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

Department of Chemistry, Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, United States†Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 2, 8093 Zurich, 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 historicalnarratives about the challenges of developing practical radical fluorination in organic frameworks, notable advancements incontrolling both reactivity and selectivity have been achieved during this time. As one of the participants in the field, herein, wea provide brief account of research efforts in our laboratory from the initial discovery of radical monofluorination on unactivatedC−H bonds in 2012 to more useful strategies to install fluorine on biologically relevant molecules through directed fluorinationmethods. In addition, accompanying mechanistic studies that have helped guide reaction design are highlighted in context.

■ INTRODUCTION

Almost a decade ago, as players in themidst of what could be argu-ably termed a “golden era of asymmetricα-halogenation”,1 our labreported a tricomponent, catalytic, asymmetric α-fluorination ofacid chlorides usingN-fluorobenzenesulfonamide (NFSI).2 Thedevelopment of this reaction proved to be quite interesting, butnevertheless challenging, and necessitated the judicious andsometimes counterintuitive juggling of three catalysts: a cin-chona alkaloid derivative such as benzoylquinidine (BQd) toimpart enantioselectivity;3 a Lewis acid (usually Li+) to activatethe fluorinating agent;4 and finally, a transition-metal complex inorder to form a stabilized zwitterionic enolate (Scheme 1).5 Absentone of these components, the reaction veered toward loweryields 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 themost efficacious cocatalysts, although a large variety of additiveswere screened. This screening was wholly empirical and depen-dent largely on the presence of candidates already on the shelf inour laboratories. For the most part, other metal complexes gavelower yields and were quickly excluded on that basis. One strangeexception was casually noted; a Cu(I) salt, in one instance,afforded trace amounts of other products evidently derived fromfluorination of remote aliphatic positions in the substrate.Thinking nothing further about it at the time, we inadvertentlymissed an opportunity for a significant discovery based on the

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

Scheme 1. Multicomponent-Catalyzed Asymmetricα-Fluorinations

Perspective

pubs.acs.org/jocCite This: J. Org. Chem. 2018, 83, 8803−8814

© 2018 American Chemical Society 8803 DOI: 10.1021/acs.joc.8b00982J. Org. Chem. 2018, 83, 8803−8814

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fact that Cu(I) was doing something dif ferent and peculiar. Weshould have asked ourselves, “Why would such a reaction resultin any product (even trace) other than α-fluorination?” Thistype 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 fromthis initial observation. The reactions discussed herein lead tosomewhat different outcomes, butmany are linked by the centralrole that the putative Selectfluor radical dication (SRD) plays inthe chemistryas a chain carrier, a quenching agent, and anelectron or hydrogen atom abstractor (Figure 1).

Background and Seminal Developments. Our interestin fluorination chemistry stemmed not merely from purecuriositythere were compelling practical reasons as well. Forexample, nearly one-fourth of the top pharmaceuticals on themarket contain fluorine,6 placing synthetic fluorinationmethods,7

particularly those amenable to late-stage functionalization,among themore valuable “warheads” in the arsenal of themedic-inal chemist.8 “Fluorination screens”,9 in which known drugs arefluorinated methodically at each and every accessible site (to theextent that it can be accomplished) to render new candidates forevaluation, have become commonplace in pharmaceuticalchemistry; in fact, some of themost widely used pharmaceuticalscontain fluorine. From our standpoint, a largely untapped wellresided in the field of selective aliphatic fluorination, which wasstill 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

report, Sammis and Paquin and co-workers demonstrated that alkylradicals could react with mild electrophilic fluorinating agentsinstead of just F2.

10 Shortly thereafter, Li and co-workers reported acatalytic Hunsdiecker-type oxidative decarboxylation/fluorinationwith a wide-ranging substrate scope.11 MacMillan and co-workersalso expanded the field of decarboxylative fluorination by utilizinglight-promoted photoredox chemistry with aliphatic carboxylicacids to form the corresponding regiospecific alkyl fluorides.12

As recounted, we entered the arena semiserendipitously withthe idea of fluorinating unactivated C−H bonds. Over the lastseveral years, our laboratory13 and many others14 have made greatstrides in producing direct sp3 C−Hmonofluorinationmethods thatare radical in nature, in concord with the decarboxylative chemistry(Scheme 3). Groves and co-workers reported a transition-metal-

catalyzed radical fluorination of unactivated, aliphatic C−Hbonds by a manganese porphyrin complex.14a The reactionelegantly provided products with good chemoselectivity formethylene C−H bonds. Following Groves’ account, the firsttransition-metal-free direct conversion of sp3 C−H bonds to thecorresponding alkyl fluorides was reported by Inoue andco-workers.14c The reaction is proposed to involve N-oxyl radi-cals as H-atom abstractors. Another noteworthy development intransition-metal-free radical fluorination came from Chen andco-workers, who employed photoexcited aryl ketones to gener-ate benzylic radicals.14p The authors also noted selective forma-tion of mono- and gem-difluorination products by employing9-fluorenone and xanthone.

The Challenge of Unactivated C−H Fluorination. Insubstrates that contain many distinct carbon atoms and C−Hbonds, the early reports revealed the problem of “scattershot”fluorination leading to several products (A, Scheme 4). Thus,

many of the substrate tables reported in the literature are limitedtohighly symmetric compounds, such as cycloalkanes or substratescontaining more activated benzylic sites (B−C, Scheme 4).In the few known cases of directed aliphatic fluorination,15 che-lating auxiliaries prove necessary. Expanding upon our initial

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

Scheme 2. Notable Decarboxylative Fluorination Methods

Scheme 3. Direct sp3 C−H Fluorination Methods

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

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discoveries, the reader shall see our projects evolving from aprimary focus on reactivity to one based on selectivity. Directingfluorination more effectively (in our case through carbonylgroups) 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 wereonce again examining synthetic fluorination, albeit from a newdirection. Our goal was to develop a catalytic fluorination ofotherwise unactivated C−H bonds. In our lab, a number oftargets for fluorination stood out as being worthwhile. Forexample, we were interested in developing a selective fluori-nation in order to obtain a suitable precursor for the generationof a symmetrical fluoronium ion in solution (Scheme 5).16

Although this particular transformation never practically cameto 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 reac-tion could be useful, obviating the need for dangerous condi-tions or difficult-to-use reagents. We were also motivated tosome extent by a lab accident involving the hazardous fluori-nating agent CsSO4F,

17 a small amount of which detonatedunexpectedly while being weighed out (no one was injured).The reagent was supposed to be stable when wet,18 and it wasindeed wet, but its stability proved quite the opposite.Webegan our study by examining themetal-catalyzed (or, more

precisely, metal-promoted) fluorination of adamantane by thecommercially available reagent Selectfluor. Prettymuch all metalcomplexes we screened failedexcept for copper(I)! Onceagain, Cu(I) was responsible for a unique result, except that thistime we explored it in detail. After extensive optimization, wefound that a bis(imine) complex of Cu(I) worked best in the reac-tion (Scheme 6), smoothly fluorinating a series of hydrocarbons

in fairly good yields. This discovery in our laboratory13a and thework by Groves and co-workers.14a,k provided a foundationfor 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-chainmechanism (Scheme 7).19 Initiation proceeds by an inner-sphere SET from copper(I) to copper(II) accompanied by a lossof fluoride ion. The resulting SRD intermediate acts as a chaincarrier responsible for a putative H-atom abstraction (Figure 2).

Rigorous KIE experiments suggested the H-atom abstraction tobe part of the rate determining step, with a reduced primary KIE(kkH

D= 2.3) indicative of a bent, early, or late TS. We confirmed

generation of the aforementioned alkyl radicals by numerousradical clock experiments20 and radical scavengers.21

This particular finding made a lot of sense, as Sammis andPaquin and co-workers showed previously.22 Unfortunately, oncomplex substrates, the reactivity patterns were hard to predict.To the extent that predictions were possible, the major guidingprinciple is provided by the “polar effect”,23 namely, the ten-dency of free radicals to form at sites removed from electron-withdrawing substituents.Donahue’s ionic curve crossing theory24 provides a unique

basis for explaining the thermodynamic effects of ionicity on thereaction (Figure 3). The activation energy of the reaction can be

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

Scheme 5. A General Proposed Strategy To Synthesize aSuitable Fluoronium Precursor

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

Scheme 7. Proposed Mechanism Based on ExtensiveExperimental Studies

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

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

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is wholly dependent on geometry optimizations rather thantransition-state calculations. The theory accurately predicts whycyclodecane 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 usuallyobtained unless the substrate was unusually small or bereft ofactivated C−H bonds. Ideally, one would like the reaction to be“site-selective” and predictable for a wider application in organicsynthesis.New Synthetic Methods from Mechanistic Studies:

Et3B Promotion.We found that the copper-promoted reactionworked as well for certain allylic and benzylic sites, although theyields and selectivity in these cases were not very impressive.One facet of the mechanistic study bore immediate fruit anddemonstrated once again how mechanism can lead to methods,as well as the other way around. We discovered that BEt3, whichforms ethyl radicals in the presence of oxygen25 (Scheme 8),

could efficiently produce the imputed Selectfluor radical dication(SRD) by independent means. Three defining observations thatwere crucial to support the proposed radical pathway (1) fluo-roethane was observed in the crude 19F NMR spectra of all fluori-nation reactions, (2) the expected B(OEt)(Et)2 byproduct ofthe well reported BEt3 autoxidation reaction was detected by

11BNMR spectroscopy, and (3) NFSI, an ineffective chain carrier,can act as an atomic source of fluorine, but was not able to effecta similar transformation under the reaction conditions. Thetriethylborane system was optimized to be a complementary,economical synthetic method for fluorination.13d Due to its lowtoxicity and easy workup, BEt3-based initiation may be preferredin industrial processes.Benzylic Fluorination: The Iron System. Our next focus

was on benzylic fluorination, and it is here that we found a verysimple system that affords good results. Catalytic quantities ofinexpensive Fe(acac)2 in MeCN with commercially availableSelectfluor provided benzylic fluorides in good to excellentyields.13bMechanistic 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 benzylicfluorination over the expected α-halogenation backgroundreaction (Scheme 9).13c The resulting β-fluoride molecule is

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

Photochemical Fluorination: Initial Discovery Appliedto Aliphatic Substrates. Along with the putative role ofthe SRD, the conclusion that free radicals were involved in anumber of these processes opened up a spectrum of potentiallyattractive opportunities. We imagined that free radicals could beaccessed by photochemical means, and drew inspiration fromAlbini’s seminal hydrocarbon functionalization chemistry.26

Once again, using Selectfluor as a reagent, 1,2,4,5-tetracyano-benzene as a photoactivator,27 and UV light, we developed analiphatic fluorination reaction (Scheme 11).13j The reactivity

patterns proved similar, but not identical, to those observed inthe copper-promoted chemistry. Mechanistic questions aboundand have not all been answered to our satisfaction. Nevertheless,a working hypothesis is shown in Scheme 12. PhotoexcitedTCB removes an electron from the substrate, either to form aradical cation,28 or else the free radical directly through proton-coupled electron transfer (PCET)29 (to the TCB anion orMeCN solvent,30 for example). Another remaining question iswhether the “catalytic” cycle is a closed loop, or whether SRDacts as a chain carrier (or whether both situations may operatesimultaneously).One neat application of the photocatalytic reaction was found

in an examination of theα-santonin system. Photoactiveα-santoninis well-known to readily undergo different photochemical rear-rangements31 depending on conditions, especially solvent.32

Irradiation of α-santonin in the presence of TCB and Selectfluorproduces a very selective allylic fluorination instead (Scheme 13).In all likelihood, the rearrangements are shut down by theabsorption of light by TCB,33 which channels its energy toward

Scheme 8. Initiation/Propagation Mechanism for Et3B-Promoted Reactions

Scheme 9. Iron(II)-Promoted Benzylic Fluorinations

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

Scheme 11. Photochemical Fluorination of Aliphatic C−HBonds

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fluorination. It is possible that the addition of fluorine precludesthe classical isomerization as well.Photochemical Fluorination: Applied to Benzylic

Fluorination. A very similar photocatalytic system can beapplied to selective benzylic fluorination, although the yields aremoderate and the advantages of this system over iron catalysisproved to be minimal (Scheme 14). Nevertheless, preliminary

mechanistic data suggested the formation of radical cations throughsubstituting the known one-electron oxidant K5Co

IIIW12O40 inthe absence of light for TCB (Scheme 15).13e As such, thereaction of K5Co

IIIW12O40 and Selectfluor in MeCN solventafforded a 2:1 ratio of benzylic fluorinated acetal 19 to fluoro-toluene 20, just as the TCB reaction provided. Furthermore, wefound a parallel between our photochemical experiment and the

fragmentation pattern of an electron impact mass spectrometryexperiment of compound 21. The photofluorination of com-pound 21 gave an ∼5:1 ratio, and the electron impact massspectrometry experiment gave approximately 2.5:1 mixture ofthe parent ion and dioxolanyl cation fragment.

Directed C−C bond cleavage: Ring-Opening Fluorina-tion of Cyclopropanols. By late 2014, our laboratory andothers reported several radical fluorination methods, but hadmainly demonstrated selective sp3 C−H bond fluorination onhighly symmetric substrates or those containing more activatedbenzylic C−Hbonds. As another avenue of exploration, we envi-sioned the possibility of a tandem sp3 C−C bond cleavage/fluorination. Selective radical formation from strained cyclo-propanol derivatives to form β-fluoro-carbonyl containing com-pounds34 became a logical first step. The previously reportedTCB system was employed to initiate the process.35 Given thelow ionization potential of the cyclopropanols,36 one could expectfacile 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 synthe-size otherwise.37 Ring opening/fluorination is effectivelydirected to β-position in the presence of many dissimilaraccessible aliphatic C−H bonds (Scheme 16). In addition,

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

Scheme 12. AMechanistic Hypothesis for the PhotochemicalFluorination of Aliphatic C−H Bonds

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

Scheme 14. Representative Examples for the PhotochemicalFluorination of Benzylic C−H Bonds

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

Scheme 16. Substrate Scope for Ring-Opening Fluorinationof Substituted Cyclopropanols

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very similar protocol was previously employed to achieveexclusive benzylic fluorination.Directed C−C Bond Cleavage: Aminofluorination of

Cyclopropane Derivatives. Having successfully utilizedsubstituted cyclopropanols to develop a directed fluorinationmethod, next we set out to apply a similar strategy to functional-ize somewhat less activated aryl cyclopropanes. We imaginedthat a photochemical excitation/one-electron oxidation wouldfurnish ring opened products derived from the resulting radicalcations (Scheme 17).

Much to our surprise, when aryl cyclopropanes are employedas substratesinitially with a photosensitized approachanunanticipated aminofluorination reaction occurs,38 in which theSelectfluor and NFSI fragments are incorporated directly in theproducts. Later, we discovered that a similar transformation canbe accomplished through either a direct photolysis using 300 nmlight sources or by chemical means, employing protocols previ-ously developed by our laboratory; all four approaches proceed-ing through a substrate radical cation intermediate. Both Select-fluor and NFSI are competent reagents for this transformation(Scheme 18).

Beyond the initial reaction discovery, extensive mechanisticstudies were undertaken in order to establish a plausible mecha-nism under the reaction conditions. Preliminary observationsusing Hammett plots and the aforementioned alternative modesof initiation helped shape our initial hypothesis. As a result,we imagined a putative photochemical initiation leading to aradical chainmechanism that proceeds through a common chaincarrier. SRD thus plays a key role beyond the initiation step(Scheme 19). Accordingly, exhaustive mechanistic studiesconsisting of monitoring product distributions, kinetic analyses,LFERs, Rehm−Weller estimations of ΔGET, various competi-tion experiments, KIEs, fluorescence studies, transient-absorp-tion spectroscopies, and DFT calculations corroborated ourhypothesis.Directed C−C Bond Cleavage: Unstrained C−C Bond

Ring-Opening To Synthesize Distally Fluorinated Car-bonyl Compounds. C−C bond cleavage occurs readily instrained cyclopropane rings; these substrates comprise the moreintuitive candidates for applications in directed radical forma-tion.On the other hand, in unstrained ringsC−Cbond activation ismuchmore challenging. However, when the targeted C−C bond issubstituted with aryl and acetal groups that can stabilize both

radical and cationic centers,39 ring cleavage becomesmuchmorefavorable (Scheme 20). Along these lines, we discovered that

cyclic (and, in some cases, acyclic) ketone-based acetals canbe ring opened/fluorinated with Selectfluor as reagent and9-fluorenone as photosensitizer40 in moderate to good yieldsusing either 300 nm light or compact fluorescent light sources(CFLs).Due to the difficulties encountered during purification of fluo-

rinated products containing ethylene glycol esters, an aqueousLiOH workup was devised to obtain various carboxylic acidderivatives. Alternatively, an array of fluorinated products can bemade by employing different quenchers such as lithium alkoxides tomake esters or LAH reductions to synthesize alcohols withoutsignificant decreases in yields (Scheme 21). Although possessing

Scheme 17. Our Initial Concept to FunctionalizeCyclopropane Derivatives

Scheme 18. Aminofluorination of Substituted Cyclopropanes

Scheme 19. Proposed Mechanism for Aminofluorination ofCyclopropanes Based on Mechanistic Studies

Scheme 20. Reaction Design for Unstrained C−C BondCleavage/Fluorination

Scheme 21. Select Examples for Unstrained C−C BondCleavage/Fluorination

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somewhat limited scope, we found that this method can beapplied to tertiary alcohols or to dispose unwanted ketones asdemonstrated in Scheme 21.Direct Photochemical Benzylic C−H Fluorination of

Peptides. Some heavily functionalized substrates such aspeptides are not amenable to our metal-promoted protocolsinvolving iron and copper. The amide linkages essentially serveas ligands, altering the reactivity of the metal complexes inundesirable ways.41 The virtue of photofluorination, at least inprinciple, is that these functional groups should be tolerated42

(unless, of course, the peptides contain reactive chromophores).With these considerations in mind, we undertook a preliminarystudy of peptide fluorination on short chain peptide candidates.We surmised from experience that benzylic substrates (such asphenylalanine) should prove to be among the most reactive sites(Figure 4).

Accordingly, the selective fluorination of phenylalanine-likeamino acid residues in di- and tripeptides using dibenzosuber-enone, a triplet sensitizer, was achieved in a selective manner(Scheme 22).13f At first glance, this method can be seen as one of

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

role in directing C−H bond fluorination, although this is a veryspeculative hypothesis.

Enone-Directed Aliphatic C−H Bond Fluorination. Thefirst time that serendipity presented itself was recounted in theintroduction. The second time arose as we examined the photo-catalytic fluorination of complex natural products. In general, weobtained disappointing results“scattershot” fluorination, reac-tivity at unusual sites, and complexmixtures of products abounded.In one case, though, we observed an intriguingly selective fluori-nation. Steroidal enone 25, we discovered in a screen of a variety ofsubstrates, fluorinates selectively at position C15 (Scheme 23).13g

We discovered that no photosensitizer is needed, as directirradiation at 300 nm suffices.43

Initially, the result brought to mind the Norrish Type IIreaction44 and its peculiarly characteristic reactivity. In order toprobe the reactivity further, we synthesized enone-containingrigid terpenoid derivatives wherein the carbonyl group ispositioned to interact through a 5- or 6-membered transitionstate with the C−H bonds of interest. With this initial success,we quickly turned our attention to other more complex steroidalsubstrates (see Figure 7). In most cases, we obtained excellentresults, all of which proved to be site-selective. As we explored thesubstrate scope, it is clear that the enone oxygen acts as a directinggroup, either to abstract a hydrogen atom or else a proton fromthe reactive site to generate a free radical that can be efficientlyfluorinated. The reactivity of enones in the system can becharacterized by several well-defined, predictablemodes involving5- and 6-membered transition states and enone CC bondseither proximal or distal to the C−H bonds of interest (Figure 5).

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

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

Scheme 22. Representative Examples for PeptideFluorination

Scheme 23. Serendipitous Discovery of Enone-DirectedFluorination Reaction

Figure 5. Classification of reaction modes for the enone-directedfluorination.

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the electron withdrawing substituents on the ring, should betargets instead, but they are not. In one notable case, wefluorinated a complex molecule with at least 65 discrete sp3

C−H bonds selectively at one site (Figure 6).

Directed Fluorinations on Terpenoid DerivativesUsing the Ketone Functional Group. The enone-directedfluorination constituted a good start, with a caveatthe enonegroup is not all that prevalent in natural products chemistry.Ketones, on the other hand, are more common and, thus, makemore attractive targets from that standpoint. The problem is thatdirect 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 whiteLEDs combines to make a decent system for site-selectiveketone fluorination (Scheme 24).13h In this instance, classicalNorrish II type chemistry can be ruled out−triplet energies ofthe substrates45 and the sensitizer46 are presumablymuch too farapart to allow for efficient energy transfer.47 In addition, weapplied the BEt3 protocolpreviously demonstrated to gener-ate SRD to effect aliphatic fluorinationsto terpenoidal ketonesin the absence of light and found similar product distributions asin the sensitized approach, although the yields are diminished.Thus, mechanistic possibilities gravitate toward electron transfer(ET), which can happen sequentially or simultaneously withproton transfer (PCET), employing the ketone carbonyl as aninternal base. As with the enones, the reaction works best onrigid 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 reactwell (Figure 8). This may be due to an entropic effect that disfa-vors intramolecular proton transfer.Application of the Sensitized Approach for Enone-

Directed Fluorination.Having successfully utilized the ketone

carbonyl group to direct radical fluorination with the sensi-tized approach, we asked if this milder procedure could pro-vide a more practical and economical alternative to our ultra-violet light-initiated enone-directed fluorination procedure.After a quick screen for visible light photoinitiator, benzilonce again was found to deliver higher chemical yields andimproved regioselectivity in comparison to our earlier fluori-nation of steroidal enones (Scheme 25).13i As we explored the

amenability of the reaction conditions to larger scale, a gram-scale fluorination was accomplished without a significant loss inchemical yield. In addition, using a rudimentary set up, we dem-onstrated the applicability of the directed fluorinations (appliedto complex biologically active molecules) to microflow con-ditions using visible light sources or a Rayonet photoreactor(Figure 9).

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

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

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

Scheme 25. Selected Examples of Substrate Scope with theSensitized Approach

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

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■ CONCLUSIONWhat began as an overlooked experiment on the Cu(I)-promotedα-fluorination of enolates led to a serendipitous rediscoverysome time later of Cu(I) as a promoter of alkane fluorination.The reaction was then found to proceed through radical inter-mediates, echoing the seminal precedents of Sammis and Paquinand contemporaneous work of Groves. For our part, the newproject was off to the races, so to speak, focusing thereafter ondifferent 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 numberof challenges remainsuch as the fine control of diastereose-lectivity, enantioselectivity, and functional group direction andtolerance. We are nevertheless optimistic about how this fieldwill continue to evolve in the near future to face these challenges.

■ AUTHOR INFORMATIONCorresponding Authors*E-mail: lectka@jhu.edu.*E-mail: pitts@inorg.chem.ethz.ch.ORCIDDesta Doro Bume: 0000-0003-2015-9599Cody Ross Pitts: 0000-0003-1047-8924NotesThe authors declare no competing financial interest.Biographies

Dr. Cody Ross Pitts obtained his B.S. from Monmouth University in2010, completing his honors thesis research under Prof. MassimilianoLamberto. Cody joined the Lectka group at Johns Hopkins Universityin 2011. After completion of his Ph.D. research, he began pursuingpostdoctoral research with Prof. Antonio Togni at ETHZurich in 2017.

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

McMurry, finishing in 1990. He undertook postdoctoral studies as anAlexander von Humboldt Fellow at Heidelberg in 1991 with RolfGleiter, followed by an NIH Fellowship at Harvard University withProf. David Evans. He joined the Johns Hopkins chemistry faculty in1994, where he is now Jean andNorman Scowe Professor of Chemistry.

■ ACKNOWLEDGMENTST.L. thanks the NSF (CHE1465131) for support. C.R.P. thanksthe ETH Postdoctoral Fellowship Program for support.

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

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