HETEROCYCLES

■ Contents

■ Heterocycles Award

HETEROCYCLES Announcement*

*The Japan Institute of Heterocyclic Chemistry, 1-1-7, 503 Motoakasaka, Minato-ku, Tokyo
107-0051, Japan

■ The Azalogues of Pyrrolotetrazole – An Overview

Dietrich Moderhack*

*Institute of Medicinal and Pharmaceutical Chemistry, Technical University, D-38106 Braunschweig, Germany

Abstract

This overview is dealing with the seven azalogues of pyrrolotetrazole, i.e., the systems A–G, in all their manifold forms. Major interest is directed to the preparative chemistry, but theoretical work, in particular on the azolotetrazole–azidoazole isomerism ('ring–chain tautomerism'), will be looked at as well.

■ Design, Synthesis and Biological Evaluation of Pyrimidinamine Derivatives Containing Urea Moiety

Weiqin Liu, Mi Hou, Qin Wang, Huayuan Tan, Litao Ji, Congyu Wang, Xuesha Long, Zhenchao Wang,* and Guiping Ouyang*

*School of Pharmaceutical Sciences, Guizhou University, Guizhou Guiyang, 550025, China

Abstract

New series of 17 pyrimidinamine derivatives containing urea moiety were designed and synthesized. Their antitumor activity was investigated by MTT method. The results showed that some of these compounds exhibited moderate to good antitumor activities against all four cancer cell lines. The IC50 value of compound HD-6 on PC-3 cells was better 2.37 μM than the positive control drug sorafenib (3.66 μM). The inhibitory activity of most target compounds on HepG2 cells was better than that of positive drug sorafenib (10.70 μM). Among them, the IC50 value of compound HD-6 on K562 cells was 6.80 μM, which close to solafinib (4.62 μM). Further studies revealed that compound HD-6 clearly possessed apoptosis inducing effects, increased the level of reactive oxygen species, arrested the cycle in the G2/M phase and regulated the expression of tyrosine kinase EGFR in PC-3 cells.

■ Comprehensive Synthesis of 20 Fentanyl Derivatives for Their Rapid Differentiation by GC-MS Analysis

Takashi Kurohara, Takahito Ito, Genichiro Tsuji,* Takashi Misawa,* Hidetomo Yokoo, Maiko Kawamura, Takuji Shoda, Ruri Hanajiri-kikura, and Yosuke Demizu

*National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan

Abstract

Fentanyl, a selective agonist of opioid μ receptors, is a broadly used clinical agent for anesthesia and pain relief. Despite its clinical benefits, the abuse of fentanyl and its derivatives causes a number of health concerns, which are increasing at an alarming rate; its abuse has become a serious social problem. These compounds are often difficult to obtain as reagents, which hinders forensic toxicological analysis. Therefore, it is important to address their unavailability by synthesizing the structural derivatives of fentanyl. In this study, we synthesized 20 fentanyl derivatives, such as o- or p-fluorofentanyl and furanylfentanyl, and determined their purities using HPLC (95.2%−100%). Moreover, the GC-MS analysis of the synthesized fentanyl derivatives was performed for the rapid differentiation of the synthesized fentanyl derivatives. We demonstrate that our method achieves a convenient and efficient synthesis of fentanyl derivatives.

■ Synthesis and Antitumor Activity of Heterocylic Aurone and Its Analogue Indanone Derivatives

Heng Wu, Ayitila Maimaitijiang, Dan Tang, Baoxing Xie, Chao Niu,* and Haji Akber Aisa*

*State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, CAS Key Laboratory of Chemistry of Plant Resources in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011 China

Abstract

Based on non-classical bioisosterism and the rule of alkene insertion, thirty-five heterocyclic aurones and its analogue indanones derivatives were designed and synthesized. They were evaluated for inhibitory activity against HELA, HT-29 and A549 and HepG2 human cancer cell lines. Among them, twenty-five compounds exhibited moderate to excellent antitumor activity. The minimum value of IC50 was 1.649±0.083 μM (compound B1). The SAR showed that aurone with B ring as aromatic heterocycles such as 4-bromothiophene, quinoline, carbazole and indanone derivatives and some or indanone were more potent than others. Besides, the introduction of acetylated glycosides was beneficial to the activity. Compounds A1, B1, C5, C8, C10, C11, C12 and D1 were promising antitumor agents. Among them, compounds molecular docking studies were performed between B1, C8 and potential targets Aurora B (PBD: 2BFY). On the basis, the chemical and physical properties, as well as ADMET of active compounds were predicted and analyzed. And it showed that most of compounds had good pharmacokinetic profiles and high safety profiles.

■ Synthesis and Characterization of Some Novel Heteroannulated Chromeno[4,3-b]quinolines

Najla A. Alshaye and Magdy A. Ibrahim*

*Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, Heliopolis 11757, Cairo, Egypt

Abstract

The recently synthesized 1-chloro-11-oxo-3,4-dihydro-11H-chromeno[4,3-b]quinoline-2-carboxaldehyde (1) was efficiently utilized as a key precursor to construct a diversity of polyfused systems containing chromeno[4,3-b]quinoline. Reaction of compound 1 with some substituted hydrazines afforded pyrazoles annulated chromeno[4,3-b]quinoline. Treatment of compound 1 with a diversity of 1,3-N,N-binucleophiles led to pyrimidines annulated chromeno[4,3-b]quinoline. In addition, a diversity of fused pyridines annulated chromeno[4,3-b]quinoline were synthesized from condensation of compound 1 with a variety of 1,3-C,N-binucleophiles. Finally, the reactivity of compound 1 was tested towards a diversity of 1,4-binucleophilic reagents. Structures of the new compounds were established using spectral and analytical data.

■ Catalyst-Free Green Synthesis of Phthalazinones at Room Temperature

Kang Lv, Zixi Xie, Xi Chen, Weiwei Yao,* and Mengtao Ma*

*Department of Chemistry and Material Science, College of Science, Nanjing Forestry University, Nanjing 210037, China

Abstract

An efficient catalyst-free synthesis of phthalazinones from 2-formyl/acetyl/benzoylbenzoic acids and substituted hydrazines is described. The direct cyclocondensation of a series of aryl/alkylhydrazines and various 2-formyl/acetyl/benzoylbenzoic acids was performed at room temperature to afford the corresponding phthalazinones in very high isolated yields. The gram-scale reaction and application in the biological activity phthalazinone derivative demonstrated its practical potential. The plausible reaction mechanism was proposed based on the corresponding DFT calculations.

■ Direct Arylation of Benzothiophene and Benzofuran Catalyzed by a Dinuclear Palladium Complex

Takuma Mochizuki, Keiryu Seto, Yuma Sugiyama, and Naofumi Tsukada*

*Department of Chemistry, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan

Abstract

Direct arylation of benzothiophene and benzofuran with iodoarenes proceeded in the presence of a dinuclear palladium complex formed by a chelate-bridging ligand. In the reaction of benzothiophene, β-arylbenzothiophenes were selectively obtained by using silver acetate as an additive. In the reaction of benzofuran, α-arylbenzofurans were selectively obtained by using silver sulfonate as an additive.

■ Simultaneous Denitrative C–C Bond Formation and Construction of Pyrazole Ring Leading to 1,1'-Diphenyl-4,4'-bipyrazole

Kento Iwai, Nana Hatayama, and Nagatoshi Nishiwaki*

*School of Environmental Science and Engineering, Kochi University of Technology, Kami Kochi 782-8502, Japan

Abstract

β-Formyl-β-nitroenamine reacts with phenylhydrazine to afford 1,1'-diphenyl-4,4'-bipyrazole. The unusual C–C bond formation was found to proceed in an ionic mechanism initiated by excess amount of hydrazine. This reaction is interesting from a viewpoint of synthetic chemistry because it simultaneously involves the construction of a pyrazole ring and the formation of a C–C bond under neutral conditions.

■ Concise Synthesis of (±)-Cephalotaxine

Jian Zhang,* Huili Ding, Yuxue Fan, Hui Chen, Hongxia Dai,* and Ming Jing

*School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, P. R. China

Abstract

The construction of 1-azaspiro[4.4]nonane framework was achieved via the key Stevens rearrangement reaction of the Weinreb amide. And the subsequent steps mediated by the carbonyl of Weinreb amide led to the concise formal synthesis of (±)-cephalotaxine. Further development and application of asymmetric Stevens rearrangement of the Weinreb amide are underway.

■ Synthesis and Biological Activity of Aminoisoquinoline Schiff Bases

He Li, Jiangyu Ji, Chi Liu, Change Dong, Yapeng Zhang, Jinghan Hong, Runlai Li,* and Zhenming Zhang*

*College of Pharmacy, Jiangsu Ocean University, Lianyungang, China, 222005

Abstract

Twelve new isoquinoline Schiff bases were prepared in excellent yields by the condensation reaction of different aromatic aldehydes with 1-chloro-5-aminoisoquinoline. The structures of the synthesized compounds were confirmed by nuclear magnetic resonance and mass spectrometry. All new compounds were tested against 3 microorganisms: Staphylococcus aureus, Escherichia coli and Candida albicans. The results showed that compounds 3d, 3k and 3l exhibited excellent antibacterial activity against Escherichia coli with diameters of 16.9, 16.7 and 15.5 mm, respectively. The antibacterial diameter of compound 3e against Staphylococcus aureus was 14.5 mm, and it demonstrated good antibacterial action.

■ Acid, Metal and Peroxide-Free Synthesis of 2,4,5-Trisubstituted Imidazoles Commencing from Internal Alkenes Using an Iodine/DMSO System

Nonhlelo Majola and Vineet Jeena*

*School of Chemistry and Physics, University of KwaZulu-Natal, Scottsville, Pietermaritzburg, 3209, South Africa

Abstract

An efficient acid, metal and peroxide-free synthesis of 2,4,5-trisubstituted imidazoles commencing from internal alkenes and aldehydes using an inexpensive and eco-friendly iodine/DMSO system has been reported. This simple methodology affords a plethora of 2,4,5-trisubstituted imidazoles in moderate to good yields under mild reaction conditions. Based on preliminary control studies, a reasonable mechanism to the target imidazole is proposed.