HETEROCYCLES

■ Contents

■ Total Syntheses of Conhydrines via Ruthenium-Catalyzed Ring-Closing Metathesis (RCM) Reactions

Tian Jin,* Lu Zhao,* Hong-Ping Wang, Chichong Lu,* Zong-He Li, Zhe-Bin Zheng, and Won-Hun Ham*

*Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Huaguan Road 168, Chengdu City, China

Abstract

Conhydrines are extremely interesting target molecules in organic synthesis because of their unique structural motifs and potent bioactivities. The ring-closing metathesis (RCM) reaction has received considerable attention for a long time. In this review, we highlight 13 total syntheses of conhydrines by using RCM reaction as the key step from different research groups during the period 2000 to 2021.

■ Synthesis and Utilization of Tetrahydronaphthalene-1,3-dicarbonitrile as a Source of Benzo[f]quinazoline, Pyridine, Imidazole Derivatives with Antitumor Activity and Molecular Docking and Dynamics Studies

Marwa El-Hussieny, Fatma A. A. El-Hag, Ahmed A. El-Rashedy, and Ewies F. Ewies*

*Organometallic and Organometalloid Chemistry Department, National Research Centre, ElBohouth St., Dokki, Giza, Egypt

Abstract

Seventeen new compounds of benzo[f]quinazoline, pyridine, and imidazole derivatives were prepared via reaction of 2-amino-4-phenyl-5,6,7,8-tetrahydronaphthalene-1,3-dicarbonitrile (1) with carbon disulfide, urea, thiourea, formic acid, formamide, acetonitrile, acetic anhydride, phenyl isocyanate, phenyl isothiocyante, and triethyl orthofromate followed by cyclization with hydrazine hydrate to give pyrimidine derivatives 2-10. Besides that, reaction of compound 1 with 2-benzylidenemalononitrile or with ethyl acetoacetate afforded pyridine derivatives 11 and 12. Also, compound 1 reacted with ethylenediamine or o-phenylenediamine to give imidazole derivatives 13a-d. Structures of the isolated new products were elucidated by compatible analytical and spectroscopic measurements. Moreover, antitumor activity of all new compounds is studied. Compound 3b is the most active compound among these derivatives against two cancer cell lines (MCF7, HepG2) in comparison with Doxorubicin as a reference drug. Computational modeling of studied DNA-ligands systems reveals that 3b compound can potentially inhibit DNA dodecamerd target thereby creating a pathway toward DNA targeting approach in the anticancer treatment.

■ Reaction Pathway and Kinetic Study of 4,5-Dihydroxyimidazolidine-2-thione Synthesis by HPLC and NMR

Liudmila Kalichkina,* Dmitry Novikov, Oleg Kotelnikov, Viktor Malkov, and Alexey Knyazev

*Chemical department, Tomsk state university, 36 Lenin Ave., Tomsk, Russia, Russia

Abstract

Process of 4,5-dihydroxyimidazolidine-2-thione (DHIT) synthesis from thiourea and glyoxal is studied. Formation of imidazole-2-thiones and 4,5-dihydroxyimidazolidin-2-one as byproducts is confirmed by NMR. The kinetics of the scalable DHIT synthesis process is studied by HPLC, and the kinetic parameters of the model based on the proposed reaction scheme are calculated. The model correctly describes the kinetics of the DHIT formation and thiourea consumption.

■ Regiodivergent Medium-Ring Oxasilacycle Synthesis from Diallylsilanes

Inna A. Fomina, Christopher R. Myers, Cierra L. M. Soumis, Margaret L. Scheuermann, James McCarty, Timothy B. Clark, and Gregory W. O'Neil*

*Chemistry, Western Washington University, MS 9150, 516 High Street, U.S.A.

Abstract

Medium-ring (7-9 membered) oxasilacycles were synthesized by sequential electrophile-promoted rearrangement of diallylsilanes, etherification with an alkene-containing alcohol, and ring-closing metathesis (RCM). Depending on the choice of catalyst for the RCM, different oxasilacycle products could be obtained. The first-generation catalyst cleanly afforded allyl ether oxasilacycles whereas the second-generation Grubbs catalyst selected for the regioisomeric cyclic enol ether, resulting from RCM followed by isomerization. Isomerization during RCM was suppressed by substitution at the allyl ether position. The use of homoallyl ether- or non-ether substrates, and/or the addition of benzoquinone also prevented isomerization during RCM, suggestive of a ruthenium hydride-based double bond migration mechanism. Both product subclasses represent useful synthetic intermediates. As an initial demonstration, this sequence was used to prepare the side-chain of the natural product psymberin, as well as a ulosonic acid analogue.

■ Synthetic Approaches for Construction of Novel Angular Heterocyclic Systems Containing Chromeno[2,3-b]quinoline

Magdy A. Ibrahim,* Sami A. Al-Harbi, Esam S. Allehyani, Esam A. Alqurashi, and Fatmah M. Alshareef

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

Abstract

Cyclic β-chloroenaldehyde 1 was used to create a novel series of angular heteroannulated chromones. Condensation of β-chloroenaldehyde 1 with hydrazine derivatives produced chromeno[2,3-b]pyrazolo[3,4-f]quinolines 2, 5 and 6. Also, condensation of compound 1 with some 1,3-N,N-binucleophiles yielded chromeno[2`,3`:6,5]pyrido[2,3-h]quinazolines 7-9. Treating compound 1 with some 1,3-N,C-binucleophiles produced chromeno[2,3-J]phenanthrolines 10, 11, benzoimidazo[1,2-a]chromeno[2,3-J]phenanthroline 12 and chromeno[2,3-J]- pyrazolo[3,4-b]phenanthrolines 13, 14. Reacting compound 1 with a diversity of 1,4-binucleophiles produced chromeno[2,3-b][1,4]diazepino[2,3-f]quinoline 15, chromeno[2,3-b][1,4]benzodiazepino[2,3-f]quinoline 16, chromeno[2,3-b][1,4]- benzoxazepino[2,3-f]quinoline 17 and chromeno[2,3-b][1,4]benzothiazepino- [2,3-f]quinoline 18. The in vitro antimicrobial activity seemed variable inhibitory effect for the prepared compounds.

■ A Transition Metal-Free System for C3-H Nitrosation of Imidazo[1,2-a]pyridine Using Sodium Nitrite at Room Temperature

Liting Yang, Ya Chen, Kun Zhao, Hongyi Zhou, Qiaochu Zhang, Chunxia Qin, Baiwei Ma, Dehong Yang, Haiyan Yang, Guoqun Liu,* Huijie Qiao,* and Liwei Mi*

*School of Materials and Chemical Engineering, Henan Key Laboratory of Functional Salt Materials, Zhongyuan University of Technology, 41 Zhongyuan Middle Road, Zhengzhou City, Henan Province, China

Abstract

Most current strategies for the direct nitrosations (nitrosylations) of imidazo[1,2-a]pyridines employ NaNO2/AcOH system, which generally need low temperatures to ensure safety and suffer acidic conditions, or flammable, explosive tert-butyl nitrite, which releases toxic gases when heated, as the NO source. Therefore, a novel strategy to prepare these 3-nitrosoimidazo[1,2-a]pyridines is necessary. Here, a transition metal-free C3–H nitrosation of imidazo[1,2-a]pyridine was developed using low-cost, stable NaNO2 as the nitrosylation source in the presence of K2S2O8 at room temperature under an air atmosphere. Imidazo[1,2-a]pyridine derivatives with different substituents were efficiently converted to their respective nitrosylation products in moderate-to-good yields under mild conditions via ion processes. Moreover, the successful gram-scale reaction and post-synthetic transformations reveal the potential of this strategy for application in industrial production, drug synthesis, and other fields.

■ Inhibition of Amyloid-β Aggregation by p-Terphenyls from the Mushroom Polyozellus multiplex and Their Neuroprotective Effects

Shoko Nakabayashi, Ayaka Ishikura, Koji Fujihara, Shuntaro Hirabayashi, Shin Koike, Hiroaki Sasaki, Yuki Ogasawara, Kiyotaka Koyama, and Kaoru Kinoshita*

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

Abstract

The main pathogenesis of Alzheimer’s disease (AD) is related to the accumulation of amyloid- (A) peptides in the brain that leads to neuronal cell death. In this study, we identified compounds in a methanol extract of the fruiting body of Polyozellus multiplex that inhibited A aggregation and are neuroprotective. Seven compounds against A40 aggregation were obtained through bioactivity-guided fractionation of the extract, including polyozellin (1), kynapcin-12 (2), NSC617425 (3), cycloleucomelone (4), Bl-V (5), succinic acid (6), and protocatechuic acid (7). Compounds 1–5 inhibited A40 aggregation in a dose-dependent manner. Moreover, compounds 2–5 protected SH-SY5Y cells from Atoxicity. Therefore, these compounds are potential agents in AD treatment.

■ Antimicrobial Activities of Heliciopsis terminalis Trunk Extract

Charinrat Saechan, Uyen Hoang Nguyen, Zhichao Wang, Sachiko Sugimoto, Yoshi Yamano, Supinya Thanapongpichat, Katsuyoshi Matsunami, Hideaki Otsuka, Giang Minh Phan, Viet Hung Pham, Natakorn Nokchan, Jisnuson Svasti, Hansuk Buncherd,* and Jasadee Kaewsrichan*

*Faculty of Medical Technology, Prince of Songkla University, Songkhla 90110, Thailand

Abstract

Phenolic glucosides, methyl 5-(1,3-dihyroxyphenyl)pentanoate 1-O-β-D-glucopyranoside (1), ethyl 5-(1,3-dihyroxyphenyl)pentanoate 1-O-β-D-glucopyranoside (2), along with 2-(3-methoxy-4-hydroxyphenyl)propane-l,3-diol (3), C-veratroylglycol (4), 6'-[(E)-2''-hydroxymethyl-2''-butenoyl] arbutin (5), and (8'Z)-1,3-dihydroxy-5-[16'-(3'',5''-dihydroxyphenyl)-8'-hexadecen-1'-yl]benzene (6), were isolated from Heliciopsis terminalis. Their molecular structures were determined by extensive spectroscopic analyses. The antimicrobial activities of all compounds were evaluated. The results showed that only compound 6 expressed strong antimicrobial activity against Gram-positive bacteria.

■ Novel Benzofuranoid Norlignans from the Aerial Parts of Asparagus cochinchinensis and Their Biological Activity

Baixiang Cai,* Jingyi Yue, Tao Xu, Jutao Wang , and Yang Yu*

*School of Pharmacy, Anhui University of Chinese Medicine, Yaohai District of Hefei City, Anhui Province, Mo Dian Xiang Anhui University of Chinese medicine shaoquan Lake Campus, 230012, China

Abstract

Three new benzofuranoid norlignans asparlignan A (1), B (2), and C (3) were isolated from the aerial parts of Asparagus cochinchinensis, in addition to previously known metabolites (4-6). The structures of these compounds were elucidated using a combination of spectroscopic analyses, including UV, IR, HRESIMS, 1D, and 2D NMR. Further, all compounds were evaluated for their anti-inflammatory activity and capability to inhibit nitric oxide (NO) production by RAW 264.7 macrophages and anticancer activity against three tumor cells.

■ Synthesis of New Multivalent Furo[3,2-c]pyridine and Bifuro[3,2-c]pyridine Derivatives

Maurice Taszarek and Hans-Ulrich Reissig*

*Institut für Chemie und Biochemie, Freien Universität Berlin, Takustr. 3 Berlin, Germany

Abstract

A series of furo[3,2-c]pyridine derivatives was prepared by an efficient cascade process involving Sonogashira reactions of 4-hydroxy-3-iodopyridine with suitable terminal alkynes followed by an immediate 5-endo-dig cyclization to generate the furan ring. Several multivalent furo[3,2-c]pyridines were prepared by employing dialkynes or trialkynes. Two bifuro[3,2-c]pyridine derivatives were prepared by alternative coupling methods. The photophysical properties of several of these compounds are compared.