HETEROCYCLES

■ Contents

■ Biologically Active Marine Natural Products

Kazuhiko Nakamura, Makoto Kitamura, and Daisuke Uemura*

*Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Yokohama 223-8522, Japan

Abstract

The discovery of new biologically active molecules contributes to the development of basic scientific concepts in the field of biological sciences. These compounds often lead to the development of valuable drugs, and to new pharmacological reagents. They also lead to a better understanding of ecological phenomena. Newly discovered substances can even be responsible for the creation of new scientific fields. Due to the radically different habitats of marine organisms, several notable examples of secondary metabolites from marine organisms have been isolated. Two of the most remarkable properties of these compounds are their structural and physiological diversities. Palytoxin is a polyol compound that shows extreme acute toxicity. Halichondrins are remarkable antitumor macrolides from sponge. Pinnatoxins, potent shellfish poisons, cause food poisoning. The compounds controlling the ecological behaviors of coral reveal to us a wonder of nature. And, the compounds produced by symbiotic microorganisms always inspire us by chemical interests. This paper describes bioorganic studies that are helping to develop new research fields.

■ Chemistry of 1-Methylenesugars: Synthetic Utilizations to 1’-C-Methyl-saccharides and Related Carbohydrates

Rie Namme and Shiro Ikegami*

*Faculty of Pharmaceutical Sciences, Teikyo University, 1091-1, Sagamiko, Kanagawa 299-0195, Japan

Abstract

The efficient synthesis of protected 1-methylenesugars and their acid-catalyzed O-glycosidation are mentioned in connection with that of 1-C-methyl-pyranoses. Application of this process to synthesis of the pentasaccharide PI-88 analogue was accomplished in a protected form. Also the syntheses of trehalose analogues and ulsonic acid derivatives were successful in the similar process. 1,3-Dipolar cycloaddition with nitrones provides the new types of spiro-heterocycles combined with carbohydrates. The closely related methylene-carbohydrates also provide a novel synthetic process for cyclitols that are useful synthetic intermediates for voglibose and related drugs.

■ Cyclothiomethylation of Functional Substituted Anilines by CH₂O and H₂S

Vnira R. Akhmetova,* Guzel R. Nadyrgulova, Zalifa T. Niatshina, Regina R. Khairullina, Zoya A. Starikova, Alexandra O. Borisova, Michail Yu. Antipin, Raihana V. Kunakova, and Usein M. Dzhemilev

*Laboratory of Heteroatomic Compounds, Institute of Petrochemistry and Catalysis, RAS, 450075, Ufa, Prospekt Oktyabrya,141, Russia

Abstract

N-Aryl substituted 1,3,5-dithiazinanes have been synthesized (20-60 °C) in 32-95% yield by cyclocondensation of o-, p-aminobenzoic, 4-, 5-aminosalicylic acids, p-aminobenzoic acid ethyl or (β-diethylamino)ethyl esters and p-aniline sulfamide with CH₂O and H2S (1:3:2 ratio). At ambient temperature p-aminobenzoic acid, 5-aminosalicylic acid and p-aminobenzoic acid ethyl ester together with 1,3,5-dithiazinanes form appropriate N-aryl substituted 1,3-thiazetidines. Cyclothiomethylation of p-aminobenzoic acid ethyl ester (0 °C) results in N,N-diaryl-1,3,5-thiadiazinane. Heterocyclization of p-aniline sulfamide with CH₂O and H₂S at a molar ratio of 1:6:4 (pH 1.3-1.5) was found to afford bis-1,3,5-dithiazinanes involving two amino groups. Condensation of p-aniline sulfacetamide with 37% formalin (CH₂O) and H₂S (pH 2.5) led to the compound, which was built as macroheterocycle from two fragments of p-aniline sulfacetamide molecule bound to each other by sym-dimethyl sulfide chain (CH₂SCH₂).

■ Synthesis of Azole Derivatives from 3-Phenylaminopropanhydrazide and Evaluation of Their Antimicrobial Efficacy

Ingrida Tumosiene, Kristina Kantminiene, Alvydas Pavilonis, Zaneta Mazeliene, and Zigmuntas J. Beresnevicius*

*Department of Organic Chemistry, Kaunas University of Technology, Radvilenu pl. 19, Kaunas LT-50254, Lithuania

Abstract

Novel pyrrole and pyrazole derivatives containing phenylaminopropanoyl moiety were synthesized from 3-phenylaminopropanohydrazide through its condensation with diketones. The intramolecular cyclization reaction of disubstituted semicarbazides and thiosemicarbazides was used to prepare new 1,3,4-thiadiazole, 1,3,4-oxadiazole and 1,2,4-triazole compounds. Some of the synthesized compounds were evaluated for in vitro antimicrobial activity.

■ Diversity-oriented Synthesis of Substituted Pyrazolo[4,3-d][1,2,3]triazin-4-ones

Daniel Meibom,* Marcus Bauser, Heinrich Meier, Dirk Schneider, Nils Svenstrup, and Dieter Haebich

*Medical Chemistry, Bayer Health Care AG, D-42096 Wuppertal, Germany

Abstract

An efficient synthesis of 3,7-disubstituted 3,5-dihydro-4H-pyrazolo[4,3-d][1,2,3]triazin-4-ones (2), especially suited for late-stage decoration, is described. Diverse 3-benzyl analogs were obtained by amidation-cyclization in one pot and various pyrazolotriazinone-7-bromides were employed in Suzuki and Sonogashira cross-coupling reactions.

■ Synthesis of 4- and 7-Quinolinesulfonamides from 4,7-Dichloroquinoline

Krzysztof Marciniec and Andrzej Maslankiewicz*

*Department of Organic Chemistry, The Medical University of Silesia, Jagiellonska 4, 41-200 Sosnowiec, Poland

Abstract

Action of sodium methanethiolate (in boiling DMF) towards 4,7-dichloroquinoline (1) or 7-chloro-1-methyl-4(1H)-quinolinone (11) occured via chlorine ipso-substitution followed by methanethiolato-S-demethylation to yield dithiolate 1A or thiolate 18A, which were: i) subjected to S-methylation, ii) oxidatively chlorinated to quinolinesulfonyl chlorides (5 or 14 and 15). Oxidative chlorination of 4,4’-bis (7-chloroquinolinyl) disulfide (7) led to 7-chloro-4-quinolinesulfonyl chloride (8). All quinolinesulfonyl chlorides 5, 8, 14 and 15 were effectively converted to corresponding azinesulfonamides 6, 9, 16 and 17.

■ Synthesis and Sulfuration of 2’-Adamantylidene-9-benzonorbornenylidenee

Yoshiaki Sugihara,* Ayumi Kobiki, and Juzo Nakayama*

*Department of Chemistry, Faculty of Science, Saitama University, Urawa, Saitama 338-8570, Japan

Abstract

A novel alkene, 2’-adamantylidene-9-benzonorbornene 6, was synthesized from 2-adamantanone 7 in three steps resulting in a good overall yield. The alkene 6 reacted with elemental sulfur in refluxing o-Cl₂C₆H₄ to give syn-thiirane 14, anti-thiirane 15, and 6. Almost the same ratio of the products was obtained when 14 or 15 was reacted with and without elemental sulfur under the same conditions. Sulfuration with Ph₃CSCl in CH₂Cl₂ at -78 °C afforded 14, and that at room temperature furnished a 3:1 mixture of 14 and 15. In contrast, although the sulfuration with Ph₃CSCl in CH₂Cl₂ at room temperature afforded 14 quantitatively, that at -78 °C gave 14 and 15 in 12 and 3% yields, respectively. Sulfuration by 1 molar equiv. of S₂Cl₂ or SCl₂ afforded 14 and vic-dichloride 28.

■ Dibromides of BOC-Protected 1-Aminopyrrole and 4-Amino-1,2,4-triazole: Synthesis, X-Ray Molecular Structure, and NMR Behavior

Takakazu Yamamoto,* Gentaro Tanaka, Hiroki Fukumoto and Take-aki Koizumi

*Chemical Resources Laboratory, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan

Abstract

α-Dibromides of BOC-protected 1-aminopyrrole and 4-amino-1,2,4-triazole have been prepared and their molecular structures have been confirmed by X-ray crystallography. They can be used for polymer synthesis.

■ Preparation of Unsymmetrical 1,4-Bis[2-ethynyl-3-thienyl]benzene Derivatives

Kozo Toyota,* Yasutomo Tsuji, Kazuyuki Okada, and Noboru Morita

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

Abstract

Unsymmetrically substituted 1,4-bis(2-ethynyl-3-thienyl)benzene derivative was prepared, utilizing 1-bromo-4-(2-iodo-3-thienyl)benzene and 5-alkyl-3-bromo-2-ethynylthiophene derivatives as key intermediates.

■ Reaction of Isatins with Active Methylene Compounds on Neutral Alumina: Formation of Knoevenagel Condensates and Other Interesting Products

Manas Chakrabarty,* Ratna Mukherjee, Shiho Arima, and Yoshihiro Harigaya

*Department of Chemistry, Bose Institute, 93/1, A. P. C. Road, Kolkata-700009, India

Abstract

Isatin and its N-methyl and 5-nitro derivatives underwent smooth reaction with a variety of acyclic and cyclic active methylene compounds on neutral alumina at room temperature to efficiently furnish Knoevenagel condensates in the majority of the cases and tandem Knoevenagel condensation-Michael addition products including spiro compounds in two cases.

■ Synthesis and Antimicrobial Evaluation of New Thiophene and 1,3,4-Thiadiazole Derivatives

Mohamed R. Shaaban, Tamer S. Saleh, and Ahmad M. Farag*

*Department of Chemistry, Faculty of Science, University of Cairo, Giza 12613, Egypt

Abstract

A Facile route to some new thiophene derivatives via the reaction of 3-mercapto-2-(1-methylbenzimidazole-2-carbonyl)-3-phenylaminopropenal (3) with 1-aryl-2-bromoethanones, chloroacetonitrile and ethyl bromoacetate is reported. Reaction of 3 with hydrazonoyl halides afforded 1,3,4-thiadiazole derivatives incorporating a benzimidazole moiety. Antimicrobial and antifungal activities of selected examples of the new products were evaluated.

■ One-Pot Synthesis of 1-Arylindole-3-carboxylates from 2-(2-Isocyanophenyl)acetates

Shuhei Fukamachi, 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

An efficient method for the preparation of 1-arylindole-3-carboxylates under mild conditions has been developed. Thus, cyclization of ethyl 2-(2-isocyanophenyl)acetates using sodium hydride at room temperature was followed by 1-arylation of the resulting ethyl 1-sodioindole-3-carboxylates with fluoro(di)nitrobenzenes to give ethyl 1-(di)nitrophenylindole-3-carboxylates in generally good yields. This method also allows preparation of 1,1’-(4,6-dinitro-1,3-phenylene)diindole derivatives by using 1,3-difluoro-4,6-dinitrobenzene.

■ Synthesis of 2-Benzothiophene-1(3H)-thione and Isothiochromene-1-thione Derivatives by Iodine-mediated Cyclization of Lithium 2-(Vinyl)dithiobenzoate Derivatives

Shuhei Fukamachi, 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

Successive treatment of α-substituted 2-bromostyrenes with butyllithium and carbon disulfide generates lithium 2-(vinyl)dithiobenzoates, which are then allowed to react with iodine to give 3-substituted 3-iodomethyl-2-benzothiophene-1(3H)-thiones and/or 4-substituted isothiochromene-1-thiones in one-pot. Some of the former products can be transformed into the corresponding latter products on treatment with sodium hydrogencarbonate in refluxing acetonitrile.

■ Synthesis and Some New Inolizine and Pyrrolo[1,2-a]quinoline Derivatives via Nitrogen Ylides

Nabila A. Kheder, Elham S. Darwish, and Kamal M. Dawood*

*Department of Chemistry, Faculty of Science, University of Cairo, Giza 12613, Egypt

Abstract

The pyridinium bromides 2a,b reacted with dimethyl acetylene-dicarboxylate (DMAD) to give the indolizine derivatives 6a,b. Bromide salts 2a,b reacted also with β-nitrostyrene, ethyl acrylate and with acrylamide to give the corresponding indolizine derivatives 8a,b and 10a-d. Reaction of the quinolinium salts 12a,b with DMAD, β-nitrostyrene and with ethyl acrylate as dipolarophiles furnished the corresponding pyrrolo[1,2-a]quinoline derivatives 16a,b, 18a,b and 20a,b, respectively. Bromide salts 2b and 22 underwent intramolecular cyclization via elimination of water and hydrogen bromide molecules when heated at reflux condition to give the angularly fused indolizine and pyrrolo[1,2-a]quinoline structures 21 and 23, respectively.

■ Synthesis of Related Substances of Cilostazol

Jin Zheng, Zheng Liu, Yiru Dai, Qingjie Zhao, and Jingshan Shen*

*Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zuchongzhi Rd., Zhangjiang Hi-Tech Park, Shanghai, 201203, China

Abstract

The impurities in API of cilostazol were detected by LC/MS during the process development. The structures of two impurities 6 and 7 and the related formation mechanisms were proposed. Synthesis of 6 and 7 was conducted for confirmation of the speculated structures.

■ A Novel and Efficient Approach to Pyrazolo[1,5-a]pyridine Derivatives via One-Pot Tandem Reaction

Yan-Qing Ge, Jiong Jia, Yan Li, Ling Yin, and Jianwu Wang*

*School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, China

Abstract

An unusual intramolecular condensation of α,β-unsaturated esters with aldehydes was discovered and the pyrazolo[1,5-a]pyridine derivatives were conveniently synthesized by this novel tandem reaction under very mild conditions. The reaction mechanism was also proposed.

■ First Synthesis of Racemic Methylophiopogonanone B and Its Inhibitory Activity of Hypoxia-inducible Factor-1α

Mikio Fujii, Kiyoshi Egawa, Yasuaki Hirai, Masato Kondo, 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

Methylophiopogonanone B, a constituent of Ophiopogonis tuber, found to be a potent inhibitor of hypoxia induced factor-1α (HIF-1α) activity, was synthesized from 2,4,6-trihydroxy-3,5-dimethylacetophenone in 57% yield. The synthetic methylophiopogonanone B inhibited the reporter activity at 3 to 10 μg/mL.

■ A Synthetic Application of β-Aminoalanines to Some New 5-Dialkylaminomethyl-3-phenylhydantoin Derivatives

Fumiko Fujisaki, Kaori Shoji, and Kunihiro Sumoto*

*Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

Abstract

5-Dialkylaminomethylhydantoins (3) were synthesized from β-aminoalanines (1) as the starting materials in two stages. Intermediate urea derivatives (2) prepared from the addition reaction of β-aminoalanines to phenyl isocyanate are easily cyclized to 5-dialkylaminomethylhydantoins (3) with good yields. The deamination reaction of some of the hydantoin derivatives (3a, 3b) in water were observed and resulted in the formation of 3-phenyl-5-methylenehydantoin (4). The hydantoin derivative (3b) regenerated a urea derivative (2c, d) by treatment with excess amounts of pyrrolidine or piperidine.