Visible-Light-Promoted Activation of Unactivated C(sp3)-H Bonds and Their Selective Trifluoromethylthiolation

Article abstract of DOI:10.1021/jacs.6b09970

Selective functionalization of ubiquitous C(sp³)-H bonds using visible light is a highly challenging yet desirable goal in organic synthesis. The development of such processes relies on both rational design and serendipitous discoveries from innovative tools such as screening technologies. Applying a mechanism-based screening strategy, we herein report photoredox-mediated hydrogen atom transfer catalysis for the selective activation of otherwise unactivated C(sp³)-H bonds, followed by their trifluoromethylthiolation, which has high potential as a late-stage functionalization tool. The generality of this method is exhibited through incorporation of the trifluoromethylthio group in a large number of C(sp³)-H bonds with high selectivity without the need for an excess of valuable substrate.

Full text of DOI:10.1021/jacs.6b09970

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Communication
Visible light-promoted activation of unactivated C(sp3)–
H bonds and its selective trifluoromethylthiolation
Satobhisha Mukherjee, Biplab Maji, Adrian Tlahuext-Aca, and Frank Glorius
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b09970 • Publication Date (Web): 28 Nov 2016
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Visible light-promoted activation of unactivated C(sp3)–H
bonds and its selective trifluoromethylthiolation
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Satobhisha Mukherjee,‡ Biplab Maji,‡ Adrian TlahuextꢀAca, Frank Glorius*
OrganischꢀChemisches Institut, Westfälische WilhelmsꢀUniversität Münster, Corrensstrasse 40, 48149 Münster, Germany.
Supporting Information Placeholder
ABSTRACT: Selective functionalization of ubiquitous C(sp3)–H bonds
using visible light energy is a highly challenging yet desirable goal in
ic properties. We reasoned that the direct and selective functionalization of
C(sp3)–H bonds on a target molecule under mild redox neutral conditions
without using an excess of valuable substrate would obviate the need of
preꢀfunctionalization steps. And we anticipated that this would create the
opportunity to modify natural and bioactive molecules–amenable for
further drug discovery.
organic synthesis. Developments of such processes rely both on rational
design and serendipitous discoveries from innovative tools such as screenꢀ
ing technologies. Applying a mechanism based screening strategy, herein,
we thus report the photoredoxꢀmediated hydrogen atom transfer catalysis
for the selective activation of otherwise unactivated C(sp3)–H bonds,
followed by its trifluoromethylthiolation, which has high potential as a
late stage functionalization tool. The generality of this method is exhibited
through incorporation of the trifluoromethylthio group in a large number
of C(sp3)–H bonds with high selectivity without the need for excess of
valuable substrate.
Visibleꢀlight promoted photoredox catalysis has recently emerged as a
powerful tool for generating highly reactive openꢀshell species under mild
and controlled conditions.13 Recently, we had reported a novel mechaꢀ
nismꢀbased screening method for accelerated reaction discovery.14 This
approach focused on the luminescence quenching step in a photocatalytic
cycle and proved to be a useful tool to facilitate the development of new
reactions. Building on this concept, we found that the strongly oxidizing
excited
state
of
the
iridiumꢀbased
(Ir-F, (dF(CF3)ppy)
photoredox
catalyst
2ꢀ(2,4ꢀ
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6
=
difluorophenyl)ꢀ5ꢀ(trifluoromethyl)pyridine, dtbbpy = 4,4’ꢀdiꢀtertꢀbutylꢀ
2,2’ꢀbipyridine) was quenched by tetrabutylammonium benzoate
(Bu4N+BzO–) in acetonitrile solution at room temperature. Further investiꢀ
gation revealed a SternꢀVolmer constant of 128 M–1, corresponding to a
quenching rate of kq = 5.60 × 107 M–1s–1 (See Figure S1).15 Based on this
analysis, we hypothesized that under catalytic conditions the benzoyloxy
radical (BzO•) could be generated upon reductive quenching of Ir-F by
BzO– (Figure 1B).16, 17 We envisioned that at room temperature, the elecꢀ
trophilic BzO• radical could undergo a fast yet selective hydrogen atom
abstraction from electronꢀrich hydridic C(sp3)–H bonds of an alkane
substrate R–H.18 The generated nucleophilic alkyl radical R• would then
react with the shelfꢀstable electrophilic trifluoromethylthiolating reagent
Phth–SCF319 to form the product R–SCF3 along with the phthalimide
radical. Oxidation of the reduced photocatalyst with phthalimide radical
via single electron transfer would regenerate the photocatalyst and
phthalimide anion. The latter then readily deprotonates benzoic acid (pKa
= 8.3 for phthalimide against 4.2 for benzoic acid in water) to regenerate
the HAT catalyst and complete the catalytic cycle (Figure 1B).
The functionalization of abundant C–H bonds in chemical synthesis is
an attractive concept due to their inherent economic and environmentally
benign nature. However, controlling the siteꢀselectivity, given that most
organic molecules contain a large number of methyl, methylene, and
methine groups, represents perhaps the biggest challenge in the developꢀ
ment of such processes. Enzymes have evolved to selectively oxidize
these inert C–H bonds by their inherited protein embedded active core.
Chemists, on the other hand have utilized either a directing group,2 or the
electronic properties of the molecule for selective oxidation of C(sp3)–H
bonds.3 In this regard, using visible light photoredox catalysis, small
molecule hydrogen atom transfer (HAT) catalysts were developed to
selectively activate weak allylic (bond dissociation energy (BDE) = 88.8
kcal/mol), benzylic (BDE = 89.7 kcal/mol), and αꢀheteroatom C–H bonds
(BDE ~ 92 kcal/mol) under mild reaction conditions.4 Recently, we beꢀ
came interested in utilizing HAT catalysis for the activation of more
challenging unactivated C(sp3)–H bonds (BDE for (CH3)2CH–H = 98.6
kcal/mol and for (CH3)3C–H = 96.5 kcal/mol).5 In particular, in line with
our current research, we focused on the direct C(sp3)–H trifluoromethylꢀ
thiolation reaction employing visible light as the energy source.6 It was
envisioned that the key to success would be the identification of a highly
hydridophilic small molecule organocatalyst to selectively activate elecꢀ
tronꢀrich C(sp3)–H bond of an organic substrate (Figure 1A).
Based on our mechanistic hypothesis, we performed the direct trifluoꢀ
romethylthiolation of 5ꢀmethylhexanꢀ2ꢀyl benzoate (1 equivalent) using
IrꢀF (2 mol%) as photocatalyst, tetrabutylammonium benzoate (5 mol%)
as HAT catalyst and PhthꢀSCF3 (1.5 equivalent) in acetonitrile under
irradiation of 5 W blue LEDs (λmax = 455 nm) at room temperature (Figure
1B). To our delight, we observed the formation of the desired trifluoromeꢀ
thylthiolated product in 96% isolated yield with very high selectivity for
the tertiary C–H bond over several secondary and primary C(sp3)–H bonds
present in the molecule (>20:1). We found that reducing the photocatalyst
loading to 1 mol% and changing the HAT catalyst to more convenient
sodium benzoate do not change the outcome of the reaction. A series of
control experiments were then performed to confirm the absolute necessity
of each reaction component light, photocatalyst, and HAT catalyst. As
expected, no product was formed in the absence of any of these compoꢀ
nents (See Table S1).
The trifluoromethylthio (SCF3) group is under investigation due to its
potential in modern drug design.7 By protecting from in vivo enzymatic
metabolism, it can improve the pharmacokinetics and efficiency of a drug
candidate owing to its high electronꢀwithdrawing power (Hammett conꢀ
stants σp = 0.50, σm = 0.40) and lipophilicity (Hansch parameter π = 1.43).8
However, the growth of trifluoromethylthiolated drugs and lead comꢀ
pounds is hampered by the lack of synthetic tools, especially ones that can
be applied under mild conditions with broad functional group tolerance.9
Traditionally, SCF3 groups were introduced by halogenꢀfluorine exchange
reactions or trifluoromethylation of disulfide and thiols.10 Recently, a
number of electrophilic SCF3ꢀcontaining reagents were introduced for the
functionalization of C–H bonds.11 Impressive trifluoromethylthiolation of
benzylic and nonꢀactivated C(sp3)–H bonds were achieved using AgSCF3
as reagent.12 However, these methods require either a large excess of
starting material, or super stoichiometric amounts of oxidant. Moreover,
use of a strong oxidant often deflates the selective functionalization when
the molecule contains more than one C−H bond with comparable electronꢀ
With this conditions in hand, we explored the scope of this direct triꢀ
fluoromethylthiolation reaction. As shown in Figure 2A, a range of funcꢀ
tionalized hydrocarbons were trifluoromethylthiolated in high yields and
selectivities for the electron rich tertiary C–H bonds over secondary and
primary ones. The reaction was also found to tolerate the strained cycloꢀ
proyl ring. We then evaluated the inherent reactivity and selectivity for
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this C–S bond forming reaction in substrates with multiple tertiary C–H
bonds (Figure 2B). Dihydrocitronellol derivatives, having two electroniꢀ
cally comparable
However, the reaction was not compatible for benzylic C–H trifluoroꢀ
methylthiolation and a complicated reaction mixture was formed. 22
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Figure 1. Photoredox-mediated HAT catalysis enables highly selective
trifluoromethylthiolation of C(sp3)–H bonds. A) Selective activation of
methine C–H bond on a substrate containing multiple C(sp3)–H bonds. B)
Mechanistic hypothesis and reaction development. HAT, hydrogen atom
transfer; SET, singleꢀelectron transfer; BDE, bond dissociation energy;
LED, lightꢀemitting diode; Bz, benzoyl; Phth, phthalimidyl.
tertiary and many secondary C–H bonds were chosen as model substrates
for this purpose. As shown in Figure 2B, the C–H trifluoromethylthiolaꢀ
tion takes place at the distal C–H bond in high selectivities, while toleratꢀ
ing a range of functional groups such as protected alcohols, amines, esters
and amides, and the major products were isolated in good yields (67–
75%).20 The trifluoromethylthiolation of 4ꢀisoꢀpropylcyclohexanone also
took place selectively at the remote C–H bond. High selectivity of the
trifluoromethylthiolation reaction for the most hydridic C–H bonds was
also observed for the more complex fenchyl ester and the adamantaneꢀ
carboxylate substrate with multiple tertiary C–H bonds, where the trifluoꢀ
romethylthiolated products were iso lated in 71% and 84% yields, respecꢀ
tively.
Figure 2. Scope of the photoredox-mediated HAT-catalyzed direct
C(sp3)–H bond trifluoromethylthiolation. A) Evaluation of the selectiviꢀ
ty between methylene and methine C–H bonds. B) Evaluation of the
selectivity between methine C–H bonds on a multiple methine C–H bond
containing substrates. C) Evaluation of the reactivity of methylene C–H
bond containing substrates. D) Evaluation of the reactivity of the subꢀ
strates containing heterocyclic core. Isolated yields are given. See suppleꢀ
mentary material for experimental details. The site selectivities for reacꢀ
tion at two or multiple C–H bonds were determined by 19F NMR of the
a
crude reaction mixture. Two equivalents of the substrate were used and
the yield were determined by 1H NMR. Ac, acetyl; NMR, nuclearꢀ
magnetic resonance.
Substrates with secondary C–H bonds generally reacted only sluggishꢀ
ly. Nevertheless, cyclohexane and cycloheptane were trifluoromethylthioꢀ
lated in 40% and 70% yields, respectively with two equivalents of the
substrate (Figure 2C). On the other hand, methylene C–H bonds adjacent
to heteroatoms were easily functionalized. For example, ambroxide, a
naturally occurring terpenoid–responsible for the odor of Ambergris, was
selectively trifluoromethylthiolated in high yield.21
To demonstrate the amenability of this mild trifluoromethylthiolation
strategy for late stage synthetic applications, we have subjected bioactive
molecules to our protocol to prepare their SCF3ꢀanalogues (Figure 3). In
all cases, the SCF3ꢀgroup was introduced selectively at the most electronꢀ
rich hydridic C–H bond which are generally more susceptible to metabolic
degradation. Pregabalin, a drug marketed as Lyrica®, is used to treat
epilepsy, neuropathic pain, fibromyalgia, and generalized anxiety disorꢀ
der.23 Steroid derivatives were trifluoromethylthiolated with our reaction
conditions. A derivative of the steroid hormone 3βꢀandrosterone was
trifluoromethylthiolated at the methine position of the side chain. Similarꢀ
ly, SCF3ꢀmodified 3αꢀcholestanꢀ3βꢀacetate was synthesized in very high
selectivity. We have further applied this method for the modification of
amino acids, demonstrating its potential for late stage peptide functionaliꢀ
Heterocycles are prevalent units in a vast majority of the marketed
drugs. We thereby, wanted to test the tolerance of such motifs under our
reaction conditions. To our delight, we found that substrates containing
thiophene, pyridine, thiazole, and quinoline (Fig 2D) cores smoothly gave
their corresponding trifluoromethylthiolated derivatives in high selectivity
and good isolated yields 72ꢀ80%.
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zation. Thus, upon subjecting the protected amino acid leucine NꢀPhthꢀLꢀ
We thank the Deutsche Forschungsgemeinschaft (Leibniz Award and SFB
858) and the Humboldt Foundation (B.M.) for generous financial support.
LeuꢀOMe to the C–S bond forming reaction conditions, the SCF3ꢀ
modified leucine was isolated in 68% yield. At present, further research is
ongoing in our group to selectively put SCF3 group into long chain pepꢀ
tides and protein molecules.
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Figure 3. Direct trifluoromethylthiolation of biologically active mole-
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See supplementary material for experimental details. The site selectivities
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excited state of the photocatalyst and either the substrate or the SCF3–
reagent (See Figure S2). Further, considering that a radical chain is inꢀ
volved in many photochemical processes,15,24 one can assume that
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either by abstracting a hydrogen atom from benzoic acid or from the
substrate. The first scenario can be ruled out by taking into account the
bond dissociation energies (Figure 1B).5,25 The second possibility cannot
unambiguously be ruled out. However, it is less likely to contribute subꢀ
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secondary C–H bonds in this reaction. The selectivity >20:1 for methine
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phthalimidyl radical, which is known to be less selective [3o:2o (C(sp3)–H)
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formation.Visible light promoted photoredox catalysis has recently been
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direct catalytic activation of otherwise unactivated C(sp3)–H bonds folꢀ
lowed by its trifluoromethylthiolation. We could envision its potential to
accomplish other direct unactivated C(sp3)–H functionalizations in near
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ASSOCIATED CONTENT
Supporting Information
Supporting Information is available free of charge via the Internet at
http://pubs.acs.org.
Figure S1, S2, S3 Table S1, S2, Experimental procedures and characteriꢀ
zation data.
AUTHOR INFORMATION
Corresponding Author
glorius@uniꢀmuenster.de
(13) (a) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev.
2011, 40, 102. (b) Prier, C. K.; Rankic, D. A.; MacMillan, D. W.C. Chem.
Rev. 2013, 113, 5322.
(14) Hopkinson, M. N.; GómezꢀSuárez, A.; Teders, M.; Sahoo, B.;
Glorius, F. Angew. Chem. Int. Ed. 2016, 55, 4361.
Author Contributions
‡These authors contributed equally.
ACKNOWLEDGMENT
(15) Cismesia, M. A.; Yoon, T. P. Chem. Sci. 2015, 6, 5426.
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(16) For an example of the formation of 2ꢀaryl benzoyloxy radicals under
(19) Bootwicha, T.; Liu, X.; Pluta, R.; Atodiresei, I.; Rueping, M. Anꢀ
photoredoxꢀpromoted conditions see: N. P. Ramirez, I. Bosque, J. C.
GonzalezꢀGomez, Org. Lett. 2015, 17, 4550.
gew. Chem. Int. Ed. 2013, 52, 12856.
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(20) Due to the well stablished reductive quenching ability of amines in
photoredox catalysis and potential degradation pathways of the electroꢀ
philic PhthꢀSCF3 reagent, protection of such units as well as other nucleoꢀ
philic moieties in our substrates is required to successfully promote the
trifluoromethylthiolation process.
(21) Fahlbusch, K.ꢀG.; Hammerschmidt, F.ꢀJ.; Panten, J.; Pickenhagen,
W.; Schatkowski, D.; Bauer, K.; Garbe, D.; Surburg, H. In Ullmann's
Encyclopedia of Industrial Chemistry; WileyꢀVCH Verlag GmbH & Co.
KGaA: 2000.
(22) Probably because of the comparable oxidation potential of benꢀ
zylic substrates and the benzoate catalyst, the substrates might interfere in
the oxidative quenching step. (a) Merkel, P. B.; Dinnocenzo, J. P.; Farid,
S. J. Org. Chem. 2009, 74,5163.
(17) Redox potentials generally provide a starting place for the evaluation
of the thermodynamic accessibility of a reaction, but solvent effects and
errors in measurements always mean these should be taken only as guideꢀ
lines. Despite the reported potentials showing thermodynamic disfavoraꢀ
bility (Ir*III/IrII = 1.21 V, BzOꢀ/BzO. = 1.4 V), the SternꢀVolmer analysis
clearly shows BzOꢀ to be a good quencher (Ksv = 5.60 × 107 M–1s–1 ),
indicating feasibility of the proposed oxidation. In such cases, where the
potentials are within roughly 200 mV, thermodynamically disfavored
electron transfers can succeed if the two species diffuse away from each
other fast enough, which is apparently the case here. see: (a) Skubi, L. K.;
Blum, T. R.; Yoon, T. P.Chem. Rev. 2016, 116, 10035−10074. (b) Levin,
M. D.; Kim, S.; Toste, F. D. ACS Cent. Sci. 2016, 2, 293−301.
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(18) (a) The competing unimolecular rate of decarboxylation is slow at
(23) Frampton, J. E. CNS Drugs 2014, 28, 835.
(24) Majek, M.; Filace, F.; von Wangelin, A. J. Beilstein J. Org. Chem.
2014, 10, 981.
(25) Arnett, E. M.; Venimadhavan, S.; Amarnath, K. J. Am. Chem. Soc.
1992, 114, 5598.
(26) See Table S2 for the comparison of selectivity with the change in
electronic nature of benzoyloxy radical and source of SCF3 reagents.
(27) Day, J. C.; Govindaraj, N.; McBain, D. S.; Skell, P. S.; Tanko, J.
room temperature k = 2.0 × 106 s–1; See ref (18).
(b) The rate constant for hydrogen abstraction of 4ꢀClC6H4C(O)O• with
cyclohexane is very high (k = 1.2 × 107 M–1 s–1). Moreover, it shows high
selectivity for 3o over 2o secondary (C(sp3)–H) >60), see: Chateauneuf, J.;
Lusztyk, J.; Ingold, K. U. J. Am. Chem. Soc. 1988, 110, 2886.
(18) (b) Fokin, A. A.; Schreiner, P. R. Chem. Rev. 2002, 102, 1551. (c)
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