HETEROCYCLES

Published online: 11th April, 2019

■ An Efficient Two-Step Synthesis of 3-Aroyl-2,3-dihydro-1,4,2-benzodithiazine 1,1-Dioxides from Secondary Benzenesulfonamides, Sulfur, and Phenacyl Bromides

Kazuhiro Kobayashi* and Daiki Fujiwara

*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

An efficient method for the synthesis of 2-substituted 3-aroyl-2,3-dihydro-1,4,2-benzodithiazine 1,1-dioxides has been developed. Thus, 2,N-dilithio compounds of secondary benzenesulfonamides, generated by treating secondary benzenesulfonamides with two equivalents of butyllithium, are allowed to react with elemental sulfur and then phenacyl bromide and its derivatives to give N-substituted o-[(aroylmethyl)sulfanyl]benzenesulfonamides in moderate to good yields. Oxidative coupling of these precursors to the desired products can be achieved in moderate to good yields on successive treatment with sodium hydride and iodine under mild conditions.

Published online: 10th April, 2019

■ An Efficient Enantiospecific Synthesis of Neuroactive Glutamate Analogs

Shuntaro Tsukamoto, Hiyori Itagaki, Kenji Morokuma, Kei Miyako, Yuichi Ishikawa, Ryuichi Sakai, and Masato Oikawa*

*Yokohama City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan

Abstract

Herein we report improved enantiospecific synthesis and some structure-activity relationships of our heterotricyclic artificial glutamate analogs bearing seven-membered ring for the C-ring. Starting from readily available oxanorbornene rac-3, optically pure (2R)-TKM-107, (2R)-IKM-154, and the antipodes were synthesized in total nine steps for each. Mice in vivo assay indicated that only the (2R)-enantiomer was active in both cases. Behaviors phenotypes observed in the mice assay suggested that these compounds are similar in mode of action to that of IKM-159 but with discrete potency.

Published online: 10th April, 2019

■ Planar Chiral Phosphino[2.2]paracyclophanol-Catalyzed Highly Regio- and Stereoselective [3+2] Annulation Reaction of Morita–Baylis–Hillman Carbonates with Dicyanomethylideneoxindoles

Shinji Kitagaki,* Mayuka Tsuji, Hideki Teramoto, Naoko Takenaga, and Keisuke Yoshida

*Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan

Abstract

To demonstrate the utility of [2.2]paracyclophane as a chiral organocatalyst backbone, we examined a planar chiral pseudo-ortho-diarylphosphino[2.2]paracyclophanol, phosphino-PCP-ol, which has a spacer aryl group between the pseudo-ortho-substituted PCP-ol backbone and the diarylphosphino group. We tested this catalyst in the [3+2] annulation reaction of Morita–Baylis–Hillman carbonates, derived from aromatic aldehydes and methyl acrylate, with 3-(dicyanomethylidene)-2-oxindole. The catalyst produced the desired 3-spirocyclopentene-2-oxindoles in high yields, and high regio-, diastereo-, and enantioselectivities.

Published online: 28th March, 2019

■ Synthesis of N-alkyl Substituted Azasugar-tetrazole Hybrid Molecules via Ugi-azide Reaction

Hairong Luo,* Bangjian Xu, Lingyu Zhang, and Meihang Chen

*College of Material and Chemical Engineering, Tongren University, Tongren,Guizhou 554300, China

Abstract

An effective and facile method for the synthesis of N-alkyl substituted azasugar-tetrazole hybrid molecules is described. The one-pot Ugi-azide reaction provides convenient access to synthesis of α-tetrazolyl azasugar scaffolds as potential glucosidase inhibitors in moderate to good yields in methanol catalyst by lewis acid under mild conditions.

Published online: 28th March, 2019

■ Correction to “Facile and Efficient Access to Tetrahydrobenzo[b]pyrans Catalyzed by N,N-Dimethylbenzylamine”: HETEROCYCLES, 2016, 92, 75, DOI: 10.3987/COM-15-13360

Hamzeh Kiyani* and Mozhgan Sadat Jalali

*School of Chemistry, Damghan University, 36719-41167 Damghan, Iran

Published online: 28th March, 2019

■ Correction to “One-Pot and Efficient Synthesis of 5-Aminopyrazole-4-carbonitriles Catalyzed by Potassium Phthalimide”: HETEROCYCLES, 2017, 94, 276, DOI: 10.3987/COM-16-13623

Hamzeh Kiyani* and Maryam Bamdad

*School of Chemistry, Damghan University, 36719-41167 Damghan, Iran

Published online: 28th March, 2019

■ Correction to “Synthesis of Erlenmeyer-Plöchl Azlactones Promoted by 5-Sulfosalicylic Acid”: HETEROCYCLES, 2017, 94, 1314, DOI: 10.3987/COM-17-13711

Hamzeh Kiyani* and Shiva Aslanpour

*School of Chemistry, Damghan University, 36719-41167 Damghan, Iran

Published online: 28th March, 2019

■ Correction to “Sulfanilic Acid-Catalyzed Green Synthesis of 4-Arylidene-2-phenyl-5(4H)-oxazolones”: HETEROCYCLES, 2018, 96, 297, DOI: 10.3987/COM-17-13847

Hamzeh Kiyani* and Shiva Aslanpour

*School of Chemistry, Damghan University, 36719-41167 Damghan, Iran

Published online: 27th March, 2019

■ Conformational Control of a Pyrrole-Based Amide Pentamer by Dihydrogen Phosphate Anion Binding

Jiulong Li, Guoping Li,* Chaocao Lu, Bu Htan, Chunmiao Ma, and Quan Gan*

*School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, China

Abstract

Conformational control is of importance for compounds to implement their properties and functions. In this work, a pyrrole-based amide pentamer 1 was synthesized. NOESY NMR experiments show it adopts two main conformations, one of which can be sorted out and stabilized via binding of a dihydrogen phosphate anion.

Published online: 27th March, 2019

■ Visible-Light-Enabled C(sp2)–H Difluoroalkylation of Aldehyde-Derived Hydrazones Under Metal-Free Conditions

Wen-Qiang Liu, Wei-Hao Chen, Xiao-Xuan Li, Wei-Ke Tang, Ting-Ting Tao, and Yi-Si Feng*

*School of Chemistry and Chemical Engineering, Hefei University of Technology, Anhui 230009, China

Abstract

A Eosin Y-catalyzed C(sp2)-H difluoromethylation of aldehyde-derived hydrazones between difluoroalkyl bromides and aldehyde-derived hydrazones is reported. This reaction has a wide range of substrates and occurs under metal-free condition. A mechanism that involves a difluoroacetate radical via single electron transfer (SET) pathway is proposed for this reaction.

Published online: 27th March, 2019

■ Diastereoselective Synthesis of 3-Alkylindoloquinolizine Derivatives via Regiospecific Oxidative Cyclization

Susana Morales-Barba, Joel L. Terán, Dino Gnecco, María L. Orea, David M. Aparicio, Víctor Gómez-Calvario, and Jorge R. Juárez*

*Centro de Química, Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Edif. IC8, Ciudad Universitaria 72570, Mexico

Abstract

3-Alkylindoloquinolizine alkaloids were synthetized in two steps from enantiopure 3-alkylpiperidines through sequential N-alkylation and regiospecific and diastereoselective oxidative cyclization.

Published online: 27th March, 2019

■ The Use of Formaldehyde in the Rhodium-Catalyzed Linear-Selective Hydroformylation of Vinylheteroarenes

Jian Pan, Tsumoru Morimoto,* Hideyuki Kobayashi, Hiroki Tanimoto, and Kiyomi Kakiuchi

*Division of Materials Science, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan

Abstract

An accessible protocol for the linear-selective hydroformylation of vinylheteroarenes using formaldehyde as a substitute for syngas is reported. The simultaneous use of BIPHEP and Nixantphos ligands permitted a high regioselectivity (linear/branched = up to 93/7) and moderate yield of isolated product (up to 84%) to be obtained. Under such catalytic conditions, vinylheteroarenes containing a vinyl group at the 2-position in the heterocycle ring reacted more linear-selectively with formaldehyde than at the 3-position.

Published online: 25th March, 2019

■ An Efficient Synthesis of N-Aryl-2-(indol-3-yl)acetamides via Multi-Component Reactions

Guo-Ning Zhang, Mengye Zhang, Xiaonan Du, Mei Zhu, Juxian Wang,* Daqing Shi,* and Yucheng Wang*

*Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China

Abstract

An efficient synthesis of N-aryl-2-(indol-3-yl)acetamide derivatives via a four-component reaction of arylglyoxal monohydrate, Meldrium’s acid and anilines under microwave irradiations is described. This protocol has the advantages of high efficiency, mild reaction conditions, a one-pot procedure, and materials available.

Published online: 25th March, 2019

■ Preparation of Some Novel Trisubstituted 1,3,5-Triazines and Hybrid Linker Mode 1,3,5-Triazine Derivatives and Their Biological Evaluation

Nobuko Mibu, Kazumi Yokomizo, Kanae Yamada, Junko Matsuyama, Syoko Tomonaga, Izumi Sakai, Ryo Sato, Yuki Kawano, Yumemi Matsumoto, Yuka Fujita, Yusuke Inoue, Masaya Iida, Kaneto Hashiguchi, Jian-Rong Zhou, Makoto Furutachi, and Kunihiro Sumoto*

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

Abstract

We report a new route to the preparation of C3-symmetrical multivalent hybrid-type molecules having a tris-aminoethylamine (TAEA) linker group and 1,3,5-triazine recognition moieties in the molecule and we also report the results of biological evaluation of their anti-herpes simplex virus type 1 (anti-HSV-1) activity and cytotoxic activity against Vero cells. Among the tested compounds, a new mid-size C2-symmetrical multivalent hybrid-type molecule (10aq) showed a high level of anti-HSV-1 activity (EC50 = 19.7 μM) with low cytotoxicity (CC50 > 200 μM) against Vero cells. A new CS-symmetrical multivalent derivative (4ab) also showed high anti-HSV-1 activity (EC50 = 1.77 μM) with low cytotoxicity (CC50 > 200 μM). The hybrid-type C2-symmetrical multivalent mid-size molecule (10aq) seems to be an interesting new lead in the search for new hybrid-type symmetrical multivalent antiviral compounds.

Published online: 15th March, 2019

■ Synthesis of [1,4]Oxathiino[2,3-d]pyrimidines Starting with 4,6-Dichloro-2-(methylsulfanyl)pyrimidine

Kazuhiro Kobayashi,* Kota Yamasaki, 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 convenient method for the preparation of 7-(het)aryl[1,4]oxathiino[2,3-d]pyrimidine derivatives using an easily operated two-step sequence starting from 4,6-dichloro-2-(methylsulfanyl)pyrimidine (DCSMP) have been developed. Thus, the starting material is treated with LDA to generate the 5-lithio derivative, which is allowed to react with sulfur and then phenacyl bromide and its derivatives to give 1-(het)aryl-2-{[4,6-dichloro-2-(methylsulfanyl)pyrimidin-5-yl]sulfanyl}ethanones. These pyrimidinyl ketones undergo ring closure upon treatment with triethylamine to provide the corresponding desired products in reasonable overall yields from DCSMP.

Published online: 14th March, 2019

■ Agesamines A and B, New Dibromopyrrole Alkaloids from the Sponge Agelas sp.

Ayako Katsuki, Hikaru Kato, Yuji Ise, Fitje Losung, Remy E. P. Mangindaan, and Sachiko Tsukamoto*

*Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-hon-machi, Kumamoto 862-0973, Japan

Abstract

New dibromopyrrole alkaloids, agesamines A (1) and B (2), were obtained as an inseparable epimeric mixture from a marine sponge Agelas sp., collected in Indonesia. The planar structures were elucidated by analysis of spectroscopic data, and the absolute configuration was determined by the calculated ECD spectrum.

Published online: 12th March, 2019

■ Synthesis of 1,2-Benzothiazole-3(2H)-thione 1,1-Dioxides by DBU-Promoted Cyclization of 2-(Aminosulfonyl)-N-methylbenzothioamide Derivatives

Kazuhiro Kobayashi* and Daiki Fujiwara

*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

An efficient method for the preparation of 2-alkyl-1,2-benzothiazole-3(2H)-thione 1,1-dioxides has been developed. Thus, the reaction of 2,N-dilithio derivatives of N-alkylbenzenesulfonamides with methyl isothiocyanate affords 2-[(alkylamino)sulfonyl]-N-methylbenzothioamides, which are treated with a catalytic amount of DBU in refluxing toluene to provide the desired products in moderate to good yields.

Published online: 27th February, 2019

■ Design and Synthesis of Artificial Ladder-Shaped Polyethers for Exploring Biological Functions

Tohru Oishi*

*Department of Chemistry, Faculty of Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan

Abstract

Ladder-shaped polyethers (LSPs) are marine natural products produced by dinoflagellates. The unique molecular structure and interesting biological activities have attracted considerable attention of the synthetic community. On the other hand, artificial ladder-shaped polyethers (ALPs) have been designed and synthesized for exploring biological functions. In this review, design and synthesis of ALPs are summarized focusing on the development of synthetic strategies and methodologies.

Published online: 27th February, 2019

■ Diastereo–/Enantioselective Diels–Alder Synthesis of 14β-Hydroxysteroid Scaffolds: A Combined Experimental and DFT Study

Clovis Peter, Philippe Geoffroy, Takatsugu Murata, Takayuki Tonoi, Isamu Shiina,* and Michel Miesch*

*Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan

Abstract

Natural, non-natural and ent-14β-hydroxyandrostane derivatives closely related to the cardenolide and bufadienolide skeletons were readily available through highly diastereo-/enantioselective Diels–Alder reactions calling for high pressure or Lewis acid activation. Moreover, in the presence of (R)- or (S)-carvone as chiral dienophile, the Diels–Alder reaction took place under chemodivergent parallel kinetic resolution control. Based on experimental and DFT studies, reasonable mechanism insights were postulated to explain the concave/convex and endo/exo selectivities observed for the formation of the different Diels–Alder and Diels–Alder–Michael adducts.

Published online: 25th February, 2019

■ Study toward an Asymmetric and Catalytic Synthesis of Koumine

David Reyes Loya, Jacques Maddaluno, and Michaël De Paolis*

*Normandie Université, UNIROUEN, INSA de Rouen, CNRS, Laboratoire COBRA (UMR 6014 & FR 3038), 76000 Rouen, France

Abstract

A synthetic study of koumine, a natural product with a densely functionalized and inspiring heterocyclic skeleton, was conducted by exploring a strategy of desymmetrization of 1,3-cyclohexanedione by an intramolecular vinylation reaction of an enolate under palladium catalysis to give a strained bridgehead 1,3-cyclohexanedione scaffold. In the course of the study, a domino ring expansion was discovered and developed.

Published online: 25th February, 2019

■ The Effect of Lithium Ion on the Stereoselectivity of the Intramolecular Michael Addition of an N-Arylsulfoximine Anion

Aswin Garimalla, Quin Long, Christopher J. Cramer,* and Michael Harmata*

*Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA.

Abstract

The stereochemical outcome of the intramolecular Michael addition of a sulfoximine carbanion to a Z-configured α,β-unsaturated ester is dependent on lithium ion coordination between the oxygen on the sulfoximine and the carbonyl oxygen of the ester, based on both experimental and computational studies. Formally, this leads to a more sterically congested structure than might otherwise be preferred. Indeed, addition of HMPA, a substance capable of effective solvation of lithium cations, changes the stereochemical course of the reaction dramatically.

Published online: 20th February, 2019

■ 1,2-cis-Selective Formation of a Unique Amino-Containing Amino Glycoside by Endocyclic Cleavage Strategy

Shino Manabe* and Yukishige Ito*

*Synthetic Cellular Chemistry Laboratory, RIKEN, Hirosawa, Wako, Saitama 351-0198, Japan

Abstract

2-Acetamido-4-amino-2,4,6-trideoxy-α-D-galactopyranoside (AAT), a unique aminated sugar unit, is often found in zwitterionic polysaccharides. Stereoselective formation of the 1,2-cis linkage of these unique sugar derivatives was achieved by an anomerization reaction based on an endocyclic cleavage process.

Published online: 20th February, 2019

■ Construction of Pinpoint-Fluorinated Benzothiophene Frameworks Using Palladium-Catalyzed Cyclization of o-(Fluorovinyl)phenyl-Substituted Thiophenes

Kohei Fuchibe, Nobushige Tsuda, Kento Shigeno, and Junji Ichikawa*

*Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Ten-nodai, Tsukuba-shi, Ibaraki 305-8571, Japan

Abstract

o-(2,2-Difluorovinyl)phenyl- or o-(1,2,2-trifluorovinyl)phenyl-substituted thiophenes underwent palladium(II)-catalyzed Friedel–Crafts-type cyclization on the fluorovinyl moieties to construct regioselectively monofluorinated or difluorinated benzothiophene frameworks (pinpoint-fluorinated naphtho[b]thiophenes). The cyclization of less nucleophilic 2-substituted thiophenes was effectively promoted by the addition of a CuOTf complex. Cyclization was also conducted in a tandem process, which facilitated the rapid synthesis of higher-order pinpoint-fluorinated PAHs (polycyclic aromatic hydrocarbons) bearing thiophene rings. Furthermore, cyclization was applied to the corresponding furan systems, which led to pinpoint-fluorinated naphtho[b]furans.

Published online: 18th February, 2019

■ Synthesis of Di(3-thienyl)benzoporphyrin

Tetsuo Okujima,* Kota Muramatsu, Shigeki Mori, Masayoshi Takase, and Hidemitsu Uno

*Graduate School of Science and Engineering, Ehime University, Matsuyama 790-8577, Japan

Abstract

We have successfully synthesized 2,3-di(3-thienyl)benzo[b]porphyrin based on retro Diels–Alder reaction of bicyclo[2.2.2]octadiene(BCOD)-fused porphyrin and investigated its photoisomerization reaction.

Published online: 15th February, 2019

■ Synthesis of a Poly-Heterocyclic Tetra-Substituted Alkene via a Palladium-Catalyzed Four-Fold Domino Reaction for the Design of Polymeric Molecular Switches

Taukeer A. Khan and Lutz F. Tietze*

*Institute of Organic and Biomolecular Chemistry, University of Goettingen, Tammannstrasse 2, 37077 Goettingen, Germany

Abstract

A facile synthesis of a complex poly-heterocyclic tetrasubstituted alkene 4 with intrinsic helical chirality containing two acrylate moieties suitable for polymerization is described. Compound 4 can act as a molecular switch and was prepared via a palladium-catalyzed four-fold domino reaction including two Sonogashira reactions and two domino-carbopalladation/C‒H-activation reactions.

Published online: 15th February, 2019

■ Optimized Synthesis and Solid State Investigations on the Drug Candidate Encenicline Hydrochloride

Gerhard Laus, Sandro Neuner, Ramona Metz, Thomas Müller, Volker Kahlenberg, Thomas Gelbrich, Sven Nerdinger,* Erwin Schreiner, Verena Adamer, Klaus Wurst, and Herwig Schottenberger

*Global Portfolio, Sandoz GmbH, Biochemiestrasse 10, 6250 Kundl, Austria

Abstract

For the production of drug substances a robust, scalable process delivering the active pharmaceutical ingredient (API) in excellent chemical and polymorphic purity is required. For this purpose we developed a novel imidazole-mediated one-pot procedure for the preparation of encenicline hydrochloride monohydrate, which crystallizes directly from the reaction mixture as pure non-hygroscopic polymorph (Form I). Solid state studies revealed a series of additional new physical forms for which crystal structures have been determined by single crystal X-ray diffraction.

Published online: 14th February, 2019

■ Preparation of Tricyclic Analog as CDE Ring Model of Renieramycin Marine Natural Product by Novel Photo-Induced Transformation of 6-Methoxy-1,2,3,4-Tetrahydroisoquinoline-5,8-dione

Masashi Yokoya, Shohei Takahashi, and Naoki Saito*

*Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan

Abstract

2-Acetyl-6-[(benzyloxy)methyl]-9-methoxy-8-methyl-11,11a- dihydro-2H-pyrazino[1,2-b]isoquinoline-1,4,7,10(3H,6H)-tetraone (11a) was prepared as the CDE ring model of renieramycins, and its novel photo-induced transformation was demonstrated to construct a 1,3-dioxol ring.

Published online: 14th February, 2019

■ Synthesis of Furan-Fused Silole and Phosphole by One-Pot Halogen Dance/Homocoupling of Bromofurfural Derivative

Kentaro Okano,* Yuki Murase, and Atsunori Mori

*Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan

Abstract

Synthesis of a furan-fused silole and phosphole was achieved through a one-pot halogen dance/homocoupling of a bromofurfural derivative followed by the formation of the silole and phosphole skeleton.

Published online: 13th February, 2019

■ Asymmetric Synthesis of t-Butyl 3-Alkyl-oxindole-3-carboxylates via Chiral Phosphoric Acid Catalyzed Desymmetrization of Di-t-butyl 2-Alkyl-2-(2-aminophenyl)malonates

Kyoji Ishida, Masahiro Shimizu, Yu-suke Yamai, Itaru Natsutani, Shinichi Uesato, Yasuo Nagaoka, and Takaaki Sumiyoshi*

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

Abstract

We describe the asymmetric desymmetrization of di-t-butyl 2-alkyl-2-(2-aminophenyl)malonates to prepare enantioenriched t-butyl 3-alkyl-oxindole-3-carboxylates using (S)-TRIP, a chiral phosphoric acid. Optimization study increased the enantioselectivity up to 66% ee.

Published online: 8th February, 2019

■ Tripeptide-Catalyzed Asymmetric Aldol Reaction of Trifluoromethylated Aromatic Ketones with Acetone

Kazumasa Kon, Yoshihito Kohari,* and Miki Murata

*School of Earth, Energy and Environmental Engineering, Faculty of Engineering, Kitami Institute of Technology, 165 Koen-Cho, Kitami, Hokkaido 090-8507, Japan

Abstract

The development of H-Pro-Gly-Ala-OH (3d) to realize an inexpensive and simple organocatalytic system for the direct asymmetric aldol reaction of trifluoromethylated aromatic ketone 1 with acetone was achieved. The 3d-catalyzed aldol reaction of 1a–1j provided various aldol adducts 4a–4j with up to 81% yield and 77% ee. An investigation of the transition state via DFT calculations revealed that hydrogen bonding was important for the revelation of the enantioselectivity.