HETEROCYCLES

■ Contents

■ 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

Abstract

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.

■ Click Chemistry toward the Synthesis of Anticancer Agents

Ashutosh Pal* and Bimal Krishna Banik*

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

Abstract

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.

■ 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

Abstract

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.

■ 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

Abstract

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.

■ 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

Abstract

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.

■ 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

Abstract

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.

■ 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

Abstract

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.

■ 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

Abstract

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 Mcule.com was carried out, for the most potent compounds 6Ab and 6Ba, against two protiens which are EGFR and DHFR.

■ 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

Abstract

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.

■ 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

Abstract

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.

■ 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

Abstract

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.

■ 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

Abstract

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.