Regular & Special Issues

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Published online: 24th January, 2022

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14618
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


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.

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Published online: 21st January, 2022

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14586
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


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.

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Published online: 21st January, 2022

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14603
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


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.

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Published online: 21st January, 2022

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14613
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


A novel cembrane diterpenoid, odosinularol (1), featuring an uncommon 13,15-ether bridge, along with nine known casbane diterpenoids (210) 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).

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Published online: 20th January, 2022

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14589
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


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.


Published online: 19th January, 2022

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14612
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


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.

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Published online: 11th January, 2022

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14607
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


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.


Published online: 4th January, 2022

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14599
Development of a Scalable Synthesis of SIRT1 Modulator Macrocycles

János Tatai, Márk Molnár, Maud Villeneuve, Laure Haberkorn, and Miklós Nyerges*

*Servier Research Institute of Medicinal Chemistry, 7 Záhony utca, 1031, Budapest, Hungary


An improved multigram route to key intermediate 26 for macrocyclic SIRT1 modulators has been developed. The increasing demand for this key intermediate caused the rerouting of the initial discovery route resulted in increase of overall yield to 8.3% over 8 steps, with the elimination of some tedious chromatographic purifications, and the substitution of critical reaction steps, which hindered a feasible scale-up. The key modification was the introduction of the microwave assisted intramolecular Suzuki reaction for the macrocyclization step, which provided in a reliable and reproducible manner of the targeted product 40. This newly developed synthetic access to this first described macrocyclic ring system was capable of ensuring the supply of our medicinal chemistry program.

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Published online: 4th January, 2022

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14600
One-Pot Synthesis of Fully Substituted Oxazol-2-amines via Staudinger/Aza-Wittig/Isomerization Reaction

Hai Xie,* Qing-Qing Hu, Xiu-Ting Qin, Jia-Min Liang, Lu- Li, Ya-Li Zhang, and Zhen Lu

*College of Chemistry and Chemical Engineering, Shanxi Datong University, Datong, 037009, People’s Republic of China


Readily available vinyl azide alcohols reacted with triphenylphosphine and aromatic isocyanates via sequential Staudinger reaction and intramolecular aza-Wittig reaction to afford the corresponding isoxazole intermediates, which can isomerize into aromatic oxazol-2-amines in situ without addition of catalyst under 115 ℃. This methodology provided a new and efficient one-pot approach for fully substituted oxazol-2-amines.

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Published online: 24th December, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14588
Chemical Reactivity of 1H-Benzimidazol-2-ylacetonitrile and Dimedone toward Simple Condensates Derived from 3-Formylchromone

Magdy A. Ibrahim*

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


The chemical reactivity of 1H-benzimidazol-2-ylacetonitrile and dimedone was investigated towards some simple condensates (1a-d and 2a-c) obtained from condensation reaction of 3-formylchromone with some active methylene compounds. Mainly, the used nucleophiles undergo nucleophilic addition at the olefinic carbon with concomitant cycloaddition or cyclocondensation. Chromonylacrylonitrile 1a reacted with 1H-benzimidazol-2-ylacetonitrile through γ-pyrone ring opening followed by cyclocondensation giving pyrido[1,2-a]benzimidazole derivative 5. The simple condensates 2b and 2c showed similar behavior towards 1H-benzimidazol-2-ylacetonitrile and dimedone leading to the same products which are identical with those obtained from 3-formylchromone with the same reagents. Structures of the new synthesized products were established based on elemental analysis and spectral data.


Published online: 24th December, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14598
Synthesis of Trifluoromethyl Derivatives of Quinoline and Isoquinoline

Aki Fujisaka, Daiki Aomatsu, Yoichiro Kakutani, Ryuya Terai, Kumiko Sakaguchi, Masahiro Ikejiri, and Kazuyuki Miyashita*

*Faculty of Pharmacy, Osaka Ohtani University, Nishikiori-Kita 3-11-1, Tondabayashi, Osaka 584-8540, Japan


Trifluoromethyl derivatives of quinoline and isoquinoline were synthesized using phosphonium salts with a trifluoroacetamide group in the presence of 1,8-diazabicyclo[5.4.0]-7-undecene. The quinoline skeleton was formed from a phenethylphosphonium salt with a trifluoroacetamide NH proton, whereas the isoquinoline formation required masking of the amide proton of trifluoroacetamide in the benzylphosphonium structure.

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Published online: 22nd December, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14592
A New C,C-Linked Functionalized Bipyrazole: Synthesis, Crystal Structure, Spectroscopies and DFT Studies. Evaluation of the Antibacterial Activity and Catalytic Properties

Ibrahim Bouabdallah, Tarik Harit,* Yahya Rokni, Mahmoud Rahal, Monique Tillard, Driss Eddike, Abdeslam Asehraou, and Fouad Malek*

*Laboratory of Applied Chemistry and Environment, Faculty of Sciences, Mohammed First University Bd Mohamed VI, 60 000 Oujda, Morocco


The synthesis of new C,C-linked functionalized bipyrazole is reported. Its molecular structure has been confirmed by spectroscopic and spectrometric methods and its single crystal structure determined by X-ray analysis. The ligand 2 has been subjected to DFT and TD-DFT theoretical calculations and results are consistent with the experimental chemical analyses. The compound possesses no antibacterial activity up to 256 g/mL. However, its complexes with copper(II) salts are found to be good catalysts for the oxidation of 3,5-di-tert-butylcatechol (DTBC) into 3,5-di-tert-butylquinone (DTBQ) with a rate varying from 9.58 μmol L-1min-1 for the 2-[Cu(MeCO2)2] complex to 5.27 μmol L-1min-1 for the 2-[Cu(BF4)2] complex.

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Published online: 22nd December, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14594
Development of 5-Trifluoromethylpyrimidine Derivatives as Dual Inhibitors of EGFR and Src for Cancer Therapy

Qin Wang, Nian Rao, Li Liu,* Yi Le, and Longjia Yan*

*School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, China


In this paper, we reported a new series of 5-trifluoromethylpyrimidine derivatives (4a-4f, 6a-6j) for cancer therapy. They were tested for antitumor activity in vitro on four human cancer cell lines including A549, K562, HepG2, MCF-7 and two kinase including wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) and c-Src. The results suggested that some of the compounds (4a, 4b, 4c, 4e, 6b, 6d, 6e, 6f, 6g, 6h) performed well activities. Especially 2-((2-((4-((2-(cyclohexylamino)-3,4-dioxocyclobut-1-en-1-yl)aminophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (6g) showed high antitumor activities against four cancer cell lines with 1.08 μM, 2.06 μM, 1.24 μM and 2.57 μM, respectively. Furthermore, compound 6g inhibited EGFRwt and Src at the values of 0.75 μM and 0.15 μM.

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Published online: 17th December, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14593
Design, Synthesis and Insecticidal Activity of 3-Arylisoxazoline-N-alkylpyrazole-5-carboxamide Derivatives against Tetranychus urticae Koch

Shuhao Qu,* Lifei Zhu, Qiang Wang, and Xiaoli Wang

*School of Veterinary Medicine, Henan University of Animal Husbandry and Economy, Zhengzhou 450046, China.


Starting from ethyl 5,5-dimethoxy-2,4-dioxopentanoate 2, 3-arylisoxazoline-N-alkylpyrazole-5-carboxamide derivatives 1a-1d were designed and synthesized with the key steps of 1,3-dipolar cycloaddition and EDCl coupling. Their insecticidal activity against Tetranychus urticae Koch was further evaluated and the results indicated that, compared with Fluralaner, all 1a-1d showed moderate and less activity at 500 mg/L and 250 mg/L, respectively. This study complements the structure-activity relationship of N-alkylpyrazole-5-carboxamides to Fluralaner, giving further guidance in Fluralaner-based pesticide drug design and discovery.

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Published online: 15th December, 2021

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-21-S(R)8
Abnormal Strecker Reaction of 3-formylindole and Aniline

Tomohiro Yazawa, Masaya Nakajima,* and Tetsuhiro Nemoto*

*Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan


Reaction of 3-formylindole, aniline, and TMSCN under conditions of the Strecker reaction yielded a Friedel-Crafts reaction product rather than the usual aminonitrile. This abnormal Strecker reaction can be applied to various aniline and 3-formylindole derivatives. DFT calculations revealed that the most thermodynamically stable product is generated in the reaction.

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Published online: 8th December, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14587
A New Iridoid Glycoside from Santisukia pagetii

Poolsak Sahakitpichan, Nitirat Chimnoi, Chutima Srinroch, Chaleaw Petchthong, Somsak Ruchirawat, and Tripetch Kanchanapoom*

*Chulabhorn Research Institute, Kamphaeng Phet 6, Talat Bang Khen, Lak Si, Bangkok 10210, Thailand


A new iridoid glycoside, 6-O-[(2E,6R)-8-hydroxy-2,6-dimethyl-2-octenoyl]-catalpol (kanchanikoside, 1) was isolated from the leaves and twigs of Santisukia pagetii. In addition to the new compound, the 17 known glycosides were isolated: nemoroside, 6"(Z)-nemoroside, ambiguuside, specioside, verminoside, 6-trans-feruloylcatalpol, 6,6'-di-O-caffeoylcatalpol, amphicoside, 6-O-veratroylcatalpol, citrusin B, (7R,8S)-balanophonin 4-O-β-D-glucopyranoside, (7R,8S)-dehydrodiconiferyl-O-β-D-glucopyranoside, martynoside, benzyl O-β-D-xylopyranosyl-(1→6)-β-D-glucopyranoside, benzyl O-β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside, icariside D1 and (6S,9R)-roseoside. Their structures were determined based on the spectroscopic evidence including 1D and 2D NMR, and HR-ESI-TOF-MS experiments.

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Published online: 6th December, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14574
Functionalization of Meldrum’s Acid by Diels‒Alder Approach

Sambasivarao Kotha* and Vidyasagar Gaikwad

*Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai - 400076, India


We have synthesized several Meldrum’s acid derivatives using Diels‒Alder reaction as a key step. Here, the key sultine derivative is prepared by rongalite and the sultine derivative is useful as a latent diene.

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Published online: 2nd December, 2021

Communication | Special issue | Prepress
DOI: 10.3987/COM-21-S(R)7
The Synthesis of Simplified Analogues of Crambescin B Carboxylic Acid and Their Inhibitory Activity of Voltage-Gated Sodium Channels: New Aspects of Structure–Activity Relationships

Atsuo Nakazaki,* Shunsuke Mouri, Yoshiki Nakane, Yuki Ishikawa, Mari Yotsu-Yamashita, and Toshio Nishikawa

*Faculty of Science and Engineering, Iwate University, Ueda, Morioka 020-8551 (Japan)


We describe the synthesis of six new analogues of crambescin B carboxylic acid from L-aspartic acid and the elucidation of their structure-activity relationships by a cell-based colorimetric assay. All the synthesized analogues except for the C4-analogue were found to have inhibitory activities against voltage-gated sodium channels (VGSCs) in nM order in a cell-based colorimetric assay.

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Published online: 2nd December, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14578
Novel Pyrazolines and Benzothiazepines as Tubulin Polymerization Inhibitors: Synthesis, Biological Evaluation, and Molecular Docking

Alaadin E. Sarhan,* Ashraf A. Sediek, Nagy M. Khalifa, and Essam E. Hasan

*Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Institute, National Research Centre, Dokki, Cairo, 12622 Egypt


Synthesis, biological evaluation, and molecular docking of pyrazoline-linked benzenesulfonamides and diaryl 1,5-benzothiazepines prepared from new chalcones are described and elucidated. Novel compounds were studied for their in vitro anticancer profiles on HepG2, HEK-293, MCF-7, and MDA-MB-231 cancer cell lines, where, compounds IIb, III, and IVe demonstrated high to moderate cell proliferation inhibition activity. Compound IIb was further assessed for tubulin polymerization inhibition effects due to its high potency, which showed superior suppression compared to the reference drug. It induced cell cycle cessation at the G2/M phase and accumulation of cells in the pre-G1 phase, preventing its mitotic cycle. In addition, compound IIb activated caspase-7, mediating apoptosis of HepG2 cells. These findings, along with molecular docking and pharmacophore constructed models, provide a new scaffold of cytotoxic agents targeting tubulin.


Published online: 2nd December, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14580
An Unprecedented Synthesis of 8b-Hydroxy-3a-(1H-pyrrol-2-yl)/(1H-indol-3-yl)-3a,8b-dihydroindeno[1,2-b]pyrrol-4(1H)-one Derivatives from Pyrrole/Indole with Ninhydrin and β‑Enaminocarbonyls

Mozhgan Masoudi*

*Department of chemistry, Rafsanjan Branch, Islamic Azad University, Rafsanjan, Iran


Heterocyclic systems containing (1H-pyrrol-2-yl) or (1H-indol-3-yl)-dihydroindenopyrrole moieties were synthesized using heterocyclization of pyrrole or indole with ninhydrin and β‑enaminocarbonyls in water under reflux conditions. An efficient, facile, and environmentally friendly protocol was found for the production of new heterocyclic compounds. This reaction was used to gain access to a wide range of pyrrole/indole derivatives. Plate chromatography was utilized to isolate the products whose structures were established from their spectroscopic data.

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Published online: 30th November, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14577
Synthesis and Radical Scavenging Activity of Substituted Dihydrobenzofuran-5-ols

Keiko Inami,* Hiromasa Minami, Tsunahito Hayashi, Yuta Okayama, and Masataka Mochizuki

*Division of Pharmaceutical Organic Chemistry, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, 1-1-1 Daigakudori, Sanyo-Onoda-shi, Yamaguchi 756-0884, Japan


Antioxidants are important in preventing oxidative stress by scavenging oxygen free radicals. In this study, a series of 2,2-dimethyl-2,3-dihydrobenzofuran-5-ols with amino, methoxy, chloro and nitro groups at the ortho position relative to the phenolic OH group were newly synthesized, and their galvinoxyl and hydroxyl radical scavenging activities were measured. Substituted 2,3-dihydrobenzofuran-5-ols showed higher activity than the corresponding 6-chromanols, especially 6-amino-2,2-dimethyl-2,3-dihydrobenzofuran-5-ol, which possessed the highest activity among the tested compounds. The results demonstrated that the planarity and electron-donating capacity of these molecules enhanced their radical scavenging activities, as is known for 6-chromanols.

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Published online: 30th November, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14585
Reaction of an Overcrowded 1,2-Diaryl-1,2-dibromodisilene with 1-Vinylcyclohepta-1,3,5-triene: Isolation of a 2-Vinylsilacyclopropane Derivative and Its Thermal Conversion to a Silacyclopent-3-ene Derivative

Taku Oshiro, Yoshiyuki Mizuhata,* and Norihiro Tokitoh*

*Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan


We examined the reactions of a bulky aryl-substituted 1,2-dibromodisilene with 1-vinylcyclohepta-1,3,5-triene to investigate the reaction mechanism of a bromosilylene with a buta-1,3-diene. The reaction proceeded selectively with the exocyclic vinyl group and gave the corresponding [1+2]-adduct, i.e., 2-cyclohepta-1,3,5-trien-1-ylsilacyclopropane derivative, as an isolable compound. The following thermal reaction of the adduct resulted in the stereo-selective formation of a 1,2,4,8a-tetrahydrocyclohepta[b]silole skeleton, the formal [1+4]-adduct between the bromosilylene and 1-vinylcyclohepta-1,3,5-triene. Several experimental verifications suggested that the conversion of the [1+2]- to [1+4]-adducts proceeded via 1,3-sigmatropic rearrangement.

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Published online: 29th November, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14579
Synthesis, Cytotoxicity and Docking Simulation of Bioactive [1,2,4]Triazolo[3,4-α]dihydroisoquinoline Chalcone Derivatives

Mohamed A. M. Teleb, Nourhan Hassan, Hamdi M. Hassaneen,* Huwaida M. E. Hassaneen, Yara N. Laboud, and Fatma M. Saleh

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


1-(1-Aryl-8,9-dimethoxy-1,5,6,10b-tetrahydro-[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)ethan-1-ones 4 were prepared via reaction of C-acetylmethanohydrazonoyl chlorides 1A,B with 6,7-dimethoxy-3,4-dihydroisoquinoline 3. Treatment of the latter products 4 with 3-aryl-1-phenyl-1H-pyrazole-4-carbaldehyde derivatives 5 in ethanol in the presence of sodium hydroxide solution at room temperature afforded chalcones 6. Cytotoxic assay was performed for in vitro antitumor screening against caucasian breast adenocarcinoma (MCF7) and hepatocellular carcinoma (HepG2) cell lines. Chalcones 6Ab and 6Ba have promising cytotoxic effects against MCF7 with IC50 values 8.0 and 7.5 µg/mL, respectively. Molecular docking using was carried out, for the most potent compounds 6Ab and 6Ba, against two protiens which are EGFR and DHFR.

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Published online: 26th November, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14569
Rapid, Environmentally Greener and Ultrasound-Assisted One-Pot Synthesis of Quinoline, Benzimidazole and Pyrimidine Combined Moiety as Potential Antimicrobial Agents

Tejal D. Bhatt and Hitendra S Joshi*

*Department of chemistry, Saurashtra University, Rajkot, Gujarat, India


An efficient and environmentally benign greener synthesis of 2-amino-4-(substituted quinoline)-1,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carbonitriles under ultrasonic irradiation was achieved. Here, we have developed a one-pot three-component reaction between 2-chloroquinoline-3-carbaldehyde, malononitrile, and 2-aminobenzimidazole in the presence of ammonium acetate as a catalyst and ethanol solvent. All the synthesized compounds (TF-1 to TF-8) were characterized by FT-IR, 1H NMR, 13C NMR, and Mass spectroscopic analysis. All the synthesized compounds were screened and evaluated for their antimicrobial activities.

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Published online: 19th November, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14573
Design and Synthesis of New Quinoline Linked to Pyranotriazolopyrimidines Conjugates as Novel Targets to Discover Promising Anti-SARS-COV-2

Faisal K. Algethami,* Salma Jlizi, Mansour Znati, Naoufel Ben Hamadi, Anis Romdhane, Mohamed R. Elamin, Lotfi Khezami, and Hichem Ben Jannet*

*Laboratory of Heterocyclic Chemistry, Natural Products and Reactivity (LR11ES39), Team: Medicinal Chemistry and Natural Products, Faculty of Science of Monastir, University of Monastir, Avenue of Environment, 5019 Monastir, Tunisia


Simple one-pot synthesis of 2-aminopyranoquinoline-3-carbonitriles 2a-d at room temperature from available 8-hydroxyquinaldine, malononitrile, and substituted aromatic aldehydes was realized. Compounds 2a-d were converted into iminoethers 3a-d, condensed with a series of hydrazide under microwave irradiation to yield novel pyranotriazolopyrimidines fused to quinoline 4a-f. Compound 4c, with a cyanomethyl group, was treated with some salicylic arylaldehydes to give the corresponding new pyranotriazolopyrimidine-chromen 5a-c in good yields. Finally a new series of arylidenes linked to triazolopyrimidopyrano[3,2-h]quinoline 6a-h were designed and synthesized by the reaction of 4a,c, both bearing a cyanomethyl group, with a series of arylaldehydes. The structures of all the compounds were evidenced by 1H/13C NMR, IR, and ESI-HRMS. The present study focuses also to predict the theoretical assembly of the COVID-19 protease (SARS-CoV-2 Mpro) and to find in advance whether this protein can be targeted by the compounds 4c, 4f, 5a-c and 6a-h thus synthesized. The docking scores of these compounds were compared to that of the co-crystallized native ligand inhibitor (N3) used as a reference standard. The results showed that all the synthesized compounds (4c, 4f, 5a-c and 6a-h) gave interesting binding scores compared to the N3 inhibitor. It has been found that compounds 4c, 4f, 5a and 5b achieved considerably similar binding scores and modes of interaction than the co-crystallized inhibitor N3 indicating good affinity towards SARS-CoV-2 Mpro. Conversely, the derivatives 6h and 5c showed binding energy scores (-8.9 and -8.8 kcal/mol, respectively) higher than the Mpro N3 inhibitor (-7.0 kcal/mol), revealing, in their turn, strong interaction with the target protease. However, their interactions were not entirely comparable to those of reference N3.


Published online: 18th November, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14576
Metal-Free C3-H Hydrazination of Imidazo[1,2-a]pyridine with Azodiformates in Water at Room Temperature

Huijie Qiao,* Liting Yang, Wuxuan Sun, Ya Chen, Jialin Wang, Yunwei Wang, and Haobo Dong

*School of Materials and Chemical Engineering, Zhongyuan University of Technology, Henan 450007, P. R. China


An efficient synthesis of imidazo[1,2-a]pyridine-hydrazines was accomplished by making imidazo[1,2-a]pyridine substrates and azodiformates react in water phase. This reaction features mild and green conditions (proceeding without transition-metals and phase transfer catalyst in water under air at room temperature) as well as good tolerance of substrates. Note that electron-donating groups on the imidazo[1,2-a]pyridine substrates are benefit for this reaction, affording target products in excellent yields. Besides, this aqueous phase reaction could also tolerate the solid azodiformates.

FREE:Supporting Info. (4.6MB)PDF (617KB)

Published online: 16th November, 2021

Communication | Regular issue | Prepress
DOI: 10.3987/COM-21-14566
Heterogeneously Organocatalytic, Enantioselective Friedel-Crafts Alkylation of Indole with 3,3,3-Trifluoropyruvate

Pei Wang,* Jinhui Ni, Yong An, Xiaojiang Chen, Weiwei Zhang, Yang Zhang, and Guorong Ma

*School of Basic Medicine, Ningxia Medical University, Yinchuan, 750004, China


The bifunctional tertiary amine-squaramide catalyst was synthesized with diphenylethylenediamine as the chiral framework and successfully catalyzed the asymmetric Friedel-Crafts alkylation reaction between indole and trifluoropyruvate. A series of trifluoromethylated indole derivatives were obtained with high yield (up to 95%) and moderate to good enantioselectivity (up to 76% ee). The reaction proceeds in heterogeneous system, the catalyst can be recovered by simple filtration and recycled.

FREE:Supporting Info. (1.7MB)PDF (343KB)

Published online: 15th November, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14570
Synthesis and NMR Spectroscopic Characteristics of Novel Polysubstituted Quinolines Incorporating Furoxan Moiety

Trinh Thi Huan, Le Thi Hoa, and Nguyen Huu Dinh*

*Department of Chemistry, Hanoi National University of Education, 136 Xuan Thuy, Hanoi, Vietnam


5,6-Dimethoxy-8-(3-methylfuroxan-4-yl)-2-methylquinoline (1) and 5,6-dimethoxy-8-(3-methylfuroxan-4-yl)quinoline-2-carbaldehyde (2) were synthesized. The condensation of 1 with some nitrobenzaldehydes catalyzed by acetic acid under mild conditions gave four styrylquinolines (1a-d). The condensation of 2 with methyl phenyl ketones catalyzed by potassium hydroxide at room temperature afforded six polysubstituted α,β-unsaturated ketones (2a-f). All proton and carbon signals of obtained compounds were assigned based on analyzing the spin–spin splitting patterns and on the cross peaks in their HSQC and HMBC spectra. ROESY spectrum analysis showed that for (E)-3-(quinolin-2-yl)-1-phenylprop-2-en-1-ones Hα resonated in a weaker field as compared to Hβ.


Published online: 11th November, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14575
Synthesis of Novel 2,3-Disubstituted Thiophenes via Tandem Thia-Michael/Aldol Reaction of Allenyl Esters

Michiyasu Nakao, Munehisa Toguchi, Ken Horikoshi, Syuji Kitaike, and Shigeki Sano*

*Graduate School of Pharmaceutical Sciences, Tokushima University, Sho-machi, Tokushima 770-8505, Japan


A tandem thia-Michael/aldol reaction of allenyl esters and mercaptoacetaldehyde in the presence of triethylamine provided 2,3,4-trisubstituted tetrahydrothiophenes. Novel 2,3-disubstituted thiophenes were obtained in high yield by the subsequent dehydration of the 2,3,4-trisubstituted tetrahydrothiophenes using p-toluenesulfonic acid monohydrate as an effective catalyst.


Published online: 5th November, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14572
Substituent Effects on Physical Properties of Azole Based Ionic Liquids

Satoshi Kitaoka,* Shinnosuke Nishinaka, and Kaoru Nobuoka

*Department of Biotechnology and Chemistry, Faculty of Engineering, Kindai University, Umenobe 1, Takaya, Higashihiroshima 739-2116


We investigated the effect of the substituents on the physical properties of azole based ionic liquids, such as melting point and viscosity. The introduction of electron-withdrawing groups to azolate anions and electron-donating groups to azolium cations delocalized the charge of anion or cation, and reduced the viscosity and melting point of the ionic liquids. The charge of the azolium cations and the azolate anions are distributed not only on the azole ring but also on the substituents. The decrease in the charge density of anions and cations in ionic liquids weakens the interaction between the anions and the cations, resulting in a decrease in the viscosity of the ionic liquids. Such a method of delocalizing the anion and cation charges of triazole-based ionic liquids by introduction of the substituents can be applied to reduce the viscosity of various ionic liquids as reaction medium and electrolytes.

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