Catalytic Defluoroalkylation of Trifluoromethylaromatics with Unactivated Alkenes

Article abstract of DOI:10.1021/jacs.7b12590

We describe a new catalytic approach to selective functionalization of the strong C-F bonds in trifluoromethylaromatic (Ar-CF₃) systems. In this approach, single electron reduction of Ar-CF₃ substrates (using a photoredox catalyst) r

Full text of DOI:10.1021/jacs.7b12590

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Communication
Catalytic Defluoroalkylation of
Trifluoromethylaromatics with Unactivated Alkenes
Hengbin Wang, and Nathan T. Jui
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b12590 • Publication Date (Web): 19 Dec 2017
Downloaded from http://pubs.acs.org on December 19, 2017
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Catalytic Defluoroalkylation of Trifluoromethylaromatics with
Unactivated Alkenes
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Hengbin Wang and Nathan T. Jui*
Department of Chemistry and Winship Cancer Institute, Emory University, Atlanta, GA 30322
Supporting Information Placeholder
ABSTRACT: We describe a new catalytic approach to selec-
tive functionalization of the strong C–F bonds in trifluoro-
Figure 1. Strategies for defluorinative C–C bond-
formation in trifluoromethylaromatics.
methylaromatic (Ar–CF ) systems. In this approach, single
3
electron reduction of Ar–CF substrates (using a photoredox
3
catalyst) results in difluorobenzylic radical formation through
a C–F cleavage mechanism. These radicals undergo efficient
intermolecular coupling with simple alkenes in a defluoroal-
kylation process where radical termination is accomplished by
a polarity reversal catalyst. This mild catalytic protocol engag-
es a wide range of substrates to give medicinally relevant
fluorinated substructures with complete regiocontrol.
The selective functionalization of strong chemical bonds
is an important goal in chemical synthesis. While
tremendous progress has been made in the manipulation
1
–4
of aryl and alkenyl C–F bonds,
selective
functionalization of aromatic trifluoromethyl groups
remains challenging. Cleavage of the C–F bonds in Ar–
CF3 substrates can be accomplished using
5
,6
7–9
electrochemistry, reducing metals, transition metal
complexes,
10–14
14,15
or main-group Lewis acids.
Although these approaches are diverse in nature, they
are united in their propensities to perform exhaustive
defluorination of the trifluoromethyl unit; in part
because C–F bond strength decreases as defluorination
activation, where single electron reduction could be
generally utilized in the formation and reaction of α,α-
difluorobenzylic radicals. We hypothesized that the use
16
proceeds. In this context, the selective exchange of a
single C–F bond for a C–C bond would be valuable
because it would allow for structural diversification
while retaining benzylic fluorination. Toward this aim,
there are two general approaches (illustrated in Figure 1)
that operate through complementary ionic intermediates.
Périchon detailed electrochemical conditions for α,α-
difluorobenzylic anion formation and subsequent
19,20
of highly reducing photoredox catalysts
would grant
access to this pathway, and that the resulting radical
species could be employed in a number of catalytic
21
processes. Here, we describe the ability of this
approach to perform intermolecular defluorinative
coupling of trifluoromethyl arenes with simple,
unactivated alkenes (Figure 1).
1
7
trapping with carbonyl-based electrophiles.
More
recently, Yoshida and Hosoya described a cationic
intermolecular coupling of trifluoromethyl arenes with
allyl silanes. Because this system operates through
intramolecular fluoride abstraction, it is limited to
substrates that contain an ortho-silyl group. We were
interested in developing a different approach to Ar–CF3
In medicinal chemistry, the introduction of benzylic
difluorination is a powerful strategy for tuning the
properties of a given small molecule. Synthetic
approaches to this motif include deoxyfluorination of
ketones with the indiscriminately reactive reagent
18
22
diaminosulfur trifluoride (DAST), benzylic C–H
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Figure 2. Proposed Mechanism for This Dual Catalytic Defluoroalkylation Process.
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Single Electron Transfer (SET) catalyst
O
Hydrogen Atom Transfer (HAT) catalyst
+ Na+
CO
2
NaO
H
S
S
H
PTH
=
=
CySH
N
PTH+
e– SET – e–
– H• HAT + H•
+
Ph
CyS•
SET
catalytic cycle
HAT
F
F
F
F
H
catalytic cycle
F
3
C
F3C
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F
n-hex
e– SET – e–
CySH
– H• HAT + H•
+
PTH
1
5
hv
PTH*
F
F
F
F
F
n-hex
•
–
F
•
F
3
C
F
3
C
3
F C
F
F
n-hex
•
mesolytic cleavage
1-octene
radical anion 2
electrophilic radical 3
nucleophilic radical 4
2
3
difluorination, and Stephenson’s photocatalytic Smile2s5
consequently delivering electrophilic radical 3.
Intermolecular radical addition to 1-octene would afford
nucleophilic radical 4, which would be polarity matched
for hydrogen atom transfer (HAT) from the electrophilic
polarity reversal catalyst, cyclohexane thiol (CySH,
BDE = 86.8 kCal/mol). This step would concurrently
2
4
rearrangement. In addition, Minisci radical arylation
26
and
strategies have effectively produced this valuable
substructure in modular manner. However,
regioselectivity in radical arylation is largely substrate-
transition
metal-catalyzed
cross-coupling
30
a
31
27
controlled,
and both of these strategies require
deliver the desired defluoroalkylation product 5 and the
•
preparation of a different fluoroalkyl coupling partner
for each difluorobenzylic target. In contrast,
thiyl species CyS . Regeneration of both catalysts by
32
sodium formate (through HAT and SET) would close
both catalytic cycles, liberating carbon dioxide and
sodium fluoride as the only stoichiometric byproducts.
An alternative radical chain mechanism involving
formate radical anion as propagating reductant is also
consistent with our observations.
defluoroalkylation of Ar–CF substrates would permit
3
flexible variation of both the aromatic and alkyl
fragments, where a vast array of simple olefins would
function as alkyl sources. Because radical addition to
simple olefins is a regioselective process that occurs
with high fidelity in the presence of many functional
groups, we anticipated that this system would be useful
for the synthesis of a wide range of complex fluorinated
organics.
This novel dual catalytic approach to Ar–CF3
activation is attractive, in part, because it employs
inexpensive, readily accessible organic catalysts (no
precious metals are required) and consumes light and
formate as stoichiometric reagents. The optimal
conditions for this process utilize the trifluoromethyl
arene as limiting reagent with excess alkene and sodium
formate (3.0 equivalents each), and 10 mol% of each
catalyst at room temperature in aqueous DMSO (5%
Our proposed mechanistic approach to Ar–CF3
defluoroalkylation is shown in Figure 2, where two
different catalysts would operate in concert to
accomplish the transfer of electrons and hydrogen
atoms. Under irradiation by a commercial blue LED,
excitation of the organic photoredox catalyst N-
phenylphenothiazine (PTH), first introduced by Read de
Alaniz and Hawker, would generate the highly reducing
H O (v/v)). Control experiments indicated that both
2
catalysts are required for effective reaction of the
otherwise inert starting materials, as are light and
sodium formate (see SI for details).
28
excited state PTH* (E * = –2.10 V vs. SCE). Single
1/2
electron transfer (SET) to 1,3-bistrifluoromethylbenzene
As illustrated in Table 1, this light-driven system
effectively couples a wide range of unactivated alkene
structures with the bis(trifluoromethyl)aromatic 1 to give
0
29
1
(E
= –2.07 V vs. SCE) would deliver the key
1/2
radical anion 2, as well as the oxidized ground state
+
catalytic species PTH . This electron transfer event was
the
corresponding
defluoroalkylation
products.
studied using Stern-Volmer experiments where
quenching of the excited catalyst (PTH*) was only
observed in the presence of 1 (none of the other
reactants or reagents quenched PTH*). Radical anion 2
would undergo mesolytic cleavage to expel fluoride,
Transformation of monosubstituted, 1,1-disubstituted,
and trisubstituted alkenes gave rise to compounds 5–7 in
good yield (78–85%) with complete regiocontrol. More
nucleophilic olefins like allyltrimethylsilane, ethyl vinyl
ether, and isopropenyl acetate smoothly participated
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Table 1. Dual Catalytic Defluoroalkylation: Substrate Scope
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9
1
1
1
1
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0
a
Reaction conditions: Ar–CF (0.5 mmol), alkene (1.5 mmol), PTH (10 mol%), CySH (10 mol%), HCO Na (1.5–2.0 mmol), 5% (v/v)
3
2
b
c
H O/DMSO (5.0 mL), blue LED, 23 °C, 24 h, isolated yields shown. Reaction was conducted for 48 h. N-(1-Np)-phenothiazine (10
mol%) was used in place of PTH. Reaction was conducted on 0.1 mmol scale
2
d
here (8, 9, 14: 59–86% yield). This method accepts
olefinic coupling partners that contain many important
functional groups, including acetals, Weinreb amides,
carbamates, esters, alcohols, alkyl chlorides, and
carboxylic acids (10–17; 55–87% yield). Radical
addition to the bicyclic terpene β-pinene is accompanied
by ring opening to afford the functionalized cyclohexene
18 (80% yield), which is consistent with the proposed
radical nature of this defluorination. Critically, substrate
activation under this model is guided by reduction
potential rather than C–F bond strength. Because single
electron reduction of these defluoroalkylation (ArCF R)
2
products is more difficult than reduction of the
6
corresponding starting material (ArCF
)
species,
3
selective activation of only one C–F bond was observed
in all cases.
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We then applied this system to the reductive
Notes
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defluoroalkylation of other electron-deficient Ar–CF3
systems, using 3-buten-1-ol as the coupling partner.
Bis(trifluoromethyl)benzenes are good substrates in this
process, regardless of the relative locations of the CF3
groups (19 and 20 were both formed in 80% yield).
Evaluation of a small series of 5-substituted 1,3-
bis(trifluoromethyl)benzene substrates indicated that this
aromatic scaffold could be altered without significant
loss of chemical efficiency (21–23: 60–89% yield).
Trifluoromethylaromatics that bear nonfluorinated
electron-withdrawing groups also undergo regioselective
olefin addition to give the diethylarylphosphonate 24
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This project was supported by funds from Emory Universi-
ty and Winship Cancer Institute. We thank Brooke Andrews
(
Emory) for experimental assistance. This material is based
upon work supported by the National Science Foundation
under CHE (MRI)-1531620.
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(12)
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(
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(
In summary, we have described a catalytic system that
accomplishes selective cleavage of a single C–F bond in
trifluoromethylaromatic substrates. We demonstrate that
this approach delivers novel radical intermediates and
that these intermediates effectively couple with a broad
collection of unactivated alkene subtypes. These
conditions are mild, tolerant of many valuable functional
groups, and provide the desired products with complete
selectivity for the linear isomers. This protocol, driven
by the action of two organic small molecule catalysts,
can be employed in the activation of different
trifluoromethyl aromatic substructures. Mechanistic
studies and the application of this strategy to the
synthesis of other high value product classes are
currently underway in our laboratory.
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AUTHOR INFORMATION
1
991, 95, 4423.
Corresponding Author
(33)
Pan, X.; Fang, C.; Fantin, M.; Malhotra, N.; So, W. Y.; Peteanu,
L. A.; Isse, A. A.; Gennaro, A.; Liu, P.; Matyjaszewski, K. J.
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njui@emory.edu
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F
F
F
F
mild
F
R2
R1
R2
R1
conditions
Ar–CF
3
Simple Alkene
Defluoroalkylation
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