HETEROCYCLES

■ Contents

■ 3-[2-Oxo-2H-chromen-3(6)(8)-yl]-1-aryl/heteroaryl-1H-pyrazole-4-carbaldehydes: Synthesis, Reactions and Applications

Ayat K. Alsolimani, Mohammed A. Assiri, and Tarik E. Ali*

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

Abstract

The chemistry of 3-(2-oxo-2H-chromen-3(6)(8)-yl)-1-aryl/heteroaryl-1H-pyrazole-4-carbaldehydes has gained increased interest in both synthetic organic and biological fields, since a large number of developments in the use of such compounds seem to be of considerable value. This review describes all the available synthetic methods for diverse 3-(2-oxo-2H-chromen-3(6)(8)-yl)-1-aryl/ heteroaryl-1H-pyrazole-4-carbaldehydes in the literature survey. It also summarizes thier chemical behaviors as building blocks towards a variety of chemical reagents to construct related compounds as well as their biological applications.

■ Utility of 6-Aminouracils for Building Substituted and Heteroannulated Pyrimidines: A Comprehensive Review

Magdy A. Ibrahim, Zeinab Hussain,* Nasser M. El-Gohary, Yassin A. Gabr, Hassan A. Allimony, and Al-Shimaa Badran

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

Abstract

6-Aminouracils are very useful intermediates for building different categories of heterocyclic compounds. 6-Aminouracils are electron rich compounds due to the presence of free amino group which can initiate interactions with electron deficient centres or activate the nearby C-5 position to start the reaction followed by cyclization in most cases. The present review summarizes the different reactions developed for the synthesis of substituted and annulated pyrimidines. A diversity of substituted pyrimidines was prepared directly from reactions of 6-aminouracils with some electrophilic reagents, meanwhile formation of fused pyrimidines were
achieved by reaction of 6-aminouracils with a variety of reagents such as aromatic and aliphatic aldehydes, acyclic and cyclic methylene ketones, cyclic enols, alkynes, iminium salts and a diversity of other reagents.

■ Synthesis of Maleimide-Fused Aceheptylenes from Guaiazulene

Taku Shoji,* Mayumi Uda, Tetsuo Okujima, Ryuta Sekiguchi, and Shunji Ito

*Department of Chemical Biology and Applied Chemistry, College of Engineering, Nihon University, Koriyama 963-8642, Fukushima, Japan

Abstract

Maleimide-fused aceheptylenes were prepared using guaizulene as a starting material. The condensation reaction of 3,4-diformylguaiazulene derivative, which was prepared in three steps from guaiazulene, with maleimides in the presence of tri-n-butylphosphine and 1,8-diazabicyclo[5.4.0]undec-7-ene afforded the maleimide-fused aceheptylenes. Structural feature of the aceheptylenes prepared was revealed by 1H NMR spectroscopy and nucleus-independent chemical shift calculations.

■ Stereocontrolled Synthesis of Nitrogen-Substituted Quaternary Stereogenic Centers: Lessons from a Synthetic Route to the Core Structure of Sphingofungin E

Yoshiyasu Ichikawa,* Takahiro Kinutani, Yoshimine Sakogawa, Keisuke Nakanishi, Rika Ochi, Seijiro Hosokawa, and Toshiya Masuda

*Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan

Abstract

A strategy has been developed for stereocontrolled synthesis of nitrogen-substituted quaternary stereogenic centers that utilizes enantioselective addition of diethylzinc to α,β-unsaturated aldehydes and allyl cyanate-to-isocyanate rearrangement as key steps. The power and flexibility of this approach was demonstrated by its use in a stereocontrolled synthesis of the core structure of sphingofungin E and its epimer.

■ Synthesis of 1,2-Dicarbonyls from Five-Membered Cyclic Enamines and Arylglyoxal Hydrates under Metal-Free Conditions

Wei Fan*

*Science and Technology Office, Chuzhou City Vocation College, Chuzhou, 239000, Anhui, P. R. China

Abstract

An efficient and practical protocol for O2-enabled oxidative 1,2-dicarbonylation of five-membered cyclic enamines with arylglyoxal hydrates is developed, producing 32 examples of functionalized 1,2-dicarbonyls in good to excellent yields. Notable features of this transformation include wide substrate scope, excellent yields and metal-free conditions as well as O2 from air as the green oxidant with H2O as sole by-product.

■ Synthesis and Radical Scavenging Activities of Tocopherol Analogs Containing Heterocyclic Rings

Yuta Okayama,* Masataka Mochizuki, and Keiko Inami*

*Division of Pharmaceutical Organic Chemistry, Faculty of Pharmaceutical Science, Sanyo-Onoda City University, 1-1-1 Daigakudori, Sanyo-Onoda-shi, Yamaguchi 756-0884, Japan

Abstract

Antioxidants play an essential role in preventing oxidative stress. In this study, we synthesized novel tocopherol analogs with heterocyclic rings such as quinoline (5), indole (6), and benzimidazole (7), and evaluated their radical scavenging activities. The results showed that 6 has excellent radical scavenging activity. The data suggested that radical scavenging activity was enhanced in compounds containing heterocyclic rings with sufficient π-electrons and decreased in compounds with heterocyclic rings deficient π-electrons.

■ Synthesis of 2-Aryloxy-2,4,4,6,6-pentachlorocyclotriphosphazenes (N3P3Cl5(OAr)): Monoaryloxylatioin of Hexachlorocyclotriphosphazene (N3P3Cl6) and Mass Spectra of Chlorocyclotriphosphazene Derivatives. Difference between EI vs. ESI Methods

Manabu Kuroboshi,* Ryota Takahashi, and Hideo Tanaka

*Tsushima-naka 3-1-1, Kita-ku, Okayama, Okayama, Japan

Abstract

Hexachlorocyclotriphosphazene (HCCP, N3P3Cl6) was treated with Li aryloxide in THF at -40 ºC to give monoaryloxypentachlorocyclotriphosphazene (N3P3Cl5(ArO)) selectively. N3P3Cl5(ArO) did not give further aryloxylated products N3P3Cl6-n(ArO)n (n ≥ 2) under the same reaction conditions. In mass spectra (MS) of N3P3Cl5(ArO), [N3P3Cl5(ArO)]+ were detected by EI method, whereas partially hydrated products [N3P3Cl4(ArO)(O-)] were detected instead of [N3P3Cl5(ArO)]+ by ESI method.

■ Chemical Structures and Cell Death Inducing Activities of the Metabolites of Aspergillus terreus

Takahiro Matsumoto,* Masaya Okayama, Hayato Yoshikawa, Shifu Maeda, Takahiro Kitagawa, and Tetsushi Watanabe*

*Department of Public Health, Kyoto Pharmaceutical University, Misasagi, Yamashina-Ku, Kyoto 607-8412, Japan

Abstract

A new steroid, terreus steroid (1), and eight known compounds (2–9) have been isolated from the airborne-derived fungus Aspergillus terreus. The structure of terreus steroid (1) was elucidated based on the chemical/physicochemical evidence. The cell death-inducing activities of the isolated compounds with or without Adriamycin (ADR) were observed using time-lapse cell imaging. Among the isolated compounds, terreus steroid (1) and territrem B (3) significantly reduced the number of mitotic entry cells at 60 μM. In addition, terreus steroid (1), territrem C (2), territrem B (3), epi-aszonalenin A (5), and methyl 3,4,5-trimethoxy-2-(2-(nicotinamido)benzamido)benzoate (6) significantly increased the number of dead cells on Adriamycin-treated HeLa cells.

■ A Convenient Synthesis of 5-Trifluoromethyl-5-cyclopropyl-Substituted Pyrazolines

Yong-Bin Xie, Xiao-Dong Liu, Ming-Xu Zhang, Wen-Bo Chen,* Chun-Hui Xing,* and Long Lu*

*CAS Key Laboratory of Energy Regulation Materials, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, 200032 Shanghai, China

Abstract

A new method for the preparation of 5-trifluoromethyl-5-cyclopropylpyrazoline derivatives via cesium hydroxide mediated condensation reaction of ꞵ-trifluoromethyl-ꞵ-cyclopropyl-substituted unsaturated ketones with hydrazines was reported. The approach featuring mild reaction conditions, broad substrates scope and good functional group tolerance, provided a strategy to synthesize new functionalized pyrazolines bearing both trifluoromethyl and cyclopropyl groups.

■ One-Pot Synthesis of Carbazoles by a Domino Reaction Using Microwave Heating and Antiproliferative Activities of Constituents from Murraya Plants Against Cancer Stem Cells

Kouta Ugawa, Momona Nakao, Chikako Sawada, Takahiro Matsumoto, Takahiro Kitagawa, Yutaro Ohki, Kousuke Araki, and Seikou Nakamura*

*Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan

Abstract

Carbazoles could be easily and rapidly synthesized in a one-pot synthesis using 4-methyl-1-cyclohexanone and p-anisidine in a continuous microwave-heated reaction (1 h, 140 °C). Eustifoline-B, a trace constituent of the roots of Murraya euchrestifolia, was synthesized using the carbazole derivative glycozoline obtained by this method. Next, nine carbazoles isolated from the leaves of M. koenigii and three synthetic carbazoles were evaluated for their antiproliferative activities against human astrocytoma U-251 MG cells [that is, non-cancer stem cells (non-CSCs)] and cancer stem cells (CSCs) isolated by sphere formation. Carbazoles with geranyl or prenyl moieties showed antiproliferative activity against U-251 MG CSCs. In particular, the synthetic compound eustifoline-B showed significant antiproliferative activity against U-251 MG CSCs (IC50 = 2.9 μM). Interestingly, eustifoline-B showed an approximately 10-fold higher antiproliferative activity against U-251 MG CSCs than against U-251 MG non-CSCs (IC50 = 29.4 μM).

■ Synthesis and Photophysical Properties of Diethynylated Bibenzofuran and Benzodifuran Derivatives

Takaya Hibino and Rui Umeda*

*Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan

Abstract

The 3,3'-diethynyl-substituted 2,2'-bibenzofuran derivatives 1 and 3,7-diethynyl-substituted benzodifuran derivatives 2 were prepared from 1,4-bis(2-methoxyphenyl)-1,3-butadiyne and diethynyldimethoxybenzene by iodocyclization followed by Sonogashira coupling reaction, respectively.

■ Synthesis and Biological Evaluation of 5-Methylpyrimidine Derivatives as Dual Inhibitors of EGFR and Src for Cancer Treatment

Yaqing Zuo, Kehui Chen, Ying Xu, Yi Le, and Longjia Yan*

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

Abstract

In this paper, a series of new 5-methylpyrimidine derivatives was designed as dual inhibitors of EGFR and Src for cancer treatment. Twenty new compounds were synthesized and evaluated for antitumor activity with A549, HepG2, and K562 cells. Compounds 8f, 8p, and 8q showed better antitumor activity than Gefitinib and Dasatinib. They were selected for testing inhibition of EGFR and Src. The IC50 values of the most potent compound 8p was reached to 1.56 μM and 0.74 μM. In addition, the ADMET properties of compounds 8f, 8o-8q were predicted with ADMETlab 2.0.