Nickel-catalyzed Csp2i￡Csp3 bond formation by carboni￡fluorine activation

Article abstract of DOI:10.1002/chem.201303809

We report herein a general catalytic method for Csp²i ￡Csp³ bond formation through Ci￡F activation. The process uses an inexpensive nickel complex with either diorganozinc or alkylzinc halide reagents, including those with β-hydrogen atoms. A variety of fluorine substitution patterns and functional groups can be readily incorporated. Sequential reactions involving different precatalysts and coupling partners permit the synthesis of densely functionalized fluorinated building blocks. Gently does it! A general catalytic method for Csp ²i￡Csp³ bond formation through Ci￡F activation with an inexpensive nickel complex with either diorganozinc or alkylzinc halide reagents, including those with β-hydrogen atoms, is described (see scheme; DGa=adirecting group). A variety of fluorine substitution patterns and functional groups (FGs) are readily tolerated. Sequential reactions involving different precatalysts and coupling partners permit the synthesis of densely functionalized fluorinated building blocks.

Full text of DOI:10.1002/chem.201303809

DOI: 10.1002/chem.201303809
Full Paper
&
Cross-Coupling Reactions
Nickel-Catalyzed Csp2ÀCsp3 Bond Formation by CarbonÀFluorine
Activation
Alex D. Sun,[b] Kaylyn Leung,[a] Anita D. Restivo,[a] Nicole A. LaBerge,[a] Harumi Takasaki,[a] and
Jennifer A. Love*[a]
Abstract: We report herein a general catalytic method for
Csp2ÀCsp3 bond formation through CÀF activation. The pro-
cess uses an inexpensive nickel complex with either diorga-
nozinc or alkylzinc halide reagents, including those with b-
hydrogen atoms. A variety of fluorine substitution patterns
and functional groups can be readily incorporated. Sequen-
tial reactions involving different precatalysts and coupling
partners permit the synthesis of densely functionalized fluo-
rinated building blocks.
Introduction
but the alkyl groups are still derived from Grignard reagents,
which would significantly limit their functional group compati-
bility.[5i]
Fluorine atoms form the strongest carbon–element single
bond, and the challenge of activating such strong CÀF bonds
has inspired considerable research effort, resulting in reports of
both stoichiometric and catalytic CÀF activation.[1,2] In particu-
lar, catalytic CÀC bond formation through CÀF activation has
been reported for Kumada–Tamao–Corriu,[3] Suzuki–Miyaura,[4]
Negishi,[5] and Stille[6] cross-coupling protocols, as well as CÀH
activation.[7] Notwithstanding these significant achievements,
only a few of these processes permit the catalytic formation of
Csp2ÀCsp3 bonds. Of these, all have significant limitations. For
example, Csp2ÀCsp3 coupling was reported in Kumada’s pio-
neering paper,[3a] but the highly basic Grignard reagents are in-
compatible with many functional groups. Moreover, some of
these reactions involve partial or complete isomerization of
the alkyl coupling partners.[3a,q] Although stoichiometric meth-
ylation has been achieved by sequential Ni-mediated CÀF acti-
vation and transmetalation with dimethylzinc, the only catalyt-
ic reactions reported have very limited scope with respect to
aliphatic nucleophiles.[3f,5i,8] In addition, 4-fluorostyrene can
serve as a catalytic promoter for Ni-catalyzed Negishi coupling
reactions, which suggests that the CÀF bond is not reactive
under the reported conditions.[9] We have recently reported Pt-
catalyzed Negishi coupling reactions, but the coupling partner
is mainly limited to the use of methyl nucleophiles. More re-
cently, an aryl–alkyl Negishi cross-coupling has been reported,
We have reported an efficient Ni-catalyzed Suzuki–Miyaura
CÀF cross-coupling of polyfluoroarenes as a means to synthe-
size a wide range of highly functionalized, fluorinated biaryl
compounds under mild conditions [Eq. (1)].[4d] However, alkyl
organoboron reagents are not reactive under those conditions
and no alkyl–aryl coupling products, such as 3, were produced
[Eq. (2)].
Motivated by the increasing importance of catalytic CÀF ac-
tivation methods, we have developed a general catalytic
method for Csp2ÀCsp3 bond formation through CÀF activation.
This process uses an inexpensive Ni complex with either dia-
lkylzinc or alkylzinc halide reagents, including those with b-hy-
drogen atoms. The zinc reagents are significantly less reactive
towards functional groups than many other organometallic re-
agents and therefore offer high synthetic utility.[10] In addition
to the limited number of diorganozinc reagents that are com-
mercially available, many organozinc halides can be either pur-
chased or synthesized by using well-established protocols.[11] It
is also worth noting that the aryl fluoride products of cross-
coupling have potential use in the construction of pharma-
[a] K. Leung, A. D. Restivo, N. A. LaBerge, H. Takasaki, Prof. Dr. J. A. Love
Department of Chemistry, University of British Columbia
2036 Main Mall, Vancouver, British Columbia, V6T 1Z1 (Canada)
Fax: (+1)604-822-2847
E-mail: jenlove@chem.ubc.ca
[b] Dr. A. D. Sun
WuXi AppTec (Shanghai) Co., Ltd., 288 Fute Zhong Road
Waigaoqiao Free Trade Zone, Shanghai 200131 (China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303809.
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ceuticals, agrochemicals, and materials, many of which contain
functionalized fluoroarenes.[12]
Results and Discussion
Reactions with diorganozinc reagents
We began our investigation by looking at the reaction be-
tween 2,4-difluorophenyl imine 1 and dimethylzinc in CH3CN
with catalytic amounts of various nickel salts. To our delight,
a number proved to be competent precatalysts for this trans-
formation. For instance, with 5 mol% [NiCl2(PEt3)2] as the pre-
catalyst, the signal in the 19F{1H} NMR spectrum corresponding
to the 2-position CÀF bond in 2,4-difluorophenyl imine 1 disap-
peared completely after 8 h, and the methylated product 4
was formed quantitatively according to 19F{1H} NMR spectro-
scopic analysis [Eq. (3)]. The same pre-catalyst was also able to
catalyze the reaction between 1 and diethylzinc, producing
the ethyl-substituted product 5 [Eq. (4)]. There was no evi-
dence of any b-hydride elimination from presumed Ni-alkyl in-
termediates, which preludes a significant problem in cross-cou-
pling reactions involving alkyl coupling partners with b-hydro-
gen atoms. In addition, the phenyl-substituted product was
obtained from the reaction of 1 and diphenylzinc. After hydrol-
ysis and column chromatography, aldehyde 2 was isolated in
76% yield [Eq. (5)] and shown to be identical to the compound
obtained from the reaction between 1 and phenylboronic acid
in Ni-catalyzed Suzuki–Miyaura cross-coupling [Eq. (1)].[4d] Over-
all, however, the Negishi reaction conditions are more user-
friendly than those of our previously reported Suzuki–Miyaura
protocol. Rigorously dried solvents are not required because
commercially available solvents were successfully employed
without compromising the yields. Furthermore, these reactions
do not require the rigorous exclusion of air. It is noteworthy
that no products from potential imine-assisted CÀH activation
were observed, despite well-established selective catalytic and
stoichiometric CÀH bond activation of fluoroarenes.[13,14] CÀH
activation may indeed be occurring, but could be reversible.[14]
Whereas in the case of diphenylzinc the product could easily
be isolated in the form of an aldehyde after hydrolysis and pu-
rification, the same procedure could not be extended to the
methylated and ethylated aldehydes, because of their high vol-
atility. We were also unable to isolate the imine products by
column chromatography because of gradual decomposition.
Nevertheless, these preliminary experiments established the
feasibility of Ni-catalyzed Negishi coupling of aryl fluorides
with organozinc reagents. We were thus poised to explore the
substrate scope of this reaction.
Reactions with preformed organozinc halides
Compared with diorganozinc reagents, organozinc halide re-
agents are more readily available from commercial sources.
Benzylzinc bromide was selected for initial optimization stud-
ies, because it is relatively stable and inexpensive. [NiCl2(PEt3)2]
catalyzed the reaction between 2,4-difluorophenyl imine 1 and
benzylzinc bromide, generating benzyl-substituted compound
6 in 85% yield after hydrolysis and column chromatography.
CÀF activation took place exclusively at the ortho position and
no CÀH activation was observed. Encouraged by this result, we
modified a number of parameters with the hope of optimizing
the reaction conditions so as to maximize the yield; the results
are summarized in Table 1.
A variety of Ni complexes were found to catalyze the Negishi
cross-coupling reaction. One significant discovery was that,
unlike our previously reported Suzuki–Miyaura reaction, in
which only Ni0 complexes were competent precatalysts, both
Ni0 and NiII complexes could be employed. We also found that
the reaction yields were significantly influenced by the nature
of the ligand. Triethylphosphine had a significant advantage
over other ligands, both as a preformed complex (Table 1,
entry 1) and when reacted with [Ni(COD)2] in situ (Table 1,
entry 4); triphenylphosphine (Table 1, entry 3) and an N-hetero-
Table 1. Exploration of reaction conditions for Ni-catalyzed Negishi cross-
coupling of polyfluoroaryl imines.
Entry
Changes from conditions listed above
Yield [%][a]
1
2
3
4
5
6
no change
no NiCl2(PEt3)2
NiCl2(PPh3)2 instead of NiCl2(PEt3)2
5 mol % Ni(COD)2/ 10 mol % PEt3
1 mol % NiCl2(PEt3)2
85
0
27
82
53
17
5 mol % Ni(COD)2,
1,3-diisopropyl-imidazol-2-ylidene
608C instead of 708C
aldehyde instead of imine
7
8
0
0
[a] Isolated yields.
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cyclic carbene (Table 1, entry 6) were not as effective. For prac-
tical purposes, we chose [NiCl2(PEt3)2] as our preferred precata-
lyst because it was easy to synthesize, relatively stable, and af-
forded excellent results.
Table 2. Scope and limitations of fluoroaryl imines.
We discovered a rather unexpected strong influence of the
reaction temperature in this cross-coupling reaction. Whereas
608C was the optimal temperature for Ni-catalyzed Negishi
cross-coupling of diorganozinc reagents [Eqs. (3)–(5)], no reac-
tion was observed at this temperature with benzylzinc bro-
mide as the coupling partner. The temperature must be raised
to 708C for CÀF cross-coupling to take place (Table 1, entry 7).
At present, we do not have an explanation for this observation.
Reactions were generally completed overnight (12–14 h), but
certain substrates required longer reaction times. Therefore, re-
actions were allowed to continue for 24 h to ensure that all
were completed with satisfactory yields. It is noteworthy that
we did not observe product decomposition with longer reac-
tion times. Further extension of reaction duration offered no
additional benefits. It is also clear that a sufficiently strong di-
recting group must be used, because no reaction took place in
the absence of a directing group. Likewise, an aldehyde direct-
ing group was unable to promote CÀF activation. However,
other directing groups could be used (see below), although
we preferred an imine directing group because of its synthetic
versatility (via the aldehyde).
Entry Imine
1
Product
Isolated yield [%]
7
8
84
2
3
4
5
6
91
33
88
84
79
9
10
11
12
We then turned our attention to the scope of the fluorine
substitution pattern on these polyfluoroaryl imines. The results
with benzylzinc bromide as coupling partner are summarized
in Table 2. As expected, only the products derived from ortho
CÀF cross-coupling were isolated, and there was no evidence
of CÀH activation or CÀF activation/CÀH formation. Most sub-
strates underwent smooth cross-coupling reactions, resulting
in high yields. However, in the case of 2,5-difluorophenyl imine
(Table 2, entry 3), the yield was considerably lower than those
of other substrates, providing aldehyde 9 in only 33% yield. It
is worth noting that this substrate showed no reactivity at all
under Suzuki–Miyaura reaction conditions. At this point, we do
not have a definitive answer for why this particular substrate is
so problematic in Ni-catalyzed CÀF activation. One possible ex-
planation is that this substrate underwent irreversible CÀH
bond activation, which would consume the Ni complex rapidly.
It has been suggested that the imine directing group and the
fluorine substituent adjacent to the CÀH bond could facilitate
CÀH activation.[15] The same 2,5-difluoro-substitution pattern
can also be found in Table 2, entries 5 and 6, but these imines
reacted without difficulty, suggesting that if CÀH activation is
occurring for those substrates, perhaps it is more easily reversi-
ble for them than for 2,5-difluoroimine. More kinetic and
mechanistic studies are underway.
7
8
9
13
14
15
90[a]
86[a]
83[a]
10
11
12
13
16
17
18
19
71
75
–
–
[a] 3.0 equiv benzylzinc bromide was used.
Dialkylation took place with substrates containing two
chemically equivalent ortho CÀF bonds (Table 2, entries 8 and
9). The monoalkylated compounds for each substrate could be
detected as minor products by 19F{1H} NMR spectroscopy and
mass spectrometry at incomplete conversion, but could not be
isolated due to their very similar physical and chemical proper-
ties. Dialkylation was also observed for a 2,3,6-trifluoroaryl
imine (Table 2, entry 7). This result was very intriguing because
only the CÀF bond at the 2-position was activated under the
Suzuki–Miyaura conditions. In other words, Ni-catalyzed Ne-
gishi cross-coupling was able to achieve the second CÀF acti-
vation whereas Ni-catalyzed Suzuki–Miyaura cross-coupling
was only good for the first, for yet unknown reasons. We an-
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ticipated that this difference in reactivity between the two cat-
alytic systems would provide a valuable opportunity for se-
quential cross-coupling reactions (see below).
Table 3. Scope of in situ-generated organozinc reagents.
The chemoselectivity on the fluoroaryl rings is worth men-
tioning. As expected, CÀBr and CÀCl bonds are reactive under
Negishi conditions, and coupling reactions would take place
preferentially at these bonds. Despite reports of Ni-catalyzed
CÀO activation reactions,[16] an aryl–OMe moiety was tolerated
under the reaction conditions, both at the ortho- (Table 2,
entry 10) and para-positions (Table 2, entry 11). In contrast,
arylÀCN bonds either ortho- or para- to the directing group,
were not tolerated.
Entry R–X
Product
Isolated
yield [%]
1
2
6
87
90
20
Reactions with organozinc halides generated in situ
3
4
5
6
21
22
23
24
86
84
92
83
Zinc reagents used in Negishi cross-coupling reactions are sig-
nificantly more tolerant towards functional groups than lithium
or magnesium-based reagents. In addition to the limited
number of diorganozinc and organozinc halide that are com-
mercially available, there are well-established protocols to syn-
thesize organozinc reagents with diverse functional groups.
We decided to utilize the Huo protocol, which is a highly effi-
cient, general method for the preparation of alkylzinc halide
reagents from unactivated alkyl bromides and chlorides under
mild conditions.[11c] Table 3 summarizes the results from the re-
actions between alkylzinc halides and imine 1 under the cata-
lytic conditions. In general, this procedure offered good-to-ex-
cellent yields and great functional group compatibility. For ex-
ample, benzylzinc bromide was prepared in situ by using
5 mol% I2, 2.0 equiv benzyl bromide, and 1.5 equiv zinc dust in
dimethylacetamide (DMA) at 808C for 3 h. The resulting mix-
ture was then transferred to a solution of 1.0 equiv 2,4-difluor-
oimine and 5 mol% [NiCl2(PEt3)2] in CH3CN, while maintaining
the temperature at 708C for 24 h. After hydrolysis, workup and
column chromatography, the same aldehyde 6 was isolated in
comparable yields (87 vs. 85% from commercially available
BnZnBr solution, Table 3, entry 1).
7
8
25
26
81
75
9
27
28
78
69
10[a]
The use of octylbromide resulted in high yield (Table 3,
entry 2). A potentially reactive CÀCl bond did not react under
the reaction conditions and the chlorine-containing product
was successfully isolated (Table 3, entry 3). Two types of pro-
tected alcohols were tested. Both benzyl (Table 3, entry 4) and
tert-butyldiphenylsilyl (Table 3, entry 5) groups survived under
the reaction conditions and the desired products were isolated
in excellent yields. Likewise, both of the tested ester-contain-
ing substrates (Table 3, entries 6 and 7) generated their corre-
sponding products. An alkyl cyano group was also tolerated
(Table 3, entry 8). This methodology could be further extended
to phthalimide-protected amino groups, as well as sulfones
(Table 3, entries 9 and 10), respectively. Notably, alkylzinc chlor-
ides could be also be used, which is particularly significant
when the corresponding alkyl bromides are not readily avail-
able (Table 3, entry 10). Likewise, by using benzyl chloride and
n-tetrabutylammonium bromide as the halide transfer agent,
aldehyde 6 could be isolated in 81% yield [Eq. (6)], which is
comparable to those obtained by using either commercially
available benzylzinc bromide (85%; Table 1, entry 1) or benzyl-
[a] 2.0 equiv n-tetrabutylammonium bromide was added, heated for 12 h
in DMA.
zinc bromide generated in situ (87%; Table 3, entry 1). A few
functional groups were not tolerated. Not surprisingly, acidic
functionalities were incompatible with the reaction conditions,
presumably because of quenching of the organozinc reagent.
Alkyl halides bearing a leaving group attached to the b-carbon
could not be used because of instability of the zinc reagent. As
with our previously reported Suzuki–Miyaura cross-coupling,[4d]
some sulfur-containing functional groups were not compatible.
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Whereas a sulfone was tolerated (see above), sulfide and sulf-
oxide groups shut down the reactions completely and the pol-
yfluoroimines were recovered. At present, our explanation is
that the Ni complex reacts preferentially with the CÀS bonds
of sulfide and sulfoxide substrates, precluding CÀF activation.
Ni-catalyzed sequential CÀF cross-coupling of polyfluoroaryl
imines
benzylzinc bromide provided 80–85% monoalkylated product
34, along with 15–20% unreacted starting material (Scheme 2).
Fortunately, by controlling the reaction stoichiometry, no dia-
lkylated product was detected. Excess diethylzinc was added
to the crude mixture, along with an additional 5 mol% [NiCl2-
(PEt3)2], which was necessary for the reaction to proceed. The
remaining ortho CÀF bonds of 29 and 34 were replaced with
We have become interested in the possibility of Ni-catalyzed
sequential cross-coupling reaction with unsymmetrically-substi-
tuted substrates. We selected 2,3,6-trifluorophenyl imine 29 as
the substrate, given that monoarylation prevailed under
Suzuki–Miyaura conditions, but dialkylation occurred under Ne-
gishi conditions. We hypothesized that after selective activa-
tion of the CÀF bond in the 2-position under Suzuki–Miyaura
conditions, Negishi coupling would be possible for functionali-
zation at the 6-position, resulting in the generation of highly
functionalized fluorine-containing building blocks. Imine 29
was subjected to Suzuki–Miyaura cross-coupling conditions
with 4-methoxyphenylboronic acid in tetrahydrofuran (THF). As
expected, CÀF activation took place exclusively at the 2-posi-
tion, resulting in the formation of imine 30 [Eq. (7)]. After rapid
workup, the crude material was dissolved in CH3CN and sub-
jected to Negishi cross-coupling conditions with dimethylzinc,
diethylzinc, and diphenylzinc (Scheme 1a, b, and c), respective-
1
an ethyl group, according to H and 19F{1H} NMR spectroscopy,
as well as mass spectrometry. Upon hydrolysis, aldehyde 35
Scheme 2. Sequential Ni-catalyzed Negishi/Negishi cross-coupling with dif-
ferent organozinc reagents.
Scheme 1. Sequential Ni-catalyzed Suzuki–Miyaura/Negishi cross-coupling.
ly. Upon hydrolysis, aldehydes 31 and 32 were isolated in 80
and 75%, respectively. The phenyl-substituted aldehyde 33
was generated in approximately 80% conversion with diphe-
nylzinc (based on integration of the 19F{1H} NMR spectrum),
but could not be fully separated from the aldehyde derived
from remaining starting material.
Imine 29 could also be reacted with two different alkyl zinc
reagents, added sequentially. For example, use of 1.0 equiv
Scheme 3. Sequential Ni-catalyzed CÀCl/CÀF cross-coupling.
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was isolated from the diethyl byproduct (derived from 29) in
61% yield after column chromatography.
Table 4. Scope and limitations of directing groups in Nickel catalyzed
Negishi cross-coupling.
Capitalizing on the greater reactivity of aryl CÀCl bonds rela-
tive to aryl CÀF bonds, we were able to achieve a sequential
CÀCl/CÀF cross-coupling. Consistent with our expectations, ac-
tivation of the chloro-substituent does not require a directing
group, allowing for selective CÀCl Suzuki–Miyaura cross-cou-
pling of aldehyde 36 to generate intermediate 37 (Scheme 3).
Addition of 2.0 equiv benzyl amine provided imine 38, which
was then subjected to Negishi coupling with diethylzinc to
generate, after hydrolysis, aldehyde 39.
Entry
Directing group (DG)
Isolated yield [%]
1
2
3
21
27
0
Ni-catalyzed Negishi cross-coupling of polyfluoroarenes
with different directing groups
The synthetic versatility of aldehydes means that aldehyde-de-
rived directing groups are among the most desirable. Never-
theless, we were interested in determining whether or not
other directing groups could function under the Negishi cou-
pling conditions. Whereas oxygen-based directing groups were
ineffective (presumably due to the inability to promote CÀF ac-
tivation), other nitrogen-based directing groups permitted
cross-coupling. For example, pyridine-based 2,4-difluoroarene
40 reacted smoothly with 4-methoxybenzylzinc chloride to
produce 41 in 88% yield [Eq. (8)].
coupling partners permit the synthesis of densely functional-
ized fluorinated building blocks, and the catalytic procedure
can be applied to other directing groups. Mechanistic analysis
of this reaction will be reported in due course.
Experimental Section
Reaction between 2,4-difluoroimine and benzylzinc bromide
solution
In a glovebox, imine (116 mg, 0.5 mmol, 1.0 equiv), [NiCl2(PEt3)2]
(9.1 mg, 0.025 mmol, 5 mol%), and benzylzinc bromide (0.5m in
THF, 1.5 mL, 0.75 mmol, 1.5 equiv) were dissolved in acetonitrile
(10 mL) in a 20 mL vial. The vial was capped, removed from the
glovebox and subsequently heated to 708C for 24 h. The solution
was cooled to RT, aqueous hydrochloric acid (3m) was added, and
the mixture was stirred at RT for 30 min. The mixture was then ex-
tracted with diethyl ether (3ꢁ25 mL). The combined organic ex-
tracts were dried over sodium sulfate, filtered, and concentrated
by rotary evaporation to provide the crude aldehyde product. Fur-
ther separation by column chromatography (SiO2, 230–400 mesh;
n-pentane/EtOAc=100:1) provided clean product.
In comparison, lower yields were found when preformed
benzylzinc bromide was used. Pyridine 40 provided 21% yield
of the corresponding benzylated product (Table 4, entry 1).
Likewise, an oxazoline-based 2,4-difluoroarene reacted with
benzylzinc bromide to generate the corresponding benzylated
product in 27% yield, with the remaining mass balance being
recoverable starting material (Table 4, entry 2). An isooxazole
(Table 4, entry 3) was ineffective at promoting the transforma-
tion.
Reaction between 2,4-difluoroimine and benzylzinc bromide
generated in situ
A dry 25 mL one-neck round-bottom flask was charged with anhy-
drous DMA (5 mL), I2 (7 mg, 0.025 mmol, 5 mol%), and zinc dust
(50 mg, 0.75 mmol, 1.5 equiv) under N2. The mixture was stirred at
RT for 5 min until the iodine color disappeared. Benzyl bromide
(171 mg, 1.0 mmol, 2.0 equiv) was added by using a syringe and
the resulting mixture was heated for 3 h at 808C. The mixture was
then added to a solution of 2,4-difluoroimine (116 mg, 0.5 mmol,
1.0 equiv) and [NiCl2(PEt3)2] (9.1 mg, 0.025 mmol, 5 mol%) in CH3CN
(10 mL), while maintaining the temperature at 708C for 24 h. The
mixture was cooled to RT and stirred for 30 min following the addi-
tion of aqueous hydrochloric acid (3m). The mixture was then ex-
tracted with diethyl ether (3ꢁ25 mL) and the combined organic
extracts were dried over sodium sulfate, filtered, and concentrated
by rotary evaporation to provide the crude aldehyde product. Fur-
ther separation by column chromatography (SiO2, 230–400 mesh;
n-pentane/EtOAc=100:1) provided clean product.
Conclusion
We have reported a new way to generate alkyl-substituted aryl
fluorides through Ni-catalyzed Negishi cross-coupling reac-
tions. A diverse array of polyfluoroaryl imines are able to react
with organozinc reagents, with high functional-group compati-
bility. Sequential reactions involving different precatalysts and
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Acknowledgements
We thank the following for support of this research: NSERC
(Collaboration Research and Development Grant, Research
Tools and Instrumentation Grant), AstraZeneca Canada (2008
Award in Chemistry to J. A. L.) and the University of British Co-
lumbia. We thank Nicholas Cowper and Philip Provencher for
preliminary investigations, and Matthew Wathier for analyzing
NMR spectra.
[5] For examples of Negishi type aryl fluorine cross-coupling reactions see:
Pt: a) T. Wang, B. J. Alfonso, J. A. Love, Org. Lett. 2007, 9, 5629–5631;
b) T. Wang, J. A. Love, Organometallics 2008, 27, 3290–3296; c) H. L.
Buckley, A. D. Sun, J. A. Love, Organometallics 2009, 28, 6622–6624;
d) A. D. Sun, J. A. Love, J. Fluorine Chem. 2010, 131, 1237–1240; e) L.
Keyes, A. D. Sun, J. A. Love, Eur. J. Org. Chem. 2011, 3985–3994; f) T.
Wang, L. Keyes, B. O. Patrick, J. A. Love, Organometallics 2012, 31,
1397–1407; Ni: g) B.-J. Li, Y.-Z. Li, X.-Y. Lu, J. Liu, B.-T. Guan, Z.-J. Shi,
Angew. Chem. 2008, 120, 10278–10281; Angew. Chem. Int. Ed. 2008, 47,
10124–10127 (a Ni-catalyzed CÀF activation was discussed on page
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Keywords: cross-coupling
methods · zinc
· fluorine · nickel · synthetic
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Received: September 29, 2013
Published online on February 12, 2014
Chem. Eur. J. 2014, 20, 3162 – 3168
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