Synthesis of α,β-unsaturated ketones through nickel-catalysed aldehyde-free hydroacylation of alkynes

Abstract

In this thesis, the importance of α,β-unsaturated ketones in the fields of pharmaceuticals, functional materials, and organic synthesis was highlighted, and the developed synthetic method using these materials in the classical and the recent transition metal-catalyzed chemistry was introduced. As a method for accessing α,β-unsaturated ketones, advanced synthetic routes using transition metal catalysts such as Rh, Co, and Ru are presented beyond the scope of classical chemistry such as aldol condensation. In particular, we presented the examples of intramolecular and intermolecular reactions of alkene and alkyne using aldehydes and transition metals, pointed out their limitations, and presented concepts for overcoming them. Hydroacylation using conventional transition metal catalysts mostly used aldehydes. The disadvantage is that transition metals and aldehydes form the complex through an oxidative addition, and the formed acyl-metal-H complex is unstable, causing a decarbonylative side reaction, which results in an undesired CO free R-H product. Various transition metals have been presented to replace Rh, but the underlying decarbonylative problem has not been resolved. The introduction of heteroatom (P, N, O, S) chelating groups was suggested as a feasible solution. It was possible to stabilize the unstable acyl-metal-H complex and suppress the side reaction of decarbonylation via the introduction of the chelating group, but the scope is limited because the chelating groups are always required for the substrates. The step economy is not good in that it requires additional steps to remove the chelating group. Herein, we have introduced three strategies to overcome these limitations. First, by using a thioester with thiopyridine that can act as a leaving group as well as a chelating group instead of an oxidative addition mechanism through aldehyde, a traceless reaction was approached with the good step economy without the remained chelating group after the reaction. Second, using water as a hydrogen donor with a reducing agent to replace H of the aldehyde, the proton could be supplied stably and a mild condition was established without a hydride source like the conventional dangerous silyl hydride. Third, suggesting nickel as a catalyst which is relatively cheap instead of previous Rh, Co, Ru and Pd, synthetic route could be designed economically. By forming a stable acyl-nickel-thiopyridine complex, it was possible to effectively suppress the R-H decarbonylative side products which were critical issues in the previous transition metal catalyzed hydroacylation. Based on these strategies, hydroacylation reaction was applied to terminal alkynes, internal alkynes and electron withdrawing group attached alkenes. Regio- and stereoselective desired products in the form of α,β-unsaturated and β,γ-unsaturated ketones could be obtained. Especially, in the case of terminal alkyne, a product could be afforded with a high yield up to 82%. Surprisingly, not only the simple aryl compounds, but also simple alkyl compounds, which was almost difficult to access via previous hydroacylation due to weak binding with carbonyl carbon, could also be included in the scope through acyl radical process and expanded the scope. Not only that, ethisterone, which is a complex drug structure, was also applied in the g-scale with moderate 56% yield, suggesting the possibility of application for pharmaceutical production. Through this thesis, it is possible to overcome the challenging part of the existing hydroacylation while presenting the concept of hydroacylation using nickel catalyst and thioester at an affordable price under mild conditions, and the range of application is expanded to polymerization and pharmaceutical. Finally, a new paradigm of hydroacylation using thioester was developed beyond the existing hydroacylation using aldehyde.