HETEROCYCLES

■ Contents

■ One-Pot Asymmetric 6π-Azaelectrocyclization as a New Strategy for Alkaloid Synthesis

Toyoharu Kobayashi, Taku Sakaguchi, and Shigeo Katsumura*

*Department of Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337, Japan

Abstract

The one-pot asymmetric 6π-azaelectrocyclization of alkenyl vinyl stannane, ethyl (Z)-2-iodo-4-oxobutenoate, and (–)-7-isopropyl-cis-aminoindanol in the presence of a Pd(0) catalyst stereoselectively produced the tetracyclic aminal compounds, resulting from the four-bond formation by controlling the stereochemistry at the two created asymmetric centers. This asymmetric one-pot protocol was developed based on the studies of the previously established asymmetric azaelectrocyclization, and the produced cyclic aminals can be regarded as synthetic precursors of 2,4-disubstituted chiral piperidines. Furthermore, we also developed a new version of the one-pot asymmetric 6π-azaelectrocyclization using t-butyl (Z)-3-formyl-2-iodopentenoate instead of ethyl (Z)-2-iodo-4-oxobutenoate, which directly afforded the precursors of the 2,4,5-trisubstituted piperidines. The syntheses of the 2,4- and 2,4,5-substituted piperidines were realized by the chemoselective reduction of the conjugated double bond to the ester group in the one-pot azaelectrocyclization products. The synthesis of the 2,4,6-trisubstituted piperidines was achieved by the stereocontrolled alkylation of the aminal moiety in the resulting cyclized products as a key step. The 2,3,4-trisubstituted piperidines were also synthesized utilizing the stereoselective 1,4-addition reaction of the unsaturated ester with a Grignard reagent resulting from the novel neighboring group participation. By applying this protocol, the total syntheses of (–)-dendroprimine, an indolizidine alkaloid, containing the 2,4,6-trisubstituted piperidine motif and (–)-20-epiuleine, a strychnos-type indole alkaloid, containing the 2,3,4-trisubstituted piperidine motif, were achieved.

■ Recent Progress in Organocatalytic Asymmetric Halocyclization

Kenichi Murai and Hiromichi Fujioka*

*Graduate School of Pharmaceutical Science, Osaka University, 1-6 Yamadaoka, Suita, Osaka 560-0871, Japan

Abstract

In this review, recent progress made in the development of organocatalytic asymmetric halocyclization reactions that form heterocyclic compounds is described. New reactions and their mechanistic features are discussed in the context of an outline based on catalyst types, including biscinchona alkaloids, amino ureas, amino thioureas, amino thiocarbamates, chiral phosphoric acids, and trisimidazolines.

■ FACILE SYNTHESIS OF GUAIAZULENE-HETEROCYCLE HYBRIDS VIA MULTICOMPONENT REACTIONS INVOLVING FORMATION OF ZWITTERIONIC INTERMEDIATES

Koichi Sato,* Erina Yokoo, and Naoko Takenaga

*Faculty of Bioscience and Applied Chemistry, Hosei University, 3-7-2 Kajino-cho, Koganei, Tokyo 184-8584, Japan

Abstract

The synthesis of a series of guaiazulene-heterocycle hybrids via zwitterionic intermediates was performed. The multicomponent reactions of 3-isocyano-7-isopropyl-1,4-dimethylazulene 1, dimethyl acetylenedicarboxylate 2, and a third reactant 3 (cyclic CH-acids, phenols, aldehydes or amines) proceeded to afford heterocyclic guaiazulene derivatives 4.

■ Synthesis of Nitrogen Bridgehead Heterocycles with Phosphonates via a Novel Tandem Process

Ya-Fei Xie, Yan-Qing Ge, Lei Feng, Hua-Qiang Xu, Song Meng, Gui-Long Zhao, Wei-Ren Xu, Jiong Jia,* and Jian-Wu Wang*

*School of Chemistry and Chemical Engineering, Shandong University, 27 Shanda Nanlu, Jinan,Shandong, 250100, China

Abstract

A novel and efficient method was developed for the synthesis of nitrogen bridgehead heterocycles with phosphonates. Nitrogen containing five-membered heterocyclic aldehyde and diethy 3-bromoprop-1-enylphosphonate were used as substrates. Bridgehead nitrogen-containing arylphosphonates were obtained via one-pot reaction including four steps: SN2, deprotonation followed by electron flow, nucleophic additon and elimination of water.

■ PREPARATION OF IMIDES vIA THE PALLADIUM-CATALYZED COUPLING REACTION OF ORGANOSTANNANES WITH METHYL N-[METHOXY(METHYLTHIO)METHYLENE]CARBAMATE

Kohei Orimoto, Takuhei Tomizawa, Yuki Namera, Harufumi Oyama, Takashi Niwa, 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 preparation of imides via the palladium-catalyzed coupling reaction of organostannanes is described. The palladium-catalyzed coupling reaction of aryl-, heteroaryl-, and alkenyl(tributyl)stannanes with methyl N-[methoxy(methylthio)methylene]carbamate in the presence of Cu(I) thiophene-2-carboxylate (CuTC) affords imino ethers, which are converted to the corresponding imides in high yield through acid hydrolysis.

■ Synthesis and Biological Evaluation of Some New Pyrimidine Derivatives

Kamelia M. El-mahdy and Azza M. El-Kazak*

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

Abstract

Reaction of 2-mercaptopyrimidine 1 with ethyl chloroacetate afforded isomeric pyrimidines 2 and 3. Interaction of 3 with bifunctional nitrogen nucleophiles yielded pyrimidotriazine 5 and 7. Hydrazinolysis of 2 by hydrazine hydrate afforded hydrazinopyrimidine 8. Treatment of 8 with acetophenone gave 9. Cyclization of 9 with Vilsmeier reagent afforded the pyrazole carbaldehyde 10. Interaction of 8 with benzylidenemalononitrile and/or ethyl ethoxymethylene- cyanoacetate afforded the pyrazoles 11 and 12. The reaction of 8 with p-chlorobenzaldehyde yielded 13, which was cyclized with thioglycolic acid to give thiazolidinone 14. The biological activity of selected compounds was investigated.

■ A MILD AND CONVENIENT ONE-POT SYNTHESIS OF 4-ARYL-N-OH-HANTZSCH ESTERS

Chun-Bao Miao,* Chun-Ping Dong, Yan-Hong Wang, Hai-Tao Yang, Qi Meng, Shu-Jiang Tu, and Xiao-Qiang Sun*

*School of Petrochemical Engineering, Changzhou University, Gehu Road 1#, Wujin Area, Changzhou City, China

Abstract

A general methodology to prepare a series of 4-Aryl-N-OH Hantzsch esters was developed. The key factor is to control the first-step of Michael addition at 0 °C. The method was practical to produce symmetrical and unsymmetric N-OH-Hantzsch esters in moderate yield. This class of compounds might have use in medicinal and material science.

■ Aculeatusquinones A-D, Novel Metabolites from the Marine-Derived Fungus Aspergillus aculeatus

Li Chen,* Wei-Wei Zhang, Qiu-Hong Zheng, Qin-Ying Liu, Ping Zhong, Xiao Hu, Zhe-Xiang Fang, and Qi-Qing Zhang*

*Institute of Biomedical and Pharmaceutical Technology & College of Chemistry and Chemical Engineering, Fuzhou University, No. 523, Gongye Road, Fuzhou City, 350002, China

Abstract

Four new aculeatusquinones A–D (1–4) and five known compounds, (5aS,6S,7S)-3,7-dihydroxy-6-methoxy-1,4,6,9-tetramethyl-6,7-dihydro-5aH-dibenzo[b,e][1,4]dioxepine-8,11-dione (5), 3,8-dihydroxy-1,4,6,9-tetramethyldibenzo[b,e][1,4]dioxepin-11-one (6), 4-O-demethylbarbatic acid (7), atraric acid (8), and 2,5-dimethyl-1,3-benzenediol (9), were isolated from the marine-derived fungus Aspergillus aculeatus. The structures of the new compounds were elucidated by spectroscopic methods, including one- and two-dimensional NMR and high-resolution mass spectrometric analyses. Two new compounds (2 and 4) showed cytotoxic effects on the HL-60, K562, and A-549 cell lines, with IC50 values ranging from 5.4 μM to 76.1 μM.

■ A New Method for the Synthesis of [1,2,4]Triazolo[1,5-a]pyridine Derivatives

Wei-Ming Zhao, Yan-Qing Ge,* Wei-Ren Xu, Gui-Long Zhao, Jiong Jia, and Jian-Wu Wang*

*School of Chemistry and Chemical Engineering, Shandong University, 27 Shanda Nanlu, Jinan,Shandong, 250100, China

Abstract

[1,2,4]triazolo[1,5-a]pyridine derivatives were conveniently synthesized by tandem reaction under mild conditions. The reaction mechanism was also proposed.

■ A Facile and Efficient Ultrasound-Assisted Synthesis of 1,3,5-Tris-arylhexahydro-1,3,5-triazine through Mannich Reaction

Xiaoxing Zhong and Guolan Dou*

*School of Safety Engineering, China University of Mining & Technology, Xuzhou 221116, China

Abstract

In this paper, we report a facile and efficient method for the synthesis of 1,3,5-tris-arylhexahydro-1,3,5-triazines by reaction of formaldehyde and aromatic amines catalyzed by triethylamine (Et3N) and assisted by ultrasound at room temperature. This method has the advantages of short reaction times, good yields and mild reaction conditions.

■ Synthesis of 7H-Thiopyrano[2,3-d]pyrimidines by Hydrobromic Acid-Mediated Cyclization of 1-[4-(1,1-Dimethylethylsulfanyl)pyrimidin-5-yl]prop-2-en-1-ols

Kazuhiro Kobayashi,* Teruhiko Suzuki, Ayumi Imaoka, Hidetaka Hiyoshi, and Kazuto Umezu

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

Abstract

7-Aryl- or 5,7-diaryl-4-methoxy-2-methylsulfanyl-7H-thiopyrano[2,3-d]pyrimidines have been prepared in satisfactory overall yields starting from 4-chloro-6-methoxy-2-(methylsulfanyl)pyrimidine by a facile three-step sequence. 4-Chloro-5-lithio-6-methoxy-2-(methylsulfanyl)pyrimidine was generated by the treatment of 4-chloro-6-methoxy-2- (methylsulfanyl)pyrimidine with LDA and was allowed to react with 3-arylprop-2-enals (cinnamaldehyde and its derivatives) or 1,3-diarylprop-2-en-1-ones (chalcone and its derivatives) to give the corresponding 3-aryl- or 1,3-diaryl-1-(4-chloropyrimidin-5-yl)prop-2-en-1-ol derivatives, respectively. Substitution of the 4-chloro group with sodium 1,1-dimethylethylthiolate gave 3-aryl- or 1,3-diaryl-1-[4-(1,1-dimethylethylsulfanyl)-pyrimidin-5-yl]prop-2-en-1-ol derivatives, of which treatment with an equivalent of hydrobromic acid provided the desired products.

■ Synthesis of 1,3-Dialkylperhydrobenzimidazolinium Salts and Their Catalytic Properties in Heck Reactions

Murat Yiğit,* Gülin Bayam, Beyhan Yiğit, and İsmail Özdemir

*Department of Chemistry, Faculty of Arts and Sciences, Adıyaman University, 02040 Adıyaman, Turkey

Abstract

Novel eight 1,3-dialkylperhydrobenzimidazolinium chloride salts 3a-h were prepared as precursors of N-heterocyclic carbenes by reacting N,N’-dialkylcyclohexandiamine, triethyl orthoformate and ammonium chloride. The salts were characterized spectroscopically and the complexes formed in situ from Pd(OAc)2 and 3 have been tested as catalysts in homogenous Heck coupling reactions.

■ First Total Syntheses of 1,3-Disubstituted β-Carboline Alkaloids, Dichotomide I and Marinacarbolines A-D: HETEROCYCLES, 2013, 87, 357, DOI: 10.3987/COM-12-12630

Shinji Tagawa, Tominari Choshi,* Asuka Okamoto, Takashi Nishiyama, Shiroh Watanabe, Noriyuki Hatae, and Satoshi Hibino*

*Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan