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«Yosuke Ashikari 2013 ii Preface The studies presented in this thesis have been carried out under the direction of Professor Jun-ichi Yoshida at the ...»

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Reaction Integration Using Electrochemically

Generated Cationic Species

Yosuke Ashikari




The studies presented in this thesis have been carried out under the direction of Professor

Jun-ichi Yoshida at the Department of Synthetic Chemistry and Biological Chemistry of

Kyoto University during 2007−2013. The studies are concerned with reaction integration

using electrochemically generated cationic species.

The author would particularly like to express his sincerest gratitude to Professor Jun-ichi Yoshida for his kind guidance and valuable discussions throughout this work. The author appreciates the circumstance to investigate in the field of the chemistry. The author is greatly indebted to Professor Seiji Suga of Okayama University for his fruitful consultation and valuable discussions. The author deeply appreciates to Associate Professor Toshiki Nokami of Tottori University for his helpful advice and kind guidance. The author owes a very important debt to Dr. Akihiro Shimizu for his dedicated support and insightful comments. The author is also thankful to Dr. Aiichiro Nagaki and Dr. Keisuke Asano for their encouragement and meaningful suggestions.

The author would like to special thanks to Dr. Keiko Kuwata, Messrs. Haruo Fujita, Tadashi Yamaoka and Mses. Sakiko Goto, Eriko Kusaka, and Karin Nishimura of the Technical Center of Kyoto University for the measurement of MS and NMR spectra.

The author must make special mention of Mr. Koji Ueoka, Dr. Kouichi Matsumoto, Messrs.

Ikuo, Shimizu, Shunsuke Fujie, Hiroaki Tsuyama, Yuki Nozaki, Dr. Takeshi Yamada, Messrs Christian Hempel, Kimitada Terao, Takayuki Nakatsutusmi, Kazutomo Komae, Takafumi Suehiro, Yoshihiro Saigusa, Takahiro Matsuo, Naoki, Musya, Tatsuya Morofuji, Koen Tijssen, Hiroki Kuramoto, Keiji Takeda, Chih-Yueh Liu, Masahiro Takumi, Yutaka Tsujii, Ryutaro Hayashi, Shota Mishima, Yusuke Yaso for their great assistance and collaborations.

The author has learned much working with Dr. Yutaka Tomida, Dr. Heejin Kim, Dr.

Hidekazu Kataoka, Dr. Eiji Takizawa, Dr. Kodai Saito, Dr. Shigeyuki Yamada, Messrs Yuji Hagiwara, Akito Shibuya, Kousuke Ohata. The author is also thankful to them for their advice and collaborations.

The author heartily thanks to Messrs. Naofumi Takabayashi, Masafumi Inoue, Ms Chika Matsuo, Messrs Takashi Watanabe, Atsuo Miyazaki, Yusuke Takahashi, Yuya Moriwaki, Masatomo Doi, Keita Imai, Yuki Uesugi, Shinya Tokuoka, Ms. Songhee Kim, Mr. Suguru Haraki, Ms. Kana Akahori, Messrs. Ryo Murakami, Satoshi Ishiuchi, Yuta Tsuchihashi, Mses.

Mari Ishizuka, Kuniko Eguchi, Misako Wakazono, Yoko Uekawa, Messrs. Yosuke Ushiogi, iii Shuji Takaishi, Atsushi Hayashi, Tatsuro Asai, Naoki Okamoto, Dr. Toshikazu Tanaka, Messrs.

Daisuke Ichinari, Nobuhiko Hojo, Ms. Maria W. Baltussen, Mr. Francisco Corral Bautista, Dr.

Arianna Giovine, Dr. Leonardo Degennaro, Mr. Stefan Roesner, Ms. Andrea Henseler, Mr.

Stefan van der Vorn, Professor Gerhard Hilt and all other members of Professor Yoshida’s group for their active collaborations and kindness.

The author acknowledges financial support from Japan Student Services Organization, and from Kyoto University Global COE Program, International Center for Integrated Research and Advanced Education in Materials Science (employment of research assistant).

Finally, the author would like to express his deepest appreciation to his parents, Dr.

Toshihiko Ashikari and Mrs. Kyoko Ashikari for their constant assistance and encouragement.

–  –  –

General Introduction……..……………………………….………………………………….1 Integrated Electrochemical−Chemical Oxidation via Alkoxysulfonium Ions…9 Chapter 1 Integration of Electrooxidative Cyclization and Chemical Oxidation via Chapter 2 Alkoxysulfonium Ions

Electrochemical Oxidative Hydroxylation via Alkoxysulfonium Ions…….....53 Chapter 3 Halogen and Chalcogen Cation Pools Stabilized by DMSO. Versatile Reagents Chapter 4 for Alkene Difunctionalization………

The Reaction of -Acyliminium Ion Pools with Alkenes Having a Chapter 5 Nucleophilic Moiety..………………………………………………………..111 List of Publications………….……………………………..……...…………..……………131

–  –  –

I. Reaction Integration Organic synthesis has made considerable contribution to the progress of our society by creating and producing a variety of compounds having various biological activities and physical functions. However, the construction of highly designed organic molecules always needs to multi-step reactions, leading time-consuming and costly processes. Therefore, the power and speed of organic synthesis should be enhanced to meet such demands by minimization of synthetic steps with maximization of complexity of molecules.

Accordingly, conventional step-by-step synthesis should be supplemented with new synthetic strategy, which combines multiple transformations in a single pot.

Reaction integration1 is the concept of combining multiple reactions, where intermediate products are further utilized for subsequent reactions without any purification and isolation.

Various types of such transformations have been reported, and because many terminologies have been used, some confusion in this field is caused. Recently Yoshida and co-workers have proposed a new terminology;2 (a) time and space integration,3 where all reaction components are mixed at once to perform a sequence of reactions simultaneously in a single batch reactor, (b) time integration,4 where reaction components are added at intervals of time to perform a sequence of reactions in a single batch reactor, and (c) space integration,5 where a sequence of reactions is performed in different reactors using a flow system (Scheme 1).

Scheme 1. Classification of Reaction Integration. A: Starting Material, B: Intermediate, C:

Product, R1 and R2: Reagents.

–  –  –

from reaction integration using stable intermediates, which is basically possible in a traditional step-by-step synthetic method, would allow a novel transformation which conventional methods will never achieve.

II. Electroorganic Synthesis Organic electrochemistry provides a powerful means for synthesizing and modifying organic molecules.6,7 The advantages of this technique lie in its utility for selective oxidation and reduction of functional groups, generation of highly reactive intermediates, and reversing the polarity of functional groups. Because electrochemical processes utilize neutral reaction conditions and are applicable to organic compounds of a wide range of oxidation and reduction potentials, many of these transformations are unique to electrochemistry. Therefore, use of the electrochemical method to complement conventional methods can open new strategies for the synthesis of complex molecules.

Especially, electrochemical oxidation allows irreversible generation of transient cationic species, which play a key role in organic synthesis. Conventionally, carbocations can be generated by “acid-promoted” method, where a proton or a Lewis acid activates a leaving group leading to the heterolysis of the bond between the carbon and the leaving group to generate the carbocation. Because these steps are reversible, several species often exist in the solution as an equilibrium mixture. By contrast, anodically oxidation allows for irreversible generation of carbocations. Furthermore, the oxidation method does not need heteroatomic leaving groups; oxidative cleavage of carbon−carbon, carbon−hydrogen bond gives the corresponding carbocations.8 Although plenty of electrochemical oxidative reactions have been developed, the organic cations are usually generated in the presence of a nucleophile, which swiftly traps the cations in situ.

Recently, Yoshida and co-workers have developed low-temperature electrochemical oxidation method called the “cation pool” method,6c providing a new method in the chemistry of organic cations. In this method, anodic oxidation is carried out at low temperature such as −78 oC in order to avoid decomposition of the carbocations. The

-acyliminium ions,9 “cation pool” method allows the carbocations, such as alkoxycarbenium ions,10 and diarylcarbenium ions,11 to be accumulated in relatively high concentrations in the absence of nucleophiles (Scheme 2). After electrolysis, the organic cation pools are subsequently allowed to react with carbon nucleophiles to form a carbon−carbon bond giving desired products (time integration).

Scheme 2. Cation Pools of Carbocations.

–  –  –

III. Reaction Integration Using Electrochemically Generated Cationic Species This thesis focuses on the integration of electrochemical oxidation and chemical reactions using electrochemically generated cationic reactive intermediates. Different from the conventional anodic oxidation method, an electrochemically generated cationic intermediate is directly converted to another reactive intermediate which is used in a subsequent chemical reaction. It means that reactive species, which should be swiftly converted to the neutral final product because of their instability, are treated as “starting materials” of sequential reactions. Reaction integration, which provides the way for combining multiple organic reactions by means of reaction intermediates, and electrochemical organic synthesis, which provides the way for irreversible generation of various cationic species, are integrated. (Scheme 3).

Scheme 3. Reaction Integration Using Electrochemically Generated Cationic Species.

In Chapter 1, the integrated electrochemical−chemical oxidation via alkoxysulfonium ions is described (Scheme 4). An electrochemically generated carbocations are reacted with dimethyl sulfoxide (DMSO) to give the corresponding alkoxysulfonium ions, which are well-known as key intermediates of Swern−Moffatt oxidation.12 The accumulated alkoxysulfonium ions are reacted with triethylamine to give the corresponding carbonyl compound. Thus, the electrochemical oxidation and the chemical oxidation are integrated by the intermediacy of alkoxysulfonium ions, providing a novel four-electron oxidation method. Moreover, reaction integration solves the problem of overoxidation because the conditions of the last step are very mild, and final products are never exposed to the oxidative conditions. This chapter demonstrates an example of the use of electrochemically generated cationic intermediates for a subsequent chemical reaction.

–  –  –

Chapter 2 describes the integration of the electrooxidative cyclization and the chemical oxidation using alkoxysulfonium ion intermediates (Scheme 5). Electrooxidative cyclization13 is the anodic oxidation of alkenes having a nucleophilic moiety, where one electron oxidation of the olefinic part is attacked by the intramolecular nucleophilic group generating the corresponding cyclized radical cations. Further oxidation followed by the intermolecular attack of the second nucleophile (usually solvent molecule) gives the final products. It was found that the electrooxidative cyclization can be effectively integrated with Swern−Moffatt type chemical oxidation using dimethyl sulfoxide as the second nucleophile. This chapter suggests a potential synthetic utility of the present approach for constructing cyclic molecule backbones.

Scheme 5. Integration of Electrooxidative Cyclization and Chemical Oxidation via Alkoxysulfonium Ions.

In Chapter 3, the electrochemical oxidative hydroxylation via alkoxysulfonium ions is described (Scheme 6). Electrochemically generated alkoxysulfonium ions, which are converted to carbonyl compounds in Chapter 1 and 2, can also be converted to the corresponding alcoholic products by treatment of methanol or aqueous sodium hydroxide.

It means that a reagent for the second step changes the oxidation state of the final products;

four-electron oxidation or two-electron oxidation. The oxidation of carbon−hydrogen bond and carbon−carbon double bond to carbon−oxygen bond generally needs special methods because the alcoholic products are often more oxidatively active than the starting materials, therefore the overoxidation easily occurs. This present approach allows for the selective synthesis of alcohols and diols by means of alkoxysulfonium ion intermediates.

Scheme 6. Electrochemical Oxidative Hydroxylation Mediated by Alkoxysulfonium Ions.

-4General Introduction

Chapter 4 describes halogen and chalcogen cation pools stabilized by dimethyl sulfoxide, and their synthetic utility for alkene difunctionalization (Scheme 7). It was found that cations of halogens (bromine and iodine) and chalcogens (sulfur and selenium), whose high instabilities make it difficult or impossible to be stored, can be stabilized by dimethyl sulfoxide enabling their accumulation in the solution. The resulting cation pools serve as versatile reagents for alkene difunctionalization; both a halogen or chalcogen atom and dimethyl sulfoxide are introduced to the carbon−carbon double bond. The resulting alkoxysulfonium ions are converted to carbonyl compounds by treatment with triethylamine. In addition, the halogen and chalcogen cation pools reacted with alkenes having a nucleophilic moiety and dienes to give cyclized products.

Scheme 7. Halogen and Chalcogen Cation Pools Stabilized by Dimethyl Sulfoxide, and Their Reactions with Alkenes.

Chapter 5 describes the reactions of -acyliminium ion pools with alkenes having a nucleophilic moiety such as a hydroxyl group, a carboxylic acid moiety, and an oxime moiety to construct a cyclic structure (Scheme 8). -acyliminium ion pools generated from low temperature anodic oxidation reacted with alkenes bearing a hydroxyl group in an appropriate position to give compounds having a tetrahydrofuran ring. The reaction proceeded via diastereospecific manner indicating a concerted mechanism, where an intramolecular hydroxyl group participates. -acyliminium ions also reacted with an alkene having a carboxylic acid moiety to generate a lactone ring backbone, and reacted with an alkenyl oxime giving a 2-isoxazoline structure.

-5General Introduction

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