HETEROCYCLES

■ Contents

■ The Chemistry of 2H-Cyclohepta[b]furan-2-one: Synthesis, Transformation and Spectral Properties

Noboru Morita,* Kozo Toyota, and Shunji Ito

*Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan

Abstract

Overview of data, obtained in the last 60 years, concerning the synthetic methodology for 2H-cyclohepta[b]furan-2-one, their reactivity and mechanistic aspects, the synthetic potential for the extended π-electronic systems, and their spectral properties, are described.

■ Regio and Stereo Selectivity on the α-Aryl-δ-epoxynitrile Anionic Cyclization Reactions: Modulation towards a 5-Endo or 4-Exo Process

Jesús Armando Luján-Montelongo, Adrián Vázquez-Sánchez, and José Gustavo Ávila-Zárraga*

*Facultad de Química, Ciudad Universitaria, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico

Abstract

Here we present a study focused on the regio and stereoselectivity of the anionic intramolecular cyclization reactions of several 4-(3,3-dimethyloxiran-2-yl)-2-arylbutanonitriles. The first part comprises the exploration of the reaction varying the temperature/solvent as well as the base counter-ion; switching between Li, Na and K that companies hexamethyldisilylamide anion. This is a well-known base used widely. In the second part, we provide a pair of methodologies that lead almost exclusively to pentacarbocycles through a 5-endo pathway, although is known to be a non-favored process in many cases. We found that both the metal counter-ion and the temperature have an important effect on the regioselectivity of the reaction and, independently of the pathway presented, the preferred diastereoselectivity is trans.

■ Reactivity of Arylnitrile Oxides and C-Aroyl-N-phenylnitrones with 3-Methylenedihydro-(3H)-furan-2-one and Itaconic Anhydride

Christophe Roussel, Kabula Ciamala,* Joël Vebrel, and Claude Riche

*Institute of UTINAM UMR CNRS 6213, Faculty of Science and Technology, University of Franche-Comté, 16 Route de Gray, F-25030 Besançon, France

Abstract

1,3-dipolar cycloaddition is a powerful route for the synthesis of five-membered heterocycles. The [3+2] cycloadditions of some α-methylene-γ-buryrolactones, namely 3 methylenedihydro-(3H)-furan-2-one (1) and itaconic anhydride (2) were studied. Their reactions with arylnitrile oxides (3) and C-aroyl-N-phenylnitrones (7) proceed with complete regioselectivity. From a stereochemical point of view, the addition of arylnitrile oxides (3) leads to the unique spiroheterocycles (4-5). Actually, a single stereocenter is generated during the reaction. In the particular case of p-nitrophenylnitrile oxide (3d), only the diacidic form (10d) of the spiroheterocyle (5d) was isolated. In contrast, the addition of C-aroyl-N-phenylnitrones (7) produces a couple of diastereoisomers, since two stereocenters are generated simultaneously. Nevertheless, the reaction is regioselective and stereospecific leading also to the single spiroheterocycles (19-20). The proposed stereochemistry of spiranic compounds (19d) and (20d) has been corroborated by two single crystal X-ray crystallographic analysis.

■ Two New Hydrolyzable Tannins, Carpinerins A and B, from Galls of Carpinus tschonoskii

Takako Ono and Hideyuki Shigemori*

*Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305, Japan

Abstract

Two new hydrolyzable tannins, carpinerins A (1) and B (2), together with ten known tannins 3-12, were isolated from the galls on bud of Carpinus tschonoskii, and the structures of 1 and 2 were elucidated using spectroscopic data, primarily NMR and MS, and chemical means. Most of isolated tannins including carpinerin B (2) exhibited inhibitory effects on the growth of the root of cress (Lepidium sativum L.) seedling at 1×10-4 mol/L.

■ Synthesis of Fused Pyrazolo[1,5-a]pyrimidine Derivatives under Microwave Irradiation and Ultrasound, as Ecofriendly Energy Sources

Khadijah M. Al-Zaydi*

*Chemistry Department, Girl’s College of Education, King Abdul-Aziz University, Jeddah 21533 P.O.Box 50918, Saudi Arabia

Abstract

4-(4-Chlorophenylazo)-1H-pyrazole-3,5-diamine reacted with ethyl acetoacetate, benzylidenemalononitrile, ethyl propiolate and malononitrile under microwave irradiation to afford pyrazolo[1,5-a]pyrimidine derivatives in high yields. The structures of compounds were confirmed by 1H, 13C NMR, MS, elemental analyses and X-ray crystallography.

■ A Simple N-Substitution of Pyrrole and Indole Using Basic Ionic Liquid [BmIm][OH] as Catalyst and Green Solvent

Zhang-Gao Le,* Tao Zhong, Zong-Bo Xie, and Jian-Ping Xu

*Department of Applied Chemistry, East China Institute of Technology, Fuzhou, 344000, China

Abstract

In basic ionic liquids, 1-methyl-3-butylimidazolium hydroxide, [BmIm][OH], pyrrole and indole replaced the halogen atom of an alkyl halide to give the corresponding N-substituted pyrrole and indole in excellent yield. Benzenesulfonyl chloride, p-methylbenzenesulfonyl chloride and benzoyl chloride reacted similarly with pyrroles to afford the N-substituted pyrroles in quantitative yield.

■ Preparation of 5-Amino-1,2-dihydro-4-(1-methyl-4-piperidinyl)pyrrol-3-ones

Bohdan A. Chalyk, Anton V. Tverdokhlebov,* Rustam T. Iminov, and Andrey A. Tolmachev

*Enamine Ltd. Co., Alexandra Matrosova Str. 23, 01103 Kiev, Ukraine

Abstract

Acylation of (1-methyl-4(1H)-pyridinylidene)acetonitrile with chloroacetyl chloride was found to occur at the exocyclic carbon atom leading to 4-chloro-2-(1-methyl-4(1H)-pyridinylidene)-3-oxobutanenitrile. Its reaction with primary amines furnished 4-(2-amino-4,5-dihydro-4-oxo-1H-pyrrol-3-yl)- 1-methylpyridinium chlorides. Hydrogenation of these quaternary salts afforded 5-amino-1,2-dihydro-4-(1-methyl-4-piperidinyl)-3H-pyrrol-3-ones in nearly quantitative yields.

■ Synthesis of Bis(indolyl)methane Derivatives by Acid-Catalyzed Reactions of Indoles with Vinyl Ethers

Kazuhiro Kobayashi,* Yuu Shirai, and Hisatoshi Konishi

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

Abstract

2,2-Bis(indol-3-yl)propane derivatives have been synthesized by the reaction of 3-nonsubstituted indoles with 2-methoxypropene in dichloromethane in the presence of a catalytic amount of (±)-camphor-10-sulfonic acid. The similar treatment of 3-substituted indoles with 2-methoxypropene under the same conditions has resulted in the formation of 2,2-bis(indol-2-yl)propanes. The reaction of 3-substituted indoles with ethoxyethene has afforded bis(indol-1- yl)ethanes. Subsequently, 3-substituted indoles have proved to react with excess vinyl ethers under the same conditions to afford the corresponding 1-(1-alkoxyalkyl)indoles.

■ Synthesis of Aryltetralin Type 2-Azalignans Using Schöllkopf ’s Bislactim-Ether Methodology

Yoshihide Usami,* Masao Arimoto,* Kiyomi Kobayashi, Mikiko Honjou, Masako Yamanaka, Misaki Miyao, Hayato Ichikawa, Kenneth F. Bastow, and Kuo-Hsiung Lee

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

Abstract

Synthesis of (1S,3R)-2-aza-4-deoxypodophyllotoxin has been accomplished in 6 steps using Schöllkopf’s bislactim-ether methodology in 12% total yield. Bislactim-ether, which was originally prepared from commercially available L-valine and glycine, was used as the starting material. Our synthetic route was allied to easy access to aryltetralin type 2-azalignan analogues. Synthesized 2-azalignans were tested for in vitro anticancer activity using a panel of human cancer cell lines. Both of two (1S)-diastereomers (9a and 9b) of 2-aza-4-deoxypodophyllotoxin showed significant activity against human cancer cell lines: A-549 (lung), HTC-8 (ileocecal), and MCF-7 (breast cancer).

■ New Alkaloids from Conchocarpus gaudichaudianus

Lucia E. Ranieri Cortez, Diógenes A. Garcia Cortez,* João B. Fernandes, Paulo C. Vieira, Antonio G. Ferreira, and M. Fátima das G. F. da Silva

*Department of Pharmacy and Pharmacology, State University of Maringá, Av. Colombo, 5790
CEP 87020-090, Maringá, Paraná, Brazil

Abstract

The methanol extract from stems of Conchocarpus gaudichaudianus yielded four new alkaloids: 3-(2-(7,7-dimethyl-3,7-dihydropyrano[3,2-e]indol-1-yl)ethyl)quinazoline-2,4(1H,3H)-dione (1), 3-(2-(7,7-dimethyl-3,7-dihydropyrano[3,2-e]indol-1-yl)ethyl)-1-hydroxyquinazoline-2,4(1H,3H)-dione (2), 3-(2-(7,7-dimethyl-3,7-dihydropyrano[3,2-e]indol-1-yl)ethyl-1-methylquinazoline-2,4(1H,3H)-dione (3), (E)-3-(6,7-dihydroxy-3,7-dimethyloct-2-enyl)-4-methoxy-1-methylquinolin-2(1H)-one (6), in addition to the known alkaloids N-trans-coumaroyltyramine and N-trans-feruloyltyramine. The structures of these compounds were identified by IR, UV, 1H and 13C NMR spectroscopy, gHSQC and gHMBC spectral analysis and comparison of data from the literature.

■ Dihydrochalcone Designed from Methylophiopogonanone B Strongly Inhibits Hypoxia-inducible Factor (HIF)-1α Activity

Mikio Fujii,* Kiyoshi Egawa, Yasuaki Hirai, Masato Kondo, Kotaro Fujii, Hidehiro Uekusa, Hiroyuki Akita, Kiyoshi Nose, Kazuo Toriizuka, and Yoshiteru Ida

*School of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan

Abstract

Inhibition of hypoxia-inducible factor (HIF)-1α activity of methylophiopogonanone B (1) and its derivatives were investigated. As the modification of the structure of 1, dihydrochalcone (11) was leaded and showed one order higher activity (IC50: 0.2 μg/mL) than methylophiopogonanone B (1) (IC50: 2.2 μg/mL).

■ Alkylheteroaromatic-carbonitriles as Building Blocks in Heterocyclic Synthesis: Synthesis of Ethyl 1-Substituted 5-Cyano-4-methyl-6-oxopyridine-3-carboxylates; Versatile Precursors for Polyfunctionally Substituted Isoquinolines and Pyrido[3,4-c]pyridine

Khaled D. Khalil, Hamad M. Al-Matar,* and Mohamed H. Elnagdi

*Department of Chemistry, Faculty of Science, Kuwait University, Safat 13060, P.O. Box 5969, Kuwait

Abstract

The title compounds were prepared via reacting diethyl 2-cyano-4-dimethylamino-methylene-3-methylpent-2-enedioic acid 2 with hydrazine hydrate and with ethyl amine. The formed pyridones 3a condensed with dimethylformamide dimethyl acetal to yield the corresponding enamine 4 that could be cyclised into the pyrido[3,4-c]pyridine 5 by reflux in acetic acid in presence of ammonium acetate. The reaction of 3a with elemental sulfur afforded the thienopyridine 6 that reacted readily with electron poor olefins and acetylenes to yield isoquinolines 8, 10 and 11. Compound 3a reacted with benzylidene-malononitrile to yield the isoquinoline 14.

■ One-Pot Synthesis of 4-Substituted Isothiochroman-1-thiones from α-Substituted 2-Bromostyrenes and Carbon Disulfide

Shuhei Fukamachi, Miyuki Tanmatsu, Hisatoshi Konishi, and Kazuhiro Kobayashi*

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

Abstract

A facile method for the preparation of isothiochroman-1-thiones has been developed. Thus, treatment of a-substituted 2-lithiostyrenes, generated in situ from bromine-lithium exchange between the respective 2-bromostyrenes and butyllithium, with carbon disulfide, followed by workup with saturated aqueous ammonium chloride, affords 4-substituted isothiochroman-1-thiones in reasonable yields.

■ α’-Oxoperakensimines A - C, New Bisbenzylisoquinoline Alkaloids from Alseodaphne perakensis (Gamble) Kosterm

Mat Ropi Mukhtar, Mohd Azlan Nafiah, Khalijah Awang, Noel F. Thomas, Kazumasa Zaima, Hiroshi Morita, Marc Litaudon, and A. Hamid A. Hadi*

*Department of Chemistry, Faculty of Science, University of Malaya, Pantai Valley, 50603 Kuala Lumpur, Malaysia

Abstract

Three new bisbenzylisoquinolines, α′-oxoperakensimines A – C (1 – 3) have been isolated from the bark of Alseodaphne perakensis (Gamble) Kosterm (Lauraceae). Their structures were elucidated by two-dimensional NMR techniques. α′-Oxoperakensimines A – C (1 – 3) showed vasorelaxant activity on rat aorta.

■ A Convenient Method for the Synthesis of 2-Oxazolidinones from Ethylene Carbonate and Primary Aryl Amines

Hang Gong and Nian-fa Yang*

*Key Laboratory of Environment-Friendly Chemistry and Applications of Ministry of Education, College of Chemistry, Xiangtan University, Hunan, Xiangtan 411105, China

Abstract

One-step procedure for the synthesis of 2-oxazolidinones from ethylene carbonate and primary aryl amines in the presence of amine catalysts was described. Various reaction parameters including catalyst, temperature, reaction time, solvent and the amount of catalyst were investigated. Excellent results were obtained using DBU as catalyst at 100 °C within 2 h free of solvent.

■ X-Ray Structure of Two Stephacidins, Heptacyclic Alkaloids from the Marine-Derived Fungus Aspergillus ostianus

Keijiro Kito, Ryuhei Ookura, Takenori Kusumi, Michio Namikoshi, and Takashi Ooi*

*Faculty of Pharmaceutical Sciences, The University of Tokushima, Sho-machi, Tokushima 770-8505, Japan

Abstract

Two stephacidins, 21-hydroxystepahcidin and notoamide F, were isolated from the cultivation medium of the marine-derived fungus Aspergillus ostianus, and their structures were confirmed by X-ray crystallography.

■ First Synthesis of Racemic Concentricolide, an Anti-HIV-1 Agent Isolated from the Fungus Daldinia concentrica

Li-Zhen Fang and Ji-Kai Liu*

*State Key Laboratory of Phytochemistry and
Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Heilongtan, Kunming 650204, Yunnan, China

Abstract

Concentricolide, a novel compound with anti-HIV-1 activity and isolated from ascomycete Daldinia concentrica, has been synthesised for the first time as a racemate from furan-3-carbaldehyde and dihydrofuran-2(3H)-one via a Diels-Alder reaction. The identity of the synthetic sample was verified by comparison of its spectral data with those of an authentic sample.

■ A New Coumarin from Clausena excavata

Surat Laphookhieo,* Tawanan Sripisut, Uma Prawat, and Chatchanok Karalai

*School of Science, Mae Fah Luang University, 333 Moo 1, Tasud, Muang, Chiang Rai, 57100, Thailand

Abstract

Chemical investigation of the fruits and stems of Clausena excavata led to the isolation and identification of a new coumarin namely clausenaexcavin (1) along with five known compounds (2-6). All structures were characterized by extensive 1D and 2D NMR spectroscopic methods.