HETEROCYCLES

■ Contents

■ Heterocycles Award

HETEROCYCLES Announcement*

*The Japan Institute of Heterocyclic Chemistry, 1-7-17, Motoakasaka, Minato-ku, Tokyo 107-0051, Japan

■ Aryne-Mediated Synthesis of Oxygen Heterocycles and Application to Cysteine-Selective Trapping

Hideto Miyabe*

*Laboratory for Medicinal Chemistry, School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe City, 650-8530, Japan

Abstract

The use of arynes as the highly reactive intermediates in organic synthesis has attracted substantial attention. Particularly, the introduction of ortho-(trimethylsilyl)aryl triflates as easily activatable aryne precursors led to growing activity in this field. Most reactions using these aryne precursors proceed through the addition of nucleophiles to arynes and the subsequent trapping with electrophiles to give the multisubstituted arenes with structural diversity and complexity. Based on our studies, this review highlights the insertion of arynes, generated from ortho-(trimethylsilyl)aryl triflates, into C=O π-bond of formamides. Initially, the representative examples for formal [2+2] cycloaddition of arynes with the carbon–heteroatom double bond or the heteroatom–heteroatom double bond are shown. Next, the studies on the insertion of arynes into the N−C and C=O bonds of amide group including our three-component coupling reaction leading to oxygen heterocycles are summarized. The SN2’ reaction of tricyclic oxygen heterocycles, obtained by three-component coupling reaction, was studied by using carbon and sulfur nucleophiles. The SN2’ reaction was expanded to four-component coupling reaction. Finally, the application of tricyclic oxygen heterocycles to cysteine-selective trapping is described.

■ Elucidation of Absolute Configuration of Ophiorrhiside A by Comparison of ECD Spectra with That of Model Chiral Compound Having a 1,2,3,4-Tetrahydro-β-carbolin-3-one Skeleton

Tadayoshi Onozawa, Noriyuki Kogure, Hiromitsu Takayama, and Mariko Kitajima*

*Department of Biofunctional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan

Abstract

A chiral 1,2,3,4-tetrahydro-β-carbolin-3-one having a substituent at C-1 was synthesized from L-leucine and used to elucidate the absolute configuration at C-3 of ophiorrhiside A, a monoterpenoid glucoindole alkaloid.

■ Synthesis, Structures, and Interactions with CT-DNA/BSA of Three New Acylhydrazones Containing Oxazole Ring

Lingling Chang, Xiangrong Liu,* Zaiwen Yang, Shunsheng Zhao, Xinjuan Chen, and Bosen Dai

*College of Chemistry and Chemical Engineering, Xi’an University of Science and Technology, Xi’an 710054, China

Abstract

Three new acylhydrazones containing oxazole ring C11H8N3O2X (X = F, 1; Br, 2; I, 3) have been synthesized. The single crystal XRD presented that 1 belonged to the monoclinic system, while 2 and 3 belonged to the triclinic systems. TG-DTG results showed that the maximum thermal decomposition temperatures of 1-3 were more than 260 °C. The UV-vis spectra, fluorescence spectra and microcalorimetry measurements indicated that each acylhydrazone bound to calf thymus DNA (CT-DNA) via groove binding mode and interacted with bovine serum albumin (BSA) by static quenching effect and the corresponding interaction processes were all exothermic. The molecular docking showed that each acylhydrazone bound to CT-DNA and BSA mainly through hydrogen bonding. The minimum inhibitory concentrations of 1-3 against Escherichia coli, Staphylococcus aureus, Bacillus subtilis, and Pseudomonas aeruginosa were all about 0.25 mg·mL-1.

■ Practical Synthesis of 1-Substituted 5-Aminopyrazolo[4,3-d]pyrimidin-7-ones Using Intramolecular Friedel–Crafts Type Cyclization and Its Application to the Synthesis of Pharmaceutically Active Compounds

Takashi Goi,* Tetsuji Matsudaira, and Koichi Fukase*

*Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aobaku, Yokohama, 227-0033, Japan

Abstract

Intramolecular Friedel–Crafts type cyclization is known as an efficient method of synthesizing fused bicyclic pyrimidones. However, the synthesis of 1-substituted pyrazolo[4,3-d]pyrimidin-7-ones using this cyclization method has not been achieved. Herein, we describe the synthesis of various 1-substituted pyrazolo[4,3-d]pyrimidin-7-ones using practical intramolecular Friedel–Crafts type cyclization, which was carried out in N, N-dimethylformamide in the presence of chlorotrimethylsilane. A hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) inhibitor was efficiently synthesized by this method.

■ Probing the Reaction of N,N-Dimethyformamide Dimethyl Acetal with p-tert-Butylthiacalix[4]arene Tetrahydrazides: A Facile Approach for the Synthesis and Application of Novel Metal Receptors

Omran A. Omran and Ayman Nafady*

*Chemistry Department, Faculty of Science, Sohag University, 82524, Sohag, Egypt

Abstract

Recent developments in the field of sensing and recognition revealed that artificial receptors based on calix[4]arenes with π-conjugated fluorophoric or chromophoric moieties are efficient in enhancing selectivity/sensitivity as well as the binding affinity for ionic or molecular recognition. Herein, via studying the reaction of dimethylformamide dimethyl acetal (DMF–DMA) with p-tert-butylthiacalix[4]arene tetrahydrazides in three different conformers (i.e., cone, partial-cone, and 1,3-alternate), the formation of novel lower rim p-tert-butylthiacalix[4]arene derivative (cone, partial-cone, and 1,3-alternate) conformers in high yields (80, 95, and 85%, respectively) was achieved. The structure of isolated products was confirmed using different spectroscopic and analytical techniques such as FT-IR, 1H NMR, 13C NMR, and elemental analysis. Importantly, the synthesized receptors showed preferential uptakes of alkali (Na+, K+ and Cs+), heavy (Pb2+, Cd2+, Hg2+, and Ag+) and transition (Ni2+, Co2+, and Cu2+) metal ions via liquid–liquid extraction method. The finding of this work adds new compounds to the growing family of thiacalix[4]arenes and validates their high sensitivity and selectivity in detection of heavy metal ions.

■ Double Michael Addition of Oxindoles to Dienones Catalyzed by TBAB: An Efficient Route to Spirocyclic Oxindoles

Haiyong Cao, Yan Lin, Pingnan Wan, Wenqin Liu, Jinxiang Zeng,* and Hanfeng Cui*

*School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China

Abstract

The efficient synthesis of biologically active spiro compounds is a challenge for organic chemists and pharmaceutical chemists. Herein we describe a synthesis strategy of spirocyclic oxindoles via double Michael reaction of N-protected-oxindoles to dienones using tetrabutylammonium bromide (TBAB) as catalyst. The desired spirocyclic oxindoles were obtained with both high yields up to 99% and diastereoselectivity up to >95:5 dr.

■ A Simple Route for Synthesis and Evaluation of Antioxidant Activity of (Guaiazulen-1-yl)furans

Si-Tong Guo, Jiao Xu, Xiao-Liang Zhang, Xin-Shuang Xiong, Lu Zhang, Dao-Lin Wang,* and Shu-Quan Zhang*

*College of Chemistry and Material Science, Bohai University, Jinzhou, China

Abstract

An effective protocol for the synthesis of guaiazulene substituted furan derivatives via three-component reactions of guaiazulene, α-ketoaldehyde, and 1,3-dicarbonyl compound under mild conditions in good yield is reported. All of these compounds were evaluated for their antioxidant properties in vitro against lipid peroxidation and several compounds were found to have good activities.

■ Liquid-Assisted Mechanosynthesis of trans-2,3-Dihydropyrroles from Chalcones and Enaminones

Ming-Yue Weng, Hui Xu,* Hong Chen, and Ze Zhang*

*Anhui Province Key Laboratory of Functional Coordinated Complexes for Materials Chemistry and Application, and School of Chemical and Environmental Engineering, Anhui Polytechnic University, Wuhu 241000, P. R. China

Abstract

An efficient synthesis of a variety of trans-2,3-dihydropyrroles via iodine-promoted cyclization between chalcones and enaminones has been demonstrated under liquid-assisted grinding conditions. The present protocol provides a practical, fast and green alternative to traditional solvent-based methods due to its notable advantages such as significantly higher yield, much shorter reaction time, good functional group tolerance and mild reaction conditions.

■ Improved Synthesis of a Smad3 Phosphorylation Inhibitor Lingzhifuran A via Condensation Reaction

Weiming Chen, Xiaoling Xu, Mingfeng Sun, Xuelong Huang, Weiping Ma,* and Feng Jiang*

*School of Pharmaceutical Sciences, Gannan Medical University, Ganzhou 341000, Jiangxi, China

Abstract

A facile and high-efficient synthesis of lingzhifuran A, a Smad3 phosphorylation inhibitor isolated from Ganoderma lucidum, was developed from commercially available dibenzo[b,d]furan. The crucial step of this strategy was achieved via condensation reaction using key intermediate 8-hydroxydibenzo[b,d]furan-4-carbaldehyde and commercially available (E)-2-methylbut-2-enal. By this strategy, lingzhifuran A was obtained in 5 steps with up to 57.6% yield.