HETEROCYCLES

■ Contents

■ Direct Enantioselective Alkynylation of α-Ketoesters and α-Ketiminoesters Catalyzed by [bis(Oxazoline)phenyl]rhodium(III) Complexes

Kazuhiro Morisaki, Hiroyuki Morimoto, Kazushi Mashima, and Takashi Ohshima*

*Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan

Abstract

This review summarizes our studies of the direct enantioselective alkynylation of α-ketoesters and α-ketiminoesters catalyzed by [bis(oxazoline)phenyl]rhodium(III) ((phebox)Rh(III)) complexes. The reactions provide chiral α-tetrasubstituted propargyl alcohols and propargylamines under proton-transfer conditions in high yield and with high enantioselectivity. The unique nature of (phebox)Rh(III) complexes allows the reactions to occur in the presence of various functional groups, including an electrophilic aldehyde functionality. Mechanistic studies revealed that the generation of (alkynyl)Rh(III) complexes limited the overall reactivity, which led us to use (trimethylsilylethynyl)(phebox)Rh(III) complexes as efficient pre-catalysts. The use of (trimethylsilylethynyl)(phebox)Rh(III) complexes reduced catalyst loading to as low as 0.5 mol%, and expanded the substrate scope to unprecedented α-ketiminophosphonate and cyclic N-sulfonyl α-ketiminoesters.

■ Synthesis of Caprazamycins and Related Natural Products

Takumi Watanabe*

*Institute of Microbial Chemistry, Tokyo (BIKAKEN), 3-14-23 Kamiosaki Shinagawa-ku, Tokyo 141-0021, Japan

Abstract

Caprazamycins are the lead compound for CPZEN-45, which exhibits activity against extensively drug resistant tuberculosis (XDR-TB) and is currently under preclinical studies. The development of an efficient synthetic route to caprazamycins and related compounds is expected to facilitate structure-activity relationship studies on anti-TB agents. This review summarizes current synthetic strategies for caprazamycins, liposidomycins, caprazol, and CPZEN-45, with a particular focus on stereocontrol and diazepanone ring formation.

■ Synthetic Methods for Ring-Fluorinated Pyrrole Derivatives

Takeshi Fujita and Junji Ichikawa*

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

Abstract

The synthesis of pyrrole ring-fluorinated heterocyclic compounds has been increasingly studied in response to the rising demand for these compounds as potential drugs, agrochemicals, and advanced materials. The approaches to their synthesis are grouped into two categories in terms of how the fluorine substituents are introduced: (i) direct fluorination of the existing pyrrole and related rings and (ii) the construction of pyrrole rings via fluorine-containing precursors. This review overviews recent synthetic methods for ring-fluorinated pyrrole derivatives according to the types of reactions.

■ Huisgen Cycloaddition with Acetylene Gas by Using an Amphiphilic Self-Assembled Polymeric Copper Catalyst

Yoichi M. A. Yamada,* Hiroshi Yoshida, Aya Ohno, Takuma Sato, Toshiaki Mase, and Yasuhiro Uozumi*

*Institute for Molecular Science (IMS), 5-1 Higashiyama, Myodaiji, Okazaki, Aichi 444-8787, Japan

Abstract

A copper-mediated Huisgen cycloaddition, aka the copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC), of flammable acetylene gas and a variety of organic azides proceeded smoothly by using our amphiphilic self-assembled polymeric copper catalyst MPPI-Cu to give the corresponding triazoles in high yield. MPPI-Cu was readily reused without loss of catalytic activity. The XAFS and DFT calculation studies revealed the local structure near Cu atom of an active species MPPI-Cu(I).

■ Ni-Catalyzed Three-Component Coupling of 4-Methylene-2-oxazolidinones, Alkynes, and Trimethylaluminum

Tatsuya Yamahira, Ryo Ninokata, Gen Onodera, and Masanari Kimura*

*Graduate School of Engineering, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

Ni(0) catalyzes the three-component coupling reactions of 4-methylene-2-oxazolidinones, alkynes, and trimethylaluminum accompanied by extrusion of carbon dioxide to furnish 2-methyl-3-amino-2,5-heptadiene with high regio- and stereoselectivities.

■ Kinetic Switching of Achirality/Chirality Memorization of meta-Ethynylpyridine Polymer by Coordination of Cu(II) Outside the Polymer

Hajime Abe,* Shunsuke Takashima, and Masahiko Inouye*

*Graduate School of Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan

Abstract

Memorization of achirality and chirality of meta-ethynylpyridine polymer with amino side chains was actualized by cross-linking with Cu(OTf)2 as a precursor. When β-D-glucopyranoside and Cu(OTf)2 were added to the coordinative polymer in this order, a CD band was induced around 340 nm and enhanced by Cu(II)-coordination. On the other hand, in the case Cu(OTf)2 and β-D-glucopyranoside were added to the polymer in this order, only a weak CD band was induced because achirality was memorized before the addition of the glucoside. For the chiral helical complex with enhanced CD, a chiral memorization effect was assured by the addition of β-L-glucopyranoside causing very slow decay of the CD band.

■ α-Functionalization of Tetrahydroisoquinolines with Activated Alkyl Bromide under Photoredox Catalysis

Takafumi Ide, Kazunori Shimizu, Yuji Kawato, Hiromichi Egami, and Yoshitaka Hamashima*

*School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan

Abstract

Benzylic C-H functionalization of N-aryl-tetrahydroisoquinolines (THIQs) with various benzyl bromides was developed using a photoredox iridium (Ir) catalyst under blue LED irradiation, affording arylmethyl group-substituted THIQs in moderate to good yields (up to 82%). This photoredox catalyst-mediated reaction was also applicable to other activated bromides, including allyl bromide, cinnamyl bromide, propargyl bromide, and α-bromoacetate. We propose that photoredox catalyst-mediated electron transfer generates a radical species from the THIQ and another radical from the bromide, and then radical-radical cross-coupling occurs to form a new carbon-carbon bond.

■ Chemistry of Renieramycins. 16. Structure of 7-Desmethylrenieramycin O (= 14α-Hydroxyrenieramycin S) from Blue Sponge, Xestospongia sp.

Naoki Saito,* Ai Hiramatsu, Hiromi Hirade, Mitsue Kubota, Ryoko Toyoshima, Akiya Fujino, Natchanun Sirimangkalakitti, Khanit Suwanborirux,* and Gisela P. Concepcion

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

Abstract

A new renieramycin-type marine natural product was isolated from the blue sponge Xestospongia sp. found in the Philippines and Thailand, and its structure was elucidated to be 7-demethylrenieramycin O (= 14α-hydroxyrenieramycin S, 1) by comparing its spectral data with those of renieramycins O and S. Exposure of a dichloromethane solution of renieramycin O to sunlight gave compound 1 along with renieramycin U. Compound 1 showed weak cytotoxicity to several human cancer cell lines.

■ Palladium- and Norbornene-Catalyzed Synthesis of Highly Functionalized Thiophenes: The Remarkable Effect of Electron-Poor Olefins as Ligand

Nicola Della Ca’,* Elena Motti, Giovanni Maestri, and Max Malacria*

*ICSN CNRS UPR2301, 1 Av. de la Terrasse, Bat. 27, 91198 Gif s/Yvette, France

Abstract

Highly functionalized heterocyclic compounds were synthesized by palladium and norbornene catalysis starting from ortho-substituted aryl iodides, aryl bromides and 3,4-ethylenedioxythiophene. The addition of methyl cinnamate to the reaction mixture was found to be crucial in order to obtain selectively the unsymmetrical product.

■ Facile Synthesis of Spirooxindoles via an Enantioselective Organocatalyzed Sequential Reaction of Oxindoles with Ynone

Shinobu Takizawa,* Kenta Kishi, Miki Kusaba, Bai Jianfei, Takeyuki Suzuki, and Hiroaki Sasai*

*The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan

Abstract

The reaction of oxindole 1a with phenylprop-2-yn-1-one (2a) was promoted by the chiral multifunctional phosphine catalyst 4a derived from (S)-valine, giving spirooxindole 3a in good yield and high enantioselectivity. The obtained spirooxindole forms a common scaffold of a vast number of natural products exhibiting various biological activities.

■ Synthesis of Porphyrin-Polythiophene Nanotubes and Their Zinc Complex and Silver Nanoparticle Composites

Noritaka Takeuchi, Saya Ueda, Tsukasa Nakahodo, and Hisashi Fujihara*

*Department of Applied Chemistry, Kindai University, Kowakae, Higashi-Osaka 577-8502, Japan

Abstract

The template-based electropolymerization of terthienyl-porphyrin, 1, and its zinc porphyrin, Zn-1, in a nanoporous alumina template produced the corresponding new porphyrin nanotubes, poly-1 NTs and poly-Zn-1 NTs, respectively. The encapsulation of silver nanoparticles into the inner cavity of the poly-1 NTs provides the silver nanoparticle-porphyrin hybrid NTs.

■ Depsidones and Diaryl Ethers from the Vietnamese Lichen Parmotrema mellisii

Duy Hoang Le, Yukiko Takenaka, and Takao Tanahashi*

*Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan

Abstract

The Vietnamese lichen Parmotrema mellissii of the family Parmeliaceae was chemically investigated to isolate five new depsidones (1, 6, 9–11) and three new diaryl ethers (3, 4, 7) along with seventeen known lichen substances. Their structures were determined by spectroscopic methods.

■ Triphosgene-Mediated Chlorolactamization and Aminolactamization of Homoallylic Amines

Yuika Nishida, Norihiko Takeda, Okiko Miyata,* and Masafumi Ueda*

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

Abstract

Two types of aminocarbonylation reaction of homoallylic amines have been developed. The treatment of homoallylic amines with triphosgene in dichloromethane led to formation of the corresponding β-chlorolactams via Prins-type cyclization of a carbamoyl chloride intermediate. For the reaction in acetonitrile, β-aminolactams were obtained via sequential Prins-type cyclization and Ritter-type reactions.

■ Stylissamide I, a New Cyclic Heptapeptide from an Okinawan Marine Sponge Stylissa sp.

Takaaki Kubota,* Kenta Nakamura, Shin-ichiro Kurimoto, Kanae Sakai, Jane Fromont, Tohru Gonoi, and Jun'ichi Kobayashi*

*Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan

Abstract

A new cyclic heptapeptide, stylissamide I (1), was isolated from an Okinawan marine sponge Stylissa sp. The structure of stylissamide I (1) was elucidated to be cyclo-(L-Tyr1-L-Tyr2-L-Tyr3-L-Pro1-L-Pro2-L-Val-L-Pro3) by extensive spectral analyses and Marfey’s method. Stylissamide I (1) showed antifungal activity against Aspergillus niger.

■ Effect of Leaving Group Substituents on the Microfluidic Synthesis of [18F]3-Fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ([18F]FPEB)

Thomas M. Moore, Murthy R. Akula, Lee Collier, Gilles Tamagnan, Caroline Papin, David Alagille, and George W. Kabalka*

*Departments of Chemistry and Radiology, University of Tennessee, Knoxville, Tennessee, 37996-1600, U.S.A.

Abstract

A commercial microfluidic reactor system has been used to synthesize the mGLUR5 receptor imaging agent [18F]FPEB. To study the effect of leaving group substituents on the synthesis of the desired compound, the chloro-, bromo-, iodo-, and nitro-substituted precursors for FPEB were evaluated. Precursor concentrations of 4 – 10 mg/mL were evaluated in various solvents, with temperature ranges between 120 and 220 oC, and total processing times of less than five minutes. Optimized incorporation yields ranged from 5% to 69.4% depending on the precursor used.

■ Oxidative Desulfurization of Electron-Donating 5,5,7,7-Tetraaryl-5,7-dihydrodibenzo[c,e]thiepins and the Related Heterocycles: Generation of Dicationic Dyes upon Two-Electron Oxidation

Takanori Suzuki,* Takuma Kuroda, Hitomi Tamaoki, Sho Higasa, Tatsuo Nehira, Ryo Katoono, Yusuke Ishigaki, Kenshu Fujiwara, Takanori Fukushima, and Hidetoshi Yamada

*Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Hokkaido 060-0810, Japan

Abstract

Upon oxidation of the title heterocycle (1A) with dimethylamino groups, elemental sulfur is extruded to form dicationic dye (1B2+), from which the starting dibenzothiepin derivative was generated by the reaction with Na2S. The bay-region substituents enhance configurational stability, so that, the optically pure heterocycles [(M)-2A, (M)-3A)] can be obtained in terms of helicity of one-handedness by starting with the corresponding optically pure dicationic dyes [(R)-2B2+, (R)-3B2+)]. Similar oxidative desulfurization occurs in dibenzo-1,5-oxathiocin 4A, a structurally related 8-membered heterocycle.

■ Synthesis of Multi-Substituted 1,4-Benzoxazine Using an Umpolung Reaction with 2-Oxo-1,4-benzoxazine-3-carboxylates

Takanori Tanaka, Isao Mizota, Kazuto Umezu, Akinori Ito, and Makoto Shimizu*

*Department of Chemistry for Materials, Graduate School of Engineering, Mie University, 1577 Kurimamachiya-cho Tsu, Mie 514-8507, Japan

Abstract

This report describes a one-pot synthesis of multi-substituted 1,4-benzoxazine derivatives by atom economical N,C-dialkylation reaction of 1,4-benzoxazine derivatives with various organozinc reagents and ketene silyl acetals (KSA).

■ Nucleophilic Substitution Reactions on Indole Nucleus: Formation of (3a,8a-cis)-1,2,3,3a,8,8a-Hexahydropyrrolo[2,3-b]indoles Having a Substituent at the 3a-Position

Fumio Yamada, Aya Goto, Masakazu Hasegawa, Kensuke Kobayashi, and Masanori Somei*

*Faculty of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan

Abstract

Various nucleophiles, such as indole, 1,2,3-trimethoxybenzene, anisole, phenol, and pyrrole, reacted with 1-hydroxy-Nb-trifluoroacetyltryptamine under the presence of mesyl chloride to give novel series of (3a,8a-cis)-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indoles having a substituent at the 3a-position. Their structures and by-products were strictly determined.

■ Synthesis of Benzyl Tetra-O-acetyl-α-L-glucopyranoside from Benzyl 2,3-Dideoxy-β-D-erythro-hex-2-enopyranoside

Hayato Okazaki, Yuji Ueda, Kengo Hanaya, Mitsuru Shoji, and Takeshi Sugai*

*Department of Pharmaceutical Science, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo 105-8512, Japan

Abstract

Benzyl tetra-O-acetyl-α-L-glucopyranoside was synthesized from benzyl 2,3-dideoxy-β-D-erythro-hex-2-enopyranoside in six steps and 19% overall yield. Epoxidation from the β-side of the double bond between C-2 and C-3 of the starting material along with the subsequent regioselective ring opening by the backside attack of a hydroxide ion at C-3 furnished an intermediate with D-ido-stereochemistry. The inversion at C-5 was performed by an epimerization, by way of an N-cyclohexylenamine, after the chemoselective oxidation at primary hydroxy group of the C-6 to an aldehyde. The present synthesis of L-glucose derivatives implies the sequential stereochemical inversion of C-2 to C-5 of D-glucose. As the present synthesis keeps the whole skeleton and the order of carbon atoms based on the original numbering of D-glucose, it would work well for the synthesis of specifically labeled derivatives, beginning from isotopically labeled D-glucoses.

■ Catalytic and Enantioselective Diels-Alder Reaction of Silyloxydiene That Incorporates a Pyrrolidine Ring, and Its Application to the Construction of Chiral Tri- and Tetracyclic Skeletons

Shinji Harada, Saki Nakashima, Wataru Yamada, Takahiro Morikawa, and Atsushi Nishida*

*Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan

Abstract

The enantioselective Diels-Alder reaction of silyloxydiene that incorporates a pyrrolidine ring was studied. This reaction was catalyzed by a chiral holmium complex and gave multi-substituted chiral hydroindoles that contained a silyl enol ether, which is a key functional group for further transformations. We demonstrate here the synthesis of chiral pyrroloacridine, dibenzodiazocine, and pyrrolocarbazole skeletons.

■ A Remarkably Useful Sulfur Bridge as Synthetic Lever in an Approach to Javanicin B

Amélie Dion and Claude Spino*

*Département de chimie, Université de Sherbrooke, 2500 Boul. Université, Sherbrooke, QC, J1K 2R1, Canada

Abstract

A concise and efficient synthesis of a non-racemic advanced intermediate to the quassinoid javanicin B is disclosed. The strategy is centred on a triple diene-transmissive Diels-Alder cycloaddition to form the four rings of javanicin B. A sulfur bridge plays several crucial roles allowing an intramolecular cycloaddition to occur with complete stereoselectivity, controlling the stereochemical outcome of another cycloaddition, and transforming into a pivotal electrophile for the introduction of a particularly hindered methyl group.

■ Simultaneous Functionalization and Cyclization of 2-Ethynylaniline Derivatives to Indoles

Kou Hiroya,* Shin Itoh, Kiyofumi Inamoto, Hiroki Shigehisa, and Takao Sakamoto

*Faculty of Pharmacy, Musashino University, 1-1-20 Shin-machi, Nishitokyo-shi, Tokyo, Japan

Abstract

Two different kind of sequential cyclization-functionalization are developed. Namely, cyclization-chlorination of 2-ethynylaniline derivatives using CuCl2 gave 3-chloro- and 3,5-dichloroindole derivatives. The plausible mechanism for this reaction is also discussed. On the other hand, the reaction between 2-ethynylaniline derivatives and Cu(NO3)2·3H2O in THF provided C4-nitro compound. After being changed the solvent from THF to DMF, followed by heating, 5-nitroindole derivatives was afforded.

■ A Double Hemiketal Formation/Hetero-Michael Addition Approach to the [6,5,5]-Dispiroketal System of Spirolides

Hiroyuki Yamakoshi, Akinori Toita, Toshihiro Igari, Keisuke Takeda, Shunichi Hashimoto, and Seiichi Nakamura*

*Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan

Abstract

An approach to the [6,5,5]-dispiroketal ring system of spirolides is described. It was found that cisoid isomers, which suffered from a destabilizing dipole–dipole interaction, were preferentially formed over transoid isomers by a double hemiketal formation/hetero-Michael addition sequence regardless of the reaction conditions used. However, the stereochemistry at C12 was controlled by the methyl group at C13, resulting in the preferential formation of undesired 12S isomers. As expected from precedents, the desired isomer could be obtained upon exposure of the 12R isomer, formed by the sequence, to TsOH in benzene, albeit in a ratio of 1:3 favoring its C15-epimer.

■ Synthesis of Lamellarins via Regioselective Assembly of 1,2-Diarylated [1]Benzopyrano[3,4-b]pyrrol-4(3H)-one Core

Tsutomu Fukuda,* Takatoshi Katae, Issei Harada, and Masatomo Iwao

*Division of Chemistry and Materials Science, Graduate School of Engineering, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

A modular synthesis of lamellarins has been developed. The key reactions in this synthesis are the assembly of 1,2-diarylated [1]benzopyrano[3,4-b]pyrrol-4(3H)-ones from a preexisting [1]benzopyrano[3,4-b]pyrrol-4(3H)-one core and the appropriate arylboronic acids. The obtained 1,2-diarylated [1]benzopyrano[3,4-b]pyrrol-4(3H)-ones could be easily converted into the corresponding lamellarin derivatives by intramolecular annulation between the pyrrole nitrogen and the C2 aromatic ring.

■ Absorption and Fluorescence Properties of Chalcones Having Pyrrole or Indole Moiety

Yukino Shinozaki and Tatsuo Arai*

*Graduate School of Pure and Applied Science, University of Tsukuba, Tennodai, Tsukuba, Ibaraki 305-8571, Japan

Abstract

2'-Hydroxychalcone derivatives having pyrrole ring have been synthesized and their absorption and fluorescence properties have been examined in connection to intramolecular hydrogen bonding.

■ An Enantioselective Synthesis of 2-Imidazolidinones through Bifunctional Thiourea-Catalyzed Tandem Mannich/Cyclization of Isocyanatomalonate Diester

Yusuke Kobayashi, Takuma Yoshida, Takuya Uno, Chihiro Tsukano, and Yoshiji Takemoto*

*Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-machi, Sakyo-ku, Kyoto 606-8501, Japan

Abstract

A chiral bifunctional thiourea-catalyzed Mannich reaction of diethyl 2-isocyanatomalonate with N-sulfonylimines was described. The tandem cyclization proceeded smoothly after Mannch reaction, directly furnishing chiral 2-imidazolidinones in 72‒99% yields with 83‒98% ees. Sterically demanding sulfonyl group was crucial for aliphatic imines to afford the corresponding product in high enantioselectivity.

■ Alpha-Oxidation of Amine Derivatives by bis(2,2,2-Trichloroethyl) Azodicarboxylate and Application of Its Products as Iminium Ion Equivalents

Shinobu Honzawa,* Mitsuaki Uchida, Takuya Tashiro, and Takumichi Sugihara*

*Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences (NUPALS), Niigata 956-8603, Japan

Abstract

Alpha-oxidation of amine derivatives by azodicarboxylate was examined. Among several azodicarboxylate esters and amides tested, bis(2,2,2-trichloroethyl) azodicarboxylate, that has highly electrophilic 2,2,2-trichloroethoxycarbonyl functional groups, was found to have excellent oxidation reactivity. Acylated or carbamoylated amines were suitable substrates for this reaction condition. Tertially amines could react in the same manner, but spontaneous elimination of hydrazinyl group occurred to give dimerized products. The reaction products were found to react with nucleophiles in the presence of Lewis or Brønsted acid catalyst. This strongly suggests that the reaction products, alpha-hydrazinated amine derivatives, might serve as carbonyl group equivalents, very useful intermediates in synthetic organic chemistry.

■ Reversibility of 3-Phenyl-2-oxindole Dimer Formation: Application to Construct Compounds with Two Distinct Vicinal All-Carbon Quaternary Centers

Yoshihiro Sohtome,* Masumi Sugawara, Daisuke Hashizume, Daiki Hojo, Miki Sawamura, Atsuya Muranaka, Masanobu Uchiyama, and Mikiko Sodeoka*

*Synthetic Organic Chemstry Laboratory, RIKEN, 351-0198, Japan

Abstract

Here we describe the critical role of the C(3) phenyl ring in providing selective access to the meso-dimer of N-Boc-3-phenyl-2-oxindole, which contains two contiguous all-carbon quaternary centers. Solid-state analysis of the meso-dimer suggested that weak CH/O and CH/ interactions cooperatively decrease the energy of the ground state in the (±)-sc (synclinal) conformation. Solution-state analyses and DFT calculations revealed that the C(3)–C(3’) σ-bond of the meso-dimer is labile, and the phenyl group at the C(3) position makes a key contribution to stabilizing the monomeric radical species. Based on these findings, we developed a facile radical-based transformation of the meso-dimer to construct a variety of compounds with two distinct contiguous all-carbon centers.

■ Diastereoselective Synthesis of 2,4-Substituted Tetrahydroquinolines via Hf(OTf)4-Catalyzed Substitution/Cyclization of 2-Aminobenzyl Alcohols with Styrenes

Masahiro Noji,* Hiroto Kadowaki, Yuuki Kubota, Tomomi Yoshida, Noriko Saito, Subaru Yamaguchi, Ren Ohata, Keitaro Ishii, and Toshikatsu Takanami

*Department of Life and Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

Abstract

An efficient and convenient stereoselective synthetic approach to 2,4-substituted 1,2,3,4-tetrahydroquinoline has been developed. This catalytic procedure involves a sequential reaction of 2-aminobenzyl alcohol with styrenes in the presence of Hf(OTf)4 catalyst followed by intramolecular cyclization of the resulting cation species to give a variety of cis-2,4-substituted tetrahydroquinolines in good yield and diastereoselectivity.