Development of Shelf-Stable Reagents for Fluoro-Functionalization Reactions

Abstract

It is highly probable that the first impression that organic chemists would have of fluorine, F, is that it is "dangerous". Elemental fluorine, F 2 , is a gas that reacts with all elements quickly and violently. The oxidation power of F 2 is extraordinarily strong and even the noble gases such as Kr and Xe react with F 2 forming the corresponding fluorides. Fortunately, the receptiveness to fluorine chemistry by synthetic chemists has gradually changed in the late 20th century with the development of shelf-stable reagents for fluorination and trifluoromethylation reactions. In this account, I introduce our recent contributions to the development of shelf-stable reagents for the synthesis of organofluorine compounds. Electrophilic reagents for fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation are discussed. Nucleophilic reagents for monofluoromethylation are also described including enantioselective reactions.

Current Contributions of Organofluorine Compounds to the Agrochemical Industry

“…Significantly, these results suggest that biological efficacy is becoming more important than the disadvantages associated with the cost of producing fluorinated compounds. This shift could be related to progress in the synthetic methodology used to obtain organofluorine compounds ( Shibata, 2016 ; Wang et al., 2014 ; Ojima, 2009 ), since cost-friendly synthetic tools for fluorination and trifluoromethylation have been a focus over the last 20 years or so.

Figure 3 Prevalence of Fluoro/Non-fluoro-Agrochemicals Assigned New ISO Common Names (1998–2020 (June)) The list of all agrochemicals (238 compounds) including the fluoro-agrochemicals (127 compounds) is provided in Table S4 .

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“…Currently, a new agrochemical cannot be approved unless its effects on air, water, soil, and human health are known (Vaz, 2019;Delorenzo et al, 2001;Ames and Gold, 1997;Bhattacharyya et al, 2009). Inspired by the potential efficiency of fluoro-DDT as an insecticide, the first fluoro-herbicide, trifluralin (Epp et al, 2018) introduced by Eli Lilly & Co. in 1963 (Figure 1C, also one of the most globally used herbicides), as well as our ongoing research into biologically active organofluorine compounds (Shibata, 2016), we were interested in the contributions of fluorine-containing agrochemicals (fluoro-agrochemicals) to the wider field of agrochemicals (Cartwright, 1994;Theodoridis, 2006;Fujiwara and O' Hagan, 2014;Jeschke, 2004;Haufe and Leroux, 2019;Pazenok and Leroux, 2020). Organofluorine compounds have emerged as attractive synthetic building blocks in the pharmaceutical industry (Wang et al, 2014;Ojima, 2009) following the use of the first successful fluoro-pharmaceutical, Florinef acetate, in 1954 (Figure 1D).…”

Asymmetric Fluorination Reactions promoted by Chiral Hydrogen Bonding‐based Organocatalysts

“…Although several strategies have been developed for the construction of chiral fluorinated organic structures using both nucleophilic [21] and electrophilic [22] sources, the catalysts revised in this work are mostly involved in electrophilic fluorination reactions with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborates) (Selectfluor) or N-fluorobenzenesulfonimide (NFSI) ( Figure 2). However, some other fluorinating sources will be also illustrated and commented on this revision.…”

Kitamura Electrophilic Fluorination Using HF as a Source of Fluorine

“…For example, as presented in Figure 1, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate) (1), introduced by Professor E. Banks [72], also known as Selectfluor, is one of the best reagents used as a source of "electrophilic fluorine". Other reagents, developed by Professor N. Shibata [73][74][75][76], are N-fluoro-N-(methylsulfonyl)methanesulfonamide (Me-NFSI) (2), 3,5-di-tert-butyl-N-((3,5-di-tert-butyl-4-methoxyphenyl)sulfonyl)-N-fluoro-4-methoxybenzenesulfonamide (NFBSI) (3) and axially chiral NFSIs (4), which can be used for enantioselective fluorination [77]. All these reagents are shelf-stable, easy to handle and operationally convenient to use for various synthetic applications [78][79][80][81].…”