Generation of Carbocations under Photoredox Catalysis: Electrophilic Aromatic Substitution with 1-Fluoroalkylbenzyl Bromides

Article abstract of DOI:10.1021/acs.orglett.0c03258

A novel Friedel-Crafts-type alkylation of arenes to access valuable 1-fluoroalkyl-1,1-biaryl compounds is established under mild conditions. The key to success is the efficient generation of a destabilized benzylic carbocation intermediate via two consecutive single-electron transfer processes by virtue of visible-light photoredox catalysis. This unique activation pattern avoids using strong Lewis acids and high temperatures that are required for generation of destabilized carbocations in traditional Friedel-Crafts reactions. This protocol demonstrates the first example of photoredox-catalyzed heterolysis of electronically deactivated benzylic C-Br bonds for the formation of destabilized carbocation intermediates.

Full text of DOI:10.1021/acs.orglett.0c03258

pubs.acs.org/OrgLett
Letter
Generation of Carbocations under Photoredox Catalysis:
Electrophilic Aromatic Substitution with 1‑Fluoroalkylbenzyl
Bromides
Cuiwen Kuang, Xin Zhou, Qiqiang Xie, Chuanfa Ni, Yucheng Gu, and Jinbo Hu*
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ABSTRACT: A novel Friedel−Crafts-type alkylation of arenes to access valuable 1-fluoroalkyl-1,1-biaryl compounds is established
under mild conditions. The key to success is the efficient generation of a destabilized benzylic carbocation intermediate via two
consecutive single-electron transfer processes by virtue of visible-light photoredox catalysis. This unique activation pattern avoids
using strong Lewis acids and high temperatures that are required for generation of destabilized carbocations in traditional Friedel−
Crafts reactions. This protocol demonstrates the first example of photoredox-catalyzed heterolysis of electronically deactivated
benzylic C−Br bonds for the formation of destabilized carbocation intermediates.
Scheme 1. Generation of Carbocations by Activation of the
C−X Bond
he applications of fluorine-containing organic molecules
T
in pharmaceuticals and materials1 have attracted much
attention due to their unique physical, chemical, and biological
properties.2 As ubiquity of the 1,1-diaryl motif in drug target3
and the profound changes can be imparted by the introduction
of fluorine-containing moieties, it is of particular interest to
access 1-fluoroalkyl-1,1-diaryl compounds. However, there are
only limited methods available to achieve this goal. The groups
led by Molander, Loh, Tredwell, and Shen demonstrated that
the cross-coupling reactions under nickel or palladium catalysis
represent a powerful strategy to synthesize 1-fluoroalkyl-1,1-
diaryl compounds,4 but the facile β-fluoride elimination of
benzylpalladium intermediates bearing CF2H and CFH2
motifs4c and the lower efficiency with nickel catalysts4a,d
limited their practicability in synthesis. An alternative approach
was reported by Moran and co-workers using a Friedel−Crafts-
type reaction,5 but the functional group tolerance was low
because of the harsh reaction conditions (high temperature
and strong acid).6 Therefore, the development of a new
strategy to synthesize 1-fluoroalkyl-1,1-diaryl compounds with
broad substrate scope and good functional group compatibility
under mild conditions is highly desirable.
amount of a silver salt9 is necessary for the generation of a
destabilized carbocation that is adjacent to an electron-
Received: September 28, 2020
Friedel−Crafts alkylation is a powerful method for the
construction of 1,1-diaryl motifs from benzylic halides.7
However, traditional methods are depending predominantly
on the use of strong acids such as AlCl3 to activate C−X bonds
to deliver the key carbocation intermediate (Scheme 1, pattern
1).8 Moreover, the use of high temperature5 or stoichiometric
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© XXXX American Chemical Society
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Letter
a
withdrawing group. The heterolysis of C−X bond to generate
carbocation intermediates has also been reported under
ultraviolet light (pattern 2)10 or supercritical carbon dioxide
(pattern 3)11 conditions; however, uncontrollable side
reactions and harsh conditions have limited their applications.
Given the facts that carbocations possess diverse reactivity and
are widely utilized in organic synthesis, developing a novel
protocol to forge carbocations, especially the destabilized ones
under mild conditions, is of great significance.
Table 1. Optimization of Reaction Conditions
Recently, remarkable progress has been made in photo-
redox-catalyzed reactions.12 In these reactions, the generation
of radicals reduced from C−X bonds (pattern 4, step i) was
studied extensively,13 but the further oxidation process
between the newly born radicals and photocatalysts was rarely
explored14 (pattern 4, step ii). Based on the roles (both as a
reductant and an oxidant) of a photocatalyst played in a
photoredox-catalyzed reaction, we surmised that a photo-
catalyst-promoted C−X bond heterolysis to generate a
carbocation might be possible via an initial reduction followed
by a subsequent oxidation process (pattern 4). In this regard,
we envisioned that two challenges might exist in the whole
process: (a) the reversed electronic demand on the substrate
during the reduction and oxidation processes is an unmet
challenge15 and (b), with the high reactivity of radical
intermediates, how to avoid the radicals-involved side reactions
(such as homocoupling and hydrogen abstraction) before the
subsequent oxidation by a photocatalyst is another concern.
Despite these difficulties, herein we report our success in the
formation of destabilized carbocations via C−Br bond cleavage
by means of photoredox catalysis, followed by a subsequent
reaction with a variety of arenes (Scheme 1, this work). The
key to success lies in the appropriate electronic density of
substrates and the enough lifetime of radical intermediates (via
the stabilization with an aryl group and the steric hindrance of
the secondary alkyl radical). To the best of our knowledge, this
represents the first example of Friedel−Crafts-type alkylation
reaction between electronically deactivated benzylic bromides
and arenes enabled by photoredox catalysis.
equiv of
additive
(equiv)
3aa
entry
2a
solvent
(%)
6 (%) 7 (%)
1
2
3
4
5
6
7
8
5
5
5
5
5
8
6
2
5
5
5
5
5
5
5
5
ZnF2 (1)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
81
81
74
60
3
91
88
73
91
<5
<5
55
10
12
20
7
9
10
3
3
ZnF2 (0.5)
ZnF2 (0.2)
ZnF2 (0.1)
none
ZnF2 (0.5)
ZnF2 (0.5)
ZnF2 (0.5)
ZnF2 (0.5)
AlF3 (0.5)
TiF4 (0.5)
ZnBr2 (0.5)
MgF2 (0.5)
8
3
7
2
trace
6
trace
3
8
3
24
2
b
9
6
3
10
11
trace
trace
26
trace
trace
2
b
12
b
13
trace
trace
0
trace
trace
1
b
14
b
Li2CO3 (0.5) CH3CN
ZnF2 (0.5)
ZnF2 (0.5)
15
CH2Cl2
1,4-
dioxane
b
16
0
trace
b
17
5
5
5
5
ZnF2 (0.5)
ZnF2 (0.5)
ZnF2 (1)
ZnF2 (1)
DMF
0
90
0
0
7
0
0
0
3
0
0
bc
,
18
19
20
CH3CN
CH3CN
CH3CN
d
e
0
a
Reactions of 1a (0.2 mmol), 2a, Ir(ppy)3 (1 mol %), additive, and
solvent (2 mL) were irradiated by blue LEDs at room temperature for
24 h. Yields were determined by 19F NMR yield with PhOCF3 as an
b
internal standard. ppy = phenylpyridine. 1a (0.25 mmol) in 1 mL of
solvent. 0.5 mol % of Ir(ppy)3. Without Ir(ppy)3. Without blue
LED irradiation.
c
d
e
Initially, α-trifluoromethyl 4-phenylbenzyl bromide 1a,
which is slow to generate a carbocation by traditional means
due to the strong electron-withdrawing ability of the α-
trifluoromethyl group16 (for details, see Scheme S1, eq 3), and
methoxybenzene 2a were selected as the model substrates to
investigate the photoredox-catalyzed Friedel−Crafts reaction.
To our delight, the para-alkylated product 3aa was observed in
81% yield at room temperature by using Ir(ppy)3 as the
photocatalyst, ZnF2 as the additive, and CH3CN as the solvent
(Table 1, entry 1). Meanwhile, the product 7 with ortho-
selectivity was only detected in 3% yield. The reaction was
accomplished smoothly with a catalytic amount of ZnF2
(entries 2−4), but an extraordinary low reaction rate was
observed without ZnF2 (entry 5), indicating the critical role of
ZnF2 played in the reaction. As Ritter-type reaction product 6
is the major side product, higher efficiency might be obtained
by increasing the loading of 2a or the concentration of the
reactants 1a and 2a (entries 6−9). Gratifyingly, 91% yield was
obtained when the reaction was carried out in higher
concentration (entry 9). Further additive screening revealed
that ZnF2 was the optimal Lewis acidic additive (entries 10−
14). Solvent screening revealed that both a less polar solvent
such as CH2Cl2 or dioxane and a more polar solvent such as
DMF were not suitable, giving the desired product in low or no
yield (entry 15−17). Therefore, acetonitrile was still proved to
be the optimal solvent even though Ritter-type reaction
byproduct 6 was inevitably formed. Notably, decreasing the
photocatalyst loading to 0.5 mol % had no obvious influence
on the yield (entry 18). Finally, the control experiments
without either Ir(ppy)3 or light irradiation (entry 19−20)
revealed that ZnF2 alone could not catalyze the Friedel−Crafts
reaction.
With the optimized conditions in hand (Table 1, entry 18),
various electronically deactivated benzylic bromides were
tested first to evaluate the practicability of this methodology.
With 2a as the model substrate, a variety of α-trifluoromethyl
benzylic bromides 1 bearing electron-rich and electron-neutral
substituents could be transformed to the desired products in
high yields and with good para/ortho selectivity (Scheme 2,
3aa−3ha). However, α- trifluoromethyl benzylic bromide with
an electron-withdrawing group on the phenyl ring (1t) was not
an amenable substrate, giving rise to the homocoupling
product as the main product, and no desired product was
detected (Scheme S3). It is noteworthy that α-difluoromethyl
(CF2H) and α-monofluoromethyl (CH2F) groups were also
amenable to this reaction, affording the arylation products
(3ia−3ma; these are difficult to prepare by other methods4) in
moderate to high yields. Remarkably, apart from fluorinated
B
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a
a
Scheme 2. Scope of Benzyl Bromides
Scheme 3. Scope of Arenes
a
Reactions of 1 (0.5 mmol), 2 (5 equiv), ZnF2 (0.5 equiv), Ir(ppy)3
a
(0.5 mol %) and CH3CN (2 mL) were irradiated by blue LEDs at
Reactions of 1 (0.5 mmol), 2 (5 equiv), ZnF2 (0.5 equiv), Ir(ppy)3
(0.5 mol %), and CH3CN (2 mL) were irradiated by blue LEDs at
room temperature for 24 h. The para-/ortho-isomer ratio of isolated
products is shown in parentheses. For those without an isomer ratio,
b
room temperature for 24 h. Ts = p-toluenesulfonyl. 1 mL of p-xylene.
c
The para/meta regioisomer ratio of isolated products is shown in
parentheses. For those without an isomer ratio, only the para-isomer
was isolated.
b
only the para-isomer was isolated. PMP = 4-methoxyphenyl. 6 h,
Ir(ppy)3 (0.2 mol %). 12 h. No reaction without Ir(ppy)3. Yield
determined by H NMR without Ir(ppy)3 is shown in parentheses.
c
d
e
1
was observed; however, under traditional Friedel−Crafts
conditions using AlCl3 as Lewis acid, selective arylation of
relatively electron rich primary benzylic bromide to form 4b
was observed (Scheme 4). This orthogonal reactivity indicates
methyl groups, the benzylic bromides bearing other electron-
withdrawing functionalities such as CN (3na) and COOMe
(3oa−3pa), adjacent to the benzylic carbon, underwent
reactions smoothly. Furthermore, electron-rich α-methyl 4-
phenylbenzyl bromide 1q was also a viable substrate, leading to
the desired product 3qa in 74% yield; however, the control
experiment in the absence of the photocatalyst Ir(ppy)3
supports the important role of ZnF2. Interestingly, 4-phenyl-
benzyl bromide 1r remains mostly under the present reaction
conditions (for more discussions, see Scheme S4).
Scheme 4. Orthogonal Transformation of Electronically
Biased Benzyl Bromides
Next, our attention was turned to the scope of arenes with
1a as a model substrate (Scheme 3). Generally, electron-rich
arenes could provide the products smoothly (3ab−ah). C-
Alkylation products were formed in good yields and with good
selectivity with phenols (3af and 3ag). Amides, which are
usually incompatible with traditional Friedel−Crafts reac-
tions5,6 because of the strong coordination of amides to
Lewis acids, were amenable to the current reaction (3af and
3ag), highlighting the mildness of our new method.
As a normal benzylic bromide such as 4-phenylbenzyl
bromide was not reactive under photoredox-catalyzed
conditions and destabilized benzylic carbocation was difficult
to generate under traditional Friedel−Crafts conditions (see
Schemes S1 and S4), we surmised that orthogonal trans-
formation of the ambident substrate that contains electroni-
cally biased benzylic bromide might be possible. As expected,
when 1s was subjected to the photoredox-catalyzed conditions,
selective arylation of deactivated benzylic bromide to give 4a
that our photoredox catalyzed Friedel−Crafts alkylation is
suitable for electron-deficient benzyl bromides, while tradi-
tional Friedel−Crafts conditions prefer less electron-deficient
benzyl bromides.
To gain mechanistic understandings of the reaction, a series
of experiments were conducted (Schemes 5 and 6 and the
Supporting Information). When the reaction was carried out in
the presence of TEMPO as a radical scavenger, no desired
product 3aa was formed and product 5a was detected in 86%
yield (Scheme 5, eq 1), suggesting the presence of benzylic
radical intermediate. When 2-propanol or fluoride was used
instead of p-methoxybenzene, the corresponding product 5b or
C
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Scheme 5. Mechanistic Studies
Scheme 7. Proposed Mechanism
Scheme 6. Role of ZnF2
regenerates the [IrIII] catalyst and produce the key carbocation
intermediates, which are separated with bromide by the
solvent. Capture of bromide by ZnF2 inhibits the recombina-
tion of carbocations with bromide, thus increasing the reaction
rate. The carbocations add to arenes to give the desired
products after deprotonation. Finally, reaction of [ZnF2Br]−
with H+ regenerates the ZnF2 catalyst.18
In conclusion, a new method to generate deactivated
carbocations, which is previously difficult to access, for
Friedel−Crafts-type alkylation of electron-rich arenes has
been developed under mild conditions (at room temperature
and without strong acid). A myriad of structurally diverse 1-
fluoroalkyl-1,1-diarylmethanes can be smoothly obtained,
which are useful scaffolds in drug development. The key to
success is the generation of deactivate carbocation inter-
mediates via C−Br bond heterolysis, which is enabled by two
consecutive single-electron transfer processes by virtue of
photoredox catalysis. Our protocol not only provides a novel
method for the formation of deactivated carbocation
intermediates, but also demonstrates the new application of
photoredox catalysis from radical generation to carbocation
generation. Further efforts to extend the deactivated
carbocation chemistry and make use of the unique activation
pattern under photoredox catalysis in carbocation formation
are currently ongoing in our laboratory.
5c was isolated in 93% (Scheme 5, eq 2) and 20% yield
(Scheme 5, eq 3), respectively, suggesting the presence of
benzylic carbocation intermediate (for more detailed dis-
cussions, see Scheme S6).
The role of ZnF2 was also investigated (Scheme 6; for
details, see the Supporting Information). When triethylamine
was used instead of ZnF2, the radical homocoupling product 8
was formed in 79% yield, and when CsF was used instead of
ZnF2, the desired product 3aa was formed in 31% yield
(Scheme 6a). These results indicate that ZnF2 was not
essential for the generation of both benzylic radical and
benzylic carbocation. In the absence of ZnF2, the rate of
transformation of 1a to 3aa was quite low, and adding 0.2
equiv of ZnF2 enhanced the rate significantly. However,
addition of 1.0 equiv of NaBr decreased the reaction rate until
more amount of ZnF2 was added (Scheme 6b). These data
suggest that ZnF2 may function as a bromide anion scavenger,
preventing the recombination of bromide anion and the newly
generated carbocation.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03258.
Detailed experimental procedures, characterization data,
1
and copies of H, 19F, and 13C NMR spectra of new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
On the basis of mechanistic studies, a possible mechanism is
proposed (Scheme 7).17 For substrates in which FG = EDG
(1q), ZnF2 itself is enough for the generation of benzylic
cation. For substrate in which FG = H (1r), because of the
absence of α-electron-withdrawing group, reduction of benzylic
bromide failed, leading to no desired product. For substrates in
which FG = EWG, reduction of this type of benzylic bromides
by excited [IrIII]* gives radical anions, which decompose to
radicals and bromide ion. Oxidation of the radicals by [IrIV]
Jinbo Hu − Key Laboratory of Organofluorine Chemistry, Center
for Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, Shanghai 200032, China; orcid.org/
0000-0003-3537-0207; Email: jinbohu@sioc.ac.cn
Authors
Cuiwen Kuang − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai Institute
of Organic Chemistry, Shanghai 200032, China
D
https://dx.doi.org/10.1021/acs.orglett.0c03258
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Letter
Xin Zhou − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai Institute
of Organic Chemistry, Shanghai 200032, China
Qiqiang Xie − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai Institute
of Organic Chemistry, Shanghai 200032, China
Chuanfa Ni − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai Institute
of Organic Chemistry, Shanghai 200032, China
Yucheng Gu − Syngenta, Jealott’s Hill International Research
Centre, Bracknell, Berkshire RG42 6EY, U.K.; orcid.org/
0000-0002-6400-6167
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03258
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by the National Key Research and
Development Program of China (2016YFB0101200), the
National Natural Science Foundation of China (21632009
and 21421002), the Key Programs of the Chinese Academy of
Sciences (KGZD-EW-T08), the Key Research Program of
Frontier Sciences of CAS (QYZDJ-SSW-SLH049), and
Shanghai Science and Technology Program (18JC1410601).
C.K. acknowledges financial support from a Syngenta Student
Fellowship.
DEDICATION
■
This paper is dedicated to Professor Youyou Tu, the 2015
Nobel Prize laureate of physiology or medicine, on the
occasion of her 90th birthday.
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E
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Schmalzbauer, M.; Ghosh, T.; Konig, B. Anthraquinones as
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(14) Although similar protocols were reported, the SET reduction
and SET oxidation processes did not take place on the same carbon
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(15) The reduction process prefers electron-deficient substrates,
while the oxidation process prefers electron-rich ones. Therefore, it is
generally difficult to oxidize a radical (in situ generated by reduction)
to give a carbocation species. For example, an electron-deficient
radical reduced from 1t (Scheme S3) can not be oxidized (Scheme
1d, step ii), and 1r (Scheme S4) can not be reduced to a radical
(Scheme 1d, step i).
(16) α-CF3 for α-CH3 substitution causes a 105−109-fold decrease in
the rate constant for solvolysis. (a) Richard, J. P. Aromatic
Substitution Reactions of Amines with Ring-substituted 1-Phenyl-
2,2,2-trifluoroethyl Carbocations. J. Am. Chem. Soc. 1989, 111, 6735−
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6744. (b) Allen, A. D.; Ambidge, C.; Che, C.; Micheal, H.; Muir, R. J.;
Tidwell, T. T. Solvolysis of 1-Aryl-2,2,2-trifluoroethyl Sulfonates.
Kinetic and Stereochemical Effects in the Generation of Highly
Electron-deficient Carbocations. J. Am. Chem. Soc. 1983, 105, 2343−
2350.
(17) For more discussion on ruling out other pathways, see the
Supporting Information.
(18) There are two possible catalytic cycles for ZnF2: [ZnF2Br]−/
ZnF2 or [ZnF2Br2]2−/ [ZnF2Br]−. One of them is illustrated in
Scheme 7.
F
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