Regular & Special Issues

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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 Dihydrobenzofran-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 Overowded 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.

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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.

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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: 8th November, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14561
Chiral 1,2-Diaminocyclohexane-α-Amino Acid-Derived Amidphos/Ag(I)-Catalyzed Divergent Enantioselective 1,3-Dipolar Cycloaddition of Azomethine Ylides

Haifei Wang, Chuliang Gong, Zhipeng Zhou, Qingxia Zhou, Youshi Liu,* and Jie Luo*

*College of Packaging and Materials Engineering, Hunan University of Technology, Zhuzhou 412007, China


A series of chiral 1,2-diaminocyclohexanes-α-amino acids-derived amidophosphanes in combination with silver(I) salts, have been developed to cooperatively catalyze the azomethine ylides-involved 1,3-dipolar cycloaddition with different electron-deficient alkenes. Among these, the (1S,2S)-1,2-cyclohexanediamine-L-tert-leucine-derived amidphos/Ag(I) has been demonstrated as being a highly efficient catalytic system in the cis-1,2-disubstituted electron-deficient olefins-involved 1,3-dipolar cycloaddition of azomethine ylides, including a series of aromatic, heteroaromatic, aliphatic, and 2-substituted azomethine ylides, affording various fully substituted pyrrolidines in high to excellent yields (up to 97% yield) and enantioselectivities (up to 97% ee). Interestingly, the (1R,2R)-1,2-cyclohexanediamine-L-tert-leucine-derived amidphos/Ag(I) can efficiently catalyze terminal electron-deficient olefin-involved 1,3-dipolar cycloaddition, giving a series of 2,4,5-tri-substituted pyrrolidines with up to 92% yield and 92% ee.

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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.


Published online: 4th November, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14565
A New Natural Butenolide, (5R)-3-Tetradecyl-5-methyl-2(5H)-furanone, from Octocoral Cladiella conifera

Jhao-Syuan Zeng, Shun-Hua Chen, Yi-Hao Lo, Nan-Fu Chen, Zhi-Hong Wen, Jih-Jung Chen, Chia-Ching Liaw,* and Ping-Jyun Sung*

*Department of Planning and Research, National Museum of Marine Biology and Aquarium, 2 Houwan Road, Checheng, Pingtung, Taiwan 944, Taiwan


A chemical examination of Cladiella conifera, octocoral collected in the waters of Taiwan, resulted in isolation of a new natural butenolide, (5R)-3-tetradecyl-5-methyl-2(5H)-furanone (1). The structure, including the absolute configuration, of 1 was established by spectroscopic analysis and 1 was found to inhibit the generation of COX-2 from RAW 264.7 stimulated by LPS.

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Published online: 2nd November, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14567
Isolation of Peptidolipin NA Derivatives from the Culture of Nocardia arthritidis IFM10035T in the Presence of Mouse Macrophage Cells

Yasumasa Hara,* Daiki Tanimura, Teruhisa Manome, Midori A. Arai, Takashi Yaguchi, and Masami Ishibashi*

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


We isolated two peptidolipin NA derivatives, L-Val (6) peptidolipin NA and peptidolipin NA, named as compounds 1 and 2, respectively. These compounds were produced in the co-culture extracts of Nocardia arthritidis IFM10035T and the mouse macrophage cell line J774.1, but not in the single culture of N. arthritidis. Among the two compounds along with nocarjamide (3) isolated from the co-culture of N. tenerifensis and J774.1, compounds 1 and 3 showed higher cytotoxicity against J774.1, with IC50 values of 116 μM and 25 μM, respectively. In addition, compound 1 showed a TRAIL-resistance-overcoming activity in the human gastric adenocarcinoma AGS cells.


Published online: 28th October, 2021

Review | Regular issue | Prepress
DOI: 10.3987/REV-21-973
A Comprehensive Study of Pyrimidine and Its Medicinal Applications

Vikas Vilas Borge* and Juilee Vaze

*Department of Chemistry, University of Mumbai, Vidyanagari, Kalina, Santacruz (E), Mumbai, India


Pyrimidine is a heterocyclic aromatic organic compound which is versatile lead compound for designing potent therapeutic agents. Different pyrimidine derivatives have been synthesized by various conventional methods and also from green methods. The pyrimidine moiety widely occurs in biologically occurring compounds, such as nucleic acids components, folic acid and vitamin B1 etc. This compound has various biological activities like anticancer, antitubercular, antimicrobial, antifungal, antibacterial, antioxidant, anticonvulsant, analgesic, CNS depressant, anti-inflammatory, anti-HIV, antihelmentic and herbicidal activity. Available data represents pyrimidine being heterocyclic six membered ring systems has various pharmacological actions and synthesis of pyrimidine and their derivatives are discussed.


Published online: 28th October, 2021

Review | Regular issue | Prepress
DOI: 10.3987/REV-21-975
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


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.


Published online: 27th October, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14563
Design and Synthesis of 1,3-Bis(3-(trifluoromethyl)diazirin-3-yl)phenylalanine for Efficient Photo Cross-Linking

Yuta Murai,* Takuma Yoshida, Zetryana Puteri Tachrim, and Makoto Hashimoto*

*Faculty of Advanced Life Science, Hokkaido University, Kita 21 Nishi 11, Sapporo 001-0021,


Photoreactive α-amino acids are powerful chemical tools for elucidating interactions in protein networks. Typically, photophores are required for stability and generation of high-reactive species. Additionally, orientation of photophores is one of the significant issues for performing photoaffinity labeling. Therefore, we rationally designed a bis-diazirinyl-phenylalanine for which photo cross-linking efficiency could be increased. In this study, we synthesized a new 1,3-bis(3-(trifluoromethyl)diazirin-3-yl)phenylalanine and demonstrated further study in terms of photoactivation.


Published online: 25th October, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14510
Nucleophilic Substitution of 2,2-Bis(arylthio)-4,4,6,6-tetrachlorocyclotriphosphazene with Ammonia, Phenoxide, and Thiophenoxide

Manabu Kuroboshi,* Ayako Ueno, Ayane Kawano, and Hideo Tanaka

*Division of Chemsitry and Biochemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Okayama 700-8530, Japan


Nucleophilic substitution of hexachlorocyclotriphosphazene (HCCP) with arylthiol gave 2,2-bis(arylthio)-4,4,6,6-tetrachlorocyclotriphosphazene. Aminolysis of 2,2,4,4-teterachloro-6,6-bis(4-methoxyphenylthio)-
cyclotriphosphazene with gaseous ammonia gave
gem-disubstituted 2,2-diamino-4,4-dichloro-6,6-bis(4-methoxyphenylthio)cyclotriphosphazene in Et2O and tetrasubstituted 2,2,4,4-tetraamino-6,6-bis(4-methoxyphenylthio)-
cyclotriphosphazene in acetonitrile, respectively. The reaction of
with 4-chlorophenol gave a mixture of
gem-disubstituted 2,2-dichloro-4,4-bis(4-chlorophenoxy)-6,6-bis(4-methoxyphenylthio)cyclotriphosphazene and tetrasubstituted 2,2,4,4-tetrakis(4-chlorophenoxy)-6,6-bis(4-
methoxyphenylthio)cyclotriphosphazene, whose ratio depended on the reaction solvent. On the other hand, in reaction of 2,2-bis(arylthio)-4,4,6,6-tetrachlorocyclotriphosphazene with another arylthiol, ArS-groups were scrambled


Published online: 21st October, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14559
Optimization of NAMPT (Nicotinamide Phosphoribosyltransferase) Activators: Discovery of N,N-Diethyl-1,2-benzoxazole-3-carboxamide Derivatives as Potent NAMPT Activators with Mitigated Mutagenic Risks

Mayuko Akiu,* Takashi Tsuji, Yoshitaka Sogawa, Koji Terayama, Mika Yokoyama, Daigo Asano, Tomohiro Honda, Tomomichi Ishizaka, Tomoko Hasegawa, Anthony B. Pinkerton, and Tsuyoshi Nakamura

*Group I, Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan


DS68702229, a potent NAMPT activator developed from HTS followed by a hit-to-lead campaign, is a promising candidate compound that significantly reduced body weight when orally administered to mice with high fat diet-induced obesity. However, in vitro toxicology profiling of DS68702229 revealed bacterial mutagenicity using Salmonella typhimurium TA98 and TA100 strains upon S9 activation. Hypothesizing that DNA intercalation is the likely cause, we employed several approaches to disrupt the putative DNA intercalation, including modulation of the molecular shape. Our efforts culminated in the discovery of compounds 20k and 20l, which increased intracellular NAD+ levels in a cell-based assay without inducing mutagenicity, along with acceptable plasma exposure in mice after oral administration.


Published online: 21st October, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14562
A New Template of MIitsunobu Acylate Cleavable in Non-Alkaline Conditions

Yoshimichi Sakakibara, Yusuke Sai, Yasumitsu Uraki, Makoto Ubukata, and Kengo Shigetomi*

*Research Faculty of Agriculture, Hokkaido University, Kita 9 Nishi 9, Kita-ku, Sapporo, Hokkaido 060-0589, Japan


The Mitsunobu inversion is one of the reliable methods for stereospecific substitution of chiral alcohols, but its deacylation step has limited the substrate scope. Here, we propose a new template of the Mitsunobu acylate that can be deacylated in non-alkaline treatments. The 3,4-dihydroxy-2-methylenebutanoate was selected as a template structure, and its acetonide- or bisTBS derivatives were synthesized. The latter especially showed excellent inversion efficiency (up to >99% ee) and good elimination performance for a series of secondary alcohols in near-neutral conditions. The results demonstrated the applicability of the new template for the substrates labile in alkaline conditions, such as α-hydroxyesters.


Published online: 20th October, 2021

Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14553
Synthesis and Reactivity of Novel 5-Imino-1,2-oxazole

Khalid Widyan*

*Department of Chemistry, Tafila Technical University, P.O Box 179, Tafila-Jordan, Jordan


A convenient synthetic approach towards 5-imino-1,2-oxazoles beginning from N-substituted C-benzotriazolated nitrones and Reformatsky reagent is developed. The conversion of trisubstituted 5-imino-1,2-oxazoles into the corresponding 5-functionalized 1,2-oxazoles by interactions with phenyl isocyanates and 20% HCl is provided. In addition, one-pot synthesis of 1,2-oxazole-5-ones is achieved with yield of 85-90%


Published online: 19th October, 2021

Short Paper | Regular issue | Prepress
DOI: 10.3987/COM-21-14542
MS 4A-Promoted Aqueous Phospho-Aldol-Brook Rearrangement Reaction of Isatins

Fan Liu, Wei Han,* and Takeshi Oriyama*

*Department of Chemistry, Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito, Ibaraki 310-8512, Japan


An efficient, simple, environment-friendly, and low-cost protocol for the hydrophosphonation of isatins using inexpensive and non-toxic MS 4A as a recyclable additive in water has been developed. This protocol is also suitable for the aldol reaction of isatin with acetone or acetophenone.

FREE:Supporting Info. (1.6MB)PDF (651KB)

Published online: 18th October, 2021

Review | Regular issue | Prepress
DOI: 10.3987/REV-21-970
Click Chemistry toward the Synthesis of Anticancer Agents

Ashutosh Pal* and Bimal Krishna Banik*

*Department of Chemistry, Raja Peary Mohan College, West Bengal, India


The copper(I)-induced synthesis of 1,2,3-triazoles using azides and alkynes (click chemistry) has become extremely significant. Click chemistry has been used in all aspects of drug discovery research. The product triazole serves as a linker as it readily combines with targets through hydrogen-bonding and dipole interaction. This review summarizes the application of click chemistry and triazoles as anticancer drugs. These types of reactions proceed with high selectivity, specificity, and yields. A variety of complex molecules are synthesized by this method.


Published online: 17th September, 2021

Review | Regular issue | Prepress
DOI: 10.3987/REV-21-965
Recent Progress on Synthesis of Spirochromanone and Spirochromane Derivatives

S. Chakroborty,* P. Panda, S. C. Ramírez-Lopìez, M. A. Garcia Eleno, E. C. Yañez, L. Strekowski, and M. V. B. Unnamatla*

*School of Sciences, Auro University, earthspace, Hazira Road, opp. ONGC, Surat, Gujarat 394510, India


Nature offers plenty of opportunities to the researchers of different communities to explore heterocyclic compounds. Among the various magic heterocyclic scaffolds, chromane and chromanone are the most privileged heterocycles due to their omnipresence in most value-added chemical entities. On the other hand, spirocyclic heterocyclic moieties offer unique three-dimensional frameworks which can fit into the cavity of the proteins, including enzymes, thereby enhancing the biological properties. Considering the remarkable significance of spirocyclic systems of chromanes and chromanones, various novel strategies such as Kabbe condensation, organocatalyzed reactions, oxa/sulfa-Michael-Aldol cascade reaction, oxa-Michael/addition and 1,3-dipolar cycloaddition, among others, have emerged to access this precious heterocyclic architecture in good to excellent yields. This review summarizes the synthesis of a variety of spirochromane and spirochromanone derivatives covering the literature from 1991-2020.


Published online: 15th September, 2021

Review | Regular issue | Prepress
DOI: 10.3987/REV-21-969
Total Synthesis of Natural Products and Medicinal Molecules via Chelation-Controlled Diastereoselective Hydride Reduction of Amino Ketones

Tian Jin,* Lu Zhao, Chichong Lu,* Zhe-Bin Zheng, and Won-Hun Ham*

*Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610106, People’s Republic of China


The chiral β-amino alcohols are widely presented in the natural products, privileged ligands, and medicinal molecules. In the past decades, the construction of anti-β-amino alcohols have attracted in the interest of synthetic chemists. A number of studies indicated that the chelation-controlled hydride reduction approach is straightforward for the preparation of anti-β-amino alcohol motifs in high yield with excellent diastereoselectivity and they can be used as chiral building block in the total synthesis of natural products and medicinal molecules. The aim of this review is to highlight application of chelation-controlled hydride reduction in total synthesis of natural products and medicinal molecules on the basis of a collection of recent literature studies.


Published online: 8th September, 2021

Paper | Special issue | Prepress
DOI: 10.3987/COM-21-S(R)6
Application of Reversible Detection Method for N-terminus Amino Groups: Solid Phase Synthesis of Stylissatin B

Ao Tan, Keigo Takamatsu, Fusheng Xu, Seren Osanai, and Hiroyuki Konno*

*Department of Biological Engineering, Graduate School of Science and Engineering, Yamagata University, Yonezawa, Yamagata 992-8510, Japan.


The first synthesis of the proline-rich cyclic heptapeptide stylissatin B is described. Reversible detection method of N-terminus amino groups using tetrachloro-N-hydroxyphthalimide was applied as the Fmoc-solid phase peptide synthesis. The end points of all reactions of solid support could be pursued by the detection methods.

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Published online: 17th August, 2021

Short Paper | Special issue | Prepress
DOI: 10.3987/COM-21-S(R)4
Isolation of Ikahonone, 4-methyl-2,4-dihydroxy-3-pentanone from Bacillus cereus IFM12235

Yasumasa Hara, Mareno Chiba, Keiichiro Watanabe, and Masami Ishibashi*

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


A new ketone, ikahonone (1), and five known compounds (2-6) were isolated from Bacillus cereus IFM12235 collected in Japan. The structure of compound 1 was elucidated using spectral studies, including NMR. The absolute configurations of 1 and 2 were determined by comparing electronic circular dichroism (ECD) spectra with known compounds and calculating the ECD spectra of 1 and 2. Three compounds (2-4) were previously prepared by synthesis, and first isolated as natural products in the present study.

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Published online: 11th August, 2021

Paper | Special issue | Prepress
DOI: 10.3987/COM-21-S(R)5
Azuleno[6,5-b]indoles: Palladium-Catalyzed Oxidative Ring-Closing Reaction of 6-(Arylamino)azulenes

Taku Shoji,* Yukino Ariga, Shunji Ito, and Masafumi Yasunami

*Department of Science, Graduate School of Science and Technology, Shinshu University, Matsumoto 390-8621, Nagano, Japan


6-Bromoazulene derivative with two n-butoxycarbonyl groups was prepared by the modification procedure of Nozoe’s azulene synthesis. The aromatic nucleophilic substitution reaction of the 6-bromoazulene derivatives having two-ester functions with aniline derivatives proceeded to give the corresponding 6-(arylamino)azulene derivatives. Palladium-catalyzed oxidative ring-closing reaction of the 6-(arylamino)azulene derivatives provided the azuleno[6,5-b]indoles in moderate to good yields.


Published online: 22nd June, 2021

Communication | Special issue | Prepress
DOI: 10.3987/COM-21-S(R)3
Synthesis and Optical Properties of Azuleno[1,2-b]benzothiophene and Selenophene

Mio Matsumura,* Taiki Kamiya, Masato Kawakubo, Yukako Hayashi, Tadashi Hyodo, Yuki Murata, Kentaro Yamaguchi, and Shuji Yasuike*

*School of Pharmaceutical Sciences, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan


Benzothiophene- and benzoselenophene-fused azulene derivatives were synthesized by Cu-catalyzed tandem cyclization via the Ullmann-type S/Se– arylation and Csp2–H chalcogenation of 2-(2′-bromophenyl)azulene. The maximum absorption of tetracyclic products was red-shifted from that of 2-phenylazulene, which does not contain a bridged chalcogen atom. Single-crystal X-ray analysis of azuleno[1,2-b]benzoselenophene revealed that the benzo[b]selenophene and azulene rings are almost coplanar.

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Published online: 22nd June, 2021

Review | Regular issue | Prepress
DOI: 10.3987/REV-21-964
Synthesis of Multisubstituted Benzofurans/Indoles Using Multichlorinated Phenols/Anilines via Palladium-Catalyzed Site-Selective Sonogashira Coupling

Miyuki Yamaguchi and Kei Manabe*

*School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga, Shizuoka 422-8526, Japan


Multisubstituted benzofurans/indoles are a critical class of compounds in the fields of pharmaceuticals and natural products. A useful method of preparing 2-substituted benzofurans/indoles is the Pd-catalyzed Sonogashira coupling of 2-halophenols/2-haloanilines and terminal alkynes, followed by cyclization. For the syntheses of multisubstituted benzofurans/indoles, the use of multichlorinated phenols/anilines as coupling partners is powerful because the synthetic steps required are reduced and all dichlorophenol and dichloroaniline positional isomers are commercially available and inexpensive. However, their use in benzofuran/indole synthesis is limited because of their low reactivity compared with those of the corresponding iodo or bromo compounds. Furthermore, site-selective Sonogashira coupling at the 2-position of the multihalogenated phenols/anilines is sterically and electronically challenging. To overcome these problems, dihydroxyterphenylphosphine (DHTP) has been developed as a ligand that enables the highly ortho-selective Sonogashira coupling of 2-chlorophenols/2-chloroanilines with terminal alkynes. Using the Pd–DHTP catalyst, chlorinated benzofurans/indoles are successfully obtained, which are easily converted to other derivatives by substitution of the chloro group. In this review, we summarize this and related studies to demonstrate the utility of this method.


Published online: 1st June, 2021

Paper | Special issue | Prepress
DOI: 10.3987/COM-21-S(R)2
New Sugar Based γ-Amino Silyl Ether Organocatalysts for Asymmetric Michael Addition of β-Keto Esters with Nitroolefins

Divakar Ganesan, Perumalsamy Parasuraman, Zubeda Begum, Rajkumar Thiyagarajan, Chigusa Seki, Yuko Okuyama, Eunsang Kwon, Koji Uwai, Michio Tokiwa, Suguru Tokiwa, Mitsuhiro Takeshita, and Hiroto Nakano*

*Graduate School of Engineering, Muroran Institute of Technology, 27-1 Mizumoto-cho, Muroran 050-8585


New sugar based γ-amino silyl ether organocatalysts were synthesized and their catalytic ability was examined in asymmetric Michael addition of β-keto esters with nitroolefins affording chiral Michael adducts with quaternary carbon stereocenter in good to excellent chemical yields, diastereoselectivities and moderate enantioselectivities (up to 97%, up to dr. 85:15, up to 56% ee).

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