HETEROCYCLES

■ Contents

■ Synthetic Methods for Phosphorus Compounds Containing Pyrazole Rings

Tarik E. Ali* and Somaia M. Abdel-Kariem

*Department of Chemistry, Faculty of Education, Ain Shams University, El-Maqreezy St, Roxy, Heliopolis, Cairo 11711, Egypt

Abstract

The present review considers all the literature data on methods developed for the synthesis of phosphorus compounds containing pyrazole rings starting from their appearance up to the 2011. The described methods for the synthesis of phosphorus compounds containing pyrazole rings can be divided into three routes: a) direct phosphorylation of pyrazole rings, b) ring closure of acyclic phosphorus compounds with different reagents into phosphono-pyrazoles and c) cyclization of side functional groups to give isolated and fused phosphorus heterocyclic systems containing pyrazole rings.

■ Anodic Selective Functionalization of Cyclic Amine Derivatives

Osamu Onomura*

*Department of Natural Product Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

Anodic reactions are desirable methods from the viewpoint of Green Chemistry, since no toxic oxidants are necessary for the oxidation of organic molecules. This review introduces usefulness of anodic oxidation and successive reaction for selective functionalization of cyclic amine derivatives.

■ Methodology to Access Tetrahydrodipyridoimidazole Derivatives

Mohamed El Bousmaqui, Marion Donnier-Marechal, Paul-Emmanuel Larchanche, Patricia Melnyk, and Pascal Carato*

*Laboratorie de Chimie Thérapeutique, Faculté Pharmcie, Université de Lille 2, 3, rue du Professeur Laguesse, BP 83, 59006 Lille Cedex, France

Abstract

While the synthesis of β and γ-carboline derivatives were well described in the literature, the preparation of their aza-analogs such as tetrahydrodipyridoimidazole derivatives were less explored. In our laboratory we developed various methods to access to these compounds using Bischler-Napieralski as well as Pictet-Spengler reactions.

■ Microwave-Assisted Synthesis of 3,1-Benzoxazin-2-ones from 3-Hydroxyoxindoles

Oscar R. Suárez-Castillo,* Claudia I. Bautista-Hernández, Maricruz Sánchez-Zavala, Myriam Meléndez-Rodríguez, Araceli Sierra-Zenteno, Martha S. Morales-Ríos, and Pedro Joseph-Nathan

*Área Académica de Química, Universidad Autónoma del Estado de Hidalgo, Mineral de la Reforma, Hidalgo, 42184, Mexico

Abstract

A general protocol for the synthesis of 3,1-benzoxazin-2-ones 18 from 3-hydroxyoxindoles 16 in a two steps sequence through phenylsuccinates or phenylpropionates 17 is described. Best reaction conditions for ring opening of 16 to succinates or propionates 17 were achieved using alcohol/silica gel, while cyclization of 17 to benzoxazinones 18 was easily done with HCl/alcohol. It was also found that 17 and 18 can be transesterified using HCl/alcohol. Most transformations were carried out by traditional heating and by microwave (MW) irradiation to accelerate reaction rates.

■ Direct Halogenation Reactions in 2,3-Dihydro-4(1H)-quinazolinones

Fanny A. Cabrera-Rivera, Claudia Ortíz-Nava, Perla Román-Bravo, Marco A. Leyva, and Jaime Escalante*

*Chemical Research Center, Morelos Autonomous State University, Av. Universidad No. 1001, Col. Chamilpa, C. P. 62210, Cuernavaca-Morelos, Mexico, Mexico

Abstract

Reaction of 2,3-dihydro-4(1H)-quinazolinones with NBS, Br2/Et3N and NCS yields 6,8-Br/Cl-2,3-dihydro-4(1H)-quinazolinones with moderate to good yield. The method does not require a catalyst and offers extremely short reaction time.

■ Regioselective Nitro Group Substitution. Synthesis of Isomeric 4-Amino-5-nitro- and 5-Amino-4-nitroimidazoles

Lucjusz Zaprutko,* Justyna Żwawiak, Dorota Olender, and Andrzej Gzella

*Department of Organic Chemistry, Pharmaceutical Faculty, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780, Poland

Abstract

On the basis of the reactions between 4,5-dinitroimidazole derivatives (1-methyl-4,5-dinitroimidazole, 1,2-dimethyl-4,5-dinitroimidazole and ethyl 2-(4,5-dinitroimidazol-1-yl)acetate) and cyclic amines (morpholine, piperidine or pyrrolidine) in mild conditions (THF or ethanolic solution), the order of nitro group substitution has been discovered for the first time. The influence of the solvent, steric effects and possibility of hydrogen bonds formation on the reaction direction has been discussed. Also, the way of formation of diamino-substitution product and interesting isomerization process is presented.

■ An Improved Synthesis of 5-Acylamino-6-oxo-2-phenyl-1(6H)-pyrimidineacetic Acid from Glycine with Readily Removable Protecting Groups

Daisuke Takahashi,* Tatsumi Kashiwagi, Hiromi Onoye, Robert M. Williams, and Kunisuke Izawa*

*Research Institute for Bioscience products and Fine chemicals, Ajinomoto Co., Inc., 1780 Hinaga, Yokkaichi, Mie, 510-0885, Japan

Abstract

Concise synthesis of N-acyl-5-amino-6-oxo-2-phenyl-1(6H)-yrimidineacetic acid was achieved by cyclization reaction of 2-alkyl-4-lkoxymethylene-5(4H)-oxazolone with N-(carboxymethyl)benzamidine, while a similar reaction with sodium salt of 2-alkyl-4-hydroxymethylene-5(4H)-xazolones gave a mixture of regioisomers of the pyrimidinone. N-Acyl groups (acetyl or phenylacetyl) of the pyrimidinone derivatives were readily cleaved under very mild conditions with weak base or enzyme. Thus, the process enabled us to synthesize the drug candidate without exchanging N-protecting group. Since the starting oxazolones were easily prepared from N-acylglycine, the synthetic route can be used for the large scale synthesis of the key intermediate for several enzyme inhibitors.

■ A New Series of Bisbenzimidazole Derivatives: Synthesis, Antitumor Activity and Low Toxicity on PBMC

Xiu-Jun Wang, Qing-He Wang,* Chao Liu, Wei Li, Jian Wang, Na Yang, and Mao-Sheng Cheng*

*School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China

Abstract

Herein, a new series of bisbenzimidazole derivatives were designed and synthesized. Most of these new compounds showed significant in vitro anticancer activity when compared to Hoechst 33258 and 5-FU. Among them, the most potent compound 8 had the IC50 values of 0.78 µM for U937 tumor cell line, 5.62 µM for HL60 tumor cell line and 6.97 µM for Hela tumor cell line. Molecular modeling, fluorescence and viscosimetry study showed that compound 8 could bind into the minor groove of DNA. Subsequent toxicity study on human peripheral blood mononuclear cells (PBMC), shows that compound 8 exhibited less toxicity than paclitaxel and 5-FU.

■ Synthesis of Procyanidins C2 and C1 Using Lewis Acid Mediated Equimolar Condensation

Yukiko Oizumi, Miyuki Katoh, Yasunao Hattori, Kazuya Toda, Koichiro Kawaguchi, Hiroshi Fujii, and Hidefumi Makabe*

*Sciences of Functional Foods, Graduate School of Agriculture, Shinshu University, 8304 Minamiminowa-mura, Kamiina-gun, Nagano 399-4598, Japan

Abstract

Synthesis of procyanidins C2 and C1 was achieved via a stereoselective intermolecular condensation of equimolar amount of dimeric catechin or epicatechin nucleophile and monomeric catechin or epicatechin electrophile using Lewis acid. In the case of synthesis of procyanidin C2, AgBF4 and AgOTf afforded condensed product in excellent yield. As to the synthesis of procyanidin C1, Yb(OTf)3 was effective for equimolar condensation.

■ Sulfur-Containing Pyridylazulenes: Synthesis and Chromogenic Behaviors for Heavy Metal Ions

Shigeharu Wakabayashi,* Rina Yamaoka, Emi Matsumoto, Mitsue Nishiguchi, Miki Ishiura, Misaki Tsuji, and Makoto Shimizu

*Department of Clinical Nutrition, Faculty of Health Science, Suzuka University of Medical Science, Suzuka, Mie 510-0293, Japan

Abstract

A facile method for the synthesis of azulene derivatives bearing 2-pyridyl group at the 1-position, and thio or methylthio group at the 2-position is described. The color and spectral changes that occur upon the addition of heavy metal ions were examined. It was found that the sulfur functional group in pyridylazulene did not effectively participate in the improvement of color selectivity for heavy metal ions, whereas the sensitivity for Hg2+ ion seemed to be slightly improved.

■ A Facile and Convenient Synthesis of Novel Pyridine Derivatives Incorporating Antipyrine Moiety and Investigation of Their Antimicrobial Activities

Nabila A. Kheder, Sayed M. Riyadh,* and Ahlam M. Asiry

*Department of Chemistry, Faculty of Science, Cairo University, Giza 12013, Egypt

Abstract

A series of potentially bioactive piperidines and pyridines, pendant to antipyrine moiety, were synthesized and evaluated in vitro for their antimicrobial potential. Condensation of acetamide 1 with arylaldehydes in (2:1 molar ratio) gave hitherto unreported novel piperidine-3-carboxamide derivatives 4a-c. Also, reaction of acetamide 1 with ethyl 2-cyano-3-(4-nitrophenyl)acrylate afforded unexpected piperidine-3-carboxamide 4c. On the other hands, treatment of acetamide 1 with (arylmethylene)malononitriles 7a,b afforded pyridine-3,5-dicarbonitrile derivatives 10a,b. The structures of the synthesized products were confirmed by IR, 1H NMR, 13C NMR and mass spectral techniques.

■ Synthesis, Characterization, and Tuberculostatic Activity of Novel Heterocyclic Compounds Derived from Dimethyl Heteroaroylcarbonohydrazonodithioates

Katarzyna Gobis,* Henryk Foks, Ewa Augustynowicz-Kopeć, and Agnieszka Napiórkowska

*Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. Hallera 107, 80-416 Gdańsk, Poland

Abstract

A series of dimethyl heteroaroylcarbonohydrazonodithioates (1-5) has been synthesized from various heterocyclic carbohydrazides. N'-(Cycloalkyldiamin-2-ylidene)heteroaroylhydrazides (9-20) were obtained by the substitution of dimethyl heteroaroylcarbonohydrazonodithioates with respective diamines in EtOH or dioxane. In water the substitution was followed by cyclization to 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidines (21-23). The compounds obtained were tested in vitro towards M. tuberculosis standard strain (H37Rv) and two “wild” strains, susceptible (Spec. 192) and resistant (Spec. 210). MIC values for all the compounds tested were within 25-100 µg/mL which indicated their activity lower than reference drugs used (INH, PZA).

■ The Structures of 8- and 10-Trifluoromethylquino[3,2-b]benzo[1,4]thiazines and Their Benzyl Derivatives

Małgorzata Jeleń, Kinga Suwińska, Céline Besnard, Krystian Pluta,* and Beata Morak-Młodawska

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

Abstract

The modification of the phenothiazine structure via the substitution of the benzene ring with the quinoline ring may proceed through the Ullmann cyclization or the Smiles rearrangement of the appropriate sulfides followed by cyclization. Reactions of 2,2’-dichloro-3,3’-diquinolinyl disulfide or pentacyclic diquinodithiin with m-trifluoromethylaniline led to two isomeric tetracyclic trifluoromethylquinobenzothiazines. The product structures as the appropriate 6H-X-trifluoromethylquino[3,2-b]benzo[1,4]thiazines (X = 8, 10) were finally confirmed by X-ray analysis (one product was transformed into N-benzyl derivative). These results exclude the possibility of the reverse Smiles rearrangement and the existence of 5H-tautomers in these conditions. Although both compounds have the same quinobenzothiazine system, they differ in the spatial structures and geometric data. Molecule 6b is unexpectedly almost planar that is the result of larger than usual the C–S–C and C–N–C angles in the thiazine ring. Molecule 14 is folded along the S–N axis with the thiazine ring in boat conformation and the benzyl group in equatorial position.

■ Enaminones as Building Blocks in Heterocyclic Preparations: Synthesis of Novel Pyrazoles, Pyrazolo[3,4-d]pyridazines, Pyrazolo[1,5-a]pyrimidines, Pyrido[2,3-d]pyrimidines Linked to Imidazo[2,1-b]thiazole System

Sobhi M. Gomha* and Hatem A. Abdel-Aziz

*Department of Organic Chemistry, Cairo University, Giza-Haram 12613, Egypt

Abstract

The unreported 2-[E-3-(N,N-dimethylamino)acryloyl]-3-methyl-5,6-diphenylimidazo[2,1-b]thiazole 3 was prepared via the reaction of 2-acetyl-3-methyl-5,6-diphenylimidazo[2,1-b]thiazole 2 with dimethylformamide dimethyl acetal (DMF-DMA). Enaminone 3 underwent regioselective 1,3-dipolar cycloaddition with nitrilimines 5a-f, to afford the corresponding pyrazoles 7a-f. The reaction of 7a,d,g with hydrazine hydrate, afforded the pyrazolo[3,4-d]pyridazines 8a-c, respectively. Enaminone 3 also reacted with a hydrazines, hydroxylamine hydrochloride, 5-aminopyrazole 11, 6-aminothiouracil 15 and hippuric acid 22. The structures of the newly synthesized compounds were confirmed by spectral data and elemental analyses.