¹⁵N-Labelling and structure determination of adamantylated azolo-azines in solution

• Sergey L. Deev,
• Alexander S. Paramonov,
• Tatyana S. Shestakova,
• Igor A. Khalymbadzha,
• Oleg N. Chupakhin,
• Julia O. Subbotina,
• Oleg S. Eltsov,
• Pavel A. Slepukhin,
• Vladimir L. Rusinov,
• Alexander S. Arseniev and
• Zakhar O. Shenkarev

Beilstein J. Org. Chem. 2017, 13, 2535–2548, doi:10.3762/bjoc.13.250

• compound 21a-15N2 (Δδ +54.2 ppm). According to the data reported for tetrazolo[1,5-a]pyridines [43], the shielding of the N2 nucleus in compound 15b-15N2 can be explained by the adamantylation of the neighbouring N1 atom in the tetrazole fragment. In contrast, the coupling of the adamantyl fragment to the

Synthesis, effect of substituents on the regiochemistry and equilibrium studies of tetrazolo[1,5-a]pyrimidine/2-azidopyrimidines

• Elisandra Scapin,
• Paulo R. S. Salbego,
• Caroline R. Bender,
• Alexandre R. Meyer,
• Anderson B. Pagliari,
• Tainára Orlando,
• Geórgia C. Zimmer,
• Clarissa P. Frizzo,
• Helio G. Bonacorso,
• Nilo Zanatta and
• Marcos A. P. Martins

Beilstein J. Org. Chem. 2017, 13, 2396–2407, doi:10.3762/bjoc.13.237

• tendency while studying a series of substituents at the 5-position of tetrazolo[1,5-a]pyridines using ab initio calculations. Their findings indicated that electron-withdrawing groups stabilize the azide isomer while electron-donating groups stabilize the tetrazole ring. Additionally, it was observed that

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

• formation inhibitors, GABA and benzodiazepine receptor agonists, and cardiotonic agents [7][8][9][10]. Further, the biological activities of imidazo[1,2-a]pyridines proved to be strongly depending upon the nature of substituents at C2 and C3 positions. For instance, the 3-aroylimidazo[1,2-a]pyridines 1c

• [24]. Herein, we report the synthesis of imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrimidines, and imidazopyridazines with fluorinated side chains following an efficient strategy developed by Hajra et al. [25]. This methodology, developed for the synthesis of 3-aroylimidazopyridines, involves a copper

• was purified by column chromatography on silica gel, using petroleum ether/ethyl acetate as eluent. Imidazopyridine 7a was isolated in 33% yield. Representative examples of bioactive imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrimidines, imidazopyridazines and our target molecules. Structures of 7a and

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

• structures that can be further transformed into interesting potential biologically active heterocyclic derivatives such as terpenoid pyranes, lactones, (hydro)chromenes or pyridines, among others [23][24][25][26]. Depending on the connection of the two isoprene units, four different kinds of dimers can be

Mechanochemical N-alkylation of imides

• Anamarija Briš,
• Mateja Đud and
• Davor Margetić

Beilstein J. Org. Chem. 2017, 13, 1745–1752, doi:10.3762/bjoc.13.169

• of imides with alkyl halogenides, and the results are presented in this paper. Until now, ball milling N-alkylations of ureas [15], hydrazones [16], imines [17][18], pyridines [19], pyrimidines [20], imidazoles [21], secondary amines [22], as well as allylic alkylation reactions [23] were reported in

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

• benzothiazolines 64 to substituted pyridines 65 and benzothiazoles 66, respectively, in moderate to excellent yields (Scheme 18) [82]. The reaction was performed in methanol at ambient temperature. The optimized procedure also generated 65 and 66 from a one-pot reaction of various dicarbonyls, formaldehyde

• oxidation. One of the early examples of such reaction was demonstrated by Han et al. in 2006 [84]. Here in pyridines 71 and pyrazoles 72 were synthesized in excellent yield by the oxidation of 4-substituted Hantzsch 1,4-dihydropyridines 69 and 1,3,5-trisubstituted pyrazolines 70 via molecular oxygen. The

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

• drug candidates. For example, Guetzoyan et al. have demonstrated the use of automation for synthesizing imidazo[1,2-a]pyridines, potential GABAA agonists [12]. II) Optimization: For a set synthesis protocol usually an optimization of conditions to maximize the yield of the desired product brings the

A practical and efficient approach to imidazo[1,2-a]pyridine-fused isoquinolines through the post-GBB transformation strategy

• Taofeng Shao,
• Zhiming Gong,
• Tianyi Su,
• Wei Hao and
• Chao Che

Beilstein J. Org. Chem. 2017, 13, 817–824, doi:10.3762/bjoc.13.82

• conditions and a broad substrate scope, allowing for the rapid construction of structurally complex and diverse heterocycles in moderate to good yields. Keywords: Groebke–Blackburn–Bienaymé reaction; imidazo[1,2-a]pyridines; isoquinolines; multicomponent reaction; Ugi reaction; Introduction Imidazo[1,2-a

• ]pyridines have been reported to display a wide range of biological activities [1][2][3][4][5], and these skeletons are found in various clinical drugs such as zolpidem (I), alpidem (II), and olprinone (III), which were approved for the treatment of insomnia, anxiety and acute heart failure, respectively

New approach toward the synthesis of deuterated pyrazolo[1,5-a]pyridines and 1,2,4-triazolo[1,5-a]pyridines

• Aleksey Yu. Vorob’ev,
• Vyacheslav I. Supranovich,
• Gennady I. Borodkin and
• Vyacheslav G. Shubin

Beilstein J. Org. Chem. 2017, 13, 800–805, doi:10.3762/bjoc.13.80

• treating asthma and post-stroke patients [16]. 1,2,4-Triazolo[1,5-a]pyridines show antifungal [17], antitumor [18], and cytotoxic [19] activities. Both types of heterocyclic cores are readily available from N-aminopyridium salts and related pyridinium-N-imines via 1,3-cycloaddition reaction [20] or

• intramolecular ring closure [21][22][23][24]. The importance of these cores for medical chemistry studies suggests that isotopically labeled pyrazolo[1,5-a]pyridines and triazolo[1,5-a]pyridines could be of interest. Recently, deuterium-labeled pyridinium-N-imines were applied to mechanistic studies of the

• conversion to pyrazolo[1,5-a]pyridines [25][26]. Such labeled N-imines were obtained starting from commercially available pyridine-d5. Since substituted deuterated pyridines are less accessible new mild and simple methods of deuterium introduction into the pyridine ring are of great interest. The N

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

• -substituted pyridines. The regioselective lithiation of halopyridines with lithium diisopropylamide (LDA) was conducted under mild conditions on substrate 6 (Scheme 10). The addition of a little amount of THF was necessary in order to avoid clogging and the tendency of the lithiated intermediate to eliminate

• products. Experimental setup for the flow synthesis of 2-fluorobi(hetero)aryls by directed lithiation, zincation, and Negishi cross-coupling. (Adapted with permission from [53], copyright 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim). Experimental setup for the coupling of fluoro-substituted pyridines

New approaches to organocatalysis based on C–H and C–X bonding for electrophilic substrate activation

• Pavel Nagorny and
• Zhankui Sun

Beilstein J. Org. Chem. 2016, 12, 2834–2848, doi:10.3762/bjoc.12.283

• the titration of L4 with TBAC [37]. Catalysts L3 and L4 were successfully applied to the asymmetric dearomatization of electron-deficient N-heteroarenes (Scheme 3). Various nitrogen-containing heterocycles such as pyridines [36], quinolines [38], isoquinolines [38], etc. were reacted with TrocCl to

• [50][51]. In 2013 Bibal and co-workers investigated the use of methylated amines, pyridines and guanidines (L11) as hydrogen bond-donor catalysts for the activation of cyclic esters toward ring-opening polymerization (ROP) [53]. Ionic catalysts L11 (5 mol %) were successfully employed in combination

Sydnone C-4 heteroarylation with an indolizine ring via Chichibabin indolizine synthesis

• Florin Albota,
• Mino R. Caira,
• Constantin Draghici,
• Florea Dumitrascu and
• Denisa E. Dumitrescu

Beilstein J. Org. Chem. 2016, 12, 2503–2510, doi:10.3762/bjoc.12.245

• syntheses of indolizines [28][29][30][31] owing to the simple working procedure and the large number of 2-substituted pyridines that are commercially available. An overview of Chichibabin indolizine syntheses has been included in the reviews dedicated to indolizine syntheses and their applications in

• heating pyridines 6a–d with 4-(bromoacetyl)-3-phenylsydnone (7, Scheme 1) in refluxing acetone [5]. The obtained pyridinium salts 8 were used in the next step without further purification. The structures of the pyridinium bromides 8a–d were assigned by 1H NMR, 13C NMR and IR spectroscopy. The chemical

• for indolizine synthesis, the “indolizination” at the C-4 position of sydnones was achieved using a procedure involving quaternization of pyridines 6 with sydnone derivative 7 to form pyridinium bromides 8, followed by their intramolecular cyclization in the presence of a base. In order to improve the

Protonated paramagnetic redox forms of di-o-quinone bridged with p-phenylene-extended TTF: A EPR spectroscopy study

• Nikolay O. Chalkov,
• Vladimir K. Cherkasov,
• Gleb A. Abakumov,
• Andrey G. Starikov and
• Viacheslav A. Kuropatov

Beilstein J. Org. Chem. 2016, 12, 2450–2456, doi:10.3762/bjoc.12.238

• dissolves in solutions of o-quinones [9][10][11]. This process is greatly accelerated by the presence of auxiliary ligands, such as phosphines or pyridines. But the oxidation of copper metal with a reduced protonated quinone, which is (1)H2 in fact, was observed for the first time. This process leads to the

A new paradigm for designing ring construction strategies for green organic synthesis: implications for the discovery of multicomponent reactions to build molecules containing a single ring

• John Andraos

Beilstein J. Org. Chem. 2016, 12, 2420–2442, doi:10.3762/bjoc.12.236

• ], [3 + 2 + 1], and [2 + 2 + 2] partitions given the symmetry elements of the pyridine ring depending on its substitution pattern. Hence, for 2- or 3-substituted pyridines we have six [4 + 1 + 1], twelve [3 + 2 + 1], and two [2 + 2 + 2] target bond dissection maps; whereas, for 4-substituted pyridines

Synthesis and properties of fluorescent 4′-azulenyl-functionalized 2,2′:6′,2″-terpyridines

• Adrian E. Ion,
• Liliana Cristian,
• Mariana Voicescu,
• Masroor Bangesh,
• Augustin M. Madalan,
• Daniela Bala,
• Constantin Mihailciuc and
• Simona Nica

Beilstein J. Org. Chem. 2016, 12, 1812–1825, doi:10.3762/bjoc.12.171

• interannular C–C bonds as previously described for similar terpyridine compounds [8][27][29]. The interannular C–C bonds are 1.484(5) and 1.487(5) Å in 4a, respectively and 1.490(5) and 1.491(5) Å in 4b. The pyridine rings are not coplanar, the torsion angles between the two terminal pyridines and the central

Rearrangements of organic peroxides and related processes

• Ivan A. Yaremenko,
• Vera A. Vil’,
• Dmitry V. Demchuk and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2016, 12, 1647–1748, doi:10.3762/bjoc.12.162

A T-shape diphosphinoborane palladium(0) complex

• Patrick Steinhoff and
• Michael E. Tauchert

Beilstein J. Org. Chem. 2016, 12, 1573–1576, doi:10.3762/bjoc.12.152

• complexes only few examples featuring a η1-type Pd→B interaction have been reported [6][7]. However, these complexes require phosphines or pyridines as a stabilizing co-ligand, which can act as an inhibitor in catalytic transformations [7]. Similarly, monometallic 14 VE palladium complexes featuring a

One-pot synthesis of tetracyclic fused imidazo[1,2-a]pyridines via a three-component reaction

• Bo Yang,
• Chuanye Tao,
• Taofeng Shao,
• Jianxian Gong and
• Chao Che

Beilstein J. Org. Chem. 2016, 12, 1487–1492, doi:10.3762/bjoc.12.145

• -component reaction has been developed to assemble biologically and pharmaceutically important tetracyclic fused imidazo[1,2-a]pyridines in a one-pot fashion utilizing readily available 2-aminopyridines, isatins and isocyanides. The three-component coupling proceeds through the Groebke–Blackburn–Bienaymé

• reaction followed by a retro-aza-ene reaction and subsequent nucleophilic reaction of the in-situ generated imidazo[1,2-a]pyridines bearing an isocyanate functional group. Keywords: Groebke–Blackburn–Bienaymé reaction; imidazo[1,2-a]pyridines; multi-component reaction; one-pot reaction; Introduction

• development of new GBB-based methods for the efficient synthesis of novel polycyclic fused imidazo[1,2-a]pyridines is highly desirable. In an earlier study, we have developed a GBB/lactamization MCR strategy, which provided the rapid access to isoquinolinone-fused imidazo[1,2-a]pyridines with potent and

Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

• Mohammad Haji

Beilstein J. Org. Chem. 2016, 12, 1269–1301, doi:10.3762/bjoc.12.121

• compound 244 which can be hydrolyzed to give quinoline-2-carboxylic acid (245) (Scheme 50) [87]. This reaction can also be applied to isoquinolines and some pyridines. Additionally, a wide range of activating groups such as chloroformates, acetylenic esters, R3SiOTf, Tf2O and various nucleophiles can be

• . Multicomponent reaction of alkanedials, acetamide and acetyl chloride in the presence of PCl3 and acetic acid. An oxidative domino three-component synthesis of polyfunctionalized pyridines. A sequential one-pot three-component synthesis of polysubstituted pyrroles. Three-component decarboxylative coupling of

A convenient route to symmetrically and unsymmetrically substituted 3,5-diaryl-2,4,6-trimethylpyridines via Suzuki–Miyaura cross-coupling reaction

• Dariusz Błachut,
• Joanna Szawkało and
• Zbigniew Czarnocki

Beilstein J. Org. Chem. 2016, 12, 835–845, doi:10.3762/bjoc.12.82

• halogenated pyridines and pyrimidines. During our search for new "route markers" of amphetamine analogues synthesized by the Leuckart method, we focused our attention on two groups of heterocycles, that were preliminary identified by GC–MS analysis as 3,4,5-triaryl-2,6-dimethylpyridines P5 [32][33] and 3,5

• teams in the construction of polyarylated benzenes [56], pyridines [57][58][59][60], thiophenes [61][62], quinoxalines [63], pyrazoles [64] pyrroles [65], pyrimidines [66][67], benzofuranes [68], imidazo[1,2-a]pyridines [69], diaryl/heteroaryl methanes [70], and indoles [71], bearing differently

• crude products revealed in most cases the presence of three major products: symmetrical triaryls P6 (4–29) along with the desired pyridines P7 (46–66) with two different aryl rings. The results were collected in Table 2. Trial reactions with mixtures of phenylboronic acids 32 with para-substituted

Creating molecular macrocycles for anion recognition

• Amar H. Flood

Beilstein J. Org. Chem. 2016, 12, 611–627, doi:10.3762/bjoc.12.60

• there must be some latent functionality deriving from the intrinsic structure of the triazole that remained unexplored. It was clear later that Stefan Hecht and Steve Craig had similar thoughts. Invoking Hoffmann’s dictum [9], I originally wondered if the triazoles were the same as pyridines for the

• bound metals, for example, Fe(II), Ru(II) and Eu(III) [11]. It was at this point that I lifted my head and asked the next critical questions: how are triazoles not the same as pyridines and what does the coordination chemistry teach us about how these 1,2,3-triazoles like to behave? All our observations

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

• reactive alkyl-substituted pyridines. Gao showed that NH4I can also be used as an organocatalyst in combination with AcOH to facilitate the oxidation of benzylpyridines to benzoylpyridines [29]. Satoh and Miura showed that when replacing O2 for Na2S2O8 chemoselective methylenation occurred over oxygenation

• basic and protonation by the acid thus becomes more difficult, using more equivalents of the acid or a stronger acid is needed to reach full conversion. When we compare the different pKa values of substituted pyridines we see that 2-benzylpyridine (16, pKa ≈ 5.2) is one of the most basic pyridines [34

A convergent, umpoled synthesis of 2-(1-amidoalkyl)pyridines

• Tarn C. Johnson and
• Stephen P. Marsden

Beilstein J. Org. Chem. 2016, 12, 1–4, doi:10.3762/bjoc.12.1

• Tarn C. Johnson Stephen P. Marsden Institute of Process Research and Development, School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK 10.3762/bjoc.12.1 Abstract A convenient, one-pot, two-component synthesis of 2-(1-amidoalkyl)pyridines is reported, based upon the

• of bioactive structures. Keywords: azlactones; pyridines; pyridine N-oxides; substitution; Introduction Pyridines constitute the most frequently observed class of heterocycles found in pharmaceutical products [1]. As such, there is significant demand for synthetic methods that enable access both to

• structurally novel and diverse substituted pyridines for new medicines discovery, and for the development of clean, efficient and robust methods for their manufacture on large scale. Pyridines bearing a 1-amidoalkyl substituent at the 2-position are found in numerous biologically active natural products such

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

• -catalyzed reactions, phosphines, N-heterocyclic carbenes, pyridines and salen ligands have been applied as ligands for controlling the stability of catalysts, and chemo-, regio- and enantioselectivities of the reactions [31][32][33][34][35][36]. Recent advances in the gold-catalyzed reactions are

Enantioselective additions of copper acetylides to cyclic iminium and oxocarbenium ions

• Jixin Liu,
• Srimoyee Dasgupta and
• Mary P. Watson

Beilstein J. Org. Chem. 2015, 11, 2696–2706, doi:10.3762/bjoc.11.290

• with pyridines. In 2011, Maruoka and co-workers investigated the use of isoquinolinium ions protected as azomethine imines [30]. The use of a CuOAc/Ph-Pybox catalyst enables the addition of a wide variety of alkynes to form isoquinolines with tertiary stereocenters in high yields and ee’s (Scheme 8A