Etherification as a general route for γ-C(sp3)–H functionalization of alcohols

• Applicant: Dr. Pit Van Bonn
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 561025375

Oxetanes, a four-membered cyclic ether, are gaining increasing importance in organic chemistry, particularly in drug development. Their unique structure endows them with high reactivity and enables a variety of applications, including the enhancement of properties such as solubility and metabolic stability of pharmaceuticals. Traditional synthesis methods for oxetanes include intramolecular nucleophilic substitution, electrophilic halocyclization of alcohols, and ring expansion of epoxides. However, these methods often require multiple steps, complicating and rendering the synthesis inefficient. The simplest synthesis of oxetanes would be from aliphatic alcohols, which are particularly attractive as they are abundant in renewable raw materials, natural products, and synthetic intermediates. Despite some progress in the direct activation of C–H bonds of unprotected aliphatic alcohols, the synthesis of oxetanes has yet to be realized. The main goal of this research project is to develop a palladium-catalyzed γ-C(sp³)–H etherification of aliphatic alcohols to enable direct access to oxetanes. The project is divided into three main parts. The first part focuses on the development of an efficient catalyst as well as the optimization of reaction conditions. Novel ligands are to be developed that improve the coordination and stability of the hydroxyl group on the metallic catalyst. Key parameters such as the choice of catalyst precursor, bases, solvents, and sustainable oxidants will be investigated to enable a more efficient and environmentally friendly synthesis. The second part of the project aims to investigate the limits of the developed protocol by testing a variety of aliphatic alcohols with different structures. The applicability of the method for synthesizing natural products and bioactive compounds will be demonstrated. Additionally, the formation of other cyclic ethers such as tetrahydrofuran and tetrahydropyran will be examined. In the third part, detailed mechanistic studies will be conducted to understand the mechanisms of C–H bond activation and etherification. By combining experimental and computational methods, the underlying reaction pathways will be elucidated to improve the efficiency and selectivity of the synthesis. Overall, the project aims to overcome existing challenges in the synthesis of oxetanes and explore their potential applications in medicinal chemistry and natural product synthesis. Through the optimization of reaction conditions, expansion of the substrate spectrum, and understanding of mechanistic processes, the efficiency of oxetane synthesis is expected to increase, which could have far-reaching implications for chemical research and industrial applications.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Jin-Quan Yu, Ph.D.