Intramolecular arylation of benzimidazoles via Pd(II)/Cu(I) catalyzed cross-dehydrogenative coupling

Article abstract of DOI:10.1016/j.tetlet.2014.01.103

Electron poor benzimidazole substrates were arylated via an intramolecular cross-dehydrogenative coupling (CDC) reaction. These CDC reactions were catalyzed by a Pd(II)/Cu(I) catalyst system, capable of producing moderate yields on a large library of substrates. The substrate scope consisted of tethered arene-benzimidazoles that upon coupling, produced a fused polycyclic motif.

Full text of DOI:10.1016/j.tetlet.2014.01.103

Tetrahedron Letters 55 (2014) 1729–1732
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Intramolecular arylation of benzimidazoles via Pd(II)/Cu(I) catalyzed
cross-dehydrogenative coupling
⇑
Kyle C. Pereira, Ashley L. Porter, Brenton DeBoef
Department of Chemistry, University of Rhode Island, Kingston, RI 02881, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Electron poor benzimidazole substrates were arylated via an intramolecular cross-dehydrogenative
coupling (CDC) reaction. These CDC reactions were catalyzed by a Pd(II)/Cu(I) catalyst system, capable
of producing moderate yields on a large library of substrates. The substrate scope consisted of tethered
arene-benzimidazoles that upon coupling, produced a fused polycyclic motif.
Received 10 January 2014
Accepted 22 January 2014
Available online 31 January 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Cross-dehydrogenative coupling
Oxidative coupling
Palladium
Dual catalysis
Biaryl
The biaryl motif is a prominent structure in many biologically
active compounds, and green methods to synthesize these biaryl
bonds are highly desired.1 Conventional aryl coupling methods
(i.e. Suzuki–Miyaura2 or Stille3 coupling) employ prefunctionaliza-
tion steps to form activated C–metal or C–halogen bonds, which
can readily undergo catalytic coupling. However, this prefunction-
alization decreases the overall step economy of the synthesis and
produces large amounts of waste. A far more advantageous
coupling method would be cross-dehydrogenative coupling
(CDC). It can be used to inter- and intramolecularly couple two aryl
hydrocarbon bonds, requiring no prefunctionalization of substrates
and affording high yields with minimal byproducts and waste
(Scheme 1).
Much attention has been given to incorporating heterocycles
into biaryl CDC reactions, since heterocyclic components are often
found in nature and play a prominent role in pharmaceutical can-
didates.1 The benzimidazole moiety alone has been shown to have
many important uses including an antiviral for HIV,4 antibacteri-
als5,6 and possible anticancer agents.7 However, imidazoles are
rarely found as a coupling substrate in CDC reactions. Mori and
co-workers have shown an efficient homocoupling reaction for
imidazoles,8 and the You group has found success in coupling
imidazoles to thiophenes,9,10 but CDC between imidazoles and
benzenes has proved to be a challenging task. Dominguez and
Dubois have arylated imidazoles using aryl iodides,11,12 but, to
our knowledge, the only examples of coupling imidazoles with
simple arenes via CDC are the recent examples of Bao and Guo.13
With this in mind, we decided to explore palladium catalyzed
CDC reactions between benzimidazoles and arenes. To help over-
come coupling difficulties, the arene was tethered to the benzimid-
azole prior to coupling by installing an N-benzyl substituent. The
tether would help in the metalation of both coupling partners by
keeping them in close proximity to each other, and at the same
time reducing unwanted dimerization. CDC should cause this teth-
ered substrate to cyclize into a fused polycyclic system.
The optimization studies for this reaction were performed on
N-benzyl benzimidazole, substrate 1, which was synthesized through
a substitution reaction using deprotonated benzimidazole and
benzyl chloride. Substrate 1 was then purified by column chroma-
tography and afforded a 70% yield. Initially, we thought that a Cu(I)
salt would be a beneficial catalyst since it has been shown that CuI
Pd-catalyzed
Halogenation
Suzuki-Miyaura
& Borylation
I
Coupling
B(OH)2
H
Cross-Dehydrogenative
Coupling (CDC)
H
⇑
Corresponding author. Tel.: +1 401 874 9480; fax: +1 401 874 5072.
E-mail address: bdeboef@chm.uri.edu (B. DeBoef).
Scheme 1. The conventional Suzuki–Miyaura cross-coupling method versus CDC.
http://dx.doi.org/10.1016/j.tetlet.2014.01.103
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

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K. C. Pereira et al. / Tetrahedron Letters 55 (2014) 1729–1732
can arylate the C2 position of azoles via intramolecular coupling
with aryl iodides.11 Since 1 did not contain a halogen, it was also
theorized that a catalyst such as Pd(OAc)2 would be needed to
activate the aryl C–H bond. However both Pd(OAc)2/CuI and
Pd(OAc)2/CuCl catalyst systems proved to be ineffective, since they
both gave low conversion of starting materials and a mixture of
byproducts. Next, a rhodium based catalyst, [RhCl(coe)2]2, was
tried, but it suffered from low yields and dimerization. Simply
using Pd(OAc)2 as the catalyst with a Cu(OAc)2ÁH2O oxidant
proved the yield slightly, producing the best isolated yield of 58%
(Table 1, entry 10).
Another interesting observation during the optimization of this
reaction was the copper color present in the organic layer while
extracting the product. Cu(II) has been known to coordinate to
pyrazole ligands in isolatable complexes;17 thus we speculated
that copper was forming a complex with our benzimidazole
products, and therefore lowering the isolated yield. A stronger
ligand was perhaps needed to coordinate to the copper and liberate
the final product. Immediately following the coupling reaction,
Na2SÁ9H2O was added to the reaction and stirred at room temper-
ature for an hour. This removed all copper color from the organic
extract, and simultaneously increased the yields of the coupled
product.
provided
a superior system; therefore, further optimization
reactions were run with this catalyst system (Table 1).
At the outset, undesired byproducts including the dimer 4 and
the acetoxylated compound 3 plagued the reaction. It was found
that lowering the amount of Cu(OAc)2ÁH2O oxidant helped reduce
the amount of acetoxylated products since the amount of acetate
anion was reduced. Also lowering the temperature and time of
the reaction helped lower byproduct formation. Interestingly, the
addition of CsOPiv (Table 1, entry 5) eliminated compound 3, most
likely due to the steric nature of the pivalate anion. It has been sug-
gested by Fagnou that the addition of pivalate helps facilitate the
C–H bond cleavage by forming Pd(OPiv)2 prior to palladation.14–16
Fagnou and co-workers also showed that reactions performed in
pivalic acid instead of acetic acid greatly reduced unwanted
oxidative byproducts including dimers.14
Upon doubling the amount of Pd(OAc)2, compound 2 was recov-
ered in a nearly double yield (Table 1, entry 6), suggesting that cat-
alyst turnover was a problem in the reaction. After many trials, the
optimal time and temperature for the coupling reaction were
found to be 3 h at 150 °C using microwave heating (Table 1, entry
8). The longer reaction times led to a decrease in product yield, per-
haps due to decomposition (Table 1, entry 9). Finally, we were
excited to discover that the addition of 0.5 equiv of CuOAc im-
Next, an array of substrates was screened with the optimized
conditions to determine the scope of the reaction (Table 2). The
presence of an electron donating group on the benzimidazole
Table 2
Scope of the cyclization of N-benzylbenzimidazolesa
20mol % Pd(OAc)2
N
N
N
N
0.5 equiv CuOAc
H
R1
1.5equiv Cu(OAc)2•H2O
2.0 equiv CsOPiv
dioxane, 3 h, 150 °C (MW)
R1
R2
R2
H
Me
Me
Me
N
N
N
N
N
N
Me
Cl
2, 58%
5, 62%
6, 24%
N
N
N
O2N
MeO
N
N
N
Table 1
Cl
Optimization of the reaction conditions
7, 15%
8, 40%
9, 29%
N
N
Me
O
N
N
N
N
Pd(OAc)2, CuOAc
Me
N
N
H
2
N
N
O
N
N
Me
Me
N
N
Cu(OAc)2• H2O
NO2
+
CF3
10, 0%
11, 50%
CsOPiv, dioxane
1
12, traceb
Bn
H
N
N
N
AcO
3
Me
Me
N
N
N
N
N
N
N
Me
Bn
4
O
13, 47%
14, 0%
15, 54%
OMe
Pd(OAc)2
(mol %)
Cu(OAc)2
(equiv)
CsOPIv
( mol %)
CuOAc
(equiv)
Temp.
(Time)
% Yield
2:3:4a
Me
Me
N
N
N
N
N
N
OMe
OMe
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
20
20
20
20
20
4
0
0
160 °C
(1 h)
120 °C
(1 h)
120 °C
(8 h)
120 °C
(4 h)
120 °C
(4 h)
120 °C
(4 h)
120 °C
(6 h)
150 °C
(3 h)
0:21:11
19:0:<1
31:0:<1
23:12:<1
28:0:0
OMe
16, 63%
17, 54%
18, 57%
2
0
0
2
0
0
N
N
N
N
2
0
0
O
19, traceb
20, no reactionc
2
2.5
2.5
2
0
N
N
N
N
2
0
47:0:0
1.5
2
0
41:0:<1
56:0:0
21, 48%
22, 0%d
2
0
a
Reaction conditions: 0.384 mmol substrate, 20 mol % Pd(OAc)2, Cu(OAc)2ÁH2O
(0.768 mmol), CuOAc (0.192 mmol), CsOPiv (0.960 mmol) in 5 mL of 1,4-dioxane at
150 °C for 3 h under microwave heating. Isolated yields following work-up with
Na2SÁ9H2O. See Supporting information for a representative procedure.
2
2
0
150 °C
(4 h)
150 °C
(3 h)
46:0:0
1.5
2
0.5
58:0:0
b
A small amount of the desired product was detected by GC–MS.
c
Only starting materials were observed by GC–MS.
a
d The starting material was completely consumed, but the desired product was not
observed.
Isolated yield following a work-up with Na2SÁ9H2O. See Supporting information
for a representative procedure.

K. C. Pereira et al. / Tetrahedron Letters 55 (2014) 1729–1732
1731
moiety increased the coupling yield, as evidenced by comparing
H
H
N
N
N
N
H
H
H
compounds 2, 5, 16, and 17, and electron withdrawing functional-
ities on the benzimidazole (9) seemed to hinder coupling. When
comparing electron rich and electron poor arene coupling partners,
there appeared no significant trend in reactivity. The starting
materials for products 8, 9, and 13 were synthesized in inseparable
mixtures, thus the cyclization reactions produced mixtures of
H
H
KH/KD = 1.03
H
+
H
D
+
same conditions
as before
D
N
N
D
D
D
D
N
D
N
D
isomers. The cyclization was successful in forming
a new
D
D
D
six-membered ring, compound 21, but failed to couple compounds
19 and 20, which would have produced seven membered rings.
This indicated that the length of the tether highly influenced the
success of the reaction.
D
D
Scheme 2. KIE study of the intramolecular benzimidazole-arene CDC.19
Intramolecular coupling reactions between benzimidazole and
other heterocycles, such as furan, imidazole, and the caffeine deriv-
ative, benzyl theophylline, were also tried under our optimized
conditions; however, the attempts were unsuccessful (12, 14, and
22, Table 2).
Kinetic isotope effects of the reaction were evaluated by carry-
ing out competition studies. The first competition study employed
equimolar amounts of N-benzylbenzimidazole and deuterated
N-benzyl-d7-benzimidazole, and subjected both substrates to the
optimized coupling conditions. Relative amounts of the products
were obtained from GC–MS analysis and a KIE of 1.03 was obtained
(Scheme 2). This indicated that the metalation of the arene
coupling partner was facile and not rate limiting.18 A second
competition study was carried out with equimolar amounts of
N-benzylbenzimidazole and N-benzyl-2-deuterobenzimidazole,
but the KIE results of this test proved to be inconclusive due to
H/D scrambling.
With the KIE studies in hand, we sought to propose a plausible
mechanism for this unique intramolecular CDC reaction. Based on
all data, it seemed that the coupling was taking place through a
PdII/CuI catalyzed system. Our reasoning behind the dual metal
catalysis was supported by several factors. It was known from
previous studies that Cu(I) was capable of enhancing azole
coupling,8–11 so we speculated that Cu(I) was needed to activate
the C2 position of the benzimidazole. Because the addition of
Cu(I) only raised the percent yield slightly (Table 1, entry 10), we
needed to be sure that the addition of Cu(I) was essential in the
formation of the product. Since the Cu(OAc)2 oxidant could dispro-
portionate into Cu(I), we theorized that there was perhaps some
Cu(I) present to catalyze the reaction even in the absence of added
CuOAc. This would explain why we did not see a significant raise in
yield upon the addition of a Cu(I) source.
N
N
20mol % Pd(OAc)2
2 equiv AgOAc
.
+
4
AcO
3
Both reaction have
low conversion.
Only detected
N
N
products shown.
Bn
1
N
N
Bn
N
20 mol % CuI
N
2 equiv AgOAc
4
Scheme 3. Control reactions using AgOAc as an oxidant.19
N
N
Cu(OAc)2
CuOAc
N
H
2
Pd0
N
reductive
1
oxidation
elimination
H
electrophilic
metallation
N
Pd
Pd(OAc)2
N
AcOH
transmet-
alation
electrophilic
metallation
N
N
Cu
H
N
N
Cu
CuOAc
AcOH
AcOPd
To further test whether Cu(I) was involved in the mechanism,
we had to eliminate the use of Cu(OAc)2 as an oxidant (Scheme 3).
A control reaction was carried out using AgOAc as an oxidant and
Pd(OAc)2 as the only catalyst. The GC–MS results showed that
there was low conversion of the starting material into a small
amount of the acetoxylated product 3 and dimer 4. None of the
desired arylation product 2 was observed, though it is the presumed
precursor of 3. This indicated that the Pd(II) catalyst was capable of
metallating both the C2 position of the benzimidazole and the
ortho carbon of the tethered arene. However, the low conversion
indicated that this process, involving two C–H palladations, was
not likely the mechanism by which the reactions shown in Table 2
occurred.
We next ran a second control using only a Cu(I) catalyst and
AgOAc as the oxidant. The GC–MS results showed there was a
low conversion of the starting material into the dimer 4 (Scheme 3).
Consequently, we concluded that Cu(I) could activate the benz-
imidazole moiety and form the benzimidazole dimer. This control
reaction also indicated that Pd played a pivotal role in the activa-
tion of the arene for coupling.
Scheme 4. Proposed mechanism for the Pd(II)/Cu(I) catalyzed cyclization of
N-benzylbenzimdazoles.
benzimidazole, forming acetic acid and a Cu(I)-benzimidazole
complex. Next, the arene is palladated, again producing acetic acid
as a byproduct. At this point, a transmetalation could occur in
which CuOAc is released and a biaryl Pd(II) complex is formed.
The final step of the reaction would include a simple reductive
elimination to form the coupled aryl-benzimidazole product and
Pd(0). Subsequent oxidation of the Pd by the Cu(OAc)2 oxidant
would regenerate both the Pd(II) and Cu(I) catalysts. To our
knowledge, two independent C–H activations by different metals
followed by a transmetalation, is an intriguing mechanism, and
would warrant future investigations.
In conclusion, we have developed an intramolecular coupling
reaction between the 2-position of benzimidazole and a tethered
arene to form fused polycyclic heterocycles. The use of cross-dehy-
drogenative coupling in this reaction makes it highly atom
economical and cost efficient, since no prefunctionalization is
required. Mechanistic investigations led us to propose that the
reaction proceeds via a dual PdII/CuI catalyst system with a
Our proposed mechanism (Scheme 4) utilizes two independent
metalation steps. First, Cu(I) inserts in the 2-position of

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K. C. Pereira et al. / Tetrahedron Letters 55 (2014) 1729–1732
3. Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636.
4. Kim, D.; Wang, L.; Caldwell, C. G.; Chen, P.; Finke, P. E.; Oates, B.; MacCoss, M.;
Mills, S. G.; Malkowitz, L.; Gould, S. L.; DeMartino, J. A.; Springer, M. S.; Hazuda,
D.; Miller, M.; Kessler, J.; Danzeisen, R.; Carver, G.; Carella, A.; Holmes, K.;
Lineberger, J.; Schleif, W. A.; Emini, E. A. Bioorg. Med. Chem. Lett. 2001, 11, 3103.
5. Chaturvedi, A. K.; Negi, A. S.; Khare, P. RCS Adv. 2013, 3, 4500.
6. Sharma, S.; Gangal, S.; Rauf, A. Eur. J. Med. Chem. 2009, 52, 514.
7. Penning, T. D.; Zhu, G.-D.; Gandhi, V. B.; Gong, J.; Liu, X.; Shi, Y.; Klinghofer, V.;
Johnson, E. F.; Donawho, C. K.; Frost, D. J.; Bontcheva-Diaz, V.; Bouska, J. J.;
Osterling, D. J.; Olson, A. M.; Marsh, K. C.; Luo, Y.; Giranda, V. L. J. Med. Chem.
2009, 52, 514.
8. Monguchi, D.; Yamamura, A.; Fujiwara, T.; Somete, T.; Mori, A. Tetrahedron Lett.
2010, 51, 850.
9. Wang, Z.; Li, K.; Zhao, D.; Lan, J.; You, J. Angew. Chem., Int. Ed. 2011, 50, 5365.
10. Xi, P.; Yang, F.; Qin, S.; Zhao, D.; Lan, J.; Gao, G.; Hu, C.; You, J. J. Am. Chem. Soc.
2010, 132, 1822.
Cu(OAc)2 oxidant. A large library of electron poor and electron rich
arene-benzimidazoles were coupled in moderate yields, suggesting
that this reaction could be a valuable tool in the synthesis of
biologically useful heterocyclic compounds.
Acknowledgments
This work was funded by the National Science Foundation
(CAREER 0847222) and the National Institutes of Health (NIGMS,
1R15GM097708-01).
Supplementary data
11. Barbero, N.; SanMartin, R.; Dominguez, E. Org. Biomol. Chem. 2010, 8, 841.
12. De Figueiredo, R. M.; Thoret, S.; Huet, C.; Dubois, J. Synthesis 2007, 2007, 529.
13. These two communications were published while this manuscript was in
preparation: (a) Sun, M.; Wu, H.; Zheng, J.; Bao, W. Adv. Synth. Catal. 2012, 354,
835; (b) Meng, G.; Niu, H.-Y.; Qu, G.-R.; Fossey, J. S.; Li, J.-P.; Guo, H.-M. Chem.
Commun. 2012, 48, 9601.
Supplementary data (experimental procedures as well as
characterization of previously unknown compounds) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2014.01.103.
14. Liegault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org. Chem. 2008,
73, 5022.
References and notes
15. Stuart, D. R.; Fagou, K. Science 2007, 316, 1172.
16. Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496.
17. Gamez, P.; van Harras, J.; Roubeau, O.; Driessen, W. L.; Reedijk, J. Inorg. Chim.
Acta 2001, 324, 27.
18. Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51, 3066.
19. Reaction conditions are similar to those shown in Table 2.
1. Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.; Leazer, J. L., Jr.;
Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B.; Wells, A.; Zaks, A.; Zhang,
T. Y. Green Chem. 2007, 9, 411.
2. Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 1979, 866–867.