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«Tatsuya Morofuji 2015 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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Electrooxidative C–H Functionalization of

Aromatic Compounds Based on Rational Design

Tatsuya Morofuji



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 2010-2015. The studies are concerned with development of new

electrochemical reactions.

The author would 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 Dr. Akihiro Shimizu for his constant advice and valuable discussions during the course of this work. The author deeply appreciates to Dr. Aiichiro Nagaki and Dr. Heejin Kim for their kind guidance and encouragement. The author is also thankful to Associate Professor Toshiki Nokami of Tottori University and Dr. Keisuke Asano for their helpful advice.

The author wishes to thank to Dr. Keiko Kuwata, Mses. Eriko Kusaka, Karin Nishimura, Sakiko Goto, Mr. Haruo Fujita and Mr. Tadashi Yamaoka and staff of the Microanalysis Center of Kyoto University for the measurement of Mass spectra.

The author has learned much working with Dr. Yutaka Tomida, Dr. Eiji Takizawa, Dr.

Heejin Kim, Dr. Kodai Saito, Dr. Shigeyuki Yamada Dr. Yosuke Ashikari, Dr. Yuya Moriwaki, Messrs. Yusuke Takahashi, Daisuke Ichinari, Atsuo Miyazaki, Yuki Nozaki, Kazutomo Komae, Takafumi Suehiro, Naoki Musya, Yoshihiro Saigusa, Takahiro Matsuo.

The author is also thankful to them for their advice and collaborations.

The author heartily thanks to Messrs. Keita Imai, Yuki Uesugi, Shinya Tokuoka, Mses.

Songhee Kim, Kana Akahori, Messrs. Keiji Takeda, Hiroki Kuramoto, Suguru Haraki, Masahiro Takumi, Ryo Murakami, Ryutaro Hayashi, Yutaka Tsujii, Satoshi Ishiuchi, Yuta Tsuchihashi, Shota Mishima, Yusuke Yaso, Shumpei, Kajita, Takaaki Kitamura, Katsuyuki Hirose, Keisuke Takenaka, Shun Horiuchi, Keita Inoue, Hideya Tanizawa, Daiki Torii, Satori Moronaga, Song Yetao, Mses. Mari Ishizuka, Yoko Uekawa, Messrs. Tatsuro Asai, Hisakazu Tanaka, Naoki Okamoto, Dr. Takashi Mizuno, Koen Tissen, Dr. Arianna Giovine, Messrs. Chih-Yueh Liu, Stefan Rosener, Ms. Andrea Henseler, Mr. Stefan van der Vorn, Professor Gerhard Hilt, Messrs. Steven Street, Lars Wesenberg and all other members of Professor Yoshida’s group for their active collaborations and kindness.

i The author acknowledges financial support from Japan Society for the Promotion of Science (JSPS Research Fellowships for Young Scientists) and Department of Synthetic Chemistry and Biological Chemistry (Employment of Research Assistant).

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

Takeshi Morofuji and Mrs. Shitsuko Morofuji, and his brothers, Messrs. Tetsuya Morofuji and Shinya Morofuji for their constant assistance and encouragement.

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I. Rational Design of Organic Reactions In organic synthesis, we build up small molecules into desired target molecules step-by-step using suitable reactions. Achievements in organic synthesis in the last several decades are beyond all expectations. In fact, organic synthesis plays a major role to develop new medicinal compounds, agrochemicals, and functional materials. Despite such extraordinary achievements, organic synthesis is still far from ideal synthesis because it is time and labor-consuming and significant amounts of wastes are usually produced to synthesize complex organic molecules. Therefore, development of new organic reactions which make organic synthesis much more efficient is highly desired.

To design highly efficient organic reactions, the following three points should be considered (Figure 1). At first, a desired reaction pathway to give a desired product is rational and efficient. To achieve such a desired pathway, the use of highly reactive catalysis and/or reagents is often needed. Second, undesired reaction pathways to give byproducts should be avoided or such side reactions should be suppressed. Third, desired products should be stable under the reaction conditions. If overreactions occur, a desired product cannot be obtained in a high yield and in high purity. These points should be the key to the success of developing new organic reactions that have been believed to be difficult or impossible.

Figure 1. Design Points of Organic Reactions This thesis proposes a rational design for electrooxidative C–H functionalization of organic compounds, which avoids the overoxidation that is usually problematic in conventional electrooxidative methods.

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II. Electroorganic Synthesis Electrochemical organic synthesis is a long-established methodology since Kolbe electrolysis was reported in 1848.1 Electrolysis of organic compounds can generate highly reactive species such as carbocations, carbanions, radical ions, and free radicals under mild conditions via single electron transfer.2 Notably, chemical oxidants or chemical reductants, which inevitably produce stoichiometric amounts of byproducts, are not required. Taking such an advantage, electroorganic reactions have been applied to synthesis of various complex organic molecules,3 and some electroorganic reactions have been used for industrial production.4 Electrochemical oxidation is, in particular, attractive because it enables straightforward functionalization of carbon–hydrogen (C–H) bonds of organic molecules. For example, Csp3–H bonds5 as well as aromatic Csp2–H bonds (Scheme 1) 6 can be functionalized by anodic oxidation. Single electron transfer from an aromatic compound gives the corresponding open-shell radical cation. The radical cation reacts with a nucleophile such as fluoride ion, cyanide ion, and trifluoroacetic acid to give the corresponding functionalized product. Usually, overoxidation does not occur in these cases because the products are less reactive toward the electrochemical oxidation because of a strong electron-withdrawing effect of the substituent that is introduced by the transformation.

Scheme 1. Electrooxidative Transformation of Aromatic Csp2–H Bond

However, when the substituent introduced to the aromatic ring is electron-donating, the oxidation potential of the product is lower than that of the starting material, and therefore the transformation suffers from further oxidation of the product, which is called overoxidation.7 Anodic methoxylation of naphthalene reported by Fritz in 1976 is such a case (Scheme 2).7a Electrochemical oxidation of naphthalene in the presence of methoxide gives polymethoxynaphthalene. Because an oxidation potential of methoxynaphthalene is lower than that of naphthalene,8 overoxidation is unavoidable. For the same reason, electrooxidative introduction of other electron-donating groups such as electron rich aryl groups, or amino groups into aromatic rings still remains challenging.

-2General Introduction

Scheme 2. Anodic Methoxylation of Naphthalene

In 1999, Yoshida and coworkers reported the generation and accumulation of N-acyliminium ions by low temperature electrochemical oxidation, and this method is called the cation pool method (Scheme 3A).9 After the electrolysis, the accumulated cation can be used for the reactions with various nucleophiles under nonoxidative conditions. The method was successfully applied to alkoxycarbenium ions,9b diarylcarbenium ions,9c and heteroatom cations.9d,9e They also reported integrated reactions involving conversion of electrochemically generated cationic species to another cationic species using the chemical method (Scheme 3B).10 However, these methods are limited to use closed-shell cationic intermediates having a formal charge on a sp3 carbon atom because closed shell cationic species having a formal charge on a sp2 carbon atom are too unstable to generate. Therefore, the method cannot be applied to Csp2–H bond functionalization.

Scheme 3. (A) Cation Pool Method.

(B) Integrated Electrochemical–Chamical Reaction via Alkoxysulfonium Ions.

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III. Contents of This Thesis This thesis described a new reaction design inheriting the essence of the cation pool method and the reaction integration, which solves the overoxidation problem in electrooxidative Csp2–H bond functionalization. Based on the rational designs, electrooxidative C–H arylation and C–H amination of aromatic compounds have been achieved.

In chapter 1, metal- and chemical-oxidant-free C–H/C–H cross-coupling11 of aromatic compounds using electrochemical oxidation is described. In general, such transformations suffer from overoxidation because oxidation potentials of biaryl products are lower than that of starting materials. The present approach is outlined in scheme 4. The key design of the method is generation and accumulation of radical cations of aromatic compounds by low temperature electrolysis. Because another aromatic compound can be added after the electrolysis under nonoxidative conditions, overoxidation is intrinsically avoided. The method was named the radical cation pool method.

Scheme 4. C–H/C–H Cross-Coupling of Aromatic Compounds Using Radical Cation Pools From chapter 2 to chapter 5, C–H amination reactions using electrochemical oxidation are described.

In general, installation of nitrogen functionalities into aromatic rings by the electrooxidative method is challenging because oxidation potentials of aromatic amines are usually lower than those of starting materials, and this situation inevitably leads to overoxidation. To circumvent the overoxidation problem, the transformations involving conversion of radical cation of aromatic compounds to closed-shell cationic intermediate was designed as outlined in scheme 5. Electrochemical oxidation of an aromatic substrate in the presence of an appropriate nitrogen source gives a cationic intermediate.

Overoxidation is suppressed because of strong electron-withdrawing effect of a positive charge. After the electrolysis, the cationic intermediates are converted to desired neutral aromatic amines under nonoxidative conditions. Based on this rational design, overoxidation is intrinsically avoided because aromatic amines as final products are not exposed to oxidative conditions.

-4General Introduction

Scheme 5. Electrooxidative C–H Amination of Aromatic Compounds via Cationic Intermediate In chapter 2, a method for synthesizing aromatic primary amines is described.

Electrochemical oxidation of aromatic compounds in the presence of pyridine followed by the treatment with piperidine gives corresponding aromatic primary amines (Scheme 6).

The key design of the reactions is intermediacy of electrooxidatively inactive N-arylpyridinium ions. Overoxidation is suppressed because of strong electron-withdrawing effect of a positive charge on the pyridinium nitrogen. Synthetic utility of the present method is demonstrated by C–H amination of aromatic compounds bearing a nitro group to give a key intermediate for the synthesis of VLA-4 antagonist.12 The transformation proves the rationality of the reaction design described in scheme 5.

Scheme 6. Synthesis of Aromatic Primary Amines via N-Arylpyridinium Ions

In chapter 3, an intramolecular version of the amination is described (scheme 7).

Electrochemical oxidation of 2-pyrimidyloxybenzenes and 2-pyrimidylthiobenzenes, which can be easily prepared from phenols and thiophenols, respectively, followed by the treatment of the resulting pyrimidinium ions gives 2-aminobenzoxazoles and 2-aminobenzothiazoles, respectively. The method serves as metal- and chemical-oxidant-free routes to the benzoxazoles and benzothiazoles having a variety of functionality. The transformation indicates the power of the reaction design in the synthesis of heterocyclic compounds.

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Scheme 7. Intramolecular C–H Amination via Cyclized Cationic Intermediates Chapters 4 and 5 describe the application of the present reaction design to the electrooxidative C–H aminations by modification of nitrogen sources are prior to electrooxidative generation of cationic intermediates.

Chapter 4, describes electrooxidative coupling of imidazoles with aromatic or benzylic compounds based on this approach (scheme 8). An appropriate protecting group is introduced to imidazoles in advance. Electrochemical oxidation of aromatic or benzylic compounds in the presence of the protected imidazoles gives electrooxidatively inactive imidazolium ions. After electrolysis, the imidazolium ions are converted to the desired C–N coupling products by deprotection under nonoxidative condition. To demonstrate the power of the method, a P450 17 inhibiter13 and an antifungal agent14 having N-substituted imidazole structures were synthesized. The successful transformations achieved by modification of nucleophiles prior to electrochemical oxidation open the possibility of developing new electrochemical transformations that are impossible by the conventional ways.

Scheme 8. Electrooxidative C–N Coupling of Imidazoles with Aromatic or Benzylic Compounds

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