Nickel-Catalyzed Heteroarenes Cross Coupling via Tandem C-H/C-O Activation

Article abstract of DOI:10.1021/acscatal.8b03436

Inert aryl methyl ethers as coupling components via C-O activation have been established with a Ni catalyst for C-H activation of heteroarene. The key to simultaneous C-H/C-O bond activation is the use of sterically demanding o-tolylMgBr. The protocol is effective for a wide scope of substrates including naphthyl methyl ethers, anisoles, and a variety of other heteroarene derivatives. Detailed mechanistic studies indicated that the C-O cleavage is assisted via synergistic effect of nickel and Grignard reagent in this C-H/C-O reaction, which is supported by DFT calculation. At this stage, single-electron transfer can be ruled out as a main operative process for this tandem strategy.

Full text of DOI:10.1021/acscatal.8b03436

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Article
Nickel-Catalyzed Heteroarenes Cross
Coupling via Tandem C–H/C#O Activation
Ting-Hsuan Wang, Ram Ambre, Qing Wang, Wei-Chih Lee,
Pen-Cheng Wang, yuhua liu, Lili Zhao, and Tiow-Gan Ong
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03436 • Publication Date (Web): 25 Oct 2018
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Page 1 of 10
ACS Catalysis
1
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Nickel-Catalyzed Heteroarenes Cross Coupling via Tandem C–H/C‒O
4
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6
Activation
Ting-Hsuan Wang,†,‡,¶ Ram Ambre,†,¶ Qing Wang$, Wei-Chih Lee,£ Pen-Cheng Wang,‡ Yuhua Liu,§
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Lili Zhao,*,$ and Tiow-Gan Ong*,†
† Institute of Chemistry, Academia Sinica, No. 128, Sec. 2, Academia Road, Nangang, Taipei, Taiwan, ROC.
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$ Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center
for Advanced Materials, Nanjing Tech University, Nanjing 211816, China
‡ Department of Engineering and System Science, National Tsing Hua University, Hsinchu, Taiwan, ROC.
£ Green Energy and Environment Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan, ROC.
§ School of Chemistry and Chemical Engineering, Guangzhou University, Guangzhou, 510006, China.
ABSTRACT: Inert aryl methyl ethers as coupling components via C‒O activation has been established with Ni catalyst for
C‒H activation of heteroarene. The key to simultaneous C‒H/C‒O bond activation is the use of steric demanding
o-tolylMgBr. The protocol is effective for a wide scope of substrates including naphthyl methyl ethers, anisoles and a variety
of other heteroarene derivatives. Detailed mechanistic studies indicated that the C‒O cleavage is assisted via synergistic
effect of nickel and Grignard reagent in this C‒H/C‒O reaction, which is supported by DFT calculation. At this stage, single
electron transfer can be ruled out as a main operative process for this tandem strategy.
Keywords: Tandem catalysis; C–H activation; C–O cleavage; nickel; carbodicarbene; cross-coupling.
INTRODUCTION
Since the 1970’s, metal-mediated cross-coupling
coupling partners for the C‒H activation of arenes bearing a
convertible directing group using a rhodium bis(N-
heterocyclic carbene) catalyst.9 Other notable cases could
also be found in seminal works by Ackermann and Song
utilizing aryl carbamates via a cobalt catalyzed process.10 In
spite of methoxy being a pervasive motif, it is surprising that
cross coupling reaction of heteroarene using C‒O
activation’s strategy of aryl methyl ethers as coupling is not
reported, as C‒OMe has the highest energy dissociation and
is generally considered as a poor leaving group (Scheme
1).1b Herein we report a proof-of-concept strategy to forge a
coupling product derived from simultaneous cross coupling
reaction manifolds based on C‒H cleavage of benzimidazole
and heteroarene derivatives by Grignard reagent and nickel
mediated C–O bond activation of aryl methyl ethers. The
present work also performed detailed experimental and
computational study of the reactions in this tandem process
in an effort to understand what factors (Grignard reagent,
ligand) govern these simultaneous bond cleavages
C‒H/C‒O as well as the nature of mechanism.
reactions have emerged as a significant and versatile
synthetic strategy to streamline a variety of biaryl skeletons.
In common practice, aryl halides are frequently used as
electrophilic synthons, which currently appear to be less
environmentally benign. For that reason, O-derived
electrophiles have been promoted as a potential surrogate.1
In 1979 Wenkert reported the pioneering work of nickel
catalyzed cross-coupling of aryl ethers with Grignard
reagent via C‒O bond cleavage,1e however this reaction
remained overlooked for 30 years until late 2000s. Since
then, several examples of halide-free coupling reactions
have been reported for carbamates,2 carbonates,3 ethers,4
and some limited cases in phenols5 and alcohols. Nickel
appears to be the superior catalyst for the process of
activating the inert C(aryl)–O bond.1b,c Our group has a long-
standing interest in nickel directed C‒H activation
reactions,6 as these methods generate less chemical waste
by circumventing additional steps associated with
prefunctionalized substrates. Ultimately, a protocol relying
on tandem C‒H/C‒O bond activation would not only fulfill
the tenets of a “green” process, but also further empower
the utility of the cross-coupling paradigm, as both C‒H and
C‒O moieties are pervasively present in many molecules.
To date, efforts for C‒H functionalization with O-
derived electrophiles, namely phenol derivatives have
found limited success. Itami and co-workers first reported
the nickel-catalyzed reaction of aryl pivalates with azoles.7
Shi and co-workers recently demonstrated that the
coupling reaction is viable based on Ni/Cu mediated dual
catalysis for C‒H activation of perfluorinated arenes with
C‒O activation of aryl carbamates.8 Similarly, Chatani,
Tobisu and co-workers employed aryl carbamates as
easy of C(Ar)-O bond breaking
carbamate
O
ester
O
Ar
Ar
Ar
O
NR2
O
O
R
O
O
O
O
O
Ar
S
Ar
S
Ar
Me
O
P
O
CF3
O
p-tol
Ar
aryl methyl
ether
O
OR
O
OR
triflate
tosylate
OR
phosphate
carbonate
good availability, low cost
Scheme 1. Ability of C‒O bond cleavage.1b
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ACS Catalysis
Page 2 of 10
RESULTS AND DISCUSSION
yield into practical range,11 though these conditions were
1
2
3
4
5
6
7
8
Reaction Evaluation on Simultaneous C‒H/C‒O
Activation. To test our thought, we began with the coupling
reaction of 2-methoxynaphthalene (1a) and 1-
methybenzimidazole (2a) (Scheme 2). In screening A, 10
mol% Ni(cod)2 and PPh3 ligand appeared as an optimal
catalyst system to generate preferred product 3aa in 46%
yield at 130 °C (blue column in Scheme 2). Inclusion of
PhMgBr (1.0 equiv) in the reaction was necessary to
facilitate C‒O cleavage of 1a, but it also generated 20%
undesired 5aa and trace amount of Kumada byproduct 11
(red column represent all minor side-products shown in
Scheme 2). Selecting m- or o-xylene solvent in method B
(63%) or adding LiCl salt in method C (60%) pushed the
still plagued by side reactions (25%). Next, we varied ligand
selection with a series of ligands in method D. Interestingly,
sterically demanding scaffolds like P(o-tolyl)3, IPr and 4,5-
Me2IMes consistently afforded high chemo-selectivity for
3aa. Furthermore, the use of bulky reagent o-tolylMgBr in
method E reinforced the notion that high steric favored
productive reaction for 3aa, as clearly reflected by the very
low yield in 5 (~5%). Finally, we successfully attained 92%
yield with no byproduct at a lower temperature of 90 °C
using a slight excess of 1a in method F based on selecting
best of the best from methods A to E. We additionally note
that the carbodicarbene (CDC), electron-rich ligand is also
effective for this catalytic C‒H/C‒O protocol.12
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A.
B.
C.
D.
E.
[M] 10 mol%
Solvent
Additive 1 equiv
Ligand 10 mol%
R-MgX 1 equiv
N
O
N
N
R
R
+
+
H
+
N
N
N
1a
2a
3aa
C
: additive
5
11
A
B
: catalyst selection
: solvent variations
Ni(cod)2, toluene, PPh3, PhMgBr,
cat, toluene, PPh3, PhMgBr, 130°C
solvent
Ni(cod)2,
, PPh3, PhMgBr, 130°C
additive
130°C,
F:
A
B, C, D
E
The best optimized condition via
,
&
64%
63%
51%
60%
51%
57%
Temp
Ni(cod)2, m-xylene, iPr, p-tolylMgBr,
, LiCl
46%
20%
46%
41%
25%
33%
29%
27%
92%
88%
25%
25%
21%
22%
20%
15%
13%
75% 75%
4%
CsCl
MgCl2
130°C
LiCl
None
Ni(cod)2
Ni(OAc)2
NiCl2(PPh3)2
O
O
40%
D
: ligand selection
E
: grignard variation
ligand
Ni(cod)2, toluene,
, PhMgBr, 130°C
RMgBr,
Ni(cod)2, toluene, PPh3,
oC =
90
90 (CDC)
N
N
130
90
70
1.5 equiv
2a
60%
58%
61%
60%
iPr
50%
46%
37%
N
C
N
PPh2 PPh2
31%
21%
N
20%
N
20%
15%
18%
14%
0%
iPr
12%
12%
9%
7%
10%
N
10%
6%
5%
-tolyl
8%
3%
3%
carbodicarbene :CDC
R= Me
Et
Cy Benzyl
Ph
p-tolyl
o
P(o-tolyl)3
PCy3
N
N
N
Scheme 2. Optimization procedure.
Substrate Scope and Limitation. With the optimized
conditions in hand, we examined the reaction scope with a
series of methoxynaphthalene derivatives 1 and 1-
methylbenzimidazole 2a (Table 1). Excellent yield was
attained for 1a to afford coupling product 3aa (92%).
Variations at C6 of methoxynaphthalene were first
examined. 1b bearing silyl group was used to afford product
3ba in moderate yield (50%). Pyridyl (1c) and
diphenylamino (1d) derivatives were also effectively
converted to the desired coupling product 3ca (79%) and
3da (82%), respectively by CDC as the supporting ligand.
Encouragingly, 2-methoxy-6-phenylnaphthalene (1e) could
also undergo C‒O activation to afford the corresponding
coupling product 3ea in 60% yield. In addition, we
performed several 2-methoxy-6-arylnaphthalenes (1f-j),
which proved suitable for this protocol, affording moderate
to good yields. It is worth mentioning that a synthetic
strategy using naphthalenes containing aryl and
polyaromatic rings would be useful for constructing organic
photosensitizer materials, which are further exemplified by
the formation of 3ka (carbazole),13 3la (pyrene),14 and 3ma
(styryl).15 Regrettably, neighboring steric hindrance has
adverse effect on the yield of 1s. Finally, representative
samples of naphthalene with electronic variation at C7 (1n-
r) and commercially available 1-methoxynapthalene (1t)
are effective coupling partners. It is noted that substrates
bearing withdrawing groups are not suitable in this catalytic
protocol, as they would interact with the Grignard reagents.16
The Scope of Aryl Methyl Ethers. At present, nickel-
promoted C‒OMe cleavage for carbon-carbon bond
forming reactions remains largely confined to the
naphthalene moieties as coupling partners. The existing
catalytic state-of-the-art takes advantage of the π-extended
backbones of naphthalene for a strong π-coordination to Ni
complexes, prior to C‒O functionalization.17 Such a C‒O
transformation is less likely to occur in anisole because of
higher energy penalty for the loss of ring aromaticity.18 To
address this challenge, we sought to extend the catalytic
utility to aryl methyl ethers 4x (Table 2). Under similar
reaction conditions, we were pleased to discover that
anisole 4a is an effective substrate to afford coupling
product 5aa in 82% yield. The methyl substituents at meta
(4c) and para (4d) positions are tolerated affording good
y i e l d s ( 6 6 % a n d 5 5 % , r e s p e c -
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Page 3 of 10
ACS Catalysis
a,b
Table 1. Scope of Methoxynaphthalene Derivatives
Electron-donating substrates like dimethyamino and
diphenylamino at different positions relative to the
methoxy group also afforded effective transformations
(4m-p) (68-87%). Finally, other less conventional
substrates like 1-methoxy-4-styrylbenzene (4q), pyrrole
(4r) and carbozole (4s) proved equally effective in this
method, reinforcing its broad-scope applicability. The
demonstrated protocol of simultaneous C‒H activation was
further extended for the C‒O cleavage of steroidal hormone
Ni(cod)2, IPr
o-tolylMgBr (1.5 equiv)
LiCl (1 equiv)
N
1
2
3
4
5
6
7
8
O
N
Me
Ar
R1
+
N
90 o C, 16 hrs
m-xylene
N
2a
3xa
1x
20 examples
variaiton at 6-position:
OMe
OMe
OMe
OMe
TMS
OMe
N
Ph2
N
c,d
c,d
R
1a,
92%
N
1c,
1b,
66% (79%
)
50%
1d
, 82%
1e
, R=H
60%c,d
57%c,d
60%c,d
45%c,d
45%c,d
61%c,d
OMe
OMe
1f,
1g
1h
R=2-Me
, R=3-Me
, R=4-Me
R=4-tBu
OMe
-esterdiol
methoxy
derivative
(4t)
with
1-
Ph
1i
,
9
1j
,
R=2-Mes
c,d
c,d
methylbenzimidazole (2a) under general nickel catalyzed
reaction conditions readily accomplished corresponding
product (5ta) with 74% yield leaving aliphatic methoxy
group intact (Scheme 3).
1k
, 71%
variation at 7-position:
Ph2 OMe
1l
, 52%
1m
, 41%
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variation at 1-position:
R
N
OMe
OMe
CH3 OMe
c,d
1n
, 81%
CH3 OMe
OMe
O
OMe
H
Ni(cod)2, CDC
o-tolylMgBr
LiCl
N
N
85%c,d
83%c,d
76%c,d
c,d
1p,
1q,
1r,
R=H
R=Me
R=t-Bu
H
1t
, 60%
+
H
H
c,d
1s
, 35%
N
1o
, 46%
H
H
m-xylene
90oC, 16 hrs
MeO
N
aCondition: 1 (0.75 mmol), 2a (0.5 mmol), Ni(cod)2 (0.05 mmol), IPr
(0.05 mmol), o-tolylMgBr (0.75 mmol) and LiCl (0.5 mmol) in m-xylene
(0.7 mL) at 90 oC for 16 hours unless otherwise noted. b Isolated yield. c
CDC is used instead of IPr. d w/o LiCl.
2a
4t
5ta (74%)
Scheme 3. Simultaneous C‒H activation and C‒O cleavage
of steroid hormone -Esterdiol derivative.
Table 2. Scope of Various Anisole Analogues a,b
Table 3. Scope of Heteroarenes a,b
R
Ni(cod)2, IPr
o-tolylMgBr (1.5 equiv)
LiCl (1 equiv)
N
N
N
N
O
+
Me
Ni(cod)2, IPr
O
R
o-tolylMgBr (1.5 equiv)
90 o C, 16 hrs
m-xylene
19 examples
LiCl (1 equiv)
+
HeteroAr
HetroAr
90 o C, 16 hrs
4x
2a
5xa
m-xylene
1a :
4a:
Naph-OMe
Anisole
2x
6xa 7xa
or
22 examples
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Benzimidazole derivatives
Imidazole derivatives
CH3
N
N
N
N
N
N
N
N
N
N
N
N
N
CH3
CH3
H3C
CH2CH3
tBu
N
N
CH3
N
Ph
2l,
4b
25%
4c
66%
4e
Ph
4f
4g
40%
4a
4d
Mes
Bn
76%c,d
75%c,d
82%c,d
e
55%c,d
e
2k,
2n,
31%
c
53%
30%
2m
, 35%
2a,
2b, 81%
92%
2c,
75%
2d,
30%
R=H
63%d
Other heteroarene derivatives
2e,
N
N
OMe
OMe
OMe
OMe
OMe
OMe
2f,
2g,
2h,
2i,
R=2-Me N.D.
R=3-Me 68%d
R=4-Me 57%d
R=4-tBu 86%d
R=4-OMe 43%d
4i
4j
4k
R=H
83%c,d
R=Me 65%c,d
N
N
N
N
R= Bu 68%c,d
NPh2
t
NMe2
R
Ph
NMe2
2j,
NPh2
2q,
2p, 60%
33%
2o,
60%
R
4m
68%c,d
4h
4n
4o
4p
87%c,d
62%c,d
75%c,d
78%c,d
Benzimidazole derivatives with anisole (4a)
N
N
N
N
N
N
N
N
OMe
2e,
2i,
R=H
56%e
R=4-tBu 60%e
MeO
MeO
N
N
MeO
e
e
e
2a,
2c,
72%
82%
2b,
65%
OMe
R
a
4s
58%c,d
4r
50%c,d
4q
33%
4l
71%c,d
Condition: 1a/4a (0.5 mmol), 2 (0.75 mmol), Ni(cod)2 (0.05 mmol), IPr
(0.05 mmol), o-tolylMgBr (0.75 mmol) and LiCl (0.5 mmol) in m-xylene
(0.7 mL) at 90 oC for 16 hours unless otherwise noted. b Isolated yield.
c p-tolylMgBr is used instead of o-tolylMgBr. d P(o-tolyl)3 is used instead
a
Condition: 1 (0.5 mmol), 2a (0.75 mmol), Ni(cod)2 (0.05 mmol), IPr
(0.05 mmol), o-tolylMgBr (0.75 mmol) and LiCl (0.5 mmol) in m-xylene
(0.7 mL) at 90 oC for 16 hours unless otherwise noted. b Isolated yield. c
CDC is used instead of IPr. dw/o LiCl.
of IPr w/o LiCl. e CDC is used instead of IPr w/o LiCl.
The Scope of Heteroarenes. As benzimidazole and its
derivatives are inherent structures present in many
biologically active natural products,19 pharmaceuticals,20
and optoelectronic materials,21 we next examined the scope
of this reaction with its C–H manifold substrates (Table 3).
Under similar reaction conditions, the electron-rich 1,5,6-
trimethyl-benzimidazole (2b) was coupled with 2-
methoxynapthalene (1a) to give 6ba in excellent yield
(81%). Similarly, coupling with 1-ethylbenzimidazole (2c)
afforded 75% yield, whereas coupling with 1-
benzylbenzimidazole (2d) afforded only 30% yield, likely
due to the presence of its bulky dangling benzyl group. 1-
Phenylbenzimidazole (2e), 1-meta-tolylbenzimidazole (2g),
1-para-tolylbenzimidazole (2h), and more bulky 1-para-
tertiarybutyl phenyl benzimidazole (2i) generated coupling
tively), but 4b bearing the ortho methyl group affords lower
yields. We believed that the proximal steric influence was a
contributing factor. In addition, the catalytic reaction could
be performed with several anisoles possessing different
alkyl substitutions (4e, 4f, and 4g), including a more bulky
t-butyl group, albeit the latter resulted in lower yield. Next,
we investigated 4-methoxy-1,1'-biphenyl (4h), 3-methoxy-
1,1'-biphenyl (4i) and other similar counterparts (4j and 4k)
for coupling reactions which also afforded good yields. The
success of constructing these end products (5ha, 5ia, 5ja
and 5ka) represents a complementary method for
polyaromatic
compounds.
Interestingly,
1,3-
dimethoxybenzene (4l) underwent only single-fold C–O
cleavage, leaving the other methoxy functionality intact.
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Page 4 of 10
products with moderate to good yields (57-86%), whereas can be easily excluded because of the very high barrier of
1
2
3
4
5
6
7
8
1-ortho-tolylbenzimidazole (2f) did not provide the
expected product due to steric hindrance. It is noteworthy
33.4 kcal/mol (TS1’’, see Figure S2 for details), which is
mainly due to the larger steric effects. Alternatively, the
addition of 2a lead to the intermediate IM1’ (see Figure S2),
with one ether ligand 1a released from the Mg-center. The
C–H activation barrier is predicted to be 22.8 kcal/mol (IM1’
→TS1’, Figure S2), which is in the range for experimental
that
the
electron
donating
1-para-
methoxyphenylbenzimidazole (2j) was successfully
coupled with 2-methoxynaphthalene to construct 43% of
6ja, leaving the methoxy functional group intact.
The reaction was not kept limited to the benzimidazole
moiety but also extended to imidazole derivatives and other
heteroarene compounds. Imidazole derivatives (2k-n)
produced fused products in low to moderate yields. Other
heteroarene compounds such as isoquinoline (2o), 3-
methylisoquinoline (2p), and imidazo[1,5-a]pyridine (2q)
afforded coupling products 6oa (C–H activation at 1-
position), 6pa (C–H activation at 1-position), and 6qa (C–H
activation at 3-position), respectively. The C–O cleavage of
anisole 4a with representative benzimidazole derivatives
(2a, 2b, 2c, 2e, and 2i) was also applied to produce their
coupling products 5aa, 7ba, 7ca, 7ea, and 7ia respectively
in good yields.
realization under high temperature. This agrees with the
experimental verification as shown in Scheme 4.
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13
14
15
16
17
18
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22
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60
Mechanistic Studies: The Nature of C‒H Bond Activation.
Given the unique reactivity of the Ni-catalyzed tandem
C‒H/C‒O activation, we are interested to gain further
insight into the reaction mode. First, it is important to
examine the nature of the CH functionalization in this
catalytic reaction. A reaction of 2a in presence of o-
tolylMgBr was stirred at 90 °C for 30 minutes followed by
D2O treatment (Scheme 4.1), affording only deuterium
Figure 1. Computed energy profiles of C‒H activation with
Ni-catalyst and Grignard reagent at the BP86/def2-
TZVPP(PCM, solvent=m-xylene)//BP86/def2-SVP level. Key
bond distances are given in Å. Trivial hydrogen atoms have been
omitted for clarity. Color code: Ni, purple; N, blue; O, orange; C, gray; H,
white; Mg, yellow; Br, dark red.
1
substituted-2a in H NMR analysis. A similar outcome was
Nonetheless, the addition of the nickel complex in the
reaction system can further reduce the energy barrier. As
shown in Figure 1, the addition of IPrNi(COD) in presence
of [RMgX(1a)2] and 2a can firstly generate the intermediate
IM1, with one 1a and COD ligand released. Subsequently, C–
H activation can be easily achieved via a low barrier of 7.4
kcal/mol (IM1→TS1), leading to IM2, in which the
activated H-atom is bonding to Ni-center. The Ni-H moiety
in IM2 then slightly adjust position to transfer the H atom
to the phenyl group by passing a barrier of 10.3 kcal/mol
(TS2), leading to IM3 and PhCH3. The feasible kinetics and
thermodynamics imply that the nickel complex indeed
participates in C‒H bond activation or the deprotonation
step. This calculation result is further confirmed by
performing reactions with 2a at 35 °C and 60 °C in Scheme
5. No deprotonation was observed in presence of o-
tolylMgBr (Scheme 5.1) at both temperatures, after reaction
was quenched with excess of D2O in 45 minutes.
Nevertheless, we witnessed 35 % and 42 % yield of
deuterium substituted-2a when the reaction is conducted
in the presence of Ni(cod)2 (10 mol %) and o-tolylMgBr (1
equiv) at 35 °C and 60 °C, respectively (Scheme 5.2). These
outcomes obviously highlight the importance of both nickel
and Grignard reagent in assisting the C‒H bond activation.
observed with the reaction with PhMgBr (Scheme 4.2).
These results indicate the possibility that the C‒H activation
of 2a might occur via deprotonation process by Grignard
reagent to generate Hetero-MgBr species (2a-MgBr).
Nevertheless, the known nickel-mediated C‒H activation
process could not be ruled out at this stage.22 Regardless to
the nature of C‒H activation, the studies on kinetic isotope
effect of 2a-D and 2a in Scheme 4.3 and 4.4 showed there
are no significant intermolecular KIE value (kH/kD ≈ 1.1).
in situ generation
N
N
N
N
N
N
D2O
o-tolylMgBr
H/D
H
MgBr
(1)
(2)
(3)
90 oC, 30 mins
(H:D = 0:100)
2a
2a-MgBr
N
N
N
N
D2O
PhMgBr
H/D
N
H
MgBr
90 oC, 30 mins
N
2a
2a
(H:D = 0:100)
2a-MgBr
OMe
N
+
+
H
N
1a
1.5 equiv
Ni(cod)2 / IPr 10 mol%
N
o-tolylMgBr 1.5 equiv
m-xylene, 90 oC, 45 mins
N
N
N
OMe
3aa
(4)
D
KIE = 1.1
2a-D
1a
1.5 equiv
Scheme 4. Reaction studies pertaining C‒H activation.
N
N
N
o-tolylMgBr (1 equiv)
D2
O
H
H
D
+
(1)
T oC, 45 mins
N
N
N
To understand the nature of C‒H bond activation, DFT
calculations were further performed to the study the role of
nickel complex in the deprotonation process. Inspired by
the previous study23, the structure of Grignard reagent
could be calculated as the simplified model [RMgX(ether)2]
(i.e., [RMgX(1a)2]). As shown in Figure 1, the reaction
pathway for the C‒H activation mediated by [RMgX(1a)]2
2a
T = 35
T = 60
0 %
0 %
100 %
100 %
Ni(cod)2, IPr (10 mol%)
N
N
N
N
D2
O
-tolylMgBr (1 equiv)
o
H
D
+
H
(2)
N
T oC, 45 min
N
2a
T = 35
T = 60
35 %
42 %
65 %
58 %
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Scheme 5. Reaction studies about the synergistic roles of bond activation is rested upon the dual ability synergistic
1
2
3
4
5
6
7
8
Ni-ArMgBr in assisting C‒H bond activation.
effect invoked by Grignard reagent and nickel to
deprotonate 2a, and to hinder the reaction pathway
favoring undesirable coupling products in the C‒O bond
cleavage. The contemporary mechanistic argument hinged
on Ni(0)-Ni(II) cycle should well explain about the side
reaction for the formation of Kumada byproducts 11a-d,
when less bulky Grignard reagent is used. However, it could
not account for the formation of other side-products for 5aa,
The Role of Grignard Reagents in C‒O Cleavage.
Undoubtedly, the Grignard reagent is essential for the
coupling reaction with 1-benzimidazole 2a. Thus, it should
make no difference in the reactivity topology of which type
of Grignard reagents were used if the deprotonation
process is a true operative mechanism. However, we were
also puzzled by the necessity of employing an excess
amount of Grignard reagent (~1.5 equiv) in this tandem
catalytic manifold. In practice, only one equivalent of
Grignard reagent is needed in this catalytic reaction to
generate a HeteroMgBr 2a-MgBr, which would be, in theory
capable of assisting C‒O bond cleavage. Interestingly, o-
tolylMgBr, a sterically demanding reagent appeared much
more effective than PhMgBr (see optimization process in
Scheme 2). These observations hinted that ArMgBr had
more roles other than a simple possible deprotonation. We
elected to study this reaction by using one equivalent of
Grignard reagent stirred with 2a for 30 minutes with Ni/IPr
catalyst’s addition (Scheme 6). The reaction with one
equivalent o-tolylMgBr yielded product 3aa (52%) and
other unproductive couplings 5ba (4%), 11a (7%) and 12a
(0%) (Scheme 6.1). Unproductive coupling of 5aa (27%),
11b (20%) and 12a (9%) increased even substantially in
the expense of the productive 3aa’s formation (30%), when
a catalytic reaction used a less bulky PhMgBr (Scheme 6.2).
The alkyl Grignard reagent MeMgI have suffered an even
lower yield of 3aa (11%) (Scheme 6.3) The outcome in
Scheme 6 demonstrated the spatially crowded Grignard
was critical to the success of the reaction, particularly in the
aspect of assisting C‒OMe bond cleavage. It is plausible to
infer that in-situ formation of Grignard adduct of 2a was not
as effective as o-tolylMgBr in assisting C‒O/C‒H bond
5ab and 12a-b (homo-coupling byproducts) in Scheme 6.
9
unproductive couplings
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
N
N
N
N
MgBr
Nap
tol
Nap tol
Nap Nap
(1)
(2)
(3)
3aa
5ab
11a
12a
52%
4%
7%
0%
N
N
N
N
MgBr
Ph
Nap
Nap Ph
Nap Nap
3aa
5aa
11b
12a
N
N
30%
27%
20%
9%
N
N
N
N
2a
Me
Nap
Me MgI
Nap Me
Nap Nap
3aa
10a
11c
12a
11%
trace
35%
0%
N
N
MgBr
O
N
N
tol
Ph
Ph tol
Ph Ph
(4)
5aa
5ab
11d
12b
34%
5%
8%
trace
Scheme 6. Reaction studies pertaining the ArMgBr’s roles.
We suspected that the single electron transfer process with
Ni(I) intermediate species might come into play. The results
of several studies involving Ni and Pd catalysts have
provided evidence that radical pathways, including single-
electron-transfer processes, are involved in the cross-
coupling reactions.24 A radical scavenger such as TEMPO
was employed to probe this catalytic reaction.25 Under the
exact catalytic conditions, the CDC-promoted reaction was
partially inhibited by the addition of TEMPO (~10 mol%),
as the catalytic efficiency has been diminished from its
original of 88% to 26% (Scheme 7.1). Interestingly, we also
found that increasing the amount of TEMPO up to 50 mol%
did not completely impede the catalytic activity (22%).
Similar trend of observation is also witnessed in the
reaction using IPr ligand.
cleavage, resulting
a
non-productive formation of
undesirable coupling product. To further verify the
postulation, a reaction of anisole 4a in presence of o-
tolylMgBr (1 equiv) was conducted (Scheme 6.4), and its
high proportion of productive coupling is indeed consistent
with our thought that the Grignard plays a secondary role in
minimizing non-productive coupling and assisting
C‒H/C‒O bond activation.
Additional reaction was subsequently carried out under the
standard reaction conditions with 1,1’-diphenylethylene
treatment (1,1’-DPE, Scheme 7.2) in hope to recapture any
the aryl or naphthyl radial species in the reaction to afford
the corresponding coupling product of 21 and 22.26 Despite
of slightly lower yield (~78%) than the normal condition,
no any trace amount of 21 and 22 was detected by GC-MS.
Notably, no EPR signal was detected in the reaction solution
in ambient or low temperature (10K). With these results,
we have some reasonable doubts about the main operative
pathway involving a continued generation of the aryl or
naphthyl radical. More importantly, the sheer volumes of
literatures of the C‒O bond transformation reported
mechanistic evidence involved 2-electron process so far.27
For example, a recent comprehensive theoretical and
experimental study by Tobisu, Chatani and Mori indicated
nickel-promoted cross-coupling of methoxyarenes via C‒O
cleavage revolved around Ni(0)-Ni(II).27a
The Scheme 6 also revealed the noticeable discrepancy of
the yield for 3aa using different Grignard reagents, strongly
suggesting that a simple deprotonation of 2a by Grignard
might not be the key reaction in C‒H bond activation. It
suggests that nickel complex is playing a significant role not
only in C‒H bond activation with Grignard reagent (Figure
1 and Scheme 5), but also in C‒O bond cleavage process.
This agrees well with the DFT calculations. The very high
≠
barrier (∆G =66.2 kcal/mol, Figure S3 in Supporting
Information) excluded the possibility of the direct reaction
of methoxyarenes with Grignard reagent. As expected, the
inclusion of the Ni-complex can significantly promote the
C‒O bond cleavage, with an activation barrier of 25.7
kcal/mol (IM9→TS5) (see Figure S3), which demonstrates
the significant role of nickel catalyst and Grignard reagent
in the C‒O cleavage process.
Possibility of Radical Intermediate? The key to the
successful catalytic reaction for simultaneous C‒H and C‒O
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The Ni(I) Complex in the Catalytic Cycle. Next, we turned invoked between RMgBr and nickel is essential for not only
1
2
3
4
5
6
7
8
our attention to postulate that the nickel(I) species might be
responsible for the formation of side products in the
catalytic reaction. To further confirm this postulation, a
carbodicarbene Ni(I) complex 20 was prepared via
comproportionation reaction of Ni(cod)2 and Ni(PPh3)2Cl2
in presence of CDC ligand and its structural identity was
confirmed as a distorted trigonal Ni(I) chloride complex
bearing both CDC and PPh3 ligands (see Scheme 8.1).
lowering the activation energy barrier of the C‒O/C‒H
cleavage but a more sterically demanding Grignard reagent
is also important to suppressing the unproductive products
in this reaction. Subsequently, the reductive elimination of
complex V completes the catalytic cycle to deliver desired
product 3aa. At this juncture, we also performed a series of
intermolecular competition experiments with various aryl
methyl ethers (Scheme 10). The results revealed that
biphenyl 4h (36 %) was favorably functionalized, while the
analogous 4p (6%) underwent low reactivity (Scheme 10.1).
More importantly, we also observed similar result
positively correlated with intermolecular competition
reactions between 1a and 4a, in which the substrate
bearing more π-conjugation reacted more favorably
(Scheme 10.2). These results thus highlight that π-
coordination of Ni complex with the assistance of Lewis acid
is important to lower C‒O activation barrier. Moreover,
Lewis acid promoted C‒O cleavage assisted by π-
coordination with Ni complex has been well-documented in
recent theoretical and experimental works by Chatani,
Tobisu and Mori27 and many other related literatures.3e,4a,4e
It should be noted that control experiments to test eletronic
influnce arisen from substituents (Scheme 10.3) show no
major difference between 4p and 4a in the yield of the
reaction, indicating the slowest stage may not related to the
oxidative addition of C‒O bond.17e
Ni(cod)2 10 mol%
9
N
N
O
N
N
ligand 10 mol%
o-tolylMgBr 1.5 equiv.
X mol% TEMPO
90 oC, 16 hrs
(1)
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2a
1a
3aa
TEMPO
0 mol% 10 mol% 20 mol% 50 mol%
L
L = CDC
88%
92%
26%
23%
22%
15%
19%
14%
3aa
yield
L = IPr
3aa
yield
Ni(cod)2 10 mol%
ligand 10 mol%
o-tolylMgBr 1.5 equiv.
X mol% 1,1'-DPE
90 oC, 16 hrs
N
N
O
N
Nap
non-detected
Ph
(2)
+
N
3aa
2a
1a
1,1'-DPE
Nap
Ph
0 mol% 10 mol% 20 mol% 50 mol%
21
L
Ph
Ph
L = CDC
88%
92%
80%
83%
80%
81%
75%
77%
3aa
o-tolyl
yield
L = IPr
22
3aa
yield
Scheme 7. Reactions to probe possibility of radical reaction.
Performing the catalytic reaction with 20 under similar
reaction conditions furnished a good conversion of product
3aa in 72% yield, a sign that Ni(I) species was possible part
of the intermediacy or resting state in this catalytic process
(Scheme 8.2). Based on the recent seminal work on
dinuclear system in the efficient nickel-catalyzed Kumada-
Tamao-Corriu cross-coupling of aryl halide,28 we have
reason to believe that the tentatively non-radical bimetallic
mechanism could be the key for generating byproducts 5,
11 and 12 as illustrated in Scheme 9. Yet, Ni(0)-Ni(II)
catalytic cycle cannot be rule out as a possibility at this stage.
This minor amount of Ni(I) appeared in the catalytic
reaction perhaps resulted from the comproportionation
reaction between the mixture of Ni(0) and Ni(II) species.29
II
Ni
N
R H
Ln
N
N
N
H
Ni
Ln
III
1a
byproducts
R
Mg
1a
Br
Mg
1a
RMgBr(
)
2
Br
1a
R
R
N
N
OMe
NiILn
NiILn
H
II III
or
2a
1a
Ln Ni0
I
Ln NiI
R
N
Ln
Ni
N
Ln
Ni
1a
RMgBr(
)
1a
2
O
N
Mg Br
3aa
Me
N
1a
Me
Mg
O
IV
Br
V
1a
iPr
N
Scheme 9. Proposed mechanism of C‒H and C‒O activation.
Ph3P
Cl
C
N
N
iPr
Ni
N
N
N
C
(1)
+
Ni(cod)2
N
Ni(PPh3)2Cl2
iPr
OMe
OMe
0.5 mmol
N
N
N
iPr
N
N
N
N
Ni(cod)2 10 mol%
C2-allene 10 mol%
90 %
+
+
(1)
Ph
N
20
o-tolMgBr 1.5 equiv
m-xylene, 90 oC, 45 mins
N
Ph
5ha
5pa
20
complex
10 mol%
4h
4p
O
N
36%
N
6%
o-tolylMgBr 1.5 equiv
(2)
1.5 equiv
1.5 equiv
+
90 oC, 16 h
N
N
N
2a
3aa
1a
72 %
OMe
0.5 mmol
N
OMe
+
N
N
Ni(cod)2 10 mol%
IPr 10 mol%
Scheme 8. CDC-Ni(I) complexes and the catalytic reaction.
(2)
+
N
N
o-tolMgBr 1.5 equiv
m-xylene, 90 oC, 45 mins
1a
4a
1.5 equiv
3aa
5aa
Taking into account of all mechanistic studies
considerations, a general proposed mechanistic cycle is
outlined in Scheme 9. The nickel-promoted deprotonation
reaction of 1-methylbenzimidazole 2a with excess RMgBr
affords the intermediate II, which undergoes C‒H activation
step generating the complex III. The addition of 2-
methoxynaphthalene 1a to III would deliver a Ni(0)
complex IV (see Figure S4 and Table S7 in SI for details),30
which can further be transformed to intermediate V via the
oxidative addition step. Importantly, cooperative effect
1.5 equiv
34%
12%
N
0.5 mmol
N
OMe
H
OMe
Ni(cod)2 10 mol%
C2-allene 10 mol%
N
N
N
N
H
+
N
(3)
+
o-tolMgBr 1.5 equiv
m-xylene, 90 oC, 45 mins
N
5aa
24%
5pa
18%
4a
4p
1.5 equiv
1.5 equiv
Scheme 10. The intermolecular competition experiments.
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Finally, we also carried out an experiments, as illustrated in
Scheme 11 to demostrate the high energy barrier in the
1
2
3
4
5
6
7
8
reductive elimination step, which may required high
temperature condition. In Scheme 11.1, we can witness a
complete conversion of 2a to deuterium substituted-2a at
slightly lower temperature 60 °C in presence of 1 equiv of
Ni catalyst and ArMgBr for 45 minutes, a strong
experimental evidence of a cooperative role of Ni and
Grignard reagent in the C‒H and C‒O activation. At the
same time, we also continued to heat the reaction at 90 °C
for 45 minutes (see Scheme 11) to afford coupling product
3aa in 66% yield. With these results, it is no surprise to find
out that the rate determining step of this catatytic reaction
hinged on the C‒H/C‒O activtion is reductive elimination
with high temperature.
ORCID ID:
Tiow-Gan Ong: 0000-0001-9817-6300
Author Contributions
¶These authors contributed equally to this work. All authors
have given approval to the final version of the manuscript
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was financially supported by the Ministry of Science
& Technology of Taiwan (MOST-104-2628-M-001-005-MY4
grant) and Academia Sinica Career Development Award (104-
CDA-M08). L.Z is acknowledge the high performance center of
Nanjing Tech University for supporting the computational
resources, the financial support from Nanjing Tech University
(grant number 39837123) and SICAM Fellowship from Jiangsu
National Synergetic Innovation Center for Advanced Materials,
Natural Science Foundation of Jiangsu Province for Youth
(grant no: BK20170964), and National Natural Science
Foundation of China (grant no. 21703099).
Ni(cod)2, IPr (1 equiv)
N
N
N
N
N
N
D2O
o-tolylMgBr (1 equiv)
+
H
D
H
(1)
60 oC, 45 min
2a
100 %
0 %
Ni(cod)2, IPr (1 equiv)
90 o
45 min
C
N
N
N
D2O
o-tolylMgBr (1 equiv)
(2)
H
D/H
+
3aa
N
LiCl (1 equiv)
60 oC, 45 min
OMe
2a
trace
66 %
(1 equiv)
Scheme 11. The experimental studies for establishing a
possible rate determining step.
CONCLUSION
REFERENCES
In summary, we have demonstrated nickel-catalyzed cross
coupling reactions of inert methoxyarenes with
heteroarene derivatives based on a tandem strategy of C–
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Grignard reagent and nickel complex are responsible for not
only the C‒H activation of heteroarene, but its critical role
to minimize non-productive coupling in the C‒O bond
transformation. Additionally, the single electron process is
ruled out as main operative process for this tandem strategy,
and Ni(I) is believed to be accountable for homo-coupling
product via dimerization pathway. The influence of the
catalyst/ligand and the mechanism and further scope of this
prove-of-concept are the subject of ongoing studies in our
group now.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge via the
Internet at http://pubs.acs.org. Detailed experimental
1
procedures, characterization data, H and 13C NMR spectra of
all compounds. Computational details, C‒H/C‒O activation
mechanism, energies and coordinates of the optimized
structures. The Supporting Information is available free of
charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
* ias_llzhao@njtech.edu.cn
* tgong@gate.sinica.edu.tw
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ACS Catalysis
πLinker: Optical, Electrochemical, and Photovoltaic Properties.
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N
N
Ni(cod)2 10 mol%
N
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N
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H
O
IPr 10 mol%
Ar-MgBr 1 equiv
LiCl 1 equiv
m-xylene
Ar
+
+
Kumuda coupling product
92%
60 examples
Not observed
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