HETEROCYCLES

■ Contents

■ 1,3,5-Triazine-Cored Star-Shaped (D-π)3-A Molecules Based on 2,4,6-Tris(5-arylthiophen-2-yl)-1,3,5-triazine

Hiroki Muraoka* and Satoshi Ogawa

*Department of Chemistry and Bioengineering, Faculty of Engineering, Iwate University, 4-3-5 Ueda, Morioka, Iwate 020-8551, Japan

Abstract

Star-shaped (D–π)3–A molecules consist of three parts: an electron-accepting core (A), π-conjugated bridges (π), and electron-donating terminals (D). These molecules are commonly designed using a π (thiophene)3–A (1,3,5-triazine) segment composed of 2,4,6-tri(thiophen-2-yl)-1,3,5-triazine (TTT), which offers geometric and electronic structural advantages. By structurally and electronically modifying TTT with different types of electron-donating aryl terminals, we systematically construct TTT-based star-shaped (D–π)3–A molecules with controlled molecular properties attributed to a special structure in which the star-shaped and D–π–A structures are hybridized. This review summarizes our researches on the synthesis, optical and electronic characterization, and application of a series of 2,4,6-tris(5-arylthiophen-2-yl)-1,3,5-triazines based on our concept.

■ Fischer Glycosidation Using Organotitanium Catalyst ORGATIX

Nana Yanagida, Keita Kato, Mako Matsushita, and Minoru Izumi*

*Graduate School of Environmental and Life Science, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan

Abstract

Fischer glycosidation was performed at room temperature and 60 °C using the organotitanium compound ORGATIX, especially TC-310, which worked as an acid catalyst in the presence of alcohol. ORGATIX could be readily quenched by water and removed by simple filtration using silica-gel column chromatography.

■ Design, Synthesis, and Biological Evaluation of 4H-Pyrido[1,2-a]pyrimidin-4-one Derivatives as Anticancer Agents via ROR1 Inhibition

Mei-Tao Yuan, Xin-Ran Zhao, Liang Xiong, Ting Zhong, Fang Luo, Qing Li, Mei Li, Hong-Shan Wu, Ai-Ling Linghu, Xiao-Sheng Yang,* and Yan-Hua Fan*

*State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, No. 9, Beijing Road, Guiyang, 550014, China

Abstract

Based on the chroman-4-one ROR1 inhibitor ARI-1, two new series of 4H-pyrido[1,2-a]pyrimidin-4-one derivatives were designed and synthesized, and their biological activities were investigated. In vitro biological activity assays showed that compound 10b exhibited the best antiproliferation activity against H1975 (IC50 = 0.572 μM), which was superior to the lead compound ARI-1 (IC50 = 3.51 μM). Compound 10b also dose-dependently induced G0/G1 phase block and apoptosis. In addition, 10b exhibited inhibitory activity against ROR1 and modulated the ROR1 signaling pathway in a dose-dependent manner to exert anticancer activity. In conclusion, our data suggest that 10b may be a new lead compound for further development of ROR1 inhibitors as anti-cancer agents.

■ Synthesis of C4' Uridyl Aryloxazoles: A 'Heterohomologative' Approach

Paige J. Monsen and Frederick A. Luzzio*

*Department of Chemistry, University of Louisville, 2320 South Brook Streeet, Louisville, KY 40292, U.S.A.

Abstract

A series of uridine-based compounds homologated at C-4' with an aryl-substituted oxazole ring were prepared. Conversion of 2',3'-O-cyclopentylidene uridine to the corresponding 4'-carboxylate followed by Steglich ester coupling with a series of azidoalcohols gave the corresponding azidoesters. The azidoesters were cyclized to the substituted oxazolines using Staudinger aza-Wittig conditions (PPh3/THF). Direct treatment of the substituted oxazolines with nickel peroxide or DDQ provided the corresponding C4' uridyl aryloxazoles. Removal of the 2',3'- O-cyclopentylidene group was accomplished using 70% aqueous trifluoroacetic acid which afforded the target C4'-heterocyclic nucleoside analogues. The sequence could be accomplished with nitrogen or oxygen-substituted aryl azidoalcohol precursors which gave rise to the corresponding aryl-substituted C4'-oxazolyl uridine derivatives. The oxygen or nitrogen-substituted aryloxazoles underwent further derivatization to deliver ester and amide derivatives.

■ Synthesis, Characterization, and Computational Studies of Some Perfluorinated Cyclopentapyridazines for Biological Applications

Nathan C. Tice,* Steven Wild, Hannah Dendinger, Bangbo Yan, and Pauline Norris

*Department of Physical Sciences, The University of Findlay, 1000 North Main Street, Findlay, OH 45840, U.S.A.

Abstract

Fluorinated heterocycles are a major component of the field of modern medicinal chemistry due to the widespread presence of heterocyclic ring structures in naturally occurring biological molecules. The effect of the presence of fluorinated heterocyclic moieties on chemical properties such as intermolecular interactions and solubility can be used to impart synthetic molecules with useful, drug-like characteristics. Pyridazines, which are aromatic six-membered rings with a chemical formula (CH)4N2 and adjacent nitrogens, afford important biological activities to drug molecules by increasing their solubility and ability to complex with target molecules. Our method of synthesizing fluorinated pyridazines incorporates an SNAr reaction on 5,6-fused ring pyridazines with a variety of aryl substituents at the 1- and 4-positions with pentafluoropyridine. The target products were identified by spectroscopic characterization and confirmed via X-ray crystallography. Computational studies were also performed on the phenyl-substituted case, including the calculation of an optimized structure using PBE with a cc-pVTZ basis. This analysis found the addition of perfluorinated pyridine significantly altered the esp mapping, HOMO-LUMO, and NBOs of the modified pyridazine compared to other 5,6-fused ring heterocycles.

■ Selective Protection and De-protection of Phenolic Hydroxy Groups of Naringenin

Xiaolong Hu and Guo-Chun Zhou*

*School of Pharmaceutical Sciences, Nanjing Tech University, 30 Puzhu S Rd,211816, China

Abstract

Naringenin (1, Scheme 1) is a flavanone belonging to a part of a huge group of bioactive polyphenols. In order to selectively modify desired phenol/s, in this study, we developed some methods for selective protections of three hydroxy groups of 1. The 1st method is to silylate two hydroxy groups of 1 and then selectively de-protect the silylation product followed by site-selective acetylation, or site-selective silylation of 7-OH and then acetylation of 4’-OH. The 2nd synthetic method was started from triacetyloxylated naringenin (10), which was conducted in specific solvents to remove the distinctive acetyl protection by TFA, TsOH or imidazole. After protection of 4’,5-dihydroxynaringenin (12) by TBS at 7-OH to form 7-t-butyldimethylsilyloxy-4’,5-diacetyloxynaringenin (13), in the 3rd method, 4’-OAc or 5-OAc of 13 was selectively de-protected under acidic conditions to afford 4’-OH-5-OAc-7-OTBS naringenin (14) or 4’-OAc-5-OH-7-OTBS naringenin (6) as mixed protection derivatives. These methods have the advantages of mild reaction conditions, easily handled reagents and satisfactory yields.

■ Theoretical Investigation of Cp*Co(III)-Mediated Regioselective [4 + 2]-Annulation of N-Chlorobenzamide with Vinyl Acetate for the Synthesis of Isoquinolone

Nan Lu,* Chengxia Miao, and Xiaozheng Lan

*College of Chemistry and Material Science, Shandong Agricultural University, No.61 Daizong Street, Taian 271018, China

Abstract

The mechanism is investigated for regioselective [4 + 2]-annulation of N-chlorobenzamide catalyzed by Cp*Co(III). The CoCp*(OAc)2-mediated ortho-cobaltation via acetate-aided N-H and C−H deprotonation furnishes a five-membered intermediate, which is coordinative inserted into alkene by giving seven-membered cobaltacycle. The reductive elimination and oxidative addition of CoCp*(I) species afford six-membered ring. The recovery of CoCp*(III) is assisted by one AcOH for vinyl acetate with OAc group available to cleavage as one ligand. Two OAc ligands are both supplied by AcOH for vinyl ketone with COMe group difficult to break. The acetate-assisted tautomerization produces isoquinolin-1(2H)-one. The 3-acetylisoquinolin-1(2H)-one is given by dehydrooxidation. The promotion of Cp*Co(III) lies in the barrier decrease of most steps especially N-H and C−H deprotonation. AcOH functions in the protonation of Cl, N and as sources of acetate ligands for the recovery of CoCp*(III). These results are supported by Multiwfn analysis on FMO of specific TSs and MBO value of vital bonding, breaking.

■ Efficient One-Pot, Three-Step Synthesis of 1,2,3,5-Tetrasubstituted Pyrroles via Aza-Michael Addition of Methyl 3-Iminoacrylates

Michiyasu Nakao,* Ken Horikoshi, Syuji Kitaike, and Shigeki Sano*

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

Abstract

An efficient one-pot, three-step procedure for the aza-Michael addition of methyl 3-iminoacrylates with secondary amines followed by intramolecular cyclization and silylation successfully afforded novel 1,2,3,5-tetrasubstituted pyrroles in high yields.