Aromatic C-H borylation by nickel catalysis

Article abstract of DOI:10.1246/cl.150154

The first nickel-catalyzed aromatic C-H borylation is described. In the presence of catalytic amounts of [Ni(cod)₂], tricyclopentylphosphine, and CsF, benzene and indole derivatives can be borylated with B₂pin₂. The N-heterocyclic carbene IPr was also found to be an effective ligand. Kinetic isotope effect experiments showed that C-H cleavage is likely involved in the rate-determining step.

Full text of DOI:10.1246/cl.150154

Received: February 20, 2015 | Accepted: March 10, 2015 | Web Released: March 14, 2015
CL-150154
Aromatic C-H Borylation by Nickel Catalysis
Hua Zhang,1 Shinya Hagihara,1 and Kenichiro Itami*1,2
1Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science,
Nagoya University, Chikusa-ku, Nagoya, Aichi 464-8602
2JST-ERATO, Itami Molecular Nanocarbon Project, Nagoya University, Chikusa-ku, Nagoya, Aichi 464-8602
(E-mail: itami@chem.nagoya-u.ac.jp)
The first nickel-catalyzed aromatic C-H borylation is
described. In the presence of catalytic amounts of [Ni(cod)2],
tricyclopentylphosphine, and CsF, benzene and indole deriva-
tives can be borylated with B2pin2. The N-heterocyclic carbene
IPr was also found to be an effective ligand. Kinetic isotope
effect experiments showed that C-H cleavage is likely involved
in the rate-determining step.
The list in Figure 2 contains some examples of variations
from the standard conditions. In the absence of [Ni(cod)2] or
using nickel(II) salts, essentially no C-H borylation reaction
occurred. The use of HBpin resulted in a much lower yield of
2a (29%). The product 2a was obtained in lower yield without
PCyp3. Triisopropylphosphine (PiPr3) and tributylphosphine
(PnBu3) showed less efficiency than PCyp3, and triphenylphos-
phine (PPh3) was completely ineffective for C-H borylation.
Bidentate ligands such as 1,2-bis(dicyclohexylphosphino)ethane
(dcype) and 4,4¤-di-tert-butyl-2,2¤-dipyridyl (dtbpy),3 the stand-
ard ligands for iridium-catalyzed C-H borylation, were also not
effective. However, we found that the N-heterocyclic carbene
ligand 1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-
2-ylidene (IPr) showed efficiency similar to PCyp3 under these
conditions and a dramatic additive effect of CsF was notable. No
products were obtained in the absence of CsF or presence of
other alkali fluorides. Lowering the temperature led to decreased
yield.
In recent years, C-H functionalization has been extensively
investigated and widely used as it allows the streamlined
synthesis of functional molecules such as pharmaceuticals,
natural products, and organic materials.1 For example, increas-
ing efforts have been devoted to the development of C-H
borylation for aromatic compounds, due to the significant
opportunity of using organoboron compounds in synthesis
(Figure 1).2 For C-H borylation, various transition-metal cata-
lysts have been developed, among which iridium3 and rhodium4
complexes have proved to be the most effective. Although these
precious metals exhibit high efficiency, the utilization of
inexpensive catalysts in C-H borylation is attractive for good
reasons. Recently, several non-noble metal catalysts such as
cyclopentadienyl iron N-heterocyclic carbene,5 Fe2O3 nano-
particles,6 heterobimetallic copper complexes,7 and pincer-
ligated cobalt complexes8 have been reported to catalyze C-H
borylation reactions. On the other hand, nickel has not been
utilized as a catalyst for C-H borylation although various nickel-
catalyzed C-H functionalizations have been reported in recent
years.9 We herein report our discovery of enabling ligands and
additives to achieve the first nickel-catalyzed C-H borylation
(Figure 1).
With the optimized conditions in hand, the substrate scope
of the [Ni(cod)2]/PCyp3-catalyzed C-H borylation was inves-
tigated (Table 1). The borylation of toluene afforded 2a in 74%
CH3
CH3
Ni(cod)2 (10 mol%)
PCyp3 (20 mol%)
+
B2pin2
Bpin
P
CsF (25 mol%)
140 °C, 24 h
1a
56 equiv
1 equiv
2a
PCyp3
88% yield
(o/m/p = 8:61:31)
Effect of parameters (deviation from "standard" conditions)
We began our study by examining various nickel salts,
ligands, and additives in the reaction of toluene (1a) and
bis(pinacolato)diboron (B2pin2). After extensive screening, we
determined that the reaction of 1a (56 equiv, 3 mL) with B2pin2
(0.5 mmol, 1.0 equiv) in the presence of [Ni(cod)2] (10 mol %;
cod: 1,5-cyclooctadiene), tricyclopentylphosphine (PCyp3,
20 mol %), and CsF (25 mol %) at 140 °C for 24 h afforded the
corresponding borylated product 2a in 88% GC yield (based
on B2pin2) as a mixture of regioisomers (o/m/p = 8:61:31)
(Figure 2).
1. Nickel source
2. Boron source
none (0%), NiCl2 (0%), [Ni(acac)2] (0%)
HBpin (29%)
3. Ligand
none (66%)
P
P
P
PPh3 (0%)
N
PiPr3 (71%)
tBu
PnBu3 (21%)
tBu
N
transition-metal
Cy2P
PCy2
H
B2pin2
or
Bpin
catalyst
N
N
+
Ar
Ar
dcype (0%)
dtbpy (0%)
IPr (79%)
HBpin
4. Additive
none (0%), NaF (0%), LiF (0%)
5. Reaction temperature
standard catalysts
Ir Rh
this work
Ni
120 °C (69%), 90 °C (53%), 60 °C (15%)
Figure 2. Discovery of nickel-catalyzed C-H borylation and effect
of parameters.
Figure 1. Transition-metal-catalyzed aromatic C-H borylation.
Chem. Lett. 2015, 44, 779–781 | doi:10.1246/cl.150154
© 2015 The Chemical Society of Japan | 779

Table 1. C-H borylation of benzene derivativesa
Table 2. C-H borylation of indole derivativesa
B2pin2 (1 equiv)
[Ni(cod)2] (10 mol%)
PCyp3 (20 mol%)
R
B2pin2 (1.5 equiv)
[Ni(cod)2] (10 mol%)
PCyp3 (20 mol%)
R
H
Bpin
Ar
Ar
H
Bpin
N
R'
N
CsF (25 mol%)
140 °C, 24 h
CsF (25 mol%)
THF, 80 °C, 24 h
R'
1 (solvent)
2
3 (1.0 equiv)
4
product (2), isolated yield based on B2pin2
product (4), isolated yield based on 3
CH3
Bpin
CF3
H3C
Bpin
Bpin
Bpin
N
Bpin
Bpin
N
2a, 74%
2b, 81%
2c, 35%c
CH3
CH3
(o/m/p = 8:61:31)b
(o/m/p = 0:65:35)d
4a, 61%
4b, 78%
aReaction conditions: 1 (3 mL), B2pin2 (0.5 mmol), [Ni(cod)2]
(10 mol %), PCyp3 (20 mol %), CsF (25 mol %), 140 °C, 24 h.
bDetermined by GC analysis. cConditions: Trifluoromethylben-
zene (1c: 1.5 mL), B2pin2 (0.2 mmol), IPr¢HCl (10 mol %),
H3CO
Bpin
N
N
CH3
Bn
NaOtBu (50 mol %). Determined by H NMR analysis.
d
1
4c, 86%
4d, 63%
aReaction conditions: 3 (0.2 mmol), B2pin2 (0.3 mmol), [Ni(cod)2]
(10 mol %), PCyp3 (20 mol %), CsF (25 mol %), THF (1 mL),
80 °C, 24 h.
isolated yield as a mixture of ortho-, meta-, and para-borylated
products, among which the meta-borylated product was pre-
dominant. This selectivity is similar to the iridium-catalyzed
process, which is controlled by steric effects.2,3 Benzene (1b)
worked well under the standard conditions, giving C6H5Bpin
(2b) in 81% isolated yield. The C-H borylation of electron-
deficient benzene derivatives is sluggish with [Ni(cod)2]/PCyp3
catalyst. However, we found that the use of the carbene ligand
IPr helps promote such processes. For example, trifluorome-
thylbenzene (1c) was borylated under the catalytic influence of
[Ni(cod)2]/IPr to furnish the corresponding borylated product 2c
in 35% isolated yield. In this reaction, the meta- and para-
products were formed in a ratio of 65:35 and the ortho-product
was not observed.
We also investigated the applicability of [Ni(cod)2]/PCyp3/
CsF catalysis to heteroarene C-H borylation. Although electron-
deficient heteroarenes such as pyridine were completely inactive,
electron-rich heteroarenes underwent C-H arylation (Table 2).
For example, N-methylindole (3a: 1.0 equiv) was borylated with
B2pin2 (1.5 equiv) in THF at 80 °C under the influence of the
[Ni(cod)2]/PCyp3/CsF catalytic system to afford 2-borylated
indole 4a in 61% isolated yield. The reaction occurred
exclusively at the C2 position. It should also be mentioned
that, unlike benzene derivatives, 3a is so reactive to allow using
3a as the limiting reagent. The C-H borylation of N-methyl-
indoles substituted with methyl and methoxy groups at the C5
position produced the corresponding boronic esters 4b and 4c
in 78% and 86% yield, respectively. In a similar manner, N-
benzylindole (3d) reacted smoothly resulting in 63% yield of
desired product 4d. Similar to the case of benzene derivatives,
electron-rich indoles were converted to the borylation products
in higher yields. We also investigated other electron-rich
heteroarenes such as pyrroles, thiophenes, and furans. However,
C-H borylation was sluggish with these substrates and the yield
was generally less than 10%.
(a)
B2pin2 (0.2 mmol, 1 equiv)
[Ni(cod)2] (10 mol%)
PCyp3 (20 mol%)
Bpin
Bpin
H
H
H
H
D
D
D
D
+
C6H6 + C6D6
(0.75 mL each)
CsF (25 mol%)
140 °C, 24 h
H
D
2b
2b'
82% yield
2b/2b' (kH/kD) = 1.99
(b)
B2pin2 (0.5 mmol, 1 equiv)
[Ni(cod)2] (10 mol%)
PCyp3 (20 mol%)
toluene (1a)
or
2a or 2a' (C7D7-Bpin)
CsF (25 mol%)
toluene-d8
(3.0 mL)
140 °C
kH/kD = 2.71
Figure 3. Determination of KIE values by (a) competition experi-
ment and (b) independent kinetic analysis.
[Ni(cod)2]/PCyp3/CsF catalysis (Figure 3a). Under the standard
conditions, C6H5Bpin (2b) and C6D5Bpin (2b¤) were obtained in
82% combined yield in a ratio of 1.99:1. We also independently
monitored the reaction progress10 of the C-H borylation of
toluene (1a) and toluene-d8 with B2pin2 under [Ni(cod)2]/
PCyp3/CsF, from which the KIE value (kH/kD) of 2.71 was
determined (Figure 3b). These experiments indicate that C-H
cleavage is probably involved in the rate-determining step of
Although mechanistic details such as the mode of C-H
cleavage and the effect of PCyp3 and CsF remain unclear at
present, we conducted several experiments to determine the
kinetic isotope effect (KIE) values of present nickel-catalyzed
aromatic C-H borylation. For example, the competition experi-
ments of benzene and benzene-d6 were performed under
780 | Chem. Lett. 2015, 44, 779–781 | doi:10.1246/cl.150154
© 2015 The Chemical Society of Japan

C-H borylation. However, we must stress that extensive studies
are needed to elucidate the mechanism of current nickel catalysis.
In summary, we have developed the first nickel-catalyzed
aromatic C-H borylation. The use of PCyp3 or IPr as ligands and
the use of CsF as an additive are crucial to render nickel
functional as a catalyst. Although the substrate scope is rather
limited, electron-neutral and -rich benzene derivatives and
indoles can be borylated efficiently under nickel catalysis.
Further studies expanding the substrate scope and elucidating the
mechanism are currently underway.
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This work was supported by the ERATO program from JST
(K.I.). H.Z. thanks the JSPS Postdoctoral Fellowship for Foreign
Researchers. ITbM is supported by the World Premier Interna-
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Supporting Information is available electronically on J-STAGE.
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Chem. Lett. 2015, 44, 779–781 | doi:10.1246/cl.150154
© 2015 The Chemical Society of Japan | 781