HETEROCYCLES

■ Contents

■ First Synthesis of Piperazine-derived [1,2,4]Triazolo[1,5-a]pyrazine as an Adenosine A_2A Receptor Antagonist

Hairuo Peng,* Li Sha, He Xi Chang, Jeffery T. Vessels, Serajul Haque, Patrick R. Conlon, James E. Dowling, Joy Wang, Thomas M. Engber, Gnanasambandam Kumaravel, Daniel M. Scott, and Russell C. Petter

*Departments of Medicinal Chemistry and Pharmacology, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, MA 02142, U.S.A.

Abstract

Synthesis of piperazine-derived 2-furan-2-yl-[1,2,4]triazolo[1,5-a] pyrazines was achieved using methyl 3-amino-2-pyrazinecarboxylate. Introduction of the piperazine to the pyrazine template was achieved through a pteridin-4-one intermediate (7). Cyclization of the [1,2,4]triazolo[1,5-a]pyrazine ring was accomplished by amination of pyrazine (8) followed by condensation with 2-furaldehyde. Curtius rearrangement installed the amine to afford template (11). As one example of derivatizing 11, 6N-(4-(2,4,6-trifluorobenzyl)piperazin-1- yl)-2-(furan-2-yl)-[1,2,4]triazolo-[1,5-a]pyrazin-8-amine (12) showed moderate adenosine A_2a receptor binding affinity and selectivity over the A₁ receptor.

■ Synthesis of New Trifluoromethyl Substituted 11H-Isoindolo[2,1-a]benzimidazol-11-one Derivatives

Boddupally P V Lingaiah, Tallapally Yakaiah, Pamulaparthy S Rao,* and Banda Narsaiah

*Fluoroorganic Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India

Abstract

A convenient method has been developed for the synthesis of new trifluoromethyl-substituted 11H-isoindolo[2,1-a]benzimidazol-11-one derivatives from 3-nitro-5-trifluoromethyl-o-phenylenediamine and aromatic anhydrides on the surface of silica gel impregnated with ZnCl₂ under solvent free microwave irradiation conditions.

■ Synthesis of Porphyrin — Acetylene and Porphyrin-Diene Building Blocks for New Dyads Preparation

Stanislaw Ostrowski* and Agnieszka Mikus

*Institute of Chemistry, University of Podlasie, ul. 3-go Maja 54, 08-110 Siedlce, Poland

Abstract

A new synthetic approach to porphyrin-acetylene and porphyrin-diene derivatives utilizing tetraphenylporphyrin (TPP) and two new reactions (vicarious nucleophilic substitution and metathesis) is described. 5-(4-Nitrophenyl)-10,15,20-triphenylporphyrin zinc complex reacts with ^-CHXY type carbanions, affording the nucleophilic substitution of hydrogen products containing CH₂SO₂Tol, CH₂SO₂Ph, CH₂SO₂NMe₂, and CH₂CN groups, respectively. The products obtained when alkylated with alkyl halides, bearing an acetylenic function in the terminal position, resulted in the formation of TPP-acetylene building blocks. These systems were subjected to cross-enyne metathesis reaction with ethylene (with the use of efficient ruthenium catalysts) to give the porphyrin-diene dyads - the excellent substrates for further transformations.

■ One-Pot Synthesis of 3-Aryl-3H,4H-[1,2]-dithiolo[3,4-b]benzothiopyran-4-ones and 1-(o-Bromophenyl)-3-aryl-2-prop-2-en-1-ones

Chandrani Mukherjee, Hongming Zhang, and Edward R. Biehl*

*Chemistry Department, Southern Methodist University, Dallas, TX 75275-0314, U.S.A.

Abstract

3-Aryl-3H,4H-[1,2]dithiolo[3,4-b]benzothiopyran-4-ones were prepared by the reaction of 1 equiv. of 2’-bromoacetophenone with 3.5 equiv. of potassium O-ethyl xanthate and 1 equiv. of an appropriate aromatic or heteroaromatic aldehyde. The yields of the thiopyran-4-ones are high. The key step of the reaction appears to be the conversion of the aldehyde to the corresponding thioaldehyde by the xanthate. The thioaldehyde is subsequently trapped by the anion of 2-thioxothiochroman-4-one intermediate. The intermediacy of thioaldehydes was confirmed by treating aldehydes with potassium ethyl xanthate in the absence of 2’-bromo ketones. Additionally, chalcones were readily prepared by the condensation of 2’-bromo ketones with appropriate aldehydes in the presence of potassium O-ethyl xanthate.

■ Five Monoterpene Glycosides from Zingiberis Rhizome (Shokyo)

Yumiko Hori, Tsuyoshi Miura, Yukiye Wakabayashi, Motonori Fukumura, Yasuaki Hirai, Kazuo Toriizuka, Yoshiyuki Kuchino, and Yoshiteru Ida*

*School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan

Abstract

Five monoterpene glycosides were isolated from Zingiberis rhizome (Japanese name: Shokyo). They were characterized to be (+)-angelicoidenol 2-O-β-D-glucopyranoside (1), (+)-angelicoidenol 2-O-β-D-glucopyranosido-5-O-β-D-glucopyranoside (2), (+)-angelicoidenol 2-O-β-D-apiofuranosyl(1→6)-β-D-glucopyranoside (3), (+)-angelicoidenol 2-O-[6’-O-S-3-hydroxy-3-methylglutaryl]-β-D-glucopyranoside (4) and its methyl ester (5), respectively, by means of spectroscopic and chemical methods. Of them, the new glycosides (2, 3 and 4) were named zingiberosides A, B and C, respectively.

■ Synthesis of Thienoimidazo[4,5-b]pyridines and Thenylidenoimidazolinones

Malin Björk and Spiros Grivas*

*Unit for Organic Chemistry, Department of Biosciences, Karolinska Institutet, Södertörn University College, Novum Research Park, SE-141 57 Huddinge, Sweden

Abstract

The two isomers 2-amino-1-methylimidazo[4,5-b]thieno[3,2-e]pyridine (3) and 2-amino-1-methylimidazo[4,5-b]thieno[2,3-e]pyridine (4) were synthesized by the Friedländer reaction starting from creatinine and the appropriate aminothiophenecarbaldehydes (11 and 13). Creatinine was also condensed with 2-nitro-3-thiophenecarbaldehyde (10) in ethylene glycol to yield the 2-amino-1-methyl-5-[2-(2-nitro-3-thenylidene)]-2-imidazolin-4-one (7a), with 3-amino-2-thiophenecarbaldehyde (13) under Perkin conditions to yield 2-acetamido-5-[2-(3-acetamido-2-thenylidene)]-1-methyl-2-imidazolin-4-one (8), and with 4-azido-3-thiophenecarbaldehyde (17) in acetic acid to yield 2-amino-5-[2-(4-azido-3-thenylidene)]-1-methyl-2-imidazolin-4-one (9). The thenylidenoimidazolinone (8) was converted into compound (4).

■ Manganese(III) Acetate Mediated Oxidative Free Radical Reactions between Indole Derivatives and 1,3-Dicarbonyl Compounds

An-I Tsai, Chia-Hui Lin, and Che-Ping Chuang*

*Department of Chemistry, National Cheng Kung University, 1, Ta-Shiueh Rd., Tainan, 70101, Taiwan, R.O.C.

Abstract

Manganese(III) mediated oxidative free radical reactions between indole derivatives and 1,3-dicarbonyl compounds are described. In the presence of dimethyl malonate, the oxidative free radical reaction of 3-unsubstituted indoles resulted in the formation of 2-(3-oxo-2-indolylidene)malonates and these malonates can be prepared in much better yields from corresponding 3-indolecarboxylic acids. On the contrary, the oxidative free radical reaction between 3-unsubstituted indoles and 2,4-pentanedione or ethyl acetoacetate gave furo[3,2-b]indoles.

■ 1,3-Benzodioxole-based β- and γ-Peptide Linkages Exhibiting Unique Fluorescence, Conformation, and Self-association Properties

Masaya Suzuki, Yuya Ohguro, Kazukiyo Kobayashi, and Yoshihiro Nishida*

*Department of Molecular Design and Engineering, Graduate School of Engineering, Nagoya University, Chikusa, Nagoya, Aichi 464-8601, Japan

Abstract

Four types of β- and γ-peptide models were prepared from our previous asymmetric 1,3-benzodioxole and characterized by means of fluorescence and ¹H NMR spectroscopy. A β-peptide model carrying secondary amide linkages at both of the C- and N-termini took a rigid coplanar conformation, emitting the strongest fluorescence [Ex.(max) 340 nm and Em.(max) 424 nm] among the four models. Dual intra-molecular hydrogen bonds were associated with the stable coplanar conformation. A tertiary β-peptide model carrying a tertiary amide linkage at the C-terminus took a twisted conformation around the C-terminal to afford a pair of rotational isomers (atropisomers) detectable with ¹H NMR spectroscopy. Both secondary and tertiary γ-peptide models showed a notable self-association property to afford dimers made of complementary intra- and intermolecular hydrogen bonds.

■ Synthesis and Unambiguous Stereochemical Determination of 1-exo- and 1-endo-1-Aryl-1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones

Masayuki Yamashita, Yadav Navnath Dnyanoba, Masaki Nagahama, Tomoki Inaba, Yuka Nishino, Kumiko Miura, Sachiko Kosaka, Junko Fukao, Ikuo Kawasaki, and Shunsaku Ohta*

*Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan

Abstract

Stereoselective preparation of 1-exo-substituted 1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones (2) was achieved by photo [2+2] cycloaddition of olefins to 3-substituted coumarins (1). 1-endo-Substituted 1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones (3) were stereoselectively prepared by hydrogenation over the Pd-carbon of 2a,8b-dihydro-3H-benzo[b]cyclobuta[d]pyran-3-ones (5), which were obtained by photo [2+2] cycloaddition of the coumarins (1) to acetylenes. The stereochemistry of 1-exo- and 1-endo-arylcyclobutanes (2 and 3) could be easily determined on the basis of the ¹H-NMR spectrum, in which the C8-proton in 3 was strongly shielded by the 1-aryl ring but that in 2 was not.

■ Isolation, Synthesis and Biological Activity of Grifolic Acid Derivatives from the Inedible Mushroom Albatrellus dispansus

Toshihiro Hashimoto, Dang Ngoc Quang, Makiko Nukada, and Yoshinori Asakawa*

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

Abstract

Grifolin, grifolic acid, grifolic acid methyl ester and a new compound grifolinol were isolated from methanolic extract of the inedible mushroom Albatrellus dispansus (Scutigeraceae). Their structures were established by a combination of 2D NMR, MS spectrum and chemical reaction. In addition, (+)- and (-)-daurichromenic acids were obtained by cyclization of grifolic acid. The inhibitory activity of TNF-α, anti HIV and antimicrobial activity of grifolic acid derivatives were examined.

■ One-pot Synthesis of A₂BC-Type Free Base Porphyrins

Yasser M. Shaker and Mathias O. Senge*

*Department of Chemistry, Trinity College Dublin, Dublin 2, Ireland

Abstract

Treatment of 5,15-diarylporphyrins with a combination of organolithium and alkyl iodide reagents followed by hydrolysis with water and oxidation with DDQ gives convenient access to A₂BC-type meso-tetrasubstituted free base porphyrins in a one-pot synthesis. Key intermediates are mesomeric phlorin- and porphodimethene-type anions, the latter one being able to react with electrophiles under thermodynamic control.

■ Syntheses and Reactions of 2-Cyclohexyl-1,3,4,5-tetrahydro-10H-pyrrolo[3,4-b][1,5]benzodiazepine-1,4-dione and 4-Aryl-2-cyclohexyl-1,3,4,10-tetrahydropyrrolo[4,3-c][1,5]benzothiazepin-1-ones

Keizo Matsuo,* Junko Kawanishi, Mariko Kobayashi, and Sachiko Ueno

*Faculty of Pharmaceutical Sciences, Kinki University, 3-4-1, Kowakae, Higashi-Osaka 577-8502, Japan

Abstract

2-Cyclohexyl-1,3,4,5-tetrahydro-10H-pyrrolo[3,4-b][1,5]benzodiazepine-1,4-dione was synthesized by heating a solution of ethyl 1-cyclohexyl-2,3-dioxopyrrolidine-4-carboxylate and o-phenylenediamine in acetic acid. Alkylation and acylation of the synthesized compound were examined. 4-Aryl-2-cyclohexyl-1,3,4,10-tetrahydropyrrolo[4,3-c][1,5]benzothiazepin-1-ones were synthesized by Michael addition of 2-aminothiophenol to 4-arylidene-1-cyclohexyl-2,3-dioxopyrrolidines and concomitant dehydrative cyclization.

■ Three New Stilbeneoligomers from the Roots of Vitis vinifera ‘Kyohou’

Fuko Fujii, Yue-Hua He, Kenji Terashima, Yoshiaki Takaya, and Masatake Niwa*

*Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpaku, Nagoya 468-8503, Japan

Abstract

Three new stilbeneoligomers named (+)-viniferol E, (+)-viniferether A and (+)-viniferether B were isolated from the roots of Vitis vinifera ‘Kyohou’ and the structures were elucidated on the basis of the spectral evidence.

■ 1H,6H-Triazolo[4,5-e]benzotriazole-3-oxides and 5,5’-(Z)-Diazene-1,2-diylbis(2-methyl-2H-1,2,3-benzotriazole) Derived from Chloronitrobenzotriazoles and Hydrazine

Antonio Carta,* Sandra Piras, Gianpiero Boatto, and Giuseppe Paglietti

*Department of Medicinal and Toxicological Chemistry, University of Sassari, Via Muroni 23, 07100 Sassari, Italy

Abstract

Nitration of 5-chlorobenzotriazole (1) and its N1-methyl derivatives (2 and 3) produced 5-chloro-4-nitrobenzotriazole (5), 5-chloro-1-methyl-4-nitrobenzotriazole (6) and 6-chloro-1-methyl-7-nitrobenzotriazole (7) respectively. Nitration of 5-chloro-2-methylbenzotriazole (4) gave either 5-chloro-2-methyl-4-nitrobenzotriazole (8) or 5-chloro-2-methyl-4,6-dinitrobenzotriazole (9). Introduction of the nitro group activated chlorine atom that underwent nucleophilic displacement by hydrazine to give rise to a new tricyclic system 1H,6H-triazolo[4,5-e]benzotriazole-3-oxide compounds (10 and 11) in the case of 5 and 6. From 9 no linear or angular tricyclic triazolobenzotriazole was obtained but instead the 5,5’-(Z)-diazene-1,2-diylbis(2-methyl-2H-1,2,3-benzotriazole) (18).

■ A Simple Method for the Synthesis of 1-Substituted β-Carboline Derivatives from Tryptamine and Carboxylic Acids in Polyphosphoric Acid

Iliyan Ivanov,* Stoyanka Nikolova, and Stela Statkova-Abeghe

*Department of Organic Chemistry, University of Plovdiv, 24, Tsar Assen Str. 4000 Plovdiv, Bulgaria

Abstract

A number of 1-substituted 3,4-dihydro-9H-β-carboline derivatives (4) with high purity and yields have been synthesized by treating of tryptamine (1) with carboxylic acids (2) in polyphosphoric acid. 3,4-Dihydro-9H-β-carbolines (4) were successfully transformed to 1,2,3,4-tetrahydro-9H-β-carbolines (5) and 9H-β-carbolines (6).

■ One-pot Synthesis of trans-7-Aryl-6H-6a,7-dihydro[1]benzopyrano[3,4-c][1,5]benzothiazepines

Ramadas Sathunuru, Benjamin Koh, Hongming Zhang, and Ed Biehl*

*Chemistry Department, Southern Methodist University, Dallas, TX 75275-0314, U.S.A.

Abstract

Green chemical approaches for the condensation reaction of benzenethiols and 3-arylidenenchroman-4-ones as synthons for the synthesis of a series of newtrans-7-aryl-6H-6a,7-dihydro[1]benzo pyrano[3,4-c][1,5]benzo- thiazepines which may possess potential biological activity are described.

■ Synthesis of Quinolyl- and Isoquinolyl Heteroarylamines Using Palladium Catalyzed Suzuki Cross-Coupling Reaction

Ihl Young Choi Lee,* Myung Hee Jung, Hee-Jeong Lim, and Hyo Won Lee*

*Medicinal Chemistry, Korea Research Institute of Chemical Technology, 100 Jang-dong, Yuseong, Daejon 305-600, Korea

Abstract

Quinolyl- and isoquinolylboronic acids are prepared from 5-bromoquinoline and 5-bromoisoquinoline, respectively, via halogen-metal exchange. Suzuki cross-coupling of these compounds with haloheteroarylamine leading to the corresponding heteroarylamine derivatives is described.

■ Stereoselective Cycloadditions of Nitrilimines as a Source of Enantiopure Heterocycles

Giorgio Molteni

*Dipartimento di Chimica Organicane Industriale , Università digli Studi di Milano, Via Golgi 19, I-20133 Milano, Italy

Abstract

Stereoselective 1,3-dipolar cycloadditions of nitrilimines represents a useful tool in the obtainment of a number of enantiopure heterocycles containing the 4,5-dihydropyrazole ring. The literature data on this subject are reviewed in a systematic way for both inter-and intramolecular processes, with an emphasis to their versatile potential in heterocyclic synthesis.