trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis

8/3/2019 Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis

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LETTERdoi:10.1038/nature10647

Trifluoromethylation of arenes and heteroarenes bymeans of photoredox catalysisDavid A. Nagib1 & David W. C. MacMillan1

Modern drug discovery relies on the continual development of syn-thetic methodology to address the many challenges associated withthe design of new pharmaceutical agents1. One such challenge arisesfrom the enzymatic metabolism of drugs in vivo by cytochromeP450 oxidases, which use single-electron oxidative mechanisms torapidly modify small molecules to facilitate their excretion2.Acom-monly used synthetic strategy to protect against in vivometabolisminvolves the incorporation of electron-withdrawing functionality,such as the trifluoromethyl (CF3) group,into drug candidates

3.TheCF3 group enjoys a privileged role in the realm of medicinal chem-

istry because its incorporation into small molecules often enhancesefficacy by promoting electrostatic interactions with targets,improving cellular membrane permeability, and increasing robust-ness towards oxidative metabolism of the drug46. Although com-mon pharmacophores often bear CF3 motifs in an aromatic system,access to such analogues typically requires the incorporation of theCF3 group, or a surrogate moiety, at the start of a multi-step syn-thetic sequence. Here we report a mild, operationally simple strat-egy for the direct trifluoromethylation of unactivated arenes andheteroarenes through a radical-mediated mechanism using com-mercial photocatalysts and a household light bulb. We demonstratethe broad utilityof thistransformationthroughaddition of CF3 to anumber of heteroaromatic and aromatic systems. The benefit tomedicinal chemistry and applicability to late-stage drug develop-

ment is also shown through examples of the direct trifluoromethy-lation of widely prescribed pharmaceutical agents.

The CF3 moiety is typically installed by means of cross-couplingtechnologies catalysed by transition metals. These methodshistoricallyrequired the stoichiometric use of metal salts or organometallic com-plexes, and have shown limited generality7. Recently, however, copperand palladium complexes have been successfully shown to enable thistransformation in a catalytic fashion8. Using either a nucleophilic orelectrophilic source of CF3 (RuppertPrakash or Umemotos reagent,respectively), it is nowpossibleto install an aryltrifluoromethyl moietyin place of halides and boronic acids, or adjacent to tailored directinggroups (Fig. 1b)912. These cross-coupling reactions have facilitated thesynthesis of a range of CF3 analogues without the reliance on pre-fluorinated building blocks. However, the ideal position of CF3 sub-

stitutionon a drug candidate must still be determined throughparallel,multi-step syntheses employing aryl precursors bearing activatinggroups at various positions around an aromatic ring. Therefore, aremaining challenge in the synthesis of organofluorine drugs is thisreliance on substituted precursors and their varying amenability tocross-coupling reactions.

To address this challenge, we reasoned that the direct installation of aCF3 group to a drug candidateideally at the position(s) of metabolicsusceptibilitywould obviate the need for pre-functionalization. Thus,thisdirecttrifluoromethylation of aryl andheteroaryl compoundswould,in a single chemical operation, preclude the needforredundant syntheticeffortsandsimultaneously protectagainst metabolic oxidation invivo. Inthe first part of our design plan, we proposed that a single-electronpathway might provide such an approach to address the unsolved

challenge of trifluoromethylation of non-activated arenes (Fig. 1c).Specifically, we sought to take advantage of photoredox catalysis, whichprovides a mild and efficient method for accessing electrophilic radicals,such as

N

CF3, by means of photosynthesis-inspired redox chemistry1315.

This mode of reactivity employs polypyridyl organometallic complexes,suchas Ru(phen)3Cl2 (1 inFig.2,phen5phenanthroline), whoseexcita-tion by visible light (for example, a household light bulb) at room tem-perature provides a strongly oxidizing or reducing catalyst that canrapidly engage a variety of substrates to generate high energy, reactivespecies16.

As a secondpartof ourdesign plan, we recognizedthatthe moderateto low nucleophilicity of many classes of unfunctionalized arenes hasbeen typically underemployed in substitution reactions, presumablyowing to the harsh conditions required to manipulate such aromaticrings via two-electron pathways (for example, nucleophilic or electro-philic aromatic substitution). As an alternative, we considered that astrategy based on radical addition could exploit this large area ofaromatic structural space, thereby rendering a more general approachto CF3 incorporation. Our strategy, outlined in Fig. 1, involvessite-specific incorporation of electrophilic radicals at metabolicallysusceptible positions of arenes and heteroarenesin analogy to thesingle-electronaryl modification processes employed by enzymes. Thisapproach precludes the need for pre-functionalization of arenes, andoffers a complementary methodof accessingaryl trifluoromethyl func-

tionality from late-stage synthetic intermediates.

1Merck Center for Catalysis at Princeton University, Department of Chemistry, 192 Frick Laboratory, Princeton, New Jersey 08540, USA.

CF3

arene

R

CF3

Medicinal

agent

R R

OH

Photoredox

catalysis

H

R

X

CF3

arene or

heteroarene

X

R

CF3

Arene or

heteroarene

X

R

H

X = Cl, I, B(OH)2

Inactive

metabolite

Cytochrome

P450

CF3SO2Cl

Pre-unctionalized

arene

Transition metal

catalysis

a

b

c

Figure 1 | Direct trifluoromethylation of aryl and heteroaryl CH bonds.The excretion of medicinal agents is facilitated by remote functionalization ofaromatic moieties (a). A common medicinal chemistry approach to block thiscatabolism involves cross-coupling of CF3 reagents to pre-functionalizedarenes (b). In analogy to enzymatic processes, our photoredox strategy(c) enables the direct CH functionalization of unfunctionalized arenes andheteroarenes with the CF3 pharmacophore using a cheap and easy to handleN

CF3 source.

2 2 4 | N A T U R E | V O L 4 8 0 | 8 D E C E M B E R 2 0 1 1

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Building on our recent investigations of the a-trifluoromethylationof carbonyls with CF3I as a

N

CF3 source17, our initial exploration of a

photoredox strategy towards the development of this transformationwas successful within the limited context ofp-rich arenes. We quicklyobserved, however, that reaction efficiency was diminished by com-petitive aryl iodination, presumably as a result of CF3I homolysis.Our mechanistic understanding of this undesired pathwaywhereininitiation of the photocatalytic cycle relies on sacrificial oxidation of an

electron-rich areneprompted us to seek an alternative method ofcatalytic initiation. Because direct reduction of CF3I (at a potentialof21.52V versus the saturated calomel electrode, SCE, in cyclic

voltammetry)18 by visible-light-excited photocatalyst *Ru(phen)321

2 (Fig. 2; 20.90 V versus SCE)19 is thermodynamically challenging,we questioned whetherthe incorporationof an electron-deficient systemsuch as SO2 within CF3X might enable more facile reduction

20. Ourinvestigations led us to the use of trifluoromethanesulphonyl chloride(known as triflyl chloride, TfCl), which has been employed in a non-general sense to effect aryl trifluoromethylation of benzene and othersimple arenes via atom transfer catalysis2123. In particular, the relativecost and ease of handling of TfCl in comparison to other

N

CF3 sourcesrendered this a highly attractive reagent.

For the proposed photoredox catalytic cycle, we assumed that

single-electron transfer (SET) reduction of triflyl chloride should beconcurrent with oxidation of *Ru(phen)3

21 2 to Ru(phen)331 3

(Fig. 2). The ensuing CF3SO2Cl radical anion should then rapidlycollapse to generate the stabilized

N

CF3, a process that should beentropically driven by the release of SO2 and chloride

24. This electrondeficient trifluoromethyl radical is then well-suited to addin a selec-tive fashionto the most electron-rich position of any arene orheteroarene25,26. In the case of benzene, the resultant cyclohexadienylradical 4 (Fig. 2;20.1 V versus SCE)27 should then undergo a secondSETevent withthe nowstrongly oxidizing Ru31photocatalyst 3 (Fig. 2;11.31V versus SCE) to regenerate ground-state photocatalyst 1.

Finally, facile deprotonation of the cyclohexadienyl cation 5 (Fig. 2) witha suitable base would provide the desired trifluoromethyl arene in aredox, catalyticfashionwithout the needfor arene pre-functionalization.

As illustrated in Fig. 3, we found that this new photoredox protocolallows the direct incorporation of CF3 into a broad range of arene andheteroarene rings using only TfCl and a household light bulb. In con-trast to atom transfer pathways for trifluoromethylation that requirehigh temperature (120 uC), our photoredox strategy is successful at

roomtemperature, allowingefficient productionof the trifluoromethylradical. Our initial studies revealed that exposure of five-atom hetero-cycles to a household 26-W fluorescent light source in the presence oftriflyl chloride, Ru(phen)3Cl2 (1) photocatalyst, and base, enabledtrifluoromethylation with excellent levels of efficiency (Fig. 3a).More specifically, the fluoroalkylation of pyrroles, furans andthiophenes occurred with excellent selectivity and yield (compounds612, 7894% yield). Our rationale for the observed selectivity at theC2 position of these heteroaromatics relies on the formation of theconjugated (rather than cross-conjugated) radical and cationic inter-mediates. We also found that both mono- and bis-trifluoromethyla-tion could be obtained by varying the amount of CF3 source used (8and 9, 88 and 91% yield, respectively). Additionally, a wide range ofring substitution and heteroatom protecting groups are well tolerated

(1017, 7087% yield). Electron-deficient five-atom heterocycles suchas thiazoles are also amenable to this trifluoromethylation protocol,and useful levels of efficiency are obtained by increasing equivalents ofthe CF3 source (14, 70% yield).

We next turned our attention to six-atom heterocycles with theknowledge that there is an unmet need for CF3 cross-coupling tech-nologies for these valuable pharmacophores. As shown in Fig. 3b, wefound that an array of pyrazine, pyrimidine, pyridine and pyrone sub-strates are compatible with this new trifluoromethylation approach(1832, 7094% yield). We further observed that radical addition andthe ensuing oxidation of electronically deficient halide-substitutedheteroaromatics (such as 2,6-dichloropyrazine) were also operative.Unsubstituted analogues of each of these heterocycles can also betrifluoromethylated, albeit with somewhat diminished efficiency.Notably, the commercial photocatalyst Ir(Fppy)3 (Fppy5 2-(2,4-difluorophenyl)pyridine, see Supplementary Informationforcom-mercial sources, synthesis and photophysical properties) is capable ofproviding higher levels of reactivity (presumably due to a longer-livedexcited state), although lower levels of regiocontrol are observed withthis system(the role of catalyst reduction potentials in these outcomesis being explored). Finally, the trifluoromethylation of arenes (shownin Fig. 3c) demonstrates the complementary reactivity offered by thisradical process. Ortho-trifluoromethyl containing anilines, anisoles,thioanisoles and xylenestypically challenging motifs to access viacross-coupling strategiesare also readily prepared using thismethodology (3440, 7084% yield). Tolerance of halides, multiplesubstitution and large steric bulkare additionalbenefitsof this radical-based process (3847, 7292% yield).

Our mechanistic hypothesis for the photoredox process describedabove is supported by emissionquenching experiments as well as cyclic

voltammetry. In the first case, no quenching interactions are observedbetween excited state 2 (Fig. 2) and a range of electronically diversearenesand heteroarenesthat arecompetent partners in thistransforma-tion; whereas triflylchlorideexhibits significantfluorescencequenching(SternVolmer constant, 22 M1; Supplementary Fig. 1). Furthermore,we have determined the oxidation potential of triflyl chloride (0.18 V

versus SCE; Supplementary Fig. 2) to be in accord with the proposedreduction step using excited state 2, as shown in Fig. 2. It is alsonoteworthy that decreased reactivity is observed in the absence of base,presumably due to HCl formation in the reaction. Inorganic bases arepreferred to organic bases, as pyridines are trifluoromethylated andalkyl amines are prone to oxidative decomposition.

Ultimately, a major benefit of our mild, visible-light-induced

trifluoromethylation procedure is its amenabilityto late-stage synthetic

Household

light

Ru(phen)33+

oxidant 3

+1.31 V

Ru(phen)32+

photocatalyst 1

Photoredox

catalysis

4

CF3

5

CF3

H H

0.90 V

R R

CF3SO

2Cl

F3C S

O

O

Cl

0.18 V

0.1 V

SET

*Ru(phen)32+

reductant 2

CF3

arene

R

CF3

H+

Arene

R

H

FF

F

Cl

SO2

SET

Figure 2 | Proposed mechanism for the direct trifluoromethylation of arylCH bonds via photoredox catalysis. The photoredox catalytic cycle isinitiated via excitation of photocatalyst 1 to excited state 2 with a householdlight bulb. Subsequent reduction of triflyl chloride by reductant 2 (via singleelectrontransfer,that is, SET)provides oxidant 3 alongwith theradicalanionoftriflyl chloride. This high energy species spontaneously collapses to form CF3radical (top left), which selectively combines with aromatic systems enablingdirect CF3 substitution. Catalyst 3-promoted oxidation of the ensuing radical4 completes the catalytic cycle and provides cyclohexadienyl cation 5, whosefacile deprotonation provides the desired CF3 arene. This mechanism isconsistent with measured redoxvalues (shown belowrespective compounds, inmaroon).

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applications. To demonstrate thispotential, biologicallyactive molecules(Fig. 4) were subjected to our photoredox trifluoromethylation pro-tocol to obtain their CF3 analogues. In some cases, highly regioselectiveaddition is observed, presumably corresponding to positions of highelectron density and potential metabolic susceptibility (Fig. 4a). Inmedicinal chemistry, the simultaneous identification and blocking ofsuch positions with a CF3 groupmay prove quite useful. Forinstance, aDNA base (uracil) analogue, an Alzheimers drug (Aricept) precursor,and a vitamin (flavone) were each selectively trifluoromethylated at asingle position with excellent efficiency (8594% yield). The firstexample represents a facile, one-step synthesis of a known CF3-uracilderivative fromits abundantnon-fluoro analogue. These uridines havebeen extensively studied owing to their anti-viral and cancer-treatingproperties28.

Alternatively, a successful drug discovery programme is likely toeliminate potential sites of metabolic reactivity from a medicinal agentduring the course of its development29. Without an especially electron-rich p-system present, competitive trifluoromethylation of theremaining aromatic sites should be observed. Not surprisingly, radical

trifluoromethylation of lidocaine and ibuprofen results in alkylation at

both of their available aromatic positions (Fig. 4b). Subjection of thecholesterol-lowering statin, Lipitor, to our protocol similarly results inpromiscuous functionalization at three positions (Fig. 4c; 74% yield,1:1:1). In the context of drug discovery, the isolation of these separateisomers offers the potential for rapid testing of fluorinated analoguesfor biological activity from a single late-stage synthetic product. Thisstreamlined process represents an attractive alternative to multi-step,parallel syntheses. Perhaps most importantly, this technology providesa strategically new approach to the introduction of metabolism-blocking fluoroalkyl groups at the end of a medicinal chemistrydevelopment effort.

In this work, we have introduced a photoredox-based method thatallows for facile trifluoromethylation of aromatic and heteroaromaticsystems without the need for aryl ring pre-activation. The value of thistransformation has been highlighted via the trifluoromethylation ofbiologically active molecules with commercially availablephotocatalystsanda household light bulb. Whilethis manuscript wasunderreview, acomplementary method for heterocyclic trifluoromethylation wasreported by others30. Their approach also employs radical inter-

mediates to harness innate chemical reactivity of unactivated

NMe

CF3

OCF3Me

10: 87%

6: 94%

SCF3Me

11: 82%

OCF

3Me

12: 80%

SCF

3

13: 76% (3:1)*

Me

NBoc

CF3

7: 78%

Me

5

O

CF3

15: 84%

Me

N

SCF

3

14: 70%

Me

NH

16: 72% (4:1)*

CF3

17: 81% (3:1)*

NAc

CF33

2

a

NH

CF3 NH

CF3F3C

8: 88% 9: 91%

Five-atom

heteroarenes

Y

XH

Six-atom

heteroarenes

BA

C

H

CF3

arenes

CF3

Five-atom CF3

heteroarenes

Y

XCF

3

CF3SO

2Cl (14 equiv.)

Photocatalyst (12%)

K2HPO4, MeCN, 23 C

26-W light sourceUnactivated

arenes

H

Six-atom CF3

heteroarenes

B

C

A CF3

N

N

N

N

Me

MeS

N

Me

N

N

OMe

OMe

26: 86%

MeO

CF3

25: 72%

29: 78%

21: 70%

CF3

CF3

CF3

ClN

N

N

N

Me

19: 78%

CF3CF3

Me Me

Me

N

N CF3

OMe

18: 82%

N

Me

27: 81%

CF3

20: 94%

N

N

Me

24: 85%

CF3

Me

Me

OH

23: 74%

HN

N

CF3

O

Cl

Me

31: 90%

O

CF3

O Me

Me

32: 88%

O

CF3

O

Me Me

N

CF3

Me Me

22: 73%

30: 87%

NO

b

Me

N

28: 78% (3:1)*

CF3

OMe

5

OMe

CF3

Me

Me

CF3

41: 92% (5:1)*

43: 77% 47: 78% (5:1)

CF3

Me

39: 77% (2:1)*

Me

37: 70%

CF3

CF3

CF3

33: 74%

Me

CF3Me

BF3K

CF3

42: 74% (2:1)*

NHBoc

34: 80% (3:1)*

OMe

35: 84% (2:1)*

SMe

36: 73% (2:1)*

CF3

CF3

CF3

46: 85% (4:1)

CF3

45: 76%

CF3

38: 75% (4:1)

Br CF3 CF3

40: 72% (2:1)

44: 85%

OMe

CF3MeO

c

3

Me

Me

tBu

Me Me

Me3Si

OMe

Me

OMe

O

O

MeO3

MeO

3

Me Me

Me

Me

4 44

Figure 3 | Radical trifluoromethylation of five- and six-membered heteroarenes and CH arenes via photoredox catalysis. Aromatic and heteroaromaticsystems with varying stereoelectronics are efficiently trifluoromethylated under these standard conditions (top, generalized reaction). Substrate scope includeselectron-rich five-atom heteroarenes (a), electron-deficient six-atom heteroarenes (b), and unactivated arenes (c). Isolated yields are indicated below each entry (19FNMR yields for volatile compounds). See Supplementary Information for experimental details. Abbreviations: X, Y, A, B, C represent either C, N, O, or S; MeCN,acetonitrile; Me, methyl; Boc, tert-butoxycarbonyl; Ac, acyl; tBu, tert-butyl. *The minor regioisomeric position is labelled with the respective carbon atom number.

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Acknowledgements Financial support was provided by the NIH General MedicalSciences (R0101 GM093213-01) and gifts from Merck, Amgen, Abbott andBristol-Myers Squibb. We thank C. Kraml and N. Byrne of Lotus Separations LLC fortheir development of preparatory supercritical fluid chromatography (SFC) methodsand for the separation of all three CF3-Lipitor analogues.

Author Contributions D.A.N. performed and analysed experiments. D.A.N. andD.W.C.M. designed experiments to develop this reaction and probe its utility, and also

prepared this manuscript. Correspondence and requests for materials should beaddressed to D.W.C.M. ([email protected]).

Author Information Reprints and permissions information is available atwww.nature.com/reprints . The authors declare no competing financial interests.Readers are welcome to comment on the online version of this article atwww.nature.com/nature. Correspondence and requests for materials should beaddressed to D.W.C.M. ([email protected]).

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trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis

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