Chunping Dong

称号及び氏名博士（工学）

学位授与の日付

2019 年 3 月 31 日

論「Studies on the Development of Metal-Free Oxidation Reactions ofAmine Derivatives(メタルフリー条件下におけるアミン誘導体の酸化反応の開発に関する研究)」

文

論文審査委員

名

主査

小川昭弥

副査

八木繁幸

副査

松岡雅也

論文要旨
Oxidation is one of the most important organic reactions that has been used in many fields,such as organic synthesis, material science, biology, and industry. Besides, oxidation
reactions play important roles in our daily life, including photosynthesis, respiration,combustion, and corrosion. Therefore, the research of oxidation reactions attracts
considerable attention in many areas. For the organic chemistry, many oxidation methods
have been developed for the demand of industry. Up to today, most of the oxidation methods
are based on metal catalysis, organocatalysis, or biocatalysis. Metal catalysis is always
associated with drawbacks such as the presence of metal-containing residues, toxic waste
water, and complicated purification. From the perspective of green chemistry, scientists pay
more attention to the investigation of organocatalysis and biocatalysis. Compared withbiocatalysts, organocatalysts feature cheap, simple structure, and easily available.
Amines are the most basic class of nitrogen-containing organic compounds. They areorganic derivatives of ammonia, in which one, two, or all three of the hydrogens of ammonia
are replaced by organic groups. According to the number of carbon substituents adjacent to
the nitrogen, amines are classified to three subcategories: primary, secondary, and tertiaryamines. The chemistry of amines was discovered in the nineteenth century by pioneeringchemists such as Hofmann and Knoll. At the beginning of the twentieth century, theintroduction of the Cyanamide Process and Electric Arc Process made amines commerciallyavailable for the first time at low cost. Then, the implementation of the Haber-Bosch Process
in Eastern Germany in 1917 marked the beginning of the modern age of amine chemistry.
Amines exist widely in nature and are also the major industrial chemicals. Naturally
occurring amines include the alkaloids, which are present in certain plants, the catecholamine
neurotransmitters, and a chemical mediator, histamine, that occurs in most animal tissues. In
industry, amines are used widely in making rubber, dyes, pharmaceuticals, and synthetic
resins and fibers.
The oxidation of amines offers great opportunities for the production of key N-containing
building-blocks for the modern chemical industry. Many important nitrogen-containing
compounds, such as oximes, imines, amides, nitriles, amine oxides, and azo compounds, areobtained from the oxidation of an appropriate amine precursor. Since the beginning of thepast century, transition metal complexes and enzymes have been considered to be the main
two classes of efficient catalysts for the oxidation of amines. About twenty years ago, fromthe viewpoint of green and sustainable chemistry, organocatalysis was emerged as analternative method. However, compared with traditional oxidative methods of amines, thedevelopment of metal-free, efficient, and eco-friendly methods for the oxidation of amines isstill strongly desired.
In this thesis, the author has developed metal-free oxidative methods of benzylamines andarylhydrazines. Using salicylic acid derivatives as organocatalysts, benzylamines could beoxidized to imines, and this amine oxidation could also be applied to the synthesis ofnitrogen-containing heterocycles, bis-amides, and blue dyes. Arylhydrazines could beoxidized by diiodine to form aryl radicals and then combined with iodine radical to afford
aryl iodides. This thesis consists of seven chapters and the outlines of each chapter aresummarized as follows.
Chapter 1 describes the background, general objectives, and the contents of this thesis.
Chapter 2 describes the oxidative coupling of benzylamines using salicylic acidderivatives as organocatalysts under an oxygen atmosphere and its application to synthesis ofnitrogen-containing heterocycles. Salicylic acid derivatives are usually used as ligands formetal complexes, but in this study, salicylic acid and its derivatives themselves were found tobe efficient organocatalysts and could catalyzed amines oxidation. In particular, electron-richsalicylic acid derivatives such as 4,6-dimethoxysalicylic acid and 4,6-dihydroxysalicylic acidexhibit excellent catalytic activities for the oxidative coupling of benzylamines to give thecorresponding imines. For the perspective of the sustainable chemistry, recyclability of thecatalyst was also investigated. Silica gel supported with 4.7 wt% of 4,6-dihydroxysalicylic
acid was prepared as a recyclable catalyst, which successfully oxidized benzylamines toimines four times. Besides, this amine oxidation can also be applied to the synthesis ofnitrogen-containing heterocycles such as benzimidazoles, benzoxazoles, and benzothiazoles.
Using 4,6-dimethoxysalicylic acid or 4,6-dihydroxysalicylic acid as the organocatalyst, theoxidative cyclization of benzylamines with o-substituted aniline derivatives, i.e.,o-phenylenediamines, o-aminophenols, and o-aminothiophenols, proceeded well to afford thecorresponding N-heterocycles in good yields.
Chapter 3 describes a metal-free oxidative coupling reaction of benzylamines andacetophenones to synthesize 2,4,6-trisubstituted pyridines in the presence of
4,6-dihydroxysalicylic acid and BF3.Et2O. Pyridines are another kind of important
nitrogen-containing heterocycles. In this study, the aforementioned amine oxidation method
was successfully applied to the synthesis of 2,4,6-trisubstituted pyridines in good to highyields with a broad substrate scope. During this oxidative coupling reaction, benzylaminesplay a dual role of providing the aryl moiety at 4-position of pyridines and also acting as thenitrogen donor. 2,4,6-Trisubstituted pyridines are a class of G-quadruplex binding ligands tostabilize G-quadruplex DNA (G4-DNA) and provide an efficient approach to cancer
treatment. To avoid the metal contamination of these precursor drugs, the development ofmetal-free synthetic method is strongly desired. It is gratifying that this salicylic acidderivatives-catalyzed synthetic method of 2,4,6-trisubstituted pyridines can be applied to thefacile synthesis of G-quadruplex binding ligands by the addition of 4-chlorobutyryl chloride
and pyrrolidine subsequently. This synthesis procedure started from the oxidative coupling
reaction of benzylamines and 4-aminoacetophenones, and then the resulting mixture wasallowed to directly react with 4-chlorobutyryl chloride without any purification. After simple
work-up, the residue next reacted with pyrrolidine to afford G-quadruplex binding ligands inmoderate yields.
Chapter 4 describes a metal-free organocatalytic oxidative Ugi reaction promoted by
4,6-dihydroxysalicylic acid. The traditional Ugi four-component reactions (U-4CRs) usuallycombine an amine, an aldehyde, an isocyanide, and a carboxylic acid. During this reaction,imine or iminium, which was considered as the key intermediate, was in situ generated bycondensation of an amine and aldehyde. As described in Chapter 2, imines were formed
efficiently via the homo-coupling of benzylamines in the presence of 4,6-dihydroxysalicylic
acid as organocatalyst. Based on the previous work, the oxidative Ugi reaction, wherein theimine intermediate was in situ formed by oxidative coupling of amines, was described in thischapter. Catalyzed by 4,6-dihydroxysalicylic acid, bis-amides were synthesized from threecomponents (benzylamines, isocyanides, and carboxylic acids) in good to high yields.
Besides, the cross-coupling reaction of benzylamines with aliphatic amines also proceeded
successfully using 4,6-dihydroxysalicylic acid as organocatalyst. Therefore, thiscross-coupling reaction was involved in the oxidative Ugi reaction, and provides acomplementary method for the synthesis of bis-amides bearing aromatic and aliphatic groups
simultaneously.
Chapter 5 describes a convenient, novel, and metal-free method for the synthesis of4,4′-diaminotriarylmethanes (DTMs). As dye precursors, DTMs can be oxidized to produce
malachite green derivatives, which are one of the most important dyes. Owing to theimportance of triarylmethane compounds, considerable attention has been paid to thedevelopment of efficient methods for the synthesis of DTMs and a variety of chemicaltransformations have been reported. However, the synthesis of DTMs from benzylamine
substrates has not yet been reported. In this study, a one-pot condensation of benzylamines
with N,N-dimethylaniline derivatives using 4,6-dihydroxysalicylic acid as a co-oxidant andN-iodosuccinimide as an oxidant was investigated. The present method provides the firstreported synthesis of DTMs from benzylamines via oxidative C–N bond cleavage andsubsequent double C–C bond formations. During this oxidation reaction, radical derived from
4,6-dihydroxysalicylic acid was confirmed by ESR spectroscopy (g = 2.00336). The obtained
DTMs were easily converted into a series of blue dyes upon treatment withtetrachloro-1,4-benzoquinone (chloranil). The chloroform solutions of these dyes showedgreen to blue colors. This blue dye synthetic method is advantageous in that it is a metal-free,straightforward process, and does not require the use of toxic heavy metals, corrosive acids,or hazardous reagents.
Chapter 6 describes a metal- and base-free method for the synthesis of aryl iodides fromarylhydrazine hydrochlorides and iodine. Arylhydrazine hydrochlorides are usually used as
the source of aryl radicals, and most of the oxidative methods for arylhydrazinehydrochlorides to aryl radicals need additional oxidants or additives such as base. The
Sandmeyer reaction is a classic method to synthesize aryl iodides via the diazotization ofaromatic amines, followed by iodination with iodides. However, this method usually requires
corrosive nitrous acid and a strong acidic medium for the diazotization step. In this study, awide variety of aryl iodides can be conveniently synthesized by an equimolar reaction ofarylhydrazine hydrochlorides and I2 in the absence of any metal catalysts and additives.
During this iodination, iodine plays a dual role: (1) an oxidant for converting arylhydrazines
to arenediazonium salts, which subsequently undergo single-electron transfer (SET) to form
aryl radicals; (2) an iodination reagent to afford aryl iodides. Compared to the Sandmeyer
reaction, this protocol is safer, easier to execute, involves simpler work-up, and has higherefficiency.
Chapter 7 describes the conclusion of this thesis.

In conclusion, this thesis describes a series of benzylamines and arylhydrazines wereoxidized by metal-free methods, and based on this oxidation of nitrogen compounds, theorganocatalyzed oxidative coupling method of benzylamines to synthesis ofnitrogen-heterocycles(i.e.,benzimidazoles,benzoxazoles,benzothiazoles,andtriarylpyridines), bis-amides, and blue dyes have been developed successfully. The author
believes that these works will open up a new field for eco-friendly oxidation of amines byorganocatalysis.

審査結果の要旨
本論文は、メタルフリー条件下でベンジルアミン類およびアリールヒドラジン類を酸化する手法を開発し、この酸化手法に基づいて、含窒素複素環化合物、ジペプチド、青色色素、およびヨウ化アリールを合成する研究について述べたものであり、以下の成果を得ている。
（１） サリチル酸誘導体を有機触媒として用いることにより、ベンジルアミン類からイミン類への酸素酸化反応が効率良く進行することを明らかにしている。サリチル酸誘導体をシリカゲルに固定化した触媒が、本アミン酸化反応において回収・再使用できることも見出している。さらに、本酸化手法に基づいて、ベンジルアミン類と o –置換アニリン誘導体から含窒素複素環化合物を合成することにも成功している。これらの反応は、安価なサリチル酸誘導体を有機触媒として、温和な条件下、簡便な操作で進行するという優位性を有している。
（２） ベンジルアミン類とアセトフェノン類の酸化的カップリング反応が、サリチル酸誘導体を有機触媒に用いたメタルフリー条件下で進行し、2,4,6–三置換ピリジン類が生成することを見出している。さらに、本ピリジン合成法を応用して、グアニン四重鎖結合性リガンドの簡便合成も達成している。
（３） サリチル酸触媒によるメタルフリーな酸化的 Ugi 反応に成功している。本反応では、ベンジルアミン類の酸化的ホモカップリングだけではなく、ベンジルアミン類と脂肪族アミン類との酸化的クロスカップリングも進行し、芳香族基および脂肪族基を有する様々なジペプチドのメタルフリー合成が可能である。
（４） サリチル酸誘導体を共酸化剤とし、N –ヨードスクシンイミドを酸化剤として用いたベンジルアミン類と N,N–ジメチルアニリン誘導体のワンポット縮合反応により、4,4’–ジアミノトリアリールメタン類 (DTMs) が得られることを明らかにしている。本手法は、ベンジルアミン類を基質として DTMs を合成した最初の例である。さらに、得られた DTMsをクロラニルで酸化することにより、青色色素を合成することにも成功している。これ
らの研究成果は、有毒な重金属、腐食性の酸、および危険性のある試薬を必要とせず、メタルフリーかつ直截的に一連の青色色素を合成できるという点で有用である。
（５） アリールヒドラジン類とヨウ素の反応により、アリールヨージド類をメタルフリーかつ塩基フリーで合成することに成功している。アリールヒドラジン類を酸化するとアリールラジカルが発生するが、その一般的な酸化手法としては酸化剤や塩基を必要としている。また、アリールヨージドを合成する古典的な手法に Sandmeyer 反応があるが、ジアゾ化に腐食性のある強酸が用いられる。これらに対して、本手法は安全、簡便、かつ高効率な合成手法である。

以上の諸成果はメタルフリー条件下でアミン誘導体の酸化を達成し、この酸化手法を応用して、グアニン四重鎖結合性リガンド、ジペプチド、青色色素などの合成にも成功しており、有機合成化学の分野に大きく貢献するものである。また、申請者が自立して研究活動を行うにあたり、十分な能力と学識を有することを証するものである。