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Selective Single C(sp)#F Bond Cleavage in Trifluoromethylarenes: Merging Visible Light Catalysis with Lewis Acid Activation Kang Chen, Nele Berg, Ruth M. Gschwind, and Burkhard König J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b10755 • Publication Date (Web): 28 Nov 2017 Downloaded from http://pubs.acs.org on November 28, 2017
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Journal of the American Chemical Society
Selective Single C(sp3)－ －F Bond Cleavage in Trifluoromethylarenes: Merging Visible Light Catalysis with Lewis Acid Activation Kang Chen, Nele Berg, Ruth Gschwind,*and Burkhard König* University of Regensburg, Faculty of Chemistry and Pharmacy, 93040 Regensburg, Germany.
Supporting Information Placeholder ABSTRACT:The conversion ofeasily available trifluoromethylarenes into aryl difluoromethyl compounds, which are valuable motifs in pharmaceutical chemistry, is highly atom- and step-economic. However,the single C(sp3)－F bond cleavage of ArCF3 is a great challenge owing to the inert chemical property of the C(sp3)－F bond and the difficult selectivity control of mono-defluorination.We report here the first example of single C(sp3)－F functionalization of trifluoromethylarenesvia visible lightcatalysis merged with Lewis acid activation. The method allows goodchemo-selectivity control andshows a good functional group tolerance. Mechanistic studies suggest an insitugenerated borenium cationic species as the key intermediate for C(sp3)－F bond cleavage in this reaction.
Organofluorine compounds are important in pharmaceutical chemistry and agrochemistry due to theirspecial chemical and biological properties.1As the demand of novel organofluorine compounds grows, organofluorine chemistrydeveloped rapidlyin recent years.2Conventionalstrategies for the synthesis oforganofluorine compoundsmainly focus onnew C － F(or Fcontaining moieties) bond formation.3Alternatively, theselective C －F bond cleavage of multi-fluorinated compounds canalso provide facile access to complex fluorinated molecules, which has recently drawn increasing attention.4 Aryldifluoromethylderivatives (ArCF2R) are important building blocks in many bioactive compounds (Scheme 1A).5It is an appealing goal to achieve the straightforward synthesis of valuable ArCF2R derivatives fromeasily available trifluoromethylarenes (ArCF3)via selective single C(sp3)－F bond cleavage. Since no pre-activation of starting material is required and only the F- anion is released as byproduct, this transformation is highly atom- and step-economic.However, single C(sp3) － F bond cleavage of ArCF3is a challenging problem in organic synthesis:Thehigh bond dissociation energy6makes C(sp3)－F bonds usually quite inert under various reaction conditions.Furthermore, the dissociation energy of the remaining C(sp3)－F bonds decreases after one C(sp3) － F bondis cleavedin the trifluoromethyl group.Thus, avoidingmultiple defluorination is rather difficult.68 3 Inseveralprevious reports, all three C(sp )－F bonds in ArCF3 were cleaved without selectivity9and only very fewmethods forsingle C(sp3) － F bond cleavage ofArCF3have beendeveloped. Thevery recent work by Hosoya usedortho-silyl cation activation,10while Lalic employed transition metal catalysis to realize the mono-hydrodefluorinationof ArCF3.11Other reportsmainly
reliedon thesingle electron transfer (SET)strategy viaactive metal reduction (usually Mg), electrochemistry or UV light irradiation (Scheme 1B).12-14These reactions still suffer fromthe use of large excess of reductants,limited substrate scopes and sometimes low selectivity of mono-defluorination. Moreover, no catalytic SET reaction system has been established, yet. Visible light induced photoredox catalysismay facilitate the SET process under mild conditions.15Elegant examples of visible light induced C－F bond cleavage have been reported.Weaver realizedthe selectivearomatic C－F bond functionalization of multifluoarenes.16 Hashmideveloped radical-radical cross coupling between amines and Fcontaining compounds.17Zhou and Molander managedto preparegem-difluoroalkenes from α-trifluoromethyl olefinsviaradicalpolar crossoverprocess.18, 19 Despite the above achievements,single C(sp3)－F bond cleavage of ArCF3 driven by visible light catalysis remainedan untouched challenge. Herein we report the first mono-defluorination of ArCF3via visible light catalysis merged with Lewis acid activation.
Scheme 1. Design of Photocatalytic Selective Single C(sp3) －F bond Cleavage of Trifluoromethylarenes A. Selected Bioactive Aromatic Difluoromethylene Compounds MeO
S
O N
F
F
Ph
OMe
N N
O
MeO
O
N
N F F
HIV-1 reverse transcriptase inhibitor
FKBP12 rotamase activity inhibitor CN O
N F F
N H
NH O
N H
F thrombin inhibitor
N H
NH2
B. Selective Single C(sp3)-F Cleavage in Trifluoromethylarenes (Ref. 10-14) Pd-Cu catalysis ArCF2H
3
2
R
1
R
Si
F
HSiEt3
F F R F
R1
Ph3CB(C6F5)4
Ar
F F
Metal, e- or UV light
ortho-silyl directed defluorination
F
F
SET reduction
R
Ar
R = H, alkyl, silyl No catalytic reaction reported
C. Our Design (This Work) CF3
CF3 Photocatalysis Ar
Ar SET reduction radical anion
F
Lewis acidic F- scavenger Ar
Radical F trapping
F Ar
F R
In our design, a stepwise activation of the inert ArCF3 molecule is envisaged. First, ArCF3 isconvertedinto the corresponding radical anion viaphotocatalytic SET reduction in the presence ofa
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suitable photocatalyst and electron donor.This radical anionwould be able to release F-to form the aryldifluoromethyl radical (ArCF2•) albeit in very slowrate, because of the poor leaving group ability of F-.8Since this radical anion is not reactive enough, we speculated thatthe use of a proper Lewis acidic fluoride scavenger20, 21 couldfurther accelerate the radicalgeneration and suppress the back-electron transfer.22An appropriate interaction between Lewis acid (fluoride scavenger) and base (electron donor) would be the key to successful reaction. Finally, the aryldifluoromethyl radical could be captured by a trapping reagentto give the corresponding ArCF2R product (Scheme 1C).We hypothesize the combination of electronic control of photocatalyst and steric control of the Lewis pair may offer more opportunities to realize mono-defluorination selectivity than a sole activation system. With this design in mind, we chose fac-Ir(ppy)3 as photocatalyst (Ir(III)/Ir(II), Ered = -2.19V vs. SCE),23N-methyl-N-phenylmethacrylamide2a as the trapping reagent to initiate the optimization of a selective single C(sp3)－F cleavage of 1ainDCE solution under blue light irradiation (455 nm).To our delight, the combination of HBpin (pinacolborane)with the steric hindered,α-H atom freeamine TMP (2,2,6,6-tetramethylpiperidine) remarkably improvedthe reaction efficiency, while in the absence of HBpin (Table S1, Entry 3) or TMP (Table S1, Entry 4), the reaction did not afford thedesired product. The inferior results of other amineboron or silicon reagent combinations indicatedthat the chemical properties of both additives werecriticalfor this reaction (Table S1 and S2). Control experiments showed that theIr catalyst (Table S3, Entry 5) and blue light irradiation (Table S3, Entry 6)were essential for this reaction. After an extensive screening of photocatalysts, solvents, reaction time and equivalents of components (Table S3-5), we found the optimal conditions by using 1.0 mol% of the Ir catalyst, 2.0 eq. of TMP and 2a, 3.0 eq. ofHBpin in 1.0 mL of DCE under 24 h blue light irradiation (455 nm) (Table S5, Entry 6).Good selectivity ofsingle C(sp3) － F cleavage was achieved under this conditions, and less than 5% di-defluorinated product was detected in the crude reaction mixture.
With the optimized conditions in hand, we tested the scope of methacrylamides2as trapping reagents (Table 1).The reaction between 1a and amide 2a gave product 3a in good isolated yield under standard conditions. Generally, electron-rich methacrylamides facilitated the capture of the electron-deficient aryldifluoromethyl radical and the following cyclization step, which resulted in better yields for 3b and 3c compared to their electrondeficient analogs 3e and 3f. Steric hindrance of the substrate affected the cyclization step to giveslightly lowerproduct yields of3d. Notably, even the presence of a C(sp2)－Cl bond was tolerated under this condition, which illustrates the good chemoselectivity forthe specific C(sp3) － F bond (3f). The biphenyl derivative 2g gave the lowest product yield (3g). Methacrylamides bearing different N-protecting groups gave the corresponding products in goodyields (3h-3j). Next, we further investigated the scope of ArCF3 compounds (Table 2). Compared to the para-cyanosubstituted benzotrifluoride, the ortho-isomer showed similar reactivity (4b), while the meta-cyano substituted benzotrifluoride did not yield any product (4c). Even methyl group substitution significantly slowed down the reaction (4d) and biphenyl substrates showed lower reactivity than phenyl derivatives (4e). Though bearing two strong electronwithdrawing groups (-CF3 and -CN) on the aromatic ring, the aryl C(sp2)－F bond in 1f still remained untouched and the C(sp3)－F bond cleavage product was obtainedinstead (4f). A4CF3benzenesulfonyl protected acyclic secondary amine,synthetically useful heterocycles (pyrrolidine, morpholine, N-Boc-piperazine)and a glycine derivative gave the corresponding products (4g-4k) in moderate to good yields albeit in longer reaction time (48-72 h). However, aromatic carboxylic esters do not convert well in this transformation. The ethyl ester 1l was less than 50% converted even after 48 hours’ of reaction time. Poor mono-defluorination selectivity was observed in the case of the nicotinic ester derivative1m.
Table 2. Substrate Scope of Trifluoromethylarenes
Table 1. Substrate Scope of Methacrylamides
a
a
Reactions were performed in 0.1 mmol scale and isolated yields were reported. b 2-CF3benzonitrile was used for 36 h reaction.
Reactions were performed in 0.1 mmol scale and isolated yields were reported. Yields in parenthesis were based on the recovered starting materials. b19F NMR yield of di-defluorinated product. c19 F NMR yield of the desired product.
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Journal of the American Chemical Society With a series of experiments we investigated the reaction mechanism.TEMPO and 1,1-diphenylethylene were used as radical scavengers and the corresponding trapping adducts were detected (Scheme S1 and S2), which indicated that the aryldifluoromethyl radicalwas involved in this reaction. From the reaction profile, we observed a relatively slow reaction rate in the first hourwith an induction period of about 0.5 h(Figure S17). This may indicatethe generation and accumulation of an active speciesfor theC(sp3)－F bond cleavage at the early stage of the reaction.During in situ illuminationinside the NMR spectrometer,the formation of a new boron species (11B NMR, δ = 25.0 ppm in CD2Cl2) was detected in low concentration(Figure 1A).The observed species had the same 11B chemical shift astheborenium cationic species 5,which could be prepared independently fromTMP, HBpin and [Ph3C]+[B(C6F5)4]-following a reported procedure(Figure 1B).24Upon addition of trifluoromethylbenzonitrile1ato a sample of 5, a low field shift of the N－H proton in 5was observed, whileits 11B spectrum was not affected at all and its 19F signal shifted only by 0.1 ppm. (Figure S21-S23).Further investigationsvia1H-19F HOESY showed no interaction between 5 and the trifluoromethyl group of 1a, anda1H-1H NOESY corroborated a preferred interaction to the CN group of 1a (Figure S25 and S26) according to its better H-bond acceptor properties.25 These observations contradicta direct C(sp3)－F bond activation in the non-charged molecule1a by the borenium cationic species5. Interestingly, when the photo reduction system and the in-situ generated 5 were combined together, 1a underwentthe desired mono-defluorinationreaction to afford3a (Scheme 2, Eq. 1), which suggeststhat 5 prefers to abstract a fluoride anion from the radical anion of 1a.Based on the above results, the borenium cation 5’observed in our reaction could act as a fluoride scavenger. Furthermore, we suggest that 5’isin-situ generated from the reaction of TMP, HBpin and a proton.Notably, the methacrylamide hasa dual role as trapping reagent and proton source. It releasesone proton in every catalytic cycle during the radical trapping/intramolecular cyclization/rearomatizationcascade, which continuously provides the driving forcefor the generation of 5’and the C(sp3) － F bond cleavage. Thisproposal was supported by another control experiment: Without 2a, most of the starting material was recovered and C(sp3) － F bond cleavage hardly proceedseven afterirradiation for 24 h(Scheme 2, Eq. 2).
Figure 1. 11B NMR studies of the reaction intermediate: (A)In situ irradiation of the singleC(sp3)－F cleavage reaction of1a(450 nm, 22 h) in CD2Cl2(0.1 M) inside the NMR spectrometer show the generation of 5’. (B)Generation ofborenium cationic spe-
cies5in a mixture containing[Ph3C]+[B(C6F5)4]- (0.1 M), HBpin (0.11 M) andTMP (0.1 M) in CD2Cl2. Finally, we explored the origin of the chemo-selectivity in this reaction. Although the reduction potential of 3a (Ered = -1.91 V vs. SCE) was even slightly more positive than the starting material 1a (Ered = -1.94 V vs. SCE),26 compound 3a remained stable under the reaction condition. Only ca. 2% of 7 was detected in the crude mixture and most of 3a was recovered (Scheme 2, Eq. 3). Compared to 1a, the steric hindrance of 3aincreased significantly, which likely inhibited the further defluorinationcaused by the steric bulky borenium cation 5’. Other substrates such as 1e (Ered = -1.86 V vs SCE), 1f (Ered = -1.82 V vs. SCE) and 1m (Ered = 1.82 V vs. SCE) were more susceptible to SET reduction, which decreased their selectivity of mono-defluorination.We therefore proposethat the synergy of steric and electronic factors control the chemo-selectivity of the single C(sp3)－F bond cleavage.27
Scheme 2. Mechanistic Studies.
Based on all experimental observations, we propose a plausible reaction mechanism(Scheme 3). Initially,the blue light excited fac-Ir(ppy)3is reductively quenchedby TMP resulting anIr(II) species and TMP radical cation A.28 The Ir(II) species reduces1a to its corresponding radical anion B. The reaction betweenthe protonated TMP species Cand HBpinshouldproduce the Lewis acidic borenium cation 5’,29 which abstractsa fluoride anion from the radical anion B to affordthearyldifluoromethyl radical D. Finally,compound 2a captures radical Dand subsequent cyclization and oxidative rearomatization gives product 3a.The proton released during the rearomatization step regeneratesthe protonated TMPspecies C, which is essential for thecontinuousaryldifluoromethyl radicalgeneration. In summary, single C(sp3) － F bond activation in trifluoromethylarenes has been achieved by merging Irphotoredox catalysis with Lewis acid activation. This reaction provides a high atomand step-economic approach to construct aryl difluoromethyl moieties, which are valuable in pharmaceutical chemistry. The reaction shows good chemo-selectivity control and functional group tolerance. Mechanistic studies reveal that the synergy of steric and electronic factors control the chemo-selectivity of single C(sp3) － F bond cleavage. An in-situ generated borenium cationic species is suggested as the key intermediate for the C(sp3) － F bond cleavage step.The trapping reagent methacrylamide, which also acts as a proton source, provides the pace forthe defluorination process.
Scheme 3. Proposed Mechanism
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Me Me
N H TMP
Me Me
Me Me
Ir(III)*
N H A
Me Me
Me Me
N H2 C
Me Me
Me Me H2
Lewis Acid Activation CF3 TMP-Bpin 5'
CF2
NC
blue LED
Ir(III)
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TMP-Bpin 5': (11B) 25.0 ppm in CD2Cl2
Ir(II)
SET Reduction
(8)
Me H N Me Bpin
NC B
(10)
D
TMP + F-Bpin
CF 3 NC
N Me 2a
1a
F
CN
F
F
F
CN F
F
CN
Ir(III)* or A
TMP O N Me 3a
(11) (12)
O
O
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C
N Me F
O N Me E
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ASSOCIATED CONTENT Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website. Detailed experimental procedures, characterization for new compounds and NMR spectra, CV spectra
AUTHOR INFORMATION (17)
Corresponding Author
[email protected] [email protected] (18)
Notes The authors declare no competing financial interests.
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ACKNOWLEDGMENT
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This work is supported by the German Science Foundation(DFG) (GRK 1626,Chemical Photocatalysis). KC thanks the Alexander von Humboldt Foundation for a postdoctoral fellowship. We thank Dr. R. Vasold, Ms. R. Hoheisel and Mr. F. Brandl for analytical support.
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