Organic Chemistry Frontiers Blog

Organofluorine compounds play an important role in pharmaceuticals, agrochemicals, and functional materials, due to their special chemical, physical and biological properties, such as increased electronegativity, hydrophobicity, bioavailability and metabolic stability. Therefore, great efforts have recently been devoted to the development of new methods for the synthesis of fluorinated compounds. Conventional strategies mainly focus on the selective introduction of fluorine atom or fluorine-containing moiety into organic molecules. Alternatively, the development of novel synthetic methodologies via the selective activation of C-F bond is of vital importance, which could allow for the synthesis of partially fluorinated synthetic intermediates from readily available polyfluorinated starting materials. The research of C-F bond activation is the most challenging task in organic synthesis, which has recently drawn increasing attention from chemists. In this review, we mainly focus on the C-F bond activation of CF₃ groups for the synthesis of fluorinated compounds as well as discussion of their mechanisms(Scheme 1).

Scheme 1 The C-F bond functionalization of trifluoromethyl-containing compounds.

Due to the electron-deficient property, α-trifluoromethylstyrenes exhibit unique reactivities in their C-F bonds activation, mainly including three kinds of reactions (S_N2′-type, S_NV and ipso-substitution reactions, Scheme 2).

Scheme 2 Allylic and vinylic C-F bond activation in SN2’-type, SNV and ipso-sunstitution reactions

The cleavage of C-F bond in trifluoromethylated aromatic (Scheme 3) and alkyl compounds (Scheme 4) could be achieved through using transition metal complexes, main-group Lewis acids and base-conditions. An alternative strategy mainly relied on the single-electron transfer (SET) via Low-valent metals, irradiation with visible light.

Scheme 3 Photoredox-catalyzed defluoroalkylation of ArCF3 with unactivated alkenes.

Scheme 4 Pd-catalyzed defluorination/arylation reaction of α-trifluoromethyl ketones with aryl boronic acids.

Trifluoromethyl ketones (Scheme 5) and their corresponding diazo compounds (Scheme 6) , N‑tosylhydrazones (Scheme 7) have been utilized as the coupling partners in modern synthetic organic chemistry. Recently, the C-F bond cleavage of these compounds has also been reported through transition-metal catalysts.

Scheme 5 Cu-catalyzed reaction of trifluoromethylketones with aldehydes.

Scheme 6 Cu-catalyzed gem-difluoroolefination of diazo compounds.

Scheme 7 Cu-catalyzed cross-coupling of N-tosylhydrazones with terminal alkynes.

Although great progress has been made in this rapidly developing area, these reactions still suffer from some issues of the limitation of substrates and poor regioselectivity. To overcome these central challenges, it is more important to extend the substrate scope of the existing methodologies, especial trifluoromethylated alkyl compounds. Furthermore, the robust catalytic systems will be developed for the selective activation of a single C-F bond in CF₃ groups.

 Guobing Yan

Zhejiang A&F University

Guobing Yan is a Professor in college of Jiyang at Zhejiang A&F University. He obtained B.Sc. degree from Jinggangshan Normal University, his M.Sc. degree from Suzhou University, and his Ph.D. degree from Tongji University in 2010. He spent two years in 2008 and 2009 as visiting student in professor Jianbo Wang’s laboratory at Peking University. In 2013, He joined Dr. Dong’s group at the University of Texas at Austin as a visiting professor. His current research interests focus on the transition-metal-catalyzed activation of inert chemical bonds and green synthetic chemistry. He is the author of 6 patents and more than 70 articles indexed by SCI.

Recent Advance in the C-F bond functionalization of trifluoromethyl-containing compounds

Guobing Yan, Kaiying Qiu and Ming Guo

https://doi.org/10.1039/D1QO00037C

Isocyanides have proven to be versatile building blocks in organic synthesis and medicinal chemistry due to their synthetic possibilities capable of reacting with electrophiles, nucleophiles and radicals. Multi-component reactions involving isocyanides have been well developed with the advantages of diverse skeletons of products, functional group compatibility, high chemo-, regio and stereoselectivities, and atom economy. With the continuous research on isocyanides, C(sp³)–H functionalization with isocyanides has made significant progresses with the advancement of mechanistic studies, new techniques and novel strategies in recent years. In this review, the group of Xu and coworkers of Shanghai University of China highlights the most recent advances of isocyanide chemistry in the C(sp³)–H functionalization since 2015 by elaborating the strategies of state-of-the-art synthetic routes. The synergistic combination of the isocyanide insertion and the C(sp³)–H bond activation offers a novel and efficient route to establish complicated reactions and provides an effective strategy for the synthesis of various nitrogen- and oxygen-containing compounds.

Figure 1.C(sp³)–H functionalization with isocyanides

Bin Xu received his bachelor’s degree from Shanghai University of Science and Technology in 1992. He conducted his PhD research with Professor Shengming Ma at Shanghai Institute of Organic Chemistry and completed his degree in 2000. After a two-year postdoctoral training at National Institutes of Health (NIH) as a Visiting Fellow (Mentor: Dr Kenneth A. Jacobson), he joined VivoQuest as a staff scientist (2002–2005). He began his independent academic career at Shanghai University in the end of 2005 as a Full Professor. His current research interests span the development of new methodology for nitrogen-containing heterocycles and their biological applications.

C(sp³)–H Functionalization with Isocyanides

Org. Chem. Front., 2021, Accepted Manuscript

https://pubs.rsc.org/en/content/articlelanding/2021/qo/d1qo00153a#!divAbstract