Catalyzed and Promoted Aliphatic Fluorination - The Journal of

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Cite This: J. Org. Chem. 2018, 83, 8803−8814

Catalyzed and Promoted Aliphatic Fluorination Desta Doro Bume, Stefan Andrew Harry, Thomas Lectka,* and Cody Ross Pitts*,†

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Department of Chemistry, Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, United States † Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 2, 8093 Zürich, Switzerland

ABSTRACT: In the last six years, the direct functionalization of aliphatic C−H (and C−C) bonds through user-friendly, radical-based fluorination reactions has emerged as an exciting research area in fluorine chemistry. Considering the historical narratives about the challenges of developing practical radical fluorination in organic frameworks, notable advancements in controlling both reactivity and selectivity have been achieved during this time. As one of the participants in the field, herein, we a provide brief account of research efforts in our laboratory from the initial discovery of radical monofluorination on unactivated C−H bonds in 2012 to more useful strategies to install fluorine on biologically relevant molecules through directed fluorination methods. In addition, accompanying mechanistic studies that have helped guide reaction design are highlighted in context.

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Scheme 1. Multicomponent-Catalyzed Asymmetric α-Fluorinations

INTRODUCTION Almost a decade ago, as players in the midst of what could be arguably termed a “golden era of asymmetric α-halogenation”,1 our lab reported a tricomponent, catalytic, asymmetric α-fluorination of acid chlorides using N-fluorobenzenesulfonamide (NFSI).2 The development of this reaction proved to be quite interesting, but nevertheless challenging, and necessitated the judicious and sometimes counterintuitive juggling of three catalysts: a cinchona alkaloid derivative such as benzoylquinidine (BQd) to impart enantioselectivity;3 a Lewis acid (usually Li+) to activate the fluorinating agent;4 and finally, a transition-metal complex in order to form a stabilized zwitterionic enolate (Scheme 1).5 Absent one of these components, the reaction veered toward lower yields if not outright failure. The requirement for a transition-metal complex proved to be perhaps the most mechanistically notable aspect of the reaction. Ligated salts of Pd(II) and Ni(II) were demonstrated to be the most efficacious cocatalysts, although a large variety of additives were screened. This screening was wholly empirical and dependent largely on the presence of candidates already on the shelf in our laboratories. For the most part, other metal complexes gave lower yields and were quickly excluded on that basis. One strange exception was casually noted; a Cu(I) salt, in one instance, afforded trace amounts of other products evidently derived from fluorination of remote aliphatic positions in the substrate. Thinking nothing further about it at the time, we inadvertently missed an opportunity for a significant discovery based on the © 2018 American Chemical Society

Received: April 18, 2018 Published: June 12, 2018 8803

DOI: 10.1021/acs.joc.8b00982 J. Org. Chem. 2018, 83, 8803−8814

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The Journal of Organic Chemistry fact that Cu(I) was doing something dif ferent and peculiar. We should have asked ourselves, “Why would such a reaction result in any product (even trace) other than α-fluorination?” This type of tale is all too common in experimental science. In this Perspective, we chronicle the development of a series of catalyzed and promoted fluorination reactions that stem from this initial observation. The reactions discussed herein lead to somewhat different outcomes, but many are linked by the central role that the putative Selectfluor radical dication (SRD) plays in the chemistryas a chain carrier, a quenching agent, and an electron or hydrogen atom abstractor (Figure 1).

As recounted, we entered the arena semiserendipitously with the idea of fluorinating unactivated C−H bonds. Over the last several years, our laboratory13 and many others14 have made great strides in producing direct sp3 C−H monofluorination methods that are radical in nature, in concord with the decarboxylative chemistry (Scheme 3). Groves and co-workers reported a transition-metalScheme 3. Direct sp3 C−H Fluorination Methods

Figure 1. Possible roles of the Selectfluor-derived radical dication (SRD) in aliphatic fluorination.

Background and Seminal Developments. Our interest in fluorination chemistry stemmed not merely from pure curiositythere were compelling practical reasons as well. For example, nearly one-fourth of the top pharmaceuticals on the market contain fluorine,6 placing synthetic fluorination methods,7 particularly those amenable to late-stage functionalization, among the more valuable “warheads” in the arsenal of the medicinal chemist.8 “Fluorination screens”,9 in which known drugs are fluorinated methodically at each and every accessible site (to the extent that it can be accomplished) to render new candidates for evaluation, have become commonplace in pharmaceutical chemistry; in fact, some of the most widely used pharmaceuticals contain fluorine. From our standpoint, a largely untapped well resided in the field of selective aliphatic fluorination, which was still in its infancy at the time. Notable early work in the area focused on decarboxylation to generate free radicals regiospecifically (Scheme 2). In a seminal

catalyzed radical fluorination of unactivated, aliphatic C−H bonds by a manganese porphyrin complex.14a The reaction elegantly provided products with good chemoselectivity for methylene C−H bonds. Following Groves’ account, the first transition-metal-free direct conversion of sp3 C−H bonds to the corresponding alkyl fluorides was reported by Inoue and co-workers.14c The reaction is proposed to involve N-oxyl radicals as H-atom abstractors. Another noteworthy development in transition-metal-free radical fluorination came from Chen and co-workers, who employed photoexcited aryl ketones to generate benzylic radicals.14p The authors also noted selective formation of mono- and gem-difluorination products by employing 9-fluorenone and xanthone. The Challenge of Unactivated C−H Fluorination. In substrates that contain many distinct carbon atoms and C−H bonds, the early reports revealed the problem of “scattershot” fluorination leading to several products (A, Scheme 4). Thus,

Scheme 2. Notable Decarboxylative Fluorination Methods

Scheme 4. Intrinsic Reactivity of C−H Bonds and Directed Fluorination Reactions

report, Sammis and Paquin and co-workers demonstrated that alkyl radicals could react with mild electrophilic fluorinating agents instead of just F2.10 Shortly thereafter, Li and co-workers reported a catalytic Hunsdiecker-type oxidative decarboxylation/fluorination with a wide-ranging substrate scope.11 MacMillan and co-workers also expanded the field of decarboxylative fluorination by utilizing light-promoted photoredox chemistry with aliphatic carboxylic acids to form the corresponding regiospecific alkyl fluorides.12

many of the substrate tables reported in the literature are limited to highly symmetric compounds, such as cycloalkanes or substrates containing more activated benzylic sites (B−C, Scheme 4). In the few known cases of directed aliphatic fluorination,15 chelating auxiliaries prove necessary. Expanding upon our initial 8804


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The Journal of Organic Chemistry discoveries, the reader shall see our projects evolving from a primary focus on reactivity to one based on selectivity. Directing fluorination more effectively (in our case through carbonyl groups) would allow new and desirable passageways to large, unsymmetrical, selectively sp3-fluorinated bioactive molecules (D, Scheme 4). Our First Discoveries: The Copper System. Reel forward about five years from our accidental observations, and we were once again examining synthetic fluorination, albeit from a new direction. Our goal was to develop a catalytic fluorination of otherwise unactivated C−H bonds. In our lab, a number of targets for fluorination stood out as being worthwhile. For example, we were interested in developing a selective fluorination in order to obtain a suitable precursor for the generation of a symmetrical fluoronium ion in solution (Scheme 5).16

Scheme 7. Proposed Mechanism Based on Extensive Experimental Studies

Scheme 5. A General Proposed Strategy To Synthesize a Suitable Fluoronium Precursor

Figure 2. Calculated transition state for SRD engaging with a substrate for hydrogen atom abstraction.

Although this particular transformation never practically came to fruition, it helped send us on our way. At the time, little had been done in the area, so we thought it would be a good line of inquiry. We concluded that such a reaction could be useful, obviating the need for dangerous conditions or difficult-to-use reagents. We were also motivated to some extent by a lab accident involving the hazardous fluorinating agent CsSO4F,17 a small amount of which detonated unexpectedly while being weighed out (no one was injured). The reagent was supposed to be stable when wet,18 and it was indeed wet, but its stability proved quite the opposite. We began our study by examining the metal-catalyzed (or, more precisely, metal-promoted) fluorination of adamantane by the commercially available reagent Selectfluor. Pretty much all metal complexes we screened failedexcept for copper(I)! Once again, Cu(I) was responsible for a unique result, except that this time we explored it in detail. After extensive optimization, we found that a bis(imine) complex of Cu(I) worked best in the reaction (Scheme 6), smoothly fluorinating a series of hydrocarbons

Rigorous KIE experiments suggested the H-atom abstraction to be part of the rate determining step, with a reduced primary KIE ( kH = 2.3) indicative of a bent, early, or late TS. We confirmed kD

generation of the aforementioned alkyl radicals by numerous radical clock experiments20 and radical scavengers.21 This particular finding made a lot of sense, as Sammis and Paquin and co-workers showed previously.22 Unfortunately, on complex substrates, the reactivity patterns were hard to predict. To the extent that predictions were possible, the major guiding principle is provided by the “polar effect”,23 namely, the tendency of free radicals to form at sites removed from electronwithdrawing substituents. Donahue’s ionic curve crossing theory24 provides a unique basis for explaining the thermodynamic effects of ionicity on the reaction (Figure 3). The activation energy of the reaction can be

Scheme 6. Optimized Protocol for Cu(I)-Catalyzed Aliphatic C−H Bond Fluorination

in fairly good yields. This discovery in our laboratory13a and the work by Groves and co-workers.14a,k provided a foundation for radical-based aliphatic C−H bond fluorination reactions. We found that UV−vis, EPR, 19F NMR, and a number of synthetic experiments corroborated our proposed radical-chain mechanism (Scheme 7).19 Initiation proceeds by an innersphere SET from copper(I) to copper(II) accompanied by a loss of fluoride ion. The resulting SRD intermediate acts as a chain carrier responsible for a putative H-atom abstraction (Figure 2).

Figure 3. Application of Donahue’s theory to study ionicity of a radical during hydrogen atom abstraction.

derived from the relative energies of the curve crossing point (CP) and the reactants. The lines of intersection connect ionic and neutral states of the reactants and products, and the analysis 8805


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The Journal of Organic Chemistry

in a sense the retrosynthetic product of a 1,4-conjugate addition of a fluoride anion to the equivalent α,β-unsaturated ketone. This method provides a mild, economical route to benzylic and β-fluorinated products of 3-aryl ketones. However, the scope of the reaction is limited to benzylic systems that are neither too electron rich nor electron poor (Scheme 10).

is wholly dependent on geometry optimizations rather than transition-state calculations. The theory accurately predicts why cyclodecane fluorinates more rapidly than fluorocyclodecane. Thus, the reaction is selective for symmetrical substrates (resistant to polyfluorination) but is otherwise “scattershot”, in which a mixture of fluorinated regioisomers was usually obtained unless the substrate was unusually small or bereft of activated C−H bonds. Ideally, one would like the reaction to be “site-selective” and predictable for a wider application in organic synthesis. New Synthetic Methods from Mechanistic Studies: Et3B Promotion. We found that the copper-promoted reaction worked as well for certain allylic and benzylic sites, although the yields and selectivity in these cases were not very impressive. One facet of the mechanistic study bore immediate fruit and demonstrated once again how mechanism can lead to methods, as well as the other way around. We discovered that BEt3, which forms ethyl radicals in the presence of oxygen25 (Scheme 8),

Scheme 10. Representative Examples for the Substrate Scope of Fe(II)-Catalyzed Benzylic Fluorinations

Scheme 8. Initiation/Propagation Mechanism for Et3BPromoted Reactions

Photochemical Fluorination: Initial Discovery Applied to Aliphatic Substrates. Along with the putative role of the SRD, the conclusion that free radicals were involved in a number of these processes opened up a spectrum of potentially attractive opportunities. We imagined that free radicals could be accessed by photochemical means, and drew inspiration from Albini’s seminal hydrocarbon functionalization chemistry.26 Once again, using Selectfluor as a reagent, 1,2,4,5-tetracyanobenzene as a photoactivator,27 and UV light, we developed an aliphatic fluorination reaction (Scheme 11).13j The reactivity

could efficiently produce the imputed Selectfluor radical dication (SRD) by independent means. Three defining observations that were crucial to support the proposed radical pathway (1) fluoroethane was observed in the crude 19F NMR spectra of all fluorination reactions, (2) the expected B(OEt)(Et)2 byproduct of the well reported BEt3 autoxidation reaction was detected by 11B NMR spectroscopy, and (3) NFSI, an ineffective chain carrier, can act as an atomic source of fluorine, but was not able to effect a similar transformation under the reaction conditions. The triethylborane system was optimized to be a complementary, economical synthetic method for fluorination.13d Due to its low toxicity and easy workup, BEt3-based initiation may be preferred in industrial processes. Benzylic Fluorination: The Iron System. Our next focus was on benzylic fluorination, and it is here that we found a very simple system that affords good results. Catalytic quantities of inexpensive Fe(acac)2 in MeCN with commercially available Selectfluor provided benzylic fluorides in good to excellent yields.13b Mechanistic details of this reaction remain to be “ironed” out, but some indication that benzylic radicals are involved (instead of carbocations) was obtained. As we further explored a substrate scope, we also found that carbonyl-containing compounds exhibited selectivity to benzylic fluorination over the expected α-halogenation background reaction (Scheme 9).13c The resulting β-fluoride molecule is

Scheme 11. Photochemical Fluorination of Aliphatic C−H Bonds

patterns proved similar, but not identical, to those observed in the copper-promoted chemistry. Mechanistic questions abound and have not all been answered to our satisfaction. Nevertheless, a working hypothesis is shown in Scheme 12. Photoexcited TCB removes an electron from the substrate, either to form a radical cation,28 or else the free radical directly through protoncoupled electron transfer (PCET)29 (to the TCB anion or MeCN solvent,30 for example). Another remaining question is whether the “catalytic” cycle is a closed loop, or whether SRD acts as a chain carrier (or whether both situations may operate simultaneously). One neat application of the photocatalytic reaction was found in an examination of the α-santonin system. Photoactive α-santonin is well-known to readily undergo different photochemical rearrangements31 depending on conditions, especially solvent.32 Irradiation of α-santonin in the presence of TCB and Selectfluor produces a very selective allylic fluorination instead (Scheme 13). In all likelihood, the rearrangements are shut down by the absorption of light by TCB,33 which channels its energy toward

Scheme 9. Iron(II)-Promoted Benzylic Fluorinations

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The Journal of Organic Chemistry Scheme 12. A Mechanistic Hypothesis for the Photochemical Fluorination of Aliphatic C−H Bonds

Scheme 15. Preliminary Experiments To Probe the Possibility of Electron-Transfer Processes

fragmentation pattern of an electron impact mass spectrometry experiment of compound 21. The photofluorination of compound 21 gave an ∼5:1 ratio, and the electron impact mass spectrometry experiment gave approximately 2.5:1 mixture of the parent ion and dioxolanyl cation fragment. Directed C−C bond cleavage: Ring-Opening Fluorination of Cyclopropanols. By late 2014, our laboratory and others reported several radical fluorination methods, but had mainly demonstrated selective sp3 C−H bond fluorination on highly symmetric substrates or those containing more activated benzylic C−H bonds. As another avenue of exploration, we envisioned the possibility of a tandem sp3 C−C bond cleavage/ fluorination. Selective radical formation from strained cyclopropanol derivatives to form β-fluoro-carbonyl containing compounds34 became a logical first step. The previously reported TCB system was employed to initiate the process.35 Given the low ionization potential of the cyclopropanols,36 one could expect facile formation of radical cations as part of the mechanism. Using this strategy, we discovered an efficient route to make β-fluorinated products that are a bit challenging to synthesize otherwise.37 Ring opening/fluorination is effectively directed to β-position in the presence of many dissimilar accessible aliphatic C−H bonds (Scheme 16). In addition,

Scheme 13. Selective Fluorination of α-Santonin Using the TCB-Catalyzed Protocol

fluorination. It is possible that the addition of fluorine precludes the classical isomerization as well. Photochemical Fluorination: Applied to Benzylic Fluorination. A very similar photocatalytic system can be applied to selective benzylic fluorination, although the yields are moderate and the advantages of this system over iron catalysis proved to be minimal (Scheme 14). Nevertheless, preliminary Scheme 14. Representative Examples for the Photochemical Fluorination of Benzylic C−H Bonds

Scheme 16. Substrate Scope for Ring-Opening Fluorination of Substituted Cyclopropanols

mechanistic data suggested the formation of radical cations through substituting the known one-electron oxidant K5CoIIIW12O40 in the absence of light for TCB (Scheme 15).13e As such, the reaction of K5CoIIIW12O40 and Selectfluor in MeCN solvent afforded a 2:1 ratio of benzylic fluorinated acetal 19 to fluorotoluene 20, just as the TCB reaction provided. Furthermore, we found a parallel between our photochemical experiment and the

selective C−C bond cleavage/directed fluorination can be achieved in the presence of benzylic positions, even though a 8807


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The Journal of Organic Chemistry very similar protocol was previously employed to achieve exclusive benzylic fluorination. Directed C−C Bond Cleavage: Aminofluorination of Cyclopropane Derivatives. Having successfully utilized substituted cyclopropanols to develop a directed fluorination method, next we set out to apply a similar strategy to functionalize somewhat less activated aryl cyclopropanes. We imagined that a photochemical excitation/one-electron oxidation would furnish ring opened products derived from the resulting radical cations (Scheme 17).

Scheme 19. Proposed Mechanism for Aminofluorination of Cyclopropanes Based on Mechanistic Studies

Scheme 17. Our Initial Concept to Functionalize Cyclopropane Derivatives

radical and cationic centers,39 ring cleavage becomes much more favorable (Scheme 20). Along these lines, we discovered that

Much to our surprise, when aryl cyclopropanes are employed as substratesinitially with a photosensitized approachan unanticipated aminofluorination reaction occurs,38 in which the Selectfluor and NFSI fragments are incorporated directly in the products. Later, we discovered that a similar transformation can be accomplished through either a direct photolysis using 300 nm light sources or by chemical means, employing protocols previously developed by our laboratory; all four approaches proceeding through a substrate radical cation intermediate. Both Selectfluor and NFSI are competent reagents for this transformation (Scheme 18).

Scheme 20. Reaction Design for Unstrained C−C Bond Cleavage/Fluorination

cyclic (and, in some cases, acyclic) ketone-based acetals can be ring opened/fluorinated with Selectfluor as reagent and 9-fluorenone as photosensitizer40 in moderate to good yields using either 300 nm light or compact fluorescent light sources (CFLs). Due to the difficulties encountered during purification of fluorinated products containing ethylene glycol esters, an aqueous LiOH workup was devised to obtain various carboxylic acid derivatives. Alternatively, an array of fluorinated products can be made by employing different quenchers such as lithium alkoxides to make esters or LAH reductions to synthesize alcohols without significant decreases in yields (Scheme 21). Although possessing

Scheme 18. Aminofluorination of Substituted Cyclopropanes

Beyond the initial reaction discovery, extensive mechanistic studies were undertaken in order to establish a plausible mechanism under the reaction conditions. Preliminary observations using Hammett plots and the aforementioned alternative modes of initiation helped shape our initial hypothesis. As a result, we imagined a putative photochemical initiation leading to a radical chain mechanism that proceeds through a common chain carrier. SRD thus plays a key role beyond the initiation step (Scheme 19). Accordingly, exhaustive mechanistic studies consisting of monitoring product distributions, kinetic analyses, LFERs, Rehm−Weller estimations of ΔGET, various competition experiments, KIEs, fluorescence studies, transient-absorption spectroscopies, and DFT calculations corroborated our hypothesis. Directed C−C Bond Cleavage: Unstrained C−C Bond Ring-Opening To Synthesize Distally Fluorinated Carbonyl Compounds. C−C bond cleavage occurs readily in strained cyclopropane rings; these substrates comprise the more intuitive candidates for applications in directed radical formation. On the other hand, in unstrained rings C−C bond activation is much more challenging. However, when the targeted C−C bond is substituted with aryl and acetal groups that can stabilize both

Scheme 21. Select Examples for Unstrained C−C Bond Cleavage/Fluorination

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role in directing C−H bond fluorination, although this is a very speculative hypothesis. Enone-Directed Aliphatic C−H Bond Fluorination. The first time that serendipity presented itself was recounted in the introduction. The second time arose as we examined the photocatalytic fluorination of complex natural products. In general, we obtained disappointing results“scattershot” fluorination, reactivity at unusual sites, and complex mixtures of products abounded. In one case, though, we observed an intriguingly selective fluorination. Steroidal enone 25, we discovered in a screen of a variety of substrates, fluorinates selectively at position C15 (Scheme 23).13g

somewhat limited scope, we found that this method can be applied to tertiary alcohols or to dispose unwanted ketones as demonstrated in Scheme 21. Direct Photochemical Benzylic C−H Fluorination of Peptides. Some heavily functionalized substrates such as peptides are not amenable to our metal-promoted protocols involving iron and copper. The amide linkages essentially serve as ligands, altering the reactivity of the metal complexes in undesirable ways.41 The virtue of photofluorination, at least in principle, is that these functional groups should be tolerated42 (unless, of course, the peptides contain reactive chromophores). With these considerations in mind, we undertook a preliminary study of peptide fluorination on short chain peptide candidates. We surmised from experience that benzylic substrates (such as phenylalanine) should prove to be among the most reactive sites (Figure 4).

Scheme 23. Serendipitous Discovery of Enone-Directed Fluorination Reaction

We discovered that no photosensitizer is needed, as direct irradiation at 300 nm suffices.43 Initially, the result brought to mind the Norrish Type II reaction44 and its peculiarly characteristic reactivity. In order to probe the reactivity further, we synthesized enone-containing rigid terpenoid derivatives wherein the carbonyl group is positioned to interact through a 5- or 6-membered transition state with the C−H bonds of interest. With this initial success, we quickly turned our attention to other more complex steroidal substrates (see Figure 7). In most cases, we obtained excellent results, all of which proved to be site-selective. As we explored the substrate scope, it is clear that the enone oxygen acts as a directing group, either to abstract a hydrogen atom or else a proton from the reactive site to generate a free radical that can be efficiently fluorinated. The reactivity of enones in the system can be characterized by several well-defined, predictable modes involving 5- and 6-membered transition states and enone CC bonds either proximal or distal to the C−H bonds of interest (Figure 5).

Figure 4. Predicted reactivity of various C−H bonds on side chains of peptide motifs.

Accordingly, the selective fluorination of phenylalanine-like amino acid residues in di- and tripeptides using dibenzosuberenone, a triplet sensitizer, was achieved in a selective manner (Scheme 22).13f At first glance, this method can be seen as one of Scheme 22. Representative Examples for Peptide Fluorination

Figure 5. Classification of reaction modes for the enone-directed fluorination.

many extant benzylic fluorination methods in the literature; however, preliminary competition experiments and other mechanistic experiments suggest that the amide may play a

Several of the substrates possess long hydrocarbon chains; if the “polar effect” were operative, these sites, far removed from 8809


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The Journal of Organic Chemistry the electron withdrawing substituents on the ring, should be targets instead, but they are not. In one notable case, we fluorinated a complex molecule with at least 65 discrete sp3 C−H bonds selectively at one site (Figure 6).

Scheme 24. Selected Examples of the Substrate Scope Using Ketones to Direct Aliphatic Fluorination

Figure 6. Application of the enone-directed fluorination reaction to a complex triterpenoid derivative.

Figure 8. Reactivity of linear vs rigid ketones toward fluorination.

carbonyl group to direct radical fluorination with the sensitized approach, we asked if this milder procedure could provide a more practical and economical alternative to our ultraviolet light-initiated enone-directed fluorination procedure. After a quick screen for visible light photoinitiator, benzil once again was found to deliver higher chemical yields and improved regioselectivity in comparison to our earlier fluorination of steroidal enones (Scheme 25).13i As we explored the

Figure 7. Representative examples of the enone-directed fluorination using 300 nm light sources.

Directed Fluorinations on Terpenoid Derivatives Using the Ketone Functional Group. The enone-directed fluorination constituted a good start, with a caveatthe enone group is not all that prevalent in natural products chemistry. Ketones, on the other hand, are more common and, thus, make more attractive targets from that standpoint. The problem is that direct photolysis of ketones in the presence of Selectfluor yields, at best, traces of fluorinated products. On the other hand, catalytic benzil as a photosensitizer and irradiation by white LEDs combines to make a decent system for site-selective ketone fluorination (Scheme 24).13h In this instance, classical Norrish II type chemistry can be ruled out−triplet energies of the substrates45 and the sensitizer46 are presumably much too far apart to allow for efficient energy transfer.47 In addition, we applied the BEt3 protocolpreviously demonstrated to generate SRD to effect aliphatic fluorinationsto terpenoidal ketones in the absence of light and found similar product distributions as in the sensitized approach, although the yields are diminished. Thus, mechanistic possibilities gravitate toward electron transfer (ET), which can happen sequentially or simultaneously with proton transfer (PCET), employing the ketone carbonyl as an internal base. As with the enones, the reaction works best on rigid polycyclic substrates. Using this “tamed” approach, ketone-directed fluorination was demonstrated on a variety of terpenoidal substrates in up to 85% yield. However, long chains and floppy appendages do not react well (Figure 8). This may be due to an entropic effect that disfavors intramolecular proton transfer. Application of the Sensitized Approach for EnoneDirected Fluorination. Having successfully utilized the ketone

Scheme 25. Selected Examples of Substrate Scope with the Sensitized Approach

amenability of the reaction conditions to larger scale, a gramscale fluorination was accomplished without a significant loss in chemical yield. In addition, using a rudimentary set up, we demonstrated the applicability of the directed fluorinations (applied to complex biologically active molecules) to microflow conditions using visible light sources or a Rayonet photoreactor (Figure 9). 8810


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McMurry, finishing in 1990. He undertook postdoctoral studies as an Alexander von Humboldt Fellow at Heidelberg in 1991 with Rolf Gleiter, followed by an NIH Fellowship at Harvard University with Prof. David Evans. He joined the Johns Hopkins chemistry faculty in 1994, where he is now Jean and Norman Scowe Professor of Chemistry.

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ACKNOWLEDGMENTS T.L. thanks the NSF (CHE1465131) for support. C.R.P. thanks the ETH Postdoctoral Fellowship Program for support.

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Figure 9. Cross-section depiction of a preliminary microflow reactor.

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CONCLUSION What began as an overlooked experiment on the Cu(I)-promoted α-fluorination of enolates led to a serendipitous rediscovery some time later of Cu(I) as a promoter of alkane fluorination. The reaction was then found to proceed through radical intermediates, echoing the seminal precedents of Sammis and Paquin and contemporaneous work of Groves. For our part, the new project was off to the races, so to speak, focusing thereafter on different methods of catalyzing (through photosensitization) and promoting (iron(II), triethylborane) alkane fluorination. Later on, the focus evolved to tackle the problem of site-selectivity, mainly through directing groups and photoexcitation. A number of challenges remainsuch as the fine control of diastereoselectivity, enantioselectivity, and functional group direction and tolerance. We are nevertheless optimistic about how this field will continue to evolve in the near future to face these challenges.

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REFERENCES

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Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Desta Doro Bume: 0000-0003-2015-9599 Cody Ross Pitts: 0000-0003-1047-8924 Notes

The authors declare no competing financial interest. Biographies

Dr. Cody Ross Pitts obtained his B.S. from Monmouth University in 2010, completing his honors thesis research under Prof. Massimiliano Lamberto. Cody joined the Lectka group at Johns Hopkins University in 2011. After completion of his Ph.D. research, he began pursuing postdoctoral research with Prof. Antonio Togni at ETH Zürich in 2017.

Prof. Thomas Lectka graduated with a B.A. in Chemistry from Oberlin College in 1985. He then pursued his Ph.D. at Cornell with Prof. John 8811


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Catalyzed and Promoted Aliphatic Fluorination - The Journal of

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