HETEROCYCLES

■ Contents

■ Imidazolidin-4-ones: Their Syntheses and Applications

Timothy R. Blackmore* and Philip E. Thompson

*Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia

Abstract

This review focuses on the synthesis and use of the imidazolidin-4-one ring in synthetic and medicinal chemistry studies. It has remained remarkably under-utilized as a motif in drug discovery despite its obvious similarity to the widely encountered lactam pyrrolidinone, its isomer imidazolin-2-one and its oxidation state variants, the hydantoins (imidazolidendiones), imidazolidines, and imidazoles, as well as fused bicyclic ring systems. The synthesis of imidazolidin-4-one is reported in only 3 journal articles and a search for the explicit use of it in synthesis resulted in just 5 patents, and no academic journals. The specific sub-structure motif is reported in 296 journal articles and 65 patents. The different methods reported for creating substituted analogues will be discussed, as well as the application of the moiety in medicinal chemistry projects and alternative uses of these analogues as organic catalysts and prodrugs.

■ Synthesis and Donor-π-Acceptor Properties of Polyfluorene Derivatives Containing a Phenazasiline Moiety and an Electron Acceptor

Katsuhiko Ono,* Takuji Kobayashi, Yumi Sato, Katsuya Eguchi, Shinya Kato, Naoki Kishi, and Tetsuo Soga

*Graduate School of Engineering, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan

Abstract

Two polyfluorene derivatives containing a phenazasiline moiety and an electron acceptor were synthesized by the Suzuki coupling reaction. Molecular weight analysis showed that the two polymers had approximately 14 and 9 fluorene units as well as functional groups. Since these polymers had donor-π-acceptor systems, their absorption edges were red-shifted compared to that of polyfluorene. Cyclic voltammetry experiments indicated that the polymers showed amphoteric redox behavior. Bulk heterojunction solar cells were fabricated using films made of the polymers and a fullerene derivative, and their photovoltaic properties were investigated.

■ Synthesis of Fluorescent Pyrrolo[3,4-b]quinolizine Derivatives and Evaluation as a Protein-Labeling Probe

Masayori Hagimori, Naoko Mizuyama, Kenichirou Yokota, Osamu Morinaga, Yasuchika Yamaguchi, Hideo Saji, and Yoshinori Tominaga*

*School of Pharmaceutical Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

New fluorescent compounds, pyrrolo[3,4-b]quinolizines, were synthesized in good yields via a one-pot method based on the condensation of functionalized maleimides (1a–c) with 2-pyridylacetonitrile (2a), and alkyl 2-pyridylacetates (2b, c). These pyrrolo[3,4-b]quinolizine derivatives emitted over a wide wavelength range in solution (Em max: 484–604 nm) and in the solid state (Em max: 534–640 nm). In addition, we evaluated the utility of these heterocycles as fluorescent labeling probes for BSA.

■ Synthetic Studies of Substituted Pyridine Aldehydes as Intermediates for the Synthesis of Toddaquinoline, Its Derivatives and Other Natural Products

Georgeta Serban,* Hitoshi Abe, and Yasuo Takeuchi

*Pharmaceutical Chemistry Department, Faculty of Medicine and Pharmacy, University of Oradea, Nicolae Jiga 29, Oradea 410028, Romania

Abstract

The synthesis of substituted 2-bromopyridine aldehydes as intermediates in our planned approach to toddaquinoline, its derivatives and other natural products is reported. The DMF-formylation method of pyridine ring, the Vilsmeier-Haack procedure and the bromination of pyridine ring respectively, were studied in order to synthesize the above mentioned compounds. The successful methods (DMF-formylation and bromination of pyridine ring) provided the 2-bromo-4-formyl-5-tosyloxypyridine Ib and 5-benzyloxy-2,4,6-tribromo- nicotinaldehyde Ia under relatively mild conditions and in good yields.

■ Chemistry of Nitroenamines. Part 2. Synthesis of Saturated Pyrrolo-pyrimidines and -pyrazines

Pál Scheiber,* Gábor Tóth, Mihály V. Pilipecz, Támas R. Varga, and Péter Nemes

*Department of Chemistry, School of Veterinary Medicine, Szent István University, H-1400 Budapest, P. O. Box 2, Hungary

Abstract

New saturated pyrrolo-pyrimidines and pyrrolo-pyrazines were synthesized from 2-nitromethylene-pyrrolidine. Additionally, some simple aminomethylated derivatives of Mannich type were prepared. The nitro compounds were reduced into diastereomeric amines, which were separated and characterized structurally.

■ Ready Available Chiral Azapyridinomacrocycles N-Oxides; First Results as Lewis Base Catalysts in Asymmetric Allylation of p-Nitrobenzaldehyde

Maité Sylla-Iyarreta Veitía,* Mounia Joudat, Mathieu Wagner, Annie Falguières, Alain Guy, and Clotilde Ferroud*

*Laboratory of Chemical and Pharmaceutical Transformations, ERL 3193 CNRS, ESPCI ParisTech, Cnam, 2 rue Conté 75003 Paris, France

Abstract

We report here the straightforward synthesis of the first series of enantiomerically pure azapyridinomacrocycles N-oxides containing a cyclohexyl chiral moiety. These compounds were readily obtained in good overall yields by a convergent synthesis using natural amino acids as starting building blocks and macrocyclisation as the key step. This method is rapid, efficient and suitable for the introduction of various substituents at the macrocyclic skeleton. Finally, the compounds were tested as organocatalysts for the enantioselective allylation of p-nitrobenzaldehyde with allyltrichlorosilane.

■ Synthesis of Imidazole C1- and C3-Ribonucleoside Phosphoramidites for Probing Catalytic Mechanism in Ribozyme

Shinya Harusawa,* Kensuke Fujii, Masayoshi Nishiura, Lisa Araki, Yoshihide Usami, Zheng-yun Zhao, and David M. J. Lilley

*Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan

Abstract

Synthesis of C4-linked imidazole N-pivaloyloxymethyl (POM)-2’-O-cyanoethylated (CE) C1- and C3-ribonucleoside phosphoramidites 1a and 1b is described. These phosphoramidite products were incorporated into RNA sequence through solid phase phosphoramidite approach, providing RNA with imidazole linked through different length to sugar residue, to study the mechanism of a ribozyme.

■ A Novel Synthesis of 1-Aryl-1H-benzotriazoles via Oxidative C-H Amination

Zhou Zhou, Qi-Lun Liu, Wen Li, and Yong-Ming Zhu*

*School of Pharmacy, Soochow University, Suzhou 215123, China

Abstract

A facile, novel and regiospecific protocol for the synthesis of 1-ary-1H-benzotriazoles via oxidative C-H amination of corresponding 1,3-diaryltriazenes in DMF in the presence of K2CO3 at moderate temperature was developed.

■ One-Pot Synthesis of Dihydropyrimidiones via Environmentally Friendly Enzyme-Catalyzed Biginelli Reaction

Wanmei Li, Guobin Zhou, Pengfei Zhang,* Yifeng Lai, and Shifu Xu

*Chemistry and Chemical Engineering, College of Material, Hangzhou Normal University, Hangzhou 310036, China

Abstract

A novel enzyme-catalyzed Biginelli reaction of acetoacetate, aromatic aldehyde and urea (thiourea) was described. Great acceleration of the one-pot multicomponent reaction was observed by the aid of enzymes. Various dihydropyrimidiones were prepared in good yields under the conditions using trypsin from porcine pancreas as the catalyst.

■ Biflavonoids from Flowers of Butea monosperma (Lam.) Taub.

Fakhruddin Ali Ahmed, Sang-Yong Kim, Shin-ichiro Kurimoto, Hisako Sasaki, Hirofumi Shibata, Yoshiki Kashiwada,* and Yoshihisa Takaishi

*Graduate School of Pharmaceutical Sciences, University of Tokushima, Sho-machi, Tokushima 770-8505, Japan

Abstract

A new aurone glucoside (1) and three new biflavonoids (12 - 14), together with fourteen known compounds, were isolated from the flowers of Butea monosperma (Lam.) Taub. The structures of the new compounds were established by 1D, 2D NMR, MS and CD analyses. The isolated compounds were evaluated for their influenza A neuraminidase inhibitory activity and DPPH free-radical scavenging activity.

■ Polysubstituted Fused Ring Bicyclic Thiohydantoins from Aminocarbo-N-thioylpyrrolidines Derived from Azomethine Ylide 1,3-Dipolar Cycloadditions

Yahya Nural, H. Ali Döndaş,* Ronald Grigg, and Ertan Şahin

*Department of Chemistry, Faculty of Pharmacy, Mersin University, 33342, Mersin, Turkey

Abstract

Highly substituted bicyclic thiohydantoins fused to pyrrolidines were prepared from aminocarbo-N-thioylpyrrolidines derived from α-amino acid esters via imine azomethine ylide 1,3-dipolar cycloadditions and subsequent reaction with aroylisothiocyanates. Aminocarbo-N-thioylpyrrolidines efficiently undergo cyclisation in the presence of sodium methoxide to form bicyclic N-substituted thiohydantoins with concomitant cleavage of the N-acyl group in good to excellent yield. And also some interesting both regiospecific and stereospecific rearrangement to the bicyclic fused thiocarbamoil pyrrolidine and bicyclic thiohydantoin were observed.

■ Synthesis and Properties of a New Donor-Acceptor Diad Composed of DT-TTF and Dicyanomethylidene Group

Ken-ichi Nakamura, Takashi Shirahata, Hisakazu Miyamoto, and Yohji Misaki*

*Department of Applied Chemistry, Graduate School of Science and Engineering, Ehime University, 3 Bunkyo-cho, Matsuyama, Ehime, Japan

Abstract

Several derivatives of a new donor-acceptor diad 1 composed of DT-TTF and dicyanomethylidene group were synthesized. The IR spectra of 1 demonstrated considerable contribution of a polarized structure. Electronic spectra and molecular orbital calculation suggested that the absorption maximum of 1 was due to NHOMO-LUMO transition. Cyclic voltammetry revealed that the compound 1 exhibited three-stage of oxidation and one-stage of reduction processes. The bis(methylthio)-substitudted derivative 1a exhibited conductivity of 10-6 S cm-1 in spite of a single-component material.

■ Synthesis of 1,2,3,5-Tetrahydro-4,1-benzothiazepine-2-thione Derivatives via Cyclization of 2-[(2-Isothiocyanatophenyl)methylsulfanyl]acetates with Sodium Hydride

Kazuhiro Kobayashi,* Yoshinori Enmi, Daisuke Iitsuka, Yuuki Kanbe, and Hisatoshi Konishi

*Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

A convenient method for the preparation of the title derivatives, 2-thioxo-1,2,3,5-tetrahydro-4,1-benzothiazepine-3-carboxylates and 2-alkylsulfanyl-3,5-dihydro-4,1-benzothiazepine-3-carboxylates, has been developed. It is depends on cyclization of 2-[(2-isothiocyanatophenyl)methylsulfanyl]acetates, generated in situ from the corresponding isocyanides on treatment with sulfur in the presence of a catalytic amount of selenium, using sodium hydride as a base. These isocyanides can be easily prepared from N-[(2-chloromethyl)phenyl]formamides via an easy two-step sequence.

■ Estrogen Receptor α/β Ligands Derived from Thalidomide

Tomomi Noguchi-Yachide,* Kazuyuki Sugita, and Yuichi Hashimoto

*Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan

Abstract

We have developed a series of thalidomide-derived phthalimide-type estrogen receptor (ER) modulators with characteristic subtype (ERα/ERβ) selectivity, and investigated their structure-activity relationship for ER agonistic and antagonistic activities.

■ Cytotoxic Eunicellin-Type Diterpenes from the Soft Coral Litophyton viscudium

Tetsuo Iwagawa,* Daiki Kusatsu, Keiko Tsuha, Toshiyuki Hamada, Hiroaki Okamura, Tatsuhiko Furukawa, Shin-ichi Akiyama, Matsumi Doe, Yoshiki Morimoto, Fumihito Iwase, and Kaoru Takemura

*Department of Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka Kagoshima 890-8544, Japan

Abstract

Five new eunicellin-type diterpenes were isolated from the soft coral Litophyton viscudium. The structures of the compounds were elucidated mainly on the basis of extensive spectroscopic analysis. Compounds exhibited cytotoxic activity against HL-60 with IC50 values of 4.2–50 μM.

■ Aromatic Compounds from Cultured Lichen Mycobionts of Three Graphis Species

Yukiko Takenaka, Nobuo Hamada, and Takao Tanahashi*

*Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan

Abstract

Spore-derived mycobionts of three lichen species, Graphis apriens, G. handelii and G. awaensis, were cultivated on a malt-yeast extract medium supplemented with 10% sucrose and their metabolites were investigated. Two new isocoumarin derivatives 1 and 2 as well as a new thiophene derivative 3 were isolated along with six known compounds. Their structures were determined by spectroscopic methods.

■ Heterocycles [h]-Fused to 4-Oxoquinoline-3-carboxylic Acid. Part IX. Synthesis of 2,6-Dioxotetrahydro-1H-pyrrolo[3,2-h]quinoline-7-carboxylic Acid

Jalal A. Zahra,* Hala I. Al-Jaber, Mustafa M. El-Abadelah, and Mohammed M. Abadleh

*Chemistry Department, Faculty of Science, The University of Jordan, Amman 11942, Jordan

Abstract

Interaction of deprotonated malonic esters with 7-chloro-8-nitro-4-oxoquinoline-3-carboxylate (1) gave the respective 7-[bis(alkoxycarbonyl)methyl] derivatives (2, 3) which were converted into the corresponding 7-(carboxymethyl)-8-nitro-4-oxoquinoline-3-carboxylic acid (4). Reductive lactamization of the latter furnished the target tetrahydro-2,6-dioxo-1H-pyrrolo[3,2-h]quinoline-7-carboxylic acid (5). Both compounds 4 and 5 exhibited broad spectrum of high antibacterial activity against representatives of Gram-negative and Gram-positive bacteria classes, but were less potent than the reference ciprofloxacin.