Regular Issue

Vol. 23, No. 2, 1985

31 data found. 1 - 30 listed Next Last
Communication | Regular issue | Vol 23, No. 2, 1985, pp.247-250
Published online:
DOI: 10.3987/R-1985-02-0247
Anodic Oxidation of N-Alkyl-β-lactams

Makoto Okita, Miwako Mori, Takeshi Wakamatsu, and Yoshio Ban*

*Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan

Abstract

β-Lactams were electrolyzed in an undivided cell with platinum plate as anode in methanol under constant current. The oxidation of β-lactams 5 and α-methylene-β-lactams 10 proceeded both at the exo- and endo-cyclic carbons α to nitrogen, though five, six and seven membered lactams were regioselectively electrolyzed under the same conditions.

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Communication | Regular issue | Vol 23, No. 2, 1985, pp.251-256
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DOI: 10.3987/R-1985-02-0251
Approach to the Total Synthesis of Amaryllidaceae Alkaloids. Altenative Preparations of 5-Substituted 2,3,4,5-tetrahydro-1H-2-benzazepines

Ignacio H. Sánchez,* María Isabel Larraza, Humberto J. Flores, E. Alejandra Martell, Irma Linzaga, and Antoniette A. Carter

*Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitatria, Coyoacán 04510, Mexico

Abstract

The preparation of several 5-substituted 2,3,4,5-tetrahydro-1H-2-benzazepines of general structure B, versatile synthons for the total synthesis of Amaryllidaceae alkaloids, is described.

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Communication | Regular issue | Vol 23, No. 2, 1985, pp.257-260
Published online:
DOI: 10.3987/R-1985-02-0257
Amyris of Jamaica. A New Nicotinamide from Amyris plumieri D.C. (Rutaceae)

Basil A. Burke* and Saleela Philip

*Department of Chemistry, Mona Campus, University of the West Indies, Mona, Kingston 7, Jamaica

Abstract

A new nicotinamide, isolated from Amyris plumieri is assigned the structure (1) on the basis of spectroscopic and chemical evidence. Compound (1) was converted to a hydroxy oxazoline, a possible biogenetic precursor of oxazoles.

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Communication | Regular issue | Vol 23, No. 2, 1985, pp.261-264
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DOI: 10.3987/R-1985-02-0261
Formal Synthesis of Lavendamycin Methyl Ester: The Regioselective Synthesis to the Bromoquinolinequinone Systems of Key Intermediate

Satoshi Hibino,* Miko Okazaki, Masataka Ichikawa, Kohichi Sato, and Takashi Ishizu

*Graduate School of Pharmacy and Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan

Abstract

We achieved a formal synthesis of lavendamycin methyl ester as follows. The Pictet-Spengler reaction of 8-benzyloxyquinolin-2-aldehyde 4 with β-methyltryptophan ethyl ester 5, gave pentacyclic β-carboline 7. Hydrogenolysis of benzyl ether 7 and bromination of 8-hydroxyquinoline 8 afforded 5,7-dibromo-8-hydroxyquinoline 11. Oxidation of bromophenol 11 by cerium ammonium nitrate proceeded regioselectively to the desired p-quinone system 13. On the other hand, the ethyl ester 8 was converted into its methyl ester 9 and led to the methyl ester of bromoquinolinequinone 14 regioselectively in the same way, that is, Kende‘s intermediate.

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Communication | Regular issue | Vol 23, No. 2, 1985, pp.265-272
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DOI: 10.3987/R-1985-02-0265
A Novel Preparation of 4-Unsubstituted β-Lactams

Hans Rudolf Pfaendler* and Heike Hoppe

*Institut für Organische Chemie, Universität München, Karlstrasse 23, D-80333 München, Germany

Abstract

The key intermediate (1) for monobactam synthesis has been prepared from 6-aminopenicillanic acid (6-APA) without using Raney nickel. Desulfurisation was accomplished by a two step process, involving a novel reduction reaction.

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Communication | Regular issue | Vol 23, No. 2, 1985, pp.273-276
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DOI: 10.3987/R-1985-02-0273
Synthesis of Quinazolino[3,2-d]-1,4-benzodiazepin-6,9(5H,7H)-diones

Mark G. Bock,* Robert M. DiPardo, David W. Cochran, Carl H. Homnick, and Roger M. Freidinger

*Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, West Point, PA 19486, U.S.A.

Abstract

2-(2-Nitrophenyl)-3,1-benzoxazin-4-one 3 was elaborated in two ways to afford the title compounds 1 and 2 via novel cyclodehydrations.

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Communication | Regular issue | Vol 23, No. 2, 1985, pp.277-280
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DOI: 10.3987/R-1985-02-0277
Total Synthesis of Kukoamine A Using 2-Methyl-5,6-dihydro-4H-1,3-oxazine as a Carboxamide Building Block

Toshio Moriwake,* Seiki Saito, Hideaki Tamai, Hitoshi Mitsuda, and Masami Inaba

*Faculty of Engineering, Okayama University, 3-1-1 Tsushima-naka, Okayama 700-8530, Japan

Abstract

Kukoamine A, the active constituent of Oriental medicine “Jikoppi” for hypertension, has been synthesized employing a new methodology for non-spermine-based polyamine construction.

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Communication | Regular issue | Vol 23, No. 2, 1985, pp.281-286
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DOI: 10.3987/R-1985-02-0281
Facile Synthesis of Novel 3-(4-Amino-5-methyl-4H-1,2,4-triazol-3-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxaline and Related Compounds

Yoshihisa Kurasawa,* Masayo Ichikawa, Itsuo Kamata, Yoshihisa Okamoto, and Atsushi Takada

*School of Pharmaceutical Sciences, Kitasato University, Shirokane, Minato-ku, Tokyo 108-8641, Japan

Abstract

The reaction of the hydrazone (3a) with hydrazine hydrate in DBU/EtOH conveniently gave novel 3-(4-amino-5-methyl-4H-1,2,4-triazol-3-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxaline (6), which was converted into the various new 1,2,4-triazole derivatives (7-13).

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Communication | Regular issue | Vol 23, No. 2, 1985, pp.287-290
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DOI: 10.3987/R-1985-02-0287
Termolysis of 4-Pyridylazides Leading to the Synthesis of 6H-1,4-Diazepines

Yoshihiro Ohba, Ikuo Matsukura, Yoshimasa Fukazawa, and Tarozaemon Nishiwaki*

*Department of Chemistry, Faculty of Science, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8512, Japan

Abstract

Thermolysis of a methanolic solution of 4-pyridylazides (1) at 200°C for 8-12 min was found to give unstable but isolable 5-methoxy-6H-1,4-diazepines (4) and (5), along with 32-45% yield of 5,6-dihydro-6-methoxy-7H-tetrazolo[1,5-d][1,4]diazepines (6).

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Communication | Regular issue | Vol 23, No. 2, 1985, pp.291-293
Published online:
DOI: 10.3987/R-1985-02-0291
Reaction of Chromone Epoxides. I. Reaction of 2,3-Epoxyisoflavone with Alkylamines

Ichiro Yokoe,* Kumiko Nakamura, Kyoko Higuchi, Yoshiaki Shirataki, Manki Komatsu, and Hiroshi Miyamae

*Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan

Abstract

The reaction of 2,3-epoxyisoflavone (1) with primary alkylamines gave 2’-hydroxy-[1-phenyl-1-(N-formyl)alkyiamino]acetophenones (2a- d), whose structures were determined on the basis of spectroscopic properties and X-ray Crystallographic analysis for N-propyl derivative (2c).

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Communication | Regular issue | Vol 23, No. 2, 1985, pp.295-300
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DOI: 10.3987/R-1985-02-0295
Reaction of 2-Lithiobenzothiazole with Electrophiles and a Synthesis of α-Hydroxy Aldehydes and Ketones

Hidenori Chikashita* and Kazuyoshi Itoh

*Department of Applied Chemistry, Faculty of Engineering, Kansai University, Suita, Osaka 564-8680, Japan

Abstract

The reaction of 2-lithiobenzothiazole with a variety of electrophiles, except for alkyl halides and styrene oxide, could be effectively accomplished to give the expected products in high yields. The adducts of lithiobenzothiazole to carbonyl compounds could be effectively transformed into α-hydroxy aldehydes and ketones through three steps without masking the α-hydroxy group.

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Communication | Regular issue | Vol 23, No. 2, 1985, pp.301-303
Published online:
DOI: 10.3987/R-1985-02-0301
Andesine: An Alkaloidal Naphthalenopyrone

Inge Weiss, Emir Valencia, Alan J. Freyer,* Maurice Shamma, Victor Fajardo, and Alejandra Urzúa

*Department of Chemistry, The Pennsylvania State University, York Campus, P1031 Edgecomb Avenue, York, Pennsylvania 17403, U.S.A.

Abstract

Berberis actinacantha and B. darwinii (Berberidaceae) of Chilean origin have furnished the alkaloid andesine (4) which is probably derived biogenetically from (+)-magnoflorine (1) and magnoflorinemethine (2).

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Communication | Regular issue | Vol 23, No. 2, 1985, pp.305-308
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DOI: 10.3987/R-1985-02-0305
A Stereoselective Construction of a D-Normorphinan Ring System

Tetsuji Kametani,* Yukio Suzuki, and Toshio Honda

*Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

An intramolecular Diels-Alder reaction of a benzocyclobutene derivative (7) afforded a tricyclic compound (8a), which was converted into a D-normorphinan derivative (13), stereoselectively.

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Report | Regular issue | Vol 23, No. 2, 1985, pp.309-312
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DOI: 10.3987/R-1985-02-0309
5’-Methoxyyatein and 5’-Methoxypodorhizol New Lignans Isolated from Hernandia cordigera Viell

Pascal Richomme, Jean Bruneton,* and Adrien Cavé

*U.E.R. de Pharmacie, CEPM, 16 Boulevard Davirs, 49000-Angers, France

Abstract

Two new dibenzylbutyrolactone lignans have been isolated from Hernandia cordigera : 5’-methoxyyatein and 5’-methoxypodorhizol. Their structures have been determined by means of high resolution 1H nmr spectra, CD curves and acidic cyclization.

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Report | Regular issue | Vol 23, No. 2, 1985, pp.313-316
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DOI: 10.3987/R-1985-02-0313
Applicability of the Oglialoro Condensation in the Reaction with 3-Indolocalbaldehyde

Grace Karminski-Zamola,* Leija Fiser-Jakic, and Miro Bajic

*Organic Chemistry Department, Faculty of Technology, University of Zagreb, Marulicev trg 20, 41000 Zagreb, Croatia

Abstract

3-lndolcarbaldehyde exibits in Oglialoro condensation different behaviour than 2-furancarbaldehyde and 2- and 3-thiophencarbaldehydes which with substituted acetic acids give 3-(2-furyl), 3-(2-thienyl) and 3-(3-thienyl)-2-substituted acrylic acids. It is noticed that under the same reaction conditions the main product in the reaction of substituted acetic acids with 3-indolcarbaldehyde is not the corresponding 3-(3-indolyl)-2-substituted acrylic acid but the mixed anhydride 2 or 4.

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Report | Regular issue | Vol 23, No. 2, 1985, pp.317-323
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DOI: 10.3987/R-1985-02-0317
Debenzylation of N-Benzyl-β-lactams by Use of Anodic Oxidation

Miwako Mori and Yoshio Ban*

*Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan

Abstract

Anodic oxidation of N-benzyl-3-methylene-β-lactam 1a followed by hydrolysis with TsOH in 2-butanone gave 3-methylene-β-lactam 4a. To examine the effect of the substituents on the aromatic ring of N-benzyl group for the anodic oxidation, N-p-carbomethoxy, N-p-methyl and N-p-methoxybenzyl-3-methylene-β-lactams were electrolyzed under the same conditions. N-p-Methyl and N-p-methoxybenzyl-β-lactams gave only the exo-methoxylated compounds.

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Report | Regular issue | Vol 23, No. 2, 1985, pp.325-330
Published online:
DOI: 10.3987/R-1985-02-0325
The Trapping of Sulfenic Acids from Penicillin Sulfoxides. Heterocyclic Mercaptans

Ronald G. Micetich,* Samarendra N. Maiti, Motoki Tanaka, Tomio Yamazaki, and Kazuo Ogawa

*Faculty of Pharmacy , University of Alberta, Edmonton, Alberta T6G, 2N8, Canada

Abstract

Various heterocyclic thiols have been used for trapping the azetidinone sulfenic acids obtained by the thermolysis of penicillin sulfoxides. The ester function was found to be important in determining the unsym-azetidinone disulfide (α,β- or β,γ-unsaturated) isomer formed. All β,γ-isomers prepared reacted with cupric chloride to give the 2-chloromethylpenams.

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Report | Regular issue | Vol 23, No. 2, 1985, pp.331-338
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DOI: 10.3987/R-1985-02-0331
Alkaloidas of Aconitum columbianum Nutt.

S. William. Pelletier,* Santosh K. Srivastava, Balawant S. Joshi, and John D. Olsen

*Department of Chemistry, Institute for Natural Products Research, The University of Georgia, Chemistry Building, Athens, Georgia 30602-2556, U.S.A.

Abstract

The alkaloidal constituents of Aconitum columbianum Nutt. ssp. columbianum have been investigated. In addition to the known alkaloids cammaconine (12), deltaline (10), dictyocarpine (11), talatizamine (3), and 8-O-methyltalatizamine (7), a new base columbidine (4) has been isolated and its structure elucidated. The structure was derived on the basis of spectral data and chemical correlation with talatizamine. Synthesis of 7 from talatizamine is described and the 13C-nmr spectrum of 14-dehydrotalatizamine has been recorded. Certain 13C-nmr signals for these compounds have been reassigned.

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Report | Regular issue | Vol 23, No. 2, 1985, pp.339-343
Published online:
DOI: 10.3987/R-1985-02-0339
Noncarbonylsiiron-induced Reaction of 2-Oxo-3-azabicyclo[3.2.0]hepta-3,.6-diene System. Preparation and Thermal Behavior of the Cyclobutene-iron Complex

Makoto Nitta* and Tomoshige Kobayashi

*Department of Chemistry, School of Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan

Abstract

The reaction of 4-phenyl-2-oxa-3-azabicyclo[3.2.0]hepta-3,6-diene with [Fe2 (CO) 9] afforded tetracarbonyl(h2-4-phenyl-2-oxa-3-azabicyclo[3.2.0]hepta-3,6-diene)iron along with 2-phenylpyridine. Thermal behavior of the complex and the reaction of the related compounds with [Fe2 (CO)9] giving pyridine derivatives were also studied.

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Report | Regular issue | Vol 23, No. 2, 1985, pp.345-348
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DOI: 10.3987/R-1985-02-0345
Synthses of Benzoylpiperazine Diones from Their Benzyl Counterparts

Michel Barbier*

*Institut des Chimie des Substances Naturelles, C.N.R.S., 1 avenue de la Terrasse, Bat. 27, 91198 Gif-sur-Yvette Cedex, France

Abstract

The first synthesis of 2,5-dibenzoylpiperazine-3,6-diones through a selective FeCl3-H2O-UV promoted photooxidation of the corresponding benzyl methylene groups is reported.This reaction has been also applied to NN’-dibenzylpiperazine-2,5-dione and to a p-methoxy-beneyl-substituted hydantoin chosen as a model, resulting in the expected product. By modifying the experimental conditions, the unsymetrically substituted benzyl-benzoyl derivatives may be obtained.

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Report | Regular issue | Vol 23, No. 2, 1985, pp.349-355
Published online:
DOI: 10.3987/R-1985-02-0349
Imidazolecarboxalic Acids and Their Derivatives. Synthesis of 10H-Imidazo[1,5-a]pyrido[1,2-d]pyrazin-10-one, a Novel Ring System

Elena Belgodere, Ricardo Bossio, Stefano Marcaccini, Sandro Parti, and Roberto Pepino*

*CNR, Centro di Studio Sulla Chimica e la Struttura dei Composti Eterociclici e lolo Applicazioni, c/o Dipartimento di Chimica Organica "Ugo Schiff", Università di Firenze, Via Gino Capponi 9, I-50121 Firenze, Italy

Abstract

Some derivatives of 10H-imidazo[1,5-a]pyrido[1,2-d]pyrazin-10-one (XV), a novel ring system, were prepared starting from 2-mercapto-1-(2-pyridylmethyl)-1H-imidazole-5-carboxylic acid (VIa)1 and acetic or propionic anhydride. Analogously the synthesis of the unsubstituted ring was achieved starting from 1-(2-pyridylmethyl)-1H-imidazole-5-carboxylic acid (XIV).

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Report | Regular issue | Vol 23, No. 2, 1985, pp.357-363
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DOI: 10.3987/R-1985-02-0357
Metalation of 2-Trifluoromethylphenothiazine: Synthesis and Reactions of Trimethylsilyl Derivatives

Arne Svensson and Arnold R. Martin*

*Department of Pharmaceutical Sciences, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, U.S.A.

Abstract

Dimetalation of 2-trifluoromethylphenothiazine followed by reaction with electrophiles such as carbon dioxide, DMF, hexachloroethane and 1,2-dibromoethane gives 1-substituted 2-trifluoromethylphenothiazines with only traces of the 9-substituted products being formed. Reaction of 1,10-dilithio-2-trifluoromethylphenothiazine with an excess of trimethylysilyl chloride gave a mixture of 2-trifluoromethyl-10-trimethylsilylphenothiazine and 2-trifluoromethyl-1,10-di(trimethylsilyl)phenothiazine. The 10-trimethylsilyl- and 2-trifluoromethyl-1,10-di(trimethylsilyi)phenothiazines were prepared from 10-lithio- and 1-lithio-2-trifluoromethylphenothiazine, respectively. The basis for the unusual stability of 1,10-dilithio-2-trifluoromethylphenothiazine is discussed.

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Report | Regular issue | Vol 23, No. 2, 1985, pp.365-369
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DOI: 10.3987/R-1985-02-0365
New Functionalized Pyrazoles from Isoxazolopyridazinones

Vittorio Dal Piaz,* Giovanna Ciciani, and Stefano Chimichi

*Dipartimento di Scienze Farmaceutiche, Università di Ferrara, via Fossato di Mortara 17, I-44100, Ferrara, Italy

Abstract

Treatment of 3-methylisoxazolo[3,4-d]pyridazin-7(6H)-ones (1a-d) with dilute NaOH affords in good yields new pyrazole derivatives which can be regarded as building blocks for condensed heterocycles with potential biological activity.

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Report | Regular issue | Vol 23, No. 2, 1985, pp.371-375
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DOI: 10.3987/R-1985-02-0371
A 400 MHz 1H NMR Study of Four Basic Reserpine Alkaloids

Mauri Lounasmaa,* Arto Tolvanen, and Siew-Kwong Kan

*Laboratory of Organic Chemistry, Helsinki University of Technology, P.O. Box 6100,FIN-02015 HUT, Espoo, Finland

Abstract

The chemical shifts and most of the main coupling constants of four basic reserpine alkaloids 1 - 4 have been ditermined in a 400 MHz 1H NMR study.

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Report | Regular issue | Vol 23, No. 2, 1985, pp.377-381
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DOI: 10.3987/R-1985-02-0377
Chemical Transformation of Aromaticin into Pulchellin — A Formal Synthesis of Pulchellidine

Seiichi Inayama, Kenzo Harimaya, Nobuko Shimizu, Hitoshi Hori, Tamiiko Ohkura, Yoichi Iitaka, and Takeshi Kawamata*

*Pharmaceutical Institute, School of Medicine, Keio University, Shinanomachi 35, Shinjuku, Tokyo 160-0016, Japan

Abstract

A chemical transformation of aromaticin into pulchellin implying the formal synthesis of pulchellidine was achieved. The stereochemistry of the diol isomers of dihydropulchellin was also revealed.

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Report | Regular issue | Vol 23, No. 2, 1985, pp.383-386
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DOI: 10.3987/R-1985-02-0383
Preparation of Ethyl 1-Aryl-2-(2-pyridyl)ethynylcarbamates and Their Biological Activities

Takeo Konakahara,* Atsuo Watanabe, and Kenji Sato

*Department of Industrial Chemistry, Faculty of Science and Technology, Science University of Tokyo, 2641 Yamazaki, Noda, Chiba 278-8510, Japan

Abstract

Anions of N-silylenamines, generated from 2-(trimethylsilylmethyl)pyridine and p-substituted benzonitriles in the presenc of LDA, reacted with ethyl chloroformate to give a mixture of ethyl (E)- and (Z)-1-aryl-2-(2-pyridyl)ethenylcarbamates. Their insecticidal or fungicidal properties were evaluated.

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Report | Regular issue | Vol 23, No. 2, 1985, pp.387-390
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DOI: 10.3987/R-1985-02-0387
Synthesis of Novel Quinoline Quinols and Isoquinoline Quinols from Quinones

Akinori Kubo,* Yoshiyasu Kitahara, Katsutoshi Inaba, Shin-ishiro Sakai, and Keiichi Yamaguchi

*Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

Abstract

Quinoline quinols and Isoquinoline quinols were synthesized from the corresponding quinoline quinones and isoquinoline quinones, respectively, by the series of reactions, protection of one carbonyl with trimethylsilyl cyanide, reaction with methyl lithium or the enolate of methyl acetate, and hydrolytic deprotection with aqueous silver fluoride.

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Report | Regular issue | Vol 23, No. 2, 1985, pp.391-393
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DOI: 10.3987/R-1985-02-0391
Synthesis of a Novel Ring System: 6H-Benzimidazo[1,2-a]pyrido[2,1-d][1,3,5]triazin-6-one

Ricardo Bossio, Stefano Marcaccini,* Valerio Parrini, and Roberto Pepino

*CNR, Centro di Studio Sulla Chimica e la Struttura dei Composti Eterociclici e lolo Applicazioni, c/o Dipartimento di Chimica Organica "Ugo Schiff", Università di Firenze, Via Gino Capponi 9, I-50121 Firenze, Italy

Abstract

Methyl N-methyl-N’-(2-pyridyl)carbamimidothioate (V) on fusion with o-phenylenediamine gave 2-(benzimidazol-2-ylamino)pyridine (VI) which on treatment with phosgene underwent a ring-closure reaction to give the title compound.

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Report | Regular issue | Vol 23, No. 2, 1985, pp.395-398
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DOI: 10.3987/R-1985-02-0395
An Enantioselective Synthesis of 1-(α-Hydroxyalkyl)-1,2,3,4-tetrahydroisoquinolines through Optically Active N-Oxaacyliminium Ion Intermediates

Shinzo Kano,* Yoko Yuasa, and Shiroshi Shibuya

*School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

Abstract

An enantioselective synthesis of 1S-(1’S-hydroxyethyl)-. 1S-(1’S-hydroxybenzyl)- and 1R-(1’R-hydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline was achieved by reductive cleavage of the oxazolidinone ring of the corresponding 1-substituted oxazolo[4,3-a]isoquinolines, prepared by an application of N-oxaacyliminium ion cyclization with enantioselectivity.

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Review | Regular issue | Vol 23, No. 2, 1985, pp.399-416
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DOI: 10.3987/R-1985-02-0399
The Chemistry of Furoxans

Wanda Sliwa* and Antoni Thomas

*Department of Organic Chemistry, Pedagogical University, Al. Armii Krajowej 13/15, 42-201 Czestochowa, Poland

Abstract

Syntheses, chemical reactivity, as well as physical and biological properties of furoxans are presented.

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31 data found. 1 - 30 listed Next Last