Direct Access to Dihydrobenzoimidazo[2,1-a]isoquinolines through Ruthenium-catalyzed Formal [4+2] Annulation

Article abstract of DOI:10.1002/adsc.201801241

A facile and straightforward synthesis of benzoimidazo[2,1-a]isoquinolines through Ru(II)-catalyzed [4+2] annulation reaction of 2-aryl benzimidazole and styrene has been explored. Tentative mechanistic studies imply the current reaction involves sequential C?C/C?N bond formation through the ortho C?H activation of 2-aryl benzimidazole followed by C?N reductive elimination. This newly developed strategy is widely applicable and tolerates various 2-arylbenzimidazole and vinyl derivatives, and allows the attractive vehicle for direct construction of diverse C6-substituated benzoimidazoisoquinoline scaffold in good yields. (Figure presented.).

Full text of DOI:10.1002/adsc.201801241

Title: Direct Access to Dihydrobenzoimidazo[2,1-a]isoquinolines
through Ruthenium-catalyzed Formal [4+2] Annulation
Authors: SANDIP DHOLE and Chung-Ming Sun
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10.1002/adsc.201801241
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Direct Access to Dihydrobenzoimidazo[2,1-a]isoquinolines
through Ruthenium-catalyzed Formal [4+2] Annulation
Sandip Dholea and Chung-Ming Suna,b*
a
Department of Applied Chemistry, 1001 Ta-Hseuh Road, National Chiao Tung University, Hsinchu 300-10, Taiwan
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, 100, Shih-Chuan 1st Road,
b
Kaohsiung 807-08, Taiwan
E-mail: cmsun@nctu.edu.tw
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract.
A facile and straightforward synthesis of This newly developed strategy is widely applicable and
benzoimidazo[2,1-a]isoquinolines through Ru(II)-catalyzed tolerates various 2-arylbenzimidazole and vinyl derivatives,
[4+2] annulation reaction of 2-aryl benzimidazole and and allows the attractive vehicle for direct construction of
styrene has been explored. Tentative mechanistic studies diverse C6-substituated benzoimidazoisoquinoline scaffold
imply the current reaction involves sequential C-C/C-N bond in good yields.
formation through the ortho C-H activation of 2-aryl Keywords: Benzoimidazo[2,1-a]isoquinolines Ruthenium,
benzimidazole followed by C-N reductive elimination.
[4+2] annulation; 2-aryl benzimidazole; Styrene
and compound IV also displays the anticancer
activity[6] (Figure 1).
Introduction
Owing to the biological significance, several
attractive strategies to access benzimidazole-fused
isoquinoline have been published.[7] However, to the
best of our knowledge, only few methods reported for
the synthesis of C-6 substituted benzimidazo[2,1-
a]isoquinolines. In 2000 Dyker and co-workers
reported the oxidative cyclization of ortho-
phenylenediamine with 2-styryl benzaldehyde in o-
nitrobenzene at 150 OC.[8] Chang also achieved C6-
methyl substituted benzimidazo[2,1-a]isoquinoline
by one pot condensation/hydroamination reaction of
ortho-phenylenediamine with 2-allylbenzaldehydes.[9]
Nevertheless, the aforementioned protocols are
limited to 2-styryl/allyl benzaldehyde, and also
suffers from poor yields, longer reaction time which
lowers the synthetic efficiency and diversity of final
product. In light of these concerns, the development
of a straightforward and efficient synthesis from the
easily available substrate is still in high demand for
chemists.
Fused
N-heteroaryl
scaffolds
have
shown
unambiguous importance in medicinal chemistry as
they are embedded in many of natural products as
well as pharmaceuticals, agrochemicals, and organic
materials.[1] Benzimidazole and their derivatives are
among the well-known N-heterocycles, which have
received considerable attention due to their excellent
pharmacological and biological activities.[2] Among
the
plethora
of
compounds,
the
5,6-
dihydrobenzo[4,5]imidazo[2,1-a]isoquinoline is an
important fused tetracyclic benzimidazole derivative
with unique biological profiles.
In past decades, transition metal catalyzed cascade
cyclization through C-H bond activation has been
recognized as a powerful method to deliver the N-
containing heterocycles.[10] Recent studies reveal that
the 2-arylbenzimidazoles can participate in metal
catalyzed [4+2] annulation reactions, because they
contains an imidamide moiety as an effective
directing group for C-H functionalization and
nucleophile for C-N reductive elimination. For
example, in 2013 Kavitha reported the Ru-catalyzed
reaction of alkynes with 2-aryl benzimidazoles for the
synthesis of benzimidazoisoquinoline derivitives.[11]
Figure 1. Biologically active Benzimidazole-fused
isoquinolines
For example, Compound I is the useful potassium ion
channel modulator for treatment of neurological
disorders,[3] whereas Compound II exhibits the high
affinities for peripheral benzodiazepine receptor.[4]
Compound III has cytotoxic activity against the
human cancer cell lines (MGM, ATCC, MCF7),[5]
1
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10.1002/adsc.201801241
Advanced Synthesis & Catalysis
Later, Peng described sequential nucleophilic
addition and Pd catalyzed intramolecular C −H
vinylation of 2-aryl benzimidazole with alkynyl
bromide.[12] Villar also reported the Rh(III) catalyzed
double-oxidative annulation of 2-arylbenzimidazoles
with alkynes.[13] Our interest in transition metal
Scheme 1. A transition metal catalyzed [4+2] annulation of
2-arylbenzimidazole
catalyzed
pharmacological
reaction,[14]
and
construction
of
important
benzimidazoles[15]
motivated us to explore the Ru-catalyzed ortho
selective C-H activation/ N-H annulation of 2-
arylbenzimidazole 1 with various substituted styrene
2 for the synthesis of dihydrobenzoimidazo[2,1-
a]isoquinolines (scheme 1). Significantly this
protocol offers the exclusive synthesis of various C6
functionalized
derivatives.
benzimidazo[2,1-a]isoquinoline
Results and Discussion
Table 1. Optimization of reaction conditions.[a]
Yield[%]b
Entry Catalyst
Additive
Oxidant
-
Solvent
T[°C] Time [h]
3aa
4aa
1c
2c
3
[RhCp*Cl2]2
Co(CO)Cp*I2
Pd(OAC)2
AgSbF6
AgSbF6
-
DCE
TFE
AcOH
DCE
o-xylene
p-xylene
toluene
DMF
ACN
EtOH
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
100
100
120
100
120
120
120
140
100
100
120
120
120
120
120
120
120
120
120
120
120
120
24
24
24
12
12
12
12
12
12
12
7
12
12
12
12
12
12
12
12
12
12
12
80
0
0
20
13
10
10
70
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
40
61
54
57
0
BQ
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
-
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
KPF6
AgNTf2
AgPF6
AgOAc
KOAc
NaOAc
CsOAc
KPF6
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAC)2
0
0
80
40
60
15
Trace
Trace
Trace
78
55
35
Trace
0
KPF6
KPF6
none
KPF6
O2
-
Cu(OAc)2.H2O
Cu(OAc)2.H2O
0
[a]
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), catalyst (10 mol%), additive (20 mol%), oxidant (0.5 mmol),
solvent (3 mL). [b] Isolated yields. [c] catalyst (2.5 mol%)
2
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10.1002/adsc.201801241
Advanced Synthesis & Catalysis
Our study was commenced with a model reaction of
2-phenyl benzimidazole 1a with styrene 2a under the
various metal catalysts such as Rh(III), Co(III), Pd(II),
and Ru(II) as shown in Table 1. In the presence of
[RhCp*Cl2]2 (2.5 mol%) catalyst, AgSbF6 (20 mol%)
additive in dichloroethane at 100 °C, the ortho C-H
alkenylated product obtained in 80% yield (entry 1).
However no new products were observed when
Co(III) and Pd(II) were used and the starting material
were recovered (entries 2 and 3). To our delight,
treatment of 1a with styrene 2a (2.0 equiv) in the
presence of [RuCl2(p-cymene)]2 (10 mol%), AgSbF6
(20 mol%), and Cu(OAC)2.H2O (1.0 equiv.) as a
oxidant in DCE at 100 °C provided product 4aa in
40% yield along with 20% of alkenylated product 3aa
(entry 4). In the proton NMR spectrum of compound
4aa, the corresponding peaks of dihydroisoquinoline
ring clearly appear as doublet of doublet at 6.10, 3.90
13
and 3.47 ppm and C NMR also showed extra peaks
in aliphatic region (See SI). Subsequently, we
continued optimization using less expensive Ru(II)
catalyst with various solvents and additives to obtain
the optimal yield of the product 4aa. Next, we
screened various solvents and found that the yield was
increased to 61% in o-xylene at 120 °C (entry 5). The
other solvents p-xylene and toluene were less
effective and afforded 54 and 57 % yields
respectively (entries 6 and 7), whereas the solvent
DMF gave the 3aa in 70 % yields (entry 8). No
product formation was observed in CH3CN and EtOH
(entries 9 and 10). Afterward, the series of additives
such as KPF6, AgNTf2, AgPF6, AgOAc, KaOAc,
NaOAc, and CsOAc were evaluated (entries 11-17).
Gratifyingly, the yield of 4aa was promoted to 80%
when KPF6 was used (entry 11). Other additives did
not show any noticeable amelioration. Next, replacing
oxidant Cu(OAc)2.H2O with anhydrous Cu(OAC)2
resulted in a desired product in 78% yield (entry 18).
Utilization of O2 as an oxidant dramatically reduced
the yield of 4aa to 55% (entry 19). When same
reaction was carried out without oxidant, the 4aa was
obtained in 35% yield (entries 20). Subsequently,
several control experiments were performed to show
the essential roles of additives and Ru(II) catalyst.
The reaction delivered trace amount of product 4aa in
the absence of the chloride scavenger KPF6 (entry 21)
and failed to furnish desired product 4aa in the
absence Ru-catalyst (entry 22). With this optimization
study, the best reaction conditions were established
using 1a (1.0 eq.) and styrene (2a, 2.0 eq.) using
[Ru(p-cymene)Cl2]2 (10 mol%), KPF6 (20 mol %),
and Cu(OAc)2.H2O (1.0 eq.) in o-xylene at 120 °C for
Table 2. Substrate scope of 2-arylbenzimadazoles.[a],[b]
[a]Reaction Conditions: 1 (0.5 mmol), 2a (1.0 mmol),
[RuCl2(p-cymene)]2 (10 mol%), KPF6 (20 mol%),
Cu(OAc)2.H2O (0.5 mmol) in o-xylene (3 mL), 120 oC, 7 h.
[b] Isolated yield. [c] The regioisomeric ratio was determined
by 1H NMR analysis. [d] 2a (1.5 mmol), 170 OC
group (-Me) at the ortho and para position gave the
desired product in excellent yields (4aa, 4ba, and
4da). Whereas, when electron withdrawing (-Cl and –
CF3) were present at the ortho and para position of 2-
aryl ring reacted in a sluggish manner and resulted the
respective products in decreased yields (4ca, 4ea, and
4fa). When –OMe group introduced at the meta-
position of the 2-aryl ring, yielded the 4ga and 4'ga in
a 2:1 ratio of inseparable regioisomer with 75%
combined yield. Next, we replaced the 2-aryl ring
with heterocyclic ring. The 2-thionylbenzimidazole 1i
was smoothly reacted with 2a, delivering the
corresponding 4ia in moderate yield. In contrast, 2-
furanylbenzimidazole (1j) afforded the alkenylated
product 3ja in 47% yield. However, the 2-
pyridinylbenzimidazole 1h resulted the no product
formation due to the chelating ability of the pyridine
ring. In addition, 2-benzyl benzimidazole 1k failed to
work under standard condition owing to an inability
of substrate for distal C-H bond activation. We
subsequently examined the effect of substituents on
benzimidazole ring and found that they have
significant effect on the product formation. The
introduction of electron donating group (-Me) at 5, 6
or 4 position of benzimidazole ring, delivered the
7
h,
to
deliver
6-phenyl-5,6-
dihydrobenzo[4,5]imidazo[2,1-a]isoquinoline 4aa in
80% yield.
With the establishment of optimal reaction
condition, we then investigated the substrate scope
and limitation of 2-aryl benzimidazole for the
synthesis
of
benzimidazo[2,1-a]isoquinoline
derivatives (Table 2). Initially, various substituents on
2-aryl ring were tested (1a-1k). When 2- aryl ring
bearing electron neutral (-H), and electron donating
3
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10.1002/adsc.201801241
Advanced Synthesis & Catalysis
desired product in good yields (4la-4na). The methyl
group present at 4-position on benzimidazole moiety
afforded the single regioisomer product 4ma in 75%
yield where the C-N bond formation takes place at the
less hindered nitrogen atom, whereas –Me group on
5-postion of the benzimidazole ring afforded the
inseparable regioisomers 4na and 4'na in 3:2 ratio
with 78% isolated mixture yield. Surprisingly, The
benzimidazole ring having the electron withdrawing
group, such as –NO2 and halo (-Cl and –Br) at 5-
position did not provide the annulated product, but
resulted the alkenylated product only (3oa, 3pa, and
3qa) under the ideal reaction condition. However, the
coupling reaction did deliver the desired products
o
(4oa-qa) at 170 C with 3.0 equiv of styrene 2a.
Interestingly, the same reaction also provided the 1-
styryl-5,6-dihydrobenzoimidazo[2,1-a]isoquinoline
derivatives (6oa-qa) via di-vinylation and subsequent
C-N reductive elimination. In case of strong electron
withdrawing–NO2 group (1o), the 1-styryl-5,6-
dihydrobenzoimidazo[2,1-a]isoquinoline derivatives
(6oa+6'oa) were predominately formed in 50% yield,
along with minor amount of inseparable regioisomeric
mixture 4oa+4'oa (1:0.8) in 34% combined yields. To
our delight, the structure of minor isomer 6'oa has
unambiguously established by X-ray crystallographic
analysis (SI, S168). The regioisomers 4pa and 4'pa
were isolated in 35% and 22% yields along with 6pa
(20%) and 6'pa (12%) when -Cl group was at the 5-
position of benzimidazole ring. The 5-bromo
substituted substrates 1q yielded the 4qa and 4'qa in
1:0.9 ratios of regioisomers in 52% combined yields
and 6qa and 6'qa in 22% and 10% yields,
respectively. These results have shown that electron
withdrawing groups on the benzimidazole ring affect
the C-N reductive elimination.
Table 3. Scope of Vinyl derivatives. [a],[b]
[a]
Reaction Conditions: 1a (0.5 mmol), 2 (1.0 mmol),
[RuCl2(p-cymene)]2 (10 mol%), KPF6 (20 mol%),
o
Cu(OAc)2.H2O (0.5 mmol) in o-xylene (3 mL), 120 C, 7
h. ,[b] Isolated yield. [c] See in the text
Finally, the structure of compound 4 was further
confirmed by X-ray diffraction analysis of 4ae which
clearly revealed that newly formed six membered ring
adopts half chair form and the overall structure is
non-planar (Figure 2).
Next, we study the reactions of various vinyl
derivatives under optimized condition (Table 3). The
styrene bearing the electron donating group such as p-
OMe(2b), p-Me(2c), and m-Me(2d), afforded the
desired products 4ab, 4ac, and 4ad in 67, 70, and
70% yields, which is slightly lower than the electron
withdrawing substituents on the styrene such as p-
Cl(2e) and p-NO2(2f), yielded the products 4ae and
4af in 78 and 75 % yields. The reaction of 2-
vinylpyridine 2g with 2-phenylbenzimidazole 1a
afforded the alkylated product 5ag in 81% yield,
whereas no product formation was observed with 4-
vinylpyridine 2h. The reaction of 2-aryl
benzimidazole 1a with 1-vinyl imidazole 2i delivered
highly unstable product 4ai which was converted into
5,6-dihydrobenzo[4,5]imidazo[2,1-a]isoquinoline and
benzo[4,5]imidazo[2,1-a]isoquinoline during reaction
and column purification (See SI). To our surprise, 4-
methyl-5-vinylthiazole 2j smoothly reacted with 2-
phenylbenzimidazole to furnish the desired product
4aj in 80% yield. The substituent either at the internal
carbon (2k) or terminal carbon (2l) of the styrene did
not provide any cyclized or non-cyclized products.
Figure 2. ORTEP diagram of 4ae
To obtain the mechanistic information, a series of
controlled experiments were conducted as shown in
Scheme 2. The ruthenacycle complex II was prepared
by the reaction of 2-phenyl benzimidazole 1a with a
stoichiometric amount of [RuCl2(p-cymene)]2, KPF6
and Cu(OAC)2.H2O in o-xylene at room temperature
for 24 h (Scheme 2i). The complex II was analyzed
by LRFD and HRFD mass technique (See SI). When
the ruthenacycle complex II was applied as a catalyst
instead of [Ru(p-cymene)Cl2]2 under the standard
4
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10.1002/adsc.201801241
Advanced Synthesis & Catalysis
conditions, the desired product 4aa obtained in 65% catalyst I is generated through anion exchange by
yield (Scheme 2ii). Also, when the reaction between KPF6 or Cu(OAc)2.H2O. In the next step, cationic
ruthenacycle complex II with styrene 2aa, in the Ru(II) catalyst coordinates to a nitrogen atom of 2-
presence of KPF6, and Cu(OAc)2.H2O in o-xylene at phenyl benzimidazole 1a followed by ortho-
120 °C, resulted in the formation of 4aa in 72% yield metalation to deliver the five membered ruthenacycle
(Scheme 2iii). Next, when free –NH group of 2- II. Then, the coordination of styrene 2 to the metal
phenylbenzimidazole protected with methyl group followed by the migratory insertion gives seven
and treated with the styrene 2a, the alkenylated membered ruthenacycle intermediate IV. Finally, the
product 7aa afforded in 90% yield (Scheme 2iv). In C-N reductive elimination takes place to afford the
addition, 2-methyl benzimidazole 1r was treated with corresponding product 4, AcOH and releases the
styrene 2a, the more challenging sp3 C-H activation Ru(0) species which is then regenerated to the
did not take place under the current reaction condition reactive Ru(II) catalyst with oxidant Cu(II) to
(Scheme 2v). These observations suggest that the complete the catalytic cycle.
catalytic cycle may be initiated by the C-H bond
cleavage of the 2-phenyl group on 1H-benzimidazole
and a reservoir of active catalyst I in the catalytic
cycle. When the ortho C-H olefinated product 3aa
and alkylated product 5aa were subjected to the
standard reaction conditions, the starting material
remains unreacted after prolonged heating for 12h
(Scheme 2vi, and vii). These results clarify that the
ortho-olefin/alkyl substituted 2-phenylbenzimadiazle
3aa and 5aa were not the key intermediate for the
formation of 4aa.
Scheme 3. A proposed catalytic cycle for Ru(II) catalyzed
formal [4+2] annulation
Conclusion
In conclusion, we have developed Ru(II) catalyzed
[4+2] annulation of 2-arylbenzimidazole and vinyl
derivatives via sequential formation of C-C and C-N
bonds towards the construction of benzoimidazo[2,1-
a]isoquinoline. The Ru(II) catalyzed [4+2] annulation
includes the benzimidazole directed ortho- C(sp2)−H
activation followed by sequential C-N reductive
elimination step. Various deficient, electron rich, and
heterocyclic vinyl derivatives are compatible with the
cascade reaction, affording diverse C6-substitated
tetracyclic benzimidazole fused isoquinoline in
moderate to excellent yields. The proposed
mechanism for the formation of benzoimidazo[2,1-
a]isoquinoline is illustrated. These results might
support the development of new strategies to
synthesize useful benzoimidazo[2,1-a]isoquinolines
with biological activity and medicinal value.
Experimental Section
Experimental procedure for the Synthesis of 6-phenyl-
5,6-dihydrobenzo[4,5]imidazo[2,1-a]isoquinoline (4aa):
Scheme 2. Control experiments to investigate possible
reaction mechanism
A oven-dried 25 mL Schlenk tube is charged with 2-
arylbenzimidazole 1a (100 mg, 0.5 mmol), styrene 2a (107
mg, 1.0 mmol), [RuCl2(p-cymene)]2 (10 mol %), KPF6 (18
mg, 0.1 mmol), and Cu(OAc)2.H2O (102 mg, 0.5 mmol)
and o-xylene (3.0mL). The tube was sealed and heated at
120 °C for the 7 hours. Progress of the reaction was
monitored by TLC. After completion, the reaction mixture
was filtered through celite pad and washed with ethyl
On the basis of results from the experiments and
precedent literature,[16]
plausible reaction
mechanism for the Ru(II)-catalyzed [4+2] annulation
reaction is proposed in Scheme 3. Initially, active
a
5
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10.1002/adsc.201801241
Advanced Synthesis & Catalysis
acetate (20 mL) and the filtrate was concentrated under
reduced pressure. The crude product was purified by flash
chromatography (EA/Hex=2:8) to yield 6-phenyl-5,6-
dihydrobenzo[4,5]imidazo[2,1-a]isoquinoline 4aa.
H. Lv, L. M. Ye, Y. Hu, Y. Y. Chen, X. J. Zhang, M.
Yan, Org. Biomol. Chem. 2015, 13, 7381; e) D. Xue,
Y. Q. Long, J. Org. Chem. 2014, 79, 4727; f) T. B.
Nguyen, L. Ermolenko, A. Al-Mourabit, Chem.
Commun. 2016, 52, 4914; g) T. B. Nguyen, L.
Ermolenko, A. Al-Mourabit, Green Chem., 2016, 18,
2966.
o
1
White solid; Yield = 122 mg (80%); m.p 115-117 C; H
NMR (400 MHz, C3D6O) δ 8.30 (dd, J = 7.6, 3.8 Hz, 1H),
7.72 (m, 1H), 7.44 – 7.35 (m, 2H), 7.26 – 7.18 (m, 7H),
7.00 – 6.96 (m, 2H), 6.10 (dd, J = 6.9, 2.8 Hz, 1H), 3.93
(dd, J = 16.1, 6.9 Hz, 1H), 3.47 (dd, J = 16.1, 2.8 Hz, 1H);
13C NMR (101 MHz, C3D6O) δ 144.4, 140.3, 134.6, 133.0,
130.1, 128.7, 128.5, 128.4, 127.6, 127.3, 126.9, 125.8,
124.9, 122.4, 122.1, 119.4, 110.2, 54.8, 36.1; MS (ESI):
m/z 297 [M + H]+; HRMS (ESI): calcd for C21H17N2 [M +
H]+ 297.1386; found: 297.1384.
[8] G. Dyker, W. Stirner, G. Henkel, Eur. J. Org. Chem.
2000, 1433.
[9] M. Y. Chang, M. H. Wu, Y. L. Chen, Tetrahedron Lett.
2012, 53, 4156.
[10]For selected recent reviews on C-H bond
functionalization: a) P. Nareddy, F. Jordan, M. Szostak,
ACS Catal. 2017, 7, 5721; b) B. Ye, N. Cramer, Acc.
Chem. Res. 2015, 48, 1308; c) R. Y. Zhu, M. E.
Farmer, Y. Q. Chen, J. Q. Yu, Angew. Chem. Int. Ed.
2016, 55, 10578; d) P. B. Arockiam, C. Bruneau, P. H.
Dixneuf, Chem. Rev. 2012, 112, 5879; e) G. Rouquet,
N. Chatani, Angew. Chem. Int. Ed. 2013, 52, 11726; f)
S. I. Kozhushkov, L. Ackermann, Chem. Sci. 2013, 4,
886; g) B. Zhao, Z. Shi, Y. Yuan, Chem. Rec. 2016, 16,
886; h) L. Ackermann, Acc. Chem. Res. 2014, 47, 281.
Acknowledgements
The authors thank the Ministry of Science and Technology of
Taiwan for the financial assistance and the authorities of the
National Chiao Tung University for providing the laboratory
facilities.
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