Tran Phuc Dat

称号及び氏名博士（工学）

学位授与の日付

2021 年 3 月 31 日

論「Studies on the Development of Metal-free Functionalization ofOrganic Molecules Utilizing the Characteristic Features of Heteroatoms(ヘテロ原子の特性を活かした有機分子のメタルフリー条件下における官能基化法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

松本章一

副査

池田浩

論文要旨
The function of organic molecules often derives from the presence of heteroatoms such as
nitrogen, oxygen, halogens, sulfur, and phosphorus. By taking advantage of the uniqueproperties of heteroatoms, it is possible to impart various functions to organic molecules.
Furthermore, it is expected that it will be possible to synthesize these functional organicmolecules with high efficiency by properly combining heteroatoms. In recent years, metal
catalysts and reagents are often used for the precise synthesis of functional organic molecules,
and various novel synthesis methods using metal catalysts and reagents have been developed
for this purpose. However, the recent trend toward higher purity in materials andpharmaceuticals has made it difficult for metals to remain. From this point of view, thedevelopment of metal-free synthesis methods has recently been strongly demanded. In thisthesis, therefore, the author focuses on the development of new synthetic methods forheteroatom chemicals under metal-free conditions using the characteristics of heteroatoms. In
particular, organic halides and organophosphorus compounds are becoming increasingly
important in organic synthesis, catalyst technology, material chemistry, and medicinalchemistry. Methods for synthesizing these compounds have been developed for high purity,environmental friendliness, and simple operations.
Among organic halides, organic bromide has the appropriate carbon–halogen bond energy;
so it has the appropriate stability and reactivity. In addition, organic bromide has the higher
selectivity in chemical reactions than organic chlorides, and therefore, the bromide is widelyused in organic synthesis as a synthetic intermediate. As to the method for synthesizing organic
bromide, the aliphatic bromide can be easily synthesized by various synthetic methods, but thesynthetic method of the aromatic bromide is limited. A common bromination method for
obtaining aromatic bromides is the conversion of anilines by Sandmeyer reaction. Variousbromination reactions with aniline have been developed, but they are limited to methods thatuse metal-based catalysts under strong basic media or that require tedious workups. To
overcome these drawbacks, the development of metal- and base-free synthesis of aryl bromides
is strongly desired.

As to the synthesis of phosphorus compounds, one of the simplest methods is the additionof phosphorus compounds to carbon–carbon unsaturated compounds. To avoid the use of metal
catalysts and strong bases, radical pathways have recently received considerable interest in C–P formation methodologies. In recent years, phosphine-based organocatalysts have also madegreat strides in the development of asymmetric catalysis. Furthermore, organophosphorus
compounds also served as biophosphate mimics, antibiotics, antivirals, and antitumor agents
due to their unique chemical properties and various biological activities. Therefore, there is anincreasing demand for efficient, highly regio- and stereoselective preparation of phosphines.
In this thesis, the author has developed the metal-free functionalization of organic
molecules utilizing the characteristic features of heteroatoms. Using arylhydrazines as the aryl
sources, the author has developed a new synthetic method of aryl bromides that has been
attained by the combination of boron tribromide (BBr 3) and dimethyl sulfoxide (DMSO).
Moreover, diphenylphosphine oxide (Ph 2P(O)H) and tetraphenyldiphosphine monoxide(Ph2P(O)–PPh2) are used as phosphorus-centered radical sources which successfully add tounsaturated compounds with high regio- and stereoselectivities. All developed reactions canbe performed under metal-free conditions to reduce their harmful effects on the environments.
This thesis consists of five chapters and the outline of each chapter is summarized as follows.
Chapter 1 describes the background, general objectives, and the contents of this thesis.
Chapter 2 describes the bromination of arylhydrazine hydrochlorides using BBr 3 andDMSO. The author’s research group has previously reported that the iodinat ion ofarylhydrazine hydrochlorides with molecular iodine proceeded by a radical mechanism
involving aryl radicals as the key intermediates. Interestingly, the author has found thecombination of BBr 3 and DMSO inhibits the radical mechanism, and instead induces an ionicpathway for the bromination. A range of aryl bromides could be synthesized in moderated toexcellent yields under metal-free conditions. Several experiments, including the addition of aradical scavenger and Hammett plots (linear free-energy relationship) were also investigatedto determine whether this method proceeds via a radical or ionic pathway. The results strongly
suggested that the ionic pathway might mainly contribute to the bromination. A species
generated from BBr3 and DMSO plays an important role in the conversion of arylhydrazinehydrochlorides to aryl bromides. Taking advantage of the properties of several heteroatoms
such as N, B, S, and Br, a novel metal-free synthesis method of aryl bromides has beensuccessfully attained with a simple handling and high yields. The products, aryl bromides, areimportant synthetic intermediates for the preparation of a series of functionalized arenes.
Chapter 3 describes photoinduced selective hydrophosphinylation of allylic compoundswith Ph2P(O)H and insights into its mechanism. Phosphines are one of the representativeligands for transition-metal catalysts, and especially, bidentate ligands are very useful forcontrolling the selectivity of catalytic reactions. The 1,3-bidentate ligand can construct asterically stable six-membered cyclic metal-containing complex, and therefore, the use of a
1,3-bidentate ligand with two coordination sites composed of different heteroatoms might
control catalytic reactivity. Based on this concept, the author investigated the radical additionof Ph2P(O)H to various allylic compounds leading to γ-heteroatom-functionalized phosphineoxides as 1,3-bidentate P-ligand precursors. With allylic alcohol, ether, and ester, thecorresponding 1,3-P,O-ligands were obtained in good yields. Allylic sulfides afforded 1,3-P,Sligands, which are expected to preferentially coordinate soft metals. Besides the desired
product (namely [P]-monomer), a double addition product (namely [P]-dimer) was also formed,
when allylic ether and ester were employed as substrates. To gain insight into the formation ofmultiple addition products, reactions of diphenylphosphine oxide with allyl phenyl ether wereperformed varying the amounts of allyl phenyl ether. The results indicated that the use of excess
allylic compound induced further propagations. However, the reaction of [P]-monomer withallyl phenyl ether did not give [P]-dimer. Therefore, the proposed mechanism suggests that
Ph2P(O)• adds to two molecules of allyl phenyl ether to afford [P]-dimer. Several factors suchas electron-withdrawing ability of allylic compounds, steric hindrance, and phosphorus
substituent properties could affect to the product selectivity between [ P]-monomers and [P]dimers. The present photoinduced hydrophosphinylation of allylic compounds could occur
with excellent regioselectivity (according to anti-Markovnikov’s rule) under simplemanipulation in the absence of solvent. Therefore, this method can be accepted as an eco friendly synthesis of γ-heteroatom-functionalized phosphine oxides as 1,3-bidentate P-ligand
precursors.
Chapter 4 describes the highly regio- and stereoselective phosphinylphosphination ofalkynes with Ph2P(O)–PPh2. Chapter 3 deals with the radical addition of Ph 2P(O)H to carbon–
carbon unsaturated compounds such as allylic compounds by homolysis of P–H bond, while
Chapter 4 describes a radical addition of P–P bond compounds to alkynes by homolysis of P–
P bonds. The author’s research group has found that various P–P bond compounds such as
Ph2P–PPh2, Ph2P(O)–PPh2, Ph2P(S)–PPh2, and Ph2P(S)–P(S)Ph2 could add to carbon–carbon
unsaturated compounds upon photoirradiation. By gaining insight into these radical addition
reactions, the author noticed that Ph 2P(O)–PPh2 is not advantageous for the photoinduced
radical addition to alkynes due to its relatively low absorption. Hence, the author has developed
a novel phosphinylphosphination of terminal alkynes with Ph 2P(O)–PPh2 using radicalinitiators. Cleavage of the P V(O)–PIII bond forms two different phosphorus-centered radicals
with different reactivities. The P V radical is more reactive toward alkynes compared with thePIII radical, and the formed carbon radical is selectively captured by the P III site of Ph2P(O)–PPh2. Furthermore, the present phosphinylphosphination proceeded stereoselectively to givethe E-isomers. Both alkyl- and aryl-substituted terminal alkynes tolerated the reaction
conditions to selectively afford (E)-1-phosphinyl-2-phosphinoalkenes in moderate to goodyields. In contrast, internal alkynes could not afford the desired adducts due to the sterichindrance. Noteworthy is that the difference in the oxidation state of heteroatom clearly
controls the regioselectivity of the addition.
Chapter 5 describes the summary of this thesis.
In conclusion, this thesis describes a series of metal-free functionalizations of organic
molecules that take advantage of the characteristics of heteroatoms. By using of a system of
BBr3 and DMSO, arylhydrazine hydrochlorides are successfully converted to aryl bromides.
These products play an important role in organic synthesis. Furthermore, the author hassucceeded in developing a new synthetic method under metal-free conditions for functional
phosphorus compounds being useful as ligands. In the radical addition of Ph 2P(O)H to theallylic compounds, γ-heteroatom-functionalized phosphine oxides as 1,3-bidentate P-ligand
precursors can be easily synthesized. On the other hand, in the radical addition reaction ofPh2P(O)–PPh2 to alkynes, 1-phosphinyl-2-phosphinoalkenes are obtained regio- andstereoselectively by utilizing the characteristics of phosphorus having different oxidation states.
As described above, the author succeeded in highly selective functionalization of organic
molecules under metal-free conditions by utilizing the characteristics of heteroatoms. Thesedeveloped synthetic methods are expected to be effective for the powerful synthesis offunctional materials and pharmaceuticals.

審査結果の要旨
本論文は、ヘテロ原子の特性を活かしたメタルフリー条件下での有機分子の官能基化法の開発、およびこの手法に基づく臭素化芳香族化合物や有機リン化合物の合成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） アリールヒドラジンの臭素化が、三臭化ホウ素とジメチルスルホキシドを用いた置換型反応として効率良く進行し、アリールブロミドを選択的に合成することに成功している。さ
らに、ヨウ素分子を用いたアリールヒドラジンのヨウ素化反応がラジカル機構で進行するのに対して、本臭素化反応がイオン機構で進行することを明らかにしている。本反応で得られるアリールブロミドは、芳香族化合物の重要な合成中間体であることから、本研究は多様な芳香族化合物の調製のための効率的な合成ツールを提供するものである。
（２） ジフェニルホスフィンオキシドを用いたアリル化合物の光誘起ヒドロホスフィニレーションにより、γ 位に各種ヘテロ原子を有するホスフィンオキシドを合成することに成功している。本手法は、メタルフリーかつ無溶媒条件下での付加型反応により、アリル化合物に対してリンを位置選択的に導入可能であるという特長を有する。さらに、本反応で得られるヘテロ原子官能基化ホスフィンオキシドを還元すれば、金属との安定な錯形成が可能な1,3-二座配位子に誘導できるため、本手法は様々な 1,3-二座ホスフィン配位子前駆体の環境調和型合成手法を提供するものである。
（３） ラジカル開始剤存在下で、テトラフェニルジホスフィンモノオキシドの末端アルキンへの付加型反応がメタルフリー条件下で位置および立体選択的に進行することを明らかにしている。本反応では、V 価およびⅢ価リンのラジカル反応特性の違いを解明することにより、選択性の制御に成功している。本手法で得られた E 型アルケンは、複数の金属を架橋して階層構造を構築できる架橋配位子の前駆体として有用である。
以上の諸成果は、ヘテロ原子の特性を活かしたメタルフリーでの有機分子の官能基化法を開発し、これらの手法を応用して、芳香族化合物の官能基化に有用なアリールブロミドや、ホスフィン配位子前駆体の合成に成功しており、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。