HETEROCYCLES

■ Contents

■ Enantioselective Heterocycle Formation Using Chiral Hypervalent Iodine(III)

Morifumi Fujita*

*Graduate School of Material Science, University of Hyogo, 3-2-1 Kohto, Kamigori, Ako-gun, Hyogo 678-1297, Japan

Abstract

The field of chiral hypervalent iodine chemistry has made significant progress in the past decade. This review focuses on enantioselective heterocycle formation induced by chiral hypervalent iodine reagents and catalysts. The enantioselective heterocyclizations are classified into the dearomatization of phenols (and naphthols), α-oxidation of carbonyl compounds, and oxidative vicinal difunctionalization of alkenes. As a characteristic reaction of a hypervalent iodine oxidizing reagent, the 6-endo selective lactonization of ortho-alkenylbenzoate is selected and compared with the 5-exo selectivity induced by other electrophilic reagents. The oxidative lactonization with 6-endo selectivity afforded a 4-oxyisochroman-1-one framework, which has been found in a family of polyketide metabolites. The total syntheses of 4-oxyisochroman-1-one natural products were also summarized to assess the synthetic utility of hypervalent iodine compounds.

■ 4,5-Dihydro-1H-tetrazoles — 5-Alkyl/Aryl and 5-Alkylidene Derivatives

Dietrich Moderhack*

*Institute of Medicinal and Pharmaceutical Chemistry, Technical University, Braunschweig, Beethovenstrasse 55, D-38106, Germany

Abstract

Nine types of 5-alkyl/aryl- and 5-alkylidene-4,5-dihydro-1H-tetrazoles (A–H) are reviewed in this article. Besides their synthesis and chemical behaviour, tautomerism of representatives having electron-withdrawing substituents (E, F) as well as polarization of the semicyclic double bond of the types (C–H) are of interest.

■ Reactions of 1,3-Thiazine-2,6-dithiones. Part 8. Formation of a New Series of 2-Pyrroline-4-thiones by the Rearrangement of 1,3-Thiazine-6-spiro-2’-thiirane-2-thiones and 2-Methylthio-1,3(6H)-thiazine-6-spiro-2’-thiiranes and Some Related Reactions

Tatsuo Yamamoto,* Hiroshi Miyamae, and Motomu Muraoka

*Faculty of Science, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan

Abstract

1,3(6H)-Thiazine-6-spiro-2’-thiirane-2-thiones 2a-c and 3’,3’-disubstituted 2-methylthio-1,3-thiazine-6-spiro-2’-thiiranes 12a-f were synthesized by the reaction of 1,3-thiazine-2,6-dithiones 1 or 11a-d, which are 2-methylthio derivatives of thiazinedithiones 1, with diazomethane derivatives. 1,3(6H)-Thiazine-6-spiro-2’-thiiranes 2a-c and 12a-f rearranged into a series of 2-pyrroline-4-thione derivatives 3a-c and methyl 4-thioxopyrroline-1-dithiocarboxylates 13a-f on treatment with a base or gentle heating. 2-Pyrroline-4-thione derivative 13c, upon heating to 140 oC for 1 h, reversely rearranged into the thiirane derivative 12c. The structure of the 2-pyrroline-4-thione 13e was determined by single-crystal X-ray analysis.

■ Synthesis of Novel Angular and Linear Fused [5-6-5] Heterocycles by the Reaction of Methyl Cyano-(3-cyano-4,5-dihydro-2(3H)-furanylidene)acetate with Hydrazines and Dimethylformamide Dimethyl Acetal

Fumi Okabe-Nakahara,* Eiichi Masumoto, Hiroshi Maruoka, and Kenji Yamagata

*Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

Abstract

A convenient and efficient method for the synthesis of novel angular and linear fused [5-6-5] three heterocycles is described. Methyl cyano- (3-cyano-4,5-dihydro-2(3H)-furanylidene)acetate (1) was reacted with an excess of hydrazine monohydrate to give 3,4’-bipyrazole 5. Compound 5 was condensed with N,N-dimethylformamide dimethyl acetal (DMFDMA) to yield angular dipyrazolopyrimidine 6. On the other hand, pyrazoles 3b-d were obtained by reaction of 1 with hydrazines. Compounds 3b-d were reacted with hydrazine monohydrate, pyrazolopyridines 7a-c were taken. Compounds 7a-c were condensed with DMFDMA to give linear pyrazolotriazolopyridines 8a-c.

■ Efficient and Convenient Route to the Synthesis of Some Novel Sulfonate Ester-Based Heterocycles as Antitumor Agents

Ahmed El-Mekabaty,* Osman M. O. Habib, Mohamed Abd El-Moneim, and Ahmed S. Hussein

*Department of Chemistry, Faculty of Science, Mansoura University, El-Gomhoria Street, Mansoura, 35516, Egypt

Abstract

In the present investigation, simple and straightforward methodology for the preparation of novel thiazolidinone, thiazole, pyridinone, chromene, pyrazole, benzimidazo[1,2-a]pyrimidine and thiazolo[3,2-a]pyrimidine derivatives bearing sulfonate ester moiety through the reaction of 4-formylphenyl benzenesulfonate (1) with some nitrogen nucleophiles such as hydrazine hydrate, thiosemicarbazide and 2-cyanoacetohydrazide is described. The antitumor activities were evaluated according to the protocol of the National Cancer Institute (NCI) in vitro disease-oriented human cells screening panel assay against two human tumor cell lines namely; breast cancer MCF-7 and prostate cancer PC3. The results revealed that compounds (4), (7), (9), (13) and (16) exhibited promising antitumor activity in the two cell lines assay compared with 5-fluorouracil as a reference drug.

■ Reactivity of 6-Methylchromone-3-carbonitrile Towards Some Nitrogen Nucleophilic Reagents

Nasser M. El-Gohary, Magdy A. Ibrahim,* and Sara Said

*Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, Cairo 11711, Egypt

Abstract

The chemical reactivity of 6-methylchromone-3-carbonitrile (1) was studied towards a variety of nitrogen nucleophiles. A variety of products was obtained from the reaction of carbonitrile 1 with hydrazine hydrate, S-benzyl dithiocarbazate, isonicotinic acid hydrazide and cyanoacetohydrazide. A diversity of Schiff bases bearing 2-amino-6-methylchromone linked variable heterocyclic systems was efficiently synthesized. Reaction of carbonitrile 1 with guanidine and cyanoguanidine resulted in ring conversion producing chromeno[4,3-d]pyrimidines. Reaction of carbonitrile 1 was also studied towards some 1,4-binucleophiles.

■ An Indocyanine-Based Turn-On Fluorescent Probe for Specific Detection of Biothiols

Xiaojing Wang, Di Jin, Xue Li, Xilong Yan,* and Bowei Wang*

*School of Chemical Engineering and Technology, Tianjin University, Yaguan Road 135#, Jinnan District 300350, Tianjin, China

Abstract

A novel heptamethine cyanine-based turn-on fluorescent probe Cy-DNBS was designed and synthesized, which was used successfully to detect biothiols with high selectivity and sensitivity. With the addition of biothiols, the probe displayed ~30-fold fluorescence enhancement at 625 nm. Meanwhile, the solution color changed remarkably from green to red, which provides a method to recognize biothiols by the ‘naked eye’. The detection limit of Cys, GSH and Hcy are 2.24 nM, 1.99 nM and 4.46 nM, respectively.

■ Nucleophilic Aroylation on Fluoroquinazolines Catalyzed by N-Heterocyclic Carbenes

Masashi Tachikawa, Mizuki Nakagawa, and Yumiko Suzuki*

*Department of Materials and Life Science, Faculty of Science and Technology, Sophia University, Kioi-cho 7-1, Chiyoda-ku, Tokyo 102-8554, Japan

Abstract

We report on the synthesis of 7-benzoyl- and 7-heteroaroylquinazolines from 7-fluoroquinazolines and aromatic aldehydes by N-heterocyclic carbene (NHC)-catalyzed nucleophilic aromatic substitution, showing that the NHC derived from 1,3-dimethylimidazolium iodide outperformed those originating from other azolium (e.g., thiazolium and triazolium) salts. Additionally, the developed methodology allowed the preparation of 5- and 8-aroylquinazolines from the corresponding fluoroquinazolines.

■ An Efficient and Practical Synthesis of Remogliflozin Etabonate, a Potent Inhibitor of Low-Affinity Na+-Dependent Glucose Co-Transporter (SGLT2)

Masahiro Kobayashi* and Takayuki Ainai

*Quality Assurance, Kissei Pharmaceutical Co., Ltd, 19-48 Yoshino, Matsumoto-City, Nagano-Pref., Japan

Abstract

A practical process for the preparation of remogliflozin etabonate, a prodrug of the selective low-affinity Na+-dependent glucose co-transporter (SGLT2) inhibitor, remogliflozin, is described. We established a chemoselective synthetic route to 1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5- methyl-3H-pyrazol-3-one and an efficient O-glycosylation of this compound with 2,3,4,6-tetra-O-pivaloyl-α-ᴅ-glucopyranosyl bromide. This synthetic process provided remogliflozin etabonate in a 39% overall yield from commercially available 4-isopropoxybenzaldehyde.

■ New Bromoindole Alkaloid Isolated from the Marine Sponge Hyrtios erectus

Alaa A. Bagalagel, Hanin A. Bogari, Safwat A. Ahmed, Reem M. Diri, and Sameh S. Elhady*

*Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia

Abstract

5’-[(6-Bromo-1H-indol-3-yl)methyl]-3’-methylimidazolidine-2’,4’-dione (1), a new bromoindole alkaloid was derived from the marine sponge Hyrtios erectus (order Dictyoceratida) collected in the Red Sea. Additionally, two known indole alkaloids (2–3) were also isolated. The chemical structures of the isolated compounds were elucidated on the basis of detailed spectroscopic analysis as well as comparison with published data. Compound 1 showed weak antiproliferative activity against colorectal carcinoma (HCT-116), breast adenocarcinoma cells (MCF-7) and hepatocellular carcinoma (HepG2). Additionally, at concentration of 3 mg/mL, compound 1 displayed moderate antibacterial activity against S. aureus and E. coli.

■ A Facile Synthesis of 1,4-Dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one Derivatives from 4,6-Dichloro-2-(methylsulfanyl)pyrimidine

Kazuhiro Kobayashi,* Yuka Tsunomori, Takashi Nogi, Hidetaka Hiyoshi, and Kazuto Umezu

*Applied Chemistry Field, Chemistry and Biotechnology Course, Department of Engineering, Graduate School of Sustainability Science, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

A facile three-step sequence has been developed for the preparation of 1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one derivatives from 4,6-dichloro-2-(methylsulfanyl)pyrimidine (DCSMP) under mild conditions. Thus, the starting material is treated with LDA to generate the 5-lithiated compound, which is then allowed to react with (het)aromatic and aliphatic aldehydes to give the corresponding 1-[4,6-dichloro-2-(methylsulfanyl)pyrimidin-5-yl]alkan-1-ols. The reaction of these compounds with primary amines in the presence of triethylamine gives 1-[4-(alkylamino)-6-chloro-2-(methylsulfanyl)pyrimidin-5-yl]alkan-1-ols, of which subjection to successive treatment with an equimolar amount each of sodium hydride and ethyl chloroformate provides the desired 1,4-disubstituted 7-(methylsulfanyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones.