Article abstract of DOI:10.1016/j.tetlet.2014.05.113
A unique one-pot reaction via CC cleavage from aminomethylene benzimidazoles with commercial halides to access novel benzimidazolones is reported for the first time. The previously unexploited transformation is able to perform smoothly in the presence of
Institute of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, People’s Republic of
China
ARTICLE INFO
ABSTRACT
Article history:
Received
A unique one-pot reaction via C−C cleavage from aminomethylene benzimidazoles with
commercially halides to access novel benzimidazolones is reported for the first time. The
previously unexploited transformation is able to perform smoothly in the presence of
commercial potassium carbonate, while the stronger inorganic bases or organic amines as
catalysts are not favorable to the transformation. Significant influential factors including base,
temperature, solvent, water content, molar ratio of substrates to this reaction are investigated,
and possibly mechanistic consideration is also discussed. Some synthesized benzimidazolones
were evaluated and exhibited better bioactivities against tested strains than clinical drugs
chloromycin, norfloxacin and fluconazole.
Received in revised form
Accepted
Available online
Keywords:
benzimidazole
benzimidazolone
C−C cleavage
synthesis
2009 Elsevier Ltd. All rights reserved.
Benzimidazolones are an important type of unique
heterocycles with typical cyclic urea scaffold and large π-
conjugated backbone, and are able to exert various non-covalent
interactions such as hydrogen bond, coordination, ion-dipole,
cation-π, π-π stacking, hydrophobic effect and van der Waals
force, and thus possess a variety of potential applications not
only in medicinal aspects as antidiabetic,1 antiulcer,2 anti-
infective3 and analgesic4 agents, but also in chemical fields as
organic dyes5 and dye-sensitized solar cells.6 In particular, many
benzimidazolone derivatives have been successfully developed as
clinical drugs such as antiemetic Domperidone, antipsychotic
Pimozide and Benperidol, analgesic Bezitramide and so on.7
These extensive potential applications of benzimidazolone
compounds have attracted increasing effort to develop their
highly efficient syntheses. Currently, the reported synthetic
methods of benzimidazolones could be divided into three
pathways: cyclization of acyclic compounds,8 transformation of
benzimidazoles9 and functionalization of benzimidazolones.10
Very recently, transformation of benzimidazoles has become an
intriguing strategy to access special benzimidazolones via
cleavage of C−H, C−N, C−O, C−S bonds etc,9 but so far, to our
knowledge, the C−C bond cleavage to generate
benzimidazolones has not been observed. Furthermore, the
reported methodologies for the preparation of benzimidazolones
are expensive and multi-step synthetic procedures with harsh
conditions. This compels much effort to continuously develop the
conveniently, economically and efficiently synthetic strategies to
access benzimidazolones.
Figure 1. X-Ray single-crystal structure of benzimidazolone 7a.
In continuation of our previous researches on azoles
antimicrobial agents11 and novel fluconazole analogues,12 a series
of tertiary amine benzimidazole derivatives were designed and
synthesized.13 Accidentally, in this process the unexpected
benzimidazolones were obtained under mild reaction conditions.
This strongly attracted us with an overwhelming interest to
investigate this reaction. Primarily, we synthesized tertiary amine
4a as white solid in a low yield of 6% by the reaction of
compound 2a with 2,4-difluorobenzyl bromide (compound 3a),
and compounds 5a14 and 6a were also obtained in yields of 59%
and 13% respectively (Scheme 1). To our surprise, another new
compound was successfully separated as white solid in a yield of
1
16% and characterized to be benzimidazolone 7a. TheH NMR
spectrum of compound 7a in deuterated chloroform showed a
singlet at 5.11 ppm integrating for 4H in aliphatic area, and its
———
† Postdoctoral fellow from Department of Chemistry, Madurai Kamaraj University, India
‡ Postdoctoral fellow from Department of Chemistry, Hyderabad University, India
* Corresponding author: Tel/Fax: +86-23-68254967; email: zhouch@swu.edu.cn or zhouch6848@sina.com, gxcai@swu.edu.cn
2
Tetrahedron Letters
mass spectrum exhibited a peak at m/z equaled to 386. In order
tetrabutylammonium hydroxide as catalysts all gave quite low
yields (< 5%) (Table S1, entries 1, 4−7). These results
undoubtedly pointed out that weak potassium carbonate exerted a
good catalytic effect on this transformation, while strong bases
resulted in the unidentified byproducts rather than oxidation.9
to further deduce the unexpected structure, its single crystal was
successfully cultivated and X-ray diffraction measurement
manifested its precise structure (Figure 1).
N
Cl
N
NH2
F
F
F
F
N
H
NH
F
3a
HN
F
F
MeCN
70 oC, 12 h
F3C
CF3
N
N
2a
F
EtOH
F
F3C
CF3
F
N
H
NH
N
H
NH
reflux, 24 h
1
2Br
CF3
HBr
2Br
N
H2O
F
+
A
F3C
F
F3C
CF3
N
N
N
H
N
+
8a
F
NH
F
F
F
F3C
F
CF3
F
4a
5a
F3C
F
CF3
F
N
N
OH
NH
N
O
F
F
F
N
H
Br
CF3
7a
N
N
N
N
F
F
F3C
B
F
+
O
N
Scheme 2. Possible mechanism from aminomethylene benzimidazole to
access benzimidazolone 7a.
Table 1. Effect of solvents on the formation of benzimidazolone 7aa
6a
7a
Yieldb (%)
F3C
CF3
F
F
Scheme 1. Synthesis of aminomethylene benzimidazole 2a and its reaction
Entry
Solvent
1
EtOH
36
47
32
29
40
14
38
30
with 2,4-difluorobenzyl bromide.
2
CH3CN
DMSO
DMF
With intense purpose to further figure out this reaction,
continuous effort was made and some expectant results were
acquired. Firstly, compound 2a was reacted with excess 2,4-
difluorobenzyl bromide, and subsequently after half an hour the
reaction system was treated with potassium carbonate in one-pot
procedure to give the predicted product 7a. On the basis of our
experimental results and the related literature,9 a possible
mechanism for this reaction could be proposed. Possibly,
benzimidazolium salt 8a was first generated via the N-
quaternization of compound 2a with 2,4-difluorobenzyl bromide,
and then the C2-substituted group was lost by the attack of water
and subsequently it was hydrolyzed to give inter-cleavage of
C−C bond simultaneously with the deprotonation of the hydroxyl
group to access benzimidazolone 7a (Scheme 2). The employed
base could neutralize the generated hydracids to promote this
reaction. However, the presence of base was also unfavorable
because it could change the onium salts into alkylated
benzimidazoles. With an aim to further confirm this mechanism,
tertiary amine 4a, N-2,4-difluorobenzyl benzimidazole 5a and
compound 6a with both tertiary amine and N-2,4-difluorobenzyl
benzimidazole were respectively further stirred in the presence of
potassium carbonate, and no benzimidazolone was formed.
However, when 2,4-difluorobenzyl bromide was added to the
above three reaction systems separately before the addition of
base, the anticipated product could be obtained. This
phenomenon clearly manifested that this proposed mechanism
seems to be receivable. Furthermore, the reaction of compound
2a and 2,4-difluorobenzyl bromide was employed as a model
reaction, and some control experiments were performed in order
to investigate the effect of bases as catalysts on this reaction.
Experimental results showed that potassium carbonate was
favorable for the formation of the anticipant product with a yield
of 25% (Table S1, entry 2), and neither stronger inorganic bases
such as potassium hydroxide, sodium hydride and sodium
ethoxide nor organic amines such as triethyl amine and
3
4
5
THF
6
ethyl acetate
1,4-dioxane
H2O
7
8
9c
10c
CH3CN/H2O (1/1)43
CH3CN/H2O (5/1)54
a General conditions: A suspension of compound 2a (0.050 g, 0.139 mmol)
and 2,4-difluorobenzyl bromide 3a (0.177 g, 0.834 mmol) was stirred at 70
oC. After 0.5 h, potassium carbonate (0.010 g, 0.070 mmol) was added, and
the reaction system was continuously stirred for another 48 h. b Yield of the
isolated product after silica gel chromatography. c In this case, the reaction
was performed through the sequential addition of CH3CN followed by stirring,
and then after 0.5 h water was added. CH3CN/H2O (V/V = 1/1). CH3CN/H2O
(V/V = 5/1).
Reasonably, potassium carbonate was employed as catalyst to
further screen other reaction conditions to improve the yields.
Since temperature is one of the most important factors
influencing reactions, the suitable reaction temperature was exp-
lored for this transformation. During the screening, the highest
o
yield up to 41% for 7a was obtained at 70C, but when the
o
reaction system was stirred at 0C, no expected compound was
found even after the reaction system had been stirred for one
week (Table S2, entry 1). Meanwhile, the amount of catalyst was
also investigated to improve the transformation efficacy, and it
was found that this reaction occurred in the highest efficacy when
molar ratio of compound 2a to catalyst was 0.5 (Table S3, entry
1). As shown in Table S4, the suitable molar ratio of compound
2a and 2,4-difluorobenzyl bromide was also researched, and the
best yield (47%) was obtained when the ratio was reduced to 1/6.
So we chose 2,4-difluorobenzyl bromide ratio of 6 as the optimal
condition. These findings effectually demonstrated that the
amount of reactants and catalysts could affect the transformation
efficacy to some extent. Subsequently, the various solvents were
3
investigated, and the moderate 47% yield was obtained in
CH3CN (Table 1, entry 2), whereas ethyl acetate resulted in the
lowest yield of 14% (Table 1, entry 6) which might be attributed
to the unfavorable dissolvability of compounds. The effect of
water as the reaction solvent on this transformation was also
Table 2. Investigation of substrate scope on the formation of benzimidazolonesd
explored (Table 1, entries 8−10). The highest yield (54%) was
obtained in CH3CN/H2O (5/1), and therefore this condition was
chosen as the optimal solvent medium to perform this
transformation.
R2
N
N
O
N
N
H
NH
2
+
R
X
2
R1
3
7
R2
Entry
R1
R2
X
Product Yielde Entry
R1
R2
X
Product Yielde
No.
(%)
No.
(%)
1
3,5-2CF3
3,5-2CF3
3,5-2CF3
3,5-2CF3
3,5-2CF3
3,5-2CF3
3,5-2CF3
3,5-2CF3
3,5-2CF3
3,5-2CF3
3,5-2CF3
2,4-2FC6H3
2,4-2ClC6H3
3,4-2ClC6H3
2-ClC6H4
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Cl
7a
7b
7c
7d
7e
7f
54
46
43
36
35
39
37
35
34
25
21
12
13
14
15
16
17
18
19
20
21
3,5-2CF3
3,5-2CF3
3-CF3
CH3(CH2)4
4-NO2C6H4
2,4-2FC6H3
2,4-2FC6H3
2,4-2FC6H3
2,4-2FC6H3
2,4-2FC6H3
2,4-2FC6H3
2,4-2FC6H3
2,4-2FC6H3
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
7l
13
trace
41
37
34
28
27
24
11
8
2
7m
7a
7a
7a
7a
7a
7a
7a
7a
3
4f
2,4-2F
2,4-2Cl
2-F
5
3-ClC6H4
6
4-ClC6H4
7
2-FC6H4
7g
7h
7i
4-F
8
3-FC6H4
4-Cl
9
4-FC6H4
4-CH3
2,4-2CH3
10
4-CH3C6H4
7j
11
4-OCH3C6H4
7k
d General conditions: A suspension of compound 2a (0.050 g, 0.139 mmol) and 2,4-difluorobenzyl bromide 3a (0.175 g, 0.834 mmol) was stirred at 70 oC in
acetonitrile. After 0.5 h, potassium carbonate solution (0.010 g, CH3CN/H2O (V/V = 5/1)) was added, and the reaction system was continuously stirred for
another 48 h. e Yield of the isolated product after silica gel chromatography. f The single crystal was cultivated (please see the Supporting Information).
Table 3. Antibacterial data as MIC (µg/mL) for compounds 7a−lg,h
Gram-Positive bacteria
Gram-Negative bacteria
B. proteus
Compds
S. aureus
MRSA
B. subtilis
M. luteus
E. coli
P. aeruginosa
B. typhi
7a
7b
16
16
32
32
16
32
32
64
32
64
64
128
8
32
64
32
32
64
32
64
64
32
128
128
256
16
1
16
32
64
16
32
32
32
32
16
32
64
64
32
2
32
32
16
32
32
64
32
32
32
64
64
128
8
8
16
16
32
32
64
32
32
64
32
32
64
64
16
1
16
32
32
16
32
64
32
32
64
64
128
64
16
1
16
32
16
32
64
32
64
32
32
64
64
32
32
1
16
16
64
32
32
64
32
64
64
32
64
32
4
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
Chloromycin
Norfloxacin
8
1
g Minimal inhibitory concentrations were determined by micro broth dilution method for microdilution plates.
h
S. aureus, Staphylococcus aureus (ATCC25923); MRSA, Methicillin-Resistant Staphylococcus aureus (N315); B. subtilis, Bacillus subtilis; M. luteus,
Micrococcus luteus (ATCC4698); B. proteus, Bacillus proteus (ATCC13315); E. coli, Escherichia coli (JM109); P. aeruginosa, Pseudomonas aeruginosa; B.
typhi, Bacillus typhi; C. albicans, Candida albicans (ATCC76615); C. mycoderma, Candida mycoderma; C. utilis, Candida utilis; S. cerevisia, Saccharomyces
cerevisia; A. flavus, Aspergillus flavus.
Some commercial halides were further explored for this
reaction (Table 2, entries 1−13). Among them, it was found that
halobenzyl halides were suitable substrates, whether 2,4-2FPh-,
2,4-2ClPh-, 3,4-2ClPh-, FPh- or ClPh- moieties all successfully
produced benzimidazolones (Table 2, entries 1−9). The electron-
donating methyl and methoxyl substituted benzyl halides also
generated the desired products (Table 2, entries 10 and 11). It is
noticeable that alkyl halide also could perform this reaction in
yield of 13% (Table 2, entry 12). However, to our surprise, no
desired product was obtained when electron-withdrawing 4-
nitrobenzyl bromide was subjected to these reaction conditions
(Table 2, entry 13), and the main product 4-nitrobenzaldehyde
was observed as the literature reported.15
Experimental results showed that the strong electron-
withdrawing substituents in anilines exhibited better reactivity
than weaker ones. Noticeably, 3,5-bis(trifluoromethyl)
benzimidazole provided the highest yield up to 54% for
compound 7a, while 2,4-dimethyl substituted one gave the
lowest yield of 8% (Table 2, entries 1 and 21).
Additionally, in the process for the preparation of compound
2, it was observed that the expected aminomethylene
benzimidazoles would not be provided when aniline ring was
substituted by nitro groups. Furthermore, experiments
demonstrated that anilines with strong electron-withdrawing
nitro groups generated the byproduct 2-(ethoxymethyl)-1H-
benzimidazole as main product (Scheme S2). This phenomenon
might be ascribed to the strong electron-withdrawing property of
nitro group which made it difficult to perform the nucleophilic
substitution of 2-(chloromethyl)-1H-benzimidazole.
Various substituted anilines were also screened under the
standard conditions. Besides 3,5-bis(trifluoromethyl)aniline,
other substituted anilines including electron-withdrawing fluoro,
chloro and trifluoromethyl, and electron-donating methyl and
methoxyl ones were also tolerated (Table 2, entries 14−21).
4
Tetrahedron Letters
In addition, the synthesized benzimidazolones were
Supplementary Material
evaluated for their in vitro antimicrobial activities against four
Gram-positive bacteria, four Gram-negative bacteria as well as
five fungal strains.16 As shown in Table 3, some
benzimidazolones exhibited better bioactivities against the tested
bacteria, specially, compound 7a gave the most potent anti-B.
proteus activity with MIC value of 8 µg/mL, which was 4-fold
more active than clinical Chloromycin. The antifungal evaluation
in vitro showed that all target tertiary amine type of
benzimidazole derivatives displayed better activities against
Fluconazole-insensitive A. flavus than reference drug
Fluconazole. Particularly, compound 7a displayed 32-fold more
inhibitory activity than Fluconazole for A. flavus strains (Table
4). The bioactive results revealed that some benzimidazolone
compounds gave better bioactivities against the tested strains
than clinical drugs chloromycin, norfloxacin and fluconazole (for
details please see the Supporting Information).
Experimental procedures and full spectroscopic data for all
new compounds. This material is available free of charge via the
Internet.
References and notes
1.
Liu, W. G.; Lau, F.; Liu, K.; Wood, H. B.; Zhou, G. C.; Chen, Y.
L.; Li, Y.; Akiyama, T. E.; Castriota, G.; Einstein, M.; Wang, C.;
McCann, M. E.; Doebber, T. W.; Wu, M.; Chang, C. H.;
McNamara, L.; McKeever, B.; Mosley, R. T.; Berger, J. P.;
Meinke, P. T. J. Med. Chem. 2011, 54, 8541–8554.
2.
3.
Garcia, C. V.; Nudelman, N. S.; Steppe, M.; Schapoval, E. E. S. J.