Additive- and Oxidant-Free Expedient Synthesis of Benzimidazoles Catalyzed by Cobalt Nanocomposites on N-Doped Carbon

Article abstract of DOI:10.1055/s-0037-1610353

A one-pot direct synthesis of a wide range of biologically active benzimidazoles through coupling of phenylenediamines and aldehydes catalyzed by a highly recyclable nonnoble cobalt nanocomposite was developed. A broad set of benzimidazoles can be efficiently synthesized in high yields and with good functional-group tolerance under additive- and oxidant-free mild conditions. The catalyst can be easily recycled for successive uses, and the process permits gram-scale syntheses of benzimidazoles.

Full text of DOI:10.1055/s-0037-1610353

SYNLETT
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©
Georg
Thieme Ver-
lag Stuttgart
New York
019, 30,
A
·
2
A
–
F
Synlett
Z. Wang et al.
Letter
Additive- and Oxidant-Free Expedient Synthesis of Benzimidazoles
Catalyzed by Cobalt Nanocomposites on N-Doped Carbon
Zhaozhan Wang◊
Tao Song◊
Yong Yang*
Key CAS Laboratory of Bio-based Materials, Qingdao Institute
of Bioenergy and Bioprocess Technology, Chinese Academy
of Sciences, Qingdao, Shandong, 266101, P. R. of China
yangyong@qibebt.ac.cn
◊
These authors contributed equally.
Received: 22.10.2018
Accepted after revision: 16.11.2018
Published online: 14.01.2019
boxylic acids or their derivatives, which is often performed
2
under harsh conditions, e.g., strong acids, high tempera-
3
4
DOI: 10.1055/s-0037-1610353; Art ID: st-2018-u0689-l
tures, or the use of microwave irradiation [Scheme 1(a)].
The other is a two-step sequential procedure involving the
condensation of phenylenediamines with aldehydes fol-
lowed by the oxidative cyclodehydrogenation [Scheme
Abstract A one-pot direct synthesis of a wide range of biologically ac-
tive benzimidazoles through coupling of phenylenediamines and alde-
hydes catalyzed by a highly recyclable nonnoble cobalt nanocomposite
was developed. A broad set of benzimidazoles can be efficiently synthe-
sized in high yields and with good functional-group tolerance under ad-
ditive- and oxidant-free mild conditions. The catalyst can be easily recy-
cled for successive uses, and the process permits gram-scale syntheses
of benzimidazoles.
1
(b)]; this reaction can proceed either in the presence of a
5
6
metal catalyst or under metal-free conditions. A stoichio-
metric or excess amount of an oxidant is always necessary
to obtain the desired benzimidazoles, and the scope of
functional groups is narrow under either set of conditions.
Much worse, the use of various undesirable oxidative re-
agents generally renders the procedure less attractive, due
to the production of toxic or environmentally problematic
byproducts, laborious workup and purification, and low
isolated yields. Recently, the borrowing-hydrogen and the
acceptorless dehydrogenative coupling strategies have been
employed for the construction of benzimidazoles from al-
cohols and aromatic diamines by using well-defined transi-
tion-metal complexes or heterogeneous precious metals as
catalysts [Scheme 1(c)].7 In both cases, a large excess of
the alcohol with respect to the diamine, as well as a stoi-
chiometric or excess of a strong base, are required for effi-
cient coupling to produce benzimidazoles, although the for-
Key words cobalt catalysis, heterogeneous catalysis, benzimidazoles,
phenylenediamines, aldehydes, coupling reaction
Benzimidazole and its derivatives are useful and essen-
tial components of many biologically active molecules that
have found extensive and commercial applications in di-
verse therapeutic areas, for example as antiulcer, antihy-
1
pertensive, antiviral, or antifungal drugs (Figure 1). In light
of the widespread utility of benzimidazoles, the develop-
ment of novel methods for their expedient synthesis con-
tinues to be an active area of research.
–9
N
O
N
mation of water and/or H as the exclusive byproduct is ap-
2
HN
H
NH
pealing. Benzimidazoles can also be synthetically prepared
from various amidines as starting materials through an
intramolecular C–H bond-functionalization/C–N bond-
forming process in the combined presence of a homo-
geneous (non)noble metal and an oxidant;10 however, ami-
dines are not readily available, limiting the practical use of
this approach [Scheme 1(d)]. Overall, none of the developed
synthetic approaches permits the synthesis of a broad
range of benzimidazoles efficiently from readily available
starting materials with catalysis by a simple and highly
recyclable nonnoble metal catalyst under additive- and
N
N
MeO
N
H
N
Figure 1 Typical biologically active molecules containing benzimidaz-
ole groups
In recent decades, much attention has been devoted to
the synthesis of benzimidazoles by various synthetic ap-
proaches. In general, two classical methods are most fre-
quently used for the synthesis of 2-substituted benzimidaz-
oles. One is the coupling of phenylenediamines with car-
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

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Synlett
Z. Wang et al.
Letter
Previous synthetic approaches
NH2
O
NH2
NH2
R1
(a)
(b)
R1
+
+
R2
R2
O
X
NH2
X = OH, Cl, Br
•
Usage of strong oxidants
•
•
Harsh reaction conditions, e.g., strong
acid, high temperature, or microwave
irradiation,
N
• Need of addtives
R1
R2
• Toxic or environmentally problematic
N
H
by-products
Limited substrate scope
H
N
R2
NH2
R1
R2
R1
+
HO
NH
(
c)
(d)
X
X
X = NH2, NO2
X = H, NO2, Br, I
•
•
•
Noble metal catalysts
Use of stoichiometric strong base
Requirment of large excess of alcohol, not atom-economic
• Homogeneous (non)noble metal catalysts
• Usage of oxidants
• Not readily available starting materials
This work
NH2
N
CoOx@NC
R1
R2
R1
R2
+
O
N
H
NH2
√
√
√
Heterogeneous non-noble metal catalysis
Additive/oxidant/base-free
High yields with broad substrate scope
√
Easy separation and reusable
Scheme 1 Strategies for the synthesis of benzimidazoles
oxidant-free mild conditions; this prompted us to reinvesti-
gate the transformation of phenylenediamines and alde-
hydes for the synthesis of benzimidazoles.
ous conditions (Table 1). The reaction was initially per-
formed in the presence of CoO @NC-800 in water as a medi-
x
um at 110 °C, which were the conditions that produced the
best catalytic performance in the hydrogenation of func-
In a continuation of our studies to develop green cataly-
sis for sustainable organic synthesis, we recently developed
a highly efficient and recyclable inexpensive cobalt nano-
composite on an N-doped hierarchical carbon derived from
biomass for the chemoselective hydrogenation of function-
9
tionalized nitroarenes in our previous study. In this case,
only a 25% GC yield of 2-phenyl-1H-benzimidazole (3a) was
obtained after 24 hours (Table 1, entry 1). When we
changed the solvent to THF, a 98% GC yield of 3a was ob-
tained under otherwise identical conditions (entry 2). Fur-
ther studies showed that even milder reaction conditions
(e.g., 100 °C or 8 h) gave similar levels of reaction efficiency
(entries 3 and 4). Other solvents (DMF, methanol, ethanol,
1,4-dioxane, acetonitrile, or DMSO) were also suitable me-
dia for the reaction, but THF stood out among these investi-
gated solvents under identical conditions (entries 5–10).
Subsequently, various catalysts were employed for the reac-
tion. Catalysts CoO @NC-700 and CoO @NC-900, prepared
9
alized nitroarenes. Inspired by the impressive results that
we obtained, we were eager to extend the use of this cata-
lyst to the synthesis of a variety of biologically active ben-
zimidazoles. Here, we report that our cobalt nanocompos-
ites catalyst is capable of catalyzing a direct one-pot syn-
thesis of various benzimidazoles from phenylenediamines
and aldehydes as desirable starting materials, due to their
ready availability and their nontoxic nature, under base-
and oxidant-free mild conditions (Scheme 1; bottom). A
broad range of both diamines and aldehydes can be effi-
ciently coupled to form the desired benzimidazoles in high
yields (up to 98%). The cobalt nanocomposites catalyst can
be easily separated for successive reuse without significant
loss in activity, and the reaction can be readily scaled up for
gram-scale syntheses of benzimidazoles. More importantly,
the reaction process is atom-economic and environmental-
x
x
by pyrolysis at 700 and 900 °C, respectively, showed lower
reaction efficiencies, which followed the order CoO @C-800
x
> CoO @NC-900 > CoO @NC-700 (entries 11 and 12), in line
x
x
9
with our previous findings. A considerable lower conver-
sion into 3a was observed in the presence of CoCl , pure
2
Co O , or pure nano-Co O (100 nm) as catalyst, whereas
3
4
3
4
reaction in the absence of a catalyst showed even lower
ly friendly, with the generation of water and H as the only
activity (entries 14–17). Note that catalyst CoO @C-800,
2
x
direct waste products (see Figure S7, Supplementary Infor-
mation).
We started our study by examining the coupling of ben-
zene-1,2-diamine (1a) with benzaldehyde (2a) as a bench-
mark reaction catalyzed by the cobalt nanocomposite
prepared from activated carbon without any N-doping by
the same preparation procedure, produced only a 35% GC
yield of 3a under identical conditions (entry 13), showing
that the N-dopant in the catalyst has an essential role in the
reaction.
CoO @NC-800 on N-doped hierarchical carbon under vari-
x
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Z. Wang et al.
Letter
Table 1. Optimization of the Conditions for the Synthesis of 2-Phenyl-
1
suitable for the synthesis of the corresponding benzimidaz-
oles 3s and 3t in 77 and 75% yield, respectively, indicating
that our catalyst shows excellent compatibility with ali-
phatic aldehydes. However, when 2-phenylacetaldehyde
(1j) was subjected to the coupling, only a 35% yield of the
desired benzimidazole 3j was obtained. Furthermore, a
broad range of aromatic diamines with electron-donating
and electron-withdrawing substituents were smoothly
coupled to afford the corresponding benzimidazoles 3u–
H-benzimidazole (3a)a
NH2
N
Catalyst
O
+
Solvent (5 mL)
Temperature
N
H
NH2
1a
2a
3a
b
Entry Catalyst
Solvent
Temp (°C) Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
CoO
CoO
CoO
CoO
CoO
CoO
CoO
CoO
CoO
CoO
CoO
CoO
CoO
x
@NC-800
@NC-800
H
2
O
110
110
100
90
24
24
8
25
98
98
92
73
57
66
84
69
84
61
80
35
30
33
35
25
3ad in high yields. Substituents on various positions of the
x
THF
aryl ring (para-, meta-, or ortho-position) had no significant
influence on the efficiency of this transformation. More-
over, combinations of substituted benzaldehydes and
phenylenediamines also coupled smoothly to afford struc-
turally more complex benzimidazoles 3ae–3ag in yields of
x
@NC-800
THF
x
x
x
x
x
x
x
x
x
x
@NC-800
@NC-800
@NC-800
@NC-800
@NC-800
@NC-800
@NC-800
@NC-700
@NC-900
@C-800
THF
12
8
DMF
MeOH
EtOH
1,4-dioxane
MeCN
DMSO
THF
100
100
100
100
100
100
100
100
100
100
100
100
100
8
8
0–89%, highlighting the generally synthetic utility of our
procedure. Note that many valuable functional groups (–Cl,
Br, –CN, –NO , –OMe, –C≡CH, –OH, and –CO Me) are com-
8
8
–
2
2
8
patible with this catalyst system.
To confirm the practical feasibility of our synthesis, we
performed a gram-scale reaction of benzene-1,2-diamine
1
0
1
2
3
4
5
6
7
8
1
1
1
1
1
1
8
(
1a) (1 g, 9.25 mmol) with benzaldehyde (2a) under the op-
THF
8
timized conditions (Scheme 3) and we obtained 2-phenyl-
THF
8
12
1
H-benzimidazole (3a) in an isolated yield of 1.54 g (86%).
nano-Co
Co
3
O
4
THF
8
Durability and recyclability of a catalyst is critical for
practical applications. Upon completion of the coupling of
benzene-1,2-diamine with benzaldehyde, the catalyst
3
O
4
THF
8
CoCl
–
2
THF
8
CoO @NC-800 was recovered by simple decantation then
x
1
THF
8
washed and dried for reuse in subsequent cycles. As shown
in Figure 2, the activity remained almost constant after five
recycling experiments, showing that the catalyst has high
durability.
a
Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), catalyst (10 mol%
Co), solvent (5 mL).
b
Determined by GC and GC/MS using mesitylene as an internal standard,
and confirmed with the corresponding authentic samples.
Having identified the optimal reaction conditions, we
screened a variety of phenylenediamines and aldehydes to
explore the scope and versatility of this procedure for the
synthesis of various substituted benzimidazoles. We were
pleased to find that moderate to excellent yields of the de-
sired benzimidazoles were obtained from the coupling re-
actions of virtually all the aryl aldehydes and phenylenedi-
11
amines that we examined (Scheme 2). Aldehydes bearing
either electron-donating or electron-withdrawing substitu-
ents all gave the corresponding desired benzimidazoles in
high yields, although those with electron-withdrawing sub-
stituents afforded relatively better yields than those con-
taining electron-donating substituents. Hetaryl aldehydes,
such as 2-furaldehyde (1p), thiophene-3-carbaldehyde (1q),
and nicotinaldehyde (1r), were all tolerated under these
mild conditions, and their coupling reactions proceeded
smoothly to afford the corresponding benzimidazoles 3p–r
in high yields. Although cinnamaldehyde (1k) is a problem-
atic substrate in the presence of oxidants due to the non-
selective oxidation of the C=C bond, it also worked well to
produce the desired 2-[(E)-2-phenylvinyl]-1H-benzimidaz-
ole (3k) in satisfactory yield. Aliphatic aldehydes were also
Figure 2 Recyclability of catalyst CoO @NC-800 under the standard
conditions
x
A plausible mechanism for this green and practical
method of constructing benzimidazoles is shown in Scheme
4. Initially, the phenylenediamine reacts with the aldehyde
to generate an imine intermediate, with concomitant release
of water. The imine intermediate is in equilibrium with the
©
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Z. Wang et al.
Letter
corresponding dihydrobenzimidazole. Subsequently, the di-
hydrobenzimidazole is catalytically dehydrogenated by
NH2
NH2
N
O
Standard conditions
+
N
H
CoO @NC-800 to form the desired benzimidazole, with lib-
x
eration of molecular hydrogen, as verified by GC analysis of
the headspace gas after reaction (Supplementary Informa-
tion; Figure S7).
1a
1 g (9.25 mmol)
2a
3a
1.54 g (86%)
Scheme 3 Gram-scale synthesis of 2-phenyl-1H-benzimidazole (3a)
NH2
N
CoOx@NC-800
R1
R2
O
R1
THF (5 mL), 100 °C, 8 h
N
H
R2
NH2
Aldehyde scope
N
CN
N
N
N
Cl
CN
N
H
N
H
N
H
N
H
3a (98%)
3b (98%)
3c (95%)
3d (91%)
NO2
N
N
N
N
NO2
N
H
N
H
N
H
N
H
3g (82%)
3h (75%)a
3e (83%)
3f (88%)
N
N
N
N
O
OH
N
H
N
H
N
H
N
H
i (70%)a
3k (68%)
N
3l (90%)
3
3j (35%)
O
N
O
N
N
O
OH
N
H
N
H
N
H
N
H
3
m (60%)
3n (98%)
3o (55%)
3p (62%)
N
N
N
N
S
N
H
N
H
N
N
H
N
H
3s (77%)b
3
t (75%)b
3q (75%)
3r (80%)
Phenylenediamine scope
N
N
N
N
N
H
N
H
N
H
N
H
O
3
u (83%)
3v (85%)
3w (90%)
3x (65%)
N
OH
N
N
N
O
N
H
N
H
N
H
N
H
NC
Br
O
y (63%)b
3z (72%)c
3ab (88%)c
3ac (85%)c
N
3
N
N
N
Cl
CN
NO2
N
H
N
H
N
H
N
H
O2N
ad (56%)c
3ae (89%)
3ag (80%)
3
3af (83%)
Scheme 2 Substrate scope. Reaction conditions: diamine (0.2 mmol), aldehyde (0.24 mmol), CoO @NC-800 (10 mol% of Co), THF (5 mL), 100 °C, 8 h.
x
a
b
c
Yields of isolated product are reported. Temperature: 120 °C. Temperature: 130 °C. Temperature: 130 °C; time 24 h.
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Letter
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NH2
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–H2O
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(
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In summary, we have developed an expedient and
atom-economic one-pot method for the synthesis of a vari-
ety of biologically active benzimidazoles. This reaction is
catalyzed by a heterogeneous and reusable inexpensive
cobalt nanocomposite and it can be performed under addi-
tive- and oxidant-free mild conditions. A broad range of
both phenylenediamines and aldehydes were efficiently
coupled to form the corresponding benzimidazoles in good
to excellent yields (up to 98%), with good tolerance of a
broad range of functional groups. The catalyst can be easily
recycled for successive cycles of use, and the reaction can be
readily scaled up to permit gram-scale synthesis.
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Funding Information
(
d) Takeyama, K.; Wada, K.; Miuras, H.; Hosokawa, S.; Abe, R.;
We acknowledge financial support from QIBEBT, DICP & QIBEBT
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Ermolenko, L.; Al-Mourabit, A. J. Am. Chem. Soc. 2013, 135, 118.
(Grant No. DICP & QIBEBT UN201704) and from the Dalian National
Laboratory for Clean Energy (DNL) of the Chinese Academy of Sciences.
(
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Supporting Information
(
strategy, see: (a) Xu, Z.; Yu, X.; Sang, X.; Wang, D. Green Chem.
Supporting information for this article is available online at
2018, 20, 2571. (b) Guan, Q.; Sun, Q.; Wen, L.; Zha, Z.; Yang, Y.;
https://doi.org/10.1055/s-0037-1610353.
S
u
p
p
orit
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p
p
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Amberg, S. M.; Bolken, T. C.; Hruby, D. E. Bioorg. Med. Chem. Lett.
(11) 2-Phenyl-1H-benzimidazole (3a); Typical Procedure
A 25 mL sealed tube equipped with a magnetic stirrer bar was
charged with catalyst CoO @NC-800 (20 mg, 10 mol%) then
x
2
013, 23, 744.
sealed with a rubber septum and evacuated to remove air.
Benzene-1,2-diamine (0.2 mmol), PhCHO (0.24 mmol), and THF
(5 mL) were injected into the tube from a syringe, and the tube
was placed in a preheated oil bath at 100 °C for 8 h. When the
(
2) (a) Grimmett, M. R. Comprehensive Heterocyclic Chemistry;
V
o
l.
5
,
C
h
a
p
.
4
.0
8
Katritzky, A. R.; Rees, C. W., Ed.; Pergamon: Oxford, 1984, 457.
b) Wright, J. B. Chem. Rev. 1951, 48, 401. (c) Middleton, R. W.;
(
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Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

F
Synlett
Z. Wang et al.
Letter
reaction was complete, the mixture was filtered and the organic
layers were collected, combined, dried (Na SO ), and concen-
trated under vacuum. The residue was purified by passage
through a column of silica gel (200–300 mesh) to give a white
(1 g, 9.25 mmol), PhCHO (13.3 mmol), and catalyst CoO @NC-
x
800 (925 mg, 10 mol%), then sealed with a rubber septum and
evacuated to remove air. THF (200 mL) was added to the flask
from a syringe, and the mixture was refluxed for 8 h. When the
reaction was complete, the mixture was filtered, and the filtrate
was concentrated in a rotary evaporator. The product was then
purified by column chromatography; yield: 1.54 g (86%). The
structure of the product was confirmed by NMR spectroscopy.
2
4
solid; yield: 38.1 mg (98%).
1
H NMR (400 MHz, DMSO-d ): δ = 8.19 (s, 2 H), 7.59 (m, 5 H),
6
13
7
.22 (s, 2 H). C NMR (101 MHz, DMSO-d ): δ = 151.7, 139.8,
6
130.5, 130.4, 129.4, 126.9, 122.6, 115.7.
(
12) Gram-Scale Synthesis of 2-Phenyl-1H-benzimidazole (3a)
A 500 mL round-bottomed flask equipped with a condenser and
a magnetic stirrer bar was charged with benzene-1,2-diamine
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F