HETEROCYCLES

■ Contents

■ Microwave Assisted Synthesis of Fused Heterocyclic Compounds

Kumar V. Srinivasan,* Pratip K. Chaskar, Satish N. Dighe, Dhanashri S. Rane, Pranav V. Khade, and Kishor S. Jain

*Sinhgad College of Pharmacy, Vadgaon (Bk.), Pune-41, India

Abstract

Microwave assisted heating under controlled conditions has been proved beneficial for medicinal chemistry and drug discovery process since it dramatically reduces reaction times, from days or hours to minutes or even seconds. Also, microwave synthesis provides higher yields, lower cost, easy workups and greater purity as compared to lower yields, tedious workups, longer reaction times, lesser purity and termination of many by-products in the conventional thermal methods.

■ Recent Advances in the Total Synthesis of Indolizidine Iminosugars

In Su Kim* and Young Hoon Jung*

*Department of Chemistry, University of Ulsan, Ulsan 680-749, Korea

Abstract

The importance of sugar-mimic glycosidase inhibitors in biochemistry, medicinal chemistry, and in the various aspects of life processes presents a challenge. The structural diversity of their multichiral architecture has long intrigued synthetic chemists to develop novel approaches to this class of compounds. Since glycosidase inhibitors have shown remarkable therapeutic potential in treating various metabolic diseases, an impressive number of synthetic routes to such compounds and their derivatives have been recently developed. This report highlights recent developments in the synthesis of indolizidine iminosugars. Different synthetic strategies have been used such as ring-closing metathesis, dihydroxylation, asymmetric epoxidation, [3,3]-sigmatropic rearrangement, desymmetrization, and amination. The potential application of our amination methodology that uses chlorosulfonyl isocyanate (CSI) for producing a variety of polyhydroxylated alkaloids will be presented.

■ A Molecular Orbital Calculation Study on Ring-Opening Reactions of Fluorine-Containing 3,4-Dihydro-2H-pyrans with Amines and Thiols

Norio Ota, Yasuhiro Kamitori,* Yusuke Tamai, Guo Feng, Mizuki Hatakenaka, and Etsuji Okada*

*Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan

Abstract

The reactions of 5-trifluoroacetyl-6-trifluoromethyl-3,4-dihydro-2H-pyran (1a) with various amines and sodium thiolates gave the corresponding 4,4-bistrifluoroacetyl-1,3-butadienyl amines (2b) and sulfides (2c), respectively, in good yields. Our DFT calculations suggested that the elimination of isobutanol from 1a and the subsequent electrocyclic ring-opening reaction on intermediate (4a) would proceed to afford 4,4-bistrifluoroacetyl-1,3-butadienyl ether (2a). Moreover, subsequent nucleophilic O-N and O-S exchange reactions on 2a which gave 2b and 2c, respectively, were also predicted.

■ Voltammetric Behavior of Mediator-Modified Electrode by Electrochemical Copolymerization of Nitroxyl Radical Precursor Containing Pyrrole Side Chain and Thiophenes

Yoshitomo Kashiwagi,* Makiko Tsunoda, and Tetsuya Ono

*School of Pharmaceutical Sciences, Ohu University, 31-1 Misumido, Tomita-machi, Koriyama, Fukushima 963-8611, Japan

Abstract

This paper describes the voltammetric behavior of the TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl)-modified electrodes prepared by the electrochemical copolymerization of TEMPO precursor containing pyrrole side chain and thiophenes. The prepared TEMPO-modified electrode with 2,2’-bithiophene exhibits a symmetrical reversible redox wave at +0.7 V versus Ag/AgCl, which originates from the electron transfer between the pyrrole and 2,2’-bithiophene-copolymerized layer and the electrode. The electrochemical copolymerization using 2,2’-bithiophene showed a nonlinear behavior between the anodic peak current in the cyclic voltammogram of the copolymers-modified electrode and the fraction of TEMPO precursor containing pyrrole side chain in solution. The copolymers-modified electrode exhibits high electrocatalytic activity for the oxidation of alcohol.

■ Novel Sulfonamide Catalyzed Asymmetric Hetero-Diels-Alder Reaction of Ethyl Glyoxylate with Danishefsky’s Diene

Takuya Kanemitsu, Yasufumi Asajima, Takashi Shibata, Michiko Miyazaki, Kazuhiro Nagata, and Takashi Itoh*

*School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan

Abstract

Novel sulfonamide organocatalysts were prepared from chiral Betti base and various sulfonyl chlorides, and applied to the asymmetric hetero-Diels–Alder reaction of ethyl glyoxylate with Danishefsky's diene. The sulfonamides exhibited catalytic activity as hydrogen bond donor. In particular, sulfonamide 3g showed highest catalytic performance for the reaction. Sulfonamide 3g catalyzed asymmetric reaction followed by treatment with TFA obtained corresponding 6-substituted 2,3-dihydropyran-4-ones in moderate yield and enantioselectivity.

■ Synthesis of Novel Methylene Bridge Functionalized Bis(indolyl)methanes through a Double Michael Addition

Mojgan Kargar, Rahim Hekmatshoar,* and AbdolJalil Mostashari

*Department of Chemistry, School of Sciences, Alzahra University, Vanak, Tehran, Iran

Abstract

A simple synthesis of a series of novel diethyl bis(indol-3-yl)methylmalonate is described. This involves domino Michael addition/ elimination/Michael addition of indoles to diethyl ethoxymethylenemalonate as double Michael acceptor.

■ A Novel Synthesis of 3,4,5,6-Tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole Derivatives from Serotonin

Koji Yamada, Sakiko Teranishi, Ayako Miyashita, Minoru Ishikura, and Masanori Somei*

*Faculty of Pharmaceutical Scicences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192,

Abstract

Utilizing novel Nb-substituted serotonins, 5- and/or 6-substituted 3,4,5,6-tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole derivatives are produced simply by treating serotonins with aldehydes under basic conditions. Synthesis of 2,2a,3,4,5,6-hexahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole-2-one derivatives is also reported.

■ Confirmation of Molecular Planarity Disruption Effect on Aqueous Solubility Improvement of β-Naphthoflavone Analogs

Yuji Fujita, Mitsuhiro Yonehara, Katsushi Kitahara, Jun Shimokawa, Yuichi Hashimoto, and Minoru Ishikawa*

*Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan

Abstract

We have reported that increasing the dihedral angle of bicyclic molecules by ortho-substitution leads to increased aqueous solubility, which is extremely important for drug candidates. Here, we investigated in detail the improvement of aqueous solubility of β-naphthoflavone analogs by means of this approach as candidate aryl hydrocarbon receptor (AhR) agonists. To confirm the contribution of molecular planarity disruption to the increased solubility, we compared the effect of ortho-substitution with that of meta- or para-substitution with the same substituent. We also compared the wavelengths of maximum UV absorption to evaluate molecular planarity in solution, and determined the X-ray crystal structures to assess molecular planarity and crystal packing. The results support the idea that disruption of molecular planarity by substituent-induced increase of the dihedral angle results in a decrease of the crystal packing energy and a lower melting point, with a consequent increase of solubility.

■ C2-Symmetric Pyrrolidine-Based Chiral Ammonium Salts as a Phase-Transfer Catalyst

Tatsuya Ishikawa, Kazuhiro Nagata, Sachiko Kani, Mamoru Matsuo, Daisuke Sano, Takuya Kanemitsu, Michiko Miyazaki, and Takashi Itoh*

*School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan

Abstract

Chiral pyrrolidinium salts having substituents at the α, α’ positions were synthesized to develop a chiral phase-transfer catalyst which have more simplified structure. The catalytic function of these synthesized catalysts was evaluated using asymmetric benzylation of N-(diphenylmethylene)glycine tert-butyl ester, and α,α’-disubstituded pyrrolidinium salts having an alkyl chain with a hydroxyl group at a chiral center were found to afford moderate enantioselectivity.

■ One-Pot Synthesis of Benzothiazol-2-amines by Cyclization of the Adducts between 2-Iodophenyl Isothiocyanates and Amines under Metal-Free Conditions

Kazuhiro Kobayashi,* Akihiro Kobayashi, Kazuya Murahashi, and Shuhei Fukamachi

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

Abstract

A convenient one-pot procedure for the preparation of N-substituted and N,N-disubstituted benzothiazol-2-amines under metal-free conditions has been developed, which employs the reaction of 2-iodophenyl isothiocyanates with primary and secondary amines followed by cyclization of the resulting thiourea precursors on treatment with triethylamine under relatively mild reaction conditions (< 70 ˚C). The reactions using diamines, such as ethylenediamines or trimethylenediamine, under similar conditions, albeit at higher temperature (130 ˚C), have proved to enable us to obtain N,N’-bis(benzothiazol-2-yl)ethane(or propane)diamines.

■ An Efficient Approach for the One-Pot Synthesis of Ethyl 4-Oxo-4H-benzo[d][1,3]oxazine-2-carboxylates

Farzad Nikpour,* Mahnaz Sharafi-Kolkeshvandi, and Asrin Bahmani

*Department of Chemistry, Faculty of Science, University of Kurdistan, Sanandaj, Pasdaran Bivd., P.O.Box 66135-416, Iran

Abstract

Simple one-pot synthesis of ethyl 4-oxo-4H-benzo[d][1,3]oxazine-2-carboxylates is described by condensation reaction of anthranilic acid derivatives with ethyl 2-chloro-2-oxoacetate in CHCl3. High yields of the products obtain in high purity with simple work-up.

■ Synthesis of (R)-(+)-Tanikolide, a Toxic and Antifungal δ-Lactone from the Marine Cyanobacterium Lyngbya majuscula

Keizo Matsuo,* Junko Hikita, and Keiji Nishiwaki

*Faculty of Pharmaceutical Sciences, Kinki University, 3-4-1, Kowakae, Higashi-Osaka 577-8502, Japan

Abstract

(R)-(+)-Tanikolide, a brine-shrimp toxic and antifungal marine metabolite, isolated from the lipid extract of a blue green algae, cyanobacterium, Lyngbia mujuscula, was synthesized starting from (-)-quinic acid.

■ Microwave-Assisted Synthesis and Bioactivity of Novel 2,2,4,5-Tetrasubstituted 3-Dichloroacetyl-1,3-oxazolidines

Ying Fu, Lei Yang, Fei Ye,* and Shuang Gao

*Department of Applied Chemistry, College of Sciences, Northeast Agricultural University, No.59 Mucai Street Harbin 150030, Heilongjiang, China

Abstract

An efficient one-pot synthesis of 2,2,4,5-tetrasubstituted-3-dichloroacetyl-1,3-oxazolidines under microwave irradiation was developed. The intermediate oxazolidines were attained by the reaction of amino alcohol with aldehyde or ketone in refluxing benzene with microwave-assisted cycloaddition, and then the acylation followed with dichloroacetyl chloride and NaOH acting as the attaching acid agent. All the compounds were characterized by IR, 1H-NMR, 13C-NMR and elemental analysis. The preliminary biological test shows that these compounds could protect maize against injury caused by acetochlor to a certain extent.

■ New Flavonol Glycosides from Cardamine komarovii

Il Kyun Lee, Eun-Kyung Jeong, Sang Un Choi, Jongki Hong, and Kang Ro Lee*

*Natural Products Laboratory, School of Pharmacy, Sungkyunkwan University, 300 Chunchun-dong, Jangan-ku, Suwon 440-746, Korea

Abstract

Seven new kaempferol glycosides (1 - 7), together with three known kaempferol glycosides (8 - 10), were isolated from a MeOH extract of Cardamine komarovii NAKAI (Cruciferae). The chemical structures of the new compounds (1 - 7) were determined on the basis of their MS, 1H-NMR, 13C-NMR, COSY, HMBC, NOESY and TOCSY data, and results of hydrolysis.

■ A New Synthetic Approach to Pentacyclic Ring, 6,7,14,15-Tetrahydro[1,5]diazocino[1,2-a:6,5-a’]-8-dihydrodiindole

Kittisak Sripha,* Darius Paul Zlotos, UIrike Holzgrabe, and Somsak Ruchirawat

*Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, 447, Sri-Ayudhya Rd. Rachatevee, Bangkok 10400, Thailand

Abstract

The construction of a new pentacyclic ring system, 6,7,14,15-tetrahydro[1,5]diazocino[1,2-a:6,5-a′]-8-dihydrodiindole (7) from simple precursors through our new synthetic route was presented to be a facile and concise method for an intramolecular N-alkylation of tosylate 12 which was obtained from N-acylation of indoline 4 with indole acid 9, followed by reduction and tosylation. This new synthetic approach can overcome the disadvantage of uncontrollable intermolecular double N-alkylation of the precursor 3 to produce the unexpected ring system 2.

■ A Convenient Synthesis of 4-Alkoxy(or Aryloxy)-3-arylisoquinolin-1(2H)-ones from 2-[Alkoxy(or Aryloxy)metnyl]benzonitriles

Kazuhiro Kobayashi,* Kota Matsumoto, Akihiro Kobayashi, and Miyuki Tanmatsu

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

Abstract

A facile two-step preparation of 4-alkoxy(or aryloxy)-3-arylisoquinolin-1(2H)-ones from 2-[alkoxy(or aryloxy)methyl]benzonitriles has been achieved. The benzylic carbanions, generated by deprotonation of the starting nitriles with lithium diisopropylamide (LDA) in diglyme at –78 ˚C, reacts with ethyl benzoates to give 2-[alkoxy(or aryloxy)(aroyl)methyl]benzonitriles. These aroylated benzonitriles can be converted into the corresponding desired isoquinolinones by hydrolysis under alkaline conditions followed by acidification of the resulting benzamide intermediates at room temperature.