HETEROCYCLES

Published online: 12th August, 2020

■ Some New C3- and Cs-Symmetrical Trialkylamino- Substituted 1,3,5-Triazines and Their Biological Evaluation

Shunsuke Shimomura, Yusuke Inoue, Yuki Kawano, Yuka Fujita, Kanae Yamada, Yumemi Matsumoto, Kazumi Yokomizo, Jian-Rong Zhou, Kaori Ota, Nobuko Mibu, Makoto Furutachi, and Kunihiro Sumoto*

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

Abstract

We report the preparation of some new additionally synthesized symmetrical 1,3,5-triazines (TAZ) and the results of biological evaluation of their anti-herpes simplex virus type 1 (anti-HSV-1) activity and cytotoxic activity against Vero cells. All of the new trisubstituted TAZ derivatives 3a-3e showed considerable levels of anti-HSV-1 activity (EC50 = 4.4 ~ 30.3 μM). Among the tested compounds, two compounds (3c-2 and 3d) that have three 3,4-methylenedioxyphenylalkylamino groups showed low levels of cytotoxicity (CC50 > 200 μM) against Vero cells. On the other hand, the C3-symmetrical TAZ derivatives 3a-2, 3b-2 and 3e　showed considerably high levels of cytotoxicity (CC50 = 8.91 ~ 15.2 μM). The structure-activity relationships for anti-HSV-1 activity and cytotoxicity of synthesized single-drug type 2,4,6-trisubstituted TAZ derivatives are also discussed.

Published online: 12th August, 2020

■ A One-Pot Four-Component Procedure for the Synthesis of Dispiro[tetrahydroquinoline-bis(2,2-dimethyl-1,3-dioxane-4,6-dione)] Derivatives

Zhaohui Xu,* Yexuan Tang, Qiang Xiao, and Chuanwen Liao*

*Department of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, P.R. China.

Abstract

A simple and efficient procedure for the diastereoselective synthesis of dispiro[tetrahydroquinoline-bis(2,2-dimethyl-1,3-dioxane-4,6-dione)] derivatives through one-pot four-component reaction of aromatic aldehydes, 2,2-dimethyl-1,3-dioxane-4,6-dione, arylamines and acetone in the presence of potassium dihydrogen phosphate (KDP) is described. The procedure involves initial Knoevenagel reaction, followed by Diels-Alder, Michael additon and intramolecular reactions. The main advantages of the protocol are the high isolated yields, broad substrate scope, mild conditions, and easy operation.

Published online: 7th August, 2020

■ Copper-Mediated Trifluoromethylation of Borylporphyrins Using An in Situ-Generated CF3 Radical from NaSO2CF3 and tert-Butyl Hydroperoxide

Satoshi Hayashi,* Daisuke Yamazaki, and Toshikatsu Takanami*

*Department of Life and Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

Abstract

We developed a method for the copper-mediated reaction of borylated Ni(II) porphyrins using NaSO2CF3 (Langlois’ reagent) and tert-butyl hydroperoxide (TBHP) to prepare trifluoromethylated Ni(II) porphyrins.Porphyrin trifluoromethylation can be carried out under mild conditions and exhibits both excellent substrate generality and functional group compatibility.

Published online: 7th August, 2020

■ Ukixanthomycin A: A Hexacyclic Xanthone from the Mudflat-Derived Actinomycete Streptomyces sp.

Yuhei Koyanagi, Teppei Kawahara, Yuki Hitora, and Sachiko Tsukamoto*

*Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-hon-machi, Kumamoto 862-0973, Japan

Abstract

A new hexacyclic xanthone, ukixanthomycin A (1), was isolated from the mudflat-derived Streptomyces sp. HGMA004 by screening based on chemical analysis by UPLC-HRMS with our in-house actinomycete extract library. The structure of 1 was elucidated by spectral analyses and quantum chemical calculations. Compound 1 showed weak antifungal activity against Candida albicans.

Published online: 4th August, 2020

■ Design and Synthesis of 4'-Cyano Dideoxy Isonucleosides and Their Activity against HIV-1 and HBV

Kengo Onitsuka, Kakeru Yamaguchi, Ryoh Tokuda, Nobuyo Higashi-Kuwata, Shunsuke Kuwahara, Hiroki Kumamoto, Kenji Maeda, Kazuhiro Haraguchi, Hiroaki Mitsuya, and Shuhei Imoto*

*Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1, Ikeda, Kumamoto-shi, 860-0082, Japan

Abstract

Nucleoside reverse-transcriptase inhibitors are major antiviral agents against HIV-1 and HBV. Here, we describe the synthesis of a novel 4'-cyano dideoxy isonucleoside 6 and its phosphoramidate prodrug 7. Intermediate 16 is a promising precursor for the preparation of isonucleosides bearing substituents at the 4' position with various nucleobases. In addition, 6 and 7 were evaluated for their antiviral properties against HIV-1 and HBV. Compound 7 displayed weak anti-HIV activity (EC50 = 61.4 μM) and had no observed cytotoxicity in two different cell systems.

Published online: 3rd August, 2020

■ Change in the Fluorescence of 1,1′-Diaryl-2,2′-biimidazoles Upon the Addition of Acid

Shoji Matsumoto,* Seigi Tachibana, and Motohiro Akazome

*Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan

Abstract

The optical properties of a series of 1,1′-diaryl-2,2′-biimidazoles were examined. Different transitions were observed in their fluorescence spectra upon changing the electronic properties of the phenyl ring at the C1 and C1′ positions. The presence of a formyl group on the phenyl ring results in fluorescence via a CT transition with a solvent effect. A bathochromic change was observed when HCl was added to a solution of compound bearing a methoxy group in CH2Cl2, whereas a hypsochromic change was observed in compound bearing a formyl group. These observations were attributed to the protonation, which causes a characteristic change in their biimidazole moieties.

Published online: 30th July, 2020

■ Catalytic Enantioselective Oxa-Hetero-Diels-Alder Reactions of Enones with Aryl Trifluoromethyl Ketones: Synthesis of Tetrahydropyranones

Maira Pasha and Fujie Tanaka*

*Chemistry and Chemical Bioengineering Unit, Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna, Okinawa 904-0495, Japan

Abstract

Diastereo- and enantioselective oxa-hetero-Diels-Alder reactions of enones with aryl trifluoromethyl ketones that afford tetrahydropyranone derivatives catalyzed by an amine-based catalyst system are reported. The major diastereomers of the tetrahydropyranone products obtained in these reactions had the relative stereochemistry different from that of the previously synthesized tetrahydropyranone derivatives.

Published online: 29th July, 2020

■ Identification of a Novel Indoleamine 2,3-Dioxygenase Inhibitor Bearing an Eight-Membered Ring Fused Indole Scaffold and Its Structure-Activity Relationship

Ayuta Yamaguchi, Shinsuke Inuki,* Katsumi Ohta, Shinya Oishi, Akira Asai, and Hiroaki Ohno*

*Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising target for cancer immunotherapy because it is overexpressed in a variety of tumor cells. IDO1 also plays an important role in the process of immune escape by tumors. In this study, we identified a novel IDO1 inhibitor KPYC12532 (5a) bearing an eight-membered ring-fused indole scaffold by screening our compound library. To develop novel IDO1 inhibitors, we conducted a structure-activity relationship study of 5a and found some compounds displaying comparable activity. These results provide useful insight for the design of novel IDO1 inhibitors.

Published online: 17th July, 2020

■ Environmentally Benign Synthesis of Cyclic Carbonates from Epoxides and Carbon Dioxide using Binary and Bifunctional Catalysts

Ken Okuno, Ryuichi Nishiyori, Mana Hiraki, and Seiji Shirakawa*

*Graduate School of Fisheries and Environmental Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

The extensive utility of five-membered cyclic carbonates has been well established in the chemical industry. Among the various methods available for the synthesis of five-membered cyclic carbonates, coupling reactions that involve epoxides and carbon dioxide are ideal. This review introduces environmentally benign catalytic systems for the synthesis of cyclic carbonates under mild reaction conditions. Application of chiral catalysts to the asymmetric synthesis of optically active cyclic carbonates is also discussed.

Published online: 17th July, 2020

■ Selective Reduction and Dihydroxylation of α,β-Unsaturated Esters in The Presence of Enals: One-Pot Synthesis of A 2,5-Disbstituted Tetrahydrofuran

Kenta Morita, Kenichi Murai, Mitsuhiro Arisawa, and Hiromichi Fujioka*

*Graduate School of Pharmaceutical Science, Osaka University, 1-6 Yamadaoka, Suita, Osaka 560-0871, Japan

Abstract

Two-way discriminative conversion, reduction and dihydroxylation of α,β-unsaturated esters were achieved in the presence of enals using two phosphonium salts as in situ protecting groups. Furthermore, a pot-economical one-pot synthesis of a tetrahydrofuran derivative was achieved.

Published online: 15th July, 2020

■ Structural and DFT Study of 1-(3-Amino-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-3,4-dichloro-1H-pyrrole-2,5-dione: Hypothesis for the Ring Closure

Bader A. Salameh* and Murad A. AlDamen*

*Department of Chemistry, Faculty of Science, the Hashemite University, Zarqa 13133, Jordan.

Abstract

The reaction of 2,3-dichloromaleic anhydride with 2,3-diamino-1,4-naphthoquinone was studied and afforded to 1-(3-amino-1,4-dioxo-1,4- dihydronaphthalen-2-yl)-3,4-dichloro-1H-pyrrole-2,5-dione (3). Experimental techniques (NMR and single-crystal structures) confirmed the structure of 3. The study was extended to explore the failure of the intramolecular cyclization of 3 to the imidazole ring. Density Functional Theory at level B3LYP/6-31G(d,p) of theory were used to examine the optimized molecular geometry and to understand the reaction mechanism which reveals that the failure of cyclization is possibly due to positive charge of the amine in addition to the high repulsion between the naphthoquinone and the maleimide oxygens.

Published online: 14th July, 2020

■ Improved Synthesis of Cyclohexane-Backbone Iridium-Complexes of Quinoline-Phosphine and Their Applications in Asymmetric Hydrogenation

Qibin Liu*

*R&D department, Dalian Allychem Co. Ltd, No 5 of Jinbin Road, Jinzhou New District 116620, China

Abstract

The iridium-complexes 3 and 4 with cyclohexane-backbone derived from quinoline were easily synthesized. The key step is cis/trans stereoselective reduction of 2-(quinolin-2-yl)cyclohexanone 5 to trans-2-(quinolin-2-yl)cyclohexanol 6 using Al(Oi-Pr)3/i-PrOH and the following diastereomeric optical resolution of racemic 6 using 0.50 equiv (S)-mandelic acid in EtOAc. These complexes were used in the asymmetric hydrogenation of (E)-1,2-diphenylpropene with up to 13% ee/48% conv. using 3 and 35% ee/9% conv. using 4. For the hydrogenation of (2H-chromen-3-yl)methanol, up to 80% ee/95% yield and 72% ee/96% yield were achieved. The same configuration of the products by using 3 and 4 suggested that the absolute configuration was controlled by the configuration of the stereogenic quinolinyl-bearing carbon of the complexes.

Published online: 14th July, 2020

■ Reactivity of the Enamine Tautomer of a Cyclic 1,4-Diazadiene with a Diketone

Kazuhide Nakahara,* Koki Yamaguchi, and Hisao Kansui

*Department of Integrative Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata-shi, Osaka 573-0101, Japan

Published online: 9th July, 2020

■ Regiodivergent Ring Opening Reactions of 2-Arylated 3-Nitrocyclopropane-1,1-Dicarboxylates Leading to Polyfunctionalized Dipoles

Haruyasu Asahara,* Rikiya Kamidate, and Nagatoshi Nishiwaki*

*Pharmaceutical Science, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0821, Japan

Abstract

Two kinds of Lewis acid induced ring-opening reactions of 2-aryl-3-nitrocyclopropane-1,1-dicarboxylates proceeded to afford 5-aryl-2-isoxazolines and γ-keto acid derivatives, respectively. Different ring-opening modes could be controlled by choosing the ligand or solvent.

Published online: 8th July, 2020

■ Synthetic Approach for Building Heteroannulated Furo[3,2-g]chromenes Using 4,9-Dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-carbonitrile and Cyclic Carbon Nucleophiles

Magdy A. Ibrahim,* Sami A. Al-Harbi, and Esam S. Allehyani

*Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, Cairo 11711, Egypt

Abstract

A novel series of polyfused heterocyclic systems containing furo[3,2-g]chromenes were efficiently synthesized. The reactivity of 4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-carbonitrile (1) was studied towards a variety of carbon nucleophilic reagents such as heterocyclic enols, heterocyclic enamines and cyclic active methylene compounds. Treatment of carbonitrile 1 with 4-hydroxycoumarin, 4-hydroxy-1-methylquinolin-2(1H)-one (3), 2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (4) afforded furodichromenopyridine 2, furochromenonaphthyridine 5, furochromenodipyridopyrimidine 6. Reaction of carbonitrile 1 with 4(6)-aminouracil and 5-amino-3-methyl-1H-pyrazole proceed through ring opening followed by cycloaddition into the nitrile group giving pyrido[2,3-d]pyrimidine 7 and pyrazolo[3,4-b]pyridine 8. Also, reaction of carbonitrile 1 with 5-amino-2,4-dihydro-3H-pyrazol-3-one (9), 2-(phenylimino)-1,3-thiazolidin-4- one (11), thiobarbituric acid and cyclohexane-1,3-dione produced the novel annulated furo[3,2-g]chromenes 10, 12-14, respectively. Cyclohexane-1,2-dione reacted with carbonitrile 1 in 1:2 molar ratio afforded bis-(furochromeno)[1,10]phenanthroline 15. The prepared compounds were screened in vitro for their antimicrobial activity and some of them appeared notable activity against the tested microorganisms.

Published online: 6th July, 2020

■ Facile Preparation of 3,4-Benzocoumarins from 2-Arylbenzoic Acids with NCS and Nai

Momoko Nakamura and Hideo Togo*

*Graduate School of Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan

Abstract

Treatment of 2-arylbenzoic acids with N-chlorosuccinimide (NCS) and NaI at 70 °C under fluorescent lighting condition gave the corresponding 3,4-benzocoumarins in good yields under transition-metal-free condition. It was found that the reactivity of NCS with NaI for the formation of 3,4-benzocoumarins from 2-arylbenzoic acids was as high as that with NIS. Thus, the formation of carboxyl radicals and their cyclization onto an aromatic ring from 2-arylbenzoic acids with much less expensive NCS and NaI, than NIS could be successfully carried out to form 3,4-benzocoumarins.

Published online: 6th July, 2020

■ Rumphellolide K, a Novel C-3/8 Ether Linkage Caryophyllane from Rumphella antipathes

Hsu-Ming Chung, Yu-Ming Chang, Wei-Hsien Wang, Jih-Jung Chen, Tsong-Long Hwang,* and Ping-Jyun Sung*

*National Museum of Marine Biology and Aquarium, Pingtung 944401, Taiwan

Abstract

Chemical examination of Rumphella antipathes, collected in the waters of Taiwan, led to the isolation of a novel caryophyllane sesquiterpenoid, rumphellolide K (1), with a C-3/8 ether linkage. The structure of 1 was established by spectroscopic analysis and this compound displayed inhibitory effects on the generation of superoxide anions and the release of elastase by human neutrophils.

Published online: 3rd July, 2020

■ Efficient Synthesis of 2-Functionalized Benzoxazoles Catalyzed by Copper Iodide

Han Cao,* Xue-Jing Liu,* Fu-sheng Bie, Peng Yan, Jie Ma, Yi-jun Shi, and Ying Han

*Engineering and Technology Research Institute of Lunan Coal Chemical,, Zaozhuang University, 1 Beian Road, China

Abstract

We reported an efficient synthesis of 2-functionalized benzoxazoles in mild condition and excellent yields. The synthetic process includes two steps. The step one contains a reaction of pendent halide formamidine derivatives and 2- aryloxyacetyl chloride generating highly selective (Z)-N-(2-halophenyl)-3-(dime- thyllamino)-2-aryloxyacrylamides, and the step two undergoes copper iodide catalyzed intramolecular C-O bond formation to yield title compounds. This strategy is not only providing newly discovered key intermediates 6a-l which contain multiple functional groups on 2-position (as building blocks), but also expanded the scope of methodologies for making diverse benzoxazoles with multiple functional groups.

Published online: 3rd July, 2020

■ Aryne-Mediated Synthesis of Oxygen Heterocycles and Application to Cysteine-Selective Trapping

Hideto Miyabe*

*Laboratory for Medicinal Chemistry, School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe City, 650-8530, Japan

Abstract

The use of arynes as the highly reactive intermediates in organic synthesis has attracted substantial attention. Particularly, the introduction of ortho-(trimethylsilyl)aryl triflates as easily activatable aryne precursors led to growing activity in this field. Most reactions using these aryne precursors proceed through the addition of nucleophiles to arynes and the subsequent trapping with electrophiles to give the multisubstituted arenes with structural diversity and complexity. Based on our studies, this review highlights the insertion of arynes, generated from ortho-(trimethylsilyl)aryl triflates, into C=O π-bond of formamides. Initially, the representative examples for formal [2+2] cycloaddition of arynes with the carbon–heteroatom double bond or the heteroatom–heteroatom double bond are shown. Next, the studies on the insertion of arynes into the N−C and C=O bonds of amide group including our three-component coupling reaction leading to oxygen heterocycles are summarized. The SN2’ reaction of tricyclic oxygen heterocycles, obtained by three-component coupling reaction, was studied by using carbon and sulfur nucleophiles. The SN2’ reaction was expanded to four-component coupling reaction. Finally, the application of tricyclic oxygen heterocycles to cysteine-selective trapping is described.

Published online: 3rd July, 2020

■ Three New Benzazepine Alkaloids from Thalictrum cirrhosum and Their Anti-Rotavirus Activity

Qiu-Fen Hu, Dian Luo, Na Lv, Ya-Ning Zhu, Lu Liu, Fan Wu, Dong Miao, Wei-Guang Wang, Qian Gao, Min Zhou,* and Guang-Yu Yang*

*Technical center, China Tobacco Yunnan Industrial Co., Ltd., Keyi Road 41#, China

Abstract

Three new benzazepine alkaloids, cirrhobenzazepines A-C (1-3), together with four known alkaloids (4-7) were isolated from the whole plants of Thalictrum cirrhosum. Their structures were elucidated by spectroscopic methods, including extensive 1H, 13C, and 2D-NMR techniques. Compounds 1-7 were tested for their anti-rotavirus activity. The results revealed that compounds 1-7 exhibited potent anti-rotavirus activity with TI valves in the range of 11.9-18.2, respectively.

Published online: 1st July, 2020

■ Reactivity of 4,6-Dimethoxy Activated Benzimidazoles

Mahiuddin Alamgir, Glenn C. Condie, Vesna Martinovic, Joanne Wood, Mohan Bhadbhade, Naresh Kumar, and David StC. Black*

*School of Chemistry, The University of New South Wales, Sydney 2052, Australia

Abstract

4,6-Dimethoxy-2-substituted-benzimidazoles undergo formylation, acylation, nitration and bromination at C7. The 7-carbaldehydes can be reduced to the corresponding hydroxymethyl compounds. Benzimidazole-2-carbaldehydes can be prepared by oxidation of 2-methyl- and 2-styryl-benzimidazoles. N-Methylation and N-allylation have also been investigated and lead to isomeric mixtures of 4,6- and 5,7-dimethoxybenzimidazoles. In general the nucleophilic capacity of the activated benzimidazoles is weaker than that of the related activated indoles, but still provides synthetic routes to a range of new heterocyclic structures.

Published online: 30th June, 2020

■ Chemical Transformations with 4,9-Dimethoxy-5-oxo-5H- Furo[3,2-G]chromene-6-carbonitrile: Construction and Antimicrobial Evaluation of the Novel Heteroannulated Furochromenopyridines

Magdy A. Ibrahim,* Sami A. Al-Harbi, and Esam S. Allehyani

*Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, Cairo 11711, Egypt

Abstract

The chemical reactivity of 4,9-dimethoxy-5-oxo-5H-furo[3,2-g]- chromene-6-carbonitrile (1) was studied towards a variety of active methylene nitriles namely; malononitrile, cyanoacetamide, N-phenylcyanoacetamide, (phenylthio)acetonitrile, ethyl cyanoacetate and benzothiazol-2-ylacetonitrile producing the novel annulated furo[3’,2’:6,7]chromeno[2,3-b]pyridines. Reactions of carbonitrile 1 with malononitrile dimer, cyanoacetohydrazide and 1H-benzimidazol-2-ylacetonitrile showed different behavior giving the novel angular heteroannulated furochromenes 10, 11 and 13, respectively. A series of novel furo[3’’,2’’:6’,7’]chromeno[3’,2’:5,6]pyrido[2,3-d]pyrimidines were also synthesized. The proposed mechanisms for the different synthetic pathways were also discussed. The prepared compounds were screened in vitro for their antimicrobial activity and some of them showed notable activity against the tested microorganisms. Structures of the synthesized products were confirmed based on their analytical and spectral data.

Published online: 23rd June, 2020

■ Bifunctional-Benzothiadiazine-Catalyzed Regio- and Stereoselective Aldol Reactions using A 1,3-Acetonedicarboxylic Acid Monoester

Yusuke Tokuhiro, Noboru Hayama, Yusuke Kobayashi, and Yoshiji Takemoto*

*Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-machi, Sakyo-ku, Kyoto 606-8501, Japan

Abstract

Regio- and stereoselective decarboxylative aldol reactions of a 1,3-acetonedicarboxylic acid monoester were achieved using an aminobenzothiadiazine organocatalyst. The products were obtained with perfect regioselectivity and moderate to good enantioselectivity using various aromatic aldehydes. Subsequently, the thus obtained adducts were efficiently converted into various chiral building blocks.

Published online: 23rd June, 2020

■ Synthesis of Pyrrolo[2,3-C]Quinoline Alkaloid Marinoquinolines

Takashi Nishiyama, Mari Murakami, Kimiko Taninaka, Erina Hamada, Mai Endo, Daiki Kinou, Noriyuki Hatae, and Tominari Choshi*

*Graduate School of Pharmacy & Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan

Abstract

In this study, the synthesis of pyrrolo[2,3-c]quinoline as a common skeleton, is described. The process is based on the thermal electrocyclization of 3-phenylpyrrole containing isocyanate as 2-azahexatriene. Using this approach, the total synthesis of three natural marinoquinolines A, B, and E can be successfully achieved.

Published online: 18th June, 2020

■ Synthesis and Biological Evaluation of New Curcumin Analogs Inhibiting Osteoclastogenesis

Aoi Sugawara, Toshika Ohashi, Satoshi Ogawa, Naomi Matsumoto, Mayumi Nakanishi-Matsui, Satoru Tamura, and Tomikazu Kawano*

*School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba , Iwate, Japan

Abstract

A series of curcumin analogs (1-3) were newly designed and synthesized for the development of therapeutic agents for osteoporosis. Among the synthesized compounds, 2,5-substituted conjugated thiophene derivative (1a) and the corresponding pyrazine derivative (1c) were shown to be potential leads for the development of anti-osteoclastogenesis agent.

Published online: 11th June, 2020

■ Synthesis of Nitrogen Heterocycles through Cyanative Cyclization and Cycloaddition Reactions under Transition Metal Catalysis

Shigeru Arai* and Atsushi Nishida

*Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan

Abstract

Synthesis of cyano-functionalized nitrogen heterocycles under palladium, nickel, and cobalt catalysis is described. These transformations include the activation of C-C multiple bonds to give the functionalized pyrrolidines and their related compounds. The palladium-catalyzed reactions promote nucleophilic cyanation to non-activated terminal alkynes. Nickel catalysis enables to install H and CN functionalities into allenes with regio- and stereoselective manner. In the case of cobalt-catalyzed hydrocyanation, hydroacylation and hydroarylation, simple olefins as well as enamines are suitable substrates to construct highly functionalized hetero- and carbocycles. The applications of the above methodologies for the synthesis of alkaloids and related compounds are also described.

Published online: 9th June, 2020

■ Synthesis of Dimethoxy Activated Benzimidazoles and Bisbenzimidazoles

Mahiuddin Alamgir, Glenn C. Condie, Vesna Martinovic, Joanne Wood, Hayat Sholihin, Paul K. Bowyer, Naresh Kumar, and David StC. Black*

*School of Chemistry, The University of New South Wales, Sydney 2052, Australia

Abstract

A range of 2-substituted-4,6-dimethoxy activated benzimidazoles and 2,2'-bisbenzimidazoles have been synthesized from 2-aminoanilide derivatives under acidic conditions. The starting materials were prepared either by acylation from 3,5-dimethoxyaniline followed by nitration, or by acylation from 3,5-dimethoxy-2-nitroaniline. The 2-nitroanilides were then reduced by palladium catalyzed reaction with hydrazine and subsequent acid catalyzed cyclization giving the corresponding 4,6-dimethoxybenzimidazoles and 4,6-dimethoxy-2,2'-bisbenzimidazoles. In addition, 2-phenyl-4,5,6-trimethoxybenzimidazole has been synthesized using a similar procedure.

Published online: 5th June, 2020

■ Preparation and Acetylcholinesterase Inhibitory Activities of Pyridine-Based 1,3,4-Oxadiazole Derivatives

Xiang Yu,* Wude Yang, Ling Huang, Xingji Zhou, and Yafang Chen*

*Department of Pharmacy, Guizhou University of Traditional Chinese Medicne, , China

Abstract

Fourteen pyridine-based 1,3,4-oxadiazole derivatives were synthesized from pyridine-2-carboxaldehyde via iodine-mediated oxidative cyclisation with substituted hydrazide by using the impregnation method. Their structures were confirmed by melting point, 1H NMR, 13C NMR and HRMS. Preliminary bioassay of these derivatives' activities inhibiting acetylcholinesterase (AChE) was also evaluated in vitro at the concentration of 1 μmol/mL. The result showed that compounds 4c, 4j and 4k had moderate inhibitory activities with 52%, 59% and 59%, respectively. The preliminary structure-activity relationships revealed that the introduction of pyridine ring could enhance the activity. Molecular docking study demonstrated that compound 4k possessed an optimal docking pose with interactions at the middle of the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE.

Published online: 5th June, 2020

■ When Hydrazonoyl Chlorides Meet Terminal Alkynes: Regioselective Copper(I)-Catalysed "Click" Sequential Reactions to 5-Substituted Pyrazoles

Giorgio Molteni*

*Department of Chemistry, University of Milano, Via Golgi 19, 20133 Milano, Italy

Abstract

In the presence of catalytic amounts of copper(I) salts, terminal alkynes underwent the formation of copper(I) acetylides that enabled their nucleophilic addition onto hydrazonoyl chlorides followed by spontaneous cyclisation of the resulting alkynylhydrazone intermediate. This sequential reaction sequence was exploited as a facile and regioselective synthesis of 1,3,5-substituted pyrazoles. A catalytic cycle has been proposed accounting for the observed results.

Published online: 2nd June, 2020

■ Studies on Rotational Stability of 2-Aryl-3-(2-Fluorophenyl)Quinazolin-4-One Derivatives

Asumi Iida, Kazuya Saito, Nanami Asada, Yuuki Fujimoto, and Osamu Kitagawa*

*Department of Applied Chemistry, Faculty of Engineering, Shibaura Institute of Technology, 3-7-5 Toyosu, Kohto-ku, Tokyo 135-8548, Japan

Abstract

The rotational barriers around an N-(2-F)C6H4 bond in 2-aryl-3-(2-fluorophenyl)quinazolin-4-ones considerably lowered (ca. 4 kcal mol-1 lower) in comparison with those of 2-alkyl-3-(2-fluorophenyl)quinazolin-4-ones. The transition state structure estimated by the DFT calculation indicates that the considerable decrease in the rotational barriers in 2-aryl derivatives is caused by the alleviation of the steric repulsion between an ortho-substituent of 2-fluorophenyl group and 2-aryl group.