HETEROCYCLES

■ Contents

■ An Enantioselective Approach to Synthesis of Advanced Chiral Templates for the Construction of Indolic and Indolizidinic Alkaloids

Radouane Affani, Sébastien Comesse,* Adam Daïch,* Louis Hamon, and Catherine Kadouri-Puchot*

*URCOM, EA 3221, CNRS-INC3M FR 3038, UFR of Sciences & Technology, Laboratory of Chemistry, University of Le Havre, 25 Rue Philippe Lebon, BP 540, F-76058 Le Havre Cedex, France

Abstract

A new approach for the syntheses of chiral indolic and indolizidinic templates is presented. They were obtained in three steps starting from a chiral primary amino-vinylsilane. The key step was the N-acyliminium π-cyclization, leading diastereoselectively to the formation of the six membered ring templates.

■ Transformation of Hydroxycycloalkanones to Oxabicycloalkenes

Guido Krämer, Heiner Detert, and Herbert Meier*

*Institute of Organic Chemistry, Johannes Gutenberg-University, Duesbergweg 10-14, D-55128, Mainz, Germany

Abstract

Oxabicycloalkenes, which represent anti-Bredt enol ethers, can be generated by catalytic dehydration of the hemiacetals of hydroxycycloalkanones (Method I). Another option is provided by the transformation of hydroxycycloalkanones to the corresponding 1,2,3-selenadiazoles and their thermal fragmentation on Cu powder (Method II). The intermediate hydroxycycloalkynes show a transannular addition of the OH group to the triple bond. Altogether seven new oxabicycloalk-1-enes were obtained by this methods.

■ Liver X Receptor (LXR) Modulators with Dibenz[b,f][1,4]oxazepin-11-one, (Z)-Dibenz[b,f]azocin-6-one, and 11,12-Dihydrodibenz[b,f]azocin-6-one Skeletons

Atsushi Aoyama, Hiroshi Aoyama, Makoto Makishima, Yuichi Hashimoto, and Hiroyuki Miyachi*

*Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama 700-8530, Japan

Abstract

Conformationally restricted heterocyclic analogs of carba-T0901317 with dibenz[b,f][1,4]oxazepin-11-one, 11,12-dihydrodibenz[b,f]azocin-6-one, and (Z)-dibenz[b,f]-azocin-6-one skeletons were prepared as candidate for liver X receptor (LXR) agonists. In vitro transactivation assay revealed that the activity depends on the nature of the linking group.

■ The Synthesis and Microbiological Activity of New 4-Chloropyridin-2-yl Derivatives

Agnieszka Bogdanowicz,* Henryk Foks, Anna Kędzia, Ewa Kwapisz, Zofia Zwolska, and Ewa Augustynowicz-Kopeć

*Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. Hallera 107, 80-416 Gdańsk, Poland

Abstract

Synthesis of 4-chloropicolinamidrazone derivatives starting from 4-chloropicolinamide is described. The desired compounds were formed by reactions of methyl 4-chloropicolinohydrazonamide or 4-chloro-N'-methylpicolinohydrazonamide with suitable counter partners (carbon disulfide, alkyl halides, aldehydes, ketones, carbohydrazonamides or isothiocyanates) or via 4-chloropicolinimidate, obtained by a convenient method from nitrile with catalytic amount of DBU. Selected products were screened for bacteriostatic and tuberculostatic activity.

■ (S)-Mandelate-Mediated Dynamic Kinetic Resolution of α-Bromo Esters for Asymmetric Syntheses of Aminoflavones, Dihydroquinoxalinones and Dihydrobenzoxazinones

Yoon Min Lee and Yong Sun Park*

*Department of Chemistry, Bio/Molecular Informatics Center, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Korea

Abstract

(S)-Mandelate-mediated dynamic kinetic resolution of α-bromo esters in nucleophilic substitution reaction has been investigated. Reactions of various aryl amine nucleophiles in the presence of TBAI and DIEA can provide the substitution products 2 and 7-19 up to 95% yield and 96:4 dr. Also, the simple procedure with spontaneous removal of the chiral auxiliary provides a practical protocol for asymmetric syntheses of dihydroquinoxalinones 20-26 and dihydrobenzoxazinones 27-30 up to 97:3 er.

■ Reactions of 9-Aryl-6-cyanopurines with Primary Amines

Amal Al-Azmi* and K. Anita Kumari

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

Abstract

Two structural isomers (9-aryl-6-cyanopurines and imidazole-4,5-dicarbonitriles) were isolated from the reaction of (Z)-N1-aryl-N2-(2-amino-1,2-dicyanovinyl)formamidines with triethyl orthoacetate or propionate. On the other hand, 9-aryl-6-cyanopurines were the only product, when triethyl orthoformate was used. The reaction of 9-aryl-6-cyanopurines with hydroxylamine hydrochloride in dichloromethane/ethanol at room temperature furnished 6-amidinopurines, while reaction with primary amines afforded pyrimido[5,4-d]pyrimidines. In addition, 9-aryl-6-cyanopurines reacted with hydrazine monohydrate under mild conditions to give 4-imino-N8-arylpyrimido[5,4-d]pyrimidines. The latter furnished novel pyrimido[4,5-e][1,2,4]triazolo[1,5-c]pyrimidines when refluxed with an excess of triethyl orthoesters. The new compounds were fully characterized and single crystal X-ray analyses have been carried out on 9-(4-methoxyphenyl)-9H-purine-6-carboximidamide and 2-methyl-1-[(E)-p-tolyliminomethyl]-1H-imidazole-4,5-dicarbonitrile.

■ Chemoselective Displacement of Methylsulfinyl Group with Amines to Provide 2-Alkylamino-4,6-disubstituted Pyrimidine-5-carboxylic Acid

Shigeki Seto* and Yasushi Kohno

*Discovery Research Laboratoires, Kyorin Pharmaceutical Co., Ltd., 2399-1 Nogi, Nogi-mcahi, Shimotsuga-gun, Tochigi, 329-0114, Japan

Abstract

An efficient and rapid method for introducing various kinds of alkylamines at C2 of methyl 6-(benzylamino)-4-chloro-2-(methylsulfinyl)pyrimidine-5-carboxylate using the chemoselective displacement of the methylsulfinyl group (SOMe) against a chlorine atom with amines was investigated. Further transformation led to the synthesis of 2-alkylamino-4,6-disubstituted pyrimidine-5-carboxylic acids that are of biological interest.

■ The Reactions of N3P3Cl4[NH(CH2)3NMe] with Difunctional Fluoro Alcohols

Esra Tanrıverdi, Adem Kılıç, Serpil Harbeck, and Gönül Yenilmez Çiftçi*

*Department of Chemistry, Gebze Institute of Technology, Gebze 41400, Kocaeli, Turkey

Abstract

The reactions of N3P3Cl4[NH(CH2)3NMe] (1) in one stoichiometry (1:1) with the sodium derivatives of the fluorinated diols 2,2,3,3-tetrafluorobutane-1,4-diol (2) and 2,2,3,3,4,4-hexafluoropentane-1,5-diol (3) in THF solution at room temperature yielded the following five products, whose structures (4-8) have been characterized by elemental analysis, mass spectrometry, FT-IR, 1H and 31P NMR spectroscopy: the mono-spiro compound, N3P3Cl2[NH(CH2)3NMe](OCH2CF2CF2CH2O) (4), a di-spiro derivative N3P3[NH(CH2)3NMe](OCH2CF2CF2CH2O)2 (6) and the mono-spiro compound, N3P3Cl2[NH(CH2)3NMe](OCH2CF2CF2CF2CH2O) (5), its ansa isomer (8), a di-spiro derivative N3P3[NH(CH2)3NMe](OCH2CF2CF2CF2CH2O)2 (7). Besides, the thermal properties of the compounds (1, 4-8) were investigated by thermal analysis, namely by DSC and TGA.

■ Flavonoid Glycosides Isolated from the Blue Flowers of Nigella damascena

Kenjiro Toki,* Norio Saito, Ai Nogami, Fumi Tatsuzawa, Atsushi Shigihara, and Toshio Honda

*Laboratory of Floriculture, Faculty of Floriculture, Minami-Kyushu University, 11609 Takanabe, Koyu-gun, Miyazaki 884-0003, Japan

Abstract

Two new kaempferol glycosides (1 and 2) were isolated from the blue flowers of Nigella damascena cv ‘Ms Jekyll Blue’ along with a known anthocyanin (3). The structures of 1 and 2 were elucidated by application of chemical and spectroscopic methods. Compound (3) was a rarely observed anthocyanin in plants.

■ Trisubstituted Double Bond in the Cyclooctene Ring. Preparation Using the RCM Reaction

Reiko Mizutani, Takuo Miki, Katsuyuki Nakashima, Masakazu Sono, and Motoo Tori*

*Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Nishihamabouji, Yamashiro-machi, Tokushima, 770-8514, Japan

Abstract

Cyclization to eight-membered rings with a trisubstituted double bond was attempted using ring closing metathesis (RCM) reactions. Although simple substrates were not good candidates, the triene with a proper configuration cyclized to the cyclooctene with a tri-cycle (5-8-6 membered) in moderate yield. The formation of one-carbon smaller rings was also observed.

■ Reactions of Radicals Generated from 1-Ethyl-1,4-diazinium-salts: Addition to the C-C Triple Bond versus Dimerization

Gennadiy L. Rusinov,* Egor V. Verbitskiy, Pavel A. Slepukhin, Olga N. Zabelina, Mikhail I. Kodess, Marina A. Ezhikova, Valeriy N. Charushin, and Oleg N. Chupakhin

*I. Postovsky Institute of Organic Synthesis, 620041 Ekaterinburg, GSP-147, S. Kovalevskoy Str., 22, Russia

Abstract

Radical species generated from 5-aryl-substituted 1-ethyl-2,3-dicyano-1,4-diazinium salts by action of sodium iodide undergo dimerization into [2,2′]bipyrazinyl derivatives, as evidenced by NMR and X-ray crystallography data. The pyrazinyl radicals can also be involved into the addition reaction on the C-C triple bond, thus demonstrating a new synthetic route to modify the structure of pyrazines. The structures of E- and Z-isomers of 1-(1′,2′-dihydropyrazinyl-2′)-2-iodoethenes have been proved by 1H and 13C NMR spectroscopy and X-ray analysis.

■ Synthesis of Quinobenzo-1,4-thiazines from Diquino-1,4-dithiin and 2,2’-Dichloro-3,3’-diquinolinyl Disulfide

Małgorzata Jeleń and Krystian Pluta*

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

Abstract

Synthesis of new type of tetracyclic azaphenothiazines, 6-, 8-, 9- and 10-substituted quinobenzo-1,4-thiazines (benzo[b]-1-azaphenothiazines) (5) and (10), has been worked out from diquino-1,4-dithiin (5,12-diaza-6,13-dithiapenta-cene) (2) as fusion reactions with aniline hydrochlorides (8)·HCl via the 1,4-dithiin ring opening and the 1,4-thiazine ring closure. The better results were obtained when 2,2’-dichloro-3,3’-diquinolinyl disulfide (9) reacted with anilines (8) in MEDG. Selected 6H-quinobenzo-1,4-thiazines (5a) (5c) and (5g) were transformed into 6-alkyl derivatives (10a-10n) by N-alkylation with alkyl halides. Homonuclear NOE experiment for the 6-methyl derivative (10a) confirmed the product structure as quino[3,2-b]benzo[1,4]thiazine.

■ Caro’s Acid-Silica Gel Catalyzed Synthesis of 2-Aryl-1H-Benzimidazoles and 2-Aryl-1-arylmethyl-1H-benzimidazoles

Ali A. Mohammadi,* Javad Azizian, and Narges Karimi

*Department of Chemistry, Faculty of Science, Islamic Azad University, Sabzevar 9618814711, Iran

Abstract

An efficient procedure for the synthesis of 2-aryl-1H-benzimidazoles and 2-aryl-1-arylmethyl-1H-benzimidazoles has been developed by simple condensation of o-phenylenediamine and aromatic aldehyde in the presence of Caro's acid supported on silica gel in ethanol under reflux.

■ Transformations of Ethyl 2-Amino-4-(2-ethoxy-2-oxoethyl)thioazole-5-carboxylate into 5-Substituted 2-Amino-4-oxo-4,5-dihydrothiazolo[5,4-c]pyridine-7-carboxylates

Alen Albreht, Uroš Uršič, Jurij Svete, and Branko Stanovnik*

*Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, 1000 Ljubljana, Slovenia

Abstract

Ethyl 4-[1-(dimethylamino)-3-ethoxy-3-oxoprop-1-en-2-yl]-2-[(dime- thylamino)methylideneamino]thiazole-5-carboxylate (2), prepared from ethyl 2-amino-4-(2-ethoxy-2-oxoethyl)thiazole-5-carboxylate (1) according to a known procedure, was transformed with aromatic amines 3a-d into 5-aryl substituted 2-aminothiazolo[5,4-c]pyridine-7-carboxylates 5a-d, while treatment of 2 with monosubstituted hydrazines 6a-h produced 5-N-amino substituted thiazolo[5,4-c]pyridine-7-carboxylates 8a-h.

■ Synthesis of Pyrrolo[2,3-d]pyrimidine Analogues: “Pyridine Ring” Analogues of Pemetrexed

Yun Xu, Mingfeng Yu, Yan Long, Han Wu, and Zhenmin Mao*

*School of Pharmacy, Shanghai Jiaotong University , 800 Dongchuan Road, Shanghai 200240, China

Abstract

Two analogues of pemetrexed with its phenyl ring replaced with pyridine ring as novel anticancer agents were synthesized. Preliminary in vitro evaluation indicated that replacement of the phenyl moiety of pemetrexed by the pyridine ring with the 6-5 bicyclic ring system showed low cytotoxicity, that departs from the findings with antifolates bearing 6-6 bicyclic ring system.

■ A New Cardenolide Triglycoside from Stems and Twigs of Nerium oleander

Liming Bai,* Ryo Hasegawa, Katsutoshi Hirose, Mariko Ando, Jun-ichi Sakai, and Masayoshi Ando

*College of Chemistry and Chemistry Engineering, Qiqihar University, 30 Wenhuadajie, Qiqihar, Heilongjian Shang, 161006, China

Abstract

A new cardenolide triglycoside, cardenolide B-3 (1) was isolated from Nerium oleander L. The structure of 1 was established to be 3β-O-[β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl-(1→4)-β-D-diginopyranosyl]-7β,8-epoxy-14-hydroxy-5β,14β-card-20(22)-enolide on the basis of their spectroscopic data.

■ A Concise Synthesis of Solamin and cis-Solamin, Mono-THF Acetogenins from Annona muricata

Hidefumi Makabe,* Asuka Kuwabara, Yasunao Hattori, and Hiroyuki Konno

*Shinshu University, 8304 Minamiminowa-mura, Kamiina-gun, Nagano 399-4598, Japan

Abstract

A concise total synthesis of solamin (1) and cis-solamin (2) was performed using an epoxy alcohol (11) as a versatile chiral building block for synthesizing the stereoisomers of the mono-THF annonaceous acetogenins.