Nickel-catalyzed Suzuki-Miyaura reaction of aryl fluorides

Article abstract of DOI:10.1021/ja207759e

Two protocols for the nickel-catalyzed cross-coupling of aryl fluorides with aryl boronic esters have been developed. The first employs metal fluoride cocatalysts, such as ZrF₄ and TiF₄, which enable Suzuki-Miyaura reactions of aryl fluorides bearing electron-withdrawing (ketones, esters, and CF₃), aryl and alkenyl groups as well as those comprising fused aromatic rings, such as fluoronaphthalenes and fluoroquinolines. The second protocol employs aryl fluorides bearing ortho-directing groups, which facilitate the difficult C-F bond activation process via cyclometalation. N-heterocycles, such as pyridines, quinolines, pyrazoles, and oxazolines, can successfully promote cross-coupling with an array of organoboronic esters. A study into the substituent effects with respect to both coupling components has provided fundamental insights into the mechanism of the nickel-catalyzed cross-coupling of aryl fluorides.

Full text of DOI:10.1021/ja207759e

ARTICLE
pubs.acs.org/JACS
Nickel-Catalyzed SuzukiꢀMiyaura Reaction of Aryl Fluorides
Mamoru Tobisu,*,‡ Tian Xu,† Toshiaki Shimasaki,†,§ and Naoto Chatani*,†
†Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
‡Center for Atomic and Molecular Technologies, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S Supporting Information
b
ABSTRACT: Two protocols for the nickel-catalyzed cross-coupling of aryl
fluorides with aryl boronic esters have been developed. The first employs metal
fluoride cocatalysts, such as ZrF4 and TiF4, which enable SuzukiꢀMiyaura
reactions of aryl fluorides bearing electron-withdrawing (ketones, esters, and CF3), aryl and alkenyl groups as well as those
comprising fused aromatic rings, such as fluoronaphthalenes and fluoroquinolines. The second protocol employs aryl fluorides
bearing ortho-directing groups, which facilitate the difficult CꢀF bond activation process via cyclometalation. N-heterocycles, such
as pyridines, quinolines, pyrazoles, and oxazolines, can successfully promote cross-coupling with an array of organoboronic esters. A
study into the substituent effects with respect to both coupling components has provided fundamental insights into the mechanism
of the nickel-catalyzed cross-coupling of aryl fluorides.
’ INTRODUCTION
Over the past few decades, the SuzukiꢀMiyaura reaction has
emerged as one of the most powerful carbonꢀcarbon bond-
forming methodologies available.1 Typical protocols employ
organic iodides, bromides, chlorides, and sulfonates, but catalytic
systems that allow the use of more inert, but widely available,
Figure 1. Highly electron-deficient aryl fluorides applicable to the
SuzukiꢀMiyaura reaction.
electrophiles would be of great value to practitioners of chemical
synthesis.2 Such processes would enable the assembly of com-
(entry 1, Table 1). Based on the successful application of
plicated molecules via sequential cross-coupling reactions or late-
stage diversification.3 Aryl fluorides represent an attractive choice
of electrophile owing to their commercial availability of diverse
derivatives.4 Furthermore, the carbonꢀfluorine bond is robust
under a range of synthetic conditions, including palladium
catalysis.5 Nevertheless, the SuzukiꢀMiyaura reaction of aryl
fluorides has only been successfully applied to a limited number
of extremely electron-deficient fluorides, including chromium-
bound,6 ortho-nitro7 and perfluorinated8 substrates (Figure 1).9
This paucity is notable, in light of successful fluoride cross-
couplings with Grignard10 and organozinc11 reagents. In these
cases, Lewis acidic magnesium or zinc ions may assist fluoride
elimination throughout the oxidative addition and/or transme-
talation processes.10d,f,g The absence of such an assistance, due to
the lower Lewis acidity of boronic acids, renders the fluoride
SuzukiꢀMiyaura reaction a significant challenge. Herein, we
report a nickel-catalyzed SuzukiꢀMiyaura reaction that is applic-
able to a wide range of aryl fluorides.
Grignard reagents in the nickel-catalyzed cross-coupling of aryl
fluorides,10 the addition of magnesium salts was examined. While
MgBr2 impeded the formation of 3a (0% yield), the yield was
slightly increased upon the addition of MgF2 (entry 2, Table 1).
This fluoride salt-specific effect led us to screen other metal
fluoride additives. Interestingly, all the metal fluorides examined
imposed a positive effect on the yields of 3a. Of those examined,
ZrF4 proved to be the optimal additive, generating a yield of 80%
(entry 7, Table 1). The application of ZrCl4 afforded no cross-
coupling product, reflecting the importance of metal fluorides.
The cross-coupling reaction did not proceed at all in the absence
of CsF, even in the presence of ZrF4, ruling out a mechanistic
scenario whereby the ZrF4 simply serves as a fluoride donor, to
convert boronic ester 2 into an activated tetra-coordinated borate
species.
To evaluate the potency of the Ni(0)/ZrF4 catalyst system,
the scope with respect to aryl fluoride was investigated (Table 2).
Under standard conditions, fluorobenzene (1b) underwent
cross-coupling to produce the biaryl product in modest yield.
As expected, the electronic nature of aryl fluorides had a
significant impact on reaction efficiency. Not unlike cross-
couplings with other halides,12 substrates bearing an electron-
withdrawing group, such as CF3 1c, ester 1d, and ketones 1eꢀ1g,
successfully coupled with 2. Remarkably, the ketone-containing
’ RESULTS AND DISCUSSION
From preliminary studies, Ni(0)/PCy3 was identified as a
promising catalyst system for the fluoride SuzukiꢀMiyaura
reaction (See Supporting Information for detailed optimization
studies). The reaction of 4-fluorobiphenyl (1a) with boronic acid
2, in the presence of Ni(cod)2/PCy3 as a catalyst and CsF as a
base, afforded the corresponding biaryl product in 38% yield
Received: August 16, 2011
Published: October 24, 2011
r
2011 American Chemical Society
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Table 1. Ni-Catalyzed SuzukiꢀMiyaura Reaction of Aryl
Fluorides: Effect of Additivesa
Table 3. Effect of Directing Groupsa
entry
additive
yield (%)b
entry
additive
yield (%)b
1
2
3
4
5
none
MgF2
ZnF2
CeF3
TiF3
38
47
56
52
61
6
7
TiF4
ZnF4
FeF3
NiF2
AlF3
77
80
48
44
43
8
9
10
a Reaction conditions: substrate (0.50 mmol), 2 (0.60 mmol), Ni(cod)2
(0.05 mmol), PCy3 (0.20 mmol), CsF (0.6 mmol), and toluene
(1.5 mL) in a screw-capped vial under N2 at 120 °C for 12 h. Isolated
yields based on aryl fluorides are shown unless otherwise noted. b Run
using 2 (1.50 mmol) for 44 h. c Run using Ni(cod)2 (0.10 mmol) and
2 (2.0 mmol). d GC yield.
a Reaction conditions: 1a (0.25 mmol), 2 (0.75 mmol), Ni(cod)2 (0.05
mmol), PCy3 (0.20 mmol), CsF (0.75 mmol), additive (0.10 mmol),
and toluene (0.75 mL) in a screw-capped vial under N2 at 100 °C for
12 h. b Isolated yield based on 1a.
Table 2. Ni-Catalyzed Cross-Coupling of Aryl Fluorides
with 2a
role in the present catalytic reaction (vide infra). This view is
further supported by the higher yield obtained for para-substi-
tuted isomer 1e compared to that for the meta-isomer 1g. As
shown in Table 1, a para-phenyl group, which is expected to exert
a negligible electronic effect at the reaction center (σP = ꢀ0.01,
ꢀ
σP = 0.02),14 dramatically accelerates the reaction. Similarly,
aryl fluorides bearing para-styrenyl 1h and meta-phenyl 1i groups
serve as suitable substrates in this nickel-catalyzed cross-cou-
pling. Moreover, fluorine atoms on the polyaromatic rings,
including naphthalene 1j and 1k and quinoline 1l, can be arylated
under these conditions. In contrast, electron-rich aryl fluorides
are less reactive under these conditions (i.e., a yield of only 28%
was obtained upon coupling 4-fluoroanisole).
Metal fluoride salts, especially ZrF4, have been identified as
effective cocatalysts to promote the nickel-catalyzed Suzukiꢀ
Miyaura reaction of aryl fluorides and allow a significant expan-
sion to the scope of the reaction. An alternative approach to
facilitate the difficult CꢀF bond oxidative addition process
involves the use of chelation assistance.15 The nickel-mediated
activation of unreactive bonds is reported to be promoted by
neighboring coordinating groups.16 Inspired by these reports, we
investigated the nickel-catalyzed SuzukiꢀMiyaura reaction of
aryl fluorides bearing ortho-directing groups (Table 3). The
treatment of 2-(2-fluorophenyl)pyridine (4a) with boronic ester
2, in the presence of catalytic Ni(cod)2 and PCy3, afforded biaryl
5a in 88% isolated yield, even in the absence of metal fluoride
salts. During the preparation of this manuscript, Love and co-
workers reported a similar imine-directed SuzukiꢀMiyaura
reaction of aryl fluorides.17 The isomeric 4-pyridinyl derivative
4h did not afford any cross-coupling product, suggesting the
2-pyridinyl moiety serves to facilitate the oxidative addition of
CꢀF bonds, not simply via an electron-withdrawing inductive
effect but by forming a stable cyclometalated intermediate.
Although carbonyl groups, like that in 4g, were poor directors,
N-heteroaromatics, such as pyrimidine 4b, pyrazole 4c, quino-
line 4e, and isoquinoline 4f, afforded the corresponding
a Reaction conditions: 1a (0.25 mmol), 2 (0.75 mmol), Ni(cod)2 (0.05
mmol), PCy3 (0.20 mmol), CsF (0.75 mmol), ZrF4 (0.10 mmol), and
toluene (0.75 mL) in a screw-capped vial under N2 at 100 °C for 12 h.
Isolated yields based on aryl fluorides are shown. b Run in the absence of
ZrF4. c Run at 80 °C.
substrates 1e and 1f exhibited reactivities superior to that of CF3-
substituted 1c, delivering the corresponding products in good
yield, even in the absence of ZrF4.13 These results suggest that
resonance effects, rather than the inductive effects, play a critical
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Table 4. Use of NiCl2(PCy3)2 as a Catalyst Precursora
Table 5. Scope of Boronic Estersa
a Reaction conditions: substrate (0.30 mmol), 4-tolylboronic acid (0.75
mmol), NiCl2(PCy3)2 (0.015 mmol), K3PO4 (1.4 mmol), and toluene
(0.90 mL) in a screw-capped vial under N2 at 120 °C for 12 h. b Isolated
yield based on aryl fluorides. c Yield using 4-tolylboronic acid (0.36
mmol) and K3PO4 (0.66 mmol). d Run at 100 °C. e Run using 4-
tolylboronic acid (0.90 mmol) and K3PO4 (1.7 mmol) at 80 °C.
a Reaction conditions: 4a (0.50 mmol), boronic ester (0.6 mmol),
Ni(cod)2 (0.05 mmol), PCy3 (0.20 mmol), CsF (0.6 mmol), and
toluene (1.5 mL) in a screw-capped vial under N2 at 120 °C for 12 h.
Isolated yield based on aryl fluorides is shown.
cross-coupling products in good yield. The observed reaction
insensitivity to electronics and sterics of coordinating sp2-hybri-
dized nitrogen atoms is notable.18 The successful application of a
nonaromatic oxazoline ring, as in 4d, is also of synthetic value, as
it can be postmodified for further functionalization.19 Pyridine
derivatives are typical directing groups in CꢀH bond activa-
tion reactions,15 but no corresponding CꢀH arylation products
were observed in any examples. The accelerating effect of a
pyridinyl group allows for the regioselective arylation of difluori-
nated substrate 4i (eq 1). Moreover, the ortho-difluoro sub-
strate 4j also produced a monoarylated product in a selective
manner (eq 2).
toluene at 120 °C for 12 h afforded 5a in 98% yield (entry 1,
Table 4). While this practical protocol proved to be applicable to
several aryl fluorides bearing directing groups (entries 2 and 3,
Table 4), aryl fluorides 1a and 1e generated no cross-coupling
products with the NiCl2(PCy3)2 catalyst (entries 4 and 5,
Table 4).
We also discovered that a broad range of aryl and heteroaryl
rings could be coupled with aryl fluoride 4a (Table 5). Both
electron-rich and electron-poor aryl groups could be introduced
efficiently. Functional groups, including methoxy 7b,21 fluoro
7d,10 ester 7h, and pyridine 7i, that are potentially reactive
toward Grignard reagents remained intact under these condi-
tions. This highlights the advantage of using boronic esters as
mild nucleophiles. It should be noted that biaryl products 7b and
7d could further be elaborated via CꢀOMe22 and CꢀF5 bond
functionalization reactions, respectively. Sterically hindered (6c)
and alkenyl (6j) boronic esters also proved to be suitable
coupling partners in this fluoride SuzukiꢀMiyaura reaction.
To gain insight into the mechanism of the present fluoride
SuzukiꢀMiyaura reaction, the electronic effect characteristics of
the boronic ester component were investigated via intermolecu-
lar competition experiments (Table 6). The Ni(0)/ZrF4-cata-
lyzed reaction of fluorobenzene (1b) with a mixture of electron-
deficient (6a) and electron-rich (6e) boronic esters was con-
ducted (5 equiv each). The corresponding biaryls were produced
in a ratio of 51:49, suggesting the electronic nature of the boronic
We typically used a Ni(cod)2/PCy3 catalyst system in our
studies, but the reaction can also be performed with NiCl2-
(PCy3)2, which is more conveniently handled.20 For example, the
reaction of 4a with 4-tolylboronic acid (2.5 equiv) in the
presence of 5 mol % NiCl2(PCy3)2 and K3PO4 (4.5 equiv) in
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Table 6. Comparing the Electronic Effects of the Boronic
Esters in the SuzukiꢀMiyaura Couplings of Aryl Halidesa
Scheme 1. Possible Mechanism
Table 7. Ni-Catalyzed SuzukiꢀMiyaura Reaction of Aryl
Fluorides: Effects of Substituentsa
a Reaction conditions: ArX (0.30 mmol), 6a (1.5 mmol), 6e (1.5 mmol),
Ni(cod)2 (0.030 mmol), ligand (0.12 mmol), CsF (3.0 mmol), and
toluene (1.5 mL) in a screw-capped vial under N2 at 120 °C for 2ꢀ3 h.
b Determined by GC. c ZrF4 (0.12 mmol) was also added. d Dppf
(0.06 mmol) was used.
yield (%)b
b
ꢀb
σP
entry
R
σP
1
2
3
4
5
6
Ac
CO2Me
CF3
0.50
0.45
0.54
0.01
0
0.84
0.74
0.65
0.02
0
78
45
39
38
10
8d
esters has a negligible impact on the cross-coupling (entry 1,
Table 6). In contrast, a similar competition reaction using an aryl
fluoride bearing a directing group, as in 4a, predominantly
furnished the coupling product with electron-deficient 6a, rather
than that derived from electron-rich 6e (ratio = 70:30, entry 2,
Table 6). This discrepancy in the product ratio, between the
nondirected and directed SuzukiꢀMiyaura reactions of aryl
fluorides, may be attributed to a change in the turnover-limiting
step. Scheme 1 illustrates a proposed mechanism for the nickel-
catalyzed cross-coupling of aryl fluorides. Similar to the mechan-
isms for typical cross-coupling reactions, the catalytic cycle
consists of three main processes: oxidative addition of the
CꢀF bond (step i), transmetalation (step ii), and reductive
elimination (step iii). The results obtained with aryl fluorides
bearing no directing group (entry 1, Table 6) are best accom-
modated by a mechanism in which step (i) is kinetically the most
difficult step in the catalytic cycle. Miyaura reported a similar
insensitivity to the electronics of boronic acids in the nickel-
catalyzed cross-coupling of aryl chlorides, in which the oxidative
addition of the CꢀCl bond was rate-determining.23 Indeed, the
electronics of the boronic ester component did not significantly
influence the cross-coupling of chlorobenzene under Miyaura’s
catalytic conditions (Ni(0)/dppf) (entry 3, Table 6). For sub-
strates bearing a directing group, the formation of a stable
cyclometalated intermediate, such as C0, drives the oxidative
addition process forward, compared to simple aryl fluorides. This
chelation assistance renders steps (ii and iii) kinetically more
important. Since transmetalation is often proposed as the rate-
limiting step in the nickel-catalyzed SuzukiꢀMiyaura reaction of
Ph
H
OMe
ꢀ0.28
ꢀ0.12
a Reaction conditions: aryl fluoride (0.25 mmol), 2 (0.75 mmol),
Ni(cod)2 (0.05 mmol), PCy3 (0.20 mmol), CsF (0.75 mmol), ZrF4
(0.10 mmol), and toluene (0.75 mL) in a screw-capped vial under N2 at
100 °C for 12 h. b See ref 14. Isolated yield based on aryl fluorides.
c
d GC yield.
aryl halides and their equivalents,2m,23,24 it is reasonable to
assume that step (ii), which requires the cleavage of an inert
NiꢀF bond, limits the overall rate of the reaction most sig-
nificantly when a directing group is present. In accordance with
this rationale, the cross-couplings of bromo- and iodobenzene, in
which transmetalation is expected to be rate-limiting, afforded
the biaryl products from electron-deficient boronic ester 6a
significantly faster than those from 6e (entries 4 and 5,
Table 6). Although the electronics of the arylboron reagent have
a profound influence on the efficiency of the transmetalation
process (step ii), an explanation for the high reactivities asso-
ciated with electron-deficient boronic esters remains elusive.
Opposing electronic effects have been reported for a set of
catalytic reactions that involve the rate-limiting transmetalation
of boronic acid derivatives.25 Electron-rich boronic acids react
faster in nickel-catalyzed SuzukiꢀMiyaura reactions with aryl
sulfamates,2m whereas electron-deficient boron reagents are
more reactive in nickel-catalyzed cross-couplings with aryl
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Scheme 2. Sequential Cross-Couplings of Aryl Iodide/
Chloride/Fluoride
oxidative addition.10b,32 The current analysis cannot explain the
exceptionally high reactivities of the p-phenyl- and p-styrenyl-
substituted aryl fluorides.33 The extended conjugation of the aryl
system may favor the prerequisite formation of a η2-nickel
complex prior to the rate-limiting oxidative addition.34
To demonstrate the synthetic utility of the fluoride Suzukiꢀ
Miyaura reaction, tandem cross-couplings were performed
(Scheme 2). The palladium-catalyzed reaction of 4-chloroiodo-
benzene (8) with 4-fluorophenyl boronic acid, under an atmo-
spheric pressure of carbon monoxide, afforded the benzo-
phenone derivative 9. The cross-coupling proceeded selectively
at the iodide site. The chloride moiety in 9 was then arylated
under Buchwald’s ligand-accelerated palladium catalysis to form
10. The π-conjugation in 10 was further extended using the
nickel-catalyzed SuzukiꢀMiyaura reaction at the fluoride site to
furnish 11. The orthogonal reactivity of the three halides (F, Cl
and I) allows three cross-coupling events to be accomplished in a
straightforward manner. The functional group tolerance with
organoboron nucleophiles is also essential for the preparation of
ketone 11 in this synthetic sequence.
tosylates20 and in other palladium26 and ruthenium2v catalyzed
methodologies. One possible explanation for the faster reactions
with electron-deficient boronic esters is that the higher Lewis
acidity of the boron center favors the formation of activated
boronate E.
’ CONCLUSION
We have developed two protocols for the nickel-catalyzed
SuzukiꢀMiyaura cross-coupling of aryl fluorides. The first uses
metal fluoride cocatalysts, including ZrF4 and TiF4, to significantly
accelerate the reaction and thus expand the substrate scope. A range
of electron-deficient aryl fluorides and those bearing extended π-
systems, such as biaryl-, stilbene-, and naphthalene-based fluorides,
can be arylated using Ni/Zr bimetallic catalysis. The second
protocol utilizes aryl fluorides bearing a directing group, which
facilitate the difficult CꢀF bond oxidative addition by forming
stable cyclometalated intermediates. Directing groups that contain
an sp2-hybridized nitrogen atom, including pyridine, pyrazole, and
oxazoline, can successfully promote the cross-coupling reaction
with an array of aryl and alkenylboronic esters. The electronic
characteristcs of the boronic esters have little impact in the
nondirected cross-coupling of aryl fluorides, whereas electron-
deficient boronic esters exhibited a superior reactivity in the
chelation-assisted reactions. We propose that the turnover-limiting
step changes from being the oxidative addition to the transmetala-
tion, through the introduction of directing groups. We hope that
the fundamental insights from these studies will guide the further
development of catalytic transformations via CꢀF bond activation.
Further investigations are currently underway in our laboratory.
The addition of metal fluoride salts, such as ZrF4, remarkably
accelerates the nondirected SuzukiꢀMiyaura reactions of aryl
fluorides (Table 1). As mentioned above, ZrF4 is unlikely to act
as a fluoride donor to assist the formation of boronate E, since
both CsF and ZrF4 are required for an efficient reaction. We
currently believe that ZrF4 acts as a Lewis acid to facilitate the
elimination of the fluorine atom in an oxidative addition and/or
transmetalation process, as we initially envisioned.10d,f,g,27,28
Based on the electronic effects of the boronic ester compo-
nent, the relative reactivities of aryl fluorides without directing
groups, toward the nickel-catalyzed cross-coupling, primarily
reflect the relative reactivities of their CꢀF bonds toward
oxidative addition. To understand the nature of the CꢀF bond
oxidative addition to the nickel complex, the substituent effects of
aryl fluorides were investigated. The yields for cross-coupling
reactions, using a series of para-substituted aryl fluorides in the
absence of ZrF4, are listed in Table 7. As expected, the yields of
biaryl products increased with more electron-deficient substrates
(entries 1ꢀ3, Table 7). Electron-rich fluorides produced only a
trace levels of corresponding biaryl (entry 6, Table 7). Among the
substituents examined, the acetyl group promoted the reaction
most significantly (78% yield, entry 1, Table 7), whereas the
more electron-withdrawing CF3 group only improved the yield
modestly (39%, entry 3, Table 7). Therefore, the accelerating
effect cannot be interpreted as a simple inductive effect repre-
sented by the Hammet ꢀσP values. There is, however, a good
correlation with the σP values, which are often applied to
reactions that involve direct resonance interactions between
the electron acceptor and the anionic reaction site.29 Although
more kinetic studies are necessary to fully interpret these results,
a charged intermediate/transition state, such as a Meisenheimer-
type σ complex H7c,30 or a radical anion I via single electron
transfer (SET) from Ni(0),31 may be involved in the CꢀF bond
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures and characterization of products are provided. This
material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: tobisu@chem.eng.osaka-u.ac.jp; chatani@chem.eng.
osaka-u.ac.jp
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Present Addresses
on a search performed on July 21, 2011 (cf. 2 825 000 for chlorobenzene
substructure and 1 039 000 for bromobenzene substructure).
(5) For reviews on the activation of CꢀF bonds, see: (a) Amii, H.;
Uneyama, K. Chem. Rev. 2009, 109, 2119. (b) Sun, A. D.; Love, J. A.
Dalton Trans. 2010, 39, 10362. (c) Braun, T.; Wehmeier, F. Eur. J. Inorg.
Chem. 2011, 2011, 613. For our work on CꢀF bond activation, see:(d)
Ishii, Y.; Chatani, N.; Yorimitsu, S.; Murai, S. Chem. Lett. 1998, 27, 157.
(6) (a) A. Widdowson, D.; Wilhelm, R. Chem. Commun. 1999, 2211.
(b) Wilhelm, R.; Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1
2000, 3808.
(7) (a) Kim, Y. M.; Yu, S. J. Am. Chem. Soc. 2003, 125, 1696. (b)
Widdowson, D. A.; Wilhelm, R. Chem. Commun. 2003, 578. (c) Mikami,
K.; Miyamoto, T.; Hatano, M. Chem. Commun. 2004, 2082. (d)
Bahmanyar, S.; Borer, B. C.; Kim, Y. M.; Kurtz, D. M.; Yu, S. Org. Lett.
2005, 7, 1011. (e) Cargill, M. R.; Sandford, G.; Tadeusiak, A. J.; Yufit,
D. S.; Howard, J. A. K.; Kilickiran, P.; Nelles, G. J. Org. Chem. 2010,
75, 5860.
§Department of Life and Environmental Sciences, Faculty of
Engineering, Chiba Institute of Technology, Narashino, Chiba
275- 0016, Japan.
’ ACKNOWLEDGMENT
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Molecular Activation Directed
toward Straightforward Synthesis” from MEXT, Japan. We also
thank the Instrumental Analysis Center, Faculty of Engineering,
Osaka University, for assistance with the HRMS.
’ REFERENCES
(8) Schaub, T.; Backes, M.; Radius, U. J. Am. Chem. Soc. 2006,
128, 15964.
(1) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.(b)
Suzuki, A.; Brown, H. C. Organic Synthesis via Boranes; Aldrich:
Milwaukee, WI, 2003. (c) Hall, D. G. Boronic Acids; Wiley-VCH:
Weinheim, Germany, 2005. (d) Miyaura, N. Bull. Chem. Soc. Jpn.
2008, 81, 1535. (e) Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6722.
(2) For selected examples of Suzki-Miyraura reactions using nor-
mally inert aryl and alkenyl electrophiles, see the following: Ethers: (a)
Kakiuchi, F.; Usui, M.; Ueno, S.; Chatani, N.; Murai, S. J. Am. Chem. Soc.
2004, 126, 2706. (b) Ueno, S.; Mizushima, E.; Chatani, N.; Kakiuchi, F.
J. Am. Chem. Soc. 2006, 128, 16516. (c) Tobisu, M.; Shimasaki, T.;
Chatani, N. Angew. Chem., Int. Ed. 2008, 47, 4866. (d) Shimasaki, T.;
Konno, Y.; Tobisu, M.; Chatani, N. Org. Lett. 2009, 11, 4890. Carboxy-
lates:(e) Quasdorf, K. W.; Tian, X.; Garg, N. K. J. Am. Chem. Soc. 2008,
130, 14422. (f) Guan, B.-T.; Wang, Y.; Li, B.-J.; Yu, D.-G.; Shi, Z.-J. J. Am.
Chem. Soc. 2008, 130, 14468. (g) Yu, J.-Y.; Kuwano, R. Angew. Chem., Int.
Ed. 2009, 48, 7217. (h) Lee, H. W.; Kwong, F. Y. Synlett 2009, 3151. (i)
Sun, C. L.; Wang, Y.; Zhou, X.; Wu, Z. H.; Li, B. J.; Guan, B. T.; Shi, Z. J.
Chem.ꢀ Eur. J. 2010, 16, 5844. Carbamates:(j) Quasdorf, K. W.; Riener,
M.; Petrova, K. V.; Garg, N. K. J. Am. Chem. Soc. 2009, 131, 17748. (k)
Antoft-Finch, A.; Blackburn, T.; Snieckus, V. J. Am. Chem. Soc. 2009,
131, 17750. (l) Xu, L.; Li, B.-J.; Wu, Z.-H.; Lu, X.-Y.; Guan, B.-T.; Wang,
B.-Q.; Zhao, K.-Q.; Shi, Z.-J. Org. Lett. 2010, 12, 884. (m) Quasdorf,
K. W.; Antoft-Finch, A.; Liu, P.; Silberstein, A. L.; Komaromi, A.;
Blackburn, T.; Ramgren, S. D.; Houk, K. N.; Snieckus, V.; Garg, N. K.
J. Am. Chem. Soc. 2011, 133, 6352. (n) Molander, G. A.; Beaumard, F.
Org. Lett. 2010, 12, 4022. Cyanides:(o) Yu, D.-G.; Yu, M.; Guan, B.-T.;
Li, B.-J.; Zheng, Y.; Wu, Z.-H.; Shi, Z.-J. Org. Lett. 2009, 11, 3374.
Phosphates:(p) Nan, Y.; Yang, Z. Tetrahedron Lett. 1999, 40, 3321. (q)
Larsen, U. S.; Martiny, L.; Begtrup, M. Tetrahedron Lett. 2005, 46, 4261.
(r) Hansen, A. L.; Ebran, J.-P.; Gogsig, T. M.; Skrydstrup, T. Chem.
Commun. 2006, 4137. (s) Kang, F.-A.; Sui, Z.; Murray, W. V. J. Am.
Chem. Soc. 2008, 130, 11300. (t) Zhao, Y.-L.; Li, Y.; Li, Y.; Gao, L.-X.;
Han, F.-S. Chem.ꢀEur. J. 2010, 16, 4991. Amines:(u) Ueno, S.; Chatani,
N.; Kakiuchi, F. J. Am. Chem. Soc. 2007, 129, 6098. (v) Koreeda, T.;
Kochi, T.; Kakiuchi, F. J. Am. Chem. Soc. 2009, 131, 7238. Naphtols:(w)
Yu, D.-G.; Shi, Z.-J. Angew. Chem., Int. Ed. 2011, 50, 7097.
(9) Supported catalysts that can effect the SuzukiꢀMiyaura reaction
of fluorobenzene were reported, but no scope or limitation studies have
been conducted. (a) Ruiz, J. R.; Jimꢀenez-Sanchidriꢀan, C.; Mora, M.
J. Fluorine Chem. 2006, 127, 443. (b) Gallon, B. J.; Kojima, R. W.; Kaner,
R. B.; Diaconescu, P. L. Angew. Chem., Int. Ed. 2007, 46, 7251.
(10) For leading references on the KumadaꢀTamaoꢀCorriu type
reaction of aryl fluorides, see: (a) Kiso, Y.; Tamao, K.; Kumada, M.
J. Organomet. Chem. 1973, 50, C12. (b) B€ohm, V. P. W.; Gst€ottmayr,
C. W. K.; Weskamp, T.; Herrmann, W. A. Angew. Chem., Int. Ed. 2001,
40, 3387. (c) Mongin, F.; Mojovic, L.; Guillamet, B.; Trꢀecourt, F.;
Quꢀeguiner, G. J. Org. Chem. 2002, 67, 8991. (d) Terao, J.; Ikumi, A.;
Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2003, 125, 5646. (e)
Dankwardt, J. W. J. Organomet. Chem. 2005, 690, 932. (f) Ackermann,
L.; Born, R.; Spatz, J. H.; Meyer, D. Angew. Chem., Int. Ed. 2005, 44, 7216.
(g) Yoshikai, N.; Mashima, H.; Nakamura, E. J. Am. Chem. Soc. 2005,
127, 17978. (h) Yoshikai, N.; Matsuda, H.; Nakamura, E. J. Am. Chem.
Soc. 2009, 131, 9590. (i) Wang, J.-R.; Manabe, K. Org. Lett. 2009,
11, 741.
(11) For leading references on the Negishi-type reaction of aryl
fluorides, see: (a) Terao, J.; Todo, H.; Watanabe, H.; Ikumi, A.; Kambe,
N. Angew. Chem., Int. Ed. 2004, 43, 6180. (b) Wang, T.; Alfonso, B. J.;
Love, J. A. Org. Lett. 2007, 9, 5629. (c) Li, B.-J.; Li, Y.-Z.; Lu, X.-Y.; Liu, J.;
Guan, B.-T.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 10124. (d) Wang,
T.; Love, J. A. Organometallics 2008, 27, 3290. (e) Buckley, H. L.; Sun,
A. D.; Love, J. A. Organometallics 2009, 28, 6622. (f) Sun, A. D.; Love,
J. A. J. Fluorine Chem. 2010, 131, 1237. (g) Ohashi, M.; Kambara, T.;
Hatanaka, T.; Saijo, H.; Doi, R.; Ogoshi, S. J. Am. Chem. Soc. 2011,
133, 3256. See also:(h) Takachi, M.; Kita, Y.; Tobisu, M.; Fukumoto, Y.;
Chatani, N. Angew. Chem., Int. Ed. 2010, 49, 8717.
(12) For an example, see: Littke, A. F.; Fu, G. C. Angew. Chem., Int.
Ed. 2002, 41, 4176.
(13) The reaction of 1e under the standard conditions shown in
Table 2 afforded 3e in 56% yield. The decrease in yield by using ZrF4
cocatalyst in this case is partly due to the decomposition of 1e; 14% of 1e
was decomposed upon exposure to the catalytic conditions for 12 h in
the absence of 2.
(14) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
(15) Topics in Organometallic Chemistry; Chatani, N., Ed.; Springer-
Verlag: Berlin, Germany, 2007; Vol 24.
(3) Another approach to sequential SuzukiꢀMiyaura cross-cou-
plings is the differentiation of the reactivity of organoboron nucleo-
philes. For leading references, see: (a) Noguchi, H.; Hojo, K.; Suginome,
M. J. Am. Chem. Soc. 2007, 129, 758. (b) Gillis, E. P.; Burke, M. D. J. Am.
Chem. Soc. 2007, 129, 6716. (c) Noguchi, H.; Shioda, T.; Chou, C.-M.;
Suginome, M. Org. Lett. 2008, 10, 377. (d) Lee, S. J.; Gray, K. C.; Paek,
J. S.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 466. (e) Gillis, E. P.;
Burke, M. D. J. Am. Chem. Soc. 2008, 130, 14084. (f) Molander, G. A.;
Sandrock, D. L. J. Am. Chem. Soc. 2008, 130, 15792. (g) Iwadate, N.;
Suginome, M. J. Organomet. Chem. 2009, 694, 1713. (h) Iwadate, N.;
Suginome, M. Chem. Lett. 2010, 39, 558. Utilizing the orthogonal
reactivities of Br and OTf:(i) Manabe, K.; Ohba, M.; Matsushima, Y.
Org. Lett. 2011, 13, 2436.
(16) (a) Kleiman, J. P.; Dubeck, M. J. Am. Chem. Soc. 1963, 85, 1544.
(b) Nakao, Y.; Yada, A.; Hiyama, T. J. Am. Chem. Soc. 2010, 132, 10024.
ꢀ
(c) Alvarez-Bercedo, P.; Martin, R. J. Am. Chem. Soc. 2010, 132, 17352.
(d) Tobisu, M.; Yamakawa, K.; Shimasaki, T.; Chatani, N. Chem.
Commun. 2011, 47, 2946. (e) Shiota, H.; Ano, Y.; Aihara, Y.; Fukumoto,
Y.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 14952.
(17) (a) The studies outlined in this manuscript were first presented
at the 91th annual meeting of the Chemical Society of Japan on
March 28, 2011 (No. 3C8ꢀ33). (b) Sun, A. D.; Love, J. A. Org. Lett.
2011, 13, 2750.
(4) SciFinder; CAS: Columbus, OH; ca. 2 122 000 substances con-
taining a fluorobenzene substructure were commercially available based
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Journal of the American Chemical Society
ARTICLE
(18) Basicity of the directing groups often affect the efficiency of the
catalytic reaction significantly. For example, see: (a) Chatani, N.;
Fukuyama, T.; Tatamidani, H.; Kakiuchi, F.; Murai, S. J. Org. Chem.
2000, 65, 4039. (b) Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am.
Chem. Soc. 2008, 130, 13285.
(19) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297.
(20) Zim, D.; Lando, V. R.; Dupont, J.; Monteiro, A. L. Org. Lett.
2001, 3, 3049.
(21) (a) Wenkert, E.; Michelotti, E. L.; Swindell, C. S. J. Am. Chem.
Soc. 1979, 101, 2246. (b) Wenkert, E.; Michelotti, E. L.; Swindell, C. S.;
Tingoli, M. J. Org. Chem. 1984, 49, 4894. (c) Dankwardt, J. W. Angew.
Chem., Int. Ed. 2004, 43, 2428. (d) Guan, B.-T.; Xiang, S.-K.; Wu, T.;
Sun, Z.-P.; Wang, B.-Q.; Zhao, K.-Q.; Shi, Z.-J. Chem. Commun.
2008, 1437. (e) Xie, L.-G.; Wang, Z.-X. Chem.ꢀEur. J. 2011, 17, 4972.
(22) For reveiws on catalytic transformations of C-O bonds, see: (a)
Yu, D.-G.; Li, B.-J.; Shi, Z.-J. Acc. Chem. Res. 2010, 43, 1486. (b) Rosen,
B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.; Resmerita, A.-M.;
Garg, N. K.; Percec, V. Chem. Rev. 2011, 111, 1346. (c) Li, B.-J.; Yu,
D.-G.; Sun, C.-L.; Shi, Z.-J. Chem.ꢀEur. J. 2011, 17, 1728. (d) McGlacken,
G. P.; Clarke, S. L. ChemCatChem 2011, 3, 1260. (e) Tobisu, M.;
Chatani, N. ChemCatChem 2011, 3, 1410.
(23) Saito, S.; Oh-tani, S.; Miyaura, N. J. Org. Chem. 1997, 62, 8024.
(24) Li, Z.; Zhang, S.-L.; Fu, Y.; Guo, Q.-X.; Liu, L. J. Am. Chem. Soc.
2009, 131, 8815.
(25) Partyka, D. V. Chem. Rev. 2011, 111, 1529.
(26) Moriya, T.; Miyaura, N.; Suzuki, A. Synlett 1994, 149.
(27) Metal halide salts have been proposed to assist transmetalation
and related processes. (a) Lin, P.-S.; Jeganmohan, M.; Cheng, C.-H.
Chem.ꢀAsian J. 2007, 2, 1409. (b) Lin, P.-S.; Jeganmohan, M.; Cheng,
C.-H. Chem.ꢀAsian J. 2007, 2, 1409. (c) Hatakeyama, T.; Hashimoto,
T.; Kondo, Y.; Fujiwara, Y.; Seike, H.; Takaya, H.; Tamada, Y.; Ono, T.;
Nakamura, M. J. Am. Chem. Soc. 2010, 132, 10674.
(28) For leading works on nickel/Lewis acid dual catalysis for the
activation of unreactive bonds, see: (a) Nakao, Y.; Yamada, Y.; Kashihara,
N.; Hiyama, T. J. Am. Chem. Soc. 2010, 132, 13666. (b) Yada, A.; Ebata,
S.; Ideki, H.; Zhang, D.; Nakao, Y.; Hiyama, T. Bull. Chem. Soc. Jpn. 2010,
83, 10483. (c) Nakao, Y.; Morita, E.; Idei, H.; Hiyama, T. J. Am. Chem.
Soc. 2011, 133, 3264 see also references therein.
(29) Carey, F. A., Sundberg, R. J. Advanced Organic Chemistry:
Structure and Mechanisms, 5th ed.; Springer Science: New York, 2007;
Part A, Chapter 3.6, pp 335ꢀ344.
(30) (a) Fitton, P.; Rick, E. A. J. Organomet. Chem. 1971, 28, 287. (b)
Fahey, D. R.; Mahan, J. E. J. Am. Chem. Soc. 1977, 99, 2501. (c) Stille,
J. K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10, 434.
(31) (a) Tsou, T. T.; Kochi, J. K. J. Am. Chem. Soc. 1979, 101, 6319.
(b) Anderson, T. J.; Jones, G. D.; Vicic, D. A. J. Am. Chem. Soc. 2004,
126, 8100. (c) Gonzꢀalez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006,
128, 5360. (d) Jones, G. D.; Martin, J. L.; McFarland, C.; Allen, O. R.;
Hall, R. E.; Haley, A. D.; Brandon, R. J.; Konovalova, T.; Desrochers,
P. J.; Pulay, P.; Vicic, D. A. J. Am. Chem. Soc. 2006, 128, 13175.
(e) Phapale, V. B.; Bu~nuel, E.; García-Iglesias, M.; Cꢀardenas, D. J. Angew.
Chem., Int. Ed. 2007, 46, 8790.
(32) Portnoy, M.; Milstein, D. Organometallics 1993, 12, 1665.
(33) A similar rate enhancement by extended conjugation has been
reported in the cross-coupling of methoxyarenes with MeMgX; see ref 21d.
(34) For the involvement of η2-arene nickel complexes prior to the
oxidative addition of CꢀF bonds, see: (a) Bach, I.; P€orschke, K.-R.;
Goddard, R.; Kopiske, C.; Kr€uger, C.; Rufiꢀnska, A.; Seevogel, K.
Organometallics 1996, 15, 4959. (b) Braun, T.; Cronin, L.; Higgitt,
C. L.; McGrady, J. E.; Perutz, R. N.; Reinhold, M. New J. Chem. 2001,
25, 19. (c) Schaub, T.; Fischer, P.; Steffen, A.; Braun, T.; Radius, U.; Mix,
A. J. Am. Chem. Soc. 2008, 130, 9304. (d) Johnson, S. A.; Taylor, E. T.;
Cruise, S. J. Organometallics 2009, 28, 3842. (e) Kanyiva, K. S.;
Kashihara, N.; Nakao, Y.; Hiyama, T.; Ohashi, M.; Ogoshi, S. Dalton
Trans. 2010, 39, 10483. (f) Johnson, S. A.; Mroz, N. M.; Valdizon, R.;
Murray, S. Organometallics 2011, 30, 441. For discussion using other
halides, see:Yoshikai, N.; Matsuda, H.; Nakamura, E. J. Am. Chem. Soc.
2008, 130, 15258.
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