HETEROCYCLES

■ Contents

■ Spiro Heterocycles: Synthesis and Application of Spiro Pyrazol-3-one Derivatives

Eiichi Masumoto and Hiroshi Maruoka*

*Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

Abstract

Spiro compounds play an important role in organic chemistry, not only as key structural units in many natural products and pharmaceuticals but also as useful building blocks in synthetic chemistry. This review deals with the synthesis and application of spiro heterocycles, especially spiro pyrazol-3-ones (SPOs). SPOs represent a common scaffold present in a wide range of biological active compounds, such as antibacterial, analgesic, phosphodiesterase, inotropic, acetyl-CoA carboxylase, PPAR, RaIA, and antitumor activities, among others. The structural features of SPOs provide them with increased reactivity, and SPOs undergo a series of interesting reactions under appropriate conditions, giving efficient methods for the construction of many useful organic compounds. The exploration of SPOs novel reaction has attracted much attention of organic chemists. Generally, SPOs reaction types include nucleophilic addition, ring-opening, and ring transformation reactions. The present review summarizes the advances on SPOs during the period of 2008 to 2021 in our laboratory.

■ Preparation of 2,3-Dihydrobenzo[b]thiophene Bearing Benzylic Quaternary Carbon by Palladium-Catalyzed Cascade Reaction

Yosuke Hosoya, Honoka Yasukochi, Kota Mizoguchi, and Masahisa Nakada*

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

Abstract

A palladium-catalyzed cascade reaction for preparing 2,3-dihydrobenzo[b]thiophenes and the corresponding 1,1-dioxides bearing the C3 benzylic quaternary carbon is described. This cascade reaction involves the oxidative addition of aryl iodide to Pd(0) to form a σ-aryl palladium intermediate, insertion of the internal alkene into the σ-aryl palladium intermediate to form a σ-alkyl palladium intermediate with concomitant formation of a heterocyclic ring bearing a benzylic all-carbon quaternary stereogenic center, which undergoes transmetalation with a TIPS ether of thiol, and finally, reductive elimination to afford the product. The use of N,O-bis(trimethylsilyl)acetamide (BSA) under previously optimized conditions is key to achieving a high yield.

■ Design, Synthesis and Biological Evaluation of Novel Indole-Containing Sorafenib Derivatives

Sili Fan, Yihong Fu, Siyu Tang, Danping Chen, Zhurui Li, Chengpeng Li, Lihui Shao, Zhenchao Wang,* and Guiping Ouyang*

*College of Pharmacy, Guizhou University, Huaxi St., Guiyang 550025, China

Abstract

Based on the molecular structure of sorafenib, a series of novel indole (ketone) semicarbazide analogs (1-30) have been designed and synthesized. All new compounds were identified by 1H, 13C NMR and HRMS, and their antiproliferative activity on four cancer cell lines A549, PC-3, K562 and HepG2 were evaluated. In particular, compared with the positive control sorafenib (18.92 μmol/L), compounds 4, 6 and 20 showed two- to three-fold improvement in inhibiting the proliferation of PC-3 cells with IC50 values of 6.75, 8.03 and 8.77 μmol/L respectively. In vitro activity evaluation experiments showed that compound 6 could significantly inhibit the proliferation and colony formation of PC-3 cells, induce apoptosis and arrest the cells in the G2/M phase. Finally, western blot speculated that compound 6 may affect the signal transduction of downstream signaling pathway PI3K/Akt by affecting EGFR protein and autophosphorylation thereby promoting cell apoptosis and inhibiting cell growth. These results provide important information for the development of new anti-cancer drugs.

■ Chemical Modifications of N,N-Dimethylalkylamino-Substituted 2-Chlorophenothiazine and Their Electrochemical Behavior

Hideki Hayashi,* Tadashi Ogawa, and Take-aki Koizumi

*Organic Materials Laboratory, Nagoya Municipal Industrial Research Institute, 3-4-41, Rokuban, Atsuta-ku, Nagoya 456-0058, Japan

Abstract

The effects of the introduction of Cl to promazine and its oxide analogue were investigated. Cyclic voltammetry (CV) of Cl-substituted promazine derivatives (chlorpromazine (ClProm) and chlorpromazine-S-oxide (ClProm-O)) showed a negative oxidation and reduction potential compared to non-substituted promazine derivatives, whereas their optical properties were not affected by Cl. The Ni-promoted coupling reaction of ClProm and ClProm-O afforded phenothiazine dimers. It was observed that optical and electrochemical properties were affected by dimerization.

■ Novel Heteroannulated Chromeno[2,3-b]pyridines and Related Compounds Using 6-Methylchromone-3-carbonitrile

Magdy A. Ibrahim* and Al-Shimaa Badran

*Department of Chemistry, Faculty of Education, Ain Shams University, Roxy 11757, Cairo, Egypt

Abstract

6-Methylchromone-3-carbonitrile (1) was utilized as synthetic intermediate for construction of a diversity of annulated chromones. Heteroannulated chromeno[2,3-b]pyridines 2-8 were synthesized from reaction of carbonitrile 1 with some methylene active nitriles and cyclic active methylene ketones. Reaction of carbonitrile 1 with isomeric cyclohexanediones in 2:1 molar ratio gave three isomeric (bischromeno)phenanthrolines. Applying Vilsmeier-Haack formylation on 8-methyl-1,2-dihydro-4H-chromeno[2,3-b]- quinoline-4,6(3H)-dione (11) produced cyclic β-chloroenaldehyde derivative 14 which upon condensation with benzylamine and p-toludine afforded the corresponding Schiff bases. Condensation reactions of β-chloroenaldehyde 14 with hydrazine hydrate and hydroxylamine hydrochloride produced the novel angularchromeno[2,3-b]pyrazolo[3,4-f]quinoline 17 and chromeno[2,3-b]isoxazo-
lo[5,4-f]-quinoline 18, Structures of the new synthesized products were deduced based on their analytical and spectral data.

■ Mechano-Biocatalytic Rapid Synthesis of 2-Amino-3-cyano-4H-pyran Derivatives

Ling Jiang, Qingqing Lu, Jingwen Dong, and Xiaohe Chu*

*Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Chaowang Road 18, Xiacheng District, Hangzhou, China

Abstract

A series of 2-amino-3-cyano-4H-pyrans 4a-4s and 5a-5r were synthesized in good to excellent yields via a simple one-pot reaction. The facile method depended on one-pot three-component reaction of aromatic aldehyde, malononitrile and dimedone or 3-(dimethylamino)phenol in the presence of bovine serum albumin (BSA) as the catalyst under ball-milling conditions. The reactions were completed in 40 min in 80-98% yields. The synthesized compounds were characterized by 1H NMR, 13C NMR and ESI-MS.

■ A New and Convenient Synthetic Method for 4-Aminoquinoline-3-carbonitrile and Its Derivatives

Amer Tarawneh*

*Chemistry and Chemical Technology, Department of Chemistry, Tafila Technical University, P.O.Box 179, Jordan

Abstract

A convenient approach is described for the general synthesis of 4-aminoquinoline-3-carbonitrile scaffolds. A series of substituted anthranilonitriles bearing electron-donating and-withdrawing groups on the arene react with 3-bromopropanenitrile and t-BuOK in anhydrous DMF at ca. 24 °C. A wide variety of bases have been used to optimize selective mono-N-alkylation. The best conditions lead to the corresponding 2-(cyanoethylamino)benzonitriles in moderate or good yields. Thorpe–Ziegler cyclization of the N-unprotected 2-(cyanoethylamino)benzonitrile analogs with t-BuLi in THF at -78 °C gives 4-amino, 4-amino-6-methyl, 4-amino-7-methyl, and 4-amino-6-fluoro-quinoline-3-carbonitriles in moderate yields. Owing to their vicinal amino and cyano functional groups that can function as enaminonitrile moieties, 4-aminoquinoline-3-carbonitriles are attractive building blocks frequently used in ring construction.

■ Alicyclic Annulated Triazoles versus Triazinediones by the Reaction of Cyclic Imidates with Methyl 2-Hydrazinyl-2-oxoacetate

Viacheslav Lysenko, Anton Portiankin, Kostiantyn Nazarenko, Kostiantyn Shvydenko, Tetiana Shvydenko, and Aleksandr Kostyuk*

*Organophosphorus, Institute of Organic Chemistry, Murmanska Str.5, 02660, Ukraine

Abstract

A simple convenient method for synthesis of esters of annulated triazole-3-carboxylic acids and/or 1,2,4-triazine-5,6-dione derivatives was proposed. Heating cyclic imidates with methyl 2-hydrazinyl-2-oxoacetate afforded either the annulated triazoles or the annulated triazinediones depending on the reaction conditions. Under heating at hydrochloric acid 1,2,4-triazine-5,6-diones were transformed into triazoles.

■ Rh(III)-Catalyzed Cascade C-H Activation/Annulation of Cyclic 2-Diazo-1,3-diketones with Benzoylacetonitriles to Polycyclic Benzo[de]chromenes

Lili Yuan, Lanlan Zhang, Youpeng Zuo, Guang Han, Xinwei He,* and Yongjia Shang*

*College of Chemistry and Materials Science, Anhui Normal University, No. 189 Jiuhua South Road, China

Abstract

The Rh(III)-catalyzed cascade C-H activation/benzannulation reactions of cyclic 2-diazo-1,3-diketones with benzoylacetonitriles leading to a simple and efficient strategy for the synthesis of polycyclic benzo[de]chromenes in good-to-high yields has been described. Four new bonds and two rings are generated through sequential C-H activation, carbenoid insertion, migratory insertion, and intramolecular annulation process in a single procedure. This protocol is features with readily available starting materials, favorable functional group compatibility, and high efficiency, atom- and step-economy.

■ Three New Quinoline Alkaloids from the Whole Plant of Thalictrum atriplex and Their Bioactivities

Qiu-Fen Hu, Ling-Fang Zhang, Bing-Biao Cai, Yong Li, Hua-Shun Wang, Hao-Cheng Cai, Ming-Xin Liu, Yin-Ke Li,* and Wen Xiong*

*Key Laboratory of Chemistry in Ethnic Medicinal Resources, Yunnan Minzu University, Kunming 650031, China

Abstract

Three new quinoline alkaloids, thalicalkaloids A-C (1-3) together with three known alkaloids were isolated from the whole plant of Thalictrum atriplex. Their structures were elucidated by spectroscopic methods, including extensive 1H, 13C, and 2D-NMR techniques. Compounds 1-6 were tested for their antibacterial and anti-rotavirus activities. The results revealed that compound 3 exhibited high anti-rotavirus activity with therapeutic index (TI) valves of 24.0, and this valve is close to this positive control. Compounds 1, 2, 4-6 also showed potent anti-rotavirus activities with therapeutic index (TI) valves in the range of 11.0~15.8, respectively. In addition, compounds 1-6 showed good anti- methicillin-resistant Staphylococcus aureus (anti-MRSA) activities with IZD of 12.2±1.5, 15.8±1.4, 14.5±1.2, 12.6±1.2, 13.4±1.4, and 14.0±1.5 mm, respectively.

■ Synthesis of Amide-Functionalized Thia[7]helicene-Like Molecule and Its Supramolecular Assembly in the Solid State

Takumi Inoue, Shohei Hamada, Rina Nakamura, Yusuke Kobayashi, Takahiro Sasamori, and Takumi Furuta*

*Department of Pharmaceutical Chemistry, Kyoto Pharmaceutical University, 1 Misasagi-Shichonocho, Yamashina, Kyoto 607-8412, Japan

Abstract

An amide-functionalized thia[7]helicene-like molecule was prepared in an optically active form through the cyclization of the corresponding axially chiral δ-amino acid. X-Ray analysis revealed its twisted helical structure with clockwise helicity and a pairwise association through hydrogen-bonding interactions. This pairwise complex accumulated in the columnar packing in the solid state.

■ Unusual Cembrane Diterpenoid Isolated from the Japanese Soft Coral Genus Sinularia

Takahiro Ishii, Kosuke Sato, Ginji Ito, Jin Kawano, Wakako Takabe, Chin-Soon Phan, Shinnosuke Ishigami, and Takashi Kamada*

*Department of Materials and Life Science, Faculty of Science and Technology, Shizuoka Institute of Science and Technology, 2200-2 Toyosawa, Fukuroi, Shizuoka 437-8555, Japan

Abstract

A novel cembrane diterpenoid, odosinularol (1), featuring an uncommon 13,15-ether bridge, along with nine known casbane diterpenoids (2–10) were isolated from the Japanese soft coral genus Sinularia, which was collected on the main island of Okinawa, Japan. The structure of compound 1 was established through spectroscopic analysis (1D and 2D nuclear magnetic resonance spectroscopy, high resolution electrospray ionization mass spectrometry, and infrared spectroscopy). Furthermore, the bioassay results indicated that the compounds showed moderate cytotoxicity against C2C12 cells (mouse myoblasts).