Facile Access to Fluoromethylated Arenes by Nickel-Catalyzed Cross-Coupling between Arylboronic Acids and Fluoromethyl Bromide

Article abstract of DOI:10.1002/anie.201502882

The nickel-catalyzed fluoromethylation of arylboronic acids was achieved with the industrial raw material fluoromethyl bromide (CH₂FBr) as the coupling partner. The reaction proceeded under mild reaction conditions with high efficiency; it features the use of a low-cost nickel catalyst, synthetic simplicity, and excellent functional-group compatibility, and provides facile access to fluoromethylated biologically relevant molecules. Preliminary mechanistic studies showed that a single-electron-transfer (SET) pathway is involved in the catalytic cycle.

Full text of DOI:10.1002/anie.201502882

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201502882
German Edition: DOI: 10.1002/ange.201502882
Fluoromethylation
Hot Paper
Facile Access to Fluoromethylated Arenes by Nickel-Catalyzed Cross-
Coupling between Arylboronic Acids and Fluoromethyl Bromide**
Lun An, Yu-Lan Xiao, Qiao-Qiao Min, and Xingang Zhang*
Abstract: The nickel-catalyzed fluoromethylation of arylbor-
onic acids was achieved with the industrial raw material
fluoromethyl bromide (CH2FBr) as the coupling partner. The
reaction proceeded under mild reaction conditions with high
efficiency; it features the use of a low-cost nickel catalyst,
synthetic simplicity, and excellent functional-group compati-
bility, and provides facile access to fluoromethylated biolog-
ically relevant molecules. Preliminary mechanistic studies
showed that a single-electron-transfer (SET) pathway is
involved in the catalytic cycle.
F
luoroalkylated arenes are present in many biologically
active molecules and advanced functional materials owing to
the unique properties caused by the fluorine atom(s).[1] Over
the past few years, substantial efforts have been made in the
preparation of such fluorinated compounds, and impressive
progress has been achieved.[2] To date, palladium[2,3] and
Scheme 1. Strategies for the fluoromethylation of aromatics.
copper[2,4] catalysts have been mainly used to form Ar Rf
Me2Zn) as coupling partners.[8] This is probably because the
most accessible methyl electrophiles (e.g. MeI) are prone to
dimerization and hydrodehalogenation.[9]
À
bonds(Rf = fluoroalkyl) and thus to access fluoroalkylated
arenes. Despite the importance of these synthetic methods,
the catalysis of the cross-coupling/fluoroalkylation of arenes
continues to attract great interest, especially the development
of more sustainable catalysts based on first-row transition
metals. Yet, except for copper, the use of other abundant first-
row transition metals as catalysts has been scarcely
explored.[5] Recently, we reported the nickel-catalyzed
difluoroalkylation of arylboronic acids with functionalized
difluoromethyl halides,[6] which represents a cost-efficient
protocol for the preparation of functionalized difluoromethy-
lated arenes. Inspired by this preliminary study, we envisioned
the feasibility of a nickel-catalyzed fluoromethylation of
arylboronic acids with a low-cost catalyst and industrial raw
material fluoromethyl halides (Scheme 1c). To the best of our
knowledge, the nickel-catalyzed direct fluoromethylation of
aromatics has not been reported thus far.[7] The reported
nickel-catalyzed methylations of aromatics are limited by the
use of methyl metal reagents (e.g. MeMgX, Me3Al, and
In 2009, a palladium-mediated fluoromethylation of aryl
boronates with fluoromethyl halides (CH2FX, X = I, Br) has
been reported (Scheme 1b).[10] Although the method is
straightforward, the requirement of a stoichiometric amount
of palladium and an excess of the aryl boronate (40 equiv)
restricts its widespread synthetic application. In this context,
a stepwise strategy for the fluoromethylation of arenes
through a copper-mediated monofluoroalkylation of aryl
iodides, followed by desulfonylation, has been developed by
Hu et al. (Scheme 1a).[11] In this method, (2-pyridyl)sulfonyl-
containing monofluoroalkylated reagents were used for the
preparation of fluoromethylated arenes. Herein, we describe
the nickel-catalyzed fluoromethylation of arylboronic acids
with the industrial raw material fluoromethyl bromide
(CH2FBr; Scheme 1c). The advantages of this reaction are
the use of a low-cost nickel catalyst, mild reaction conditions,
synthetic simplicity, and excellent functional-group compat-
ibility. To demonstrate the utility of the protocol, fluorome-
thylated bioactive molecules have been synthesized using
a late-stage fluoromethylation.
Initially, we focused our efforts on the nickel-catalyzed
cross-coupling reaction of (1,1’-biphenyl)-4-ylboronic acid
(1a) with fluoromethyl bromide (2) in the presence of
a variety of diamine ligands (Table 1, entries 1–6). We
observed that 1,10-phenathroline (phen, L5) showed higher
activity than bipyridine (bpy) and bpy-based ligands L1–L4,
providing fluoromethylated arene 3a in 41% yield (entry 6).
Other diamine ligands, such as N,N’-dimethylethane-1,2-
diamine and its derivatives, also afforded product 3a, but in
lower yields (for details, see the Supporting Information).
[*] L. An, Y.-L. Xiao, Q.-Q. Min, Prof. Dr. X. Zhang
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
E-mail: xgzhang@mail.sioc.ac.cn
[**] This work was financially supported by the National Basic Research
Program of China (973 Program; 2012CB821600 and
2015CB931900), the NSFC (21425208, 21421002, 21172242, and
21332010), and SIOC. We thank Prof. Jinbo Hu for helpful
discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502882.
Angew. Chem. Int. Ed. 2015, 54, 9079 –9083
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9079

.
Angewandte
Communications
Table 1: Representative results for the optimization of the Ni-catalyzed
fluoromethylation of 1a with 2.[a]
more, a decrease of the loading of NiCl2·DME from 10 mol%
to 5 mol% and the use of L5 (5 mol%), DMAP (10 mol%),
and K2CO3 (2.0 equiv) in a solvent mixture of DME/1,4-
dioxane[12] at 708C provided 3a in a comparable yield
(entry 14). No product formation was observed in the absence
of the nickel catalyst or the ligand L5, but 3a could be
obtained in 51% yield without DMAP, thus demonstrating
the essential roles of both the nickel catalyst and the ligand L5
for the catalytic cycle (entries 15–17).
Entry
[Ni] (x)
L (y)
Additive (z)
Yield of
3a [%][b]
1
2
3
4
5
6
NiCl2·DME (10)
NiCl2·DME (10)
NiCl2·DME (10)
NiCl2·DME (10)
NiCl2·DME (10)
NiCl2·DME (10)
NiCl2·DME (10)
NiCl2·DME (10)
NiCl2·DME (10)
NiCl2·DME (10)
NiCl2·DME (10)
NiCl2·DME (10)
NiCl2·DME (10)
NiCl2·DME (5)
–
bpy (10)
L1 (10)
L2 (10)
L3 (10)
L4 (10)
L5 (10)
L5 (10)
L5 (10)
L5 (10)
L5 (10)
L5 (10)
L5 (10)
L5 (10)
L5 (5)
–
–
–
–
–
–
–
–
29
28
34
33
35
41
49
56
60
62
71
75
91 (90)
90 (90)
NR
NR
51
Upon the establishment of viable reaction conditions,
a variety of arylboronic acids were employed as starting
materials in this transformation (Scheme 2). Overall, sub-
strates bearing electron-withdrawing substituents furnished
the corresponding fluoromethylated arenes 3 in high yields.
Electron-rich arylboronic acids also underwent the reaction
smoothly, but the resulting products 3 were unstable upon
purification by flash chromatography on silica gel (for details,
see the Supporting Information). Many versatile functional
groups, including base- and nucleophile-sensitive moieties,
such as alkoxycarbonyl, enolizable ketone, formyl, cyano,
methylsulfonyl, and sulfonamide groups, showed good toler-
7[c]
8[d]
9[d]
10[d]
11[d]
12[d]
13[d]
14[e]
15[e]
16[e]
17[e]
Py (10)
4-CF3-Py (10)
4-MeO-Py (10)
4-MeO-Py (20)
DMAP (20)
DMAP (10)
DMAP (10)
DMAP (10)
–
L5 (5)
–
L5 (5)
NiCl2·DME (5)
NiCl2·DME (5)
[a] Reaction conditions (unless otherwise specified): 1a (1.5 equiv), 2
(2 molLÀ1 in 1,4-dioxane, 0.3 mmol, 1.0 equiv), solvent (2 mL) for 12 h.
[b] Determined by 19F NMR spectroscopy using fluorobenzene as an
internal standard; numbers in parentheses are yields of isolated
products. [c] Reaction at 708C. [d] DME used as the solvent, 708C, 24 h.
[e] DME/1,4-dioxane (v/v=1:1) were used as solvent mixture.
Decreasing the reaction temperature from 808C to 708C
resulted in a slightly higher yield (49%; entry 7). Encouraged
by these results, we investigated a variety of nickel catalysts,
bases, and solvents. The combination NiCl2·DME, K2CO3,
and DME gave the best result (entry 8; for details, see the
Supporting Information); however, even under these opti-
mized reaction conditions, 3a was obtained in only 56% yield
along with unreacted substrate 2 in 38% yield. Furthermore,
the reaction conditions also resulted in the homocoupling and
deboronylation of 1a. This observation clearly suggested that
the production of 3a is slower than these competitive
reactions. In order to address this issue, we envisaged the
modulation of the steric and electronic properties of the
nickel complex by the use of another ligand, thus accelerating
the nickel-mediated catalytic cycle and improve the yield of
3a further.
Accordingly, we examined pyridine derivatives with
substituents of a different electronic nature in para position
(entries 9–13). These derivatives had a beneficial effect on the
reaction, with the electron-rich 4-methoxy pyridine leading to
a higher yield than the electron-deficient 4-trifluoromethyl
pyridine (entries 10 and 11). To our delight, when we used
N,N-dimethylpyridine-4-amine (DMAP, 20 mol%), we
obtained 3a in 90% yield upon isolation (entry 13). Further-
Scheme 2. Ni-catalyzed fluoromethylation of arylboronic acids 1 with
2.[a] [a] Reaction conditions (unless otherwise specified): 1 (1.5 equiv),
2 (2 molLÀ1 in 1,4-dioxane, 0.6 mmol, 1.0 equiv), DME/1,4-dioxane
(1:1, v/v, 4 mL) for 24 h. [b] NiCl2·DME (10 mol%), L5 (10 mol%),
DMAP (20 mol%). [c] Reaction on a gram scale. [d] 1 (2.0 equiv),
reaction on a 0.3 mmol scale. DME=1,2-dimethoxyethane.
9080 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 9079 –9083

Angewandte
Chemie
ance toward the reaction conditions (3e–n). Additionally, the
arylboronic acid bearing trimethylsilyl and chloride groups
were competent partners, providing 3o and 3p, respectively,
in moderate to good yields. Furthermore, the reactions of
boronic acids derived from 2-naphthalene, 9,9-dimethyl-9H-
fluorene, and dibenzo[b,d]furan also proceeded smoothly
(3r–t). Finally, the syntheses of 3e and 3i on a gram scale were
performed with high efficiency, and 3e was even obtained in
a higher yield (78%) compared to its synthesis on a small
scale, thus offering a reliable and practical access to highly
functionalized fluoromethylated arenes.
We next demonstrated the usefulness of this protocol by
the late-stage fluoromethylation in the synthesis of biologi-
cally active molecules. The treatment of estrone-derived
arylboronic acid 4 with 2 afforded fluoromethylated com-
pound 5 in good yield (Scheme 3a). The glucose-based
substrate 6 also reacted smoothly, thus offering a facile
access to fluorinated carbohydrates (e.g. 7), which are of great
interest in life sciences (Scheme 3b). Importantly, compound
9, an inhibitor of N-type calcium channels,[13] could be rapidly
prepared from
8 through the nickel-catalyzed process
(Scheme 3c). Thus, this transformation is highly relevant for
drug discovery and development.
Scheme 4. The role of DMAP in the fluoromethylation. All yields were
determined by 19F NMR spectroscopy using fluorobenzene as an
internal standard.
ducted to establish whether DMAP can function as a co-
ligand to coordinate to the nickel complex and thus accelerate
the catalytic cycle and improve the yields of products 3.
Product 3a was obtained in a decreased yield of 69% when
substrate 1a was treated with 2 in the presence of NiCl2-
(DMAP)4 11[14] and L5 (Scheme 4c). A similar result was
obtained in the reaction of 1a with 2 in the presence of
a nickel catalyst that was generated by the pretreatment of
NiCl2·DME with L5 and DMAP (Scheme 4d). However, no
reaction occurred in the absence of L5 (Table 1, entry 16). On
the contrary, 3a was obtained in a comparable yield of 85%
when 1a was pretreated with DMAP for 2 h, followed by the
reaction of the resulting mixture with 2 in the presence of
NiCl2·DME and L5 (Scheme 4e). Thus, these observations
suggest that one of the roles of DMAP in the current process
is the activation of the arylboronic acids to facilitate the
transmetalation.[15] However, the possibility that DMAP
coordinates with the active nickel complex to facilitate the
catalytic cycle still cannot be ruled out.
In order to obtain some insight into the mechanism of the
current reaction, several radical-inhibition experiments were
conducted (for details, see the Supporting Information).
Product 3a was obtained in dramatically decreased yields,
when the radical initiator AIBN (0.1 equiv) or the radical
inhibitor hydroquinone (0.2 equiv) were added to the reac-
tion of 1a with 2 under otherwise standard reaction con-
ditions. On the other hand, no reaction occurred when the
Scheme 3. Late-stage fluoromethylation in the synthesis of biologically
active molecules.
To understand the role of DMAP in the reaction, several
experiments were conducted (Scheme 4). First, the reaction
of DMAP with 2 was attempted in order to rule out the
possibility that this reaction occurs to give an active electro-
philic species that later on serves as a coupling partner to
produce the fluoromethylated arenes 3 (Scheme 4a). A
fluoromethyl pyridinium salt 10 was indeed generated, but
product 3a was not formed when 10 was treated with
arylboronic acid 1a under the standard reaction conditions.
Thus the role of DMAP in activating 2 could be excluded
(Scheme 4b). Second, the following experiments were con-
Angew. Chem. Int. Ed. 2015, 54, 9079 –9083
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 9081

.
Angewandte
Communications
electron scavenger 1,4-dinitrobenzene[5e] (0.2 equiv) was
added. These results clearly indicate that a pathway featuring
a single-electron transfer (SET) via a fluoromethyl radical is
involved in the catalytic cycle.
efficiency under mild reaction conditions. This protocol
features synthetic simplicity and can be used for the late-
stage fluoromethylation of biologically relevant molecules.
Preliminary mechanistic studies showed that a SET pathway
via a fluoromethyl radical is involved in the nickel-based
catalytic cycle. Further studies to uncover the detailed
reaction mechanism and to develop derivative reactions are
under way in our laboratory and will be reported in due
course.
In order to further probe the reaction mechanism, the
dependence of the initial reaction rate on the concentrations
of arylboronic acid 1a, NiCl2·DME, and 2 was examined (for
details, see Figure S2 in the Supporting Information). A zero-
order relationship of the initial rate with the concentration of
2 (Figure S2c) was observed; however both arylboronic acid
1a and NiCl2·DME showed first-order relationships (Fig-
ure S2a and b). These observations suggest that the arylbor-
onic acid and the reactive nickel species are involved in the
turnover-limiting step. Furthermore, a high concentration of
NiCl2·DME decreased the yield of 3a as a result of the
Keywords: arylboronic acids · cross-coupling ·
fluoromethylation · fluoromethylbromide · nickel
How to cite: Angew. Chem. Int. Ed. 2015, 54, 9079–9083
Angew. Chem. 2015, 127, 9207–9211
À
formation of some dimerized Ar Ar product and unidenti-
fied defluorinated by-products (for details, see Table S8 in the
Supporting Information). An increased concentration of
[1] For recent reviews, see: a) B. E. Smart, J. Fluorine Chem. 2001,
109, 3; b) P. Maienfisch, R. G. Hall, Chimia 2004, 58, 93;
c) Special issue Fluorine in the Life Sciences, ChemBioChem
2004, 5, 557; d) F. Babudri, G. M. Farinola, F. Naso, R. Ragni,
Chem. Commun. 2007, 1003; e) K. Müller, C. Faeh, F. Diederich,
Science 2007, 317, 1881; f) S. Purser, P. R. Moore, S. Swallow, V.
Gouverneur, Chem. Soc. Rev. 2008, 37, 320.
[2] For selected reviews, see: a) T. Furuya, A. S. Kamlet, T. Ritter,
Nature 2011, 473, 470; b) O. A. Tomashenko, V. V. Grushin,
Chem. Rev. 2011, 111, 4475; c) C. Hollingworth, V. Gouverneur,
Chem. Commun. 2012, 48, 2929; d) T. Besset, C. Schneider, D.
Cahard, Angew. Chem. Int. Ed. 2012, 51, 5048; Angew. Chem.
2012, 124, 5134; e) F.-L. Qing, Chin. J. Org. Chem. 2012, 32, 815;
f) X. Wang, Y. Zhang, J. Wang, Sci. Sin. Chim. 2012, 42, 1417.
[3] E. J. Cho, T. D. Senecal, T. Kinzel, Y. Zhang, D. A. Watson, S. L.
Buchwald, Science 2010, 328, 1679.
[4] M. Oishi, H. Kondo, H. Amii, Chem. Commun. 2009, 1909.
[5] For pioneering studies on fluoroalkyl nickel complexes, see:
a) G. G. Dubinina, W. W. Brennessel, J. L. Miller, D. A. Vicic,
Organometallics 2008, 27, 3933; b) A. Klein, D. A. Vicic, C.
Biewer, I. Kieltsch, K. Stirnat, C. Hamacher, Organometallics
2012, 31, 5334; c) C.-P. Zhang, H. Wang, A. Klein, C. Biewer, K.
Stirnat, Y. Yamaguchi, L. Xu, V. Gomez-Benitez, D. A. Vicic, J.
Am. Chem. Soc. 2013, 135, 8141; for Ni0-catalyzed free-radical
perfluoroalkylations of aromatics, see: d) Q.-L. Zhou, Y.-Z.
Huang, J. Fluorine Chem. 1989, 43, 385; e) X.-T. Huang, Q.-Y.
Chen, J. Org. Chem. 2001, 66, 4651; for Ni0-catalyzed difluor-
oacetylation of vinylzirconium compounds, see: f) M. K.
Schwaebe, J. R. McCarthy, J. P. Whitten, Tetrahedron Lett.
2000, 41, 791.
À
NiCl2·DME probably benefits the formation of Ar Ar
species from arylboronic acids and thus results in a Ni0
species that can react with fluorinated substrates to generate
some unidentified defluorinated products.[16]
A similar
defluorination side reaction occurred when 1a was reacted
with 2 under standard conditions with Ni(cod)2 (10 mol%;
cod = 1,4-cyclooctadiene) as the catalyst, leading to 3a in only
32% yield (determined by 19F NMR spectroscopy; for details,
see Scheme S2 in the Supporting Information).
On the basis of these results and previous reports,[17]
a plausible reaction mechanism involving a NiI/NiIII catalytic
cycle is proposed (Scheme 5). The reaction begins with the
transmetalation between arylboronic acids and [NiILn] (I),
Scheme 5. Proposed reaction mechanism.
[6] Y.-L. Xiao, W.-H. Guo, G.-Z. He, Q. Pan, X. Zhang, Angew.
Chem. Int. Ed. 2014, 53, 9909; Angew. Chem. 2014, 126, 10067.
[7] For transition-metal-catalyzed monofluoroalkylations, see:
a) N. A. Beare, J. F. Hartwig, J. Org. Chem. 2002, 67, 541; b) Y.
Guo, B. Twamley, J. M. Shreeve, Org. Biomol. Chem. 2009, 7,
1716; c) C. Guo, X. Yue, F.-L. Qing, Synthesis 2010, 1837; d) C.
Guo, R.-W. Wang, Y. Guo, F.-L. Qing, J. Fluorine Chem. 2012,
133, 86; e) Y. Liang, G. C. Fu, J. Am. Chem. Soc. 2014, 136, 5520;
f) X. Jiang, S. Sakthivel, K. Kulbitski, G. Nisevich, M. Gandel-
man, J. Am. Chem. Soc. 2014, 136, 9548; for a radical fluoro-
methylation of heteroarenes, see: g) Y. Fujiwara, J. A. Dixon, F.
O’Hara, E. D. Funder, D. D. Dixon, R. A. Rodriguez, R. D.
Baxter, B. Herle, N. Sach, M. R. Collins, Y. Ishihara, P. S. Baran,
Nature 2012, 492, 95; for the direct fluoromethylation of arenes
with fluoromethanol, see: h) G. A. Olah, A. Pavlath, Acta Chim.
Acad. Sci. Hung. 1953, 3, 425; i) G. A. Olah, A. Pavlath, Acta
Chim. Acad. Sci. Hung. 1953, 3, 203.
which may be generated through the comproportionation of
in situ generated Ni0 and the remaining NiII species.[17c,18]
Subsequently, the resulting arylnickel complex [Ar-NiILn]
(II) reacts with 2 through a SET pathway to produce
a fluoromethyl radical (III) and [Ar-NiII(Ln)Br] (IV). This is
not the turnover-limiting step in the overall catalytic cycle.
Then, the recombination of IV with the newly formed radical
III provides the key intermediate NiIII species V, which
undergoes a reductive elimination to afford 3 and regenerate I
simultaneously.
In conclusion, we have demonstrated an efficient and
straightforward method for the preparation of fluoromethy-
lated arenes. The reaction employs a low-cost nickel catalyst
and DMAP as an additive, and can be used for the
preparation of a wide range of arylboronic acids with high
[8] For selected reports, see: a) E. Wenkert, T. W. Ferreira, E. L.
Michelotti, J. Chem. Soc. Chem. Commun. 1979, 637; b) A.
9082 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 9079 –9083

Angewandte
Chemie
Sygula, Z. Marcinow, F. R. Fronczek, I. Guzei, P. W. Rabideau,
Chem. Commun. 2000, 2439.
K. S. Varma, D. E. Hibbs, M. B. Hursthouse, K. M. A. Malik, J.
Organomet. Chem. 1997, 535, 33.
0
À
[9] Z. Liang, W. Xue, K. Lin, H. Gong, Org. Lett. 2014, 16, 5620.
[10] a) H. Doi, I. Ban, A. Nonoyama, K. Sumi, C. Kuang, T. Hosoya,
H. Tsukada, M. Suzuki, Chem. Eur. J. 2009, 15, 4165; b) H. Doi,
M. Coto, M. Suzuki, Bull. Chem. Soc. Jpn. 2012, 85, 1233.
[11] a) Y. Zhao, B. Gao, C. Ni, J. Hu, Org. Lett. 2012, 14, 6080; b) Y.
Zhao, C. Ni, F. Jiang, B. Gao, X. Shen, J. Hu, ACS Catal. 2013, 3,
631. During the preparation of our manuscript, a nickel-cata-
lyzed stepwise synthesis of fluoromethylated arenes was
reported, see: c) Y.-M. Su, G.-S. Feng, Z.-Y. Wang, Q. Lan, X.-
S. Wang, Angew. Chem. Int. Ed. 2015, 54, 6003; Angew. Chem.
2015, 127, 6101. During the production of our manuscript,
a palladium-catalyzed fluoromethylation of arylboronic esters
with fluoromethyl iodide was reported; see: d) J. Hu, B. Gao, L.
Li, C. Ni, J. Hu, Org. Lett. 2015, DOI: 10.1021/acs.or-
glett.5b01361.
[16] For Ni -catalyzed C F bond activation, see: M. Tobisu, T. Xu, T.
Shimasaki, N. Chatani, J. Am. Chem. Soc. 2011, 133, 19505.
[17] For mechanistic studies of Ni-catalyzed Suzuki reactions of
unactivated alkyl electrophiles, see: a) A. Wilsily, F. Tramutola,
N. A. Owston, G. C. Fu, J. Am. Chem. Soc. 2012, 134, 5794;
b) S. L. Zultanski, G. C. Fu, J. Am. Chem. Soc. 2013, 135, 624; for
mechanistic studies of Ni-catalyzed Negishi reactions of unac-
tivated alkyl electrophiles, see: c) G. D. Jones, J. L. Martin, C.
McFarland, O. R. Allen, R. E. Hall, A. D. Haley, R. J. Brandon,
T. Konovalova, P. J. Desrochers, P. Pulay, D. A. Vicic, J. Am.
Chem. Soc. 2006, 128, 13175; d) V. B. Phapale, E. Bunuel, M.
Garcia-Iglesias, D. J. Cardenas, Angew. Chem. Int. Ed. 2007, 46,
8790; Angew. Chem. 2007, 119, 8946; e) X. Lin, D. L. Phillips, J.
Org. Chem. 2008, 73, 3680; f) N. D. Schley, G. C. Fu, J. Am.
Chem. Soc. 2014, 136, 16588; for an overview of mechanistic
issues regarding Ni-catalyzed cross-couplings of unactivated
alkyl halides, see: g) X. Hu, Chem. Sci. 2011, 2, 1867.
[12] A solvent mixture of DME/1,4-dioxane was used because of the
repeatability of the reaction.
[13] F. Radford, R. Lynch, S. L. Mellor, C. J. Hobbs, J. C. Gilbert, S.
Stokes, A. Glen, A. Fiumana, N. J. Smith, C. G. Earnshaw, L. J. S.
Knusten, WO 2005068448.
[18] a) J. Cornella, E. Gomez-Bengoa, R. Martin, J. Am. Chem. Soc.
2013, 135, 1997; b) G. Yin, I. Kalvet, U. Englert, F. Schoenebeck,
J. Am. Chem. Soc. 2015, 137, 4164.
[14] The structure of 11 was confirmed by X-ray crystallographic
analysis (see the Supporting Information). CCDC 1400297
contains the supplementary crystallographic data for this
paper. These data are provided free of charge by The
Cambridge Crystallographic Data Centre.
Received: March 29, 2015
Revised: May 13, 2015
Published online: June 11, 2015
[15] Pyridine can effectively dissociate boroxines and facilitate the
transmetalation event. See: M. A. Beckett, G. C. Strickland,
Angew. Chem. Int. Ed. 2015, 54, 9079 –9083
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 9083