Ni/Cu-Catalyzed Defluoroborylation of Fluoroarenes for Diverse C-F Bond Functionalizations

Article abstract of DOI:10.1021/jacs.5b10119

Ni/Cu-catalyzed transformation of fluoroarenes to arylboronic acid pinacol esters via C-F bond cleavage has been achieved. Further versatile derivatization of an arylboronic ester has allowed for the facile two-step conversion of a fluoroarene to diverse functionalized arenes, demonstrating the synthetic utility of the method.

Full text of DOI:10.1021/jacs.5b10119

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Article
Ni/Cu-Catalyzed Defluoroborylation of Fluoroarenes
for Diverse C–F Bond Functionalizations
Takashi Niwa, Hidenori Ochiai, Yasuyoshi Watanabe, and Takamitsu Hosoya
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b10119 • Publication Date (Web): 21 Oct 2015
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Ni/Cu-Catalyzed Defluoroborylation of Fluoroarenes
for Diverse C–F Bond Functionalizations
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Takashi Niwa,* Hidenori Ochiai, Yasuyoshi Watanabe, and Takamitsu Hosoya*
Chemical Biology Team, Division of BioꢀFunction Dynamics Imaging, RIKEN Center for Life Science Technologies,
6ꢀ7ꢀ3 Minatojimaꢀminamimachi, Chuoꢀku, Kobe 650ꢀ0047, Japan
ABSTRACT: Ni/Cuꢀcatalyzed transformation of fluoroarenes to arylboronic acid pinacol esters via C–F bond cleavage has been
achieved. Further versatile derivatization of an arylboronic ester has allowed for the facile twoꢀstep conversion of a fluoroarene to
diverse functionalized arenes, demonstrating the synthetic utility of the method.
presence of a nickel catalyst. Moreover, Tobisu, Chatani, and
INTRODUCTION
coꢀworkers achieved a nickelꢀcatalyzed crossꢀcoupling reacꢀ
tion of monofluoroarenes with arylboronic esters through the
addition of a Lewis acid to enhance the leaving group ability
of the fluoride.14 These reports suggested that using a nickel
catalyst in combination with a highly nucleophilic boron reaꢀ
gent is a promising approach for achieving the desired
defluoroborylation of fluoroarenes. We envisioned that a
borylcopper species, which has previously been used for sevꢀ
eral nucleophilic borylative reactions and demonstrates a
broad functional group tolerance, could serve as an efficient
boron source.15
Carbon–fluorine (C–F) bonds are found in a broad range of
organic molecules, including pharmaceuticals, agrochemicals,
and organic materials.1 Recent advances in lateꢀstage fluorinaꢀ
tion reactions have enabled the facile construction of C–F
bonds, significantly expanding the diversity of available fluoꢀ
rineꢀcontaining compounds.2 In light of the growing imꢀ
portance of C–F bond formation, C–F bond functionalization
has also been attracting considerable interest.3 This is because
transformation through cleavage of significantly stable C–F
bonds is challenging.4 Furthermore, the ready availability of
fluorineꢀcontaining molecules renders them a favorable platꢀ
form for further diversification of synthesizable compounds
through various derivatizations.3,5 As such, fluorineꢀcontaining
compounds are preferred over other halogenated compounds,
as a wider range of potential compounds are available due to
the chemical stability of C–F bonds, which can tolerate variꢀ
ous synthetic transformations.
Scheme 1. Proposed Strategy: Versatile Derivatization of
Fluoroarenes via Defluoroborylation
To achieve a flexible C–F bond functionalization, we develꢀ
oped a method to transform fluoroarenes into arylboronic esꢀ
ters that serve as versatile synthetic intermediates applicable to
a wide spectrum of reliable derivatizations (Scheme 1).6 Reꢀ
cently reported copperꢀmediated ipsoꢀ[18F]fluorination of arylꢀ
boronic esters7 also encouraged us to realize the
defluoroborylation of fluoroarenes. Sequential use of these
reactions was anticipated to greatly expedite the development
of 18Fꢀlabeled probes for positron emission tomography (PET)
imaging.8 We describe herein the transition metalꢀcatalyzed
ipsoꢀborylation of fluoroarenes via C–F bond cleavage, which
has enabled the facile diversification of fluoroarenes.9
The challenge of this method was to cleave a stable C–F
bond while simultaneously forming an easily transformable
C–B bond. When we started working on this project, the
defluoroborylation was limited to reactive fluoroarenes such
as polyfluorinated substrates.3b,10,11 Conversely, C–F bond
cleavage of simple fluoroarenes has often been observed in
crossꢀcoupling reactions using highly reactive nucleophiles,
such as organomagnesium12 or organozinc reagents,13 in the
RESULTS AND DISCUSSION
After extensive screening of reaction conditions using 4ꢀ
fluorobiphenyl (1a) as a model substrate, we discovered an
efficient nickel and copper coꢀcatalyst system16 that suited our
purpose (Tables 1 and S1–S617). Heating the mixture of 1a,
bis(pinacolato)diboron (2a, (Bpin)2, 2.0 equiv), Ni(cod)2 (10
mol %), PCy3 (50 mol %), CuI (20 mol %), and CsF (2.4
equiv) in toluene at 80 °C for 20 h afforded the desired
defluoroborylated product 3a in high yield (entry 1). The use
of copper sources other than CuI led to poor results (entries 2–
5 and 11). Using 3.0 equiv of CsF provided the best result
(entry 6), and the choice of CsF as the base was also crucial
(entries 7–10 and 12). Performing the reaction without PCy3 or
using other ligands instead resulted in poor yields of 3a (entry
13 and Table S117). Furthermore, defluoroborylation of 1a
using bis(neopentyl glycolato)diboron (2b) instead of (Bpin)2
(2a) under the optimal conditions did not afford the borylated
product, which is in stark contrast to a related Ni(0)ꢀcatalyzed
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borylation of fluoroarenes recently reported by Martin and coꢀ
ducing the desired defluoroborylated product (Table 2C and
workers.9
Figure S117).
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Table 1. Optimization of Reaction Conditions
Table 2. Defluoroborylation of Fluoroarenesa
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6
7
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9
entry
1
[Cu]
CuI
base
CsF
CsF
CsF
CsF
CsF
CsF
KF
x
yield 3a (%)a
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2.4
2.4
2.4
2.4
2.4
3.0
3.0
89
2
CuBr
CuCl
CuOAc
CuF2
CuI
5
3
1
4
<1
5
4
6
>99 (99)b
7
CuI
0
0
8
CuI
TBAF 3.0
KOtꢀBu 3.0
Cs2CO3 3.0
9
CuI
<1
0
10
11
12
13c
CuI
none
CuI
CsF
none
CsF
3.0
–
3
0
CuI
3.0
0
aYields determined by GC analysis, unless otherwise noted.
bIsolated yield in parentheses. cReaction performed without PCy3.
The optimal conditions were applicable to other
fluoroarenes (Table 2). Substituted 4ꢀfluorobiaryls, bearing an
electronꢀdonating group at the 4′ꢀposition, participated in the
reaction to afford defluoroborylated products 3b–h in moderꢀ
ate to high yields (Table 2, condition A). Although the C–O
bond in aryl ethers18 or the C–N bond in aniline derivatives19
can potentially be cleaved by Ni(0) complexes, borylation via
C–F bond cleavage proceeded faster in our case, demonstratꢀ
ing high chemoselectivities. Defluoroborylation of 2ꢀ
fluorobiphenyl efficiently provided product 3i, irrespective of
the steric hindrance of the 2ꢀphenyl group. The reaction of 4ꢀ
mesitylphenyl fluoride afforded desired product 3j in a lower
yield than other biaryl fluorides, indicating that substrates with
aIsolated yields are shown. bReaction time was 20 h. cThe yield of
d
3j under condition B (x = 3) in parentheses. The yield of 3k unꢀ
der condition A (x = 1) in parentheses.
Since oxidative addition of electronꢀdeficient haloarenes to
Ni(0) complexes generally proceeds faster than that for elecꢀ
tronꢀrich haloarenes,21 we currently anticipate that the active
catalyst contributing to the C–F bond cleavage is not a simple
Ni(0)ꢀphosphine complex, but a Ni(I) complex,20c which must
have been generated via oxidation of Ni(0) with Cu(I)
(Scheme 2a). In this mechanism, Ni(I) fluoride B is generated
via the oneꢀelectron oxidation of Ni(0) complex A with CuI.22
Subsequently, transmetalation of B with borylcopper complex
C, which is formed in situ, affords borylnickel(I) complex E,
which cleaves the C–F bond of fluoroarene 1 to form arylnickꢀ
el(I) complex F. Finally, borylation of F with (Bpin)2 (2a)
affords desired product 3 with regeneration of E. This Ni(I)ꢀ
catalyzed mechanism was also supported by other experiꢀ
mental results and some preliminary attempts to gain insight
into the reaction mechanism. For example, we observed that
3a was not produced at all for the first few hours under the
optimized conditions for defluoroborylation of 1a with 2a
(Table 3). The observed induction period possibly results from
the time required for the generation of E. Indeed, a cocktail
prepared separately by heating a mixture of Ni(cod)2, PCy3,
CuI, and CsF in toluene at 80 °C for 20 h effectively promoted
the defluoroborylation of 1a with 2a to afford 3a after stirring
extended πꢀsystems are favorable for this transformation. A
similar trend was reported for nickelꢀcatalyzed transformations
via cleavage of chemically stable bonds, such as C–O
bonds.14,18e,20
A threefold increase in the amounts of the catalysts and base
enabled expansion of the method to monoaryl fluorides (Table
2, condition B and Table S717). Under the modified conditions,
a variety of fluoroarenes, including 2ꢀ or 4ꢀfluorotoluene, proꢀ
tected 4ꢀfluorophenols, and 4ꢀfluoroaniline derivatives, unꢀ
derwent defluoroborylation, providing borylarenes 3k–s in
moderate to high yields. The yield of 3j was also largely imꢀ
proved. Notably, fluoroarenes bearing a pyrrole, pyrazole, or
indole ring, which are often found in bioactive compounds,
also participated in the reaction, affording boronates 3t, 3u,
and 3v, respectively, in high yields. Unexpectedly, substrates
with an electronꢀwithdrawing group, such as a trifluoromethyl
or ester group, showed unusually low reactivity without proꢀ
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at 80 °C for several hours (Table 4). These results demonstrate
that preheating of the catalyst is effective for eliminating the
induction period by generating the active catalyst.
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4
5
Scheme 2. Possible Reaction Mechanisms
entry
time (h) yield 3a (%)a
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9
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2
4.5
6
0
0
0
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9
0
10
20
4
>99
aYields determined by GC analysis.
Table 4. Time Course of the Yield of 3a Using the Precon-
ditioned Catalyst
entry
time (h) yield 3a (%)a
1
2
3
4
2
4
6
8
1
23
34
71
We also observed that defluoroborylation of 1a efficiently
proceeded using a preconditioned Ni catalyst, which was sepaꢀ
rately prepared as a “Ni(I) complex” by mixing Ni(0) and
Ni(II) complexes with PCy3 in THF at room temperature, folꢀ
lowed by evaporation of the solvent (Table 5, entry 5).23 The
reaction using this separately prepared catalyst showed an
induction period (entries 1–4) similar to that for the reaction
under the standard conditions, indicating that the ligand exꢀ
change step (B to E in Scheme 2a) to afford borylnickel(I)
complex E, which we consider to be the active catalyst, reꢀ
quires a high activation energy for its generation. Furthermore,
even using this separately prepared Ni catalyst, CuI was essenꢀ
tial for the successful defluoroborylation, which agreed with
our hypothesis assuming the Cuꢀmediated generation of
borylnickel(I) complex E (Table 5, entry 6). Although we
cannot currently provide the direct evidence for the involveꢀ
ment of borylnickel(I) complex E in the C–F bond cleavage of
1 (1 to F in Scheme 2a), a similar transformation, cleavage of
the stable Ar–OMe bonds with a silylnickel(I) complex to
afford arylnickel(I) compounds, was proposed with support
from experimental and theoretical studies.20c Additionally, we
could not disregard the contribution of Cu(I) to the Ni cycle
after initiation.
aYields determined by GC analysis.
Table 5. Defluoroborylation Using the Ni Catalyst Pre-
pared Separately from Ni(0) and Ni(II)
entry
time (h) yield 3a (%)a
1
2
1
2
0
0
3
6
0
4
7.5
24
24
27
71
1
5
6b
aYields determined by GC analysis. Reaction performed without
b
CuI.
Table 3. Time Course of the Yield of 3a
A conventional crossꢀcoupling mechanism involving C–F
bond cleavage via oxidative addition of 1 to Ni(0) is also posꢀ
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sible (Scheme 2b).9 In this mechanism, the oxidative addition
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step (A + 1 to G) would have to overcome a high barrier in
order to proceed, whereas the subsequent transmetalation (G +
2a to H + D)24 and reductive elimination (H to A + 3) could
occur much more easily. However, our results showed that the
defluoroborylation did not proceed with electronꢀdeficient
arenes (Table 2C and Figure S117), which are generally the
preferred substrates for oxidative addition of C–X bonds.21
Although we could not explain the exact role of CuI in this
mechanism, these results indicate that the simple oxidative
addition step is unlikely to contribute to the C–F bond cleavꢀ
age.
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dihydrofluvastatin derivative 1w (Scheme 4). Thus, Ni/Cuꢀ
catalyzed defluoroborylation of 1w proceeded efficiently unꢀ
der the standard conditions to afford boronic ester 3w in 69%
isolated yield,27 which served as a common intermediate for
further transformations. For example, Suzuki–Miyaura crossꢀ
coupling28 of 3w with 1ꢀfluoroꢀ4ꢀiodobenzene afforded pheꢀ
nylogous fluoroarene 4a in excellent yield. Transformations of
the C–B bond of 3w into various C–heteroatom bonds, such as
C–O,29 C–I,30 and C–N31 were also achieved efficiently under
oxidative conditions to afford hydroxyꢀ, iodoꢀ, and azidoꢀ
functionalized derivatives 4b, 4c, and 4d, respectively. The
twoꢀstep conversion of a fluoroarene to an azidoarene would
be a useful method for the development of photoaffinity labelꢀ
ing probes for identification of target proteins,32 as well as
further diversification through the use of click chemistry.33
Moreover, using the recently reported copperꢀmediated methꢀ
od,7 boronate 3w was successfully transformed into 18Fꢀ
Alternatively, a radical mechanism involving a singleꢀ
electron transfer (SET) from Ni(0) complex A to 1 to afford a
radical anion species is conceivable (Scheme S117). In this
scheme, cleavage of the C–F bond occurs to generate aryl
radical, followed by borylation with 2a to give desired product
3.25 To evaluate the probability of this mechanism, we conꢀ
ducted the defluoroborylation in the presence of radical scavꢀ
engers. Consequently, the reaction in the presence of 60 mol
%
of 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol (BHT) or 9,10ꢀ
dihydroanthracene (DHA) proceeded with comparable effiꢀ
ciency to that without radical scavengers (Scheme 3),26 sugꢀ
gesting that a mechanism involving the free radical species is
improbable. Although further mechanistic studies are required,
these experimental results suggested that the defluoroborylaꢀ
tion proceeds via C–F bond cleavage by a Ni(I) complex.
The synthetic utility of the defluoroborylation reaction was
considerably enhanced by organoboron chemistry, as demonꢀ
strated by several formal C–F bond functionalizations of
labeled compound [18F]-1w.34,35 Because shortꢀlived 18F (t1/2
=
Scheme 3. Defluoroborylation in the Presence of Radical
Scavengers
Scheme 4. Versatile C–F Bond Functionalizations of Dihydrofluvastatin Derivative 1w via Defluoroborylationa
aReagents and conditions: (i) condition B (Table 2); (ii) 1ꢀfluoroꢀ4ꢀiodobenzene, Pd(PPh3)4, Cs2CO3, toluene, H2O, 100 °C, 12 h; (iii)
H2O2, NaOH, H2O, rt, 50 min; (iv) NaI, chloramineꢀT, THF, H2O, 70 °C, 3 h; (v) NaN3, Cu(OAc)2, MeOH, 50 °C, 8 h; (vi) Py4Cu(OTf)2,
[18F]KF/K222, 110 °C, 20 min. For details, see Supporting Information. bRCY indicates the radiochemical yield calculated via radioꢀTLC of
the reaction mixture.
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(3) (a) Jones, W. D. Dalton Trans. 2003, 3991–3995. (b) Amii, H.;
110 min) must be introduced in the last stage of synthesis,
precursors of 18Fꢀlabeled PET probes are generally prepared
via a different synthetic route from that of the nonꢀradioactive
19Fꢀcontaining compounds. Our defluoroborylation approach
that enables the twoꢀstep preparation of precursors will faciliꢀ
tate the development of useful 18Fꢀlabeled PET probes for the
diagnosis of various diseases and evaluation of drug candiꢀ
dates in the early stages of drug development.1c,8,36
Uneyama, K. Chem. Rev. 2009, 109, 2119–2183. (c) Hughes, R. P.
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CONCLUSIONS
9
We have developed an efficient synthetic method for
borylarenes from fluoroarenes via Ni/Cuꢀcatalyzed C–F bond
cleavage. In combination with versatile borylarene transforꢀ
mations, this method has enabled a variety of formal C–F
bond functionalizations of a fluoroarene, involving formation
of C–C, C–O, C–I, and C–N bonds. The twoꢀstep isotopeꢀ
exchange of 19Fꢀ to 18Fꢀfluoroarene has also been achieved,
enabling expeditious preparation of 18Fꢀlabeled PET probes.
Further investigations, including detailed mechanistic studies,
expansion of the substrate scope, and application to PET imagꢀ
ing research, are currently underway in our group.
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havarren, J.; Zarate, C.; Martin, R. J. Am. Chem. Soc. 2015, 137,
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures, characterization for new compounds
including copies of NMR spectra, and HPLC chromatograms for
characterization of [18F]-1w. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*takashi.niwa@riken.jp
*takamitsu.hosoya@riken.jp
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported by JSPS KAKENHI Grant Number
15K05509 and the Incentive Research Grant from RIKEN (T.N.).
The authors thank Dr. Suguru Yoshida (Tokyo Medical and Denꢀ
tal University) for the helpful discussions, Mr. Masahiro Kuꢀ
rahashi (Sumitomo Heavy Industry Accelerator Service Ltd.) for
operating the cyclotron, and KANEKA Co. for their generous gift
(11) C–F bond cleavage of fluorobenzene to afford borylbenzene
(10% yield) was achieved by using boryllithium species. See: Segaꢀ
wa, Y.; Suzuki, Y.; Yamashita, M.; Nozaki, K. J. Am. Chem. Soc.
2008, 130, 16069–16079.
of
tertꢀbutyl
(3R,5S)ꢀ6ꢀhydroxyꢀ3,5ꢀOꢀisopropylideneꢀ3,5ꢀ
(12) For selected examples, see: (a) Kiso, Y.; Tamao, K.; Kumada,
M. J. Organomet. Chem. 1973, 50, C12–C14. (b) Böhm, V. P. W.;
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dihydroxyhexanoate.
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