• Aleksey I. Gerasyuto,
• Zhi-Xiong Ma,
• Grant S. Buchanan and
• Richard P. Hsung

Beilstein J. Org. Chem. 2013, 9, 1170–1178, doi:10.3762/bjoc.9.131

• synthesis; catalysis; enones; intramolecular aza-[3 + 3] annulation; N-heterocycles; natural product; vinylogous amides; Introduction Throughout the past decade, we have been developing an aza-[3 + 3] annulation reaction as a general and unified strategy in alkaloid synthesis [1][2][3][4][5][6][7][8][9][10

Interplay of ortho- with spiro-cyclisation during iminyl radical closures onto arenes and heteroarenes

• Roy T. McBurney and
• John C. Walton

Beilstein J. Org. Chem. 2013, 9, 1083–1092, doi:10.3762/bjoc.9.120

• (R)=N• closures are well documented. Forrester and co-workers were probably the first to utilise iminyl radicals synthetically. They obtained iminyls by persulfate oxidation of imino-oxyacetic acids in aqueous solvents and prepared azines [6], N-heterocycles [7][8], and other derivatives [9]. This

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

• [26]. In 2012, our laboratory [28] as well as that of Daugulis [27] independently reported that picolinamide substrates can undergo intramolecular dehydrogenative C–H amination reactions to afford medium-sized N-heterocycles under the catalysis of Pd(OAc)2 with PhI(OAc)2 oxidant. These discoveries led

New simple synthesis of ring-fused 4-alkyl-4H-3,1-benzothiazine-2-thiones: Direct formation from carbon disulfide and (E)-3-(2-aminoaryl)acrylates or (E)-3-(2-aminoaryl)acrylonitriles

• Qiuping Ding,
• Yuqing Lin,
• Guangni Ding,
• Fumin Liao,
• Xiaoyan Sang and
• Yi-Yuan Peng

Beilstein J. Org. Chem. 2013, 9, 460–466, doi:10.3762/bjoc.9.49

• (Scheme 1) [9]. Promoted by these results, we envisioned that (E)-3-(2-aminoaryl)acrylates or (E)-3-(2-aminoaryl)acrylonitriles could also be utilized as starting substrates for the synthesis of N-heterocycles. Therefore, we focused on the o-amino-α,β-unsaturated compound 1 (Scheme 2), which would be