Development of a Continuous Flow Stereodivergent Metallaphotoredox Semihydrogenation Process Using Water as Hydrogen Source

Semihydrogenation of alkynes is an important transformation in the chemical industry and has widespread applications in the preparation of pharmaceuticals, agrochemicals, natural products, and much more. The stereoselectivity and chemoselectivity of the semihydrogenation process to provideZ- orE-alkenes and to avoid overhydrogenation have been a major research focus in the area for the past decades. However, the methodologies and reaction setups largely remained unchanged, and there are still intrinsic and unsolved problems that are highly desirable to be addressed. A multitude of challenges have been identified with semihydrogenations, namely (1) chemo- and stereoselectivities; (2) use of noble metal catalysts; (3) excessive metal reductants; (4) toxic metal and additives; (5) poor scalability; and (6) the handling of flammable H2 gas and high-pressure equipment.  Herein, we propose to address these persistent challenges by employing continuous flow chemistry and metallaphotoredox catalysis cooperatively. Continuous flow chemistry is a powerful synthetic technology that provides many advantages relative to traditional organic synthesis, while metallaphotoredox catalysis is a versatile technique which harnesses the power of photocatalysts and reactivity of transition metal complexes to enable mild and selective transformations. Our proposed method would replace the noble metal catalysts and metal reductants with base metal catalyst and photocatalysts which reduce metal species by single electron transfer (SET) process. The system would enable the use of water as hydrogen source while the reaction conditions can be readily translated to flow for facile scale-up and improved efficiency. Our preliminary results have verified the plausibility of the proposed study, in which our metallaphotoredox semihydrogenation provided the desired alkene with excellent chemo- and stereoselectivity. The prototype flow system can significantly intensify the process and shorten the reaction time by at least 95%. The potential of our metallaphotoredox method would be fully explored in this project, including the development of a stereodivergent process, a scalable continuous flow system, and semideuterogenation reaction. The mechanistic study will guide the development of the proposed project and provide important insights to the organic synthesis community.  The fundamental and technical knowledge obtained during the development of our new metallaphotoredox semihydrogenation will be of significant value to academic interest and industrial applications. The demonstrated flow system will serve as a model for future designs of continuous flow photochemical reactions. Currently, flow chemistry is still underdeveloped in Hong Kong. Our study would attract attention on continuous flow production and help transform the fine chemical manufacturing and pharmaceutical industry.