HETEROCYCLES

■ Contents

■ Synthesis, Reaction and Biological Activity of Pyrazolo[5,1-c][1,2,4]benzotriazine 5-Oxides

Ghodsi Mohammadi Ziarani,* Manizheh Mostofi, Negar Lashgari,* and Mohammad Mahdavi

*Department of Chemistry, Alzahra University, Tehran, Iran

Abstract

[1,2,4]Benzotriazine fused to pyrazole ring is a privileged heterocyclic scaffold present in numerous pharmacologically active compounds. Till date, various pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides and their deoxy analogues, possessing a broad spectrum of potent pharmacological activities, have been reported. In this review, we highlighted synthesis, chemical reactions, medicinal chemistry aspects and applications of fused pyrazole derivatives of [1,2,4]benzotriazine analogues reported so far.

■ New Facile Synthesis of 3-Substituted 7,8-Dihydroquinolin-5(6H)-ones and [1]Benzopyrano[4,3-b]pyridin-5-ones Using 2-(Hetero)arylvinamidinium Salts

Yiyi Weng, Chen Sun, Qingwei Cao, Hantao Chen, Nanhui Li, Zhuo Chen, and Weike Su*

*Collaborative Innovation Center of Yangtze River Delta Region Green of Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China

Abstract

The method of cyclocondensation of 3-amino-2-cyclohexen-1-ones 2 or 4-aminocoumarin 3 with symmetrical 2-(hetero)aryl-vinamidinium salts 1 has been developed, providing an efficient synthetic pathway to access novel functionalized 3-substituted 7,8-dihydroquinolin-5(6H)-ones 4 or [1]benzopyrano[4,3-b]pyridin-5-ones 5 in good to excellent yields. All the aryl-substituted and heterocyclic-substituted vinamidinium salts undergo a facile electrocyclic ring closure to form pyridine ring with α,β-unsaturated ketones. A possible mechanism for the formation of pyridine ring is proposed.

■ Synthesis, Characterization and Antimicrobial Evaluation of Some Novel Fused Pyrimido[1,2-b][1,2,4]triazine, Triazino[2,3-a]quinazoline and Imidazo[1,2-b][1,2,4]triazine Derivatives

Khaled S. Mohamed* and Elsherbiny H. El-Sayed

*Engineering Chemistry Department, Higher Institute for Engineering and Technology, New Damietta, Egypt

Abstract

A novel pyrimido[1,2-b][1,2,4]triazine derivatives were synthesized by allowing 3-amino-1,2,4-triazine (1) to react with different reagents such as enaminone, enaminonitriles, 3-bromopropanenitile, 2-(2,5-dimethoxybenzylidene)malononitrile and 1,3-dicarbonyl compounds. Moreover, triazino[2,3-a]quinazoline derivatives were synthesized by reaction of 1 with 2-((dimethylamino)methylene)-5,5-dimethylcyclohexane-1,3-dione (18) and 2,6-bis(pyridin-3-ylmethylene)cyclohexan-1-one (20). On the other hand, treatment of 1 with 2-bromo-1-(naphtho[2,1-b]furan-2-yl)ethan-1-one (22) afforded imidazo[1,2-b][1,2,4]triazine derivative (23). The newly synthesized compounds were evaluated for their antimicrobial activities based on inhibition diameter zone against Gram positive and Gram negative bacteria.

■ Effect of meta-Substituents on the Radical Scavenging Activity of 6-Chromanol Derivatives

Keiko Inami,* Yuta Okayama, Mariko Suzuki, and Masataka Mochizuki

*Division of Pharmaceutical Organic Chemistry, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, 1-1-1 Daigakudori, Sanyo-Onoda-shi, Yamaguchi 756-0884, Japan

Abstract

A series of 8-substituted 6-chromanols, namely, the methyl- (4), methoxy- (5), amino- (6), methylamino- (7), dimethylamino- (8), 1-pyrrolidinyl- (9), piperidino- (10), 1-piperazinyl- (11), and morpholino- (12) derivatives, were synthesized and investigated to determine the effect of substitution meta to the phenolic OH group of a 6-chromanol on the radical scavenging activity. 7 and 9 possessed excellent radical scavenging properties. Our data showed that the lone-pair electrons on the nitrogen atom of the substituent at the m-position donated electron density into the conjugated p-orbitals on the 6-chromanoxyl radical by δ-donation through resonance, enhancing the radical scavenging activity.

■ Utilization of Chlobenthiazone and Benazolin-ethyl as 4-Substituted 2(3H)-Benzothiazol-2-one Scaffolds

Masatoshi Kakuno, Shotaro Izawa, Taichi Takemoto, and Yoo Tanabe*

*Department of Chemistry, School of Scienece and Technology, Kwansei Gakuin University, Sanda, Hyogo 669-1337, Japan

Abstract

N(3)-Substituted 4-aryl (or heteroaryl)-2(3H)-benzothiazol-2-ones were synthesized from readily accessible chlobenthiazone and benazolin-ethyl, a couple of N(3)-substituted 4-chloro-2(3H)-benzothiazol-2-one pesticides, utilizing Suzuki-Miyaura cross-coupling reactions (9 examples; 44–98% yield), although with less reactive stereocongested 4-chloro pendant substituent. In a similar fashion, N(3)-substituted 4-anilino (or BocNH)-2(3H)-benzothiazol-2-ones were synthesized from the 4-bromo analogues of the chlobenthiazone-utilizing Buchwald-Hartwig cross-coupling reactions (3 examples; 50–89% yield). In addition, a short synthesis of the key chloro-type quinone segment in natural mevashuntin with a unique 2(3H)-benzothiazol-2-one skeleton, was performed in three short steps with 61% overall yield. The obtained quinone segment functioned as a Diels-Alder reaction dienophile toward the Danishefsky-Kitahara diene as the model experiment. All schemes utilized a common cyclo-condensation using chlorocarbonylsulfenyl chloride for the construction of 4(ortho)-substituted 2(3H)-benzothiazol-2-one substrates.

■ Synhesis, Molecular Docking Studies and in vitro Antimicrobial Evaluation of Novel Pyrimido[1,2-a]quinoxaline and Triazino[4,3-a]quinoxaline Derivatives

Rania B. Bakr,* Nadia A. A. Elkanzi, Amira A. Ghoneim, and Shaima M. N. Moustafa

*Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt

Abstract

A series of 3-substituted-2,6-dihydro-1H-pyrimido[1,2-a]quinoxaline- 5-carboxylates (4a,b), (8c,d) and (13a,b) were prepared by treating ethyl 3-amino-1,4-dihydroquinoxaline-2-carboxylate (1) with alkylidenemalononitrile derivatives. Moreover, 8H-benzo[5,6][1,2,4]triazino[4,3-a]quinoxaline-7-carboxylate derivatives (18, 20, 22, 24) were synthesized from condensation reaction between diazonium salts 16 with resorcinol, 1-naphthol, malononitrile and ethyl acetoacetate respectively. Some of the newly synthesized compounds were screened for their antimicrobial activity studies. Furthermore, molecular docking were performed on the active compounds 1, 4a and 8c to predict the mode of action of these novel compounds.

■ New Prenylated Bibenzyls from Bornean Liverwort Acrobolbus saccatus

Shean-Yeaw Ng, Takashi Kamada, Chin-Soon Phan, Monica Suleiman, and Charles S. Vairappan*

*Laboratory of Natural Products Chemistry, Institute for Tropical Biology and Conservation, Universiti Malaysia Sabah, 88400 Kota Kinabalu, Sabah, Malaysia

Abstract

Liverworts are the most primitive terrestrial plant which known to produce unique and wide variety of compounds. Ethyl acetate crude extract was subjected to several chromatographic techniques for purification. Three new compounds, saccatenes A-C (1-3) were isolated together with two known prenyl bibenzyl derivative, 2,2-dimethyl-5-hydroxy-6-carboxy-7-(2-phenylethyl) chromene (4) and radulanin A-5-one (5) from the Bornean liverwort Acrobolbus saccatus (Hook.) Trevis collected from Mountain Trus Madi, Sabah, Malaysia. The structures of the three new metabolites were established by analyses of the spectroscopic data (1D NMR, 2D NMR, HRESIMS and IR), and the antibacterial activity against eight selected human pathogenic species of bacteria were tested.

■ Synthesis of 4-Arylisoquinoline-1(2H)-thione Derivatives by Sodium Hydride-Mediated Cyclizations of 2-(1-Arylethenyl)benzothioamides

Kazuhiro Kobayashi* and Takuma Ueyama

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

Abstract

A new and facile method for the general preparation of isoquinoline-1(2H)-thione derivatives has been developed. Thus, the sodium hydride-mediated cyclization of N-substituted 2-(1-arylethenyl)benzothioamides, which are derived from the reaction of 2-(1-arylethenyl)phenyllithiums with isothiocyanates, gives 2-substituted 4-aryl-3,4-dihydroisoquinoline-1(2H)-thiones. In addition, the use of N-substituted 2-(1-aryl-2-methoxyethenyl)benzothioamides from 2-(1-aryl-2-methoxyethenyl)phenyllithiums and isothiocyanates affording 2-substituted 4-arylisoquinoline-1(2H)-thiones is described.

■ An Efficient Synthesis and Evaluation of Antitumor Activities of Functionalized Pyrano[2,3-b]quinolines

Wei Lin, Mengye Zhang, Ning Wang, Wentao Xu, and Daqing Shi*

*Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, Jiangsu, China

Abstract

An efficient synthesis of novel functionalized pyrano[2,3-b]quinoline derivatives via a three-component reaction of 2-chloroquinoline-3-carbaldehydes, malononitrile and 1,3-dicarbonyl compounds under microwave irradiation is described. This protocol has the advantages of high efficiency, mild reaction conditions, a one-pot procedure, and convenient operation. All of these compounds were evaluated for their antiproliferative properties in vitro against hepatic carcinoma cells and several compounds were found to have good activities.

■ A Pair of New Non-glycosidic Iridoid Epimers from Scrophularia ningpoensis

Wei Zhang, Peng Liu, Xin-Yu Ji, Xiang-Yang Chen, Yan-Yan Jiang, and Bin Liu*

*School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China

Abstract

A pair of new non-glycosidic iridoid epimers, ningpogenins A and B (1a/1b), together with eighteen known ones (2-19) were isolated from the roots of Scrophularia ningpoensis. Their structures were elucidated by spectroscopic analyses, including 1D-, 2D-NMR, and HR-ESI-MS. Compound 1 is an unusual example of natural ningpogenin—L-pyroglutamic adducts. In addition, the cytotoxic effects of the new compound against HepG2, U251 and SH-SY5Y cell lines were evaluated.

■ Synthesis of 4H-1,3,2-Benzodithiazin-4-imine 1,1-Dioxide Derivatives by Oxidative Cyclization of 2-(Aminosulfonyl)benzothioamide Derivatives with Iodine

Kazuhiro Kobayashi* and Daiki Fujiwara

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

Abstract

An efficient method for the construction of the 4H-1,3,2-benzodithiazine structure utilizing facile experimental operations from readily available starting materials is described. 2-Substituted (Z)-N-alkyl-4H-1,3,2-benzodithiazin-4-imine 1,1-dioxides can be obtained by the treatment of 2-(aminosulfonyl)benzothioamides, derived from the reaction between 2,N-dilithio derivatives of secondary benzenesulfonamides and isothiocyanates, with iodine in the presence of two equivalents of triethylamine.