HETEROCYCLES

■ Contents

■ Aziridine-2-carboxylates: Preparation, Nucleophilic Ring Opening, and Ring Expansion

Tsutomu Ishikawa*

*Graduate School of Pharmaceutical Science, Chiba University, 1-8-1 Inohana, Chuo, Chiba, Japan

Abstract

Preparation methods of aziridine-2-carboxylates are discussed. The chemical reactivities, focusing on ring opening by various nucleophiles and ring expansion to larger heterocycles, are also surveyed.

■ Syntheses of Bilin Chromophores Toward the Investigation of Structure and Function of Phytochromes

Katsuhiko Inomata*

*Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192, Japan

Abstract

We studied on the syntheses of linear tetrapyrrole (bilin) chromophores including the sterically locked derivatives toward the investigation of structure and function of phytochromes as photoreceptors. The synthesized chromophores were successfully assembled with bacterial and plant apophytochromes in vitro and/or in vivo to demonstrate that they are valuable tools for studies on phytochromes.

■ Synthesis of (±)-Esermethole via an Intramolecular Carbamoylketene-Alkene [2+2] Cycloaddition

Tsukasa Ozawa, Makoto Kanematsu, Hiromasa Yokoe, Masahiro Yoshida, and Kozo Shishido*

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

Abstract

A synthesis of (±)-esermethole (2), a synthetic precursor of physostigmine (1), has been accomplished by using an intramolecular carbamoylketene-alkene [2+2] cycloaddition followed by nitrone-mediated regioselective ring expansion for the construction of the basic carbon framework of 2 as the key steps.

■ Synthesis and Reactivity of 2-Chloro-3-formylpyrido[2,1-a]isoquinoline Derivative. A Novel Routes to Pyrazolo[3',4':4,5]pyrido[2,1-a]isoquinoline and Isoquinolino[2,1-g][1,6]naphthyridines

Hamdi M. Hassaneen,* Wagnat W. Wardkhan, and Yasmin Sh. Mohammed

*Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt

Abstract

Treatment of 2-hydroxy-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbonitrile 2 with POCl3/DMF gave 2-chloro-3-formylpyrido[2,1-a]isoquinoline derivative 3. Compound 3 reacted with hydrazines 5a-d to give the condensation products 6a-d. Cyclization of 6a gave pyrazolo[3',4':4,5]pyrido[2,1-a]isoquinoline derivative 7. Treatment of 3 with ethoxycarbonylmethylenetriphenylphosphorane 10 afforded (E)-ethyl 3-(2-chloro-1-cyano-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-3-yl)acrylate 11. Azidation of 11 yielded the corresponding azido compound 12. Reduction of 12 gave the corresponding amino compound 13 which upon cyclization gave the novel tetracyclic product 14. Compound 12 reacted with triphenylphosphine to give phosphorane compound 15, which reacted with phenyl isothiocyanate to give a novel isoquinolino[2,1-g][1,6]naphthyridine derivative 18. Refluxing of 11 with amines 19a-c and thiophenols 22a-d in ethanol produced the corresponding substitution products 20a-c and 23a-d, respectively. Cyclization of 20a afforded isoquinolino[2,1-g][1,6]naphthyridine derivative 21.

■ A Total Synthesis of Herboxidiene Methyl Ester

Rajaratnam Premraj, Malcolm D. McLeod, Gregory W. Simpson, and Martin G. Banwell*

*Research School of Chemistry, Australian National University, Canberra, ACT 0200, Australia

Abstract

The total synthesis of the methyl ester, 35, of herboxidiene (1, a.k.a. GEX1A and TAN-1609), a polyketide displaying both herbicidal and anti-tumor activity, is described. The convergent reaction sequence involves, in its closing stages, the union of the phosphine oxide 3 with the aldehyde 21 to deliver, via a Horner–Wittig reaction with accompanying epimerization at C12, compound 33 that after deprotection affords an alcohol, 34, capable of participating in a regio- and diastereo-selective epoxidation reaction to give target 35. Phosphine oxide 3 was prepared via the intramolecular hetero-Michael addition of a secondary alcohol to a tethered and Z-configured acrylate while aldehyde 21 was generated, in the crucial step of the relevant reaction sequence, via an Ireland–Claisen rearrangement reaction.

■ Ketalization of Glycerol with Acetone to O-Heterocyclic Compounds over ZrO2-SiO2 Solid Acid Catalysts

Chunni Fan, Chenghua Xu,* Chuanqi Liu, Zunyu Huang, Jianying Liu, and Zhixiang Ye

*Air Environmental Modeling and Pollution Controlling, Key Laboratory of Sichuan Higher Education Institutes, Chengdu University of Information Technology, No. 24, Block 1, Xuefu Road, Chengdu, Sichuan Province 610225, China

Abstract

The solid acid catalysts ZrO2-SiO2 mixed oxides were prepared by sol-gel, characterized by X-ray diffraction, NH3-temperature programmed desorption, fourier transform infrared spectroscopy, and applied in the glycerol catalytic ketalization with acetone to O-heterocyclic compounds in the present work. Simultaneously, the effects of the catalysts composition, calcination temperature and ketalization parameters such as reaction time, acetone/glycerol, catalyst amount and reaction temperature on the ketalization were also investigated in detail. The results showed that the main product for the glycerol ketalization with acetone was solketal with a 5-membered ring along with a small amount of 2,2-dimethyl-1,3-dioxan-5-ol with a 6-membered ring. ZrO2-SiO2 with a Zr/Si molar ratio of 0.5 calcined at 500 oC exhibited the best catalytic property in ketalization, gave 90.91% of glycerol conversion and 89.69% of solketal selectivity under the optimum conditions. It was also found that glycerol catalytic ketalization with acetone to solketal was mainly governed by kinetics.

■ Preparation of β-Keto-β-alkanoyloxyphosphonates, Phosphine Oxides and Sulfides and Their Application to the Synthesis of Novel Phosphoryl- and Thiophosphorylpyrazoles

Hosni Slimani and Soufiane Touil*

*Department of Chemistry, Faculty of Sciences of Bizerta, 7021-Jarzouna, Tunisia

Abstract

Two synthetic methods leading to β-keto-β-alkanoyloxyphosphonates, phosphine oxides and sulfides 2 are reported. The first method involves the reaction of β-enaminoesters 1 with chlorophosphines and phosphites followed by oxidation or sulfurization and hydrolytic work-up. The second one utilizes the reaction of β-enaminoesters 1 with diethylchlorophosphate and thiophosphate followed by acid hydrolysis. On reaction with hydrazine derivatives, compounds 2 give the corresponding phosphoryl- and thiophosphorylpyrazoles 3. The structures of all obtained products were confirmed by NMR (1H, 31P, 13C) and IR spectroscopies, and by mass spectrometry.

■ The New Convenient Synthesis of 6-Fluoropurine and Its 7-/9-Unsubstituted Analogues

Mei Deng, Ning-Yu Wang, Guangming Xiang, and Luo-Ting Yu*

*State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China

Abstract

6-Fluoropurine and its 7-/9-unsubstituted analogues have good biological activity and serve as important pharmaceutical intermediates. This paper describes a new and convenient synthesis of 6-fluoropurine and its 7-/9-unsubstituted analogues, by first replacing the chlorine atoms with trimethylammonio groups through the reaction of 6-chloropurine and its 7-/9-unsubstituted analogues with trimethylamine, and then replacing the trimethylammonio groups with fluorine atoms using safe and cheap TBAF·3H2O as fluorinating agent at room temperature. Compared with reported methods, the new synthesis has milder conditions, shorter reaction times, simpler post-processing and higher (or similar) yields.

■ One-Pot Synthesis of 2-(1,4-Dihydro-2H-3,1-benzothiazin-2-ylidene)propanedioic Acid Derivatives by the Reaction of 2-(1-Bromoalkyl)phenyl Isothiocyanates with Propanedioic Acid Derivatives Using Sodium Hydride

Kazuhiro Kobayashi* and Kosuke Ezaki

*Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

An efficient one-pot procedure for the preparation of 2-(1,4-dihydro-2H-3,1-benzothiazin-2-ylidene)propanedioic acid derivatives from 2-(1-bromoalkyl)phenyl isothiocyanates with propanedioic (malonic) acid derivatives, such as propanedinitrile, ethyl cyanoacetates, 3-oxo-3-(pyrrolidin-1- yl)propanenitrile and diethyl propanedioate, has been developed. The reactions are carried out in the presence of two equivalents of sodium hydride at –20 ˚C to give the desired products.

■ Nigelactone, New Phthalide Glucoside from the Seeds Nigella glandulifera

Yu Feng, Yu-Ming Liu,* Qing-Hua Liu, and Ying-Jie Lei

*Department of Pharmacy Engineering, Tianjin University of Technology, No.391, Bin Shui Xi Road, Xi Qing District, Tianjin , China

Abstract

Chemical investigations of the seeds of Nigella glandulifera have resulted in the isolation of a new phthalide derivative, nigelactone (1), together with two known metabolites. Their structures were established by detailed analysis of their 1D and 2D NMR spectra and mass spectroscopic data. Nigelactone (1) possesses a rare structural skeleton found in nature.

■ Synthesis and Mesomorphism of the Bipedal Liquid Crystals with a Tetrathiafulvalene/dithiole and Two Cholesterol Moieties

Shan Jiang, Han Wang, Ruibin Hou, Keli Zhong,* and Bingzhu Yin*

*Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Yanbian University, Yanji 133002, China

Abstract

The bipedal 1,3-dithiole-2-thiones and the appropriate EDT-TTFs bearing two cholesteryl linked with two ω-thioalkanoyloxy spacers of varying length were synthesized. All of bipedals showed mesogenic phases in a wide temperature region, no crystallization but vitrifying to form glassy mesogens during cooling from the isotropic melt.

■ Palladium-Catalyzed Synthesis of a Phosphine Oxide with a Chiral Phosphorus Center via C-H Phosphination

Yoichiro Kuninobu,* Kazuki Origuchi, and Kazuhiko Takai*

*Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Abstract

A new phosphine oxide with a chiral phosphine center was synthesized from a bis(biphenyl)phosphine oxide by dehydrogenative intramolecular cyclization via P-H and C-H bond activation under palladium catalysis. The absolute configuration of one enantiomer of the phosphine oxide was determined by single crystal X-ray structure analysis. By reducing the phosphine oxide, the corresponding phosphine, which also has a chiral center, was produced. The phosphine compounds could be optically resolved by chiral HPLC column chromatography.

■ Three New D-Lactone Ring Isomeric Phragmalin-Type Limonoids from Chukrasia tabularis var. velutina

Yi Li, Jun Luo, Qiang Wang,* and Ling-Yi Kong*

*School of Traditional Chinese Medicine, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China

Abstract

Three new D-lactone ring isomeric phragmalin-type limonoids, tabulalins G-I (1-3), were isolated from the stem barks of Chukrasia tabularis var. velutina. Compound 1 possesses C-16/C-30 δ-lactone ring (D), which was unusual in phragmalins, and that of 2 and 3 were C-16/C-17. The structures of these three new compounds were elucidated on HR-ESI-MS, 1D and 2D NMR including HSQC, HMBC, and ROESY experiments.