HETEROCYCLES

■ Contents

■ Heterocycle Polycations – Syntheses and Reactions of (Oligo)pyridinium and (Oligo)imidazolium Salts

Jessica Hiller, Ming Liu, and Andreas Schmidt*

*Clausthal University of Technology, Institute of Organic Chemistry, Leibnizstrasse 6, D-38678 Clausthal-Zellerfeld, Germany

Abstract

The syntheses and chemical transformations of alkanes, phosphanes, alkenes, cycloalkenes, benzenes, naphthalenes, indolizines, pyridines, imidazoles, pyrimidines, pyrazines, pyridazines, purines, porphyrinazines, and porphyrins which are substituted by at least two pyridinium or imidazolium rings are reviewed up to 20-fold pyridinio-substituted systems.

■ Direct Conversion of Aromatic 1,3-Dioxanes to Hydroxypropyl Esters with Pyridinium Hydrobromide Perbromide and Sodium Acetate in Water

Shinsei Sayama*

*Department of Chemistry, Fukushima Medical University, Hikarigaoka, Fukushima, 960-1295, Japan

Abstract

Various aromatic 1,3-dioxanes were directly converted to respective hydorxypropyl esters with pyridinum hydrobromide perbromide and sodium acetate in water at room temperature.

■ Synthesis and Radical Scavenging Activity of Substituted Benzo[h]chromanols

Yuta Okayama, Masanori Harada, Mine Morita, Masataka Mochizuki, and Keiko Inami*

*Division of Pharmaceutical Organic Chemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan

Abstract

Benzo[h]chromanols, which possess a tocopherol moiety, have been reported to exhibit potent antioxidant activity. Several benzo[h]chromanols with various substituents (nitro, chloro, bromo, methyl, or amino groups at the position ortho to the phenolic OH group) were synthesized, and the second-order rate constants (k) of their reaction with the galvinoxyl radical were determined. The introduction of electron-withdrawing bromo, chloro and nitro groups decreased the activity, and the activity correlated well with the substituent effect. ortho-Aminobenzo[h]chromanol showed the highest radical scavenging activity among the compounds synthesized.

■ Highly Efficient Construction of CF3-Containing 3,3’-Pyrrolidinyl-dispirooxindoles via Base-Catalyzed Diastereoselective [3+2] Annulation

Wei-Jie Huang, Qing Chen, Wen-Run Zhu, Ning Lin,* Xian-Wen Long, Wei-Gao Pan, Jiang Weng,* and Gui Lu

*Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China

Abstract

An efficient base-catalyzed diastereoselective [3+2] cyclization of isatin-derived azomethine ylides with methyleneindolinones was developed. The process enables efficient incorporation of CF3 groups into highly functionalized 3,3’-pyrrolidinyl-dispirooxindoles bearing four contiguous chiral centers, including two adjacent spiro quaternary stereocenters, with high yields and diastereoselectivities.

■ Synthesis of γ-Keto-δ-alkenyl-phosphonates and Phosphine Oxides as Precursors of Novel Phosphono-pyrazoline and pyrazole Derivatives

Imen Lamouchi and Soufiane Touil*

*Laboratory of Heteroatom Organic Chemistry, Faculty of Sciences of Bizerte, University of Carthage, 7021-Jarzouna, Tunisia

Abstract

Herein we report the synthesis of γ-keto-δ-alkenyl-phosphonates and phosphine oxides by two versions of strategy (a) which involves the addition of dialkyl phosphites to α,α’-diarylideneketones, and by strategy (b) which utilizes the reaction of P-chlorodiphenylphosphine with diarylidene ketones in acetic acid. On reaction with hydrazine derivatives, γ-keto-δ-alkenyl-phosphonates and phosphine oxides give 3-phosphonoethylpyrazoline derivatives which can be converted into the corresponding aromatic pyrazoles by oxidative dehydrogenation, using sodium nitrite as oxidizing agent.

■ Selective N1-Alkylation of 1,3-Dibenzoyluracils: One-Pot Way to N1-Monosubstituted Uracil Derivatives

Alexander Ozerov,* Mikhail Novikov, Anastasiya Khandazhinskaya, and Pavel Solyev

*Department of Pharmaceutical & Toxicological Chemistry, Volgograd State Medical University, Pavshikh Bortsov Sq. 1, Volgograd, 400131, Russia

Abstract

A new method for synthesis of N1-monosubstituted uracils and 5- and 6-methyluracil derivatives was developed. It consists in the selective N1-deprotection of N1,N3-dibenzoyluracils in anhydrous dimethylformamide in the presence of potassium carbonate at room temperature and subsequent N1-alkylation by allyl, benzyl or phenacyl type halides or by primary alcohols toluenesulfonates conducted one-pot without isolation of the intermediates. Final N3-debenzoylation by aqueous-alcoholic solution of ammonia affords the corresponding N1-monosubstituted uracil derivatives with overall yields of 52-84%.

■ Stereoisomerization of 1,4-Dihydroarsininetetracarboxylic Acid Diimides under Non-Acidic Condition from cis- to trans-Forms

Kensuke Naka,* Takuji Kato, Koushi Abe, Makoto Ishidoshiro, Shintaro Nishiyama, Susumu Tanaka, Hiroaki Imoto, Seiji Watase, Kimihiro Matsukawa, Hiroyuki Fueno, and Kazuyoshi Tanaka

*Department of Chemistry and Materials Technology, Graduate School of Science and Technology, Kyoto Institute of Technology, Goshokaido-cho, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan

Abstract

Stereoisomerization of cis-1,4-dihydro-1,4-dimethyl-1,4-diarsininetetracarboxylic acid diimides, which were prepared from cis-1,4-dihydro-1,4-diarsininetetracarboxylic acid dianhydride with n-dodecylamine or aniline, to trans-isomers in CDCl3 proceeded at room temperature and quantitatively by repeated concentration and dissolution process in various solvents such as CHCl3, toluene, and ethyl acetate. Two stereoisomers were isolated respectively as single crystals, of which structures were determined by X-ray crystallography.

■ An Efficient and Practical Method for the Synthesis of the 5-Acylamino-4-(4-pyrimidinyl)isoxazole Derivative AKP-001, a Potent P38 MAP Kinase Inhibitor

Shuji Ohta,* Takahisa Saito, Jun-ya Kato, Shuichiro Sato, Hiroyuki Hayashi, and Koichi Hasumi

*Synthetic Research Department, ASKA Pharmaceutical Co., Ltd., 5-36-1, Shimosakunobe, Takatsu-ku, Kawasaki-shi, Kanagawa 213-8522, Japan

Abstract

5-Acylamino-4-(4-pyrimidinyl)isoxazole derivative AKP-001 is a p38 mitogen-activated protein kinase inhibitor previously developed in our laboratory as an anti-inflammatory agent. Herein, we report our studies leading to the development of an improved synthetic route to AKP-001, which shows several advantages compared to the previously reported laboratory-scale process, namely, a lower number of steps, superior chemical yield and atom efficiency, and applicability at an industrial scale.

■ Three New Isobenzofurans from the Stems of Oriental Tobacco and Their Bioactivities

Pei He, Shi-Yun Tang, Zhen-Jie Li, Chun-Bo Liu, Qinpeng Shen, Dang-Yu Tang, Feng-Mei Zhang, Zhi-Hua Liu, Yong-Kuan Chen, Jia-Qiang Wang, Neng-Jun Xiang,* and Zhang-Jie Huang*

*Key Laboratory of Tobacco Chemistry of Yunnan Province, China Tobacco Yunnan Industrial Co., Ltd, Kunming, 650231, China

Abstract

Three new isobenzofurans (1-3), together with four known furan derivatives (4-7) were isolated from the stems of oriental tobacco. Their structures were determined by means of HRESIMS and extensive 1D and 2D NMR spectroscopic studies. Compounds 1-7 were tested for their anti-tobacoo mosaic virus (TMV) activities and cytotoxicity activities. The results revealed that compounds 2 and 3 showed high anti-TMV activities with inhibition rates of 35.4, and 34.2%. These rates are higher than that of positive control. Other compounds also showed anti-TMV activities with inhibition rates in the range of 18.6~22.7%. These rates are close to that of positive control. Compounds 1-7 also showed moderate-to-weak inhibitory activities against some tested human tumor cell lines with IC50 values in the range of 2.8-9.3 μM.

■ A Facile Synthesis of Isocoumarino[3’,4’:4,5]pyrrolo[3,2-c]coumarins from 4-Aminocoumarins and Ninhydrin

Ting Zhou, Dao-Lin Wang,* Guang-Yu Pan, and Jian-Hua Qian

*Liaoning Key Laboratory of Synthesis & Application of Functional Compound, College of Chemistry & Chemical Engineering, Bohai University, Jinzhou 121001, China

Abstract

An efficient method for the synthesis of novel isocoumarino[3’,4’:4,5]pyrrolo[3,2-c]coumarins was described. The construction of this new fused heterocycles system was achieved undergo a domino reaction of 4-aminocoumarins with ninhydrin in good yields.

■ Novel Chiral Derivatizing Agents for 1H NMR Determination of Enantiomeric Purities of Carboxylic Acids

Koji Wada,* Mizuko Goto, Hiroshi Yamashita, and Kazuo Nagasawa

*School of Pharmacy, Hokkaido Pharmaceutical University, 7-15-4-1, Maeda, Teine-ku, Sapporo 006-8590, Japan

Abstract

(S)-4-(3-Aminopyrrolidin-1-yl)coumarin (1), (S)-4-(3-aminopiperidin-1-yl)coumarin (4), and (S)-4-(3-aminoazepan-1-yl)coumarin (7), prepared from 4-chlorocoumarin and (S)-pyrrolidin-3-amine, (S)-piperidin-3-amine, and (S)-azepan-3-amine, respectively, were proven to be versatile and reliable 1H NMR optical purity determination agents for chiral carboxylic acids.

■ Synthesis of Heterocyclic 1,3-Oxazolines from Aldehydes with Trimethylphenylammonium Tribromide

Shinsei Sayama*

*Department of Chemistry, Fukushima Medical University, Hikariga-oka, Fukushima 960-1295, Japan

Abstract

Various heterocyclic 1,3-oxazolines were prepared from aldehydes and aminoalcohols with trimethylphenylammonium tribromide at room temperature.