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The Development of New Reagents and Reactions for Synthetic Organofluorine Chemistry by Understanding the Unique Fluorine Effects

Qiqiang Xieand Jinbo Hu

CAS Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai, 200032, China

1.1 Introduction

For a long period of time, fluorine chemistry research was deemed to be very dangerous, in part owing to the notorious fluorination reagents such as F2 and HF, which are highly corrosive and reactive. In this context, synthetic organofluorine chemistry was only pursued by a handful of researchers for several decades after the first synthesis of F2 by Moissan in 1886. However, great changes had taken place over the past decades. With the successful application of chlorofluorocarbons (although banned later owing to their ozone-depleting character by Montreal Protocol in 1987) as refrigerants, the development of high-performance fluorinated materials such as Teflon and the development of fluorinated pharmaceuticals and agrochemicals, organofluorine chemistry has become increasingly important in satisfying the huge demand for fluorinated molecules with diverse functions [1]. To date, organofluorine chemistry has become an indispensable branch of organic chemistry and enriched many aspects of related areas such as medicinal chemistry and materials science, among others. Perhaps the most prominent application of organofluorine compounds that has close relation with our everyday life is fluorinated drugs. For example, among the 59 drugs (39 of them are small molecule drugs) approved by FDA in 2018, 18 contain at least one fluorine atom; among the 48 drugs approved by FDA in 2019, 13 contain at least one fluorine atom [2]. Some representative fluorinated drugs approved in 2018 and 2019 are shown in Figure 1.1.

In spite of the importance of fluorinated molecules in modern society, naturally occurring organofluorine compounds are rare [3]. Basically, all the commercially supplied organofluorine compounds are manmade. Thus, the development of new reagents and reactions to introduce fluorine atoms or fluorine-containing moieties into organic molecules is one of the central goals in modern synthetic organofluorine chemistry.

Figure 1.1 Fluorinated drugs newly approved by FDA in 2018 and 2019.

Figure 1.2 Organofluorine reagents developed or co-developed by us.

Over the past 15?years, our group has been interested in reaction mechanism-inspired synthetic organofluorine chemistry [4]. We have developed or co-developed a variety of reagents, including fluoroalkyl aryl sulfones [5], fluoroalkyl sulfoximines [6], fluoroalkyl heteroaryl sulfones [7], difluorocarbene reagents [8], fluorinated sulfinate salts [9], fluorinated esters [10], CpFluors [11], and SulfoxFluor [12], among others (for a review, see Ref. [4d]), for fluoroalkylation, fluoroolefination, and fluorination reactions (Figure 1.2). Our research program was triggered by two questions: (i) What are the unique features of organofluorine reactions (compared with regular organic reactions)? (ii) Is there any relationship among fluoroalkylation, fluoroolefination, and fluorination? In this review, we intend to answer these two questions by illustrating representative reagents and reactions developed (or co-developed) by us. In particular, understanding of the unique fluorine effects in organic reactions is helpful in addressing these two questions [4g].

1.2 The Unique Fluorine Effects in Organic Reactions

It is now gradually accepted that organofluorine reactions are usually distinct from regular organic reactions, and in many cases, fluorine substitution in an organic molecule imparts unique reactivity to the latter. As a result, direct application of the knowledge and experience acquired from regular organic reactions to organofluorine reactions often leads to failure or unexpected results. In this section, we provide some selected examples to highlight the unique features of organofluorine reactions. For more examples and discussions, one may refer to our recent tutorial review [4e].

1.2.1 Fluorine-Enabled Stability of "CuCF3" in Water, and the Unusual Water-Promoted Trifluoromethylation

Organocopper reagents are widely used in organic synthesis [13]; however, these reagents are typically water sensitive. In 2012, we disclosed a water-promoted trifluoromethylation of a-diazo esters to access a-trifluoromethyl esters, representing the first example of fluoroalkylation of a non-fluorinated carbene precursor (Scheme 1.1) [14]. We found that "CuCF3" (prepared from CuI/CsF/TMSCF3) in n-methyl-2-pyrrolidone (NMP) is stable even in the presence of 66?equiv of water at room temperature within five hours and only about 5% of "CuCF3" decomposed. Taking advantage of the unusual stability of "CuCF3" in water (fluorine effect), we could therefore use water (CuI is also applicable) as the iodide scavenger to enhance the activity of "CuCF3" prepared from CuI/CsF/TMSCF3 significantly by changing "CuCF3" in the form of [Cu(CF3)I]- to "ligandless" [Cu(CF3)], which is more reactive toward a-diazo esters. From an organometallic chemistry point of view, water promotes the ligand exchange in "CuCF3" by eliminating iodide, making the ligation of a-diazo esters to "CuCF3" more favorable. The stability of "CuCF3" toward water and the instability of alkylcopper intermediate 1 toward water ensure the success of this reaction.

Scheme 1.1 Water-promoted trifluoromethylation.

1.2.2 Fluorine Enables ß-Fluoride Elimination of Organocopper Species

In the abovementioned water-promoted trifluoromethylation, a stoichiometric amount of copper is required and gem-difluoroolefin was found to be formed under strictly anhydrous conditions. Inspired by this fact, we developed a copper-catalyzed gem-difluoroolefination of diazo compounds, concisely [15] (Scheme 1.2a). In this catalytic reaction, diaryl diazomethanes were used instead of a-diazo esters for two reasons: (i) diaryl diazomethanes possess higher reactivity than a-diazo esters and can react with unactivated "CuCF3" directly (without the need for eliminating ligated iodide in "CuCF3"), making the addition of excess water or CuI as iodide scavenger no longer necessary, and (ii) diaryl-substituted alkylcopper intermediate 2 readily undergoes ß-fluoride elimination (even in the presence of excess amount of water) (Scheme 1.2b), which is critical to regenerate the copper catalyst and close the catalytic cycle.

Scheme 1.2 Copper-catalyzed gem-difluoroolefination of diazo compounds.

1.2.3 The "Negative Fluorine Effect" Facilitates the a-Elimination of Fluorocarbanions to Generate Difluorocarbene Species

Based on the results described in Sections 1.2.1 and 1.2.2, we were able to achieve gem-difluoroolefination of diazo compounds under transition metal-free conditions via direct cross-coupling between a non-fluorinated carbene precursor from a diazo compound and difluorocarbene from TMSCF3 or TMSCF2Br (Scheme 1.3a) [16]. This reaction proceeds through nucleophilic addition of diazo compounds to difluorocarbene, followed by ß-N2 elimination from intermediate 3, to form gem-difluoroolefins. The most significant feature of this protocol is the broad substrate scope (compared with our previous copper-catalyzed method of diazo compounds, which is only efficient for diaryl diazomethanes). a-Diazo acetates, diaryl diazomethanes, as well as diazirines are all suitable substrates. Moreover, by simply tuning the molar ratio of diazirines and TMSCF2Br, either gem-difluoroolefins or tetrafluoropropanes can be obtained selectively (Scheme 1.3b). It should be noted that the in situ generation of difluorocarbene occurs via an a-elimination of fluoride ion from "CF3-" (in the case of TMSCF3), or via an a-elimination of bromide ion from "CF2Br-" (in the case of TMSCF2Br), which can be explained by the "negative fluorine effect (NFE)," that is, fluorine substitution on a carbanionic center will often have a negative (unfavorable) effect on the carbanion's thermal stability and its nucleophilic reactions with many electrophiles.

Scheme 1.3 Transition metal-free gem-difluoroolefination of diazo compounds.

Alkylsilane reagents are useful in cross-coupling reactions. In the presence of a Lewis base, alkylsilane can act as "R-" donor to undergo alkylation under transition metal catalysis [17]. In this context, fluoroalkylsilanes often serve as nucleophilic fluoroalkylation agents. For...