HETEROCYCLES

Published online: 14th November, 2019

■ Piperidine and Azetidine Formation by Direct Cyclization of Diols with N-Nonsubstituted Sulfonamide under The Mitsunobu Conditions Utilizing (Cyanomethylene)Tributylphosphorane (Cmbp) and Its Application to The Synthesis of Lupinine

Hiroto Kaku,* Yuhei Sonoda, Hideyuki Hishida, Yuri Taniguchi, Akiko Kubo, Takumi Hamaguchi, Mitsuyo Horikawa, Makoto Inai, Kei Kitamura, and Tetsuto Tsunoda*

*Pharmaceutical Sciences, Tokushima Bunri University, 180 Nishihamabouji, Yamashiro-machi, Tokushima, 770-8514, Japan

Abstract

(Cyanomethylene)tributylphosphorane (CMBP) can promote the Mitsunobu reaction of 1,3- and 1,5-diols with N-nonsubstituted sulfonamides, such as tosylamide (TsNH2) and 3,3-dimethoxypropylsulfonamide (DimpsNH2), to prepare azetidine and piperidine ring systems directly. Utilizing this methodology, lupinine, a biologically active piperidine alkaloid, was synthesized.

Published online: 13th November, 2019

■ Isochromophilol A, A New Azaphilone Isolated from Penicillium Sp. RO369, A Leaf Litter Inhabiting Fungus from Tsuga Diversifolia

Kan'ichiro Ishiuchi,* Dai Hirose, Yoriko Takahashi, Ryu Miyagawa, Kohei Watanabe, and Susumu Kitanaka*

*Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1, Tanabe-Dori, Mizuho-ku, Nagoya, Aichi, 467-8603, Japan

Abstract

A new sclerotiorin-type azaphilone, isochromophilol A (1), was isolated from Penicillium sp. RO369 associated with Tsuga diversifolia, along with eight known compounds (2−9). The structure of 1 was elucidated on the basis of spectroscopic data. Isochromophilol A (1) (16 μg) showed weak anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity with an inhibition diameter of 8.8 ± 1.0 mm

Published online: 8th November, 2019

■ A Propeller-Shaped Mesomeric Betaine, Tetraphenylbenzene-1-Quinolinium-2-Benzoate

Sviatoslav Batsyts, Felix Lederle, Eike G. Hübner, Jörg Adams, Jan C. Namyslo, and Andreas Schmidt*

*Institute of Organic Chemistry, Clausthal University of Technology, Leibnizstrasse 6, D-38678 Clausthal-Zellerfeld, Germany

Abstract

4-[(Quinolin-4-yl)ethynyl]benzoic acid underwent a cycloreaction with tetraphenylcyclopentadienone to give the hexa(hetero)arylbenzene- 1-(quinolin-4-yl)-2-(4-benzoic acid)-3,4,5,6-tetraphenylbenzene which was N-methylated and finally deprotonated to give the title compound. The molecule adopts a propeller-shaped configuration in which the benzoate ring as well as the phenyl ring adjacent to the quinolinium substituent display non-isochronous resonance frequencies, respectively, due to a hindered rotation. Although the molecule formally belongs to the class of pseudo-cross-conjugated heterocyclic mesomeric betaines, the propeller-shape causes a charge distribution of cross-conjugated systems. DFT-calculations (frontier orbital profiles, geometries) have been carried out.

Published online: 7th November, 2019

■ One-pot synthesis of pyrrolo[2,1-α]isoquinolines via tandem reactions of vinylselenonium salt, 2-bromoethanones, and isoquinoline

Qi Sun, Minghong Liao, Yan Zhao, Yunxia Li, Shanshan Liu, Deshou Mao,* and E Tang*

*School of Chemical Science and Technology, Yunnan University, No. 2 Green Lake North Road, Kunming 650091, China

Abstract

An convenient and one-pot synthesis of pyrrolo[2,1-a]isoquinolines via the tandem reaction of methyl(phenyl)vinylselenonium salt with isoquinoline and 2-bromoethanones has been developed, which features very mild conditions, available substrates, simple experimental procedures, moderate to good yields, and wide functional group tolerance.

Published online: 6th November, 2019

■ A Highly Selective Fluorescence-Enhanced Probe for The Rapid Detection of So2 Derivatives and Its Bio-Imaging in Living Cells

Yaogen Zhou, Yiwei Zhou, Hongying Wang,* and Baoquan Chen*

*School of Chemistry and Chemical Engineering, Tianjin University of Technology, 391 Binshui Xidao, Xiqing District Tianjin 300384, China

Published online: 5th November, 2019

■ Rearrangement Reaction in 1-Hydroxyindole Chemistry: A Synthesis of Novel 7-Substituted Yohimbine, and 4a-Substituted 1,2,3,4-Tetrahydro-β-Carboline DerivaTives1

Katsumasa Yoshino, Fumio Yamada, Koichi Noguchi, Kiyoka Kusuno, and Masanori Somei*

*Noto Marine Laboratory, Institute of Nature and Environmental Technology, Faculty of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, 56-7 Matsuhidai, Matsudo-shi, Chiba 270-2214, Japan

Abstract

X-Ray analyses of 1-hydroxyyohimbine derivatives definitely show the deviation of the N(1)—O bond from the indole molecular plane. This fact supports our working hypothesis “bishomoallylic conjugation”. The deviation is responsible for the rearrangement reaction in 1-hydroxyindole chemistry. Effective synthetic method for novel 7α- and 7β-heteroarylyohimbine, and 4aα- and 4aβ-heteroaryl-1,2,3,4-tetrahydro-β-carboline derivatives are reported.

Published online: 1st November, 2019

■ Fast, Solvent-Free, and Highly Efficient Synthesis of Pyrazolo[3,4-b]Pyridines Using Microwave Irradiation and Khso4 as A Reusable Green Catalyst

Jinjing Qin, Zhenhua Li,* Xiaomeng Sun, Yi Jin, and Weike Su

*Collaborative Innovation Centre of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, 18#, Chaowang Rd., Hangzhou, Zhejiang 310014, China

Abstract

A simple, ecofriendly, and effective method was described for forming pyrazolo[3,4-b]pyridines from 5-aminopyrazoles and 3-formylchromones, in good to excellent yields, under microwave irradiation in solvent-free conditions using KHSO4 as a reusable catalyst. Some noteworthy features of this method were its cleanliness, short reaction time, easy work-up, and broad substrate tolerance. The catalyst was reused several times without losing activity.

Published online: 1st November, 2019

■ Asymmetric Construction of Heterocycles via Dearomative Coupling and Addition Reactions of Phenol and Aniline Derivatives

Kotaro Kikushima,* Hideyasu China, and Toshifumi Dohi*

*College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan

Abstract

Efficient methods for the formation of chiral heterocycles are considerably important in the synthesis of naturally-occurring compounds and pharmaceutical products. This review highlights the formation of chiral heterocycles through dearomative bond-formations as the key reactions, wherein the phenol or aniline derivatives serve as the nucleophiles. Transition-metal-catalyzed intramolecular coupling reactions in the presence of chiral ligands afford the enantioenriched multicyclic compounds bearing heterocycles. Chiral bifunctional organocatalysts induce the formation of dearomative coupling products, which could be converted to heterocycles through further transformations.

Published online: 30th October, 2019

■ Facile Synthesis of (Guaiazulene-1-Yl)-1h-Pyrroles via Paal-Knorr Reaction

Lu Zhang, Dao-Lin Wang,* Jin-Juan Xing, and Lin Liu

*College of Chemistry and Chemical Engineering, Bohai University, 19, Keji Rd., New Songshan District, Jinzhou City, Liaoning Province 121001, China

Abstract

An efficient and simple method for the synthesis of (guaiazulen-1-yl)-1H-pyrroles was described. The construction of this new heteroarylazulene system was achieved by a the Paal-Knorr reaction of 3-acetyl-4-(guaiazulen-1-yl)hexane- 2,5-dione (4), easily preparation by a three-component condensation of guaiazulene (1), methylglyoxal (2) and acetylacetone (3), with primary amines (5).

Published online: 29th October, 2019

■ Unexpected Formation of 4,7-Dihalobenzo[B]Thiophenes Using Ohira-Bestmann Reagent and Reactivity of The Halogen-Substituted Benzo[B]Thiophenes in Suzuki-Miyaura Coupling with Phenylboronic Acid

Kozo Toyota,* Hirotaka Mutoh, Hiroki Kishi, Shinichi Mikami, Hiroki Tanaka, Shuhei Yoshida, and Daisuke Naganuma

*Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan

Abstract

Reaction of 2-(1-adamantylsulfanyl)-3,6-dihalobenzaldehydes with Ohira-Bestmann reagent gave 4,7-dihalobenzo[b]thiophenes along with normal alkyne products. Nine types of 4,7-dihalobenzo[b]thiophenes bearing chlorine, bromine, or iodine atoms, were prepared by this method. Regioselectivity in Suzuki-Miyaura cross coupling reactions of the 4,7-dihalobenzo[b]thiophenes with PhB(OH)2 was also studied.

Published online: 29th October, 2019

■ Recent Advances in Transition-Metal-Catalyzed Synthesis of 3- and/or 4-Aryl-2(1H)-Quinolones

Yoshihiko Yamamoto*

*Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8601, Japan

Abstract

2(1H)-Quinolone is a privileged nitrogen heterocycle that is found in various bioactive compounds and functional molecules. In particular, derivatives possessing aryl substituents at the 3- and/or 4-positions are significant synthetic targets as they are promising drug leads. This review surveys the synthetic methods for 3- and/or 4-aryl-2(1H)-quinolones that involve transition-metal-catalyzed construction of the 2(1H)-quinolone framework. Transition-metal-catalyzed arylations of 2(1H)-quinolone scaffolds are also surveyed.

Published online: 28th October, 2019

■ Elucidation of The Conformational Properties of 3-Pyridinoyl Indoles as Intermediates of Cannabimimetics

Hideyo Takahashi,* Koji Araki, Hidetsugu Tabata, Kosho Makino, Ryohei Ujiie, Kohei Sezaki, Hiroshi Nakayama, Tetsuta Oshitari, and Hideaki Natsugari

*Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan

Abstract

The conformations of 3-pyridinoyl indoles, which are intermediates of 5-fluoropentyl-3-pyridinoyl indole, were investigated using their X-ray crystal structures. All derivatives existed as s-trans conformers. A pseudo-planar conformation was observed in the 2'-yl isomer of 3-pyridinoyl indoles. On the other hand, twisted conformations were observed in 3-pyridinoyl 2-methylindoles. The conformations of these compounds in solution were also investigated using VT-NMR.

Published online: 25th October, 2019

■ Interaction of the Dihydropyridine/Pyridinium Redox Pair Fixed into a V-Shaped Conformation

Yasukazu Hirao,* Mitsuru Teraoka, and Takashi Kubo*

*Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan

Abstract

A new V-shaped molecule incorporating a dihydropyridine and a pyridinium moiety was synthesized and evaluated for its effect on the interaction between the hydride donor-acceptor pair. Spectroscopic, electrochemical, and computational studies have revealed the presence of the charge transfer interaction as a consequence of the electron donor-acceptor association.

Published online: 23rd October, 2019

■ Design, Synthesis and Structure-Activity Relationship Study of Pyrilamine Derivatives as Histone Deacetylase Inhibitors

Seiya Hiranaka, Mayumi Arata, Akiko Nakata, Akiko Tanaka, Yoshinobu Hashizume, Norio Kudo, Akihiro Ito, Minoru Yoshida, Shinichi Uesato, Yasuo Nagaoka, and Takaaki Sumiyoshi*

*Faculty of Chemistry, Materials and Bioengineering, Kansai University, 3-3-35 Yamate-cho, Suita, Osaka 564-8680, Japan

Abstract

For the study on the structure-activity relationship of pyrilamine-based histone deacetylase inhibitor 1, we focused on the structures of its benzyl and dimethylamino groups. Of the synthesized novel pyrilamine derivatives 2–7, compound 2 enhanced potency against hERG inhibition, as well as decreased molecular weight and topological polar surface area.

Published online: 17th October, 2019

■ Anti-Tmv Isoquinoline Alkaloids from The Whole Plants of Thalictrum glandulosissimum

Chun-Man Song,* Guang-Hui Kong, Yu-Ping Wu, Eric Yin, Bradley Liu, Zhen-Yuan Xia, Hai-Tao Huang, Guang-Yu Yang, and Qiu-Fen Hu*

*Chemistry, Cyats, Keyi Rd 653100, China

Abstract

Three new (1-3), together with three known (4-6) isoquinoline alkaloids were isolated from the whole plants of Thalictrum glandulosissimum. Their structures were elucidated by spectroscopic methods, including extensive 1H, 13C, and 2D-NMR techniques. Compounds 1-6 were evaluated for their anti-tobacco mosaic virus (Anti-TMV) activity. The results revealed that compounds 2, 3 and 4 showed potential anti-TMV activities with inhibition rates of (35.6±3.5)%, (36.2%±3.8)%, (46.3%±3.2)%, at the concentration of 20 µM, respectively. These rates are higher than that of positive control.

Published online: 16th October, 2019

■ N-Glycosylation Reaction of Thio-Glycoside Using Hypervalent Iodine(Ill) Reagent

Koji Morimoto, Kana Yanase, Takumi Ikeda, Chihiro Uchikawa, Yasuyuki Kita,* and Tetsuya Kajimoto*

*Research Organization of Science and Technology, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan

Abstract

We discovered that the hypervalent iodine(III) reagent could mediate the N-glycosylation reaction using the thio-glycoside donors with triazoles.  By using this method, glycosyl triazole could be easily synthesized under mild reaction conditions.

Published online: 16th October, 2019

■ Synthesis of Cycloalkyl/Steroidal Heteroaryl Sulfides Using Rhodium-Catalyzed Heteroaryl Exchange Reaction

Mieko Arisawa,* Katsuya Nakai, Tomoki Yamada, Ren Suzuki, and Masahiko Yamaguchi*

*Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, sendai 980-8578, Japan

Abstract

Cycloalkyl heteroaryl sulfides are efficiently synthesized by the single-bond cleavage and exchange reaction of S-cycloalkyl thioesters and heteroaryl ethers without using a base. The method is applicable to steroids at the A- and D-rings, and provides diverse heteroarylthiolated steroids with five- and six-membered heteroarenes.

Published online: 10th October, 2019

■ Lewis Acid Mediated Synthesis of Indolizidine Derivatives

Sambasivarao Kotha* and Sunil Pulletikurti

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

Abstract

Here, we have reported a short and efficient BF3•Et2O catalyzed synthesis of indolizidine derivatives. Morever, we have expanded this strategy to synthesize oxa-aza-cyclic derivatives. The stereochemistry of the indolizidine derivative 16 was confirmed by X-ray studies.

Published online: 10th October, 2019

■ Protonation-Assisted Conjugate Addition of Axially Chiral Enolates: Asymmetric Synthesis of β-Lactams with Contiguous Tetrasubstituted Stereocenters from α-Amino Acids via Memory of Chirality

Pan Yang, Tomoyuki Yoshimura, Takahiro Sasamori, Norihiro Tokitoh, Kazuhiro Morisaki, and Takeo Kawabata*

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

Abstract

A method for asymmetric synthesis of highly strained β-lactams with contiguous two tetrasubstituted stereocenters from readily available α-amino acids has been developed via MOC strategy. In situ protonation of the labile β-lactam enolate intermediates formed through 4-exo-trig cyclization of the axially chiral enolates generated from α-amino acid derivatives seems to be the key to successfully produce highly strained β-lactams. A salient feature of this transformation is that a proton source does not quench axially chiral enolate C, but accelerate the overall reaction by protonation of the intermediary β-lactam enolate D.

Published online: 9th October, 2019

■ Ligand Assessment for the Suzuki-Miyaura Cross Coupling Reaction of Aryl and Heteroaryl Bromides with n-Butylboronic Acid. The Advantages of Buchwald’s S-Phos

Thomas Jagusch, Sven Nerdinger, Bernd Lehnemann, Stefan Scherer, Andreas Meudt, Victor Snieckus,* Sandro Neuner, and Herwig Schottenberger

*Department of Chemistry, Queen's University, 90 Bader Lane K7L 3N6, Canada

Abstract

An investigation of biarylphosphine ligands for the Suzuki-Miyaura cross coupling reaction of aryl and heteroaryl bromides with n-butylboronic acid is presented. The results obtained on ligand modification and aryl as well as heteroaryl bromides variation represent a significant improvement in the state of the art of alkylboronic acid cross coupling methodology.

Published online: 8th October, 2019

■ Synthesis of Lactonized Valoneoyl Group-Containing Ellagitannins, Oenothein C and Cornusiin B

Hitoshi Abe,* Haruka Imai, Daichi Ogura, and Yoshikazu Horino

*Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan

Abstract

The total synthesis of two ellagitannins, oenothein C and cornusiin B, which involve a lactonized valoneoyl group (LVG) in the molecules, was accomplished starting from glucose and gallic acid. Classical Ullmann coupling reactions were effective for preparation of the key intermediate, the lactonized valoneic acid derivative, which was subjected to a condensation reaction with glucose, and finally converted to the ellagitannins.

Published online: 8th October, 2019

■ Synthetic Studies on Keramaphidin B: Formation of a Macrocyclic Ring by Intramolecular Diels-Alder Reaction

Hiroki Shimoda, Takahiro Shibata, Daisuke Sekine, and Masahisa Nakada*

*Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan

Abstract

The possibility of constructing the macrocyclic ring of keramaphidin B via an intramolecular Diels-Alder (IMDA) reaction has been investigated. The IMDA reaction of a substrate possessing dihydropyridone and diene moieties, which were tethered by an alkyl chain including a linear triple bond, was found to proceed in the presence of SnCl4 at 80 °C.

Published online: 8th October, 2019

■ Benzylic Oxidation and Functionalizations of Xanthenes by Ligand Trasfer Reactions of Hypervalent Iodine Reagents

Toshifumi Dohi, Keina Komiyama, Shohei Ueda, Nobutaka Yamaoka, Motoki Ito, and Yasuyuki Kita*

*Research Organization of Science and Technology, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577, Japan

Abstract

The benzylic oxidation, amidation, and unprecedented heteroarylation proceed at room temperature using iodosobenzene, (sulfonylimido)iodobenzenes, and diaryliodonium(III) salts are described for the direct Csp3-H functionalizations of xanthene molecules. This study has demonstrated that hypervalent iodine reagents serve as unified synthetic tools for versatile xanthene Csp3-H transformations based on the radical and SET oxidation processes.

Published online: 7th October, 2019

■ Synthesis and Optical Properties of L-Shaped Dinaphthofluoresceins with Two Peripheral Hydroxy Groups

Hikari Yamashita, Chihiro Minari, Eriko Azuma, Kouji Kuramochi, Ayumi Imayoshi, and Kazunori Tsubaki*

*Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Shimogamo, Sakyo-ku, Kyoto 606-8522, Japan

Abstract

The four compounds 6 and 8–10 having the same L-shaped dinaphthofluorescein skeleton were constructed. The only structural differences among these four compounds were the positions of the two peripheral hydroxy groups. Their dianion forms are a resonance system, thus 6 and 8–10 were expected to exhibit similar optical properties such as the maximum absorption wavelength, molar absorptivity, maximum emission wavelength and fluorescence quantum yield. However, 6 and 8‒10 showed quite different optical properties. For example, the maximum absorption wavelengths of 6, 8, 9 and 10 in aqueous pH 11 solution were 650 nm, 733 nm, 558 nm and 746 nm, respectively. Thus, the positions of the two peripheral hydroxy groups on the same skeleton significantly affected the optical properties.

Published online: 7th October, 2019

■ Trialkylsulfonium and Tetraalkylammonium Salts as Hydrogen-Bonding Catalysts in an Aza-Diels-Alder Reaction: Experimental and Computational Studies

Masahiro Yamanaka,* Ayaka Mochizuki, Takumi Nakamura, Keiji Maruoka, and Seiji Shirakawa*

*Department of Chemistry, Faculty of Science, Rikkyo University, 3-34-1 Nishiikebukuro, Toshima-ku, Tokyo 171-8501, Japan

Abstract

Hydrogen-bonding catalysis by cyclic trialkylsulfonium and tetraalkylammonium salts in an aza-Diels-Alder reaction was investigated. Among the examined onium salt catalysts, cyclic trialkylsulfonium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate possessing a non-coordinating counter anion was the most effective. Details of the activation modes of cyclic trialkylsulfonium and tetraalkylammonium salts were discussed on the basis of DFT calculation.

Published online: 4th October, 2019

■ The One-Pot Synthesis of Pyridine Derivatives from The Corresponding 1,5-Dicarbonyl Compounds

Hiromichi Mihara, Takeru Miyakoshi, Yui Kikuchi, and Hiroyuki Konno*

*Graduate School of Science and Engineering, Yamagata University, 3-16 Jonan 4-Chome, Yonezawa 992-8510, Japan

Abstract

The optimization of the one-pot, acid-promoted synthesis of pyridine and alkylpyridine derivatives from simple alkyl-1,5-dicarbonyl derivatives and via the corresponding oxime intermediate is described. Of all the combinations of acids and solvents tested, the use of HCl in refluxing dioxane was found to result in the highest chemical yields. Twelve pyridines were prepared using this method.

Published online: 3rd October, 2019

■ α-L-Vancosamine Aryl C-Glycosides, Less Stable Anomers: A Problem in Synthesis of Pluramycin-Class Antibiotics

Yoshio Ando, Hiromune Asahina, Kei Kitamura, Takashi Matsumoto, and Keisuke Suzuki*

*Depatrtment of Chemistry, Tokyo Institute of Technology, 2-12-1,Oh-Okayama, Meguro-ku, Tokyo 152-8552, Japan

Abstract

The pluramycin-class antibiotics have attracted considerable synthetic interest by their bioactivities and unique chemical structures. By the thermodynamic disadvantage, the selective formation of the aryl α-C-glycoside of an L-vancosamine motif, commonly embedded in this class of natural products, has been one of the problems in their total synthesis. This paper summarizes the stereochemical behavior of the pluramycin-class natural products and reports the results of our model study to address this issue by examining three L-vancosaminyl donors under Lewis acidic conditions.

Published online: 2nd October, 2019

■ Mechanistic Studies of Nickel(II)-Catalyzed Direct Alcoholysis of 8-Aminoquinoline Amides

Hiroyuki Morimoto,* Walaa Akkad, Toru Deguchi, and Takashi Ohshima*

*Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

Abstract

This paper describes the mechanistic aspects of nickel(II)-catalyzed direct alcoholysis of 8-aminoquinoline amides. Kinetic experiments suggested that the nickel(II) catalyst existed in an oligomeric form in the resting state, and the 8-aminoquinoline generated after cleavage coordinated to the nickel(II) catalyst to decelerate the reaction. In addition, density functional theory calculations revealed that the reactions proceeded via the intermediate with N,N,O-tridentate coordination of 8-aminoquinoline amides to the nickel(II) metal center, and that the alcoholysis reaction did not involve deprotonation of the N–H bond of 8-aminoquinoline amides, in contrast to the proposed mechanism for C–H bond functionalization reactions of 8-aminoquinoline amides.

Published online: 2nd October, 2019

■ Development of Near-Infrared Fluorescent Probes with Large Stokes Shifts for Non-Invasive Imaging of Tumor Hypoxia

Kensuke Okuda, Bahaa G. M. Youssif, Ryosuke Sakai, Takahiro Ueno, Takayuki Sakai, Tetsuya Kadonosono, Yasuyuki Okabe, Ola I. Abdel Razek Salem, Alaa M. Hayallah, Mostafa A. Hussein, Shinae Kizaka-Kondoh, and Hideko Nagasawa*

*Laboratory of Pharmaceutical　& Medicinal Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan

Abstract

A series of near-infrared (NIR) fluorochromes with large Stokes shifts was designed, synthesized, and evaluated for application in non-invasive imaging of tumor hypoxia. Each NIR fluorescent hypoxia probe comprised a tricarbocyanine dye and a 2-nitroimidazole-containing moiety as a hypoxia marker that binds to cellular nucleophiles via bioreductive activation under hypoxic conditions. Nucleophilic displacement of the amino-nucleophilic linker moiety of heptamethine cyanine dyes having a 2-chloro-1-cyclohexenyl ring and a 2-nitroimidazole moiety yielded various fluorochromes with different hydrophilicity. These exhibited long emission wavelengths (747–758 nm) with large Stokes shifts (111–125 nm) and high quantum yield (0.04–0.34). GPU-210, 297, and 316 showed significantly higher levels of fluorescence under hypoxic than under normoxic conditions on treating SUIT-2/HRE-Luc pancreatic cancer cells. Among these, only GPU-316 showed significant fluorescence intensity in tumor tissue in in vivo fluorescence imaging of mouse xenograft models.

Published online: 1st October, 2019

■ Synthesis of 2-Amino-1,3-benzoselenazole via Metal-Free Cyclization from Isothiocyanate and Bis(o-aminophenyl)diselenide

Hayato Ichikawa,* Naoka Miyashi, Yui Ishigaki, and Minako Mitsuhashi

*Department of Applied Molecular Chemistry, College of Industrial Technology, Nihon University, 1-2-1, Izumi-cho, Narashino, Chiba 275-8575, Japan

Abstract

Amino-1,3-benzoselenazoles were generated from the reactions of bis(o-aminophenyl)diselenide and various isothiocyanates under metal-free cyclization conditions. The cyclization of isothiocyanate bearing bulky substituents proceeded in excellent yields because the amounts of byproducts generated were reduced. Acid hydrolysis of acetamide produced 2-amino-1,3-benzoselenazole (4).