Selective C-F Functionalization of Unactivated Trifluoromethylarenes

Article abstract of DOI:10.1021/jacs.9b06004

Fluorinated organic molecules are pervasive within the pharmaceutical and agrochemical industries due to the range of structural and physicochemical properties that fluorine imparts. Currently, the most abundant methods for the synthesis of the aryl-CF₂ functionality have relied on the deoxyfluorination of ketones and aldehydes using expensive and poorly atom economical reagents. Here, we report a general method for the synthesis of aryl-CF₂R and aryl-CF₂H compounds through activation of the corresponding trifluoromethyl arene precursors. This strategy is enabled by an endergonic electron transfer event that provides access to arene radical anions that lie outside of the catalyst reduction potential. Fragmentation of these reactive intermediates delivers difluorobenzylic radicals that can be intercepted by abundant alkene feedstocks or a hydrogen atom to provide a diverse array of difluoalkylaromatics.

Full text of DOI:10.1021/jacs.9b06004

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Article
Selective C–F Functionalization of Unactivated Trifluoromethylarenes
David B. Vogt, Ciaran P. Seath, Hengbin Wang, and Nathan T. Jui
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b06004 • Publication Date (Web): 01 Aug 2019
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Selective C–F Functionalization of Unactivated Trifluoromethylarenes
David B. Vogt, Ciaran P. Seath, Hengbin Wang, Nathan T. Jui*
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Department of Chemistry and Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA
ABSTRACT: Fluorinated organic molecules are pervasive within the pharmaceutical and agrochemical industries due to the range
of structural and physicochemical properties that fluorine imparts. To date, the most abundant methods for the synthesis of the aryl
CF2–functionality have relied on the deoxyfluorination of ketones and aldehydes using expensive and poorly atom economical
reagents. Here, we report a general method for the synthesis of aryl–CF2R and aryl–CF2H compounds through activation of the
corresponding trifluoromethyl arene precursors. This strategy is enabled by an endergonic electron transfer event which provides
access to arene radical anions that lie outside of the catalyst reduction potential. Fragmentation of these reactive intermediates
delivers difluorobenzylic radicals that can be intercepted by abundant alkene feedstocks or a hydrogen atom to provide broad
structural diversity.
Introduction. The trifluoromethylaromatic (Ar–CF3) motif is
routinely utilized in drug and agrochemical design because its
incorporation can significantly alter the properties of a given
biologically active small molecule.1–4 Accordingly, a number
of methods have been reported over the past decade that
enable the efficient construction of Ar–CF3 compounds.5–10
Although trifluoromethyl units are traditionally unreactive, we
recently became interested in selective manipulation of these
compounds through a radical anion-based mechanism for
carbon–fluorine (C–F) bond cleavage. We envisioned that the
resulting radical intermediates could serve as precursors to a
number of valuable fluorinated scaffolds, including
difluoroalkyl aromatics (isosteres for aryl ethers and aryl
ketones)11 and difluoromethyl arenes (lipophilic hydrogen
bond donors).12–16 These difluorobenzylic arrays have emerged
as important components of bioactive small molecules (two of
which are shown in Figure 1). The direct molecular editing of
trifluoromethylaromatics in this way would offer a valuable
complement to technologies that grant access to these
difluorinated motifs through construction of the CAryl–CF2R/H
bond.17–23
defluorofunctionalization of specific substrate classes, a
general approach to Ar–CF3 functionalization remains elusive.
Our strategy is mechanistically founded on recent work
from our group35 and König’s,36 where the use of highly
reducing photoredox catalysts resulted in partial defluorination
of activated trifluoromethylaromatic substrates (Figure 2),
under irradiation with visible light. In our method, single
electron transfer (SET) from an organic photoredox catalyst to
the aryl substrate is followed by C–F cleavage to deliver
difluorobenzylic radicals that display unique reactivity
profiles. This system, ultimately propelled by oxidation of
formate to CO2, effectively performs mono-defluoroalkylation
reactions with a wide range of unactivated olefins as alkyl
sources. However, the utility of both of these systems is
limited by the requirement for electronic activation of the
substrates. More specifically, successful reaction has only
been demonstrated
Although reductive activation of the C–F bonds in this
substrate class can be accomplished using a range of
approaches (e.g., electrochemical reduction,24,25 low-valent
metals,26–28 or frustrated Lewis pairs29,30), preventing
exhaustive defluorination (thereby bypassing valuable di- and
mono-fluorinated intermediates) remains
a
significant
synthetic problem. This is due, in part, to the fact that C–F
bond strength decreases as defluorination proceeds.31
Troupel32 and Lalic33 reported two different systems for
interception of anionic difluorobenzylic species through
trapping with carbonyl-based electrophiles. In addition,
Prakash reported a Mg0-based system for hydrodefluorination
(HDF) of bis(trifluoromethyl)benzene derivatives.26 Yoshida
and Hosoya recently described an intermolecular coupling of
trifluoromethyl arenes that contain ortho-silyl groups with
allyl silanes, which operates through a cationic mechanism.34
While
these
systems
allow
for
selective
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Figure 1. Molecular Editing of Ar–CF3 Groups via Catalytic C–F
Functionalization.
unactivated trifluoromethylaromatics. We show that these
difluorobenzylic radical intermediates can be utilized
selectively in both alkylation and reduction processes.
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Results and Discussion. We began our study by examining
the reaction of benzotrifluoride (Ph–CF3) with 3-buten-1-ol to
afford the defluoroalkylation (DFA) product 1 (shown in
Scheme 1). After slight modification of our initially reported
conditions, we evaluated a series of photoredox catalysts, a
selection of which are shown in Scheme 1. While N-
phenylphenothiazine (PTH, P1) was ineffective at room
temperature, the use of P2–P4 afforded the desired product to
varying degrees (up to 31% yield after 24 h). Increasing
reaction temperature resulted in significantly improved yields
of the desired linear alkylation product. The most effective
catalyst (P3, developed by Miyake for organic atom-transfer
radical polymerization)37 has been reported to be highly
absorbent in the visible spectrum (λmax = 388 nm, max = 26635
M-1cm-1) with a 98% ISC efficiency to a long-lived triplet
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*
excited state that is strongly reducing (E1/2 = –1.70 V vs.
SCE).38 The use of P3 (2 mol%) at 100 °C resulted in 89%
yield of 1, as determined by NMR. Interestingly, for the
organic SET catalysts (P1, P3, P4), reaction progress is not
strongly correlated with reduction potential of the catalyst.
Rather, conversion at higher temperatures is more closely
related to excited-state lifetime. This effect is most
pronounced through the use of P4 in this process, because it is
significantly less reducing than P1, but equally effective at
high temperature.
Figure 2. Radical C–F Functionalization of Ar–CF3 Substrates via
Photoredox Catalysis.
for trifluoromethylaromatics that contain auxiliary electron-
withdrawing groups (e.g –CF3, –CN, –SO2NH2). Here, we
describe the development of conditions that overcome this
limitation, thus enabling controlled C–F functionalization of
Scheme 1. Activation of Stable C–F Bonds by Single Electron Transfer Using Photoredox Catalysisa
aReaction conditions: benzotrifluoride (0.25 mmol), 3-buten-1-ol (1.25 mmol), photoredox catalyst (P1: 10 mol%; P2–P4: 2 mol%),
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potassium formate (0.75 mmol), thiophenol (10 mol%), DMSO (2.5 mL), blue light, 24 h. Yields determined by 19F NMR analysis with
internal standard.
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Table 1. Catalytic Defluoroalkylation (DFA): Scope of Unactivated Trifluoromethylaromatic Substratesa
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aReaction conditions: Ar–CF3 substrate (0.5 mmol), 3-buten-1-ol (2.5 mmol), P3 (2 mol%), potassium formate (1.5 mmol), thiophenol (10
b
mol%), DMSO (5.0 mL), blue light, 100 °C, 24 h, isolated yields given. Reaction conducted with 2.5 mmol of potassium formate.
cReaction conducted at 23 °C. dReaction conducted with 5.0 mmol of olefin.
As shown in Table 1,
a
collection of unactivated
pyridine currently remains outside the scope of this processes;
attempted alkylation reactions largely resulted in picoline
production with only trace amounts of the desired product.
Likewise, while this protocol is effective in activating electron
deficient aromatics (such as those described in our previous
report35), the elevated temperature and more effective catalyst
typically resulted in further defluorination of these substrates.
The functionalization of marketed pharmaceuticals could also
be performed under these conditions to afford derivatives 16–
18 in 61%–73% yield, demonstrating that basic functions,
alcohols, and internal alkenes are well tolerated.
trifluoromethylaromatics could be engaged under these
conditions. In addition to carbon and oxygen-substituted
substrates, arylamine derivatives reacted smoothly to afford
the desired products 2–10 in 44–92% yield. The benzylic
carbinol was cleanly retained, giving alkylation product 11 in
82% yield. Pyridine substrates with trifluoromethyl groups at
the 2- and 3-positions gave rise to 12–15 in 41–78% yield.
These reactions were most effectively performed at room
temperature because the difluoroalkylpyridine products can be
further reductively defluorinated. In fact, 4–trifluoromethyl
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Although these conditions are able to accomplish
challenging redox events, we found that thioethers, sulfoxides,
and sulfones alike were preserved throughout the course of the
reaction without any observable alteration of the sulfur oxida
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Table 2. Scope of Olefinic Coupling Partner for Photocatalytic Difluoroalkylaromatic Synthesisa
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aReaction conditions: benzotrifluoride (3 mL), alkene (0.5 mmol), P3 (2 mol%), potassium formate (2.5 mmol), thiophenol (10 mol%),
b
DMSO (5.0 mL), blue light, 100 °C, 24 h, isolated yields given. Reaction conducted with potassium formate as limiting reagent, yields
determined by 19F NMR analysis with an internal standard.
tion states (19–21, 59–64% yield). To probe the
chemoselectivenature of heterolytic C–X cleavage within a
single π-system, we examined the reactivity of a series of 4-
halogenated benzotrifluorides. From the corresponding radical
anions, cleavage of the aryl C–I, C–Br, and C–Cl bonds (BDE
= 71.6, 80.3, and 95.5 kcal/mol, respectively; see SI for
details) occurred in preference to the stronger benzylic C(sp3)–
F bond (BDE = 118.1 kcal/mol), resulting in mixtures of
protodehalogenation and aryl radical alkylation products.39 In
contrast, the aryl C–F bond (BDE = 127.5 kcal/mol) was
completely preserved, affording 22 in 48% yield (where the
mass balance was comprised of unreacted starting material). In
addition to aryl halides, alkyl halides currently lie outside the
scope of this process where either reductive dehaogenation or
substitution with formate are primary pathways of these
substrates.
In line with our previous report, the olefin scope for
coupling with unactivated trifluoromethylaromatics is broad,
giving a range of difluoroalkylated benzene derivatives from
benzotrifluoride. The use of benzotrifluoride as a precursor to
difluoroalkyl benzene derivatives is attractive because it is
abundantly available at low cost (~ $7/mol) when compared to
conventional reagents that accomplish deoxyfluorination of
aryl ketones (e.g. DAST or Fluolead).40 While the standard
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conditions (5 equiv olefin with limiting Ar–CF3 substrate)
were effective here (see Table 1 and SI for examples), we
found that using a co-solvent quantity (50 equiv) of
benzotrifluoride could be conveniently employed for coupling
of sim
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Scheme 2. Catalytic Defluoroalkylation in the Synthesis of Medicinal Building Blocks.
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ple olefins with acetate, acetal, or Weinreb amide groups
(Table 2: 23–25, 64–78% yield). Other nucleophilic olefins
including the vinyl ether, acetate, amides, and vinyl carbazole
were also effective coupling partners under this protocol (26–
30, 55–95%). -Substitution of aliphatic olefins was also well
tolerated (31, 94% yield). Although these conditions operate at
elevated temperature, decomposition through saponification or
hydrolysis pathways was not observed. Ethylene, propylene,
isobutylene, and 2-methyl-2-butene) are attractive 2-, 3-, 4-,
and 5-carbon synthons that are produced on large scale from
hydrocarbon cracking. Performing our reductive DFA method
on Ph-CF3 under 25 psi of ethylene provided the desired
product (33) in 65% yield (based on formate as limiting
reagent). This result was replicated with propylene (34, 68%
yield), isobutylene (35, 87% yield), and 2-methyl-2-butene
(36, 46% yield).
To further illustrate the value of this photocatalytic DFA in
medicinal chemistry, we applied it in the formal syntheses of
bioactive difluoroalkylaromatic molecules (as indicated in
Scheme 2). The patent routes proceed through difluorobenzyl
arene intermediates 37, 40, and 44, all of which were
synthesized via dexoyfluorination of the corresponding
carbonyl compounds. The reported preparation of growth
hormone secretagogue 38 involves construction of a 1,3-
dithiolane intermediate from 39 and 1,2-ethanedithiol.
Subsequent desulfurative fluorination with nitrosonium cation
and Olah’s reagent delivered the geminal difluoride motif.
Ester reduction provided primary alcohol 37 in 45% yield over
3-steps.41 Using this catalytic approach, reaction of Ph–CF3
(50 equiv) with allyl alcohol provided the same intermediate
in a single step (63% yield). The reported synthesis of 41, an
RORγt modulator, also involves a dithiolation/desulfurative
fluorination sequence using ketone 43 as starting material.
Palladium-catalyzed enolate coupling and carboxylic acid
deprotection afforded 40 in 4% yield over 4-steps.42 Under our
conditions, commercial trifluoromethyl arene 42 reacted with
ethylene gas (25 psi) to afford the same intermediate, after
ester saponification, in 63% overall yield. In the reported
synthesis of amine 44, a precursor to 2 adrenergic receptor
agonist 45, DAST was employed for direct deoxyfluorination
of benzylic ketone 47. Phenethylamine 44 was then delivered
via sequential alcohol deprotection, Mitsunobu etherification,
and reduction (4% yield over 5-steps).43 Our alternative route
to this intermediate involves reacting trifluorotoluene (50
equiv) with vinyl ether 46 on 12 mmol scale (1 mol% P3) to
give the corresponding defluoroalkylation product in 92%
yield (4 g). Acidic cleavage of the Boc group gave 44 in 91%
over 2-steps. While deoxyfluorination remains an effective
tool for difluoroalkylaromatic production, these examples
illustrate the potential of this catalytic protocol to streamline
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the preparation of medicinally relevant Ar–CF2R building
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1
blocks.
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Scheme 3. Catalytic or Direct HAT Mechanisms for Defluorofunctionalization of Trifluoromethyl Arenes
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hv
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P3*
P3
PhSH
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H
F
F
F
F
catalytic SET
catalytic HAT
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F
R
SET
SET
HAT
HAT
Ar– CF3 Substrate
Defluoroalkylation
O
P3•+
PhS•
CO2 + M+
MO
H
F
F
F
F
•
F
R
– F
R
•
F
F
•
difluorobenzylic radical
(radical anion)
(alkyl radical)
direct HAT
Selective Monoreduction (limited scope)
Complete Reduction (exhaustive defluorination)
CF2H
F3C
CF2H
CF3
CH3
F
F
Ar
H
Lalic (2016)
Prakash (2017)
Many approaches (e.g. M0, Si+, FLPs)
Hydrodefluorination
Scheme
3
shows our proposed mechanism for this
quench the excited state). Although the concentration of
radical anion intermediate is low under these conditions,
fluoride expulsion provides a thermodynamic driving force for
radical formation. Indeed, the calculated thermodynamic
profile (details given in the SI) indicates that C–F bond-
elongation from benzotrifluoride radical anion is essentially
barrierless (<3 kCal/mol). Taken together, these results
indicate that, although substrate reduction is a critical step
within this pathway, mesolytic cleavage acts as the primary
determinant in radical formation.
We questioned whether the radical intermediates that are
accessible under this paradigm could be generally utilized in
the formation of other bonds. Of particular interest to us, was
the idea that interception of this species with a hydrogen atom
would grant access to the corresponding difluoromethyl arene
(Ar–CF2H). Selective HDF of trifluoromethylaromatics in this
manner would offer a novel approach to this high-value motif.
Summarized in Scheme 3 are existing strategies for
trifluoromethylaromatic HDF. In 2016, Lalic reported a
system that utilizes catalytic amounts of both palladium and
copper in conjunction with triphenylsilane and potassium tert-
butoxide to defluorinate a series of 4-trifluoromethyl biaryl
compounds, generating presumed nucleophilic addition
products to DMF.33 Reaction of these intermediates with tert-
butanol resulted in
transformation, where excitation of P3 with visible light
(through irradiation with commercial blue LEDs) delivers the
excited state reductant P3*. Reversible single electron transfer
to the trifluoromethylarene substrate gives rise to the
corresponding radical anion and the ground state catalyst
radical cation. Formation of the key difluorobenzylic radical
intermediate is then accomplished via thermodynamically
driven mesolytic C–F cleavage event. Regioselective
intermolecular addition to the olefin substrate provides an
alkyl radical adduct that undergoes polarity matched hydrogen
atom transfer (HAT) with thiophenol to furnish the
defluoroalkylation products. Regeneration of both the thiol
and photoredox catalysts occurs with formate as
stoichiometric reductant producing a metal fluoride salt and
CO2 as biproducts.
The findings that are described in this paper were enabled
by the discovery that P3 has the ability to engage unactivated
trifluoromethylaromatics. This is mechanistically interesting
because, in comparison to our initial report in this area (using
P1 and activated Ar–CF3 substrates), this substrate set is more
difficult to reduce and the most effective catalyst (P3) is not as
strongly reducing. Within this context, we propose that the
reversible SET events that are operational here are endergonic
in the forward direction. Consistent with this proposal are
Stern-Volmer excited state quenching studies which revealed
that quenching of P3* with benzotrifluoride occurs to a minute
extent (KSV = 0.02; none of the other reaction components
selective
difluoromethylaromatics. Prakash described that Mg0 can be
utilized in HDF processes of various
production
of
the
corresponding
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with varying
bis(trifluoromethyl)benzene
derivatives
effective for HDF, and that there is a pronounced effect of the
formate counterion on reactivity. The optimized conditions
(indicated in Table 3) again involve the use of P3 (2 mol%)
along with cesium formate (3 equiv) at 50 °C, which delivered
the desired difluoromethylaromatic 48 in 75% isolated yield
without detectable overreduction products. Similarly, the
isomeric trifluoromethyl-bearing acetanilides were good
substrates for this transformation, affording the corresponding
products 49–50 in 55–70% yield. Additionally, the outlined
conditions efficiently engaged compounds bearing only alkyl
substituents in the para- (51, 64% yield), meta- (52, 48%
yield), and ortho- (53, 50% yield), a significant advance over
previously reported technologies. Other oxygen- or nitrogen-
substituted substrates could be reductively defluorinated with
high selectivity for the Ar–CF2H products (54–56, 45–65%
yield).
selectivity for the corresponding reduction products.26 While
appealing for its operational simplicity, this protocol is limited
to bis(trifluoromethyl)benzene substrates, as benzotrifluoride
was reported to be unreactive and more electron-poor systems
underwent exhaustive defluorination (complete reduction of
trifluoromethylaromatics to the corresponding toluene
derivatives). Exhaustive defluorination is the major outcome
within the trifluoromethylaromatic HDF literature, where
electrochemical reduction,25 alkali metal-
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Table 3. Substrate Scope for Hydrodefluorinationa
Hydrodefluorination of 2-, 3-, and 4-trifluoromethyl
substituted pyridines 57–59 was also successful under this
protocol, giving the desired products in acceptable (42–50%)
yield. Much like we observed under DFA conditions, yields of
pyridine-based substrates were bolstered by substitution of
electron donating groups at the 2-position (60–62, 57–64%
yield). Although this substrate set underwent HDF in moderate
yield, these results demonstrate that significant structural
diversity is tolerated by this protocol including acidic protons,
heterocycles, and other reducible groups.
Conclusions. In summary, we have developed a robust
method for the defluoroalkylation and hydrodefluorination of
unactivated trifluorotoluene derivatives using the combination
of two organocatalysts (no metal is required), inexpensive
formate salts, and visible light. The use of Miyake’s
phenoxazine, P3, was key in the development and generality
of these methods. The reductive radical process, driven by the
selective cleavage of a single benzylic C–F bond, can be
employed to access a diverse range of Ar–CF2R and Ar–CF2H
substrates. Mechanistic studies and the development of
additional applications of difluorobenzylic radicals are
underway in our laboratory.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, spectral data, and computational data
(PDF)
aReaction conditions: Ar–CF3 substrate (0.5 mmol), cesium
formate (1.5 mmol), Miyake phenoxazine P3 (2 mol%),
DMSO (5.0 mL), blue light, 50 °C, 24 h; isolated yields given;
parentheses indicate the ratios of Ar–CF2H to Ar–CFH2
products, as determined by NMR analysis of the crude
AUTHOR INFORMATION
Corresponding Author
* njui@emory.edu
Notes
c
reaction mixtures. bReaction run at 23 °C Yield determined
The authors declare no competing financial interest.
by 19F NMR with an internal standard.
ACKNOWLEDGMENT
This project was supported by funds from the National Institutes
of Health (GM129495), and NMR data were collected under
support of the National Science Foundation (CHE-1531620).
reduction,26–28 or Lewis acids29,30 have been reported to
activate these strong C–F bonds.
To evaluate the feasibility of the proposed HDF pathway,
we reacted 2-trifluoromethylacetanilide with P3 and a range of
reductants in DMSO under irradiation with blue LEDs. These
studies (optimization details are given in the supporting
information) revealed that formate reductants are uniquely
ABBREVIATIONS
DFA, defluoroalkylation; HDF, hydrodefluorination.
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