HETEROCYCLES

■ Contents

■ An Improved Pictet-Spengler Condensation: A convenient Synthetic Route to Bioactive Manzamine Derivatives

Yeun-Mun Choo and Mark T. Hamann*

*Department of Pharmacognosy, Chemistry and Biochemistry and National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, Mississippi 38677, U.S.A.

Abstract

An improved Pictet-Spengler method for the construction of a modified β-carboline moiety from an α,β-unsaturated aldehyde is described. The Pictet-Spengler reactions between ircinal A (1) and tryptamine derivatives under milder conditions have resulted in shorter reaction times and higher product yields (70 to 89%) with control of stereochemistry. The Pictet-Spengler products (9 and 11) are two new manzamine alkaloids, which display strong activities against Mycobacterium intracellulare with IC₅₀ values of 0.2 and 0.06 μg/mL, respectively.

■ Synthesis, Structures, and Spectroscopic Properties of Push-Pull Heteroquinoid Compounds

Shinobu Inoue, Shinji Mikami, Kazuo Takimiya, Tetsuo Otsubo,* and Yoshio Aso

*Department of Applied Chemistry, Faculty of Engineering, Hiroshima University, 1-4-1 Kagamiyama, Higashi-hiroshima, Hiroshima 739-8527, Japan

Abstract

A variety of push-pull heteroquinoid compounds (4-10) bearing an electron-donating 1,3-dithiol-2-ylidene group and an electron-accepting dicyanomethylene group were prepared by the coupling reactions of the corresponding dicyanomethyl heteroaromatics with 2-methylthio-1,3-dithiolium methyl sulfate according to the Gompper method. All these compounds are highly colored and amphoteric. The electronic absorption spectra have revealed that their deep colors arise from a strong intramolecular charge-transfer absorption band in the visible region. The infrared nitrile vibrational spectra have indicated that these molecules exist as a resonance hybrid of the quinoid and zwitterionic forms, accordingly, assuming considerably polarizable characters. The amphoteric and polarizable characters of the simple heteroquinoid compounds (4-7) are nearly independent of the kind of the constituent chalcogen atom and of the introduction of the octylthio or hexyl groups into the frameworks. On the other hand, those of the extensive heteroquinoid compounds (8-10) are largely enhanced because of increasing gain in aromaticity of the heterocyclic rings in the zwitterionic form.

■ The Study of Cyclization of N-Acylphenacyl Anthranilates with Ammonium Salts under Various Conditions

Pavel Hradil,* Martin Grepl, Jan Hlavac, and Antonin Lycka

*Department of Organic Chemistry, Palacky University, Trida Svobody 8, 77146 Olomouc, Czech Republic

Abstract

N-Acylphenacyl anthranilates were heated with ammonium salts in organic acid or NMP, and formation of various heterocyclic compounds was observed. Reaction results are strongly influenced by reaction conditions. The most interesting are imidazole derivatives with various anelated rings.

■ The Reactions of Phenoxy Substituted Phosphazenes with 1,3-Propanediol and 3-Amino-1-propanol

Saliha Begeç,* Sümeyya Alatas, and Adem Kiliç

*Department of Chemistry, Faculty of Science and Arts, Inönü University, 44280 Malatya, Turkey

Abstract

In the present work, two phenoxy substituted phosphazene derivatives, 2-(2,4,6-tri-tert-butylphenoxo)-2,4,4,6,6-pentachlorocyclo-2λ⁵,4λ⁵,6λ⁵-triphosphazatriene (1) and 2-(2,4,6-tri-methylphenoxo)-2,4,4,6,6-pentachlorocyclo-2λ⁵,4λ⁵,6λ⁵-triphosphazatriene, were prepared. The reactions of these derivatives with 3-amino-1-propanol (3) and 1,3-propanediol (4) were studied. Novel phenoxy-substituted; two mono spiro (5, 8), and two dispiro phosphazene derivatives (6, 7) were synthesized. The structures of the compounds were defined by elemental analysis, IR, ¹H and ³¹P NMR spectroscopy.

■ Spiroheterocycles from the Reaction of Arylnitrile Oxides with Some (Z)-3-Arylidene-2(3H)-benzofuranones. New Access to Orthohydroxyphenylisoxazoline Esters

Moheddine Askri, Naffa Jgham, Mohamed Rammah, Kabula Ciamala,* Karin Monnier-Jobé, and Joël Vebrel

*Laboratory of Material Chemistry and Interfaces, UFR of Science and Technology, 16 Route de Gray, F-25030 Besançon, France

Abstract

Some 4-substituted arylnitrile oxides and (Z)-3-arylidene-2(3H)-benzofuranones undergo 1,3-dipolar cycloaddition reactions to give exclusively spirodihydroisoxazoles. These spiroadducts have be opened to the corresponding ethyl 3,4-diaryl-5-(orthohydroxyphenyl)-4,5-dihydroisoxazoline-5-carboxylates by the action of concentrated hydrochloric acid at reflux in ethanol.

■ Short and Efficient Synthesis of 3-Substituted 4-Oxazolin-2-thiones and Their Reactivity

Carlos González-Romero, Rafael Martínez-Palou, Hugo A. Jiménez-Vázquez, Aydeé Fuentes, Fabiola Jiménez, and Joaquín Tamariz*

*Department of Organic Chemistry, National School of Biological Sciences, National Polytechinic Institute, Prol. Carpio y Plan de Ayala, 11340 México, D.F., Mexico

Abstract

A new synthesis of the substituted 4-oxazolin-2-thiones (1) and (14) is described by a regioselective tandem condensation reaction between α-ketols (4a-4b) and isothiocyanates (8). The use of dioxane as the solvent promotes the formation of the 4-methylene-1,3-oxazolidin-2-thiones (7), while the mixture of hemiaminals (9/10) is obtained in the presence of DMF; this mixture undergoes dehydration to give compounds (1). The latter are also prepared by an alternative solvent-free process by MW irradiation. Treatment of heterocycles (1) with alkyl iodides leads to the generation of the oxazolium iodides (21). The reactivity and regiochemistry of this process is explained in terms of FMO calculations.

■ Practical Synthesis of (-)-α-Aminobenzolactam via Nitration-Cyclization of L-Homophenylalanine Ethyl Ester

Luoting Yu, Jiling Huang, Ching-Yao Chang, and Teng-Kuei Yang*

*Wisdom Pharmaceutical Co.Ltd., Haimen, Jiangsu, 226100, China

Abstract

A practical synthesis of chiral (-)-α-aminobenzolactam (2) is described. The target compound (2) was prepared from commercially available L-homophenylalanine ethyl ester hydrochloride (LHPE·HCl 1) with a highly enantiomeric purity (>98% e.e.) by employing simple nitration and hydrogenation-cyclization reactions.

■ Structure of New Cucurbitane-Type Triterpenes and Glycosides, Karavilagenins D and E, and Karavilosides VI, VII, VIII, IX, X, and IX, from the Fruit of Momordica charantia

Hisashi Matsuda, Seikou Nakamura, Toshiyuki Murakami, and Masayuki Yoshikawa*

*Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan

Abstract

Two new cucurbitane-type triterpenes, karavilagenins D and E, and six new cucurbitane-type triterpene glycosides, karavilosides VI, VII, VIII, IX, X, and XI, were isolated from the fruit of Momordica charantia L. (Cucurbitaceae) cultivated in Sri Lanka. Their structures were elucidated on the basis of chemical and physicochemical evidence.

■ Reaction of 1-Acyl and Aroyl-2-hydroxy-3,3-dimethylindolines with Arylamines Catalyzed by BF₃·Etherate. Formation of Dihydroindolo[1,2-c]quinazoline

Akiko Watanabe, Koki Yamaguchi, Fumikazu Ito, Yasuyuki Yoshitake, and Kazunobu Harano*

*Laboratory of Molecular Design, Sojo University, 4-22-1, Ikeda, Kumamoto-shi, 860-0082, Japan

Abstract

The reaction of (4-chlorophenyl)(2-hydroxy-3,3-dimethyl-2,3-dihydroindol-1-yl)methanone or 1-(2-hydroxy-3,3-dimethyl-2,3-dihydroindol-1-yl)ethanone with 2-aminonaphthalene in the presence of excess amounts of BF₃·Et₂O gave the 14,14-dimethyl-14,14a-dihydrobenzo[f]indolo[1,2-c]quinazoline derivatives which are derived from the dehydrative cyclization of the coupling reaction product [2-(2-aminonaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl](4-chlorophenyl)methanone or 1-[2-(2-aminonaphthalen-1-yl)-3,3-dimethyl-2,3-dihydroindol-1-yl]ethanone. The reactions of several (2-hydroxy-3,3-dimethyl-2,3-dihydroindol-1-yl)(substitutedphenyl)methanones or 1-(2-hydroxy-3,3-dimethyl-2,3-dihydroindol-1-yl)ethanone with m-anisidine gave the cyclization products together with the coupling reaction products. The structure of the cyclization product and the reaction mechanism are discussed based on the crystallographic and molecular orbital (MO) calculation data.

■ Lewis Acid-Catalyzed Michael Addition Reactions of N-Boc-2-silyloxypyrroles to 3-Acryloyl-2-oxazolidinone

Hiroyuki Suga,* Haruka Takemoto, and Akikazu Kakehi

*Department of Chemistry and Material Engineering, Faculty of Engineering, 4-17-1 Wakasato, Nagano 380-8553, Japan

Abstract

Among several Lewis acids examined, Sc(OTf)₃ (10 mol%) was found to be the most effective catalyst to promote a Michael addition reaction of N-Boc-2-(tert-butyldimethylsilyloxy)pyrrole to 3-acryloyl-2-oxazolidinone. A slow addition of the 2-silyloxypyrrole in the presence of 1,1,1,3,3,3-hexafluoro-2-propanol (5 equiv.) at -25 °C were needed to obtain good yield (77 - 80%). The asymmetric version of the reaction could be performed with good enantioselectivity (up to 82% ee) by using the chiral Sc(III) catalyst (10 mol%), which was prepared from 2,6-bis[(4S)-4-isopropyl-2-oxazolin-2-yl]pyridine and Sc(OTf)₃, in reasonable yield (60 - 70%).

■ H₄SiW₁₂O₄₀·xH₂O As a New Catalyst for the Synthesis of 3,4-Dihydropyrimidin-2(1H)-one

Khodabakhsh Niknam* and Nader Daneshvar

*Department of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran

Abstract

H₄SiW₁₂O₄₀·xH₂O catalyzed the one-pot three component condensation reactions of aldehydes, 1,3-dicarbonyl compounds and urea in refluxing acetic acid leading to 3,4-dihydropyrimidin-2(1H)-one in high yields.

■ Microwave-Assisted Dehydrosulphurization: An Efficient, Solvent-Free Synthesis of 5-(1-Adamantyl)-2-arylamino-1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles

Ebtehal S. Al-Abdullah, Ihsan A. Shehata, Omar A. Al-Deeb, and Ali A. El-Emam*

*Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh-11451, Saudi Arabia

Abstract

A fast and efficient microwave-assisted synthesis of 2-arylamino- 5-(1-adamantyl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles is described. The reaction of 3-(1-adamantyl)-5-mercapto-1,2,4-triazole (2) with arylisothiocyanates in DMF at room temperature yielded the corresponding N,N’-disubstituted thioureas (3a-e) in high yields. Compounds (3a-e) were desulfurized via microwave irradiation for 5 min to yield the corresponding 5-(1-adamantyl)-2-arylamino-1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles (4a-e). Compounds (4a-e) were also prepared in good yields via microwave irradiation of a mixture of (2) and the corresponding arylisothiocyanates for 8 minutes. Attempted preparation of the aliphatic analogues (6a-e) via microwave irradiation was unsuccessful, they were obtained in poor yields via prolonged heating of compound (2) with the corresponding aliphatic isothiocyanate in DMF. Compounds (6a-e) were independently obtained in good yields via the reaction of (2) with cyanogen bromide to yield the 2-amino analogue (7) that was subsequently reacted with the corresponding aliphatic halide.

■ Efficient Method for the Synthesis of Dibenzo[b,f]thiepin-10-ones under Mild Conditions

Qiang Zhang,* Youyi Peng, and William J. Welsh*

*Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine & Dentistry of New Jersey, 661 Hoes Lane, Piscataway, NJ 08854, U.S.A.

Abstract

A mild and efficient method to synthesize dibenzo[b,f]thiepin-10-one derivatives was achieved, with key steps of PPE mediated cyclization of seven-member ring and selective ketone α bromination with CuBr₂. Reaction of α alkylation and arylation of ketones were also optimized to finish the synthesis with good overall yield.

■ Synthesis and Fluorescence of 4-Methylsulfanyl-6-pyridyl-2H-pyran-2-ones in Solid State

Naoko Mizuyama, Shinya Kohra, Kazuo Ueda, Kyoko Hiraoka, Kojiro Takahashi, and Yoshinori Tominaga*

*School of Pharmaceutical Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

Various 4-methylsulfanyl-6-pyridyl-2H-pyran-2-one derivatives were synthesized by the reaction of ketene dithioacetals with active methyl or methylene compounds in the presence of powdered sodium hydroxide in dimethyl sulfoxide (DMSO). Among these 2-pyrone derivatives, 3-aryl-4-methylsulfanyl-6-pyrid-2-yl-2H-pyran-2-ones show strong fluorescence in the solid state.

■ Heterocycles [h]Fused on 4-Oxoquinoline-3-carboxylic Acid, II. A Facile Synthesis of Some 2,7-Dioxo[1,4]thiazino[2,3-h]quinoline-8-carboxylic Acids

Mohammed H. Al-Huniti, Jalal A. Zahra, and Mustafa M. El-Abadelah*

*Chemistry Department, Faculty of Science, University of Jordan, Amman 11942, Jordan

Abstract

Model tetrahydro[1,4]thiazino[2,3-h]quinoline-8-carboxylic acids (7a-c) are synthesized via reductive lactamisation, using sodium dithionite, of the respective 7-[(carboxyalkyl)thio]-8-nitro-1,4-dihydroquinolines (5a-c). The latter compounds are made accessible via the reaction of 7-chloro-1-cyclopropyl-6-flouro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4) with each of α-mercaptoacetic, α-mercaptopropionic and α-mercaptosuccinic acids in aqueous ethanol and triethylamine. The suggested structures of 5a-c and 7a-c are supported by microanalytical and spectral (IR, MS, NMR) data.

■ Synthesis of 5-Substituted 4,5,6,7-Tetrahydroindoles from Cyclohexanones

Chang Kiu Lee,* In-Sook Han Lee, and Wayland E. Noland

*Department of Chemistry, Kangwon National University, 192-1 Hyoja-2-dong, Chuncheon, Kangwon 200-701, Korea

Abstract

5-Substituted 4,5,6,7-tetrahydroindoles were prepared from 4-substituted cyclohexanones in three steps: conversion to an enol silyl ether, introduction of a formylmethyl group at 2-C, and the Paal-Knorr pyrrole synthesis by reacting the 1,4-dicarbonyl compounds with ammonia. The substituents are H, methyl, ethyl, tert-butyl, methoxy, and phenyl.

■ Synthesis of 5,7-Diamino[1,2,4]triazolo[1,2-a][1,3,5]triazines via Annulation of 1,3,5-Triazine Ring onto 3(5)-Amino-1,2,4-trizoles

Anton V. Dolzhenko, Anna V. Dolzhenko, and Wai-Keung Chui*

*Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore

Abstract

The 5,7-diamino[1,2,4]triazolo[1,5-a][1,3,5]triazines were synthesized by cyclocondensation of 3(5)-amino-1,2,4-triazoles with cyanoguanidine. The substituted 3(5)-amino-1,2,4-triazoles were prepared from corresponding hydrazides and S-methylisothiourea via ring closure of the intermediate acylaminoguanidines. The 3,5-diamino-1,2,4-triazoles were prepared using partial aminolysis of dimethyl N-cyanodithiocarbonimidate followed by cyclization of the obtained N-substituted N’-cyano-S-methylisothioureas with hydrazine. The structures of the prepared compound were confirmed using NMR spectral data.

■ Diastereoselective Synthesis of Chiral Methyl 2-Piperidin-2-ylpropanoates

Jennifer Pereira, Sandrine Calvet-Vitale, Marie-Claude Fargeau-Bellassoued, Virginie Mouries-Mansuy, Corinne Vanucci-Bacqué,* and Gérard Lhommet*

*Laboratory of Organic Chemsitry, University of Paris VI, 4 Place Jussieu , F-75005 Paris Cedex 05, France

Abstract

We report the synthesis of methyl (2S, 2’R)-2-piperidin-2-ylpropanoate by the diastereoselective reduction of the tetrasubtituted double bond of piperidine β-enamino ester (1).

■ Efficient Preparation of Medium Ring Oxygen Heterocycles

Atsuko Nishiguchi,* Tomomi Ikemoto, Tatsuya Ito, Shotaro Miura, and Kiminori Tomimatsu

*Chemical Development Laboratory, Takeda Chemical Industries, Ltd., 17-85 Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan

Abstract

We achieved efficient preparation of medium ring oxygen heterocycles (1), 1-benzoxepines and 1-benzoxocines, by applying intramolecular Claisen-type condensation in dialkyl carbonate with metal alcoholate. Furthermore, we accomplished the preparation of 2,3-dihydro-1-benzoxepin-4-carboxylate intermediate (1e) for orally active CCR5 antagonists by this method.

■ Expeditious Entry to 1,5-Benzodiazepines Catalyzed by Sulfamic Acid at Room Temperature in Tap Water Suspension

Zhenjiang Li,* Yingjie Sun, Xinghua Ren, Yuhu Shi, and Pingkai Ouyang

*College of Life Science and Pharmaceutical Engineering, Nanjing University of Technology, 5, Xinmofan Malu, Nanjing 210009, China

Abstract

2,3-Dihydro-1H-1,5-benzodiazepines have been synthesized in tap water suspension as well as in neat condition in good to excellent yield from direct condensations of o-phenylenediamines with ketones promoted by sulfamic acid at room temperature.

■ Concise Synthesis of Diarylmethyl-1H-pyrroles

Meng-Yang Chang,* Tsun-Cheng Wu, and Ya-Jung Ko

*Department of Applied Chemistry, National University of Kaohsiung, No. 700 Kaohsiung University Rd., Nan-Tzu District, Kaohsiung 811, Taiwan, R.O.C.

Abstract

An easy and straightforward synthesis of diarylmethyl-1H-pyrroles has been established starting from trans-(2S,4R)-4-hydroxyproline by the key combination of Grignard addition/aromatization.