Copper-Catalyzed ipso-Borylation of Fluoroarenes

Article abstract of DOI:10.1021/acscatal.7b01448

ipso-Borylation of fluoroarenes has been achieved using an air-stable copper complex as a catalyst. Mechanistic studies suggest that the reaction proceeds via an S_RN1 mechanism involving a single-electron-transfer (SET) process and not via the typical S_NAr mechanism. This method differs from the previously reported nickel/copper-cocatalyzed system in terms of scope of the substrate and has exhibited good scalability. Double and triple ipso-borylations of several di- and trifluoroarenes have been also achieved efficiently, enhancing the synthetic utility of this method.

Full text of DOI:10.1021/acscatal.7b01448

Article
Copper-Catalyzed ipso-Borylation of Fluoroarenes
Takashi Niwa, Hidenori Ochiai, and Takamitsu Hosoya
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Copper-Catalyzed ipso-Borylation of Fluoroarenes
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Takashi Niwa,* Hidenori Ochiai, and Takamitsu Hosoya*
Chemical Biology Team, Division of Bio-Function Dynamics Imaging, RIKEN Center for Life Science Technologies,
6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan
ABSTRACT: ipso-Borylation of fluoroarenes has been achieved
using an air-stable copper complex as a catalyst. Mechanistic stud-
Cu catalyst
F
Bpin
ies suggest that the reaction proceeds via an SRN1 mechanism in-
volving a single-electron transfer (SET) process and not via the
typical SNAr mechanism. This method differs the previously report-
ed nickel/copper-cocatalyzed system in terms of scope of the sub-
strate and has exhibited good scalability. Double and triple ipso-
R
R
(Bpin)2, CsF
(n = 1–3)
Fn–1
(Bpin)n–1
borylation of several di- and trifluoroarenes have been also achieved efficiently, enhancing the synthetic utility of this method.
KEYWORDS: Copper, Defluoroborylation, Fluoroarene, Arylboron, Single-Electron Transfer, Air-Stable Catalyst
report a novel method for ipso-borylation of fluoroarenes that
INTRODUCTION
is catalyzed by an air-stable copper complex (Scheme 1B).
During the course of our investigation on Ni/Cu-catalyzed
defluoroborylation,5b we unexpectedly found that ipso-
Fluoroarene structures are frequently found in a broad range
of molecules including drugs and organic materials.1 Availa-
bility of fluoroarenes has been significantly expanding with
recent advances in late-stage fluorination reactions.2 The ready
availability of fluoroarenes has stimulated considerable inter-
est in their transformation via C–F bond cleavage.3 This in-
terest arises because cleaving the stable C–F bond is a chal-
lenging issue and late-stage C–F bond derivatization enables
formation of a diverse range of molecules. In particular, ipso-
borylation of fluoroarenes has been attracting much attention
owing to the reliable and versatile organoboron chemistries4
that enable facile diversification for obtaining valuable com-
pounds such as new drug candidates and molecular probes.
borylation
of
4-fluorobiphenyl
(1a)
with
bis(pinacolato)diboron ((Bpin)2, 2a) proceeded in the absence
of the nickel reagent; heating a mixture of 1a (0.2 mmol) and
2a (2 equiv) in the presence of CuI (20 mol %), PCy3 (50
mol %), and CsF (3 equiv) in deoxygenated toluene at 80 °C
for 18 h afforded the desired arylboronic acid pinacol ester 3a
in 40% yield (Table 1, entry 1). This result indicated the pos-
sibility for achieving efficient defluoroborylation using a cop-
per catalyst alone. Whereas copper-catalyzed ipso-borylation
of haloarenes such as iodo- or bromoarenes has already been
reported (Scheme 1A),7 neither the borylation nor other trans-
formation via C–F bond cleavage of fluoroarenes catalyzed by
a copper complex has been reported.8 As copper salts are gen-
erally air-stable and easy to handle, we embarked on an opti-
mization study of this promising and mechanistically interest-
ing transformation.
Scheme 1. Catalytic ipso-Borylation of Haloarenes
A. Previous works on ipso-borylation of haloarenes
Ni or
Ni/Cu cat.
Cu cat.
(X = I, Br)
F
B(OR2)2
X
R1
R1
R1
(B(OR2)2)2
(B(OR2)2)2
B. This work: Cu-catalyzed defluoroborylation
RESULTS AND DISCUSSION
B(OR2)2
Cu catalyst, (B(OR2)2)2
F
R1
R1
Optimization Studies. Extensive screening of the condi-
tions for the reaction between 1a and 2a significantly im-
proved the yield of 3a (Table 1). Whereas changing the phos-
phine ligand from PCy3 to others were ineffective (entries 2–
11), several copper salts, such as CuCl, CuBr, CuF2, CuCl2,
CuBr2, Cu(OAc)2, and Cu(OTf)2, efficiently catalyzed the
defluoroborylation (entries 12–20). In contrast, using CsF as
the base was crucial (entries 21–25 and Table S1). Nonpolar
solvents, such as toluene, benzene, and cyclopentyl methyl
ether, were preferred for this transformation (Table S2). The
• Air-stable catalyst
• Gram-scale synthesis
• Applicable to di- and triborylation
Recently, several groups, including ours, independently re-
ported ipso-borylation reactions of fluoroarenes via C–F bond
cleavage (Scheme 1A);5,6 however, almost all of these meth-
ods utilize a severely air-sensitive low-valent nickel complex
as a catalyst and the substrate scope is still limited. Herein, we
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reaction did not proceed without either the copper salt, phos-
phine ligand, or base (Table 1, entries 26–28).
amount of complex to 2 mol % was still sufficient to obtain 3a
in acceptable yields (entries 1–8). Furthermore, this reaction
was scalable as demonstrated in a decagram scale borylation
of 1a using 5 mol % of CuCl(PCy3)2 with standard grade rea-
gents such as undried CsF and non-deoxygenized toluene (en-
try 5).11 Whereas the amount of CsF could be reduced to 1.2
equiv (entries 9–11), using an excess amount (3 equiv) showed
excellent result with high reproducibility. In some cases dur-
ing the optimization study, we observed generation of a small
amount of hydrodefluorinated biphenyl as a byproduct; how-
ever, 3-borylbiphenyl, a regioisomer of 3a, was not detected,
indicating that a benzyne intermediate was not involved in this
reaction.12 Similar to the Ni/Cu-catalyzed system,5b
bis(neopentyl glycolato)diboron (2b) was unsuitable as the
boron source.
Table 1. Optimization of ligand, copper source and base
CuI (20 mol %)
ligand (50 mol %)
CsF (3 equiv)
F
Bpin
O
O
O
O
+
B
B
toluene
80 °C, 18 h
Ph
Ph
10
11
12
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1a (0.2 mmol)
2a (2 equiv)
3a
entry
1
[Cu]
ligand
PCy3
base yield 3a (%)a
CuI
CuI
CsF
40
2
Ad2P(n-Bu) CsF
12
3
CuI
P(t-Bu)3
P(c-C5H9)3
Xphos
Davephos
P(o-tol)3
PPh3
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
RbF
KF
0
4
CuI
0
Table 2. Further Optimization Using Pre-coordinate com-
plexes
5
CuI
0
6
CuI
6
[Cu] (x mol %)
CsF (y equiv)
F
Bpin
7
CuI
0
O
O
O
O
+
B
B
toluene
80 °C, 18 h
8
CuI
<1
Ph
1a (0.2 mmol)
Ph
2a (2 equiv)
3a
9b
10b
11
12
13
14
CuI
dppf
<1
entry
1
[Cu]
x (mol %) y (equiv)
yield 3a (%)a
>99 (86b)c
CuI
dppbz
IPrAgCl
PCy3
2
CuI
2
[CuCl(PCy3)]2
[CuCl(PCy3)]2
[CuCl(PCy3)]2
[CuCl(PCy3)]2
CuCl(PCy3)2
CuCl(PCy3)2
CuCl(PCy3)2
CuCl(PCy3)2
CuCl(PCy3)2
CuCl(PCy3)2
CuCl(PCy3)2
5
2
3
3
CuBr
CuCl
CuOAc
>99
>99 (95)c
2
89
PCy3
3
1
3
32
PCy3
37
0
4
0.5
5
3
26
5
3
>99 (94, 97b, 92d)c
15 CuPF6(MeCN)4
PCy3
16
17
18
19
20
21
22
23
24
25
26
27
28
Cu(OTf)2
Cu(OAc)2
CuBr2
CuCl2
CuF2
PCy3
>99
83
>99
75
97
0
6
2
3
>99
69
PCy3
7
1
3
PCy3
8
0.5
2
3
33
PCy3
9
2.4
1.2
0.2
>99
82
PCy3
10
11
2
CuCl
PCy3
2
13
CuCl
PCy3
0
b
aYields determined by GC analysis, unless otherwise noted. Y-
c
CuCl
PCy3
NaF
Cs2CO3
CsOPiv
CsF
CsF
–
0
ields for the reaction using 2.97 mmol (511 mg) of 1a. Isolated
yields in parentheses. dYield for the reaction using 49.4 mmol
CuCl
PCy3
0
(8.51 g) of 1a with undried CsF in non-deoxygenated toluene.
CuCl
PCy3
1
–
PCy3
0
Substrate Scope. ipso-Borylation of various fluoroarenes
1 were achieved based on the optimal conditions (Table 3).
Under the standard conditions (Table 2, entry 5, using 0.200
mmol of 1), 4-fluorobiphenyls 1b–f bearing an electron-
donating group at the 4ʹ-position were transformed to the cor-
responding 4-borylbiphenyls 3b–f in high yields (Table 3A).
Notably, borylation of a 4-fluorobiphenyl bearing an electron-
withdrawing group such as 1g, to which the Ni/Cu system was
inapplicable,5b also took place, affording the borylated product
3g in good yield. 1-Fluoronaphthalene (1h), 3-fluorobiphenyl
(1i), and sterically hindered 2-fluorobiphenyl (1j) also partici-
pated in this reaction to afford 3h, 3i, and 3j, respectively.
M o n o a r y l f l u o r i d e s w e r e a l s o s u c c e s s f u l l y
defluoroborylated by increasing the amount of CuCl(PCy3)2
from 5 to 20 mol % (Table 3B). For example, fluorobenzene
(1k) and its derivatives 1l–r with an electron-donating group
CuCl
–
<1
0
CuCl
PCy3
b
aYields determined by GC analysis, unless otherwise noted. Lig-
c
and (25 mol %) was used. Isolated yield for the reaction using 5
mol % Cu of the copper complex with 2.97 mmol (511 mg) of 1a
in parentheses.
Efficient results were also obtained using pre-coordinated
copper complexes, such as [CuCl(PCy3)]2 and CuCl(PCy3)2,
instead of the CuCl/PCy3 system (Table 2). These complexes
were easily prepared on a gram-scale9 and are practically ac-
tive for more than a year without special care in storing,
making this method more practical.10 The use of 5 mol % of
each complex afforded 3a in excellent yields and reducing the
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at the para- or ortho-position were borylated to afford 3k–r in
moderate to good yields. From the reaction of 4-fluorophenyl
phenyl ether (1n), a small amount of para-diborylbenzene 3q
bearing a benzyl ether, allyl ether, acidic amide proton, or π-
conjugated C–C multiple bond were unsuccessful (Figure S1),
substrates 1t–v with nitrogen-containing heterocycles, such as
pyrrole, pyrazole, and indole, were smoothly borylated to af-
ford 3t–v in high yields. Furthermore, defluoroborylation of
blonanserin (1w), a commercial a typical antipsychotic drug
that contains a 2-piperazinylpyridine structure, afforded 3w in
high yield, demonstrating the practicality of this method.
Moreover, other electrophilic (pseudo)halobenzenes such as
chlorobenzene (4) were unfavorable substrates (Tables 3C and
S4), indicating that the copper-catalyzed ipso-borylation of
fluoroarenes proceeds via a different mechanism from the
previously reported transition metal-catalyzed borylation of
haloarenes.5,7,14
Table 3. ipso-Borylation of Various Fluoroarenesa
(Bpin)2 (2a) (2 equiv)
CuCl(PCy3)2 (x mol %)
CsF (3 equiv)
F
1
Bpin
3
R
R
10
11
12
13
14
15
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toluene
80 °C, 24 h
A Cu 5 mol %
Bpin
R = Me (3b) 90%
t-Bu (3c) 77%
OPh (3e) 96%
N-morpholinyl (3f) 96%
CO2t-Bu (3g) 54% (62%)b
OMe (3d) 81% (91%)b
R
Bpin
Scheme 2. ipso-Borylation of Aryl Phenyl Ethers via C–O
Bond Cleavage
Bpin
Bpin
3i 75%
3j 77%
3h 63%
Cu 20 mol %
A. ipso-Borylation of 1n
(Bpin)2 (2a) (2 equiv)
B
CuCl(PCy3)2 (20 mol %)
F
Bpin
Bpin
CsF (3 equiv)
Bpin
Bpin
t-BuO2C
Bpin
+
toluene
80 °C, 24 h
PhO
PhO
pinB
R
R = H (3k) 71%
Me
1n
3n 69%
3q 21%
3s 0% (32%)e
3r 79%
Me (3l) 54%
B. Attempt for ipso-borylation of diphenyl ether
OMe (3m) 42% (71%)c
OPh (3n) 69% (+ 3q 21%)d
OMOM (3o) 36%
NMe2 (3p) 21%
(Bpin)2 (2a) (2 equiv)
CuCl(PCy3)2 (20 mol %)
CsF (3 equiv)
Bpin
Bpin
+
N
Ph2O recovery
N
N
pinB
Bpin (3q) 83%
PhO
(= Ph2O)
toluene
80 °C, 24 h
3k
3t 82%
3u 79%
Et
3k : Ph2O = 2 : 98
(1H NMR ratio in the reaction mixture)
N
Bpin
N
N
C Cu 20 mol %
C. ipso-Borylation of 3n via C–O bond cleavage
(Bpin)2 (2a) (2 equiv)
Cl
CuCl(PCy3)2 (20 mol %)
CsF (3 equiv)
Bpin
Bpin
N
3n 15%
recovery
+
3v 96%
4 11%f
toluene
PhO
pinB
3w 87% from
blonansering
80 °C, 24 h
3n
3q 85%
Bpin
b
aIsolated yields are shown unless otherwise noted. Yields for the
Scheme 3. ipso-Borylation of 1a in the Presence of Other
Arenes
c
reactions using 20 mol % of CuCl(PCy3)2 in parentheses. Yield
for the reaction using 60 mol % of CuCl(PCy3)2 in parentheses.
dYield of byproduct 3q in parentheses. eYield for the reaction
performed in toluene-d8 using 100 mol % of CuCl(PCy3)2 in pa-
rentheses. fYield of 3k was determined by GC analysis. gReaction
was conducted using 0.100 mmol of 1w.
CuCl(PCy3)2 (5 mol %)
CsF (3 equiv)
Additive (30 mol %)
F
Bpin
O
O
O
O
+
B
B
toluene
80 °C, 24 h
Ph
Ph
1a
2a (2 equiv)
3a
Additive:
none >99%
OMe
was also obtained, indicating that borylative C–O bond cleav-
age also took place. Since para-borylated fluorobenzene 1q
was not detected in this reaction mixture, we assumed that
borylative cleavage of the C–F bond of 1n proceeded faster
than that of the C–O bond under these conditions. Indeed,
diphenyl ether was almost inert under the same conditions,
while borylative C–O bond cleavage of 3n proceeded to afford
para-diborylbenzene 3q in high yield (Scheme 2). These re-
sults indicate that the boryl group at the 4ʹ-position accelerated
C–O bond cleavage. Similarly, defluoroborylation of 1q took
place smoothly to give para-diborylbenzene 3q in high yield.
An attempt to defluoroborylate meta-fluorobenzoate 1s, which
has an electron-withdrawing group directly attached to the
fluoroarene ring, was unsuccessful, indicating the significantly
low reactivity of electron-deficient fluoroarenes; however,
performing the reaction of 1s in toluene-d8 using an equimolar
amount of CuCl(PCy3)2 provided the borylated product 3s in
low yield (Table S3).13 Whereas the borylation of fluoroarenes
anisole >99% naphthalene 48%
pyrene 52%
CF3
CF3
F3C
trifluoromethylbenzene
21%
1,4-bis(trifluoromethyl)benzene
<1%
Mechanistic Considerations. Since ipso-borylation of
electron-deficient fluoroarenes proceeds much slower than that
of electron-neutral ones, the reaction is unlikely to occur via
the typical SNAr mechanism.15 Other results obtained from
experiments performed to gain insights into the reaction
mechanism also support this idea. For example,
defluoroborylation of 1a was significantly inhibited by adding
a catalytic amount of an extensively π-conjugated arene, such
as naphthalene or pyrene, or an electron-deficient arene, such
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as benzotrifluoride and 1,4-bis(trifluoromethyl)benzene
because of its large size that is preferable to stabilize anion
(Scheme 3), suggesting the involvement of single-electron
transfer (SET) process.16,17 This agrees with the high reactivity
observed for fluoroarenes with an extended π-conjugated sys-
tem such as biaryl fluorides. Furthermore, addition of Gal-
vinoxyl free radical did not affect the borylation of 1a, indicat-
ing that a free radical species was not generated throughout the
transformation (Scheme 4A and Table S5). Indeed, a radical
clock experiment using 3-(3-butenyl)-4-fluorobiphenyl (1x)
did not afford an intramolecularly cyclized product such as 3xʹ
and instead borylarene 3x was obtained in good yield (Scheme
4B).
radical species such as C and D. Potential interaction between
the boron atom of the borylcopper(I) species A and the fluo-
rine atom of the substrates,22 as well as significant electro-
philicity of the ipso-carbon of fluoroarenes,23 explains the
superior reactivity of fluoroarenes when compared with that of
chlorobenzene observed in this reaction. The considerably
slow reaction observed in the borylation of electron-deficient
fluoroarene 1s indicated that the rate-determining step was
involved in the C–F bond cleavage step (C + A to D + E),
wherein the anion radical C was stabilized by the electron-
withdrawing group.
To elucidate the involvement of the SET process, we con-
ducted several experiments. For example, a competitive reac-
tion between 1e and 1g, in which the preferential consumption
of 1g was observed, indicated that electron-deficient
fluoroarenes are the favored substrates for this reaction
(Scheme 6). This result is in stark contrast to that observed in
the borylation for each substrate performed independently,
wherein electron-rich 1e reacted more smoothly than electron-
deficient 1g (Table 3A). These contradictory results can be
explained by the hypothetical mechanism, where the reaction
of fluoroarene 1 starts from the SET process; in the competi-
tive reaction between 1e and 1g, more electron-deficient 1g
favorably accepts one electron from the borylcopper(I) A to
generate the corresponding anion radical selectively, affording
the defluoroborylated product 3g and leaving 1e untouched.
10
11
12
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Scheme 4. Mechanistic Experiments Conducted to Investi-
gate the Involvement of Radical Intermediates
A Effect of addition of radical scavenger
Additive:
(Bpin)2 (2a) (2 equiv)
t-Bu
t-Bu
CuCl(PCy3)2 (2 mol %)
CsF (3 equiv)
Additive (30 mol %)
F
Bpin
O
O•
t-Bu
t-Bu
toluene, 80 °C, 24 h
87% (GC yield)
Ph
Ph
Galvinoxyl free radical
1a
3a
B
Radical clock experiment
pinB
(Bpin)2 (2a) (2 equiv)
CuCl(PCy3)2 (20 mol %)
CsF (3 equiv)
Bpin
F
Ph
Ph
Ph
toluene, 80 °C, 24 h
1x
3x 63%
3x' 0%
Scheme 6. Competition Experiment
Scheme 5. Plausible Reaction Mechanism
Bpin
F
F
R
1
–
F
Cs+
Bpin
PhO
LCuI Bpin (A) (+ CsF)
F
(Bpin)2 (2a) (100 µmol)
CuCl(PCy3)2 (10 µmol)
PhO
3e not observed
(1e 100 µmol recovered)
SET
G
[LCuII Bpin]+ (B) (+ F–)
1e 100 µmol
CsF (600 µmol)
+
+
CsF
Bpin
F
toluene
80 °C, 24 h
Bpin
3
F
LCuI Bpin
F
Bpin
F
R
Cs+
R
C
A
t-BuO2C
t-BuO2C
1g 100 µmol
3g 41.8 µmol
(1g 58.8 µmol recovered)
F
1
Bpin
D
LCuI
F
(Bpin)2
2a
Cs+
R
R
E
A spectroscopic analysis of the reaction mixtures also of-
fered us further insight into the reaction mechanism of
defluoroborylation. We focused on the color of the reaction
mixture; in the cases that the reaction proceeded successfully,
the colorless suspension gradually turned to dark red when the
reaction mixture was heated.24 The UV-visible absorption
analysis of a mixture of CuCl(PCy3)2 (1 equiv), (Bpin)2 (4
equiv), CsF (6 equiv), and 4-fluorobiphenyl (1a, 1 equiv) in
toluene, which was measured after heating for 3 h at 80 °C,
gave a spectrum with a weak peak of λmax at 572 nm (Figure 1,
green line). We assumed that this peak corresponded to a cop-
per(II) species, such as B, that was generated in the mixture
via the oxidation of the borylcopper(I) species A (Scheme 5).
The intensity of this peak observed at almost the same λmax
largely increased when 1,4-bis(trifluoromethyl)benzene was
added to the mixture instead of 1a (Figure 1, red line), indicat-
ing that a copper(II) species was generated more efficiently in
this case. This result was consistent with the significant inhibi-
tory effect of electron-deficient arenes on the defluoroboryla-
tion (Scheme 3), which was probably caused by the retardation
On the basis of these results, we currently consider that the
defluoroborylation proceeds via an SRN1 mechanism (Scheme
5).18,19 In this scheme, fluoroarene 1 reversibly accepts an elec-
tron, likely transferred from a borylcopper(I) species A gener-
ated in situ, to give an anion radical form of fluoroarene C
with copper(II) complex B.20 The subsequent nucleophilic
substitution of C with a borylcopper(I) species A affords an
anion radical of borylarene D via C–F bond cleavage, which
then returns the electron to fluoroarene 1 to regenerate C and
afford borylarene 3. Borylcopper(I) A is catalytically generat-
ed via metathesis between a fluorocopper(I) complex E and
diboron 2a to afford fluoroboronate F, which in turn reacts
with CsF to give cesium difluoroborate G. This agrees with
the experimental result that a slightly excess amount of CsF is
essential to achieve efficient borylation (Table 2, entries 10
and 11). The fluoride anion could also accelerate the SET pro-
cess (1 + A to B + C) by stabilizing the copper(II) species B.21
Further, the ineffectiveness of metal fluorides other than CsF
(Table 1) suggests partial contribution of the cesium cation
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of the SET process by irreversible oxidation of the
triborylbenzene, 3ab and 3ac, respectively, were efficiently
prepared via the triple ipso-borylation of the corresponding
trifluorobenzenes using three times the amounts of reagents.
borylcopper(I) species A that terminated or disabled the initia-
tion of the catalytic cycle. A similar color change of the reac-
tion mixture that showed a characteristic λmax peak at 585 nm
in the UV-visible absorption spectrum was observed when
2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) was added
instead of 1a (Figure 1, yellow line). This result could be at-
tributed to the generation of a piperidin-1-oxycopper(II) spe-
cies via the oxidation of borylcopper(I) complex A by
TEMPO. Although the small-intensity peak of λmax at 572 nm
was observed even in the absence of 1a (Figure 1, blue line),
indicating the generation of a copper(II) species via the dis-
proportionation of the borylcopper(I) species A,25 the in-
creased intensity of the peak of λmax at 572 nm in the presence
of fluoroarene 1a (Figure 1, green line) suggests the involve-
ment of the SET process in the formation of a copper(II) spe-
cies. Further, an electron paramagnetic resonance (EPR) anal-
ysis of several reaction mixtures resulted in the observation of
no significant peak,26 suggesting that a copper(II) species gen-
erated in the borylation reactions exists as a dimer or polymer-
ic form in the reaction mixture.27 We currently consider that
these results suggest the generation of a copper(II) species in
the reaction mixture and support the involvement of the SET
process in the reaction mechanism.
Multi-ipso-borylation
was
inapplicable
to
1,2,3-
trifluorobenzene or tetrafluorobenzenes, which resulted in no
reaction. Nevertheless, because most of reported multi-
defluorinative transformations of polyfluoroarenes are hydro-
defluorination,30 our result demonstrates a unique case for
multifunctionalization of polyfluoroarenes via sequential C–F
bond cleavage.31
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Table 4. Double and Triple Defluoroborylationsa
(Bpin)2 (2a) (2n equiv)
CuCl(PCy3)2 (20n mol %)
CsF (3n equiv)
F
Bpin
toluene
80 °C, 24 h
(n = 2 or 3)
Fn–1
(Bpin)n–1
3
1
Bpin
Bpin
pinB
Bpin
Bpin
pinB
3q 81% (59%)b
Bpin
3y 84%
3z 92%
Bpin
pinB
Bpin
pinB
pinB
Bpin
Bpin
3aa 70%
3ab 87%
3ac 73%
The effect of additives
unsuccessful
examples
F
F
F
F
F
F
F
F
F
1
p-(CF3)2C6H4
TEMPO
CuCl(PCy3)2 (1 equiv)
(Bpin)2 (2a, 4 equiv)
CsF (6 equiv)
Additive (1 equiv)
toluene, 80 °C, 3 h
F
F
F
0.8
0.6
0.4
0.2
0
F
F
F
F-Biph (1a)
none
b
aIsolated yields are shown. Yield for the reactions using 2 equiv
of 2a in parentheses.
UV-visible
spectrum
350
450
550
650
750
wavelength (nm)
CONCLUSIONS
We have demonstrated that ipso-borylation of fluoroarenes
is efficiently catalyzed by an air-stable copper complex.
Mechanistic studies suggest that the reaction proceeds via an
SRN1 mechanism involving the SET process and not via the
typical SNAr mechanism. The method shows a different sub-
strate scope with the previously reported nickel/copper-
cocatalyzed system.5b Good scalability of the method has been
also demonstrated, increasing the options of transformation via
stable C–F bond cleavage. Furthermore, an unexpected gift
has been brought to us; it has allowed for the efficient multi-
ipso-borylation of di- and trifluoroarenes to afford di- and
triborylarenes, which serve as useful building blocks for ex-
tended π-conjugated systems,12a,32 versatile components for
covalent organic frameworks,33 and structural motifs that ex-
hibit phosphorescence in the solid state.34
Figure 1. UV-Visible absorption spectra of the reaction mixtures
containing various additives measured after toluene dilution (1
mM for copper).
Multi-ipso-Borylation of Di- and Trifluoroarenes.
Copper-catalyzed defluoroborylation was applicable to the
synthesis of di- and triborylated arenes from di- and tri-
fluoroarenes (Table 4).28 Encouraged by the successful result
obtained from the ipso-borylation of para-borylated fluoro-
benzene 1q (Table 3B), we examined the double borylation of
1,4-difluorobenzene using two times the amounts of the rea-
gents, affording the desired 1,4-diborylbenzene 3q in high
yield. In this reaction, monoborylated product 1q was not de-
tected, even when the amount of (Bpin)2 (2a) was reduced to 2
equiv. This result indicates that the second borylation took
place faster than the first one, which can be explained by an
increase in the electron density on the aromatic ring after the
first C–F bond cleavage. This shows an opposite trend to the
conventional methods for transition metal-catalyzed C–F bond
functionalization of polyfluoroarenes, wherein the first C–F
bond transformation proceeded fastest.29 The utility of our
method was further demonstrated in diborylation of meta- and
ortho-difluorobenzene, 1y and 1z, and 3,4′-difluorobiphenyl
(1aa), which smoothly afforded diborylarenes 3y, 3z, and 3aa,
respectively, in high yields. Similarly, 1,3,5- and 1,2,4-
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: xxxxxx.
Experimental procedures, characterization for new compounds
including copies of NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
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Rigoli, J. W.; Schomaker, J. M. Organometallics 2015, 34, 4164–
4173.
(8) For defluorocupration of β-fluoro-α,β-unsaturated esters, see:
Yamada, S.; Takahashi, T. Konno T.; Ishihara, T. Chem. Commun.
2007, 3679–3681.
(9) Bowmaker, G. A.; Boyd, S. E.; Hanna, J. V.; Hart, R. D.; Healy,
P. C.; Skelton, B. W.; White, A. H. J. Chem. Soc., Dalton Trans. 2002,
2722–2730.
AUTHOR INFORMATION
Corresponding Authors
*takashi.niwa@riken.jp, *takamitsu.hosoya@riken.jp
Notes
The authors declare no competing financial interest.
(10) Purity of CuCl(PCy3)2 was confirmed by measuring the melt-
ing point (175–177 °C) and a mixed melting point test with a newly
synthesized one.
9
ACKNOWLEDGMENT
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The authors thank Mr. Natsuhiko Sugimura, Dr. Masahiro
Uwamori, and Prof. Masahisa Nakada at Waseda University for
their kind support for the EPR analysis. This research was sup-
ported by JSPS KAKENHI Grant Number 15K05509 (T.N.), the
Project for Cancer Research And Therapeutic Evolution (P–
CREATE) from AMED (T.N.), and Special Postdoctoral Re-
searchers Program Fellowship from RIKEN (H.O.).
(11) Borylation of 1a under open-air conditions did not proceed at
all, suggesting the catalyst poisoning by the oxygen.
(12) For borylmetalation of arynes, see: (a) Yoshida, H.; Okada,
K.; Kawashima, S.; Tanino K.; Ohshita, J. Chem. Commun. 2010, 46,
1763–1765. (b) Yoshida, H.; Kawashima, S.; Takemoto Y.; Okada,
K.; Ohshita, J.; Takaki, K. Angew. Chem., Int. Ed. 2012, 51, 235–238.
(c) Nagashima, Y.; Takita, R.; Yoshida, K.; Hirano, K.; Uchiyama, M.
J. Am. Chem. Soc. 2013, 135, 18730–18733.
(13) We assume that decomposition of borylcopper species via pro-
tonation was avoided by the use of toluene-d8.
(14) In the reactions of p-bromofluorobenzene and p-
fluoroiodobenzene under these conditions, debromo- and de-
iodoborylation proceeded selectively (Scheme S1).
REFERENCES
(1) (a) Swallow, S. In Fluorine in Pharmaceutical and Medicinal
Chemistry: From Biophysical Aspects to Clinical Applications; Gou-
verneur, V.; Müller, K., Ed.; Imperial Collage Press: London, 2012;
pp 141–174. (b) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317,
1881–1886. (c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Chem. Soc. Rev. 2008, 37, 320–330. (d) Wang, J.; Sánchez-Roselló,
M.; Aceña, J. L.; der Pozo, C.; Sorochinsky, A. E.; Fustero, S.; So-
loshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432–2506. (e) Gillis,
E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J.
Med. Chem. 2015, 58, 8315–8359.
(2) For reviews, see: (a) Furuya, T.; Klein, J. E. M. N.; Ritter, T.
Synthesis 2010, 1804–1821. (b) Furuya, T.; Kamlet, A. S.; Ritter, T.
Nature 2011, 473, 470–477. (c) Liang, T.; Neumann, C.; Ritter, T.
Angew. Chem., Int. Ed. 2013, 52, 8214–8264. (d) Campbell, M. G.;
Ritter, T. Org. Process. Res. Dev. 2014, 18, 474–480. (e) Campbell,
M. G.; Ritter, T. Chem. Rev. 2015, 115, 612–633. (f) Neumann, C.;
Ritter, T. Angew. Chem., Int. Ed. 2015, 54, 3216–3221. (g) Cham-
pagne, P. A.; Desroches, J.; Hamel, J.-D.; Vandamme, M.; Paquin, J.-
F. Chem. Rev. 2015, 115, 9073–9174. (h) Sather, A. C.; Buchwald, S.
L. Acc. Chem. Res. 2016, 49, 2146–2157. For recent examples, see:
(i) Neumann, C. N.; Hooker, J. M.; Ritter, T. Nature 2016, 534, 369–
373. (j) Schimler, S. D.; Cismesia, M. A.; Hanley, P. S.; Froese, R.
D.; Jansma, M. J.; Blamd, D. C.; Sanford, M. S. J. Am. Chem. Soc.
2017, 139, 1452–1455.
(3) (a) Jones, W. D. Dalton Trans. 2003, 3991–3995. (b) Amii, H.;
Uneyama, K. Chem. Rev. 2009, 109, 2119–2183. (c) Hughes, R. P.
Eur. J. Inorg. Chem. 2009, 4591–4606. (d) Ahrens, T.; Kohlmann, J.;
Ahrens, M.; Braun, T. Chem. Rev. 2015, 115, 931–972. (e) Chen, W.;
Bakewell, C.; Crimmin, M. R. Synthesis 2017, 49, 810–821.
(4) Boronic Acids: Preparation and Applications in Organic Syn-
thesis, Medicine and Materials, 2nd ed.; Hall, D. G. Ed.; Wiley-VCH:
Weinheim, 2011.
(5) (a) Liu, X.-W.; Echavarren, J.; Zarate, C.; Martin, R. J. Am.
Chem. Soc. 2015, 137, 12470−12473. (b) Niwa, T.; Ochiai, H.;
Watanabe, Y.; Hosoya, T. J. Am. Chem. Soc. 2015, 137, 14313–
14318. (c) Zhou, J.; Kuntze-Fechner, M. W.; Bertermann, R.; Paul, U.
S. D.; Berthel, J. H. J.; Friedrich, A.; Du, Z.; Marder, T. B.; Radius, U.
J. Am. Chem. Soc. 2016, 138, 5250−5253.
(15) Fernández, I.; Frenking, G.; Uggerud, E. J. Org. Chem. 2010,
75, 2971–2980.
(16) Electron-deficient arenes, such as 1,4-dinitrobenzene, have
been used as an anion radical scavenger via reversible electron trans-
fer. See: Rossi, R. A.; Pierini, A. B.; Peñéñory, A. B. Chem. Rev.
2003, 103, 71–167.
1
(17) H and 19F NMR spectra of 1,4-bis(trifluoromethyl)benzene
were unchanged when it was mixed with CuCl(PCy3)2, CsF, and
(Bpin)2 (2a) in toluene-d8, suggesting that inactivation of the catalyst
by π-coordination of the electron-deficient arene on the copper center
is unlikely.
(18) For a review of SRN1 reactions, see ref. 15 and: (a) Rossi, R. A.
Acc. Chem. Res. 1982, 15, 164–170. For recent examples, see: (b)
Shirakawa, E.; Hayashi, Y.; Itoh, K.; Watabe, R.; Uchiyama, N.;
Konagaya, W.; Masui, S.; Hayashi, T. Angew. Chem., Int. Ed. 2012,
51, 218–221. (c) Uchiyama, N.; Shirakawa, E.; Hayashi, T. Chem.
Commun. 2013, 49, 364–366. (d) Shirakawa, E.; Watabe, R.; Mura-
kami, T.; Hayashi, T. Chem. Commun. 2013, 49, 5219–5221. (e)
Haines, B. E.; Wiest, O. J. Org. Chem. 2014, 79, 2771–2774.
(19) For examples of C–F bond cleavage of monofluorobenzene
via SRN1 mechanism, see: (a) Rossi, R. A.; Bunnett, J. F. J. Am. Chem.
Soc. 1972, 94, 683–684. (b) Rossi, R. A.; Bunnett, J. F. J. Org. Chem.
1973, 38, 1407–1410. (c) Rossi, R. A.; Bunnett, J. F. J. Am. Chem.
Soc. 1974, 96, 112–117.
(20) One-electron transfer from an electron-rich copper(I) complex
to iodobenzene is proposed based on DFT analysis. See: Jones, G. O.;
Liu, P.; Houk, K. N.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132,
6205–6213.
(21) Hartwig, J. F. Organotransition Metal Chemistry: From
Bonding to Catalysis; University Science Books; Sausalito, CA, 2010;
pp 200–204.
(22) For the involvement of a B–F interaction assisting C–F bond
cleavage, see: Teltewskoi, M.; Panetier, J. A.; Macgregor, S. A.;
Braun, T. Angew. Chem., Int. Ed. 2010, 49, 3947–3951.
(23) Bartoli, G.; Todesco, P. E. Acc. Chem. Res. 1977, 10, 125–132.
(24) Although deiodoborylation of 4-fluoroiodobenzene proceeded
under the same conditions as those for the ipso-borylation of
fluoroarenes, the color change was not observed (Scheme S2), indi-
cating that the involvement of the SET process and the generation of a
copper(II) species were unlikely.
(25) A UV-visible absorption analysis of a mixture containing a
copper(I) complex, 2a, and CsF in cyclopentyl methyl ether (CPME),
which was measured after heating at 80 °C for 3 h, also gave a spec-
trum with the peak of λmax at 572 nm having the same intensity as that
(6) For photo-induced ipso-borylation of fluoroarenes bearing elec-
tron-donating groups, see: Mfuh, A. M.; Doyle, J. D.; Chhetri, B.;
Arman, H. D.; Larionov, O. V. J. Am. Chem. Soc. 2016, 138, 2985–
2988.
(7) (a) Zhu, W.; Ma, D. Org. Lett. 2006, 8, 261–263. (b) Kleeberg,
C.; Dang, L.; Lin, Z.; Marder, T. B. Angew. Chem., Int. Ed. 2009, 48,
5350–5354. (c) Hoveln, R. V.; Hudson, B. M.; Wedler, H. B.; Bates,
D. M.; Gros, G. L.; Tantillo, D. J.; Schomaker, J. M. J. Am. Chem.
Soc. 2015, 137, 5346–5354. (d) Ando, S.; Matsunaga, H.; Ishizuka, T.
J. Org. Chem. 2015, 80, 9671–9681. (e) Schmid, S. C.; Hoveln, R. V.;
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measured in toluene (Figure S2), suggesting that toluene did not serve
as a key one-electron acceptor in this case.
2013, 355, 632–636. (b) Xiao, J.; Wu, J.; Zhao, W.; Cao. S. J. Fluorine
Chem. 2013, 146, 76–79. (c) Sabater, S.; Mata, J. A.; Peris, E. Nat.
Commun. 2013, 4, 2553. (d) Arévalo, A.; Tlahuext-Aca, A.; Flores-
Alamo, M.; García, J. J. Am. Chem. Soc. 2014, 136, 4634–4639.
(31) Double ipso-borylation at the para-position of 1,2,4,5-C6F4H2
via Ni-catalyzed sequential C–F bond cleavage was reported. See ref.
5c.
(32) (a) Shimizu, M.; Nagao, I.; Tomioka, Y.; Hiyama, T. Angew.
Chem., Int. Ed. 2008, 47, 8096–8099. (b) Shimizu, M.; Nagao, I.;
Tomioka, Y.; Kadowaki, T.; Hiyama, T. Tetrhedron 2011, 67, 8014–
8026. (c) Shimizu, M.; Tomioka, Y.; Nagao, I.; Kadowaki, T.; Hiya-
ma, T. Chem. Asian. J. 2012, 7, 1644–1651. (d) Wu, J.-S.; Lin, C.-T.;
Wang, C.-L.; Cheng, Y.-J.; Hsu, C.-S. Chem. Mater. 2012, 24, 2391–
2399. (e) Togashi, K.; Nomura, S.; Yokoyama, N.; Yasuda, T.;
Adachi, C. J. Mater. Chem. 2012, 22, 20689–20695. (f) Biniek, L.;
Schroeder, B. C.; Donaghey, J. E.; Yaacobi-Gross, N.; Ashraf, R. S.;
Soon, Y. W.; Nielsen, C. B.; Durrant, J. R.; Anthopoulos, T. D.;
McCulloch, I. Macromolecules 2013, 46, 727–735. (g) Lin, Q.-X.; Ho,
T.-L. Tetrahedron 2013, 69, 2996–3001. (h) Pao, Y.-C.; Chen, Y.-L.;
Chen, Y.-T.; Cheng, S.-W.; Lai, Y.-Y.; Huang, W.-C.; Cheng, Y.-J.
Org. Lett. 2014, 16, 5724–5727.
(26) See Supporting Information for the detailed procedure.
(27) Some copper(II)-containing proteins, such as hemocyanin, or
model complexes for their active site were typically undetectable by
the EPR analysis, whereas weak absorbances of 500–600 nm were
observed. See: (a) Freedman, T. B.; Loehr, J. S.; Loehr, T. M. J. Am.
Chem. Soc. 1976, 98, 2809–2815. (b) Kitajima, N.; Fujisawa, K.;
Fujimoto, C.; Moro-oka, Y.; Hashimoto, S.; Kitazawa, T.; Toriumi,
K.; Tatsumi, K.; Nakamura, A. J. Am. Chem. Soc. 1992, 114, 1277–
1291.
(28) The Ni/Cu-cocatalyzed system (Ref 5b) was not effective for
the multiborylation. For example, diborylation of 1,4-difluorobenzene
(1q′) under the optimized conditions using a nickel and copper cata-
lysts resulted in no conversion.
(29) For transition metal-mediated borylation of polyfluoroarenes
or perfluoroalkenes via C–F bond cleavage, see ref 5c and: (a) Lindup,
R. J.; Marder, T. B.; Perutz, R. N.; Whitwood, A. C.; Chem. Commun.
2007, 3664–3666. (b) Braun, T.; Salomon, M. A.; Altenhöner, K.;
Teltewskoi, M.; Hinze, S. Angew. Chem., Int. Ed. 2009, 48, 1818–
1822. (c) Teltewskoi, M.; Panetier, J. A.; Macgregor, S. A.; Braun, T.
Angew. Chem., Int. Ed. 2010, 49, 3947–3951. (d) Kalläne, S. I.;
Teltewskoi, M.; Braun, T.; Braun, B. Organometallics 2015, 34,
1156–1169. (e) Guo, W.-H.; Min, Q.-Q.; Gu, J.-W.; Zhang, X. Angew.
Chem., Int. Ed. 2015, 54, 9075–9078.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(33) For selected reviews, see: (a) Feng, X.; Ding, X.; Jiang, D.
Chem. Soc. Rev. 2012, 41, 6010–6022. (b) Ding, S.-Y.; Wang, W.
Chem. Soc. Rev. 2013, 42, 548–568. (c) Waller, P. J.; Gándara, F.;
Yaghi, O. M. Acc. Chem. Res. 2015, 48, 3053–3063.
(34) Shoji, Y.; Ikabata, Y.; Wang, Q.; Nemoto, D.; Sakamoto, A.;
Tanaka, N.; Seino, J.; Nakai, H.; Fukushima, T. J. Am. Chem. Soc.
2017, 139, 2728–2733.
(30)
Representative
examples
for
catalytic
multi-
hydrodefluorination of polyfluoroarenes, see: (a) Konnick, M. M.;
Bischof, S. M.; Periana, R. A.; Hashiguchi, B. G. Adv. Synth. Catal.
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