The regioselective switch for amino-NHC mediated C-H activation of benzimidazole via Ni-Al synergistic catalysis

Article abstract of DOI:10.1021/ol300570f

We have disclosed a new mode of a chemically regioselective switch for C-H bond functionalization of benzimidazole derivatives via a cooperative effect invoked by Ni-Al bimetallic catalysis to create a steric requirement for obtaining the linear product of styrene insertion. Yet, excluding the AlMe ₃ cocatalyst switches the reaction toward branch selectivity.

Full text of DOI:10.1021/ol300570f

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2046–2049
The Regioselective Switch for
Amino-NHC Mediated CÀH Activation
of Benzimidazole via NiÀAl
Synergistic Catalysis
Wei-Chun Shih,† Wen-Ching Chen,† Ying-Chieh Lai,†,‡ Ming-Shiuan Yu,†,§
Jhao-Jhe Ho,†,‡ Glenn P. A. Yap, and Tiow-Gan Ong*,†
Institute of Chemistry, Academia Sinica, Nangang, Taipei, Taiwan, Republic of China,
Department of Chemistry and Biochemistry, National Chung Cheng University, Taiwan,
Republic of China, Taipei Municipal University of Education, Taiwan, Republic of
China, and Department of Chemistry and Biochemistry, University of Delaware,
Newark, Delaware 19716, United States
tgong@chem.sinica.edu.tw
Received March 6, 2012
ABSTRACT
We have disclosed a new mode of a chemically regioselective switch for CÀH bond functionalization of benzimidazole derivatives via a
cooperative effect invoked by NiÀAl bimetallic catalysis to create a steric requirement for obtaining the linear product of styrene insertion.
Yet, excluding the AlMe3 cocatalyst switches the reaction toward branch selectivity.
The past decade has witnessed the rapid rise of CÀH
activation and functionalization, which would obviate
the additional steps and limitations associated with the
preparation of functionalized substrates in the catalytic
coupling process.1 From the perspective of synthetic and
catalytic applications, the next conceptual hurdle would
be a facile ability to control the site selectivity. Yu and
Gaunt have addressed this challenge by relying on
specific directing groups on arenes to facilitate the site
selectivity.2 Alternatively, the design and preparation of
the ligand based on steric and electronic modulation can
be deployed to achieve the targeted selectivity in a spatially
precise manner.3 However, these strategies may have
their Achilles’ heel, as both methods required myriads of
functional group additions and laborious synthetic mani-
pulations.
† Academia Sinica.
‡ National Chung Cheng University.
§ Taipei Municipal University of Education.
University of Delaware.
(1) Selected review papers: (a) Wang, D. H.; Engle, K. M.; Shi, B. F.;
Yu, J. Q. Science 2010, 327, 315–319. (b) Chen, X.; Engle, K. M.; Wang,
D. H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094–5115. (c)
Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42,
1074–1086. (d) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem.,
Int. Ed. 2009, 48, 9792–9826. (e) Lyons, T. W.; Sanford, M. S. Chem.
Rev. 2010, 110, 1147–1169. (f) Chiusoli, G. P.; Catellani, M.; Costa, M.;
Motti, E.; Della Ca, N.; Maestri, G. Coord. Chem. Rev. 2010, 254, 456–
469. (g) McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38,
2447–2464. (h) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007,
107, 174–238. (i) Godula, K.; Sames, D. Science 2006, 312, 67–72. (j)
Albrecht, M. Chem. Rev. 2010, 110, 576–623. (k) Colby, D. A.; Bergman,
R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624–655. (h) Satoh, T.;
Miura, M. Chem. Lett. 2007, 36, 200–205.
(2) (a) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593–1597. (b)
Ciana, C. L.; Phipps, R. J.; Brandt, J. R.; Meyer, F. M.; Gaunt, M. J.
Angew. Chem., Int. Ed. 2011, 50, 458–462. (c) Wang, X.; Leow., D.; Yu,
J.-Q. J. A. J. Am. Chem. Soc. 2011, 133, 13864–13867.
(3) (a) Ye, M.; Gao, G.-L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133,
6964–6967. (b) Sanford, M. S.; Lyons, T. W.; Hull, K. L. J. Am. Chem.
Soc. 2011, 133, 4455–4464. (c) Sanford, M. S.; Hickman, A. H. ACS
Catal. 2011, 1, 170–174. (d) Yoshikai, N.; Gao, K. J. Am. Chem. Soc.
2011, 133, 400–402.
r
10.1021/ol300570f
Published on Web 04/05/2012
2012 American Chemical Society

Pd-mediated reductive elimination reactions. Similarly,
Knochel reported the direct Pd-catalyzed arylation of
methyl-substitutedpyridine promoted by ZnCl2, Sc(OTf)3,
Table 1. Screening and Optimization of Hydroheteroarylation
of Styrene with Benzimidazole (10a)a
and BF3 OEt2 with regioselectivity.4c
3
The useofnickel, a benign andlow-costtransitionmetal,
to mediate the functionalization of CÀH bonds is less
common compared to its palladium counterpart.5À8 More
recently, our group7 and Nakao, Hiyama5c utilized more
benign and economical bifunctional catalysts consisting
of Ni and a Lewis acid to derivatize the CÀH bond of
pyridine in a para selective manner. Encouraged by our
previous results, we proceeded to explore new types of
NiÀAl catalytic reactions involving the CÀH bond func-
tionalization of heterocyclic substrates. At this juncture,
we envisage that addition of AlMe3 would act coopera-
tively in a tandem fashion with nickel to invoke a new
selectivity. Herein we describe the development of a reactiv-
ity strategy for Ni-catalyzed heteroaromatic CÀH bond
functionalization based on using a chemical switch like
AlMe3 that selectively generates linear or branched adducts.
We begin our screening process by examining the CÀH
bond functionalization of 1-methylbenzimidazole10a with
styrene 11a involving the catalytic mixture of amino-NHC
1a,7,9 Ni(COD)2, and various Lewis acids in toluene
as outlined in Table 1. We first probed a range of Lewis acids
(entries 1À6), and among those examined, AlMe3 was highly
effective in yield with high linear selectivity. For example, the
addition of a 20% loading of AlMe3 in toluene at 130 °C
afforded a 80% yield of hydroheteroarylation products with a
major linear isomer 20aa (entry 1). Employing a very bulky
(2,6-t-Bu2-4-Me-C6H2O)2AlMe (MAD)10 as a Lewis acid
gave a lower yield (61%) and linear selectivity (20aa:20ab =
3:1, entry 4). Finally, use of other zinc-based Lewis acids
including ZnEt2 and ZnCl2 resulted disappointing outcomes
with poor yields and regioselectivities (entries 5À6).
Lewis acid time temp yield
ratio
entry ligand
(mol %)
(h)
(°C)
(%)
(20aa:20bb)
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
AIMe3 (20)
Alls (20)
15
15
15
15
15
15
15
2
130
130
130
130
130
130
100
100
70
80
4
12:1
0:100
4:1
2
3
AICI3(20)
MAD (20)
ZnEt2 (20)
ZnCI2 (20)
AIMe3 (10)
AIMe3 (10)
AIMe3 (10)
AIMe3 (10)
63
61
58
42
85
85
46
70
77
68
4
3:1
5
1:2
6
2:5
7
100:0
100:0
100:0
100:0
100:0
100:0
8
9
15
15
15
15
10
11
12
100
100
100
IMes AIMe3 (10)
IPr AIMe3 (10)
a The reactions were carried out using 10a (0.5 mmol) and 11a
(0.75 mmol) and determined by GC yield with 1H NMR analysis based
on 10a as the limiting reagent.
Tandem cooperative Lewis acid/transition metal ca-
talysis has attracted more interest in recent years4À7 for
its unique ability to enhance the rate or to control selectiv-
ity when compared with its respective transition metal
catalyst. For instance, Hartwig4a and Nolan4b et al. have
uncovered Lewis acid like AlCl3 and BEt3 accelerating
Toour delight, anexcellent yield of reaction (85%) could
also be achieved with a 10% loading of AlMe3 at a lower
temperature of 100 °C with no detection of the other
branched regioisomeric product 20ab (entry 7). More im-
portantly, the reaction time could be reduced to 2 h without
compromising the yield of the reaction (entry 8). It should be
noted that IMes and IPr NHC ligands could also perform in
a similar mode of reaction with yields of 77% and 68%
(entries 11À12), respectively. Lastly, a control experiment
with no carbene ligand was also performed, obtaining no
detectable amount of coupling adduct.
With the optimized reaction conditions in hand, we
examined the scope of the reaction with several styrene
derivatives (Table 2). High linear regioselectivities and excel-
lent yields were observed for 4-methyl styrene (11b), 4-methoxy
styrene (11c), 4-fluoro styrene (11d), and 4-phenyl-styrene
(11h) derivatives (entries 2À4, 8), illustrating the nonsensitivi-
ty of the reaction toward the electronic perturbation.
(4) (a) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7734–
7735. (b) Huang, J. K.; Haar, C. M.; Nolan, S. P.; Marcone, J. E.;
Moloy, K. G. Organometallics 1999, 18, 297–299. (c) Duez, S.; Steib,
A. K.; Manolikakes, S. M.; Knochel, P. Angew. Chem., Int. Ed. 2011, 50,
7686–7690.
(5) (a) Nakao, Y.; Idei, H.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem.
Soc. 2009, 131, 15996–7. (b) Nakao, Y.; Kanyiva, K. S.; Hiyama, T.
J. Am. Chem. Soc. 2008, 130, 2448–2449. (c) Nakao, Y.; Yamada, Y.;
Kashihara, N.; Hiyama, T. J. Am. Chem. Soc. 2010, 132, 13666–13668.
(d) Nakao, Y.; Idei, H.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc.
2009, 131, 5070–1. (e) Nakao, Y.; Morita, E.; Idei, H.; Hiyama, T. J. Am.
Chem. Soc. 2011, 133, 3264–3267. (f) Nakao, Y.; Kashihara, N.;
Kanyiva, K. S.; Hiyama, T. Angew. Chem., Int. Ed. 2010, 49, 4451–
4454. (g) Kanyiva, K. S.; Loberm, F.; Nakao, Y.; Hiyama, T. Tetra-
hedron Lett. 2009, 50, 3463–3466.
(6) Tobisu, M.; Hyodo, I.; Chatani, N. J. Am. Chem. Soc. 2009, 131,
12070–12071.
(7) Tsai, C. C.; Shih, W. C.; Fang, C. H.; Li, C. Y.; Ong, T.-G.; Yap,
G. P. A J. Am. Chem. Soc. 2010, 132, 11887–11889.
(8) Recent representative literatures related to Ni mediated CÀH
bond activation: (a) Muto, K.; Yamaguchi, J.; Itami, K. J. Am. Chem.
Soc. 2012, 134, 169–172. (b) Vechorkin, O.; Proust, V.; Hu, X. Angew.
Chem., Int. Ed. 2010, 49, 3061–3064. (c) Ogata, K.; Atsuumi, Y.;
Shimada, D.; Fukuzawa, S. Angew. Chem., Int. Ed. 2011, 50, 5896–
5899. (d) Shiota, H.; Ano, Y.; Aihara, Y.; Fukumoto, Y.; Chatani, N.
J. Am. Chem. Soc. 2011, 133, 14952–14955. (e) Yao, T.; Hirano, K.;
Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2012, 51, 775–779. (f)
Kumar, P.; Louie, J. Angew. Chem., Int. Ed. 2011, 50, 10768–1À769. (g)
Qu, G. R.; Xin, P. Y.; Niu, H. Y.; Wang, D. C.; Ding, R. F.; Guo, H. M.
Chem. Commum. 2011, 11140–11142. (h) Yamamoto, T.; Muto, K.;
Komiyama, M.; Canivet, J.; Yamaguchi, J.; Itami, K. Chem.;Eur. J.
2011, 17, 10113–10122.
Likewise, introduction of a methyl substitution at dif-
ferent positions of the styrene (para, meta, and ortho,
(9) Li, C.-Y.; Kuo, Y.-Y; Tsai, J.-H.; Yap, G. P. A; Ong, T.-G.
Chem.;Asian J. 2011, 6, 1520–1524.
(10) Saito, S.; Yamamoto, H. Chem. Commun. 1997, 1585.
Org. Lett., Vol. 14, No. 8, 2012
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Table 2. Hydroheteroarylation of Various Styrenes with
Benzimidazole in Presence of AlMe3 Additivea
Table 3. Hydroheteroarylation of Various Styrenes with
Benzimidazole without AlMe3 Additivea
a The reactions were carried out using 10a (0.5 mmol) and styrene
(0.75 mmol) and determined by 1H NMR analysis with isolated yield
based on 10a as the limiting reagent. Method: 10 mol % AlMe3,
10 mol % Ni(COD)2, 10 mol % 1a ligand.
a The reactions were carried out using 10a (0.5 mmol) and styrene
(0.75 mmol) and determined by 1H NMR analysis with isolated yield
based on 10a as the limiting reagent. Method: 10 mol % Ni(COD)2,
10 mol % 1a ligand. b 10 mol % IMes was used instead of 1a.
entries 2, 6À7) did not affect the rate or selectivity of the
reaction. 2-Vinylnapthalene 11e also participated in the
hydroheteroarylation reaction to give a moderate yield
(66%) of an equal amount of linear and branched
isomers. We attributed the lack of selectivity in 11e to a
more effective π-conjugated stabilization invoked by the
naphthalene ring. Finally, the most striking demonstration
of this utility is that exclusion of AlMe3 completely
switches the selectivity back to the branched product as
shown in Table 3, albeit with a lower average yield in
comparison tothe reactioncontaining Lewisacidaddition.
Interestingly, Bergman and Ellman also reported that the
linear product from styrene was afforded for the CÀH
bond functionalization of benzimidazole via cooperative
catalysis of Rh/Brønsted acid, albeit in low yield.11 In
addition, Yoshikai has also employed different ligands to
modulate cobalt-mediated regioselective switchable hy-
droarylation of styrenes on 2-phenyl-pyridine.3d
High levels of linear selectivity and yield were consistently
observed with benzimidazole bearing ethyl (10b) and benzyl
(10c) groups at the nitrogen side arm or methyl groups on the
aryl ring (10d). Such a method can also be extended to other
aryl benzimidazole derivatives with high efficiency and selec-
tivity (10eÀg), but 1-(o-tolyl) benzimidazole (10h) gave a
moderate yield (55%), which is perhaps due to an unfavor-
able steric hindrance at the ortho position. Finally, omitting
the AlMe3 additive in the reaction mixture switches the
selectivity toward the branched isomer (see Scheme 2).
At this stage, the reaction pathway of each basic step
remains to be ascertained by detailed mechanistic studies.
Based on the previous literature precedent,3d,5,12 we pos-
tulate that the preliminary hydroarylation mechanism
proceeds through the following steps: (1) oxidative addi-
tion of the CÀH bond to the Ni center to afford NiÀH
species 4, (2) insertion of styrene into the NiÀH bond,
As illustrated in Scheme 1, we can also expand the utility
of this catalytic manifold to other benzimidazole derivatives.
(11) (a) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2002, 124, 13964–13965. (b) Tan, K. L.; Bergman, R. G.; Ellman, J. A.
J. Am. Chem. Soc. 2002, 124, 3202–3203.
(12) A preliminary crystallographic study on 3, representing the best
of several trials, yielded poor data coverage but established molecular
connectivity. See Supporting Information.
2048
Org. Lett., Vol. 14, No. 8, 2012

Scheme 1. Linear Selectivity: Hydroheteroarylation of Styrene
with Various Benzimidazole Derivatives with AlMe3
Scheme 3. Plausible Mechanism for Catalytic NiÀAl CÀH
a
Activation of Benzimidazole
a The reactions were carried out using 10x (0.5 mmol) and styrene
(0.75 mmol) and determined by 1H NMR analysis with the isolated yield
based on 10x as the limiting reagent. Selectivity in bracket [linear/
branch]. bThe amount of AlMe3 was increased to 100 mol % (0.5 mmol).
2.20 ppm. Such a Lewis pair adduct 3 is further confirmed
by X-ray crystallography in which AlMe3 is datively
coordinated to the benzimidazole nitrogen (Figure S1).12
This positive result may indicate that the presence of
AlMe3 binding to the benzimidazole would impose a linear
selectivity through a steric barricade as shown in reaction
pathway A. In this respect, similar steric and mechanistic
phenomena have been reported by the Cavell group for the
Ni-mediated CÀH activation/alkene insertion to produce
linear 2-alkyl imidazolium.13 In contrast to pathway B,
adduct 4b would electronically and thermodynamically
favor hydride insertion at the Cβ position of vinylarene,
resulting in branched selectivity.
Scheme 2. Branch Selectivity: Hydroheteroarylation of Styrene
with Various Benzimidazole Derivativesa
In summary, without resorting to functional group mani-
pulations on the substrate or ligand, we have disclosed a new
mode of a chemically regioselective switch for CÀH bond
functionalization of benzimidazole derivatives. The catalytic
method features a cooperative interaction between Ni and Al
to create a steric requirement for obtaining the linear product.
Exclusion of the AlMe3 cocatalyst switches the reaction toward
branched selectivity. Ongoing work seeks to gain a detailed
mechanistic understanding of the synergism offered by NiÀAl
bimetallic catalysis. Such mechanistic insights will be crucial for
developing bimetallic catalysis on the scope of the reaction.
a The reactions were carried using 10x (0.5 mmol) and styrene
(0.75 mmol) determined by 1H NMR analysis with isolated yield based
on 10x as the limiting reagent. Selectivity in bracket [linear/branch].
b10 mol % 1a was used instead of IMes.
Acknowledgment. We thank Professor Jennifer Scott
at Royal Military College of Canada for her insightful
suggestion in our work and Dr. Mei-Chin Tseng’s gener-
ous technical support for using the Mass Analysis facility
at the Institute of Chemistry, Academia Sinica. We are
also grateful to the Taiwan National Science Council
(NSC: 97-2113-M-001-024-MY2) and Academia Sinica
for their generous financial support.
and (3) reductive elimination of 5a (pathway A) and 5b
(pathway B) to afford linear and branched products,
1
respectively (Scheme 3). Upon closer inspection via H
NMR spectroscopy, it is clear that the generation of an
Al-benzimidazole adduct (3) is observed, as the methyl
signal of benzimidazole has moved upfield from 2.61 to
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(13) (a) Clement, N. D.; Cavell, K. J.; Jones, C.; Elsevier, C. J. Angew.
Chem., Int. Ed. 2004, 43, 1277–1278. (b) Clement, N. D.; Cavell, K. J.
Angew. Chem., Int. Ed. 2004, 43, 3845–3847. (c) Normand, A. T.;
Hawkes, K. J.; Clement, N. D.; Cavell, K. J.; Yates, B. F. Organome-
tallics 2007, 26, 5352. (d) Normand, A. T.; Yen, S. W.; Huynh, H. V.;
Hor, T. S. A.; Cavell, K. J. Organometallics 2008, 27, 3153.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
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