HETEROCYCLES

■ Contents

■ Update on the Reactivity of Saccharin: An Excellent Precursor for the Synthesis of Biologically Important Molecules

Rabia Akhtar, Ameer Fawad Zahoor,* Sajjad Ahmad, Syed Ali Raza Naqvi, Samreen Gul Khan, and Muhammad Suleman

*Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan

Abstract

Saccharin is a versatile starting material for the synthesis of different biologically active molecules. Its derivatives play an important role in medicinal chemistry as they act as analgesic, anti-inflammatory, antimicrobial, antirheumatic, antipyretic, anticancer and antioxidant agents. This review article describes the recent advances in the synthesis of saccharin derivatives reported from 2010 to 2017. This article critically summarizes the methodologies and pathways adopted by various research groups for the synthesis of these important molecules.

■ Synthesis of 7,8-Dihydropyrido[2,3-d]pyrimidine Derivatives from 4,6-Dichloro-2-(methylsulfanyl)pyrimidine

Kazuhiro Kobayashi,* Ippei Nozawa, Takuma Ueyama, Hiroaki Utsumi, Hidetaka Hiyoshi, and Kazuto Umezu

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

Abstract

A new and convenient method for the preparation of 7,8-dihydropyrido[2,3-d]pyrimidine derivatives has been developed utilizing a three-step sequence starting with a commercially available 4,6-dichloro-2-(methylsulfanyl)pyrimidine (DCSMP). Thus, successive treatment of the starting material with LDA and cinnamaldehyde or its derivatives leads to the formation of 3-aryl-1-[4,6-dichloro-2-(methylsulfanyl)pyrimidin-5-yl]prop-2-en-1-ols. After replacement of one of the two chloro-substituents with primary amines, cyclization of the resulting precursors gives the desired products on treatment with methanesulfonyl chloride in the presence of triethylamine.

■ Ultrasound-Mediated Three-Component Reaction “On-Water” Protocol For the Synthesis of Novel Mono- and bis-1,3-Thiazin-4-one Derivatives

Wael A. A. Arafa,* Ashraf M. Mohamed, and Ahmed F. Abdel-Magied

*Department Of Chemistry, Fayoum University, Fayoum 12975, Egypt

Abstract

Green synthetic and catalyst-free strategy towards the synthesis of novel mono- and bis-1,3-thiazin-4-one scaffolds through a one pot, reaction of carbon disulfide, monoacetylenic esters and amines under ultrasonication has been reported. The merits of this protocol comprise no need for tedious workup steps and afforded the desired products in excellent yields make this synthetic protocol more efficient and worthy of further attentiveness. Moreover, the method exhibited excellent score in a number of green metrics.

■ Synthesis of New Azole and Azine Systems Based on Chromeno[3,4-c]pyrrole-3,4-dione and Investigation of Their Cytotoxic Activity

Islam H. El Azab,* Mohamed R. E. Aly, and Adil A. Gobouri

*Department of Chemistry, Faculty of Science, Aswan University, Aswan 81528, Egypt

Abstract

A novel series of 9-substituted-chromeno[4',3':3,4]pyrrolo[2,1-c]- [1,2,4]triazole-6,7-diones (4), chromeno[4',3':3,4]pyrrolo[1,2-d]tetrazole-6,7- dione (5), 9-phenyl-6H- chromeno[4',3':3,4]pyrrolo[2,1-c][1,2,4]triazine-6,7(11H)-dione (8), chromeno[4',3':3,4]pyrrolo[2,1-c][1,2,4]triazole-6,7,9(10H)-trione (10), (3,5-substituted-pyrazol-1-yl)chromeno[3,4-c]pyrrole-3,4-dione (15-19) and thiazole derivatives (28-37) were synthesized using 1-hydrazinylchromeno[3,4-c]- pyrrole-3,4-dione )2( as a precursor. The newly synthesized compounds were characterized and evaluated for their cytotoxic activity.

■ Reaction of Electron-Deficient 3-Acetyl-1-arylpent-2-ene-1,4-diones as a Building Block of Heterocycles

Shun Kawabata, Akihiro Oishi, and Hiroshi Nishino*

*Department of Chemistry, Graduate School of Science and Technology, Kumamoto University, Kurokami 2-39-1, Chûou-Ku, Kumamoto 860-8555, Japan

Abstract

The BF3-assisted reaction of 3-acetyl-1-arylpent-2-ene-1,4-diones 1a-c with cyclohexanones and piperidin-4-ones 2a-i gave unique 3a,6a-dihydrospirofuro[2,3-d][1,3]dioxoles 3 in good to high yields. A similar reaction with the 2,3-dihydroquinolin-4(1H)-ones did not occur, but the reaction with 4-hydroxychromenone 5 mainly produced 3-furfuryl-4-hydroxychromenone 6 along with furochromenone 7. The reaction of the electron-deficient pentenedione 1a as a Michael acceptor with indole, pyrrole, furan, and N-methylaniline produced the corresponding 1,4-adducts. Especially, the indole adduct was easily converted by the Paal-Knorr synthesis into the corresponding furanyl-, pyrrolyl-, and thiophenyl-substituted indoles. The reaction details and the structure determination of the products are described.

■ Arylation of Aniline and Amines by Pd-(N-Heterocyclic Carbene) Complexes

Neslihan Şahin, Serpil Demir Düşünceli, and İsmail Özdemir*

*Catalysis Research and Application Centre, Inönü University, 44280 Malatya, Turkey

Abstract

Aminoarenes constitute valuable building blocks in organic synthesis and an essential skeleton ubiquitously found in ligands, agrochemicals, and pharmaceuticals. This synopsis presents recent amination methods using nitrogen-heteroatom bonds as a powerful and versatile platform to rapidly synthesize diverse aminoarenes, with transition-metal catalyzed arene C-H amination. The Buchwald-Hartwig amination has been investigated theoretically and experimentally to examine the scope of possible bases under different reaction conditions. We report examples of the palladium NHC (N-heterocyclic carbene) catalyzed amination of aryl halides with anilines and amines in the presence of dimethoxyethane solvent and potassium tertiary-butoxide as a base.

■ Synthesis of Long-Wavelength Absorbing Porphyrin m-Benzoic Acids as Molecular Tectons for Surface Studies

Alina Meindl, Aoife A. Ryan, Keith J. Flanagan, and Mathias O. Senge*

*Medicinal Chemistry, Trinity Centre for Health Sciences, Trinity College Dublin, St. James's Hospital, Dublin 8, Ireland

Abstract

Porphyrins are becoming increasingly important building blocks in material science. This is due in part to several favorable characteristics; such as strong absorption into the infrared region, tunable electronic properties and the possibility to modify and define the porphyrin core in multiple ways. Herein we report synthetic methodologies for porphyrin-based molecular tectons for surface studies. The study aims to generate porphyrins with directional anchoring groups of different length and we report a library of long-wavelength absorbing porphyrins with a special focus on organometallic coupling reactions for the introduction of benzoic acid moieties as anchor groups.

■ Synthesis of Isocoumarin Compounds, 8-Hydroxy-6-methoxy-3-Pentyl-1H-Isochromen-1-one and Fusariumin Analog Using Palladium-Catalyzed Carbonylation Trapping with O-Enolate

Masaki Asai, Yasunao Hattori, and Hidefumi Makabe*

*Department of Agriculture, Division of Food Science and Biotechnology, Graduate School of Science and Technology, Shinshu University, 8304 Minami-minowa, Kami-ina, Nagano 399-4598, Japan

Abstract

Concise synthesis of 6,8-dialkoxyisocoumarin framework was achieved using Pd-catalyzed carbonylation trapping with O-enolate. This methodology was applied to the synthesis of 8-hydroxy-6-methoxy-3-pentyl-1H-isochromen-1-one isolated from Tessmannia densiflora and fusariumin analog.

■ Synthesis of 17β-N-Phenylpyrazolyl Steroidal Derivatives and Their Inhibitory Effect on Cell Proliferation

Ning-Juan Fan,* Yuan-Feng Li, Qiu-Rui He, Shuang Liang, and Jiang-Jiang Tang*

*Biochemistry and Molecular Biology Research Platform, College of Life Science, Northwest A&F University, Yangling, Shaanxi 712100, China

Abstract

The synthesis of several 17β-N-phenylpyrazolyl derivatives steroid derived from progesterone are described. The Claisen condensations of ∆1, 4-pregnadien-3,20-dione (1) and 4-chloro-∆1,4-pregnadiene-3,20-dione (2) with dimethyl oxalate afforded 21-methoxalylpregna-1,4-diene-3,20-dione (3) and 4-chloro-21-methoxalylpregna-1,4-diene-3,20-dione (4), respectively. Furthermore, the reactions of 3 and 4 with substituted phenylhydrazines yielded 5'-pyrazolyl derivatives as main products, and the 5'-pyrazolyl isomers 6a-k (and 7a-k) were isolated from the crude reaction mixture (3'-pyrazolyl regioisomers as minor products). The newly synthetized compounds were evaluated in vitro by means of SRB assays for antiproliferative activity against HepG-2 (hepatoma), HeLa (cervix adenocarcinoma) and MCF-7 (breast adenocarcinoma). The preliminary results showed that compounds 6d, 6i and 7d possessed moderate antiproliferative activities.

■ One-Pot Four Component Reaction for the Synthesis of 1-(1H-Indol-2-yl)-1H-pyrazolo[1,2-b]phthalazine-5,10-dione Derivatives by Self-Catalysis

Faruq Mohammad* and Hamad A. Al-Lohedan

*Surfactant Research Chair, Department of Chemistry, King Saud University, P.O. Box 2455, Riyadh-11454, Saudi Arabia

Abstract

In this, we performed a four component domino reaction of phthaloyl dichloride, hydrazine hydrate, indole-3-carboxaldehydes and malononitrile/ethyl cyanoacetate to form 1-(1H-indol-2-yl)-1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives by in situ generation of HCl as catalyst in refluxing ethanol for 1 h in good yields. This four component domino reaction transformation presumably proceeds via addition/dehydrohalogenation/condensation/cyclization of reactions. The material was thoroughly characterized at various stages of its formation by means of FTIR, NMR spectroscopic and Mass spectrometric analysis and is confirmed to be the derivative of 1-(1H-indol-2-yl)-1H-pyrazolo[1,2-b]phthalazine-5,10-dione.

■ Four New Cantharidin Derivatives from the Chinese Blister Beetles, Mylabris phalerata

Yuan-Yuan Deng, Wei Zhang, Xue-Ping Lei, Dong-Mei Zhang, Jun He, Lei Wang,* and Wen-Cai Ye*

*JNU-HKUST Joint Laboratory for Neuroscience & Innovative Drug Research, Jinan University, Guangzhou 510630, China

Abstract

Four new cantharidin derivatives, cantharacidines A-D (1-4) were isolated from the Chinese blister beetles Mylabris phalerata. Their structures with absolute configurations were elucidated by means of NMR spectroscopy, single-crystal X-ray diffraction and electronic circular dichroism (ECD) spectral analyses. Compounds 1-3 are the first examples of natural cantharimide-carboxylic acid adducts. The inhibitory effects of compounds 1-4 on the viability of three cancer cell lines (HepG2, MDA-MB-231 and A549 cells) were evaluated by the MTT assay.

■ Three New Isoflavones from the Root of Pueraria lobata and their Bioactivities

Feng-Mei Zhang, Jing Li, Qi-Li Mi, Shi-Yun Tang, Ye-Kun Yang, Jian-Hua Chen, Chun-Bo Liu, Qin-Peng Shen, Zhi-Hua Liu, Guang-Yu Yang, Qiu-Fen Hu, Zhong-Tao Ding,* and Xue-Mei Li*

*School of Chemical Science and Technology, Yunnan University, Kunming 650091, China

Abstract

Three new isoflavones, 4′-hydroxy-6-methoxy-7methyl-isoflavone (1), 4′,6-dihydroxy-7-methylisoflavone (2), and 4′-hydroxy-7-hydroxymethyl-6- methoxyisoflavone (3), together with two known isoflavones (4 and 5), were isolated from the root of Pueraria lobata. Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D NMR techniques. Compounds 1-5 were evaluated for their anti-tobacco mosaic virus (anti-TMV) activities. The results showed that compounds 1 and 2 exhibited comparable anti-TMV activities with inhibition rates of 34.2 and 33.5%. The other compounds also showed potential anti-TMV activities with inhibition rates in the range of 21.8-25.6%, respectively. The cytotoxicities of compounds 1-5 against five human tumor cell lines (NB4, A549, SHSY5Y, PC3, and MCF7) were also tested. The results revealed that compounds 1-5 showed weak inhibitory activities against some tested human tumor cell lines with IC50 values in the range of 3.9-9.2 μM.

■ Correction to “Regioselective Introduction of Substituents to The Meso-Position of Pyrromethenone Derivative – Application to the Synthesis of Sterically Fixed Phytochrome Chromophore Anchored to the C15 Meso-Position”: Heterocycles, 2015, 90, 883: DOI: 10.3987/COM-14-S(K)97

Yudai Tanaka, Ryoji Iwamoto, Ryo Sakata, Takahiro Soeta, Kohei Endo, Shuhei Fujinami, Katsuhiko Inomata, and Yutaka Ukaji*

*Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192, Japan