One-pot synthesis of 1 H-benzimidazole derivatives using thiamine hydrochloride as a reusable organocatalyst

Article abstract of DOI:10.1080/00397911.2011.573610

A simple and efficient one-pot synthesis of 1H-benzimidazole derivatives using thiamine hydrochloride (VB₁) as the organocatalyst from o-phenylenediamine and aldehyde in dimethylformamide is described. Compared to classical reaction conditions, this new method consistently has the advantages of excellent yields, metal-ion-free procedure, and good recovery and reusablity of catalyst.

Full text of DOI:10.1080/00397911.2011.573610

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One-Pot Synthesis of 1H-Benzimidazole
Derivatives Using Thiamine
Hydrochloride as a Reusable
Organocatalyst
Min Lei a , Lei Ma b & Lihong Hu a b
a Shanghai Research Center for Modernization of Traditional Chinese
Medicine, Shanghai Institute of Materia Medica, Shanghai, China
b School of Pharmacy, East China University of Science and
Technology, Shanghai, China
Accepted author version posted online: 10 Jan 2012.
To cite this article: Min Lei , Lei Ma & Lihong Hu (2012): One-Pot Synthesis of 1H-Benzimidazole
Derivatives Using Thiamine Hydrochloride as a Reusable Organocatalyst, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:20, 2981-2993
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Synthetic Communications1, 42: 2981–2993, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.573610
ONE-POT SYNTHESIS OF 1H-BENZIMIDAZOLE
DERIVATIVES USING THIAMINE HYDROCHLORIDE
AS A REUSABLE ORGANOCATALYST
Min Lei,1 Lei Ma,2 and Lihong Hu1,2
1Shanghai Research Center for Modernization of Traditional Chinese
Medicine, Shanghai Institute of Materia Medica, Shanghai, China
2School of Pharmacy, East China University of Science and Technology,
Shanghai, China
GRAPHICAL ABSTRACT
Abstract A simple and efficient one-pot synthesis of 1H-benzimidazole derivatives using
thiamine hydrochloride (VB1) as the organocatalyst from o-phenylenediamine and alde-
hyde in dimethylformamide is described. Compared to classical reaction conditions, this
new method consistently has the advantages of excellent yields, metal-ion-free procedure,
and good recovery and reusablity of catalyst.
Keywords Aldehyde; 1H-benzimidazole; green chemistry; o-phenylenediamine; thiamine
hydrochloride (VB1)
INTRODUCTION
1H-Benzimidazole derivatives are an important class of compounds and have
received considerable attention in recent years because of their wide range of biologi-
cal activities against several viruses,[1] such as HIV, herpes (HSV-1), RNA, influenza,
and human cytomegalovirus (HCMV). Moreover, current literature reveals that
these compounds show fungicidal, antitumor, immunosuppressant, and anticonvul-
sant properties.[2] Therefore, preparation of this heterocyclic nucleus has gained
great importance in organic synthesis.
Methods of benzimidazole synthesis include the condensation of o-aryldia-
mines with carboxylic acids or their derivatives in the presence of strong acids such
Received October 29, 2010.
Address correspondence to Lei Ma, School of Pharmacy, East China University of Science and
Technology, 130 Meilong Road, Shanghai 200237, China. E-mail: malei@ecust.edu.cn and Lihong Hu,
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. E-mail:
simmhulh@mail.shcnc.ac.cn
2981

2982
M. LEI, L. MA, AND L. HU
Figure 1. Thiamine hydrochloride.
as polyphosphoric acid[3] or mineral acids,[4] the thermal- or acid-promoted
cyclization of N-(N-arylbenzimidoyl)-1,4-benzoquinoneimines,[5] the condensation
of o-aryldiamines and aldehyde in refluxing nitrobenzene,[6] and use of various
catalysts, such as Sc(OTf)3,[7] Yb(OTf)3,[8] copper(II) acetate,[9] 2,3-dichloro-5,6-
dicyanobenzoquinone
(DDQ),[10]
I2=KI=K2CO3=H2O,[11]
oxalic
acid,[12]
L-proline,[13] microwaves (MW),[14] M(HSO4)n,[15] and SiO2-ZnCl2.[16] In recent
years, several other conditions for the preparation 1H-benzimidazole derivatives
have also been reported.[17]
However, many of these procedures require strongly acidic conditions. More-
over, many of these reported methods have one or more drawbacks, such as long
reaction times, high temperature, poor yields of products, the use of metal salts as
catalysts, and difficulty recovering the catalysts.
At the beginning of this new century, green chemistry has become a major driv-
ing force for organic chemists to develop environmentally benign routes to a myriad
of materials.[18] As environmental consciousness in chemical research and industry
increases, the challenge for a sustainable environment calls for clean procedures that
can avoid using metal ions as catalysts.
It is well known that thiamine hydrochloride (VB1) is cheap, nontoxic, and
stable and can be recovered. VB1 contains a pyrimidine ring and a thiazole ring
linked by a methylene bridge (Fig. 1). VB1 analogs have been used as powerful cat-
alysts for various organic transformations.[19] In this article, we report a simple,
efficient, and environmentally friendly procedure for the synthesis of 1H-benzimida-
zoles by the condensation of o-phenylenediamine with aldehydes in the presence of a
catalytic amount of VB1 under stirring at ambient temperture (Scheme 1).
RESULTS AND DISCUSSION
First, the mixture of o-phenylenediamine 1 and benzaldehyde 2a was chosen as
the model reaction to detect whether the use of VB1 was efficient. We carried out the
Scheme 1.

SYNTHESIS OF 1H-BENZIMIDAZOLE
2983
Table 1. Optimization of the reaction conditionsa
Entry
VB1 (mol%)
Solvent
Time (h)
Yield of 3a (%)b
1
2
0
1
DMF
DMF
DMF
10
3
Trace
72
93, 93, 90, 91
3c
4
3
1.5
1.5
1.5
2
5
DMF
DMF
92
92
80
82
30
85
84
5
10
3
6
EtOH
THF
7
3
2
8
3
DCM
Acetonitrile
1,4-Dioxane
5
9
10
3
1.5
1.5
3
aConditions: The reaction was carried out at room temperature.
bIsolated yield.
cCatalyst was reused four times.
reaction in EtOH at ambient temperature, taking a 1:1 mol ratio mixture of o-phe-
nylenediamine 1 and benzaldehyde 2a in the presence of 3 mol% VB1 for 2 h to afford
2-phenyl-1H-benzimidazole 3a in 80% yield. Encouraged by the result, we studied
different reaction parameters, and the results are summarized in Table 1.
In this condensation reaction, we found that the amount of catalyst and solvents
had significant effects on reaction time and yields (Table 1). The reaction of o-pheny-
lenediamine 1 and benzaldehyde 2a were performed in dimethylformanide (DMF) in
the presence of different amount of VB1. Only a trace amount of the target product
was observed when the mixture was stirred under similar conditions in the absence
of VB1, even after stirring for 10 h (Table 1, entry 1). As shown in table 1, the results
indicated that the reaction time was shortest and the yield was greatest when using
3 mol % VB1, hence 3 mol % was chosen as the optimum amount of catalyst.
To find the optimum solvent, the condensation reaction was carried out in the
presence of 3 mol % VB1 as the catalyst in the DMF, EtOH, tetrahydrofurean
(THF), dichloromethane (DCM), acetonitrile, and 1,4-dioxane (Table 1, entries 3
and 6–10). The reaction using DMF as the solvent gave the best result (Table 1, entry
3); consequently, all the further studies were conducted using DMF as the reaction
medium.
Furthermore, the recyclable character of VB1 was also investigated. Of parti-
cular note was the fact that the catalyst was easy to recover by simple filtration from
the reaction medium and could be reused without any loss of activity (Table 1, entry
3). We obtained the desired product in 93%, 93%, 90%, and 91% yields after runs 1–4
respectively.
Encouraged by the remarkable results obtained with these reaction conditions,
and to show the generality and scope of this new protocol, we used various aldehydes
to synthesize 2-substituted 1H-benzimidazoles (Table 2).
The results shown in Table 2 indicated that the substituted aromatic aldehydes,
bearing either electron-donating or electron-withdrawing substituents afford good
yields (88–93%). Therefore, we concluded that the electronic nature of substituents
of the aromatic aldehydes had no significant effect on this reaction. After completion
of the reaction, EtOAc was added and the catalyst could be recovered almost

2984
M. LEI, L. MA, AND L. HU
Table 2. Synthesis of 2-substituted-1H-benzimidazolesa
Product 3
Entry
1
Yield of 3 (%)b
93
2
91
3
4
5
93
92
88
6
90
7c
<15
8c
<15
aThe reaction was carried out at room temperature for 1.5 h.
bIsolated yield.
cFailed to isolate.
quantitatively by filtration. The recovered catalyst dried at 100 ꢀC for 3 h and could
be reused without any loss of activity.
Moreover, we also examined the condensation reaction using alkyl aldehydes,
such as propionaldehyde and n-butylaldehyde, as starting materials in the presence
of 3 mol% VB1 as the catalyst in DMF at ambient temperature for 1.5 h. Unfortu-
nately, in these cases, several side reaction were observed, the yields of the desired

SYNTHESIS OF 1H-BENZIMIDAZOLE
2985
Scheme 2.
Scheme 3.
products were less than 15% as indicated by thin-layer chromatography (TLC) and
the target products could not be isolated.
After successfully synthesizing a series of 2-aryl-1H-benzimidazole derivatives
in excellent yields in the presence of VB1 as catalyst, we turned our attention to the
synthesis of 2-aryl-1-arylmethyl-1H-benzimidazoles 4 by condensation of o-phenyle-
nediamine 1 and two equiv of aromatic aldehydes 2 (Scheme 2).
We carried out the reaction in DMF at ambient temperature, taking a 1:2 mol
ratio mixture of o-phenylenediamine 1 and benzaldehyde 2a in the presence of 3 mol
% VB1 as the catalyst in DMF at ambient temperature for 1.5 h. After completion of
the reaction, products 3a and 4a were found in 18% and 73% yields, respectively
(Scheme 3). Then we changed the amount of the benzaldehyde 2a from 1 to 3 equiv
and found that the amount of benzaldehyde 2a had a significant effect on the ratio of
3a and 4a. The results are summarized in Table 3.
The results of Table 3 clearly indicated that the yield of 3a was decreased as the
amount of benzaldehyde 2a increased from 1 to 3 equiv (Table 3, entries 1–7), and
only a trace amount of 3a was found when using 2.3 or more than 2.3 equiv benzal-
Table 3. Condensation of o-phenylenediamine 1 and benzaldehyde 2a under different molar ratiosa
Entry
Ratio of 1:2a
Yield of 3a (%)b
Yield of 4a (%)b
Ratio of 3a:4a
1
2
3
4
5
6
7
1:1.0
1:1.5
1:2.0
1:2.2
1:2.3
1:2.5
1:3.0
93
52
Trace
42
73
93:trace
52:42
18:73
18
6
88
91
6:88
Trace
Trace
Trace
Trace:91
Trace:92
Trace:92
92
92
aThe reaction was carried out at room temperature for 1.5 h.
bIsolated yields.

2986
M. LEI, L. MA, AND L. HU
Table 4. Synthesis of 2-aryl-1-arylmethyl-1H-benzimidazolesa
Product 4
Entry
Yield of 4 (%)b
1
91
2
90
3
92
4
93
5
90
6
88
(Continued )

SYNTHESIS OF 1H-BENZIMIDAZOLE
2987
Table 4. Continued
Product 4
Entry
Yield of 4 (%)b
7
94
8
89
aThe reaction was carried out at room temperature for 1.5 h.
bIsolated yield.
dehyde 2a. In contrast, the yield of 4a was improved as the amount of benzaldehyde
2a increased from 1 to 3 equiv (Table 3, entries 1–7). The yields plateaued when the
amount of benzaldehyde 2a was further increased from 2.3 to 3 equiv. Hence, 2.3
Scheme 4. Plausible mechanism for the formation of compound 3.

2988
M. LEI, L. MA, AND L. HU
Scheme 5. Plausible mechanism for the formation of compound 4.
equiv of benzaldehyde 2a was considered to be most suitable for the synthesis of
1-benzyl-2-phenyl-1H-benzimidazole 4a.
Then we synthesized a number of 2-aryl-1-arylmethyl-1H-benzimidazole deri-
vatives using the optimized reaction conditions, and the results are shown in
Table 4. The method has the ability to tolerate a variety of functional groups such
as methyl, methoxy, hydroxyl, chloro, nitro, and dimethylamino.
Referring to the reaction pathway that had been reported about the conden-
sation between o-phenylenediamine 1 and aldehydes 2, we can hypothesis that
VB1 probably accelerated the cyclization and airoxidation of the intermediates
(Schemes 4 and 5).
As shown in Scheme 4, the first step in this reaction is the formation of imine
intermediate 5 from o-phenylenediamine 1 and 1 equiv of aldehydes 2. Subsequent

SYNTHESIS OF 1H-BENZIMIDAZOLE
2989
cyclization of the amino to the imine affords intermediate 6, which is oxidized by air
to afford the desired compound 3.
The proposed mechanism for the synthesis of 2-aryl-1-arylmethyl-1H-
benzimidazoles 4 is shown in Scheme 5. The reaction of o-phenylenediamine 1 and
2 equiv of aldehydes 2 may occur by a mechanism of condensation, cyclization,
and isomerization. Initial condensation between o-phenylenediamine 1 and 2 equiv
of aldehydes 2 gives imine intermediate 7, and then cyclization finishes to 8, which
isomerizes to the target product 4.
In conclusion, a mild, convenient, and efficient method for the synthesis of
2-aryl-1H-benzimidazoles and 2-aryl-1-arylmethyl-1H-benzimidazoles using inex-
pensive and nontoxic VB1 as catalyst at ambient temperature has been identified.
Excellent yields, recycling of catalyst with negligible loss of activity, metal-free
procedure, and the application to a variety of substituted aryl aldehydes are some
of the salient features of this reaction.
EXPERIMENTAL
1H MNR spectra were recorded at 400 MHz, with TMS as an internal stan-
dard. Chemical shifts (d) are given in parts per million (ppm) relative to TMS and
coupling constants (J) in hertz (Hz). Melting points were measured using an electro-
thermal melting point apparatus and are uncorrected.
General Procedure for One-Pot Preparation of 2-Aryl-1H-
benzimidazols 3 Using VB1 as a Catalyst
A mixture of o-phenylenediamine 1 (5 mmol), aryl aldehydes 2 (5 mmol), and
VB1 (0.15 mmol, 3 mol %) in DMF (3 mL) was stirred at room temperature for
1.5 h. EtOAc (30 mL) was added to this solution, and the catalyst was recovered
by simple filtration. The catalyst was rinsed with a little EtOAc, dried at 100 ꢀC
for 3 h, and then could be reused without loss of activity. Then, the organic layer
was washed with H2O and brine, dried over MgSO4, and concentrated in a vacuum
to give the crude product, which was chromatographed on silca gel and eluted with
CH2Cl2–MeOH (100:1) to give pure product 3.
General Procedures for One-Pot Preparation of 2-Aryl-1-arylmethyl-
1H-benzimidazoles 4 Using VB1 as a Catalyst
A mixture of o-phenylenediamine 1 (5 mmol), aryl aldehydes 2 (11.5 mmol),
and VB1 (0.15 mmol, 3 mol%) in DMF (3 mL) was stirred at room temperature for
1.5 h. EtOAc (30 mL) was added to this solution, and the catalyst was recovered
by simple filtration. The catalyst was rinsed with a little EtOAc, and dried at
100 ꢀC for 3 h, and then could be reused without loss of activity. Then, the organic
layer was washed with H2O and brine, dried over MgSO4, and concentrated in a vac-
uum to give the crude product, which was chromatographed on silca gel and eluted
with petroleum ether–EtOAc (7:1) to give pure product 4.

2990
M. LEI, L. MA, AND L. HU
2-Phenyl-1H-benzimidazole (3a). Yield: 93%; white solid; mp 294 ꢀC (lit.[11]
1
295 ꢀC). H NMR (400 MHz, DMSO-d6): d ¼ 12.93 (brs, 1 H), 8.19 (d, J ¼ 7.2 Hz,
2 H), 7.44–7.65 (m, 5 H), 7.21 (m, 2 H). MS (EI, 70 eV): m=z (%) ¼ 193 (Mþ).
2-(4-Methyl-phenyl)-1H-benzimidazole (3b). Yield: 91%; white solid; mp
278 ꢀC (lit.[11] 277 ꢀC). MS (EI, 70 eV): m=z (%) ¼ 207 (Mþ).
2-(4-Methoxy-phenyl)-1H-benzimidazole (3c). Yield:þ93%; white solid; mp
225 ꢀC (lit.[11] 223–226 ꢀC). MS (EI, 70 eV): m=z (%) ¼ 223 (M ).
2-(4-Hydroxyl-phenyl)-1H-benzimidazole (3d). Yield: 92%; white solid;
1
mp 278 ꢀC. H NMR (400 MHz, DMSO-d6): d ¼ 12.67 (brs, 1 H), 10.01 (brs, 1 H),
8.04 (d, J ¼ 7.2 Hz, 2 H), 7.55 (m, 2 H), 7.16 (m, 2 H), 6.95 (d, J ¼ 7.2 Hz, 2 H).
MS (ESI): m=z ¼ 210 ([M þ 1]þ).
2-(4-Chlorophenyl)-1H-benzimidazole (3e). Yield: 92%; white solid; mp
1
292 ꢀC (lit.[17d] 294 ꢀC). H NMR (400 MHz, DMSO-d6): d ¼ 13.00 (brs, 1 H), 8.21
(d, J ¼ 8.4 Hz, 2 H), 7.69 (d, J ¼ 6.4 Hz, 1 H), 7.64 (d, J ¼ 8.4 Hz, 2 H), 7.55 (d,
J ¼ 6.4 Hz, 1 H), 7.23 (m, 2 H). MS (EI, 70 eV): m=z ¼ 227 (Mþ).
2-(3-Nitrophenyl)-1H-benzimidazole (3f). Yield:þ92%; yellow solid; mp
205 ꢀC (lit.[10] 204–206 ꢀC). MS (EI, 70 eV): m=z ¼ 238 (M ).
1-Benzyl-2-phenyl-1H-benzimidazole (4a). Yield: 91%; white solid; mp
1
134 ꢀC (lit.[12] 133–134 ꢀC). H NMR (400 MHz, CDCl3): d ¼ 7.81 (d, J ¼ 8.0 Hz, 1
H), 7.60 (dd, J ¼ 8.0 and 2.0 Hz, 2 H), 7.31–7.40 (m, 3 H), 7.18–7.25 (m, 5 H),
7.04–7.07 (m, 3 H), 5.41 (s, 2 H). MS (EI, 70 eV): m=z ¼ 284 (Mþ).
1-(4-Methylbenzyl)-2-(4-methylphenyl)-1H-benzimidazole (4b). Yield:
90%; white solid; mp 131 ꢀC (lit.[12] 128–129 ꢀC). 1H NMR (400 MHz, CDCl3):
d ¼ 7.83 (m, 1 H), 7.57 (d, J ¼ 8.0 Hz, 2 H), 7.28 (m, 1 H), 7.25 (d, J ¼ 8.0 Hz, 2
H), 7.20 (m, 2 H), 7.13 (d, J ¼ 8.0 Hz, 2 H), 6.97 (d, J ¼ 8.0 Hz, 2 H), 5.38 (s, 2
H), 2.39 (s, 3 H), 2.33 (s, 3 H). MS (EI, 70 eV): m=z ¼ 312 (Mþ).
1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)-1H-benzimidazole
1
(4c). Yield: 92%; white solid; mp 130 ꢀC (lit.[12] 127–129 ꢀC). H NMR (400 MHz,
CDCl3): d ¼ 7.83 (d, J ¼ 8.0 Hz, 1 H), 7.61 (d, J ¼ 8.8 Hz, 2 H), 7.20–7.30 (m, 3
H), 7.02 (d, J ¼ 8.8 Hz, 2 H), 6.95 (d, J ¼ 8.8 Hz, 2 H), 6.84 (d, J ¼ 8.0 Hz, 2 H),
5.38 (s, 2 H), 3.78 (s, 3 H), 3.84 (s, 3 H). MS (EI, 70 eV): m=z ¼ 344 (Mþ).
1-(3,4-Dimethoxybenzyl)-2-(3,4-dimethoxyphenyl)-1H-1,3-
1
benzimidazole (4d). Yield: 93%; white solid; mp 173 ꢀC (lit.[20] 171–173 ꢀC). H
NMR (400 MHz, CDCl3): d ¼ 7.80–7.90 (m, 1 H), 7.53–7.57 (m, 1 H), 7.22–7.31
(m, 4 H), 6.94 (d, J ¼ 8.4 Hz, 1 H), 6.80 (d, J ¼ 8.4 Hz, 1 H), 6.60–6.70 (m, 2 H),
5.42 (s, 2 H), 3.92 (s, 3 H), 3.84 (s, 3 H), 3.78 (s, 3 H), 3.75 (s, 3 H). MS
(EI, 70 eV): m=z ¼ 404 (Mþ).
1-(4-Hydroxybenzyl)-2-(4-hydroxyphenyl)-1H-benzimidazole
1
(4e). Yield: 90%; white solid; mp 116 ꢀC (lit.[21] 111–113 ꢀC). H NMR (400 MHz,
CDCl3): d ¼ 7.75 (d, J ¼ 8.0 Hz, 2 H), 7.19–7.22 (m, 4 H), 7.03–7.08 (m, 3 H),
6.87–6.90 (m, 3 H), 5.25 (s, 2 H). MS (ESI): m=z ¼ 317 ([M þ 1]þ).

SYNTHESIS OF 1H-BENZIMIDAZOLE
2991
1-(4-Dimethylamino-benzyl)-2-(4-dimethylaminophenyl)-1H-benzimi-
dazole (4f). Yield: 88%; white solid; mp 163 ꢀC (lit.[21] 165–167 ꢀC). 1H NMR
(400 MHz, CDCl3): d ¼ 7.78 (d, J ¼ 8 Hz, 1 H), 7.63–7.65 (m, 4 H), 7.15–7.27 (m,
3 H), 6.67–6.75 (m, 4 H), 5.35 (s, 2 H), 2.98 (s, 6 H), 2.93 (s, 6 H). MS (EI,
70 eV): m=z ¼ 370 (Mþ).
1-(4-Chlorobenzyl)-2-(4-chlorophenyl)-1H-benzimidazole
(4g). Yield:
88%; white solid; mp 136 ꢀC (lit.[12] 137–138 ꢀC). 1H NMR (400 MHz, CDCl3):
d ¼ 7.83 (d, J ¼ 8.0 Hz, 1 H), 7.56 (m, 2 H), 7.25–7.50(m, 6 H), 7.21 (d, J ¼ 8.0 Hz,
1 H), 7.02 (d, J ¼ 8.8 Hz, 2 H), 5.38 (s, 2 H). MS (EI, 70 eV): m=z ¼ 352 (Mþ).
1-(4-Nitrobenzyl)-2-(4-nitrophenyl)-1H-benzimidazole (4h). Yield: 89%;
yellow solid; mp 193 ꢀC (lit.[12] 189–191 ꢀC), 8.31 (d, J ¼ 9.0 Hz, 2 H), 8.21 (d,
J ¼ 8 Hz, 2 H), 7.91 (dd, J ¼ 8.0 and 1.0 Hz, 1 H), 7.81 (d, J ¼ 9.0 Hz, 2 H), 7.39
(td, J ¼ 7.0 and 1.0 Hz, 1 H), 7.32 (td, J ¼ 9.0 and 1.0 Hz, 1 H), 7.26 (d, J ¼ 9.0 Hz,
2 H), 7.19 (dd, J ¼ 8.0 and 1.0 Hz, 1 H), 5.52 (s, 2 H). MS (EI, 70 eV): m=z ¼ 374 (Mþ).
ACKNOWLEDGMENTS
This work was supported by the Chinese National Science and Technology
Major Project ‘‘Key New Drug Creation and Manufacturing Program’’ (Grants
2009ZX09301-001, 2009ZX09102), the National Natural Science Foundation of
China (Grants 90713046, 30772638, 30925040), and CAS Foundation (Grant
KSCX2-YW-R-179).
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