HETEROCYCLES

■ Contents

■ Mechanism of the Triplet-Sensitized Photolysis of 1-[1-(1-Naphthyl)ethoxy]-2-pyridone and Related Derivatives

Asako Watanabe, Maya Matsushita, Aya Masuda, Tetsutaro Igarashi, and Tadamitsu Sakurai*

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

Abstract

On irradiation at 366 nm in the presence of benzophenone, the title 2-pyridone derivatives (1) in nitrogen-saturated acetonitrile underwent sensitized decomposition to give arylaldehyde and 2-methoxypyridine in addition to the expected N–O bond cleavage products: 1-arylethanol, arylmethylketone, and 2-pyridone. A comparison of the quantum yields for the benzophenone-sensitized photolysis of 1 with those for the direct photolysis with 313 nm light led us to conclude that the former cleavage products were derived from the methyl shift in a 1-derived singlet caged radical pair, taking place in competition with the hydrogen shift in this pair as well as with the recombination and diffusive separation of this pair. Our conclusion was confirmed by deuterium isotope effects on the limiting quantum yields for 1-arylethanol (‘out-of-cage’ product) and arylaldehyde (‘in-cage’ product).

■ Structure-Activity Relationships of Natural Occurring Plant Growth-Inhibiting Substance Caprolactam and Its Related Compounds

Wai Wai Thet Tin,* Hisayoshi Hayashi, Toshihiko Otomatsu, Katsutoshi Hirose, Koji Hasegawa, and Hideyuki Shigemori

*Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305, Japan

Abstract

The structure-activity relationships of naturally occurring plant growth-inhibiting substance caprolactam and its related lactams, and the corresponding open-chain amino carboxylic acids were studied for the inhibition of the growth of cress radicles. The lactams ranging from six- to nine-, and thirteen-membered rings showed significant growth inhibitory activity. Moreover, the activity was found to be enhanced by increasing the carbon number of lactams, except for 2-azacyclononanone. On the other hand, the open-chain amino carboxylic acids and the smallest ring lactam 2-pyrrolidinone did not inhibit the growth of cress radicles.

■ A Facile Iodine-catalyzed Glycosylation: Enantiomerically Pure β-Lactams with the Thienamycin Side Chain

Bimal K. Banik,* Oliwia Zegrocka, Maghar S. Manhas, and Ajay K. Bose

*Department of Chemistry, College of Science and Engineering, The University of Texas-Pan American, 1201 West Univeristy Dr., Edinburg, TX 78539, U.S.A.

Abstract

A facile iodine-catalyzed glycosylation of the hydroxyethyl side chain as present in thienamycin side chain has been achieved with tri-O-acetyl-D-glucal. This method has produced two separable diasteromeric α-glycosides in excellent yields which on acid-induced cleavage have provided two optically pure alcohols. The absolute stereochemistry of the products has been determined from physiochemical data.

■ Synthesis of Isomeric Analogs of Azathioprine

Alicja Kowalska,* Krystian Pluta, and Kinga Suwińska

*Department of Organic Chemistry, The Medical University of Silesia, Jagiellonska 4, 41-200 Sosnowiec, Poland

Abstract

The effective synthesis of isomeric analogs of azathioprine - 6-substituted derivatives of 7-methyl-2-(1-methyl-4-nitroimidazol-5-ylthio)purines (2), (4) and (6-8) has been worked out using different reactivity of the imidazolylthio groups in 7-methyl-2,6-di(1-methyl-4-nitroimidazol-5-ylthio)purine (1) towards selected reagents. X-Ray analysis of compound (1) showed an unusual conformation of the imidazolylthio groups.

■ Reactions of Ninhydrin with Benzo[b]thiophenes

Nono Suzue, Rie Ishii, Ryo Kamiya, Hidetsugu Wakabayashi, and Keiji Kobayashi*

*Department of Chemistry, Faculty of Science, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan

Abstract

The reaction of ninhydrin with benzo[b]thiophene in acetic acid in the presence of a small amount of sulfuric acid afforded a novel fluorenone compound fused to benzo[b]thiophene rings. In the reaction using 2,2’-bibenzo[b]thiophene, phthalide conjoined in a spiro framework was unexpectedly isolated along with an isocoumarin derivative which is fused to benzo[b]thiophene and benzene rings. The product related to the latter was obtained in the reaction of 3,3’-bithiophene with ninhydrin. The structures of these novel heterocycles were supported by spectroscopic studies and X-ray crystallography.

■ Synthesis of Halogenated 4H-Pyrido[1,2-a]pyrimidin-4-ones

Annamária Molnár, Ferenc Faigl, Benjamin Podányi, Zoltán Finta, László Balázs, and István Hermecz*

*R & D Directorate Preclinical Development, CHINOIN Pharmaceutical and Chemical Works Ltd., P. O. Box 110, H-1325 Budapest, Hungary

Abstract

Halogenated 4H-pyrido[1,2-a]pyrimidin-4-one were synthesized by thermal cyclization and decarboxylation of isopropylidene (2-pyridylamino)methylenemalonates, prepared from 2-aminopyridines and isopropylidene methoxymethylenemalonate formed in situ. Instead of 4H-pyrido[1,2-a]pyrimidin-4-ones, the 6-chloro and 6-bromo derivatives afforded mixtures of 7-halo-1,4-dihydro-1,8-naphthyridin-4-ones and 1-(6-halo-2-pyridyl)-
3-[(6-halo-2-pyridylamino)methylene]-1,2,3,4-tetrahydropyridine-2,4-diones. The latters formed from N-(2-pyridyl)iminoketenes, the common intermediates of 4H-pyrido[1,2-a]pyrimidin-4-one and 1,8-naphthyridin-4-ones, via a “head-to-tail” [4+2] cycloaddition. 3-Halo-4H-pyrido[1,2-a]pyrimidin-4-ones were obtained from 4H-pyrido[1,2-a]pyrimidin-4-one with N-halosuccinimides. The structures of the new compounds were characterized by means of 1H NMR and 13C NMR examinations.

■ 2,8-Dithia-dibenzo[e,h]azulenes and Their 8-Oxa Analogs. Synthesis and Anti-inflammatory Activity

Ivana Ozimec Landek,* Dijana Pešić, Predrag Novak, Barbara Stanić, Krunoslav Nujić, Mladen Merćep, and Milan Mesić

*IRU Chemistry, GlaxoSmithKline Research Centre Zagreb Limited, Prilaz baruna Filipovića 29, 10000 Zagreb, Croatia

Abstract

Synthesis of 2,8-dithia-dibenzo[e,h]azulenes (III, X = S) and their 8-oxa analogs (III, X = O),1 two novel classes of fused heterocyclic compounds, is described. Starting 11H-dibenzo[b,f]thiepin-10-one, 11H-dibenzo[b,f]oxepin- 10-one and its 2-chloro derivative (1a-c) were oxidized to 1,2-diketones (2a-c) which subsequently reacted with 2,2’-dimethyl thiodiglycolate to form fused thiophene ring by Hinsberg cyclization reaction. Substituents at positions C(1) and C(3) were then further transformed in order to obtain aminoalkoxy derivatives 8-11. Structures of regioisomers 6c and 6d were elucidated using two-dimensional NMR techniques. All compounds with tetracyclic skeleton were tested in vitro for their anti-inflammatory activity.

■ Tetrazolium N-Aminides: Complementary Studies on Synthesis and Properties

Dietrich Moderhack* and Matthias Noreiks

*Institute of Pharmaceutical Chemistry, Technical University, Beethovenstrasse 55, D-38106 Braunschweig, Germany

Abstract

Attempts are made to access the title compounds from N-amido/urei¬dotetrazoles (A, B; 1H- / 2H-system). These materials are provided by acylation of the respective N-aminotetrazoles (A in one step, B partly by hydrolysis of diacylat¬ed derivatives which are obtained directly). On treatment with excess dimethyl sul¬fate only A undergoes the necessary ring quaternization, giving rise to two isomers (ratio ca. 4 : 1); work-up with base allows isolation of the major aminide (X). This technique requires that the (slow) quaternization process be fully completed, since at pH > 7 dimethyl sulfate rapidly affects the side chain of A. Concluding experi¬ments pertain to protonation and methylation of the title compounds (X–XII).

■ Synthesis of Novel Diketopiperazine-derivative and Obsevation of Self-Assembled Structure

Yosuke Ohta, Kayo Terada, Toshio Masuda, and Fumio Sanda*

*Department of Polymer Chemistr, Graduate School of Engineering, Kyoto University, Kyoudai-katsura, Nishikyo, Kyoto 615-8510, Japan

Abstract

An N-monomethylated unsymmetrical diketopiperazine was synthesized from D-p-hydroxyphenylglycine and sarcosine, and condensed with trans-1,4-cyclohexanedicarboxylic acid to obtain the ester having diketopiperazine moieties at the both termini. Atomic force microscope measurement indicated that the ester formed a supramolecular structure aligned in a circular pattern based on hydrogen bonding between the amide groups of the diketopiperazine moieties.

■ Synthetically Useful Transformations of δ-Sultones and Thiane-1,1-dioxides Obtained by C-H Insertion

Christian S. Jungong, Jinu P. John, Joseph P. Bequette, and Alexei V. Novikov*

*Chemistry Department, University of North Dakota, 151 Cornell St. Stop 9024, Grand Forks, ND 58201, U.S.A.

Abstract

δ-Sultones and thiane-1,1-dioxides that carry a carbethoxy group at α-position, easily accessible by C-H insertion, are potentially useful synthetic intermediates. Their stereoselective alkylation, rearrangement and conversion to γ-lactones have been demonstrated.

■ Flavonol Glycosides from the Native American Plant Gaura longiflora

Wen-Hui Xu, Melissa R. Jacob, Ameeta K. Agarwal, Alice M. Clark, Zong-Suo Liang, and Xing-Cong Li*

*National Center for Natural Products Research, Research of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, University , MS 38677, U.S.A.

Abstract

Phytochemical investigation of the native American plant Gaura longiflora led to the isolation of three new and eight known flavonol glycosides. The structures of the new compounds were established primarily by spectroscopic data as quercetin 3-O-(2''-O-α-L-rhamnopyranosyl-6''-O-E-p-coumaroyl)-β-D- glucopyranoside (1), kaempferol 3-O-(2''-O-α-L-rhamnopyranosyl-6''-O-E-p- coumaroyl)-β-D-glucopyranoside (2) and quercetin 3-O-(2″-O-α-L-rhamno- pyranosyl-6''-O-Z-p-coumaroyl)-β-D-glucopyranoside (3).

■ Synthesis of Two Novel Water-soluble Cleft-Type Cyclophanes Effective as N-Methyl-D-aspartate Receptor Antagonist

Takashi Masuko, Yuta Nemoto, Tadashi Kusama, Koichi Metori, Yasuo Kizawa, and Muneharu Miyake*

*College of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba 274-8555, Japan

Abstract

Novel cleft-type cyclophanes, 4,4′-bis[N-(5-dimethylaminonaphthalene-sulfonylaminoethyl)-N-(1,4,7,10-tetraazacyclododecane-1-ylacetyl)-2-aminoethoxy]diphenylmethane octahydrochloride (1a, DNCn) and 4,4′-bis[N-(p-toluene-sulfonylaminoethyl)-N-(1,4,7,10-tetraazacyclododecane-1-ylacetyl-2-aminoethoxy]diphenylmethane octahydrochloride (1b, TsDCn) having an effective role as N-methyl-D-aspartate (NMDA) receptor antagonist were synthesized. Neuroprotective effects of cleft-type cyclophanes, DNCn (1a) and TsDCn (1b) against cell damage caused by NMDA were measured in cultured rat hippocampal neurons. DNCn (1a) and TsDCn (1b) reduced the neurotoxicity and acted as open channel blocker for NMDA receptor.

■ Synthesis of 2-Thioxo-2,3-dihydropyrido[3,2-e]-1,3-thiazin-4-ones by the Reaction of N-Alkyl-2-chloropyridine-3-carboxamides with Carbon Disulfide

Kazuhiro Kobayashi,* Toshihide Komatsu, and Hisatoshi Konishi

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

Abstract

A facile method for the preparation of 2-thioxo-2,3- dihydropyrido[3,2-e]-1,3-thiazin-4-ones by the reaction of N-alkyl-2- chloropyridine-3-carboxamides with carbon disulfide in the presence of sodium hydride as a base has been developed.

■ A New Neodolastane Diterpene from Cultures of the Basidiomycete Trametes corrugata

Rong Liu and Ji-Kai Liu*

*State Key Laboratory of Phytochemistry and
Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Heilongtan, Kunming 650204, Yunnan, China

Abstract

A New diterpene with a neodolastane skeleton, named 2,5-epoxy-5,13-dihydroxyneodolast-3-en-14-one (1), was isolated from cultures of the basidiomycete Trametes corrugate together with guanacastepene E. The structure of 1 was elucidated on the basis of extensive spectroscopic analysis including IR, MS, 1D and 2D NMR experiments.

■ 3′,4′-Dihydronorstephasubine, a New Bisbenzylisoquinoline from the Bark of Alseodaphne corneri

Mat Ropi Mukhtar,* Azeana Zahari, Mohd Azlan Nafiah, A. Hamid A. Hadi, Noel F. Thomas, Hiroko Arai, Hiroshi Morita, Marc Litaudon, and Khalijah Awang

*Department of Chemistry, Faculty of Science, University of Malaya, Pantai Valley, 50603 Kuala Lumpur, Malaysia

Abstract

A new bisbenzylisoquinoline, 3′,4′-dihydronorstephasubine (1) together with two known alkaloids, norstephasubine (2) and gyrolidine (3) were isolated from the stem bark of Alseodaphne corneri (Lauraceae). The 13C-NMR data for norstephasubine (2) and gyrolidine (3) were also reported. Structural elucidation of 1 was performed by spectral methods such as 1D- and 2D- NMR, IR, UV, and HRMS. 3′,4′-Dihydronorstephasubine (1) and gyrolidine (3) showed moderate vasorelaxant effect on rat aorta.

■ One-Pot Synthesis of Benzotriazoles and Benzotriazole 1-Oxides by Reductive Cyclization of o-Nitrophenylazo Compounds with Benzyl Alcohol

Renata Farkas, Mercedes Törincsi, Pal Kolonits, Oscar Jimenez Alonso, and Lajos Novak*

*Institute for Organic Chemistry, Technical University Budapest, H-1521 Budapest, P.O. Box 91Gellért tér 4, Hungary

Abstract

Reductive cyclization of 2-[(2-nitrophenyl)azophenols 1 with benzyl alcohol and sodium hydroxide afforded 2-(2H-benzotriazol- 2-yl)phenols 3 and their 1-oxide 2 in good to excellent yields.

■ A Short Synthesis of Indolizidine (+)-209B from (3R,6S,8AS)-(-)-6-Methyl-3-phenyl-hexahydrooxazolo[3,2-a]pyridin-5-one

Dino Gnecco, Ana M. Lumbreras, Joel Luis Terán,* Alberto Galindo, Jorge R. Juárez, María L. Orea, Alejandro Castro, Raúl G. Enríquez, and William F. Reynolds

*Síntesis Orgánica, Benemérita Universidad Autónoma de Puebla, Complejo de Ciencias, Edif 103H, Ciudad Universitaria 72300, Mexico

Abstract

The synthetic potential of enantiopure (3R,6S,8aS)-(-)-6-methyl-3- phenylhexahydrooxazolo[3,2-a]pyridin-5-one 2 is illustrated by a short synthesis of the 5,8-disubstituted indolizidine alkaloid (+)-209B.

■ Curcuphenol Derivatives from the Gorgonian Echinomuricea Sp.

Hsu-Ming Chung, Tsong-Long Hwang, Wei-Hsien Wang,* Lee-Shing Fang, and Ping-Jyun Sung*

* , National Museum of Marine Biology and Aquarium, 2 Houwan Road, Checheng, Pingtung, Taiwan 944, Taiwan, R.O.C.

Abstract

Two sesquiterpenoid phenols, including a new natural product 1 [(7S,10R)-(+)-10,11-epoxycurcuphenol] and a known metabolite, (+)-curcuphenol (2), were isolated from a gorgonian coral identified as Echinomuricea sp. The structures of 1 and 2 were elucidated by interpretations of spectral data and by comparison of the related physical and spectral data with those of related metabolites. Compound 2 was found to show significant inhibitory effects on elastase release by human neutrophils.

■ Crystal Structure and Intramolecular Hydrogen Bonding of a Substituted Diaminoquinoxaline

Junpei Kuwabara, Hironori Mori, and Takaki Kanbara*

*Graduate School of Pure and Applied Sciences, Tsukuba Research Center for Interdisciplinary Materials Science, University of Tsukuba, 1-1-1 Ten-nodai, Tsukuba-shi, Ibaraki 305-8573, Japan

Abstract

A substituted diaminoquinoxaline, 2,3-diethyl-N5,N8-di(quinolin-8-yl)quinoxaline-5,8-diamine, was synthesized and characterized by a single-crystal X-ray diffraction study. The crystal structure of the molecule has a planar geometry with intramolecular hydrogen bonding. The hydrogen bonding is also evaluated in a solution state by spectroscopic techniques.