Nickel-catalyzed borylation of arenes and indoles via C-H bond cleavage

Article abstract of DOI:10.1039/c5cc01378j

The first nickel-catalyzed method for the borylation of carbon-hydrogen bonds in arenes and indoles is described. The use of an N-heterocyclic carbene ligand is essential for an efficient reaction, with an N-cyclohexyl-substituted derivative being optimal. This method is readily applied to the gram scale synthesis of 2-borylindole.

Full text of DOI:10.1039/c5cc01378j

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Nickel-catalyzed borylation of arenes and indoles
via C–H bond cleavage†
Cite this: Chem. Commun., 2015,
1, 6508
5
a
abc
a
Takayuki Furukawa, Mamoru Tobisu*
and Naoto Chatani*
Received 13th February 2015,
Accepted 11th March 2015
DOI: 10.1039/c5cc01378j
www.rsc.org/chemcomm
The first nickel-catalyzed method for the borylation of carbon–
hydrogen bonds in arenes and indoles is described. The use of an
N-heterocyclic carbene ligand is essential for an efficient reaction,
with an N-cyclohexyl-substituted derivative being optimal. This method
is readily applied to the gram scale synthesis of 2-borylindole.
Over the past few decades, substantial progress has been made
in the development of catalytic methods for C–H bond function-
1
alization. Catalytic borylation of arenes is arguably the method
of paramount importance, since it allows the introduction of a
synthetically useful boron functionality directly at the C–H bond of
2
an arene without using any directing groups. The regioselectivity
of this method is predictable based on steric factors, enabling
the widespread use of this borylation method in the late-stage
elaboration of a range of complex aromatic molecules. Iridium
complexes ligated with a bipyridine-based ligand are presently
the catalyst of choice for the efficient, regioselective borylation of
3
arenes (Scheme 1a). One remaining challenge in the catalytic
C–H borylation methodology is the development of base metal
catalysts, driven by recent concerns regarding the limited avail- Scheme 1 Catalysts for the borylation of C–H bonds of (hetero)arenes.
ability of precious metals. Although a seminal work by Hartwig
demonstrated the potential activity of base metal complexes such
as Fe and Mn in the C–H bond borylation reaction in 1995,
4
7
photochemical conditions was developed by Mankad. Chirik
catalytic variants were achieved only recently (Scheme 1b). Ohki reported a cobalt-catalyzed C–H borylation applicable to a broad
8
and Tatsumi reported an iron-catalyzed borylation of furans and range of arenes and heteroarenes. Despite these advances, the
5
thiophenes in the presence of a hydrogen acceptor, while Kuang full potential of base metals to promote C–H borylation in a
and Wang demonstrated that Fe O nanoparticles can also broader sense, to promote C–H activation, has not been explored,
2
3
9
10
catalyze the borylation of arenes in the presence of a more than especially in the case of metals other than iron and cobalt.
stoichiometric amount of tert-butyl peroxide. A mechanistically Herein, we report the first nickel-catalyzed borylation of C–H
6
unique C–H borylation using a Cu/Fe bimetallic catalyst under bonds in arenes and indoles.
During the course of our mechanistic studies of the Ni(cod)
PCy -catalyzed reductive cleavage of anilides using HBpin, we found
that the hydrogens of the aromatic ring of the toluene solvent were
interchanged with those of the HBpin. This observation clearly
indicated that the C–H bonds in simple arenes can be activated
under nickel catalysis. We were intrigued by this finding because, to
the best of our knowledge, the nickel-catalyzed C–H functionaliza-
tion of simple arenes (i.e., arenes bearing no directing group)
2
/
a
b
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita,
Osaka 565-0871, Japan. E-mail: tobisu@chem.eng.osakau.ac.jp,
chatani@chem.eng.osakau.ac.jp
3
11
Center for Atomic and Molecular Technologies, Graduate School of Engineering,
Osaka University, Suita, Osaka 565-0871, Japan
c
ESICB, Kyoto University, Katsura, Kyoto 615-8510, Japan
†
Electronic supplementary information (ESI) available: Detailed experimental
procedures and characterization of new products. See DOI: 10.1039/c5cc01378j
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a
a
Table 1 Nickel-catalyzed borylation of benzene: ligand screening
Table 2 Nickel-catalyzed borylation of various arenes
b
Entry
1
Arene
Product
b
Entry
1
Ligand
None
Yield (%)
5
0
c
2
PCy
IMesÁHCl (R = 2,4,6-Me
3
3
4
5
6
7
8
9
3
C
6
H
2
)
51
16
22
33
50
i
IPrÁHCl (2,6- Pr
2 6 3
C H )
IMeÁHCl (R = Me)
i
i
I PrÁHBF
4
(R = Pr)
2
t
t
I BuÁHCl (R = Bu)
d
ICyÁHCl (R = cyclohexyl)
75 (71)
I(1-Ad)ÁHCl (R = 1-adamantyl)
I(2-Ad)ÁHCl (R = 2-adamantyl)
SICyÁHCl
36
10
11
12
Trace
2
3
4
BICyÁHCl
69
a
Reaction conditions: HBpin (1.2 mmol), Ni(cod)
2
(0.036 mmol), ligand
c
5
t
(
0.036 mmol), NaO Bu (0.072 mmol) and benzene (1.0 mL) in a screw-
capped vial under N at 80 1C for 20 h. GC yield based on HBpin.
b
2
a
c
t
d
Reaction conditions: HBpin (1.2 mmol), Ni(cod)
2
(0.035 mmol),
NaO Bu was not added. Isolated yield.
t
ICyÁHCl (0.035 mmol), NaO Bu (0.070 mmol) and arene (1.0 mL) in a
b
screw-capped vial under N
2
at 100 1C for 20 h. Isolated yield based on
HBpin. At 80 1C. N-Methylpyrrole (2.0 mmol) in methylcyclohexane
We therefore envisaged (1.0 mL).
has not yet been reported, with the exception of the reactions
using highly fluorinated benzenes.
c
d
1
2,13
that the C–H borylation of simple arenes by nickel should be
possible if an appropriate catalyst system can be identified.
We initially examined the nickel-catalyzed reaction of HBpin with
benzene in the presence of a variety of ligands (Table 1). Although we
2
The Ni(cod) /ICy-catalyzed borylation of substituted benzene
derivatives was also investigated (Table 2). When toluene was
used as the substrate, the borylation proceeded efficiently just as
in the case of the benzene substrate (entry 1). The regioselectivity
of the borylation was found to be primarily controlled by steric
effects, forming the meta and para isomers as the major products,
2 3
previously determined that the Ni(cod) /PCy system can mediate
11
the H/D exchange reaction via C–H activation of arenes, this
catalyst system did not lead to the formation of the desired borylated
product 1 (entry 2). In contrast, the use of IMes, an N-heterocyclic
carbene (NHC) bearing a mesityl group, was found to generate 1 in
3
6
8
a result similar to those obtained using Ir, Fe or Co catalysts.
The difference between the present work and these previously
reported catalysts is that the borylation in the current study also
occurred at the benzylic position. The observed product distri-
bution was similar to that obtained using a rhodium-based
5
1% yield (entry 3). Replacing the mesityl group with either the
i
larger 2,6- Pr
2 6 2
C H group (i.e., IPr) or the smaller methyl group
(i.e., IMe) decreased the yield of 1 (entries 4 and 5). Further experi-
mentation with the substituent on the nitrogen of the NHC ligand
revealed that the cyclohexyl-substituted derivative (i.e., ICy) was the
most effective ligand among those tested, with 1 being formed in
1
4,15
catalyst,
although the rhodium system allows the benzylic
isomer to be formed as the major product. The borylation of
ethylbenzene under these nickel-catalyzed conditions also pro-
ceeded to deliver four isomers (entry 2). Disubstituted benzenes
were generally much less reactive than mono-substituted benzenes
under the current reaction conditions (entry 3). The use of anisole
as the substrate resulted in borylation products, with the ortho-
borylated isomer as the major product (entry 4). This regio-
selectivity was in sharp contrast to that observed in homogeneous
71% isolated yield (entry 8). Whereas the use of a saturated analog of
ICy (i.e., SICy) led to a complete loss of catalytic activity (entry 11), the
benzohomolog of ICy (i.e., BICy) promoted the borylation of benzene
with comparable efficiency (entry 12).
B
2
pin
nickel-catalyzed borylation, forming 1 in a 125% yield based on
pin (eqn (1)).
2
was also found to be a suitable boron source for this
B
2
2
3
7
8
Ir, Fe and Co systems, wherein the major products were the meta
and para isomers. This result indicated that a methoxy group
can serve as an ortho-directing group in the current nickel-
catalyzed borylation reaction. It is noteworthy that borylative
(1)
16
cleavage of the C(aryl)–OMe bond in anisole was also observed,
albeit in low yield (7%). Unlike the Hartwig’s hydroarylation
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2
system, 1,3-bis(trifluoromethyl)benzene was not a good sub-
strate in the present reaction (o10% yield). Halogen (Cl, Br and F)
and carbonyl-containing (ketone and ester) benzenes were found to
be inapplicable since these functionalities can react with the nickel
species under these conditions. Heteroarenes were also examined
as potential substrates for the nickel-catalyzed borylation reactions. Scheme 2 Gram scale synthesis of 2-borylindole using Ni(OAc)
Whereas furan, thiophene, pyridine and their benzo-fused deriva-
2
.
tives could not be borylated under these conditions, pyrrole was
found to be exceptionally reactive during this borylation, form- was also possible (entry 6). The reactivity and selectivity of this
ing the 2-borylated product in a regioselective manner (entry 5). borylation was unaffected by the introduction of a methoxy group
Notably, the product was obtained in good yield even when the to the indole framework (entry 7). Although a C(aryl)–F bond can
1
7
amount of pyrrole was reduced to 1.7 equivalents relative to HBpin. be activated by a low valent nickel catalyst, fluoroindole under-
The evident high reactivity of pyrrole prompted us to examine went borylation with its fluoride moiety remaining intact (entry 8).
indole derivatives in this nickel-catalyzed borylation reaction Azaindole also served as a good substrate for this borylation,
(
Table 3). As expected, the borylation occurred efficiently using generating the corresponding 2-borylated product (entry 9).
indole as the limiting agent and also took place regioselectively at Although Ni(cod) was routinely used as the catalyst for this
the 2-position. In addition to N-methylindole (entry 1), a bulkier borylation during our exploratory studies, Ni(OAc) was found
2
2
N-butyl-substituted indole successfully underwent borylation to serve as a more useful catalyst precursor. A protocol using
without any decrease in the regioselectivity of the reaction Ni(OAc) allowed the successful implementation of this borylation
2
(entry 2). An N,O-acetal moiety remained intact, serving as a on the gram-scale, highlighting the practical utility of the nickel-
suitable protecting group in this reaction (entry 3). In addition, catalyzed system (Scheme 2).
N-benzyl groups were also tolerated, leaving the aryl group free
To obtain further insights into the mechanistic aspects of
from borylation (entries 4 and 5). Installation of a boryl group the nickel-catalyzed borylation, some preliminary mechanistic
at the sterically hindered 2-position of 3-substituted indoles experiments were performed. Comparison of the initial rates of
the nickel-catalyzed borylation reactions of benzene and benzene-d
determined that k /k was 2.1, which was slightly smaller than the
6
a
Table 3 Nickel-catalyzed borylation of indoles
H D
2
7
values reported for iridium and iron systems. The nickel-catalyzed
borylation of benzene or indole was also found to be completely
inhibited when the reaction was attempted in the presence of an
excess of mercury. In addition, filtration tests indicated that the
Isolated yield (%) liquid phase of the catalytic mixture did not contain catalytically
active species (see ESI† for details). The currently available data
indicate that the borylation is likely mediated by heterogeneous
nickel species, although more detailed studies are required for a
Entry
Indole
Product
1
2
3
R = Me
R = n-butyl
R = CH
78
68
68
18
definitive understanding of the nature of the catalysis. Finally, a
t
19,20
2
OMe
recent report on the KO Bu-catalyzed silylation of heteroarenes
motivated us to examine the borylation of indole in the presence of
t
only NaO Bu. The borylation product was not observed under such
conditions, indicating that the nickel species play an essential role
in this borylation reaction.
4
5
R = H
R = OMe
82
76
In summary, we have shown for the first time that the direct
borylation of arenes can be mediated by a nickel-based catalyst.
Indoles are particularly reactive with this catalyst system, affording
the corresponding 2-borylated products. The successful use of
nickel is noteworthy because nickel is rarely employed as a catalyst
for the C–H bond activation process in the absence of a directing
6
7
87
76
12
group. The heterogeneous nature of the active species generated
under the current conditions could be important in explaining the
21
unprecedented reactivity of nickel, although further investiga-
tions are required for a complete understanding of the mechanism
of this borylation. The application of these nickel species to other
transformations as well as catalytic borylations using other base
metals are currently being investigated in our laboratories.
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas ‘‘Molecular Activation Directed
toward Straightforward Synthesis’’ from MEXT, Japan. M.T. was
b
8
82
56
b
9
a
Reaction conditions: indole (0.80 mmol), HBpin (1.2 mmol), Ni(cod)
2
t
(
0.040 mmol), ICyÁHCl (0.040 mmol), NaO Bu (0.080 mmol), and methyl-
cyclohexane (1.0 mL) in a screw-capped vial under N
2
at 80 1C for 16 h.
b
HBpin (1.2 equiv.) was used.
6
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also supported by the ‘‘Elements Strategy Initiative to Form
Core Research Center’’ from MEXT. T.F. expresses his special
thanks for a JSPS Research Fellowship for Young Scientists. We
also thank the Instrumental Analysis Center, Faculty of Engineer-
ing, Osaka University, for assistance with the HRMS analyses.
N. Yoshikai, Acc. Chem. Res., 2014, 47, 1208; (c) L. Ackermann, J. Org.
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