HETEROCYCLES

■ Contents

■ Efficient Synthesis of Heterocycles Using Highly Electrophilic Ethenetricarboxylates

Shoko Yamazaki*

*Department of Chemistry, Nara University of Education, Takabatake-cho, Nara 630-8528, Japan

Abstract

The synthesis of heterocyclic compounds utilizing highly electrophilic ethenetricarboxylates is described. Ethenetricarboxylate is a member of methylenemalonates and more reactive than frequently used alkylidenemalonates by the electron-withdrawing effect of 2-carboxyl group. They are utilized as efficient Michael acceptors or electron-deficient C=C components. Lewis acids also promote the reactions of ethenetricarboxylate derivatives efficiently. The intermolecular and intramolecular reactions of ethenetricarboxylates towards synthesis of heterocycles are presented.

■ An Efficient and Practical Preparation of a Potent Low-Affinity Na+-Dependent Glucose Cotransporter (SGLT2) Inhibitor, Sergliflozin Etabonate

Masahiro Kobayashi,* Hidetoshi Isawa, Junichi Sonehara, and Minoru Kubota

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

Abstract

The development of an efficient and practical process for the preparation of Sergliflozin etabonate (1), a prodrug of a novel selective low-affinity Na+-dependent glucose cotransporter (SGLT2) inhibitor, Sergliflozin (2), is described. Its development required a suitable process for large-scale manufacturing. We established a chromatography-free approach for 2-[(4-methoxyphenyl)methyl]phenol (5), the efficient O-glycosylation of 5 with penta-O-acetyl-β-D-glucopyranose (7) without using a trichloroimidate intermediate (9), and efficient reaction conditions to introduce an ethoxycarbonyl group onto the primary alcohol of 2 with high selectivity. This process provided 1 with a 45% overall yield from anisole (10).

■ Facile Synthesis of Sulfonyl Amidines by 1,3-Dipolar Cycloaddition between 1-Morpholinocycloalkenes and Sulfonyl Azides without Catalyst

Chiaa Adiche, Mohammed Hamadouche, and Douniazad El Abed*

*Chemistry Department, Faculty of Exact and Applied Sciences, University of Oran 1, Ahmed BenBella, BP 1524 El M’naouar, Oran 31000, Algeria

Abstract

Three new series of sulfonyl amidines were prepared by 1,3-dipolar cycloaddition reaction between 1-morpholinocycloalkenes and various substituted sulfonyl azides without catalyst at room temperature. This reaction yielded unstable bicyclic Δ2-1,2,3-triazoline intermediates which rearranged themselves in situ into amidines by elimination of a nitrogen molecule. The reactions were performed under mild conditions and with moderate to good yields.

■ A Facile Preparation of Imidazo[1,2-a]pyridin-3-amine Derivatives via a Three-Component Reaction with β-Cyclodextrin–SO3H as Catalyst

Jian Wu,* Fang-Zhou Xu, She-Lei Feng, Wei Xue, and Zhen-Zhen Wang

*Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang 550025, China

Abstract

Because heterogeneous catalysts have attracted great interest in organic chemistry, this paper reports facile β-cyclodextrin–SO3H–catalyzed cyclization to form imidazo[1,2-a]pyridin-3-amine derivatives via a three-component reaction. The main advantages of this strategy include short reaction time, practical simplicity, and high yield, and the catalyst can be separated easily by filtration and reused at least four times.

■ Synthesis of 3-Hydroxy-1,3-dihydro-2H-pyrrolo[2,3-b]-, -[2,3-c]-, or -[3,2-c]pyridin-2-ones from the Respective N-Pyridinylpivalamides and α-Keto Esters

Kazuhiro Kobayashi,* Risa Kosuna, and Yuuki Chikazawa

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

Abstract

A convenient synthesis of the title compounds utilizing the reaction of the dilithium compounds, generated in situ by the reaction between N-(pyridin-2-, -3-, or -4-yl)pivalamides and two equivalents of butyllithium in THF, with α-keto esters is described. Thus, N-(3-lithiopyridin-2-yl)pivalamide reacts smoothly leading to the formation of the corresponding α-hydroxy esters. These undergo deprotective cyclization in refluxing hydrochloric acid to afford 3-substituted 3-hydroxy-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-ones. Similarly, starting from N-(pyridin-3- or -4-yl)pivalamides, the corresponding 3-dihydro-2H-pyrrolo[2,3-c]- or -[3,2-c]pyridin-2-one derivatives, respectively, can be prepared.

■ A Green, Solvent-Free One-Pot Synthesis of Disubstituted Quinolines via A3-Coupling Using 1 Mol% FeCl3

Shivani Naidoo and Vineet Jeena*

*School of Chemistry and Physics, University of KwaZulu-Natal, Cnr Golf and Ridge Roads 3209, South Africa

Abstract

A simple and green route towards disubstituted quinolines via A3-coupling using 1 mol% FeCl3 is described. Using this approach, the above-mentioned derivatives were synthesized in moderate to good yields (45-95%) under solvent-free, microwave conditions. Preliminary investigations have indicated that a further decrease in catalyst amount is possible with a satisfactory yield still observed.

■ Skeletal Transformation of 2a,8b-Dihydrobenzo[b]cyclobute[d]pyran-3-ones into Dihydrodibenzofurans

Toru Tanaka, Masaki Nagahama, Navnath Dnyanoba Yadav, Hiroki Iwasaki, Minoru Ozeki, Naoto Kojima, and Masayuki Yamashita*

*Kyoto Pharmaceutical University, 5 Misasagi-Nakauchi, Yamashina, Kyoto, Japan

Abstract

Using dimethylsulfoxonium methylide as the methylene-transfer reagent, 8-methoxy-2a,8b-dihydrobenzo[b]cyclobute[d]pyran-3-ones were exclusively converted into the corresponding dihydrodibenzofuran derivatives. The use of a methoxy group as the substituent and its position are crucial to the success of this transformation.

■ Synthesis of Isoquinolinium via Rhodium(III)-Catalyzed Oxidative Annulation between Aldimines and Alkynes

Cheng-Qi Wang, Wei Zhang, Hui Lin, Fu Su,* and Lin Dong*

*West China School of Pharmacy, Sichuan University, 17# Third Section of South Renmin Road 610041, China

Abstract

Various isoquinolinium salts have been efficiently synthesized from aldehyde imines and alkynes via RhIII-catalyzed C–H activation and annulation reaction. A broad substrate scope has also been studied to provide various isoquinolinium triflate salts.

■ Lewis Acid-Catalyzed Borono-Minisci Reactions of Arylboronic Acids and Heterocycles

Joyce L. Biaco, Savannah L. Jones, and Timothy J. Barker*

*Department of Chemistry and Biochemistry, College of Charleston, 66 George St., Charleston, SC 29424, U.S.A.

Abstract

A Lewis acid-catalyzed Minisci reaction between arylboronic acids and heterocycles has been developed. This radical-coupling reaction was demonstrated employing several different heterocycles as well as electron-rich arylboronic acids. Quinoline substrates afforded modest regioselectivity for substitution at the 4-position under the reaction conditions, in contrast to previously reported Brønsted acid-mediated reactions with quinoline substrates that favored substitution at the 2-position.

■ KH2PO4 Promoted Practical and Environmentally Friendly Preparation of Coumarin-3-carboxylic Acids under Solvent-Free Condition

Shuangqiu Gao, Di Xiao, Ying Yang, Xiaoyü Wei, Sai Sun, Jian Lang, and Chengwei Lv*

*School of Chemistry and Chemical Engineering, Liaoning Normal University, No.850 Huanghe Road, Liaoning Province 116029, China

Abstract

An efficient and green protocol for synthesis of coumarin-3-carboxylic acids is developed in good to high yields via a Knoevenagel-intramolecular cyclization cascade reaction of Meldrum’s acid with various ortho-hydroxyarylaldehydes. This reaction is catalyzed by a combination of KH2PO4 (10 mol%) and water (100 μL). Solvent-free, cheap and eco-friendly catalyst, clean reaction conditions, simple workup procedure and easy isolation are the best features in this process.

■ Two New Alkaloids from the Seeds of Cassia alata and Their Bioactivities

Pei-Song Yang, Wei Zhang, Xiao-Feng Shen, Xin-Lin Wang, Chao Li, Xiao-Wei Gong, Xu-Dong Zheng, Dong-Lai Zhu,* and Jia-Qiang Wang*

*School of Chemical Science and Technology, Yunnan University, Kunming 650091, China

Abstract

Two new alkaloids, 6-(hydroxymethyl)-3,9-dimethyl-7H-benzo[de]quinolin-7-one (1) and 6-(hydroxymethyl)-8-methoxy-3,9-dimethyl-7H-benzo[de]quinolin-7-one (2), together with four known alkaloids (3-6) were isolated from the seeds of Cassia alata. Their structures were determined by means of HRESIMS and extensive 1D and 2D NMR spectroscopic studies. Compounds 1-6 were tested for their anti-tobacco mosaic virus (TMV) activities, and the results showed that compound 2 exhibited high anti-TMV activity with inhibition rates of 38.5%. This rate is higher than that of the positive control. The cytotoxicities of compounds 1-6 against five human tumor cell lines (NB4, A549, SHSY5Y, PC3 and MCF7) were also tested. Compounds 1-6 showed weak inhibitory activities against some tested human tumor cell lines with IC50 values in the range of 2.5-7.5 μM.

■ Three New Isoindolin-1-ones from the Leaves of Yunnan Local Sun Cured Tobacco and Their Bioactivities

Feng-Mei Zhang, Jian-Jun Xia, Pei-Song Yang, Qin-Peng Shen, Chun-Bo Liu, Pei He, Jia-Qiang Wang, Zhi-Hua Liu,* and Zhong-Tao Ding*

*Key Laboratory of Tobacco Chemistry of Yunnan Province, China Tobacco Yunnan Industry Company, Hongjin Road 181#, Kunming, 650231, China

Abstract

Three new (1-3) and one known (4) isoindolin-1-ones were isolated from the leaves of Yunnan local sun cured tobacco. Their structures were determined by means of HRESIMS and extensive 1D and 2D NMR spectroscopic studies. Compounds 1-3 were tested for their anti-tobacco mosaic virus (anti-TMV) activities and compounds 1-4 were tested for their cytotoxicity activities. The results showed that compounds 1-3 showed high anti-TMV activity with inhibition rates of 43.8, 45.6 and 52.7%. These rates are higher than that of positive control. Compounds 1-4 also showed moderate-to-weak inhibitory activities against some tested human tumor cell lines with IC50 values in the range of 2.8–8.2 μM.