HETEROCYCLES

■ Contents

■ Heterocyclic Synthesis by π-Acidic Metal Catalyzed Reactions via N-O Bond Cleavage

Itaru Nakamura* and Masahiro Terada

*Department of Chemistry, Graduate School of Science, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan

Abstract

This review contains recent progress in heterocyclic synthesis by π-acidic metal catalyzed reactions via N-O bond cleavage. The reaction involving a terminal N-O bond (R3N+-O-) predominantly proceeds via nucleophilic attack of the O atom and subsequent formation of an α-oxo carbenoid intermediate through N-O bond cleavage. In contrast, the reaction of oximes and hydroxylamine derivatives having an internal N-O bond (R2N-OR’) is initiated by the nucleophilic attack of either N or O atom. In addition, hydroxylamine derivatives have been utilized as an external reagent in the cyclization reaction. The methodology produces a wide variety of highly functionalized nitrogen and oxygen heterocycles in an efficient manner under mild reaction conditions.

■ RECENT PROGRESS IN METAL ASSISTED MULTICOMPONENT SYNTHESES OF HETEROCYCLES

Pradip Kumar Maji,* Rafique Ul Islam,* and Sujit Kumar Bera

*Department of Chemistry, Bidhan Chandra College , Asansol, Burdwan, 713304, WB, India

Abstract

This review highlights some remarkable recently made achievements in the application of metal-catalyzed processes to the design of Multicomponent syntheses of Heterocycles. The domino MCRs that are purely based upon metal catalysis opens a vast field for the discovery of new sequences in heterocyclic synthesis. Many of these methods have proven to be the most powerful and are currently applied in target- or diversity-oriented syntheses. These reactions can dramatically reduce the generation of chemical wastes, costs of starting materials, and the use of energy and manpower. Moreover, the reaction period can be substantially shortened. This review article aims at reporting the recent developments devoted to this important area, focusing on the metal catalysis in Multicomponent synthesis of heterocycles.

■ Sequential Radical Addition and Fischer-Type Indolization Reactions of Conjugated Hydrazones for the Preparation of α-Alkylindole-3-acetic Acids

Yuta Ito, Masafumi Ueda,* Naomi Matsuda, Yuika Nishida, and Okiko Miyata*

*Department of Medicinal Chemistry, Kobe Pharmaceutical University, 4-19-1, Motoyamakitamachi, Higashinada, Kobe 658-8558, Japan

Abstract

A domino reaction, consisting of sequential regioselective radical addition and Fischer-type indolization reactions, has been developed for the construction of α-alkylindole-3-acetates from conjugated hydrazones.

■ Synthesis and Photophysical Properties of New Pyrazolino[60]fullerenes with Fluorenyl and Fluorinated Phenyl Substituents

Subo Shen, Shanshan He, Haonan Cheng, Changrui Xu, Hongmei Deng, and Jianmin Zhang*

*Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver B.C., V6T 1Z1, Canada

Abstract

Two types of triads based on Pyrazolino[60]fullerenes with fluorenyl and fluorinated phenyl substituents have been synthesized via the [3+2] dipolar cycloaddition reaction between C60 and corresponding hydrazones in good yields. Photophysical properties of these triads have also been systematically investigated, and their weak emissions indicated fluorescent quenching induced by intramolecular charge transfer may occur between the donor and acceptor parts of these systems.

■ Efficient Synthesis of 2-Alkylidene-4H-3,1-benzoxathiin-4-ones and Determination of Their Double Bond Configuration

Masao Shimizu,* Masaki Yamanaka, Wataru Ando, Shigeru Shimada, Takeo Konakahara, and Norio Sakai

*Innovative Oxidation Team, Interdisciplinary Research Center for Catalitic Chemistry, National Institute of Advanced Industrial Science and Technology, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan

Abstract

2-Alkylidene-4H-3,1-benzoxathiin-4-ones were efficiently synthesized by reaction of 2-(acylthio)benzoic acids with condensation reagents in the presence of base. The E and Z isomers of the products were distinguished by comparison of the chemical shifts of the vinylic protons in the 1H NMR spectra of the 4H-3,1-benzoxathiin-4-ones and their corresponding 1-oxides.

■ New 1,2- and 1,3-Aza-Ylides of 3-Amino-2-substituted-1H-isoindoles

Hatem A. Abdel-Aziz,* Tilal Elsaman, Khalid A. Al-Rashood, and Hoong-Kun Fun

*Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh-11451, Saudi Arabia

Abstract

The reaction of 2-(bromomethyl)benzonitrile (5) with hydrazides 6a-f or heterocyclic amines 14a-c gave isoindolium bromides 7a-f and 15a-f, respectively. Deprotonation of the latter salts afforded the 1,2-aza-ylides 8a-f and 1,3-aza-ylides 16a-c instead of the analogous imines 9a-f or 17a-c, respectively. Single crystal X-ray and NMR analyses confirmed the stable ylide structures of 8a-f and 16a-c and established the presence of a complete benzenoid unit in the isoindole moiety, in both the solid state and solution phase.

■ NaHSO3-Promoted Ring Openings of N-Tosylaziridines and Epoxides with H2O

Xing Li, Bin Ni, Hong-Hong Chang, and Wen-Long Wei*

*Department of Chemistry and Chemical Engineering, Taiyuan University of Technology, 79 West Yingze Street, Taiyuan 030024, Shanxi 030024, China

Abstract

NaHSO3-oriented ring openings of a wide variety of N-tosylaziridines and epoxides with H2O under mild conditions in acetone was found to be a convenient and effective method, which provided the desired β-aminoalcohols and β-diols in good to excellent yields and with uniformly high regioselectivity.

■ Improving the Synthesis of Spiropyran Derivatives Using Microwave Irradiation Method

Atisya Rohadi, Siti Aishah Hasbullah,* Azwan Mat Lazim, and Rumaisa Nordin

*School of Chemical Sciences and Food Technology, Food Science and Chemical Technology, Faculty of Science and Technology , The National University of Malaysia, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia

Abstract

A solvent free synthesis of spiropyran derivatives has been developed from the condensation of indoline and salicylaldehyde using a microwave irradiation method. This method starts from readily available starting materials and provides biologically interesting products. The microwave irradiation method was remarkably successful and gave spiropyran derivatives in higher yield (72–99%) with a much shorter reaction time (10–15 min) compared to the conventional heating method. The chemical structures of the compounds prepared were characterized through IR, 1H NMR and 13C NMR spectral data.

■ An Efficient Synthetic Route towards Novel Furo- and Thieno-triazolopyridines

Kazuhiro Tomoike, Hiroshi Maruoka,* Fumi Okabe, Eiichi Masumoto, Toshihiro Fujioka, and Kenji Yamagata

*Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

Abstract

An efficient method for the synthesis of novel nitrogen-containing heterotricycles is described. 4,5-Dihydro-3-furan- and -3-thiophene-carbonitriles 1a,b and 2a,b having an active methylene group at C-2 position served as the precursor of enamines 3a,b and 4a,b, which were followed by an exchange reaction of amines, such as acetohydrazide and benzohydrazide, and subsequent tandem intramolecular cyclization reaction to lead the corresponding furo- and thieno-triazolopyridines 5a,b, 6a,b, 7a,b, and 8a,b.

■ Expeditious Synthesis of Ivacaftor

Yang He, Qien Xu, Wenpeng Ma, Jian Zhang, Hongbing Sun, and Jingshan Shen*

*Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zuchongzhi Rd., Zhangjiang Hi-Tech Park, Shanghai, 201203, China

Abstract

An expeditious synthesis for Ivacaftor featuring modified Leimgruber-Batcho procedure was described. The overall yield is 39% over six steps from commercially available 2-nitrobenzoyl chloride.

■ Reinvestigation of 1,3,4-Thiadiazol-2(3H)-iminium Bromide in the Two-Step Synthesis of Imidazo[2,1-b][1,3,4]thiadiazoles

Shigeki Sano,* Keisuke Matsuura, Hayato Sumiyoshi, Akira Miki, Syuji Kitaike, and Michiyasu Nakao

*Molecular Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78 Sho-machi, Tokushima 770-8505, Japan

Abstract

The synthesis of 1,3,4-thiadiazol-2(3H)-iminium bromides, which are intermediates in the most commonly used synthetic approach to imidazo[2,1-b][1,3,4]thiadiazoles, and a single crystal X-ray diffraction study of one of these iminium bromides are described. Cyclization of the resulting 1,3,4-thiadiazol-2(3H)-iminium bromides under microwave irradiation afforded imidazo[2,1-b][1,3,4]-thiadiazoles in 80-100% yields.

■ Synthesis and Antimalarial Activity of Some Neocryptolepine Analogues Carrying a Multifunctional Linear and Branched Carbon-Side Chains

Elkhabiry Shaban, Kathryn J. Wicht, Ning Wang, Zhen-Wu Mei, Ikuya Hayashi, Ahmed Abdel Aleem El Gokha, Marcel Kaiser, Ibrahim El Tantawy El Sayed, Timothy J. Egan,* and Tsutomu Inokuchi*

*Division of Chemsitry and Biochemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Okayama 700-8530, Japan

Abstract

The synthesis and in vitro antimalarial activity of several neocryptolepine analogues carrying either a linear or branched dibasic side chain at C11 are described. Many of these neocryptolepine analogues have low nanomolar antimalarial activity against the chloroquine-sensitive P. falciparum strain (NF54). The data also demonstrated that a branched structural motif is not superior for antimalarial activity over a linear side chain, but their thioureido derivatives showed lower cytotoxicity than the linear one. Ureido and thioureido derivatives also showed stronger β-haematin inhibition than the corresponding free amines.