Ligand-Free Pd/C-Catalyzed One-Pot, Three-Component Synthesis of Aryl-Substituted Benzimidazoles by Hydrogen-Transfer and Suzuki Reactions in Water

Article abstract of DOI:10.1002/ejoc.201501169

An efficient protocol for the ligand-free and heterogeneous Pd/C-catalyzed one-pot, three-component synthesis of aryl-substituted benzimidazoles from benzyl alcohols by using water as the solvent was developed. The reaction involves hydrogen-transfer and Suzuki reactions. This method is quite convenient and environmentally friendly.

Full text of DOI:10.1002/ejoc.201501169

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201501169
Ligand-Free Pd/C-Catalyzed One-Pot, Three-Component Synthesis of Aryl-
Substituted Benzimidazoles by Hydrogen-Transfer and Suzuki Reactions in
Water
Chen Xu,*[a] Zhi-Qiang Xiao,[b] Hong-Mei Li,[a] Xin Han,[b] Zhi-Qiang Wang,*[a]
Wei-Jun Fu,[a] Bao-Ming Ji,[a] Xin-Qi Hao,*[b] and Mao-Ping Song[b]
Keywords: Multicomponent reactions / Hydrogen transfer / Cross-coupling / Palladium / Nitrogen heterocycles
An efficient protocol for the ligand-free and heterogeneous
Pd/C-catalyzed one-pot, three-component synthesis of aryl-
water as the solvent was developed. The reaction involves
hydrogen-transfer and Suzuki reactions. This method is quite
substituted benzimidazoles from benzyl alcohols by using convenient and environmentally friendly.
as a “green solvent” and has clear advantages as a solvent
Introduction
in organic synthesis, because it is cheap, readily available,
and nontoxic.[7] To the best of our knowledge, there are no
reports concerning a heterogeneous catalyst for the synthe-
sis of benzimidazoles from alcohols in water.
Benzimidazoles are an important class of N-containing
heterocyclic compounds for organic and medicinal chemis-
try.[1] Commonly, they are prepared from 1,2-diamino-
arenes by condensation of carboxylic acids or aldehydes
(Scheme 1, a) under relatively harsh conditions that include
the use of strong acidic conditions and high reaction tem-
peratures.[2] Thus, efforts have been made to develop new
strategies to synthesize benzimidazoles by metal-catalyzed
intramolecular C–N cross-coupling reactions (Scheme 1, b)
under mild[3] and metal-free conditions.[2e,3g] However,
these methods require multistep reactions for the prepara-
tion of the starting materials. Recently, there has been sig-
nificant interest in metal-catalyzed hydrogen-transfer reac-
tions by alcohols as a more benign alternative to alde-
hydes.[4] This strategy can improve both the atom efficiency
and the regioselectivity of the process by producing only
water as a side product. Several groups have reported the
use of homogeneous Ir[5] and Ru[6] catalysts for the synthe-
sis of benzimidazoles from alcohols and 1,2-diaminoarenes
by hydrogen transfer (Scheme 1, c). However, in most cases
the catalysts employed need to be used with high loadings
and their recovery is poor, which negates the advantages
associated with the use of alcohols. From economic and
practical points of view, a process featuring an efficient and
recyclable catalyst in combination with the use of an inex-
pensive solvent would be highly desirable. Water is known
On the other hand, multicomponent reactions (MCRs)
are ideal synthetic tools to generate complex molecules
from readily available starting materials in a single synthetic
operation; hence, they minimize waste generation and this
renders the transformations green.[8] We also developed Ir/
Pd- and Pd/Cu-cocatalyzed three-component reactions for
the synthesis of arylquinolines from aminobenzyl alcohols
through hydrogen-transfer/Suzuki reactions.[9] However, the
reaction requires two different metals/ligands and the use
of organic solvents. Therefore, the development of a ligand-
free and single-metal-catalyzed MCR with the use of water
as the solvent is desired. Considering that Pd/C is a com-
mon heterogeneous catalyst for hydrogen-transfer[10] and
Suzuki reactions,[11] we speculated that Pd/C would be able
to catalyze the above-two distinct reactions in a MCR. In
this context, herein, we report the recyclable Pd/C-catalyzed
three-component reaction of 1,2-diaminoarenes, alcohols,
and arylboronic acids in water to provide a series of aryl-
substituted benzimidazoles (Scheme 1, d).
Results and Discussion
Initially, the reaction of 1,2-diaminobenzene with (4-
methoxyphenyl)methanol was selected as the model reac-
tion to probe the optimal reaction conditions by using
Pd/C (5 mol-% as Pd metal) as the catalyst and water as the
solvent at 100 °C for 24 h; the results are shown Table 1. It
was disappointing to find that the yield of isolated product
1 was only 14% in the absence of a base (Table 1, entry 1).
However, the yield was greatly improved by adding a base.
After screening a variety of bases, NH4HCO3 was found
[a] College of Chemistry and Chemical Engineering, Luoyang
Normal University,
Luoyang, Henan 471022, P. R. China
E-mail: xubohan@163.com
[b] College of Chemistry and Molecular Engineering, Zhengzhou
University,
Zhengzhou, Henan 450001, P. R. China
E-mail: xqhao@zzu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201501169.
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C. Xu, Z.-Q. Wang, X.-Q. Hao et al.
SHORT COMMUNICATION
Scheme 1. Main strategies for accessing benzimidazole.
to give the best result (Table 1, entry 12). (NH4)2CO3 and Table 1. Optimization of the reaction conditions.[a]
KHCO3 afforded moderate yields of the product (72 and
63%, respectively). Under the same conditions, dioxane
also gave a moderate yield of the product (Table 1, en-
try 13). Other organic solvents such as toluene, xylene, and
Entry
Base
Solvent
Yield [%][b]
DMF afforded the product in lower yields (Table 1, en-
tries 14–16). Additionally, we examined the reusability of
the Pd/C catalyst in the above reaction. After initial experi-
mentation, the reaction mixture was filtered, washed, and
dried, and the catalyst was used in a subsequent run. This
experiment and the three subsequent experiments provided
a consistent yield of the product (Table 1, entry 17). It was
observed that Pd/C could be recycled and reused four times
without any significant loss of activity.
With the optimized reaction conditions established, we
then investigated the scope of the reaction with various ar-
ylmethanols and 1,2-diaminoarenes (Table 2). Good yields
(84–85%) were obtained in the reaction of phenylmethanol
or 1-naphthalenemethanol. The electronic nature of the
substituents on the arylmethanols had an effect on the reac-
tion. Electron-donating substrates reacted to give corre-
sponding products 2c and 2d, the yields (86–87%) of which
were clearly higher than the yields (43–48%) obtained for
products 2e and 2f resulting from substrates containing
electron-withdrawing groups. For the substrate containing
1
2
3
4
5
6
7
8
–
water
water
water
water
water
water
water
water
water
water
water
water
dioxane
toluene
xylene
DMF
14
18
34
37
36
44
30
72
50
54
63
88
75
30
44
NaOH
KOH
CsOH
Na2CO3
K2CO3
Cs2CO3
(NH4)2CO3
(NH4)2C2O4
NaHCO3
KHCO3
NH4HCO3
NH4HCO3
NH4HCO3
NH4HCO3
NH4HCO3
Entry 12, runs 2, 3, 4
9
10
11
12
13
14
15
16
17
trace
85, 80, 73
[a] Reaction conditions: Pd/C (5 mol-%), 1,2-diaminobenzene
(0.5 mmol), (4-methoxyphenyl)methanol (0.55 mmol), base
(1 mmol), solvent (3 mL), 100 °C, 24 h. [b] Yield of isolated prod-
uct.
an ortho-methyl group, the yield of 2g decreased slightly. to the results of 1,2-diaminobenzene, good yields (80–90%)
The reactions of heteroarylmethanols proceeded efficiently were also obtained in the case of 1,2-diamino-3-methyl-
to form expected products 2h and 2i in good yields. Similar benzene, 3,4-diaminotoluene, and 3,4-diaminoanisole.
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One-Pot, Three-Component Synthesis of Arylbenzimidazoles
Table 2. Pd/C-catalyzed synthesis of 2-arylbenzimidazoles from 1,2-
diaminoarenes and arylmethanols.[a]
Table 3. Three-component reaction for the synthesis of 2-biaryl-
benzimidazoles.[a]
[a] Reaction conditions: Pd/C (5 mol-%), 1,2-diaminoarene
(0.5 mmol), arylmethanol (0.55 mmol), NH4HCO3 (1 mmol), water
(3 mL), 100 °C, 24 h, yields of isolated products are given.
It is known that biaryls are important structural moieties
of biologically active compounds and organic functional
materials. However, 2-biarylbenzimidazoles are less ex-
plored,[12] which were not synthesized through a multicom-
ponent reaction but by a classical step-by-step approach.
Given that Pd/C can catalyze Suzuki reactions to form a
variety of biaryls in water,[11,13] we were interested to see
whether Pd/C could catalyze the three-component reaction
for the synthesis of 2-biarylbenzimidazoles. To our delight,
the three-component reaction of 1,2-diaminobenzene, (4-
bromophenyl)methanol, and arylboronic acids gave 2-bi-
arylbenzimidazoles in moderate to good yields by using Pd/
C in the presence of NH4HCO3 (5 equiv.) in water (Table 3).
To understand the reaction pathway, several control ex-
periments were undertaken, and two possible pathways are
given in Scheme 2. For example, 2-biarylbenzimidazole 3c
was obtained from the hydrogen-transfer reaction of (4-
bromophenyl)methanol followed by a Suzuki reaction. The
hydrogen-transfer reaction only gave 2e in low yield (48%).
However, 3c was obtained in good yield (86%) by the one-
pot transformation. As an alternative to this reacting se-
quence, both reactions afforded good yields. We also inves-
tigated the above two reactions of (4-bromophenyl)meth-
anol for just 3 h and 2e was obtained in 16% yield. These
results indicate that the Suzuki reaction should be faster
than the hydrogen-transfer reaction. Moreover, by using 4-
(hydroxymethyl)phenylboronic acid instead of (4-bromo-
phenyl)methanol, this method was also successfully applied
to the one-pot synthesis of 3c (Scheme 3). Clearly, the
[a] Reaction conditions: Pd/C (5 mol-%), 1,2-diaminobenzene
(0.5 mmol), (4-bromophenyl)methanol (0.55 mmol), arylboronic
acid (0.75 mmol), NH4HCO3 (2.5 mmol), water (3 mL), 100 °C,
24 h, yields of isolated products are given.
ene, whereas the Suzuki reaction gave a good yield (89%).
On the basis of the above results and related processes,[14]
it is highly probable that the reaction pathway involves first
the reaction of the arylboronic acid with the aryl bromide
to give the biarylmethanol, which further reacts with the
1,2-diaminoarene to afford the desired benzimidazole
through a hydrogen-transfer reaction.[5,6]
Scheme 2. Control experiments and possible pathway.
In contrast to arylboronic acids, the Suzuki reactions of
hydrogen-transfer product was not obtained by the reaction 2-N-heteroarylboronic acids are less explored,[15] and this
of 4-(hydroxymethyl)phenylboronic with 1,2-diaminobenz- may be attributed to their instability.[15b,15c] Thus, the cou-
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C. Xu, Z.-Q. Wang, X.-Q. Hao et al.
SHORT COMMUNICATION
Scheme 3. An alternative method for the synthesis of 3c.
pling of 2-N-heteroaryl halides with arylboronic acids pro- Table 5. Three-component reaction for the synthesis of 2-aryl-5-
arylbenzimidazoles.[a]
vided a valuable complement for the preparation of the cor-
responding 2-aryl-N-heterocycles. Accordingly, the three-
component reaction of 1,2-diaminobenzene, 4-HOCH2-
PhB(OH)2, and 2-N-heteroaryl bromides was investigated
under the same reaction conditions (Table 4). Gratifyingly,
the desired products 4a–h were isolated in good yields. To
broaden the substrate scope, we further investigated this
MCR under the same reaction conditions by using 4-
bromo-1,2-diaminobenzene instead of 1,2-diaminobenzene.
As depicted in Table 5, corresponding 2-aryl-5-arylbenzimi-
dazoles 5a–h were also obtained in good yields. Moreover,
the detailed structure of 5b was confirmed by single-crystal
X-ray crystallography (Figure 1).
Table 4. Three-component reaction for the synthesis of 2-(1-aryl-4-
heteroaryl)benzimidazoles.[a]
[a] Reaction conditions: Pd/C (5 mol-%), 4-bromo-1,2-diami-
nobenzene (0.5 mmol), (4-methoxyphenyl)methanol (0.55 mmol),
arylboronic acid (0.75 mmol), NH4HCO3 (2.5 mmol), water
(3 mL), 100 °C, 24 h, yields of isolated products are given.
Figure 1. Molecular structure of 5b. H atoms are omitted for clar-
ity.
[a] Reaction conditions: Pd/C (5 mol-%), 1,2-diaminobenzene
(0.5 mmol), 4-HOCH2PhB(OH)2 (0.55 mmol), 2-N-heteroaryl
bromide (0.75 mmol), NH4HCO3 (2.5 mmol), water (3 mL),
100 °C, 24 h, yields of isolated products are given.
Finally, this newly developed protocol was applied to the
synthesis of larger conjugated 2-biaryl-5-arylbenzimid-
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One-Pot, Three-Component Synthesis of Arylbenzimidazoles
azoles through the three-component reactions of 4-bromo- pensive and reusable catalyst, no need for an additional li-
1,2-diaminobenzene, (4-bromophenyl)methanol, and aryl- gand, the use of water as a solvent, and environmental
boronic acids. As shown in Table 6, desired products 6a–j friendliness.
were isolated in moderate to good yields by using aryl-
boronic acids (3 equiv.) and the Pd/C catalyst (8 mol-%).
Electron-donating arylboronic acids reacted to give the cor-
responding products, and the yields were clearly higher than
those obtained with electron-withdrawing arylboronic ac-
ids.
Experimental Section
General Procedure for the Synthesis of 2-Biaryl-5-arylbenzimid-
azoles: A Schlenk tube containing a mixture of the 4-bromo-
1,2-diaminobenzene
(0.5 mmol),
(4-bromophenyl)methanol
(0.55 mmol), arylboronic acid (1.5 mmol), NH4HCO3 (4 mmol),
and Pd/C (8 mol-% as Pd metal) in water (3 mL) was evacuated
and charged with nitrogen. The mixture was heated at 100 °C for
24 h and then cooled to room temperature. After vacuum evapora-
tion of the solvent, the resulting residue was purified by silica gel
column chromatography to provide the desired product.
Table 6. Three-component reaction for the synthesis of 2-biaryl-5-
arylbenzimidazoles.[a]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, characterization data, and copies of the
1H NMR and 13C NMR spectra of all key intermediates and final
products.
Acknowledgments
We are grateful to the Innovation Scientists and Technicians
Troop Construction Projects of Henan Province (grant number
154100510015) and the Science Foundation of Henan Education
Department (grant numbers 14A150049 and 15B150008).
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the one-pot, three-component synthesis of 2,5-diarylbenz-
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The advantages of the present process include operational
simplicity, high efficiency, convenience, the use of an inex-
Eur. J. Org. Chem. 2015, 7427–7432
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Received: September 8, 2015
Published Online: November 3, 2015
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