Tran Chi Cong

称号及び氏名博士（工学）

学位授与の日付

2020 年 9 月 30 日論

「Development of Novel Synthesis Methods Using Isocyanides byTransition-Metal-Catalyzed or Photoinduced Reactions(遷移金属触媒または光誘起反応によるイソシアニドを用いた新規合成手法の開発)」

文

論文審査委員

名

主査

小川昭弥

副査

池田浩

副査

八木繁幸

論文要旨
Isocyanides are useful C1 unites in organic synthesis due to their versatility in theconstruction of imine derivatives and nitrogen-containing heterocyclic compounds, leading toa variety of significant applications such as ligands for metal complexes, pharmaceuticals,pesticides, dyes, organic electronic devices, and so on. Indeed, insertion reaction of
isocyanides has been shown as a powerful strategy to prepare various nitrogen -containing
organic compounds. A number of significant progresses have been made in transition-metalmediated or -catalyzed insertion reaction of isocyanides as well as the radical reactions
involving imidoyl radical intermediates. However, synthetic transformations of isocyanides
sometimes require excess amounts of strong base, acid, and oxidants under harsh reaction
conditions, resulting in the formation of a complex mixture involving isocyanide oligomers.
Thus, the development of highly atom-economic and efficient synthetic methods using
isocyanides is strongly desired.
Because of the unique properties of group 16 heteroatoms (especially, S and Se), the useof chalcogen compounds including organic chalcogenides and thiols has been attracted muchattention. For example, it has been proven that a lot of chalcogen compounds exhibit novel
bioactivities as well as superior properties in materials science. Therefore, investigations of
the pharmaceutical compounds such as antibacterial, antitumor, and hypotensive agents
bearing sulfur and selenium have been extensively developed in recent years. For example,
chalcogenated quinoxalines have been reported to exhibit antioxidant activities. However, thecurrent synthetic methods of them still suffer from the narrow substrate range. Therefore, newsynthetic approaches are strongly desired to extend the substrate scope of the reaction to affordchalcogenated quinoxalines.
In this thesis, the author has developed transition-metal-catalyzed arylation reactions ofisocyanides. Using tetraarylleads as arylating reagents, isocyanides could be transformed intoimines and/or α-diimines under a catalytic amount of palladium catalysts. In addition, thediarylation of isocyanides with triarylbismuthines as aryl sources has been investigated using
various catalytic transition metal systems. The synthesis of various chalcogenated, nitrogen-containing compounds has also been established under the photoirradiation conditions. In
particular, the photoinduced chalcogenated cyclization of o-diisocyanoarenes with organic
diselenides and thiols provides a useful, straightforward tool to chalcogenated quinoxalines.
All the reported reactions are carried out under additive-free conditions. This thesis consists offive chapters and the outlines of each chapter are summarized as follows.
Chapter 1 describes the background, general objectives, and the contents of this thesis.
Chapter 2 describes a palladium-catalyzed arylation of isocyanides using tetraarylleads asarylating reagents to synthesize imines and/or α-diimines. During the investigation of arylating
reagents of heavy elements, the author found that, unlike triarylbismuthines which afforded
only α-diimines under a catalytic amount of palladium catalyst, the use of tetraarylleads
provided the formation of imines as the major product in the case of some aliphatic isocyanides.
On the other hand, α-diimines were found to be formed primarily when electron-rich aromaticisocyanides were applied to the diarylation. The mechanistic investigation indicated that theselectivity and yield of products depended on the nature structure of isocyanides used.
Electron-rich aromatic isocyanides stabilized the imidoyl-metal complex; thus, secondary
insertion of isocyanide happened and α-diimine was formed as the result. Meanwhile, unstable
imidoyl-metal complexes preferred to undergo reductive elimination, affording thecorresponding imines. The reaction proceeded under additive-free and base-free conditions
without formation of polymers or oligomers of isocyanides. Even though the use oforganoleads in organic synthesis is very limited because of the toxicity of lead compounds,
this work demonstrates a very interesting organic transformation using organoleads. It is also
worth noting that α-diimines are useful synthetic precursors for a variety of N-heterocycliccarbenes (NHCs) as special ligands for transition-metal-catalyzed reactions. The author
believes that the present research provides an efficient synthetic tool for the preparation ofNHCs.
Chapter 3 describes a transition-metal-catalyzed diarylation of isocyanides withtriarylbismuthines and its synthetic application. Organobismuth compounds are well-known to
be environmentally friendly reagents and have been used as unique synthetic reagents inorganic chemistry. Indeed, the synthetic applications of triarylbismuthines have beeninvestigated, and various arylation reactions have been reported using triarylbismuthines asarylating reagents. In this study, the author investigated the diarylation of isocyanides withtriarylbismuthines in the presence of the palladium and rhodium catalysts; namely, condition
parameters such as solvent, temperature, type of catalyst, and inert atmosphere were optimized
in detail. As the results, the palladium-catalyzed diarylation afforded α-diimines as the major
products, whereas the rhodium-catalyzed reaction gave imines selectively. Besides, amides as
by-product was formed under some certain conditions. In addition, the present diarylation wassuccessfully applied to the synthesis of quinoxaline derivatives in moderate to good yields.
The synthesis of N-heterocyclic carbenes (NHCs) in one reaction bath was also carried out andthe desired N-heterocyclic carbene precursor was obtained.
Chapter 4 describes a photoinduced radical cyclization of o-diisocyanoarenes with organic
diselenides and thiols that successfully afford chalcogenated quinoxalines. The chalcogenatedquinoxalines have been known to exhibit unique bioactivities, which have been proven in many
reports. Conventionally, chalcogenated quinoxalines have been synthesized by the nucleophilic
substitution reaction of thiols (or selenides) with the corresponding chlorinated quinoxalines.
However, the methods significantly suffer from the substrate scope of quinoxalines derivatives.
It has been known that organic thiols, diselenides, and o-diisocyanoarenes are activated uponvisible light irradiation. This is because their absorptions are observed in a range of 300 -500

nm. The author expected that the photoinduced reaction of the above compounds must
efficiently provide the corresponding quinoxaline products. Hence, the photoinduced reactionof o-diisocyanoarenes with thiols or diselenides provided an effective synthetic approach tothe construction of chalcogenated quinoxaline derivatives. Some mechanistic investigationsindicated that the reaction proceeded via a radical cyclization pathway initiated by the attackof chalcogeno radicals to isocyanides. The transformation is featured by a high c onversion, abroad substrate scope, and mild reaction conditions. Moreover, the cyclization reaction isscalable to gram-scale of the starting o-diisocyanoarenes, which demonstrates thepracticability of the present cyclization reaction.
Chapter 5 describes the conclusion of this thesis.
In conclusion, this thesis describes a series of organic transformations of isocyanides undervery diverse transition-metal-catalyzed conditions. With the careful choice of catalysts (e.g.,palladium or rhodium) and arylating reagent (organolead or organobismuth compounds), thedesired imine or α-diimine can selectively be synthesized. The reported reactions provide very
powerful synthetic methods to various useful nitrogen-containing molecules including Nheterocyclic carbenes. The photoinduced reactions of o-diisocyanoarenes with chalcogenides(e.g., thiols and diselenides) contribute to very efficient and interesting synthetic methods forthio- or seleno-substituted quinoxalines with promising bioactivities. Other potential reactionsof o-diisocyanoarenes with radical sources are also expected to happen. For example, diphenyl
ditelluride or iodine are known to be very good radical trapping reagents. Thus, a newgeneration of quinoxalines can be created in this methodology. The author believes that theseworks will open up a new route to construct various bioactive and pharmaceutical compounds.

審査結果の要旨
本論文は、１６族ヘテロ原子を有する官能基と他の有用官能基の高選択的複合導入によるアセチレン類の多官能基化反応の開発を目的として、直截的かつ効率的な有機反応の開発に関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） アセチレンアルコール類を出発物質とし、コバルト触媒またはパラジウム触媒を用いることで、通常では反応が生起しにくい内部アルキンに対して、硫黄官能基と一酸化炭素を高収率かつ高選択的に導入できることを明らかにしている。本反応を用いると、硫黄官能基を有するビニリデンラクトンを効率良く合成することが可能である。これらのラクトン誘導体は有用な合成中間体であり、ビニル基、エステル基、または硫黄官能基を反応点とする様々な分子変換反応に利用できる。
（２） 内部アルキンに対するシアノチオレーションがパラジウム触媒存在下、効率的に進行することを明らかにしている。本反応は、内部アルキンに対してジスルフィドおよび tert-ブチルイソシアニドを用いることで進行する。特に、シアノ源として安全な tert-ブチルイソシアニドを用いており、有毒なシアン化物を用いることなくシアノ化を達成している点で有用である。
（３） ベンゾイルペルオキシドとジセレニドを組み合わせることで、内部アルキンに対してベンゾイルオキシセレネーションが進行することを明らかにしている。また、内部アルキンではなく、末端アルキンを用いることでアルキンの末端水素がセレン官能基に置換されたアルキニルセレニドが選択的に得られることも明らかにした。また、本反応はラジカル反応と求電子付加を組み合わせた反応機構で進行することを見出している。

以上の諸成果は１６族ヘテロ元素である硫黄、セレンと、カルボニル基、シアノ基またはエステル基などの有用官能基を直截的かつ高選択的に有機分子に導入する新規な付加反応群であり、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。