HETEROCYCLES

■ Contents

■ Recent Application of ortho-Quinodimethane Chemistry for Synthesis of Heterocyclic Compounds

Yuji Matsuya*

*Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan

Abstract

The o-quinodimethanes, generated by concerted 4π-electrocyclic ring-opening of benzocyclobutenes, have been widely utilized as a powerful intermediate for the construction of various fused-cyclic frameworks. In this review, recent applications for the construction of heterocycles as well as their biological aspects are surveyed.

■ Design, Synthesis and Insecticidal Activity of 1-Methyl-3-(5-aryl-4,5-dihydroisoxazol-3-yl)-1H-pyrazole-5-carboxamides

Liangkun Zhong, Fan Zhang, Tao Jiang, Xinghai Liu, Tianming Xu, Chengrong Ding, Jie Chen, Jing Yuan,* and Chengxia Tan*

*College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China

Abstract

Pyrazole and its derivatives are a kind of important heterocyclic compounds used in agrochemicals development. In this research, a series of novel 1-methyl-3-(5-aryl-4,5-dihydroisoxazol-3-yl)-1H-pyrazole-5-carboxamides were synthesized and confirmed by 1H NMR, 13C NMR and ESI-MS. The preliminary bioactivity indicated that most title compounds showed excellent potency against Mythimna separate (Walker) at 500 mg/L, compounds ZJ4, ZJ12, ZJ16, ZJ17 showed moderate insecticidal activity against Aphis craccivora at 500 mg/L. Especially, compounds ZJ4, ZJ12, ZJ17 exhibited around 60% insecticidal activities against M. separate at 100 mg/L. The results indicated that the potential of these pyrazole-5-carboxamides containing arylisoxazoline fragment to be utilized in pesticide discovery through further development.

■ Facile Sodium Metabisulfite Mediated Synthesis of 1,2-Disubstituted Benzimidazoles and Cytotoxicity Evaluation

Bui Thi Buu Hue,* Hien Minh Nguyen, Mai Van Hieu, Danh La Duc Thanh, Nguyen Hoang Son, Tran Quang De, and Hiroyuki Morita*

*Department of Chemistry, College of Natural Sciences, Can Tho University, Viet Nam

Abstract

A library of twenty-four, structurally diverse, 2-substituted and 1,2-disubstituted benzimidazole derivatives (4a-x) was designed and synthesized. The benzimidazole derivatives were constructed by a one-pot condensation reaction between 1,2-phenylenediamines and aromatic aldehydes under mild oxidation conditions utilizing inexpensive and non-toxic inorganic salt sodium metabisulfite. These compounds were assayed for cytotoxicities against five cancer cell lines; cervical (HeLa), breast cancer (MCF7), lung cancer (A549), stomach cancer (GSU) and Kato III cell lines in vitro. Most of the compounds had slightly inhibitory effects against all or limited tested cell lines. Among them, compound 4q showed moderate cytotoxicity against HeLa, MCF-7, A549, and Kato III cell lines with IC50 values of 28.4 µM, 28.3 µM, 30.7 µM, and 28.5 µM, respectively. The structure-activity relationship analysis suggested that the substructure combination of benzimidazole and naphthalene bearing the free hydroxy group at C-1 and the three methoxy groups at the C-6, C-7, and C-8 of the naphthalene ring may exhibit a synergistic effect and an improved anticancer activity.

■ Catalyst-Free Tandem Reaction for the Synthesis of Tetrahydro-1,2,3-triazine Derivatives

Kewei Wang, Huijun Liu, Yong Guo, Gang Yi,* Zhifang Jia,* and Feng Feng

*Department of Chemistry and Chemical Engineering, Shanxi Datong University, Datong, 037009, China

Abstract

A simple and efficient method for the synthesis of tetrahydro-1,2,3-triazine derivatives was developed through a one-pot ring-opening/ring-closing tandem reaction. By the tandem reaction, various previously unreported tetrahydro-1,2,3-triazines were prepared by cyclopropane derivatives and NaN3 with 90–97% yields under the catalyst-free conditions.

■ Practical Synthesis of Pimobendan

Ping Zou, Lin Hu, Xi-Meng Yan, Xiao-Yue Li, Wanguo Wei, Xiao-Long Qiu,* and Shao-Hua Gou*

*Wisdom Pharmaceutical Co. Ltd., No. 18, Qinghua Road, Haimen, Jiangsu, 226123, China

Abstract

Pimobendan is a calcium sensitizer and a selective inhibitor of phosphodiesterase III (PDE3) with positive inotropic and vasodilator effects. Several attempts have been made to synthesize this drug. In this work, a facile synthetic route for the preparation of pimobendan from readily available starting materials and easily handled reagents is provided.

■ Reaction of 2-Imino-2H-chromene-3-carboxamide with Phosphorus Halides: Synthesis of Some Novel Chromeno[2,3-d][1,3,2]diazaphosphinines and Chromeno[4,3-c][1,2]azaphosphole and Their Antioxidant and Cytotoxicity Properties

Tarik E. Ali,* Mohammed A. Assiri, Hafez M. El-Shaaer, Ahmed M. Fouda, Mohamed M. Hassan, and Noha M. Hassanin

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

Abstract

Novel 1,2-azaphosphole and 1,3,2-diazaphosphinines containing a chromene ring have been obtained from the treatment of 2-imino-2H-chromene-3-carboxamide (1) with some phosphorus halides. The compounds were evaluated for antioxidant and cytotoxic activities. Among the synthesized compounds, compound 4 exhibited the most potent antioxidant agents in comparison with ascorbic acid as standard antioxidant. Also, compound 4 recorded potentially cytotoxicity against all four cell lines.

■ An Efficient Two-Step Synthesis of 3-Aroyl-2,3-dihydro-1,4,2-benzodithiazine 1,1-Dioxides from Secondary Benzenesulfonamides, Sulfur, and Phenacyl Bromides

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 synthesis of 2-substituted 3-aroyl-2,3-dihydro-1,4,2-benzodithiazine 1,1-dioxides has been developed. Thus, 2,N-dilithio compounds of secondary benzenesulfonamides, generated by treating secondary benzenesulfonamides with two equivalents of butyllithium, are allowed to react with elemental sulfur and then phenacyl bromide and its derivatives to give N-substituted o-[(aroylmethyl)sulfanyl]benzenesulfonamides in moderate to good yields. Oxidative coupling of these precursors to the desired products can be achieved in moderate to good yields on successive treatment with sodium hydride and iodine under mild conditions.

■ Isobenzofuranone Derivatives from the Roots of Phlomis betonicoides and Their Bioactivity

Mu-Yao Li, Ling-Min Liao, Qi-Yan Sun, Dong Miao, Min Zhou, Yan-Qing Ye, Yi-Jian Chen, Qiu-Fen Hu,* and Wei-Guang Wang*

*Key Laboratory of Chemistry in Ethnic Medicinal Resources, Yunnan Minzu University, Kunming 650031, China

Abstract

Three new (1-3) together with three known (4-6) isobenzofuranone derivatives, were isolated from the roots of Phlomis betonicoides. Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D-NMR techniques. Compounds 1-6 were evaluated for their anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity. The results showed that compounds 1-6 showed weak inhibition with diameter of inhibition zone of (IZD) of 9.2±1.2, 8.6±1.5, 9.8±1.6, 11.4±1.2, 8.2±1.0 and, 11.6±1.3 mm, respectively. Compounds 1-6 were also tested for the antioxidant activity, and they showed good antioxidant activity with an IC50 value of 4.6±0.8, 4.4±0.6, 4.0±0.6, 4.2±0.7, 4.8±0.6, and 4.1±0.5 μg/mL, respectively.

■ Ultrafast and Diastereoselective Synthesis of 3-Spirocyclopropyl-2-oxindoles Bearing Three Continuous All-Carbon Quaternary Centers

Aixin Geng, Hao Cui, Liyuan Zhang, Tao Lu,* and Yong Zhu*

*Department of Organic Chemistry, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China

Abstract

Synthesis of 3-spirocyclopropyl-2-oxindoles bearing three continuous all-carbon quaternary centers by the domino Michael-alkylation reaction between 3-chlorooxindole and isatylidenemalononitrile is described. Remarkably, the reaction proceeded in exceptionally high efficiency (up to 99% yield within 2 min) and excellent diastereoselectivity (>25:1 dr for all the examples).