The use of functional groups or reactive chemical bonds in organic synthesis has long focused on molecular transformations. In contrast, Prof. Naoto Chatani has developed a variety of new transformations involving the activation of unreactive bonds, based on new methodologies for bond activation, which were not previously in widespread use in the field of organic synthesis. Chatani's research has investigated, not only the activation of C-H bonds, but also the activation of unreactive single bonds, such as C-C, C-O, C-N, and C-F bonds, and the activation of C-C triple bonds and C-O double bonds, in order to develop new types of transformations.
1. The use of Bidentate Chelation Assistance in C-H Activation
The transition-metal-catalyzed functionalization of C-H bonds is emerging as a powerful tool for C-C and C-heteroatom bond formation and has been the subject of a great deal of attention in recent years. The most important issue to be addressed in functionalization of C-H bonds is regioselectivity, because organic molecules contain a number of different types of C-H bonds. If it were not possible to achieve the regioselective activation of a specific C-H bond, the reaction would result in the formation of a complex mixture of molecules. The most reliable method for the regioselective functionalization of C-H bonds involves chelation-directed metalation via the use of a directing group. Chatani developed a new general and reliable chelation system for the Ni-catalyzed functionalization of C-H bonds by taking advantage of an 8-aminoqunoline as a directing group. Prior to this discovery, the Ni-catalyzed activation of C-H bonds reported had been limited to specific substrates, such as azoles, pentafluorobenzene, pyridines, and activated pyridines that contain an acidic C-H bond. A wide variety of C-H functionalization, arylation, alkylation, iodination, sulfonylation, oxidative benzylation, oxidative cycloaddition reactions with alkynes was achieved by using an 8-aminoquinoline directing group in conjunction with Ni(II) as the catalyst. The most important role of a directing group is to permit the catalyst to come into close proximity to the C-H bond, resulting in the regioselective cleavage of such a bond. However, the directing group can also have an effect on changing the reaction mechanism. Chatani found that the addition of C-H bonds to alkenes, not only activated alkenes, such as acrylic esters, styrenes, and norbornene, but also unactivated alkenes, such as 1-hexene can be achieved by using rhodium as the catalyst and an 8-aminoquinoline directing group. Remarkably, it was found that both the ortho-carbon and the ortho-hydrogen in aromatic amides could be attached to the same carbon of an alkene in the product, strongly suggesting that the generally accepted mechanism, such as hydrometalation or carbometalation is not involved, but instead, a new mechanism involving the production of a carbene intermediate is proposed. Not only nickel and rhodium complexes, but other transition metal catalysts, such as palladium, ruthenium, and cobalt complexes can be used as the catalyst in the functionalization of C-H bonds using a bidentate directing group, thereby resulting in a new type of C-H functionalization.
2. C-H Carbonylation
The direct carbonylation of C-H bonds is one of the most straightforward methods for the preparation of carbonyl compounds. Chatani succeeded in developing a series of three-component coupling reactions for C-H/CO/alkenes leading to the production of ketones from hydrocarbons. For example, the reaction of imdazoles with CO and alkenes in the presence of Ru3(CO)12 resulted in regioselective acylation at the 5-position. The reactions that were discovered can be classified into five types, depending on the position of the N(sp2) and the C-H bond that reacts, indicating that the coordination of N(sp2) to a ruthenium center is important for the success of the reaction. In fact, the reactivity of the substrates was found to be highly dependent on the basicity of the substrate. The reactivity increased with increasing basicity of the substrates. The system permitted C(sp3)-H bonds adjacent to a sp2 nitrogen atom to be carbonylated.
3. Electrophilic Activation of C-C Triple Bonds
The reaction of alkynes activated by electrophilic metals with nucleophiles is a well-known reaction. A representative reaction is the synthesis of ketones by the Lewis acid-catalyzed hydration of alkynes. In contrast, the reaction of alkynes activated by electrophilic metals with neutral alkenes or benzene is rare because of the lower nucleophilicity of alkenes or benzene. Chatani found that a variety of electrophilic transition metal halides and their corresponding cation complexes can trigger the cycloisomerization of enynes to give cyclic compounds. The first report of this involved the Ru(II)-catalyzed skeletal reorganization of 1,6-enynes to give 1-vinylcyclopentene derivatives. The electrophilic addition of a RuCl2 moiety to an alkyne, leading to the generation of a vinyl cation initiates the catalysis. In addition, Chatani succeeded in intercepting the cyclopropyl carbenoid intermediate by an intramolecular alkene, leading to the stereoselective production of polycyclic compounds. This result strongly suggests the intervention of a carbenoid intermediate in the transition-metal-catalyzed skeletal reorganization of 1,6-enynes. Various metal halides, such as PtCl2, [IrCl(CO)]n, AuCl3, GaCl3, InCl3 were also found to show a high catalytic activity for skeletal reorganization.
In summary, the use of functional groups or reactive chemical bonds in organic synthesis has long focused on molecular transformations. In contrast, Chatani developed new methodologies for bond activation, which had not been previously in widespread use in the field of organic synthesis, and developed a variety of new transformations involving the activation of unreactive bonds, based on the new methodologies. From a broad view point of unreactive bonds, Chatani's research has utilized, not only the activation of C-H bonds, but also the activation of unreactive single bonds, such as C-CN, C-OMe, C-N, and C-F, as well as the activation of C-C triple bonds and C-O double bonds, in order to develop new types of transformations. The use of such unreactive bonds in organic synthesis is expected to add additional diversity to synthetic methods. Since Chatani opened the door to a new generation of organic synthesis based on the activation of unreactive bonds, this research field has become a promising and relevant new area of research. His contributions have been recognized worldwide, making him eminently deserving of being the recipient of The Chemical Society of Japan Award.