HETEROCYCLES

■ Contents

■ Synthetic Models Related to Furanocoumarin-CYP 3A4 Interactions. Synthesis of Furanocoumarin Derivatives as Potent Inhibitors of CYP 3A4

Kazuaki Oda,* Yukio Tamai, Yuki Yamaguchi, Teruki Yoshimura, Keiji Wada, Minoru Machida, and Naozumi Nishizono*

*Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan

Abstract

We prepared a series of furanocoumarin derivatives that have inhibitory effects on the activity of human cytochrome P450 (CYP) 3A4. The reported furanocoumarin dimers paradisins A and B from grapefruit juice showed potent CYP 3A4 inhibition with an IC₅₀ value of 0.07 μM. Synthetic furanocoumarin derivatives, which are more stable and accessible than paradisins, exhibited comparable activity against CYP 3A4.

■ Diacetone-D-glucose-Mediated Asymmetric Syntheses of Dihydroquinoxalinones

Yongtae Kim, Min Hee Lee, Eui Ta Choi, Eun Sun No, and Yong Sun Park*

*Department of Chemistry, Konkuk University, 1 Hwayangdong, Seoul 143-701, Korea

Abstract

Asymmetric syntheses of dihydroquinoxalinones by diacetone-D-glucose mediated nucleophilic substitution of α-bromo esters have been investigated. Stereoselective reactions with various 1,2-phenylenediamine nucleophiles in the presence of TBAI and DIEA and following spontaneous removal of the chiral auxiliary can provide dihydroquinoxalinones (3-9) up to 92% yield and 97:3 er. In addition, we have described the regio- and stereoselective reactions of non-symmetric 1,2-phenylenediamine nucleophiles to provide 10-14 up to 90:10 regioisomeric ratio and 98:2 er.

■ Unconventional Recyclization of Cotarnine under the Action of 1,3-Dimethylbarbituric Acid

Konstantin A. Krasnov, Viktor G. Kartsev,* and Viktor N. Khrustalev

*InterBioScreen Ltd., Chernogolovka, Moscow, Russia

Abstract

The result of condensation of cotarnine with 1,3-dimethylbarbituric acid depends essentially on the temperature. In a harsh conditions (190 °C, without solvent), an unconventional tandem rearrangement proceeds to give (5aR*,9aS*)-11-methoxy-6,8-dimethyl-7,9-dioxo-5,6,7,8,9,10-hexahydro-5a-H-1,3-dioxa-6,8-diaza-cyclopenta[b]anthracene-9a-carboxylic acid methylamide. The structure of this compound was confirmed by XRD. The rearrangement proceeding via the [1,5] H-shift is similar to T-reactions.

■ Stereoselective Modification of Cytisine: T-Reaction for Construction of Benzoannelated Anagyrine Skeleton

Konstantin A. Krasnov and Victor G. Kartsev

*InterBioScreen Ltd., Chernogolovka, Moscow, Russia

Abstract

Three-step transformation of cytisine into a heterocyclic system closely related to the alkaloid anagyrine was achieved by using the T-reaction as a key stage. In this way, N-(2-formyl-4-nitro)cytisine (generated upon arylation of cytisine with 2-cloro-5-nitrobenzaldehyde) was condensed with 1,3-dimethylbarbituric acid to obtain a corresponding 5-arylidenebarbiturate. The latter was found to undergo stereoselective cyclization (T-reaction) into 1,3-dimethyl-5,13’-spiro-[5-nitro-2-(6-oxo-7,11-diazatricyclo[7,3,1,02,7]trideca-2,4-diene-11-yl)phenylmethyleno]hexahydro-2,4,6-pyrimidinetrione containing a benzoannelated anagyrine skeleton. Subsequent alkaline hydrolysis of the spiro compound led to cleavage of the spiropyrimidine moiety followed by stereoselective decarboxylation to afford an enantiomerically pure carboxylic acid derivative of the benzoanagyrine series.

■ Regioselectivity in the 1,3-Dipolar Cycloaddition Reactions of Nitrile Oxides and Organic Azides with Bromocarbazole-1,4-diones

Muriel Compain-Batissou, Jacques Gentili, Nadia Walchshofer, Monique Domard, Bernard Fenet, and Zouhair Bouaziz*

*ISPB, EZ3741, University of Claude Bernard Lyon 1, 8 Avenue Rockefeller, 69373 Lyon cedex 08, France

Abstract

The effect exerted by the presence of a bromine atom in 2 or 3 position of a carbazole-1,4-dione on the regiocontrol of 1,3-dipolar cycloaddition reactions with nitrile oxides and organic azides was investigated. Comparison with the results obtained with 2,3-unsubstituted-carbazole-1,4-dione shows that bromine substituents on para-carbazolequinones effectively orient the 1,3-dipolar cycloadditions. The regiochemistry observed may be explained by the orienting effect of the bromine atom independently of the values of the orbital coefficients.

■ One-Pot Conversion 2-Nitrobenzonitriles to Quinazolin-4(3H)-ones and Synthesis of Gefitinib and Erlotinib Hydrochloride

Venkateshappa Chandregowda, Gudapati Venkateswara Rao, and Goukanapalli Chandrasekara Reddy*

*Vittal Mallya Scientific Research Foundation, P.O. Box No. 406, K. R. Road, Bangalore-560004, India

Abstract

A simple and efficient one-pot conversion of 2-nitrobenzonitriles to quinazolin-4(3H)-ones involving reduction, formylation, hydrolysis and cyclization is reported. These quinazolinones have been used for making in economical way the anticancer drug molecules gefitinib (Iressa®) and erlotinib HCl (Tarceva®).

■ ¹H and ¹³C NMR Analysis of a 1,2-Diaryl-3-methyl-4,5-dihydro-1H-imidazolium Salts Series

Isabel Perillo, Maria C. Caterina, Carlos de los Santos, and Alejandra Salerno*

*Department of Organic Chemistry, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Junín 956 (1113) Buenos Aires, Argentina

Abstract

A study of the ¹H and ¹³C NMR spectra of a 1,2-diaryl-3-methyl-4,5-
dihydro-1H-imidazolium salt series (1) and a comparison with their 4,5-dihydro-
1H-imidazole precursors (2) are presented. Signal assignments follow the analysis of two dimensional HMQC, HMBC, HETCOR, COSY and NOESY spectra. The spectral properties of compounds (1) reflect electronic features of the imidazole ring and correlate directly with the contribution of different mesomeric structures to the stabilization of dihydroimidazolium ions. We also report examples of configurationally stable non-biaryl atropisomers, compounds (1k) and (2k), in which the Ar₁-N bond is the chiral axis. Thus, the stereochemical features of these
compounds are readily evaluated on the basis of their spectroscopic data.

■ N-(2-Alkoxycarbonylbenzenesulfenyl)benzimidazoles as Nitrogen-, Sulfur-, and Carbon-Sulfenylation Reagents

Masao Shimizu,* Hidenori Fukazawa, Jun’ichi Inoue, Yoshimoto Abe, and Takeo Konakahara

*National Institute of Advanced Industrial Science and Technology, 1-1-1 Higashi, Tsukuba, Ibaraki 305-0035, Japan

Abstract

N-(2-Alkoxycarbonylbenzenesulfenyl)benzimidazoles reacted with nucleophiles such as amides, imidates, thiols, Grignard reagents, and active methylene compounds to yield the corresponding sulfenylated products: N-acylsulfenamides, N-sulfenylimidates, disulfides, sulfides, and sulfenylated active methylene compounds, respectively.

■ Total Synthesis of (4R,5S)-Melithiazol C and (3R,4S)-Cystothiazole E

Hiroyuki Takayama, Keisuke Kato, Masayuki Kimura, and Hiroyuki Akita*

*School of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan

Abstract

A Wittig reaction between (+)-chiral aldehyde (4R,5R)-3 and the phosphoranylide derived from the mono-thiazole-type phosphonium iodide [(±)-10] using lithium bis(trimethylsilyl)amide afforded the (+)-melithiazol C (1), whose spectral data were identical with those of the natural product [(+)-1]. Moreover, the Julia’s coupling of aldehyde (21) and the bithiazole-type sulfone (5) followed by the consecutive deprotection and Dess-Martin oxidation gave the (+)-cystothiazole E (2), whose spectral data were identical with those of the natural product [(+)-2].

■ Tri- and Tetracyclic Heteroaromatic Systems: Synthesis of Novel Benzo-, Benzothieno- and Thieno-Fused Pyrano[2,3-c]pyrazol-4(1H)-ones

Gernot A. Eller,* Andreas W. Haring, Barbara Datterl, Maryam Zwettler, and Wolfgang Holzer*

*Department of Drug Synthesis, Faculty of Life Sciences, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria

Abstract

A straightforward, two-step synthesis of chromeno[2,3-c]pyrazol-4(1H)-ones, thieno[2’,3’:5,6]pyrano[2,3-c]pyrazol-4(1H)-ones, and [1]benzothieno[2’,3’:5,6]pyrano[2,3-c]pyrazol-4(1H)-ones, respectively, is presented. Hence, treatment of 1-substituted or 1,3-disubstituted 2-pyrazolin-5-ones with 2-fluorobenzoyl chloride, 2-chlorobenzoyl chloride, 3-chlorothiophene-2-carbonyl chloride, or 3-chloro-1-benzothiophene-2-carbonyl chloride using calcium hydroxide in refluxing 1,4-dioxane gave the corresponding 4-aroylpyrazol-5-ols, which were successfully cyclized into the fused ring systems (NaH/DMF). The N-unsubstituted title compounds were obtained upon treatment of 1-(4-methoxybenzyl) protected congeners with trifluoroacetic acid. Detailed NMR spectroscopic investigations (¹H, ¹³C, ¹⁵N) with the obtained compounds were undertaken.

■ Structural and Conformational Studies on 5-[1’-Methylpyrrolidin-2’-yl]-1,3-oxazolidin-2-one Free Base and Hydrochloride Form

Fiorella Meneghetti, Roberto Artali, Marco Pallavicini, Ermanno Valoti, and Gabriella Bombieri*

*Institute of Pharmaceutical Chemistry, University of Milano, Viale Abruzzi 42, 20131 Milano, Italy

Abstract

The molecular structures of (5R,2’S)-5-[1’-methylpyrrolidin-2’-yl]-1,3-oxazolidin-2-one free base (1) and its enantiomeric hydrochloride salt (2) have been determined in order to understand their interaction at neuronal acetylcholine receptor. The molecules are in a bent conformation with the pyrrolidine and the oxazolidinone rings nearly at 60° to each other. The molecular assembly is characterized by the formation of chains joined via hydrogen bonds N-H...N in 1 and N-H...Cl in 2. The solid state structures have been compared with the theoretical conformations and docked into the crystal structure of Acetylcholine Binding Protein (AChBP), homolog of the ligand binding domain of nAChR. A closer analogy between the receptor bound conformation and the solid state has been found in the hydrochoride form with respect to the free base. This latter (1) forms an hydrogen bond with Trp 6702, while 2 beside two additional interactions with Trp 6702 is linked also to Ile 118.

■ Synthesis of 5-Chloromethylene Hydantoins and Thiohydantoins

Timothy A. Cernak and James L. Gleason*

*Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, Quebec H3A 2K6, Canada

Abstract

5-Chloromethylene hydantoins were prepared by condensation of ureas with chloropyruvic acid. 5-Chloromethylene thiohydantoins were prepared by chlorination of dehydroalanines followed by condensation with thiophosgene. Convenient methods for formation of aminomethylene hydantoins and thiohydantoins using N,N,N’,N’-tetramethylformamidinium chloride are also reported.

■ Selective Synthesis of 2-Aryl-1-arylmethyl-1H-1,3-benzimidazoles Promoted by Ionic Liquid

Huiqiang Ma, Yulu Wang,* Jianping Li, and Jinye Wang*

*College of Chemistry and Environmental Science, Henan Normal University, Xinxiang, 453007, Henan, China

Abstract

Ionic liquid is used to promote the condensation of o-phenylenediamine with aldehydes and afford corresponding 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles efficiently. The absence of a catalyst and recyclability on the non-volatile IL make this an environment friendly methodology for selective synthesis of 2-aryl-1-arylmethyl-1H-1,3- benzimidazoles.

■ The Selective Functionalization of Pyridazino[4,5-d]pyridazines Using Polar Organometallic Reagents

Tibor Zs. Nagy, Krisztián Lörincz, Antal Csámpai,* and András Kotschy*

*Institute of Chemistry, Eötvös Loránd University, Pázmány Péter s. 1/A, H-1117 Budapest, Hungary

Abstract

Selected pyridazino[4,5-d]pyridazine derivatives were reacted with polar organometallic reagents to result in the addition of the organic moiety onto the 5-position of the ring system with high selectivity.

■ Positional Effect on the NMR Spectroscopy of Esters and Amides of 2- and 3-Furancarboxylic Acids

Kyu Ok Jeon, Ji Sook Yu, and Chang Kiu Lee*

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

Abstract

Eleven derivatives of esters and amides of 2- and 3-furancarboxylic acids and their NMR spectra were obtained in DMSO-d₆. The spectra of esters were also obtained in chloroform-d. The chemical shift values show good correlation with the Hammett substituent parameters. The slopes, however, show contrasting phenomena depending on the position in the furan ring.

■ Synthesis of Areno[e]indenes by the Flash Vacuum Pyrolysis of 4-Methoxystyrylarenes

Li-Tse Chu, Pin-Chih Yu, Bo-Jian Wu, Ying-Chi Liao, and Chin-Hsing Chou*

*Department of Chemistry, National Sun Yat Sen University, Kaohsiung, 804, Taiwan, R.O.C.

Abstract

Flash vacuum pyrolysis of 4-methoxystyrylarenes (1b-e) at 800 oC and ca. 1x10^-2 Torr gave the corresponding areno[e]indenes (3b-e) as the major products and 4-hydroxystyrylarenes (4b-e) as the miner ones.

■ Reactions of Some Dithiinodiquinoline 7-Oxides with Potassium Phenoxide

Maria J. Maslankiewicz and Andrzej Maslankiewicz*

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

Abstract

S-Oxides of dithiinodiquinolines (4) and (5) react with potassium phenoxide at γ-quinolinyl-sulfur bond in two manners. Sulfinyl moiety at non-aza-influenced position in sulfoxide (5) significantly activates ortho-sulfanyl substituent towards nucleophilic phenoxy-de-sulfidation to form quinolinethiolate (6A). In the case of sulfoxide (4) with sulfinyl group in aza-activated position, nucleophilic phenoxy-de-sulfinylation occurs to form quinolinesulfenate anion (7A) trapped finally by methylation to products (8), (9) and (10).

■ Dowex 50W in Aqueous Medium: Highly Efficient Biginelli Condensation Procedure for the Synthesis of 4-Aryl-3,4-dihydropyrimidones

Chhanda Mukhopadhyay,* Arup Datta, and Bimal K. Banik

*Department of Chemistry, University of Calcutta, 92, APC Road, Kolkata-700009, India

Abstract

We report here Dowex 50W-mediated efficient synthesis of 4-aryl 3,4-dihydropyrimidones in water for the first time in a one-pot operation.

■ Hafnium Chloride Catalyzed Conjugate Addition of Pyrrole, Pyrazole and Imidazole to α,β-Unsaturated Ketones

Sachiko Aburatani, Motoi Kawatsura, and Jun’ichi Uenishi*

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

Abstract

Pyrrole, pyrazole and imidazole undergo conjugate addition with α,β-unsaturated ketones in the presence of a catalytic amount of hafnium chloride at room temperature. Although the reaction of pyrrole gave 2,5-substituted C-adduct mainly, those of pyrazole and imidazole gave the corresponding N-adducts in excellent yields.