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

• target bond 3-partition dissection maps for 27 commonly found heterocyclic rings is given in the Supporting Information File 1 (see Schemes S6 to S32). These include benzimidazole, 2,3-dihydro-1H-benzo[b][1,4]diazepine, benzofuran, benzopyran, chromen-4-one, coumarin, cyclopent-2-enone, furan, Hantzsch

• benzimidazole, the 3-partitions that do not include the fused junction bond in the set of target synthesis bonds are the ones that have greatest potential for exploration. Essentially choosing starting materials that already contain the aromatic moieties will lead to more efficient and green syntheses. These

Selective and eco-friendly procedures for the synthesis of benzimidazole derivatives. The role of the Er(OTf)₃ catalyst in the reaction selectivity

• Natividad Herrera Cano,
• Jorge G. Uranga,
• Mónica Nardi,
• Antonio Procopio,
• Daniel A. Wunderlin and
• Ana N. Santiago

Beilstein J. Org. Chem. 2016, 12, 2410–2419, doi:10.3762/bjoc.12.235

• Universitaria, Córdoba, 5000 Argentina 10.3762/bjoc.12.235 Abstract An improved and greener protocol for the synthesis of benzimidazole derivatives, starting from o-phenylenediamine, with different aldehydes is reported. Double-condensation products were selectively obtained when Er(OTf)3 was used as the

• ) trifluoromethanesulfonate; green procedure; heterocycle; Introduction The formation of heterocyclic compounds is a very important task in organic synthesis, mainly because they are present in numerous biologically active compounds and in several natural products [1]. Among them the presence of benzimidazole [2][3][4][5][6

• ][12]. One frequently used protocol for the synthesis of benzimidazole derivatives is the coupling of o-phenylenediamines with carboxylic acids [13][14]. Another widely used procedure for the same synthesis represents the condensation of o-phenylenediamine with aldehydes. The latter approach has become

Bi- and trinuclear copper(I) complexes of 1,2,3-triazole-tethered NHC ligands: synthesis, structure, and catalytic properties

• Shaojin Gu,
• Jiehao Du,
• Jingjing Huang,
• Huan Xia,
• Ling Yang,
• Weilin Xu and
• Chunxin Lu

Beilstein J. Org. Chem. 2016, 12, 863–873, doi:10.3762/bjoc.12.85

• powder (64 mg, 1.0 mmol) at 50 oC for 10 h. Yield: 66 mg (57%), red crystals. 1H NMR (600 MHz, acetonitrile-d3) δ 8.75 (d, J = 8.1 Hz, 2H, benzimidazole), 8.70 (d, J = 4.9 Hz, 4H, pyrimidine), 7.88 (s, 2H, triazole), 7.79 (d, J = 7.8 Hz, 2H, benzimidazole), 7.59–7.54 (m, 2H, benzimidazole), 7.52 (t, J

• = 7.2 Hz, 2H, benzimidazole), 7.36 (t, J = 4.9 Hz, 2H, pyrimidine), 7.31–7.29 (m, 6H, phenyl), 7.19–7.18 (m, 4H, phenyl), 5.61 (s, 4H, -CH2-), 5.38 (s, 4H, -CH2-); 13C NMR (151 MHz, acetonitrile-d3) δ 191.23 (Cu-C), 158.73, 157.33 142.39, 136.17 135.75, 132.61, 129.94, 129.67, 129.17, 126.34, 126.19

• , 1H, 4-py), 8.33 (s, 1H, triazole), 8.23–8.20 (m, 1H), 7.90 (dd, J = 5.1, 1.5 Hz, 1H, benzimidazole), 7.84–7.81 (m, 1H, benzimidazole), 7.68–7.60 (m, 2H, benzimidazole), 7.44 (dd, J = 7.6, 5.0 Hz, 1H, 5-py), 7.33–7.31 (m, 3H, phenyl), 6.94–6.92 (m, 2H, phenyl), 5.84 (d, J = 15.8 Hz, 1H), 5.37 (d, J

N-Methylphthalimide-substituted benzimidazolium salts and PEPPSI Pd–NHC complexes: synthesis, characterization and catalytic activity in carbon–carbon bond-forming reactions

• Senem Akkoç,
• Yetkin Gök,
• İlhan Özer İlhan and
• Veysel Kayser

Beilstein J. Org. Chem. 2016, 12, 81–88, doi:10.3762/bjoc.12.9

• benzimidazolium salts include an acidic NCHN proton, which can be deprotonated easily to form an NHC, at the C2 position of the benzimidazole ring. The sharp salt peak indicating the synthesis of a benzimidazolium salt came quite downfield at δ 10.13, 11.10, 9.65 and 10.83 ppm in the 1H NMR spectra for 1–4

• 1444.6 cm−1 for the PEPPSI Pd–NHC complexes 5–8, respectively. The formation of a C–N module in the benzimidazole ring correlated with a shift of IR (CN) band. The complexes 6–8 were further characterized by means of HRMS which showed m/z peaks at 637.02, 691.99 and 574.99 for the cationic moieties

Recent advances in metathesis-derived polymers containing transition metals in the side chain

• Ileana Dragutan,
• Valerian Dragutan,
• Bogdan C. Simionescu,
• Albert Demonceau and
• Helmut Fischer

Beilstein J. Org. Chem. 2015, 11, 2747–2762, doi:10.3762/bjoc.11.296

• allowed the intramolecular cycloisomerization of enynes with high yields and turnover numbers. Copper-containing polymers A copper(I) complex containing a norbornene substituted with the 2-(pyridin-2-yl)-1H-benzimidazole ligand, 44, developed by Il'icheva et al. [64], came to the attention of the

Recent advances in copper-catalyzed C–H bond amidation

• Jie-Ping Wan and
• Yanfeng Jing

Beilstein J. Org. Chem. 2015, 11, 2209–2222, doi:10.3762/bjoc.11.240

• were disclosed by Wang et al. [80]. The synthesis using 92 and benzimidazoles 87 provided benzimidazole-fused cyclic sulfonamides 93. The reaction allowed the synthesis of various products with fair to high yields with the assistance of L-proline as ligand. The expected conversion took place also in

Molecular-oxygen-promoted Cu-catalyzed oxidative direct amidation of nonactivated carboxylic acids with azoles

• Wen Ding,
• Shaoyu Mai and
• Qiuling Song

Beilstein J. Org. Chem. 2015, 11, 2158–2165, doi:10.3762/bjoc.11.233

• ), inexpensive and readily available pyridine was employed as both the ligand and base in our case. Results and Discussion Our initial exploration commenced with benzoic acid (1) and benzimidazole (2) as the model substrates to investigate the copper-catalyzed oxidative direct amidation reaction (Table 1). The

• reaction cannot go to completion and part of the carboxylic acid remains when the amount of benzimidazole is not twice that of the carboxylic acid. The temperature affected this reaction dramatically and when the temperature was decreased to 120 °C, the yield of the desired product 3 was reduced to 31% of

• cyclohexanecarboxylic acid, hexanoic acid and acetic acid were all proven to be good substrates in this transformation and the desired products 24, 25 and 26 were obtained in reasonable yields. Moreover, bis-substituted benzimidazole also worked very well under the standard conditions to give the desired product 27 in

Synthesis and structures of ruthenium–NHC complexes and their catalysis in hydrogen transfer reaction

• Chao Chen,
• Chunxin Lu,
• Qing Zheng,
• Shengliang Ni,
• Min Zhang and
• Wanzhi Chen

Beilstein J. Org. Chem. 2015, 11, 1786–1795, doi:10.3762/bjoc.11.194

• formation of 3 was also confirmed by the 1H NMR and 13C NMR spectra. The 1H NMR spectrum of 3 shows characteristic resonance signals due to the pyridyl, methylene, benzimidazolylidene and acetonitrile groups. The absence of a benzimidazole acidic C2-H proton illustrates the formation of the Ru–C bond. The

A facile synthetic route to benzimidazolium salts bearing bulky aromatic N-substituents

• Gabriele Grieco,
• Olivier Blacque and
• Heinz Berke

Beilstein J. Org. Chem. 2015, 11, 1656–1666, doi:10.3762/bjoc.11.182

• and 4-Cl the synthetic procedures proceed without noticeable problems, while complications were faced in the synthesis for 1-Cl and 2-Cl, particularly during the benzimidazole ring closures. Excluding the procedure of Borguet [42][43] all the known procedures to accomplish imidazole ring formation [44

Fluoride-driven ‘turn on’ ESPT in the binding with a novel benzimidazole-based sensor

• Kai Liu,
• Xiaojun Zhao,
• Qingxiang Liu,
• Jianzhong Huo,
• Bolin Zhu and
• Shihua Diao

Beilstein J. Org. Chem. 2015, 11, 563–567, doi:10.3762/bjoc.11.61

• )imino)methyl)-5-(dimethylamino)phenol (BIP) made up of benzimidazole and phenol units with a C=N linker. Although BIP is weakly fluorescent, its anion-binding adduct is expected to be highly fluorescent by opening up ESPT channel [2][14][15][19]. In this paper, we demonstrated that BIP displayed

• the phenol and benzimidazole [2][30]. Upon addition of F− (as tetrabutylammonium salts, TBA salts), as shown in Figure 1, the intensity of the band at 410 nm decreased and broadened, and a new shoulder around 466 nm formed, meanwhile, the shoulder peak at 228 nm increased. However, no noticeable

• restricted intermolecular H-bonding ring formed. Subsequent the fluoride-triggered ESPT occurred, which displayed ‘turn-on’ fluorescence. Conclusion In conclusion, a new benzimidazole-based BIP has been developed which is selective for the recognition of F− also in the presence of anions with similar

Sequence-specific RNA cleavage by PNA conjugates of the metal-free artificial ribonuclease tris(2-aminobenzimidazole)

• Friederike Danneberg,
• Alice Ghidini,
• Plamena Dogandzhiyski,
• Elisabeth Kalden,
• Roger Strömberg and
• Michael W. Göbel

Beilstein J. Org. Chem. 2015, 11, 493–498, doi:10.3762/bjoc.11.55

• of toxic mercury(II) oxide for the formation of the benzimidazole moieties (Scheme 1) is a disadvantage of this synthesis especially with regard to future biological applications of the final product. Furthermore, conditions for these reactions are rather harsh and the yields may differ considerably

• thiocarbonyldiimidazole and methyl 3,4-diaminobenzoate (Scheme 2). The cyclisation to form the first benzimidazole unit was then achieved by reacting thiourea 3 with Mukaiyama’s reagent in the presence of NEt3 at rt yielding 88% of 4. Although the yield is slightly lower compared to the cyclisation with HgO (97% yield

• groups with H2. In the last step of the synthesis, again Mukaiyama’s reagent was used for the formation of the two benzimidazole moieties. Stirring at rt for 22 h in the presence of NEt3 yielded 56% of tris(2-aminobenzimidazole) 7 after HPLC purification. Ester hydrolysis with aq HCl led to the free

Photovoltaic-driven organic electrosynthesis and efforts toward more sustainable oxidation reactions

• Bichlien H. Nguyen,
• Robert J. Perkins,
• Jake A. Smith and
• Kevin D. Moeller

Beilstein J. Org. Chem. 2015, 11, 280–287, doi:10.3762/bjoc.11.32

• contents of the flask were extracted with EtOAc, washed with brine, and dried with MgSO4. The product was purified by column chromatography (EtOAc/hexanes 1:1) to give the benzimidazole product. Specific electrolysis procedures for other substrates may be found in the original publications for the

Cross-dehydrogenative coupling for the intermolecular C–O bond formation

• Igor B. Krylov,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2015, 11, 92–146, doi:10.3762/bjoc.11.13

• 6 to form 7) [42], benzoxazole (acetoxylation of 8 to form 9) [43], benzimidazole (alkoxylation of 10 to form 11) [44], and triazole (acyloxylation of 12 to form 13 [45], alkoxylation of 14 to form 15 [46]) moieties were also used as directing groups for the ortho-acyloxylation and alkoxylation of

Sequential decarboxylative azide–alkyne cycloaddition and dehydrogenative coupling reactions: one-pot synthesis of polycyclic fused triazoles

• Kuppusamy Bharathimohan,
• Thanasekaran Ponpandian,
• A. Jafar Ahamed and
• Nattamai Bhuvanesh

Beilstein J. Org. Chem. 2014, 10, 3031–3037, doi:10.3762/bjoc.10.321

• reductive elimination reaction yields the polycyclic triazoles 4. Conclusion In summary, we have successfully developed an efficient and convenient one-pot protocol for the synthesis of novel benzimidazole and imidazole-fused 1,2,3-triazoloquinoxaline derivatives. The key finding of this work is the

A one-pot multistep cyclization yielding thiadiazoloimidazole derivatives

• Debabrata Samanta,
• Anup Rana,
• Jan W. Bats and
• Michael Schmittel

Beilstein J. Org. Chem. 2014, 10, 2989–2996, doi:10.3762/bjoc.10.317

• Main, Germany 10.3762/bjoc.10.317 Abstract A versatile synthetic procedure is described to prepare the benzimidazole-fused 1,2,4-thiadiazoles 2a–c via a methanesulfonyl chloride initiated multistep cyclization involving the intramolecular reaction of an in-situ generated carbodiimide with a thiourea

• ]. Benzimidazole-fused thiadiazoles offer the option to accommodate various substitution patterns that could act as reactivity tuners [9] and recognition sites [10] to enrich the biological scope. Herein, we report on a convenient one-pot synthesis to prepare such 1,2,4-thiadiazoles (with two identical

• substituents) in good yield. Results and Discussion The synthesis of benzimidazole-fused 1,2,4-thiadiazoles 2a–c was accomplished by treating dithiourea derivatives with methanesulfonyl chloride in presence of triethylamine and a catalytic amount of 4-dimethylaminopyridine at 0 °C (Scheme 1). The reaction of

Encapsulation of biocides by cyclodextrins: toward synergistic effects against pathogens

• Véronique Nardello-Rataj and
• Loïc Leclercq

Beilstein J. Org. Chem. 2014, 10, 2603–2622, doi:10.3762/bjoc.10.273

• binding constants are very weak (14.2 and 22.7 M−1 for the α- and β-CDs, respectively). These results suggest that the benzimidazole nucleus can be more easily complexed by β-CD (cavity diameter = 6.0–6.5 Å) than by α-CD (cavity size diameter = 4.7–5.3 Å). With the latter, the authors have suggested that

New highlights of the syntheses of pyrrolo[1,2-a]quinoxalin-4-ones

• Emilian Georgescu,
• Alina Nicolescu,
• Florentina Georgescu,
• Florina Teodorescu,
• Daniela Marinescu,
• Ana-Maria Macsim and
• Calin Deleanu

Beilstein J. Org. Chem. 2014, 10, 2377–2387, doi:10.3762/bjoc.10.248

• . Keywords: 1,3-dipolar cycloadditions; multicomponent; one-pot three-component reactions; pyrrolo[1,2-a]benzimidazole; pyrrolo[1,2-a]quinoxalin-4-one; Introduction The pyrrolo[1,2-a]quinoxaline system has significant biological activities and is a subject fo constant interest. This skeleton is a

• quinoxalines [6] have been recently reviewed. Among other synthetic routes, the 1,3-dipolar cycloaddition of heterocyclic N-ylides with various activated alkynes or alkenes is an important method for constructing fused heterocyclic systems such as pyrrolo[1,2-a]quinoxaline and pyrrolo[1,2-a]benzimidazole [7][8

• -(methoxycarbonylmethyl)benzimidazolium bromides with dimethyl acetylenedicarboxylate (DMAD) in presence of K2CO3 in DMF [7] or in presence of triethylamine in acetonitrile [8] give a mixture of pyrrolo[1,2-a]benzimidazole (2–7%) and a compound whose formation involves the loss of an alcohol molecule for which different

An experimental and theoretical NMR study of NH-benzimidazoles in solution and in the solid state: proton transfer and tautomerism

• Carla I. Nieto,
• Pilar Cabildo,
• M. Ángeles García,
• Rosa M. Claramunt,
• Ibon Alkorta and
• José Elguero

Beilstein J. Org. Chem. 2014, 10, 1620–1629, doi:10.3762/bjoc.10.168

• C5/C6) of NH-benzimidazoles that, in some solvents and in the solid state, appear different (blocked tautomerism). In the case of 1H-benzimidazole itself we have measured the prototropic rate in HMPA-d18. Keywords: CPMAS; DNMR; GIAO; proton transfer; tautomerism; Introduction Of almost any class of

• relevant drugs (fungicides, anthelmintics, antiulcerative, antiviral,…) [2][3] are also part of some natural products (the most prominent benzimidazole compound in nature is N-ribosyl-5,6-dimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12) and have interesting ferroelectric

• properties [4]. Particularly relevant for the present work is their proton conducting abilities, based of the 1,3-N–H···N hydrogen bonds, not only in benzimidazole polymers but in molecular compounds [5][6]. Degenerated tautomerism (autotrope) [7][8] simultaneously simplifies and complicates the NMR spectra

Microwave-assisted Cu(I)-catalyzed, three-component synthesis of 2-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1H-benzo[d]imidazoles

• Yogesh Kumar,
• Vijay Bahadur,
• Anil K. Singh,
• Virinder S. Parmar,
• Erik V. Van der Eycken and
• Brajendra K. Singh

Beilstein J. Org. Chem. 2014, 10, 1413–1420, doi:10.3762/bjoc.10.145

• : benzimidazole; Cu(I) catalysis; microwave-assisted synthesis; multicomponent; three component synthesis; Introduction Due to their structural range and biological importance nitrogen-containing heterocycles have been striking targets for many years. They are found in a variety of natural products and are

• several existing drugs. Various medicinal agents are composed of several heterocyclic rings in which the benzimidazole and the 1,2,3-triazole constitute an important position. Benzimidazole derivatives have been shown to posses anticancer [1][2], antihypertensive [3], antibacterial [4] and enzyme

• were used. In general, good to excellent yields were obtained for the desired cyclized products. Plausible mechanism The desired product could be obtained by the two mechanistic pathways A and B as described in Scheme 2. The CuAAC could take place prior to or after benzimidazole formation and we do not

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

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

• ascorbate (45 mM) and copper(II) sulfate (0.1 mM) at room temperature [80]. Generally, all tris(2-benzimidazolylmethyl)amine ligands greatly accelerate this CuAAC reaction, but the rate is dependent on the nature of the heterocycle as well as on its substitution. As long as at least one benzimidazole ring

• is present in the ligand, the others can be replaced by benzothiazole rings. The rate of reaction in the CuAAC test reaction increases in the order (Bth)3 << (Bth)(BimH)2 < (BimH)3 << (Bth)2(BimH) [80][83]. With carboxylic acid or ester groups attached to the benzimidazole rings via alkyl chains (CH2

• )4 and (CH2)5, the CuAAC test reaction was substantially accelerated [(BimC4A)3, (BimC3A)3, (BimH)(BimC5A)2, (BimC5A)3, (BimC4A/Me2)3, (BimC4E)3]. On the other hand, (BimC1A)3 produced one of the worst performing catalysts as the acid group is directly attached to the benzimidazole by a CH2-linker

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• proton pump inhibitors; numerous examples such as omeprazole (1.29, Losec), rabeprazole (1.33, Aciphex), pantoprazole (1.34, Protonix) and lansoprazole (1.35, Prevacid) populate this area [28]. All these API’s contain the characteristic benzimidazole unit bearing a sulfoxide substituent at the 2-position

Synthesis of axially chiral gold complexes and their applications in asymmetric catalyses

• Yin-wei Sun,
• Qin Xu and
• Min Shi

Beilstein J. Org. Chem. 2013, 9, 2224–2232, doi:10.3762/bjoc.9.261

• quantitative yield upon treating the benzimidazole ring of (S)-12 with methyl iodide in acetonitrile under reflux (Scheme 2). Moreover, treatment of the benzimidazole ring of (S)-12 by using benzyl bromide upon heating in dioxane could produce the corresponding benzimidazolium salt (S)-14 also in quantitative

Amyloid-β probes: Review of structure–activity and brain-kinetics relationships

• Todd J. Eckroat,
• Abdelrahman S. Mayhoub and
• Sylvie Garneau-Tsodikova

Beilstein J. Org. Chem. 2013, 9, 1012–1044, doi:10.3762/bjoc.9.116

• (9) and diphenyl-1,3,4-oxadiazole (10); and thioflavin-T analogues such as benzothiazole (11), benzoxazole (12), benzofuran (13), imidazopyridine (14), and benzimidazole (15); as well as quinoline (16) and naphthalene (17) derivatives (Figure 1B). In this review, we provide an overview of these AD

• , [18F]FPM-IMPY, has shown less promising results. This compound, in which one of the N-methyl groups of IMPY was replaced with a [18F]fluoropropyl moiety, showed lower binding affinity than IMPY and poor pharmacokinetics [96]. Benzimidazoles The benzimidazole scaffold is highly similar to the

• imidazopyridine scaffold, but the benzimidazole ring has reduced lipophilicity when compared to imidazopyridines. This has the potential to reduce nonspecific binding and enhance signal-to-noise ratio. The [125I]-labeled benzimidazole analogue of 140e, compound 146, was prepared through cyclization of 4

Synthesis and physicochemical characterization of novel phenotypic probes targeting the nuclear factor-kappa B signaling pathway

• Paul M. Hershberger,
• Satyamaheshwar Peddibhotla,
• E. Hampton Sessions,
• Daniela B. Divlianska,
• Ricardo G. Correa,
• Anthony B. Pinkerton,
• John C. Reed and
• Gregory P. Roth

Beilstein J. Org. Chem. 2013, 9, 900–907, doi:10.3762/bjoc.9.103

• other NF-κB activation pathways such as those including the cytosolic proteins CARMA1, Bcl-10, MALT1, TRAF6 and Ubc13 [8]. The first probe identified within this series was the benzimidazole ML029 (4), which exhibited an IC50 of 0.07 μM in the HEK 293 cell assay with corresponding well-defined structure