HETEROCYCLES

■ Contents

■ Synthesis of Heterocycles Catalyzed by Iron Oxide Nanoparticles

Ahmed H. M. Elwahy* and Mohamed R. Shaaban

*Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt

Abstract

Heterocycles constitute the largest diversity of organic molecules of chemical, biomedical, and industrial significance. They are also among the most frequently encountered scaffolds in numerous drugs and pharmaceuticals relevant substances. Development of efficient routes to many kinds of heterocycles is an attractive area of research. This review highlights some remarkable achievements made recently in the application of MNPs, magnetite (Fe3O4), maghemite (γ-Fe2O3), and spinel ferrites (MFe2O4) as heterogeneous catalysts in heterocyclic synthesis.

■ Spontaneous α-Methylation of an α-Bromoketone from DMF: Synthesis and Crystalline Structure of 1,1'-(3,4-Diphenylthieno[2,3-b]thiophene-2,5-diyl)bis(propan-1-one)

Yahia N Mabkhot,* Salim S. Al-Showiman, Saied M. Soliman, Hazem A. Ghabbour, Taibi Ben Hadda, Ismail Warad, and Ahmed Boshaala

*Department of Chemistry, College of Science, King Saud University, P.O. Box 22452, Riyadh-11451, Saudi Arabia

Abstract

In this work, we have obtained 1,1'-(3,4-diphenylthieno- [2,3-b]thiophene-2,5-diyl-)bis(propan-1-one) (3), via recrystallization of 1,1'-(3,4- diphenylthieno[2,3-b]thiophene-2,5-diyl)-bis(2-bromoethanone) (2) from a mixture of DMF and chloroform. Structure of compound 3 was confirmed by single X-ray diffraction. The compound crystallizes in the orthorhombic, Pbcn with a =13.6934 (5) Å, b =19.3166 (6) Å, c =7.4283 (3) Å, V = 1964.86 (12) (Å3), and Z = 4. Optimized molecular structure calculations with the aid of B3LYP/6-31G (d, p) DFT agreed well with experimental results obtained from X-ray data. Calculations revealed that the two bivalent sulfur atoms have electropositive nature whereas the two O-atoms are electronegative.

■ Synthesis and Antibacterial Activities of Some New Heterocycles Attached to Pyridinecarboxamide Moiety of Potential Biological Activity

Nabila A. Kheder,* Dalia R. Emam, and Hissana Ather

*Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt

Abstract

A novel series of pyridine, quinoline, coumarin, bipyridine, pyrimidine derivatives attached to pyridinecarboxamide group were prepared by a simple, convenient and one step method using 2-cyano-N-(pyrid-2-yl)acetamide or 3-oxo-N-(pyridin-2-yl)butanamide. The structures of the novel synthesized compounds were determined by means of IR, 1H NMR, 13C NMR, MS and elemental analysis. Antibacterial evaluation of some selected examples was conducted and showed a wide range of activities

■ Synthesis and Structural Characterization of Diazulenylborinic Acid

Toshihiro Murafuji,* Kohhei Shintaku, Kouhei Nagao, Yuji Mikata, Katsuya Ishiguro, and Shin Kamijo

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

Abstract

Diazulenylborinic acid 1 was synthesized by the reaction of 1,3-dibromoazulen-2-yllithium (2) with 1,3-dibromoazulen-2-ylboronic acid ethylene glycol ester (7d). The X-ray crystallographic study of 1 revealed that it forms a dimeric structure through intermolecular hydrogen bonding between the hydroxyl groups. To obtain the tetracoordinate borinate derivative from 1, the attempted esterification of 1 with N,N-dimethylethanolamine did not give corresponding borinate 8 but resulted in the unexpected protodeboronation to give parent 1,3-dibromoazulene (4). The 13C and 11B NMR studies of 1 in the presence of Et3N revealed the change in the π-polarization of the azulenyl group accompanied by the change in the geometry of the boron to a tetracoordinate structure.

■ Synthesis and Antitumor Activities of Steroidal 5α,8α-Endoperoxide Derivatives with Side Chain of 17-Hydrazone Aromatic Heterocycle

Ming Bu, Yujie Wang, Tingting Cao, Hongxia Li, Mingzhou Guo, Yue Zhou, Na Zhang, Chengchu Zeng, and Liming Hu*

*College of Life Sciences & Bioengineering, Beijing University of Technology, Pingleyuan 100, Chaoyang District, Beijing 100124, China

Abstract

Here a series of novel 5α,8α-epidioxyandrostan-3β-ol-17-hydrazone derivatives possessing various aromatic heterocycle structures in 17-side chain of their steroidal nucleus were synthesized and characterized. The antiproliferative activity of synthesized compounds against some cancer cells was investigated. The results have demonstrated that compound 8b with quinoline and 8c with indole structure in side chain display excellent anti-proliferative activity in vitro against tested cancer cell lines.

■ A Convergent Scale-up Synthesis of A HER2/EGRF Dual Kinase Inhibitor

Osamu Yabe,* Akihiro Suzuki, and Tomomi Ikemoto

*Process Chemistry, Pharmaceutical Sciences, Takeda Pharmaceutical Company, Ltd., 17-85 Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan

Abstract

A practical and scalable synthesis of the human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual kinase inhibitor 1 has been developed. The key features of the process development include convenient construction of the benzisothiazole skeleton directly from commercially available materials in high yield, a practical O-demethylation utilizing an ethanethiol or octanethiol/aluminium chloride system without harsh conditions, and development of a more convergent alternative route that coupled two key intermediates in the final step. The novel synthesis allowed the manufacturing process to produce high quality API 1 (>99% purity (LCAP)) over 7 steps, compared to 9 steps in the original route, without chromatographic purification.

■ Synthesis of Some Novel Thiophene and Thiazole Derivatives and Their Antimicrobial Evaluation

Hanan A. Mohamed, Bakr F. Abdel-Wahab, and Gamal A. El-Hiti*

*Department of Optometry, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh 11433, Saudi Arabia

Abstract

Reactions of phenyl isothiocyanate with several active methylene compounds 1 (3-oxo-3-phenylpropanenitrile, ethyl 2-cyanoacetate, pentane-2,4- dione and ethyl acetoacetate) and a molar equivalent of potassium hydroxide in dimethylformamide afforded potassium 1-(phenylamino)ethenethiolates as intermediates 2. Reactions of 2 and 2-bromo-1-(5-methyl-1-(4-tolyl)-1H-1,2,3- triazol-4-yl)ethanone (3) afforded novel thiazole and thiophene derivatives 4, 812, 9 13 and 16a23a,b in 68–78% yields. The structures of the synthesized products were confirmed using various spectroscopic techniques and single X-ray crystal structures. The novel thiophenes and thiazoles showed good antimicrobial activities against the tested bacteria and fungi.

■ Synthesis and in vitro Antifungal Activities of α, β-Unsaturated Ketones as Analogues of Kakuol

Guoqing Sui, Jianjun Sun, Li Yang, Wen Zhang, Kun Zhou, Bingyu Zhang, Yulin Li, Guangci Liu, and Wenming Zhou*

*College of Chemistry & Pharmacy, Northwest A ＆ F University, No. 22 Xinong Road, Yangling, Shaanxi Province 712100, China,
College of Plant Protection, Northwest A&F University, Yangling 712100, Shaanxi Province, China

Abstract

As a part of our ongoing program for the development of analogues of kakuol drugs, 27 α, β-unsaturated ketones compounds with a terminal C=C bond, were synthesized and characterized by spectroscopic analysis. Their antifungal activity was evaluated at the concentration of 50 μg/mL against seven plant pathogenic fungi, and their structure-activity relationships (SAR) were also discussed. Especially compounds 9c, 9g, 10a exhibited more potent antifungal activity against A. solani than that of thiabendazole (a positive control). SAR analysis demonstrated that the conjugated terminal C=C bond is necessary for improvement of the activity.

■ Structurally Diverse Indole Alkaloids from Ochrosia elliptica

A-Hong Chen, Yan-Ping Liu, Zhi-Xin Wang, Yan-Lei Ma, Zhi-Hua Jiang, Liang Lai, Ru-Ru Guo, Jin-Tao Long, Shao-Xia Lin, Wei Xu,* and Yan-Hui Fu*

*Key Laboratory of Tropical Medicinal Plant Chemistry of Ministry of Education, Hainan Normal University, Haikou 571158, China

Abstract

A new naturally occurring indole alkaloid, 10-methoxyconolidine (1), together with seven known alkaloids (2-8), were isolated from the stems and leaves of Ochrosia elliptica. Among them, 10-methoxyconolidine (1) is a rare C5-nor stemmadenine type alkaloid, and the known compounds (2-8) possess diverse carbon skeletons. These structures were established on the basis of extensive spectroscopic methods. All isolated compounds were evaluated for their cytotoxicities and anti-inflammatory activities in vitro. New compound 1 showed no cytotoxicity while exhibited significant inhibitory activity on nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells in vitro with the IC50 value at 2.8 μM.

■ Fluorescence Quenching Induced by Sequential Addition–Aromatization of A BODIPY-Containing Dienylimine with Thiols

Norihiko Takeda, Masafumi Ueda, Nagisa Mori, Tetsuya Miyoshi, Manami Shimoda, Yumina Uno, Hiroshi Kitagawa, Noriaki Emoto, Takahiro Mukai, and Okiko Miyata*

*Department of Medicinal Chemistry, Kobe Pharmaceutical University, 4-19-1, Motoyamakitamachi, Higashinada, Kobe 658-8558, Japan

Abstract

Treatment of a dienylimine bearing a boron–dipyrromethene (BODIPY) fluorophore with aryl and alkyl thiols afforded arylthio and alkylthio–indolines through an addition–aromatization reaction sequence. The structural change from the dienylimine moiety to the indoline nucleus is important process in this fluorescence quenching.

■ Synthesis of 4-(Z)-(Halomethylidene)-1,4-dihydro-2H-3,1-benzothiazine-2-thiones and Their S-Alkylated Derivatives Based on the Reaction of 2-(2,2-Dihaloethenyl)benzenamines with Carbon Disulfide

Kazuhiro Kobayashi,* Takashi Nogi, and Miyuki Tanmatsu

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

Abstract

An efficient one-pot procedure for the preparation of 4-(Z)-(halomethylidene)-1,4-dihydro-2H-3,1-benzothiazine-2-thiones has been developed. Thus, the reaction of 2-(2,2-dihaloethenyl)benzenamines with carbon disulfide in DMF in the presence of DABCO affords the desired products. Successive treatment of these dihydrobenzothiazinethiones with sodium hydride and alkyl halides allows the preparation of 2-(alkylsulfanyl)-4-(Z)-(halomethylidene)-4H-3,1-benzothiazines.

■ Synthesis of 2-(Alkyl(or aryl)sulfanyl)benzo[b]thiophen-3-amines by LDA-mediated Cyclization of 2-{[(Alkyl(or aryl)sulfanyl)methyl]sulfanyl}benzonitriles

Kazuhiro Kobayashi* and Keita Yamashita

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

Abstract

A new and convenient method for the preparation of 2-(alkyl(or aryl)sulfanyl)benzo[b]thiophen-3-amines has been developed. Thus, 2-{[(alkyl(or aryl)sulfanyl)methyl]sulfanyl}benzonitriles, prepared by successive treatment of 2-halobenzonitriles with anhydrous disodium sulfide and chloromethyl sulfides, are cyclized to the desired products via lithiation of the carbon between two sulfur atoms with LDA, followed by addition of the resulting carbanion to the nitrile carbon.