HETEROCYCLES

■ Contents

■ Synthesis of Nitrogen Heterocycles through Cyanative Cyclization and Cycloaddition Reactions under Transition Metal Catalysis

Shigeru Arai* and Atsushi Nishida

*Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan

Abstract

Synthesis of cyano-functionalized nitrogen heterocycles under palladium, nickel, and cobalt catalysis is described. These transformations include the activation of C-C multiple bonds to give the functionalized pyrrolidines and their related compounds. The palladium-catalyzed reactions promote nucleophilic cyanation to non-activated terminal alkynes. Nickel catalysis enables to install H and CN functionalities into allenes with regio- and stereoselective manner. In the case of cobalt-catalyzed hydrocyanation, hydroacylation and hydroarylation, simple olefins as well as enamines are suitable substrates to construct highly functionalized hetero- and carbocycles. The applications of the above methodologies for the synthesis of alkaloids and related compounds are also described.

■ Rhodium-Catalyzed Oxidative Olefination of N-(2-(4,5-Dihydrooxazol-2-yl)phenyl)amides with Arylethenes via Extraordinary N-Aryl C-H Bond Functionalization

Hao Yan,* Fang-Peng Hu, Xiao-Qiang Zhou, Zhi Li, and Guosheng Huang*

*College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, 712046, P. R. of China

Abstract

Amide-tethered aryloxazoline motifs are important structural moiety because of ubiquity in medicinal chemistry, functional materials and pincer ligands. In recent years, much attention about N-(2-(4,5-dihydrooxazol-2-yl)phenyl)amides has been focused on ortho C−H functionalization of amides. Herein a highly efficient rhodium(III) catalyzed oxidative olefination of N-(2-(4,5-dihydrooxazol-2-yl)phenyl)amides with arylethenes via extraordinary N-aryl C-H bond functionalization was developed.

■ 1-Hydroxyindoles: Production of Feruloylserotonin, an Alkalid of Safflower Seed, Novel Ring System Compound, 1,10-Diaza-9,20-dioxokabutanes, 2,2’-Bisindoles, and (dl)-3a, 3a’-Bispyrrolo[2,3-b]indoles

Mutsuko Tabata, Naoki Oshikiri, Masakazu Hasegawa, Keiichi Satoh, Yoshikazu Fukui, Yoshiyuki Nagahama, Harunobu Morikawa, Fumio Yamada, and Masanori Somei*

*Faculty of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan

Abstract

Methyl 1-hydroxyindole-3-acetate (1a) produced novel hexacyclic 8,17-bis(methoxycarbonylmethyl)-1,10-diaza-9,20-dioxakabutane (3) as a major product by the reaction with 85% formic acid, while its reaction with trifluoroacetic acid generated exclusively another 2,2’-bisindole dimer, 1-hydroxy-3,3’-di(methoxycarbonylmethyl)-2,2’-bisindole (4). Reaction of 1a with mineral acid such as HCl afforded nucleophile substituted 5-chloroindole derivative (6). Products and their distribution changed depending on the structure of 1-hydroxyindole. Species of acid, reaction conditions, side chain structure of 1-hydroxyindole at the 3-position are additional factors for governing the product formation. In the cases that the side chain has a C—C—N structure, nucleophilic substitution reaction occurred effectively, and was applied for the preparation of N-feruloylserotonin (46d), an alkaloid isolated from safflower seed. 1-Hydroxymelatonin (69), having a methoxy group on the benzenoid part, afforded (dl)-3a,3a’-bis(pyrrolo[2,3-b]indole) compound (72) by the treatment with 85% formic acid. Products’ structures are unequivocally determined by X-ray single crystallographic analyses.

■ Synthesis of Pyrrolo[2,3]pyrido[2,4-d]pyrimidin-6-ones and Related New Heterocycles

Tamás Zelenyák, Imre Fejes, Jérôme-Benoît Starck, and Miklós Nyerges*

*Servier Research Institute of Medicinal Chemistry, 7 Záhony utca., 1031, Budapest, Hungary

Abstract

During our synthetic development work focused on new Bcl-2 inhibitor molecules an unexpected and interesting by-product was formed. Using this obsevation we have explored the synthesis of the hitherto unknown pyrrolo[2,3]pyrido[2,4-d]pyrimidin-6-one heterocyclic core. The study of the scope and limitations of this cyclisation resulted in other three new types of three membered heterocyclic ring systems.

■ Stereoselective Synthesis of (Z)-3-Arylidene-2-oxindoles via a Palladium-Catalyzed Tandem Reaction

Sunhwa Park, Kye Jung Shin, and Jae Hong Seo*

*College of Pharmacy, The Catholic University of Korea, 43 Jinong-ro Wonmi-gu Bucheon, Gyeonggi-do, 14662, Korea

Abstract

A novel and efficient synthetic method for the stereoselective preparation of (Z)-3-arylideneoxindoles from simple propiolamide has been developed utilizing a palladium-catalyzed tandem reaction. Two Sonogashira and reductive Heck reactions were successfully combined under microwave irradiation. The E/Z stereoselectivity of the reaction was enhanced by solvent control.

■ Five New Highly Oxidized Neoclerodane Diterpenes, Salvileucalins E-I from Salvia leucantha

Yutaka Aoyagi,* Yutaka Nakazato, Akira Yamazaki, Haruna Kondo, Ayana Ninomiya, Mari Tokuda, Haruhiko Fukaya, Reiko Yano, Koichi Takeya, and Yukio Hitotsuyanagi*

*College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyama-ku, Nagoya 463-8521, Japan

Abstract

Five new rearranged neoclerodane diterpenes (salvileucalins E-I) were isolated from Salvia leucantha (Lamiaceae), whose structures were elucidated by spectroscopic analysis and X-ray crystallographic analysis.

■ Montmorillonite K-10 Catalyzed Microwave-Assisted Synthesis of Pyrroles in Solvent Free Conditions

Chaowei Ma* and Guosheng Huang

*College of Chemistry and Environmental Engineering, Xinjiang Institute of Engineering, Xinjiang Wulumuqi Nanchang Road 830091, china

Abstract

An effective microwave-induced, montmorillonite K-10 catalyzed, environmentally benign synthesis of substituted pyrroles from α‑amino carbonyl compounds and aldehydes under solvent-free conditions is described. The reaction involving various substituted substrates proceeds smoothly, and substituted pyrroles are synthesized in moderate to excellent yields within minutes. The developed method offers advantages such as operational simplicity, solvent-free, rapid reaction rate and use of a commercially recyclable catalyst.

■ Chromone Derivatives from the Twigs of Cassia agnes and Their Anti-Rotavirus Activity

Guang-Hui Kong, Zhen-Yuan Xia, Fan Wu, Ya-Ning Zhu, Jing Li, Wei-Song Kong, Min Zhou, Guang-Yu Yang, Qiu-Fen Hu,* and Yu-Ping Wu*

*Yunnan Academy of Tobacco Agricultural Sciences, Kunming, Yunnan 650031, P. R. China

Abstract

Three new (1 - 3), together with four known chromone derivatives (4 - 7) were isolated from the twigs of Cassia agnes. Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D-NMR techniques. Compounds 1 - 7 were evaluated for their anti-rotavirus activity. The results revealed that compounds 1 - 7 exhibited potent anti-rotavirus activity with TI valves in the range of 9.4 - 14.5, respectively.

■ Reactivity of 4,9-Dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-carbonitrile towards Some Nitrogen Nucleophilic Reagents

Magdy A. Ibrahim* and Esam S. Allehyani

*Department of Chemistry, Faculty of Education, Ain Shams University, Cairo, Egypt

Abstract

The chemical behavior of 4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-carbonitrile (khellin-6-carbonitrile) (1) was examined towards a variety of nitrogen nucleophiles. Some novel Schiff bases 5-7 were prepared from reaction of carbonitrile 1 with some heterocyclic amines. Treatment of carbonitrile 1 with some hydrazine derivatives in boiling ethanol afforded pyrazole derivatives 8-13. Khellin-6-carbonitrile (1) reacted with hydrazine hydrate and phenylhydrazine in acetic acid to afford angular heteroannulated furo[3`,2`:6,7]chromeno[4,3-c]pyrazol-4(1H)-one derivatives 14 and 15. Triazolo[1,5-a]pyrimidine 16 and pyrimido[1,2-a]benzimidazole 17 were synthesized through ring opening and recyclization reactions of compound 1 with 3-amino-1,2,4-triazole and 2-aminobenzimidazole, respectively. Reaction of compound 1 with guanidine and cyanoguanidine in ethanolic potassium hydroxide solution resulted in ring conversion giving the novel angular furo[3`,2`:6,7]chromeno[4,3-d]pyrimidin-5-ones 18 and 19. The antimicrobial activity of the prepared compounds appeared distinguish activity against the selected microorganisms.

■ Synthesis of Novel Thienopyrimidines and Thienodiazepines from Ethyl 2,4-Diamino-5-{[(2E)-2-(1-phenylethylidene)hydrazino]carbonyl}thiophene-3-carboxylate

Osama Farouk and Kamelia M. El-mahdy*

*Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, 11711, Cairo, Egypt

Abstract

Ethyl 2,4-diamino-5-{[(2E)-2-(1-phenylethylidene)hydrazino]-carbonyl}thiophene-3-carboxylate (3) was synthesized via Gewald reaction that can be readily used as precursor to potentially interesting thiophenes. Compound 3 reacted with cyanoacetamide and/or malononitrile producing thienopyrimidines 4 and 5, respectively. Reaction of compound 3 with hydrazinecarbodithioic acid afforded pyrimidothienotriazepine 6. Treatment of compound 3 with ethylenediamine and carbon disulfide gave (imidazolinyl)thiophene 7. The latter compound can be used as building blocks for the synthesis of various heterocycles. Structures of the newly synthesized compounds were deduced based on their analytical and spectral data.