HETEROCYCLES

■ Contents

■ Synthesis of N-Imidazolidin-2-ylidenehydrazones and Their Transformation into 5,10,11,12a-Tetrahydro-6H,9H-imidazo[2’,1’:3,4][1,2,4]triazolo[1,5-c]quinazoline-6-thiones

Anita Kornicka* and Maria Gdaniec

*Department of Chemical Technology of Drugs, Medical University of Gdansk, Al. Gen. J. Hallera 107, 80-416 Gdansk, Poland

Abstract

The reaction of 2-chloro-4,5-dihydroimidazole (1) with 2-aminoacetophenone hydrazones (2a-b) afforded 1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolines (3a-b) in contrast to the analogues reaction of 1 with 2-aminobenzophenone hydrazones (4a-e), which led to the formation of corresponding N-imidazolidin-2-ylidenehydrazones (5a-e). Compounds (5a-d) were further treated with carbon disulfide to give 5,10,11,12a-tetrahydro-6H,9H-imidazo[2’,1’:3,4][1,2,4]triazolo[1,5-c]quinazoline-6-thiones (6a-d). The structures of all new compounds obtained were established by elemental analyses and spectroscopic data (IR, NMR) as well as X-ray crystallographic analyses of 5a and 6a.

■ Chemistry of Nitroenamines. Synthesis of Pyrrolizine Derivatives

Mihály V. Pilipecz, Zoltán Mucsi, Péter Nemes,* and Pál Scheiber

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

Abstract

2-Nitromethylene-pyrrolidine (1) readily reacts with di- and tricarbonyl compounds resulting in addition products (4a-d), which could be cyclized to substituted dihydro-1H-pyrrolizines easily (8a-e).

■ Conversion of Bacteriochlorophyll-A to Bacteriopurpurin-18: A Useful Synthon for the Construction of Bioactive Agents for Photodynamic Therapy (PDT)

Lalit N. Goswami, Yihui Chen, Joseph Missert, Guolin Li, Alex Pallenberg, and Ravindra K. Pandey*

*Medicinal Chemistry Division, Photodynamic Therapy Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA

Abstract

Bacteriochlorophyll-a 5 present in Rb. sphaeroides was converted into bacteriopurpurin-18 methyl ester 10 by following three different approaches and was used as a substrate for the preparation of a series of stable bacteriochlorins with long wavelength absorptions ranging from 760 to 824 nm. Bacteriopurpurin p₆ 17, obtained by the base hydrolysis of 10, on reacting with L-aspartyl-di-tert-butyl ester in presence of EDCI and DMAP afforded the corresponding N-aspartyl-bacteriopurpurinimide 21 in high yield, possibly by the base-catalyzed intramolecular cyclization via the isoimide intermediate(s) 19 and 20. A possible mechanism for the formation of 10 and bacteriochlorin 15-glyoxilic acid trimethyl ester 8 from 5 via hydroxylactone 11 is also discussed. Among the compounds synthesized, the bacteriochlorin 21 containing a fused cyclic imide ring system was found to be the most stable in various solvents at room temperature and exhibited the longest wavelength absorption at 824 nm in dichloromethane.

■ Utility of Cyanoacetamides as Precursors to Pyrazolo[3,4-d]pyrimidin-4-ones, 2-Aryl-6-substituted 1,2,3 Triazolo[4,5-d]pyrimidines and Pyrazolo[1,5-a]pyrimidine-3-carboxamides

Hamada Mohamed Ibrahim, Saad Makhseed,* Ramadan Maawad Abdel-Motaleb, Abdel-Moneim Abdel-Salam Makhlouf, and Mohamed Hilmy Elnagdi

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

Abstract

Cyanoacetamides (7a-c) were prepared via reacting cyanoacetic acid (5) with amines in the presence of acetic anhydride. Compounds (7a-c) coupled with benzenediazonium chloride to yield the phenylhydrazones (8a-c). These reacted with chloroacetonitrile to yield aminopyrazolecarboxamides (11a-c). Reaction of (8a,b) with hydroxylamine hydrochloride in DMF in presence of anhydrous sodium acetate afforded the amino-1,2,3-triazolecarboxamides (36a,b). Also compounds (7a-c) reacted with dimethylformamide dimethylacetal (DMFDMA) to yield the enamines (9a-c) which react with hydrazine hydrate to afford the aminopyrazoles (16a-c). Compounds (16) and (36) reacted with DMFDMA to yield the title heterocyclic derivatives.

■ Two-Stage Sonogashira Coupling Method in the Synthesis of Auxin Active Acetylenes

G. Wayne Craig,* Martin Eberle, Bruno Irminger, Anegret Schückenböhmer, Yvette Laime, and Patrick Müller

*Syngenta Crop Protection, CH-4002 Basel, Switzerland

Abstract

A sequential Sonogashira coupling of a protected acetylene precursor with aryl halides (5) followed by pyrazolyl iodides (14) allows efficient access to the unsymmetrical aryl-heteroarylacetylene (8). Subsequent regioselective lithiation exchange followed by dimethyl oxalate quench produced readily vicinal ketoesters (9) which show auxin effects in a wide variety of plant species.

■ From Haloquinolines and Halopyridines to Quinoline- and Pyridinesulfonyl Chlorides and Sulfonamides

Andrzej Maslankiewicz,* Krzysztof Marciniec, Maciej Pawlowski, and Pawel Zajdel

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

Abstract

The action of sodium methanethiolate (in boiling DMF) towards haloazines (i.e. chloro- or bromo-pyridines and quinolines) (1) (with halogen substituent in non-aza-activated position) causes sequentially halogen ipso-substitution to methylthioazines (2) and then S-demethylation to azinethiolates (3A), which were: i) subjected to S-methylation, ii) oxidized to diazinyl disulfides (4) and iii) oxidatively chlorinated to azinesulfonyl chlorides (5). α- and β-pyridine- and quinolinesulfonyl chlorides (5a, 5c, 5d and 5f) were prepared by oxidative chlorination of respective disulfides (4) performed in conc. hydrochloric acid and characterized by ¹H and ¹³C NMR spectra. All azinesulfonyl chlorides (5) were effectively converted to corresponding azinesulfonamides (6).

■ Properties of the Keto Amides Formed by Aminolysis of 3,7-Diarylpyrano[4,3-c]pyran-1,5-dione Derivatives: A Solid-State Reaction, Crystal Structures, and Thermal Analysis

Chika Kawabe, Keitaro Kawakita, Masanori Morinaga, Mitsuru Kondo, and Hajime Irikawa*

*Department of Chemistry, Faculty of Science, Shizuoka University, Ohya 836, Surugaku, Shizuoka 422-8529, Japan

Abstract

Aminolysis of 3,7-diarylpyrano[4,3-c]pyran-1,5-dione derivatives gave keto amides, which upon heating returned back to the original compounds in the solid state. X-Ray crystallographic analysis of the keto amides showed proximate orientations of the ketone and the amide groups. TGA and DTA of the keto amides clarified a kind of solid-state reaction which occurred in appearance without melting, but microscopically proceeded via melting of the keto amides, structural change, and crystallization of the products.

■ Synthesis and Properties of 3,2’-Polymethylene-2-phenylbenzo[b]-1,10-phenanthrolines

A. F. M. Motiur Rahman and Yurngdong Jahng*

*College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Korea

Abstract

Reactions of 4-aminoacridine-3-carbaldehyde with benzo[b]cycloalkanones and 3,4-dihydro-1(2H)-anthracenone afforded a series of corresponding 3,2’-polymethylene-2-phenylbenzo[b]-1,10-phenanthrolines and 3,3’-dimethylene-2-(naphth-2’-yl)benzo[b]-1,10-phenanthroline, respectively, as new N,N,C-terdentates. Dehydrogenation of dimethylene-bridged systems afforded the corresponding fully aromatized systems. Flexibility of annulated bridges is highly dependent on the length of the carbon chain, where tetramethylene-bridge is rigid enough to differentiate eight bridge protons in ¹H NMR time scale at room temperature.

■ Pilsicainide and Its Oxymethylene Analog: Facile Alternative Syntheses and in vitro Testing on Human Skeletal Muscle Sodium Channels

Claudio Bruno, Alessia Catalano, Jean-Francois Desaphy, Maria M. Cavalluzzi, Alessia Carocci, Antonella Dipalma, Carlo Franchini, Giovanni Lentini,* Diana Conte Camerino, and Vincenzo Tortorella

*Medicinal Chemistry Department, Faculty of Pharmacy, via E. Orabona 4, 70125 Bari, Italy

Abstract

Facile, alternative synthetic routes gave access to both pilsicainide [N-(2,6-dimethylphenyl)-2-tetrahydro-1H-pyrrolizin-7a(5H)-ylacetamide, 1], a well-known I_C antiarrhythmic drug, and its oxymethylene analog 2. Both compounds were tested on human skeletal muscle voltage-gated sodium channels, hNav1.4, transfected in tsA201 cells. 7a-[2-(2,6-Dimethylphenoxy)ethyl]hexahydro-1H-pyrrolizine (2) behaved as a bioisostere of 1, exerting a 4-fold more potent use-dependent block.

■ Biomimetic Aromatization of Hantzsch 1,4-Dihydropyridines by S-S Bonds under Mild Conditions

Hamid Aliyan,* Razieh Fazaeli, Ahmad Reza Moemeni, Ahmad Reza Massah, Hamid Javaherian Naghash, and Fattaneh Khosravi

*Department of Chemistry, Islamic Azad University, Shahreza branch, 86145-311, Iran

Abstract

For the first time Hantzsch 1,4-dihydropyridines were oxidized to the corresponding pyridines by diphenyl disulfide in ionic liquid.

■ Sessilifoliamide I, a New Alkaloid from Stemona sessilifolia

Yukio Hitotsuyanagi, Maho Hikita, Kazuhiro Nakada, Haruhiko Fukaya, and Koichi Takeya*

*School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

Abstract

A new alkaloid, sessilifoliamide I, was isolated from the roots of Stemona sessilifolia (Miq.) Miq. Its structure was established by interpretation of spectral data and X-ray crystallography.

■ Synthesis of 6-Cycloalkylcarbonyl-2(3H)-benzothiazolones via 6-Tributyltin Intermediates

Pascal Carato,* Kallyl Cherry, Nicolas Lebegue, Pascal Berthelot, and Saïd Yous

*Laboratorie de Chimie Thérapeutique, Faculté Pharmcie, Université de Lille 2, 3, rue du Professeur Laguesse, BP 83, 59006 Lille Cedex, France

Abstract

6-Cycloalkylcarbonyl-2(3H)-benzothiazolones cannot be prepared by classical Friedel-Crafts acylation with the corresponding cycloalkylcarbonyl chlorides. We have explored new way via stille coupling from the tributyltin intermediates which were synthesised by protection of the NH group with ethylmethyl ether or potassium salt of the corresponding 6-bromo-2-(3H)-benzothiazolone. The stille coupling reaction of these tributyltin intermediates with the desired cycloalkylcarbonyl chlorides followed by deprotection of the NH group, afforded the corresponding 6-cycloalkylcarbonyl-2(3H)-benzothiazolones.

■ Synthesis of New Heterocyclic System: 1(5)H-1,5-Diazacycl[3.3.2]azine-2,4-dione

Anton V. Dolzhenko, Anna V. Dolzhenko, and Wai-Keung Chui*

*Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore

Abstract

A synthesis of hitherto unknown heterocyclic system 1(5)H-1,5-diazacycl[3.3.2]azine-2,4-dione (5) is presented. The cyclocondensation of 2,6-diaminopyridine (1) with maleic anhydride yielded (5-amino-2-oxo-2,3-dihydroimidazo[1,2-a]pyridin-3-yl)acetic acid (2), which was converted to methyl (5-amino-2-oxo-2,3-dihydroimidazo[1,2-a]pyridin-3-yl) acetate hydrochloride (3). The ester (3) upon treatment with sodium carbonate solution underwent intramolecular cyclization to 2a,3-dihydro-1(5)H-1,5-diazacycl[3.3.2]azine-2,4-dione (4), which was oxidized in alkaline condition to provide 5.

■ Pecrassipines A and B, Seco-Bisbenzylisoquinoline Alkaloids from Phaeanthus crassipetalus

Khalijah Awang,* Saripah Salbiah Syed Abd. Azziz, A. Hamid A. Hadi, Hiroshi Morita, Yusuke Hirasawa, Toru Iizuka, Marc Litaudon, and Mat Ropi Mukhtar

*Faculty of Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

Chemical investigation on the bark of Phaeanthus crassipetalus (Annonaceae) yielded two new seco-bisbenzylisoquinoline alkaloids, (+)-pecrassipine A (1) and (-)-pecrassipine B (2), together with seven known alkaloids. Their structures were elucidated by two-dimensional NMR techniques. Pecrassipines A and B exhibited a vasorelaxant activity on isolated rat aorta ring.