HETEROCYCLES

■ Contents

■ Synthesis of Heterocycles Utilizing N-Alkoxyimines and Amides

Motohiro Yasui, Norihiko Takeda, and Masafumi Ueda*

*Department of Medicinal Chemistry, Kobe Pharmaceutical University, 4-19-1, Motoyamakitamachi, Higashinada, Kobe 658-8558, Japan

Abstract

N-Alkoxyimines and amides are unique functional groups bearing adjacent N-O bonds. Alkynes having an N-alkoxyimine or amide group generate reactive vinyl metal species through activation by a transition metal catalyst to synthesize heterocycles. This approach, which allows various sequential reactions, can be expected to directly form a complex heterocycle from a simple starting material under mild conditions. Meanwhile, these kinds of reactions require chemoselectivity between the N- and O-atoms at the nucleophilic site and/or regioselectivity at the electrophilic alkyne moiety. This review introduces intramolecular nucleophilic addition of N-alkoxyimines/amides into an alkyne moiety, followed by various transformations to synthesize heterocycles.

■ Efficient Synthesis of Fluorinated Benzimidazolines, Benzoxazolines and Benzothiazolines Catalyzed by Hf(Otf)4

Jing-Ying Wei, Shuai-Bo Han, Xiao-Chong Peng, Cheng-Jun Wang, De-Yun Zeng, Shan-Shan Gong,* and Qi Sun*

*Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science and Technology Normal University, 605 Fenglin Ave, Nanchang, Jiangxi Province, China

Abstract

Hafnium triflate was identified as a highly efficient catalyst for the synthesis of a diversity of fluorinated benzimidazolines, benzoxazolines, and benzothiozolines. For the first time, more complicated N-substituted benzimidazolines were synthesized via the Hf(OTf)4-catalyzed method. With the assistance of 19F NMR, the catalytic roles of Hf(IV) on the activation of fluorinated ketone and fluorinated imine intermediate were revealed.

■ Efficient and Divergent Synthesis of Benzoxazoles and 1,2-Benzisoxazoles from o-Hydroxyaryl Ketoximes

Zhenhua Li,* Guoqiang Jin, Jingjing Qin, Zhiyong Tan, and Jiayu He

*College of Pharmaceutical Sciences, Zhejiang University of Technology, No.18 Chaowang Road, 6th Zhaohui District, Hangzhou, Zhejiang Province 310014, China

Abstract

A bis(trichloromethyl) carbonate (BTC) / triphenylphosphine oxide (TPPO) system promoting tunable cyclization of a variety of o-hydroxyaryl ketoximes to benzoxazoles and benzisoxazoles was developed. The synthetic switch was enabled by base-free or the use of Et3N. Under base-free conditions, o-hydroxyaryl ketoximes were treated with BTC/TPPO giving corresponding 2-substituted benzoxazoles via cascaded Beckmann rearrangement and intramolecular oxa-cyclization. Analogously, the 3-substituted benzisoxazoles were obtained via intramolecular nucleophilic substitution reactions in the presence of Et3N. This process features mild reaction conditions, high chemoselectivity, and good functional groups tolerance.

■ 2-Bromo-1,3-di(methoxy)imidazolium Tribromide as Starting Salt for 2-Aryl- and 2-Heteroaryl mercapto Derivatives

Lukas Fliri, Sandro Neuner, Martin Lampl, Gabriel Partl, Holger Kopacka, Klaus Wurst, Thomas Gelbrich, Volker Kahlenberg, Sven Nerdinger,* and Herwig Schottenberger*

*Early Stage Development, Sandoz GmbH, Biochemiestrasse 10, 6250 Kundl, Austria

Abstract

A one-pot alkylation/bromination sequence of 1-hydroxyimidazole 3-oxide led to the simple isolation of new 2-bromo-1,3-di(methoxy)imidazolium tribromide 1 by spontaneous precipitation from the aqueous reaction mixture. The related bromide 2, quantitatively and cleanly derived from the tribromide 1 via sacrificial bromination of cyclohexene, as well as the hexafluorophosphate 3,easily accessible through anion metathesis, represent valuable congeners for a rich follow-up chemistry. The reactivity of the 2-bromo substituent towards nucleophilic substitution by different S-nucleophiles was chosen as a startingpoint. Thus, a series of 2-arylmercapto- and 2-hetarylmercaptoimidazolium salts, which are otherwise only elaborately to access, could be isolated with minimal effort. In addition to routine spectroscopic characterization, eleven selected compounds have been determined using single-crystal X-ray diffraction.

■ Synthesis and Evaluation of Diaminopyrimidine Derivatives as Dual Inhibitors of EGFR and SRC for Antitumor Treatment

Longjia Yan,* Yi Le, Dongmei Chen, Yumei Chen, Di Zhang, and Lan Yang

*School of Pharmaceutical Sciences, Guizhou University, 440 Chongyi Building,Guizhou University, Huaxi District, China

Abstract

In this paper, a series of novel diaminopyrimidine derivatives was designed and synthesized using palladium-catalyzed Buchwald–Hartwig-type heteroarylamination procedure. And then, they were evaluated for antitumor activity in vitro on wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK), c-Src and four human cancer cell lines including A549, PC-3, SMMC-7721 and K562. The results displayed that some of the compounds had good activities. Especially 2-(2-cycloheptylamino-5-trifluoromethylpyrimidin-4-ylamino)-N-methylbenzami-de (1h) showed high antitumor activities against four cancer cell lines with 2.33, 7.46, 1.13 and 1.28 μM. Furthermore, the IC50 values of compound 1h for EGFR and Src reached in 0.86 μM and 0.22 μM.

■ Facile Preparation of 2-Oxo-2H-1-pyran-3-carboxylates with the Electron-Withdrawing Group at the 5-Position

Toru Tanaka, Shoki Inoue, Takuya Miura, Yun-Han Hsieh, Hiroki Iwasaki, Minoru Ozeki, Naoto Kojima, and Masayuki Yamashita*

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

Abstract

A simple and facile procedure for the preparation of 2-oxo-2H-1-pyran-3-carboxylate bearing electron-withdrawing groups, such as the alkylcarbonyl and alkoxycarbonyl moieties, was developed. Various 1,3-dicarbonyl compounds were treated with dimethyl (methoxymethylene)malonate in the presence of Cs2CO3 as a base in tetrahydrofuran at room temperature. This method was particularly effective in the syntheses of bicyclic structures, such as 5,​6,​7,​8-tetrahydro-2,​5-​dioxo-​2H-​1-​benzopyran-​3-​carboxylates.

■ New Schiff Bases Based on 1-Aminopyrimidin-2-(1H)-one: Design, Synthesis, Characterization and Theoretical Calculations

Zülbiye Kökbudak, Halime Güzin Aslan, and Senem Akkoç*

*Department of Pharmacy, Süleyman Demirel University, Suleyman Demirel University, Turkey

Abstract

In this study, 1-amino-5-benzoyl-4-phenylpyrimidin-2(1H)-one (1) was synthesized from 4-benzoyl-5-phenylfuran-2,3-dione and 1-(1-phenylethylidene)semicarbazide in benzene. Since pyrimidine-based Schiff bases have an extensive working range, two new compounds (2, 3) were synthesized from the reaction of this starting material (1) with 3-bromobenzaldehyde or 4-chlorobenzaldehyde. The structures of the synthesized new compounds were clarified employing FT-IR, 1H NMR, 13C NMR, and elemental analysis. HOMO, LUMO, and energy gap between them was calculated as theoretical. On the other hand, conformation analysis studies of compounds were carried out for determining the energies of the conformers.

■ A Facile Synthesis and Antibacterial Activity of Novel Quinoxaline-Benzofuran Hybrids

Yang Li, Bingyue Tang, Shiyu Dong, Hongwei Qin, Wentao Gao,* and Yu Chen*

*Institute of Superfine Chemicals, School of Chemistry and Chemical Engineering, Bohai University, 19 Keji Road, Jinzhou 121000, China

Abstract

In the present work, a simple and facile synthesis of a series of new type of quinoxaline-benzofuran hybrids, i.e., 3-(benzofuran-2-yl)quinoxaline- 2-carboxylic acids has been achieved using the newly-synthesized ethyl 3-bromomethylquinoxaline-2-carboxylate as substrate through ultrasound-assisted one-pot sequential Rap-Stoermer type reaction with various salicylaldehydes followed by ester hydrolysis. A preliminary screening for their antibacterial activities against five bacterial strains revealed that compounds with tert-butyl and halo (Cl and Br) substituents exhibited promising inhibitory activity against B. subtilis with the MIC values of 15.625 and 7.8125 μg/mL, respectively, being equipotent or even better than the reference Ciprofoxacin.

■ New Synthesis of Apabetalone

Pengfei Wu, Han Wang,* Wenxin Chen, Cong Sun, Lei Gao, and Yongjun Mao

*College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Rd., Songjiang, Shanghai, 201620, China

Abstract

A new and convergent synthesis of apabetalone (RVX-208) is developed. The key step is to build the 2-phenylquinazolin-4(3H)-one main ring from 2-bromo-4,6-dimethoxybenzoic acid (10) and 4-(2-hydroxyethoxy)-3,5- dimethylbenzamidine hydrochloride (15) in 73% yield. 1-Bromo-3,5- dimethoxybenzene (8) and 4-hydroxy-3,5-dimethylbenzonitrile (13) are used as the starting materials, 1 was obtained in 49% yield from 8 over 3 steps, or 48% yield from 13 over 3 steps, including Vilsmeier-Haack formylation, oxidation, amination, Pinner amidine synthesis methods. Purification methods of the intermediates and the final product involved in the route were developed, which make it as a process of cost effective, environmental friendly, and feasible for scale-up operation.