HETEROCYCLES

■ Contents

■ Synthesis of Nitrogen-Containing Heterocycles Using Conjugate Addition Reactions of Nucleophiles to α,β-Unsaturated Imines

Iwao Hachiya, Isao Mizota, and Makoto Shimizu*

*Department of Chemistry for Materials, Graduate School of Engineering, Mie University, 1577 Tsu, Mie 514-8507, Japan

Abstract

Synthetic methods for the synthesis of nitrogen-containing heterocycles are of utmost interest and importance because these structures are the key components of natural and unnatural biologically active compounds and functionalized materials. This review summarizes the synthesis of nitrogen-containing heterocycles, where the conjugate addition of nucleophiles to α,β-unsaturated imines is the crucial step.

■ Rhodium-Catalyzed [2+2+2] Cycloaddition for the Synthesis of Substituted Pyridines, Pyridones, and Thiopyranimines

Ken Tanaka*

*Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Koganei, Tokyo184-8588, Japan

Abstract

The transition-metal-catalyzed [2+2+2] cycloaddition of alkynes with nitriles is a useful and atom-economical method for the synthesis of substituted pyridines. The use of isocyanates and isothiocyanates in place of nitriles affords substituted pyridones and thiopyranimines, respectively. This review comprehensively covers the [2+2+2] cycloaddition reactions catalyzed by rhodium complexes for the synthesis of substituted pyridines, pyridones, and thiopyranimines. Asymmetric variants of these rhodium-catalyzed [2+2+2] cycloaddition reactions are also described.

■ One Step Synthesis of Optically Active Diazabicyclo[3.3.0]octanones or Diazabicyclo[4.3.0]nonanones by Asymmetric Conjugate Addition of Cyclic Hydrazine

Chigusa Seki,* Masafumi Hirama, Takeshi Sato, Saya Takeda, Yoshihito Kohari, Kazuhiro Ishigaki, Masafumi Ohuchi, Kiyoshi Yokoi, Hiroto Nakano, Koji Uwai, Nobuhiro Takano, Kazuyuki Umemura, and Haruo Matsuyama*

*Department of Applied Chemistry, Graduate School of Engineering, Muroran Institute of Technology, 27-1 Mizumoto, Muroran, Hokkaido 050-8585, Japan

Abstract

Asymmetric conjugate addition-cyclization of lithium amide of 6-membered hydrazine 4, piperidazine, (or 5-membered hydrazine 6, pyrazolidine) to N-(E)-cinnamoyl-(1S)-2,10-camphorsultam (1S)-3 afforded β-amino acid derivative (S)-1 {or (S)-2} for the synthesis of polyamine alkaloids in good yield with good stereoselectivity (up to 86% ee).

■ Photoinduced Selective Transformation of N-Acyl-α-dehydro(9-phenanthryl)alaninamides into Their Cyclization Intermediates in a Polar Protic Solvent

Yuki Kawanishi, Hiroko Yoshiie, Tetsutaro Igarashi, and Tadamitsu Sakurai*

*Department of Material and Life Chemistry, Faculty of Engineering, Kanagawa University, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan

Abstract

Irradiation of the title compounds [(Z)-1] in methanol afforded trans-3,8a-dihydro-2-dibenzo[f,h]quinolinone derivatives (trans-2) in preference to cis-2, all of which serve as precursors of the corresponding 3,4-dihydrodibenzoquinolinones. An analysis of the substituent and solvent effects on the cyclization occuring from the excited-state (E)-1 showed that the reactivity of this (E)-isomer is greatly influenced by the steric bulk of the alkyl group attached to the N´-amide nitrogen of the starting 1. In addition, this analysis confirmed that the stabilization of the excited-state (E)-1 (having a zwitterionic structure), by hydrogen-bonding and charge-transfer interactions with methanol, is an essential prerequisite for the occurrence of the photocyclization reaction selectively forming trans-2 and cis-2.

■ Enantioselective Synthesis of ε-Lactones by Lipase-Catalyzed Resolution

Yasutaka Shimotori,* Masakazu Aoyama, Hidetaka Tsukasa, and Tetsuo Miyakoshi

*Department of Biotechnology and Environmental Chemistry, Kitami Institute of Technology, Koen-cho 165, Kitami, Hokkaido 090-8507, Japan

Abstract

Synthesis of optically active ε-dodecalactone (1) by lipase-catalyzed enantioselective acylation with racemic N-alkyl-6-hydroxydodecanamide (rac-2) as a substrate was attempted. Lipase PS-catalyzed acetylation using rac-2 progressed efficiently, and both enantiomers of 1 were obtained with over 90% optical purities.

■ Synthesis of Fluorene- and Spirobifluorene-Fused Thiophenes

Wen Yao, Qiancai Liu,* Yingbo Shi, and Jie Tang

*Department of Chemistry, East China Normal University, 500 Dongchuan Rd., Minhang, Shanghai 200241, China

Abstract

A novel synthetic route to fluorene- and spirobifluorene-fused thiophenes is explored by starting with ninhydrin. The Diels-Alder cycloaddition was employed to construct the key intermediate, 2,3-bis(hydroxymethyl)-1,4-diphenyl-fluorenone, which was further converted stepwise to the target molecules. All of dihydrothiophenes and final products are confirmed by 1H NMR, 13C NMR and mass spectrometry.

■ Syntheses of 5-Amino-2-phenyl-4(3H)-pyrimidinone Derivatives Starting with Glycine

Daisuke Takahashi,* Yutaka Honda, and Kunisuke Izawa*

*Research Institute for Bioscience products and Finechemicals, Ajinomoto Co., Inc., 1780 Hinaga, Yokkaichi, Mie, 510-0885, Japan

Abstract

N-Cbz derivative of 5-amino-2-phenyl-4(3H)-pyrimidinone was prepared from sodium salt of methyl hydroxymethylene glycinate and benzamidine hydrochloride in good yield. However, the reaction with N-substituted benzamidine did not proceed to give the desired pyrimidinone. In contrast, the reaction of 4-ethoxymethylene-2-phenyl-5(4H)-oxazolone readily prepared from hippuric acid and N-substituted benzamidine proceeded nicely to give 5-(benzoylamino)-6-oxo-2-phenyl-1(6H)-pyrimidineacetic acid in high yield.

■ Novel Synthesis of Carbocyclic Oxetanocin Analogs (2-Alkoxy-C.OXT-A) and Their Tube Formation Activities of Human Umbilical Vein Endothelial Cells (HUVEC)

Norikazu Sakakibara, Ikuko Tsukamoto, Takashi Tsuruta, Maki Takata, Ryoji Konishi, and Tokumi Maruyama*

*Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki City, Kagawa, 769-2193, Japan

Abstract

We succeeded in the effective synthesis of five types of 2-alkoxy-C.OXT-A analogs (9, 10a–d) by applying the de novo synthesis of 2-alkoxyadenosine derivatives (2), which was developed in our laboratory. For these synthesized compounds, the angiogenic activity was evaluated using human umbilical vein endothelial cells. Four products (10a–d) enhanced the activity of the cell; in particular, 2-methoxy-C.OXT-A (10a) and 2-isopropoxy-C.OXT-A (10c) at a concentration of 100 μM exhibited the same or stronger potency than the vascular endothelial cell growth factor.

■ Synthesis and Biological Evaluation of Oleanolic Acid Derivatives as Novel Inhibitors of Protein Tyrosine Phosphatase 1B

Hui Li, Hui Zou, Li-Xin Gao, Ting Liu, Fan Yang, Jing-Ya Li, Jia Li,* Wen-Wei Qiu,* and Jie Tang

*National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo-Shou-Jing Road, Shanghai 201203, China

Abstract

A series of oleanolic acid (OA) derivatives have been synthesized and their inhibitory effects on PTP1B, TCPTP and related PTPs are evaluated. Some compounds with five-membered heterocyclic ring-fused at C-2, C-3 positions showed a dramatic increase in inhibition, the two most potent PTP1B inhibitors 19 (IC50 = 0.91 μM) and 21 (IC50 = 0.98 μM) showed about 3-fold more potent than lead compound OA. Some C-ring modified OA analogs showed high selectivity for PTP1B over TCPTP, among them, 50 possessed the best selectivity of 6.6-fold.

■ Synthesis, Characterization and Evaluation of Antimicrobial Activity of Some Novel 1,2,4-Triazoles and 1,3,4-Thiadiazoles Bearing Imidazole Nuclues

Mohamed Reda Aouad,* Nadjet Rezki, Mohamed Kasmi, Linda Aouad, and Merieme A. Rezki

*Department of Chemistry, Faculty of Science, Taibah University, Madinah Munawwarah, Saudi Arabia

Abstract

A series of N1-[(4,5-di and 1,4,5-triphenylimidazol-2-yl)thioacetyl]-N4-alkyl/aryl-thiosemicarbazides 3-7 were synthesized from (4,5-di and 3,4,5-triphenylimidazol-2-yl)thioacetic acid hydrazide 1, 2. The treatment of compounds 3-7 with NaOH gave 5-[(4,5-di and 1,4,5-triphenylimidazol-2-yl)-3-thiomethyl]-4-alkyl/aryl-2H-1,2,4-triazoles-3-thione 8-12, while the acidic treatment of compounds 3-7 afforded 5-[(4,5-di- and 1,4,5-triphenylimidazol-2-yl)-3-thiomethyl]-2-alkyl/arylamino-1,3,4-thiadiazoles 13-17. Moreover, potassium hydrazinecarbothionates 18, 19 were obtained from the reaction of acyl hydrazides 1, 2 with carbon disulfides in basic media and converted into 4-amino-1,2,4-triazole-3-thiones 20, 21 and 1,3,4-thiadiazole-2-thiols 22, 23 by the treatment with hydrazine hydrate and sulfuric acid, respectively. All newly synthesized compounds were screened for their antimicrobial activity.

■ A Novel and Highly Efficient Protocol for the Synthesis of Chalcone Based 1,2-Diazepine and 1,2-Oxazepine Derivatives

B. Venkata Babu and Naseem Ahmed*

*Department of Chemistry, Indian Institute of Technology, Roorkee 247 667, Uttarakhand, India

Abstract

A novel and highly efficient protocol is described for the synthesis of chalcone based 1,2-diazepine and 1,2-oxazepine derivatives. Under neat condition, the mixing and grinding of 1,5-diketones and hydrazine gave the cyclocondensation products in quantitative yields within 10-20 min at room temperature. Similarly, novel chalcone based 1,2-oxazepines were synthesized in excellent yields (85-88%) in 2-3 h at refluxed by the condensation of 1,5-diktones and hydroxylamine hydrochloride in water-ethanolic base.

■ New Synthesis of Pyrvinium That inhibits the β-Catenin/Tcf4 Pathway

Yongjun Mao, Nan Lin, Wang Tian, Ziwei Huang, and Jing An*

*Department of Pharmacology, Upstate Medical University, State University of New York, 750 East Adams Street, Syracuse, NY 13210, U.S.A.

Abstract

A new and converged route is described for synthesis of pyrvinium, an anthelmintic and antitumor agent. This method uses easily obtained materials and simple and practical reactions, including the key Friedländer condensation, to form the quinoline ring. The final product is generated through eight steps, with 23% yield and 96.6% purity (HPLC). This synthetic pyrvinium effectively inhibits β-catenin/Tcf4 driven TOP-luciferase activity, with an IC50 value < 1 µM, and induces colon cancer cell death in a dose-dependent manner with an IC50 of 0.54 ± 0.06 µM.

■ Facile Synthesis of 2,3-Disubstituted Pyrroles from 2-Substituted 1-Pyrrolines

Yurie Fujiwara, Mitsunori Oda,* Taku Shoji, Takako Abe, and Shigeyasu Kuroda

*Department of Chemistry, Faculty of Science, Shinshu University, Asahi, Matsumoto 390-8621, Japan

Abstract

2-Substituted-1-pyrrolines react with various arylaldehyde acetals in the presence of a Lewis acid and base to give 2-substituted 3-arylmethylidene-1-pyrrolines, which are transformed to 2,3-disubstituted pyrroles by base-catalyzed double-bond isomerization.