Recent Advances in the Synthesis of Distal Fluorinated Ketones

Incorporation of a fluorine atom to molecules is a privileged strategy to modify the physical, chemical and biological properties, which is widely executed in pharmaceuticals, agrochemical and material sciences. Consequently, the development of efficient and direct fluorination approach is of considerable significance. In spite of the great progress made in the transition-metal catalyzed construction of sp(2) C-F bond via C-H activation and cross-coupling reactions, the direct access to aliphatic sp(3) C-F bond is relatively underdeveloped as the development of a mild and efficient method to construct.sp(3) C-F bond remains a challenging issue. Ketone is a ubiquitous and important structural motif in organic compounds. The efficient synthesis of fluorinated ketone building blocks thus provides a shortcut for the introduction of fluorinated functionalities into complex molecules. Other than alpha-fluorinated ketones, the synthesis of distal fluorinated ketones is still challenging. Herein, we highlight the recent efforts made for the synthesis of distal fluorinated ketones. Four fluorination pathways are described: (a) C-H fluorination, (b) decarboxylative fluorination and deboronofluorination; (c) olefin fluorination, and (d) ring-opening fluorination. The first and second sections briefly introduce the direct sp(3) C-H fluorination, decarboxylative fluorination, and deboronofluorination to construct aliphatic sp(3) C-F bonds, which are tolerant to carbonyl group in the substrates. The third section discusses the direct construction of beta and gamma-fluorinated ketones via the difunctionalization of olefins. The last section puts an emphasis on the latest emergence of ring-opening fluorination. Relying on the "radical clock" strategy, the distal fluorinated ketones can be obtained from the corresponding tertiary cycloalkanols. Overall, this highlight provides a new insight into the recent advances in the sp(3) C-H fluorination and the synthesis of distal fluorinated ketones.