Synthesis of Aminofuran-Linked Benzimidazoles and Cyanopyrrole-Fused Benzimidazoles by Condition-Based Skeletal Divergence

Article abstract of DOI:10.1021/acscombsci.7b00052

A condition-based skeletal divergent synthesis was explored to achieve skeletal diversity in two component condensation reaction. Cyanomethyl benzimidazole was reacted with α-bromoketone under thermal conditions to furnish 2-aminofuranyl-benzimidazoles, w

Full text of DOI:10.1021/acscombsci.7b00052

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Article
Synthesis of Aminofuran-linked Benzimidazoles and Cyanopyrrole-
fused Benzimidazoles by Condition-Based Skeletal Divergence
Wei-Shun Hsu, Min-Huan Tsai, Indrajeet J. Barve, Gorakh S. Yellol, and Chung-Ming Sun
ACS Comb. Sci., Just Accepted Manuscript • Publication Date (Web): 26 Apr 2017
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Synthesis of Aminofuran-linked Benzimidazoles and
Cyanopyrrole-fused Benzimidazoles by Condition-Based
Skeletal Divergence
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Wei-Shun Hsu,§ Min-Huan Tsai,§ Indrajeet J. Barve,§ Gorakh S. Yellol§ and Chung-Ming Sun§,†*
§Department of Applied Chemistry, 1001 Ta-Hseuh Road, National Chiao-Tung University,
Hsinchu 300-10, Taiwan
†Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, 100, Shih-
Chuan 1st Road, Kaohsiung 807-08, Taiwan
Email: cmsun@mail.nctu.edu.tw
Graphical Abstract
O
CN
+
N
N
R1
R2
MeO
Br
O
OMe
MeO
O
O
N
N
R1
N
N
R1
NH2
NC
R2
O
∆
MW
R2
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Abstract
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A condition-based skeletal divergent synthesis was explored to achieve skeletal
diversity in two component condensation reaction. Cyanomethyl benzimidazole
was reacted with α-bromoketone under thermal conditions to furnish 2-
aminofuranyl-benzimidazoles while the same reaction afforded 3-cyano-
benzopyrrolo-imidazoles under microwave irradiation. Two non-equivalent
nucleophilic centers on benzimidazole moiety were manipulated elegantly by
different reaction conditions to achieve the skeletal diversity.
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Keywords: 2-Aminofuranyl-benzimidazole, 3-Cyano-benzopyrrolo-imidazole,
Divergent synthesis, Non-equivalent nucleophilicity, Skeletal diversity
Introduction
A direct interaction of small molecules with proteins is a powerful tool to study
complex biological systems. Efficient synthesis of structurally diverse small
molecules provides a validated source of chemical probes for biomedical research.1
Consequently, diversification of the skeletal architecture of such compound
libraries is particularly desirable to address biologically relevant chemical space to
enable the discovery of new therapeutic agents with higher potency and
selectivity.2-3 In order to generate a greater degree of structural diversity in the
compound libraries, various synthetic strategies, like varying building blocks,
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functional groups, stereochemistry and scaffolds, were incorporated into the
diversity-oriented synthesis.
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8
9
In particular, the condition-based skeletal divergence represents a powerful
strategy to generate diverse compounds from the same starting materials by
altering the reaction conditions such as temperature, pressure, solvent, catalyst and
other factors.4,5 In addition to these parameters, condition-based divergent
synthesis under microwave irradiation, ultrasonication and in the presence of ionic
liquids have provided additional opportunities to tune the selectivity.6 A
challenging task in this context is the condensation of two simple subunits which
leads to different products due to the presence of least nonequivalent reaction
centers.
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Reaction
conditions
X
Y
Z
C
D
A
B
Substrates
E
Products
Figure 1. The concept of condition-based skeletal divergence in DOS.
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Conceptually, a set of inputs A and B may produce distinct scaffolds C, D and E
respectively via different mechanistic pathways under the different reaction
conditions X, Y and Z (Figure 1).
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In our previous studies, we found that the 2-alkyl benzimidazole or equivalent
skeletons in general can generate several different products due to the presence of
nonequivalent nucleophilic centers and the regioselectivity can be tuned by
activation of different nucleophilic centers under different reaction conditions
(Scheme 1).
N
N
N
N
:
B
B:
N
N
N
N
EW
EW
G
EWG
G
EWG
R
R
R
R
I
I
II
II
N
N
N
N
N
N
EW
G
EWG
N
N
EW
G
EWG
R
R
R
R
IV
IV
III
III
=
w
e ec ron
a o s
r w n r u
i
p
g g
EW
l
t
ithd
G
EWG = electron withdrawing groups
Scheme 1. Nonequivalent nucleophilic centers in 2-alkyl benzimidazole moiety
In connection with our studies on the synthesis of biologically interesting
heterocyclic systems,7 herein we demonstrated the condition-based skeletal
divergent synthesis of 2-aminofuranyl-benzimidazole and 3-cyano-benzopyrrolo-
imidazole through condensation of cyanomethylbenzimidazole with α-
bromoketones under conventional heating and microwave irradiation respectively.
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Results and Discussion
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For the current study, the key precursor, N-alkylated 2-(cyanometyl)-
benzimidazoles 7 was prepared by a literature method (Scheme 2).8
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O
O
O
H2N R1
N
F
O2
N
O2
.
N
F
O2
,
n
H
O
a
e
e
t H
C
2SO4
M
O
M
Z
H
O
NH
O
3
COO
,
4
,
,
,
re u
fl
x
e
e
M
r
M
H
O
r
t
H 2 h
t
H
l
C
2C 2
NH
R1
1
2
4
N
C
O
,
O
O
O
O
N
C
H
O
NH
N
C
NH2
N
e
e
M O
e
M
O
M
O
10 TFA
%
D
DMAP
CC
,
,
,
N
x
r
re u
H
N
t 16 h
fl
12 h
C
3C
NH
R1
NH
R1
R1
5
7
6
Scheme 2. Synthesis of cyanomethyl benzimidazoles 7.
In
a
model
reaction,
methyl
2-(cyanomethyl)-1-pentyl-1H-
benzo[d]imidazole-5-carboxylate
7{9} was treated with 4-chloro-2’-bromo
acetophenone
8
{1} using K2CO3 in toluene in a sealed tube at 110 oC for 24
h. Disappointingly, only unconsumed starting materials 7{9} and 8{1} were
recovered (Table 1, entry 1). Moreover, when the same reaction was carried
o
out at 180 C for 4 h, no coupling product was observed (Table 1, entry 2).
When the reaction was performed in 5 equivalents of K2CO3 at 180 °C for 8
h, a new spot was observed (Table 1, entry 3). The newly formed product
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was isolated (55 %) and subjected to spectroscopic analysis. Spectroscopic
analysis of the obtained product did not match the structure of the expected
7
8
9
alkylated product 9{9,1}. The corresponding peaks of the methylene protons
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adjacent to carbonyl group were not observed in the proton NMR spectrum,
while an unexpected singlet at ~6.83 ppm and a broad singlet peak for -NH2
protons at ~6.45 ppm was clearly present in the proton NMR spectrum. In
addition, the carbon NMR spectrum also showed an extra peak in the
aromatic region.
Table 1. Optimization of the condensation of
7{9} and
8{1} under
conventional heating and microwave irradiationa
O
O
H2N
N
CN
N
N
MeO
O
∆
MeO
O
intramolecular
cyclization
N
H11
C5
O
H11
C5
10
Cl
CN
N
N
MeO
9
Cl
9,1
9,1
{
}
{
}
anticipated
alkylated product
observed
product
cyclized
H11
C5
7
9
{ }
Cl
O
O
O
O
Br
intramolecular
cyclization
N
N
N
MeO
MeO
Cl
CN
H11
Cl
N
CN
H11
MW
8 1
{ }
C5
9,1
C5
}
12
{
}
11
9,1
{
observed
product
cyclized
anticipated
alkylated product
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7
8
9
base
(equiv)
8
10
9,1
{
1
{ }
temp
T
}
entry
solvent
yield (%)c
oC)
(equiv)
(h)
(
K
K
K
K
K
K
2CO
1
2
3
4
5
6
2
2
2
toluene
toluene
toluene
toluene
toluene
110
24
4
8
8
8
NR
NR
55
61
72
3 (5)
2CO
2CO
180
180
180
180
180
3 (2)
3 (5)
2CO
2CO
2CO
2
3 (10)
3 (10)
3 (10)
1.2
1.2
10
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8
5
xylene
EDC
toluene
toluene
toluene
toluene
K
K
2CO
2CO
7
8
9
10
11
12b
1.2
5
1.2
1.2
1.2
NR
10
42
NR
NR
180
180
180
180
180
8
8
8
8
8
3 (10)
3 (10)
(10)
Et N
3
t-BuOK
DMAP
(10)
(10)
K
2CO
2
toluene
150
60
NR
3 (10)
13b
14b
5
2
toluene
EDC
150
120
15
15
NR
10d
K
2CO
2CO
3 (5)
3 (2)
K
aReaction conditions:
7{9} (1 equiv), 8{1} (equiv), K2CO3 (equiv), sealed tube.
bReactions were performed under MW condition (reaction time in min). cIsolated product
after column chromatography. dIsolated product was 12{9,1}. NR- No Reaction.
Consequently, as a representative example one of the products was further
analyzed by X-ray crystallography and it revealed the structure of obtained
product was 10{9,1} rather than the expected alkylated product 9{9,1}. The
ORTEP diagram of 10{9,1} is depicted in Figure 2.9 The furan moiety is
linked to benzimidazole scaffold at 3-position with amino functionality at 2-
position. Excellent regioselectivity was observed during this condensation
under the conventional heating condition, and no traces of other products
were detected in the crude product. These combined studies clearly indicated
the intramolecular cascade cyclization between the keto and the cyano
groups of regioselective alkylated product
9{9,1} to afford the 2-
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aminofuranyl benzimidazole 10{9,1}. We next turned our attention to
improving the yield of the unexpected product 10{9,1}. Accordingly, the
condensation was carried out in 10 equivalents of K2CO3 to obtain 10{9,1}
in 61 % yield (Table 1, entry 4). Similarly, when the same reaction was done
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in 1.2 equivalents of
(Table 1, entry 5).
8{1} and 10 equivalents of K2CO3, the yield was 72 %
Figure 2. ORTEP diagram of compound 10{9,1}.
Next, the screening of solvents such as xylene, ethylene dichloride (EDC)
afforded 10{9,1} in 5 % and 0 % respectively (Table 1, entries 6, 7). The
increase in equivalents of 8{1} lowered the yield of 10{9,1} (Table 1, entry
8). The use of other bases such as triethylamine afforded 10{9,1} in 42 %
yield, whereas t-BuOK or DMAP did not afford any cyclized product
10{9,1} (Table 1, entries 9-11).
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After successful achievement of the regioselective condensation of 7{9}
5
6
7
with
8{1} by selective activation of the non-equivalent reaction centers
8
9
under the conventional heating condition, the same reaction was performed
under microwave irradiation to further improve the reaction efficiency.
Hence, initially the same reaction which was performed in toluene under
microwave irradiation failed to deliver any desired product 10{9,1} (Table 1,
entries 12, 13).
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Figure 3. ORTEP diagram of compound 12{9,5}.
However, when the reaction was carried out in EDC under microwave
irradiation, a new spot having different Rf value as compared to 10{9,1} was
observed (Table 1, entry 14). The newly formed spot was isolated in inferior
yield and subjected to characterization. Spectroscopic analysis of this
microwave product did not match the structure of either the alkylated
product
9{9,1} or the cyclized product 10{9,1}. Consequently, as a
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representative example one of the obtained products was further analyzed by
X-ray crystallography. To our surprise, it revealed the formation of
benzimidazole fused pyrrole 12{9,5}. The ORTEP diagram in Figure 39
demonstrated the benzimidazole fused pyrrole structure which can be formed
by intramolecular cyclization of N-alkylated product 11{9,5}.
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This interesting discovery motivated us to optimize the reaction conditions
for 12{9,1} and the results are summarized in Table 2. A slight increase in
the yield (15 %) was observed when the transformation was carried out at
o
150 C (Table 2, entry 2). When the amount of K2CO3 was increased (5
equiv), the desired product 12{9,1} was obtained in inferior yield (Table 2,
entry 3). The decrease in the amount of K2CO3 (0.5 equiv) afforded 12{9,1}
in slightly better yield (Table 2, entry 4). The desired product 12{9,1} was
obtained in good yield when the reaction was carried out with 5 equivalents
of 8{1} and 0.5 equivalents of K2CO3 (Table 2, entry 5). A change in the
solvent to CH3CN did not give any product (Table 2, entry 6). The screening
of other bases such as triethylamine, t-BuOK, DMAP and piperidine resulted
in 12{9,1} in low to moderate yield (Table 2, entries 7-10). We next
examined the substrate scope of this unprecedented condition-based skeletal
divergence approach for the synthesis of 2-aminofuranyl benzimidazoles 10
and 3-cyano benzopyrrolo benzimidazoles 12 (Tables 3 and 4). Accordingly,
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cyanomethyl benzimidazole derivatives
bromoketones {1-5}
7{1-9} were treated with various α-
8
7
8
9
Table 2. Optimization of the condensation reaction of
7{9} and
8
{1} under
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microwave irradiationa
O
CN
N
N
MeO
Cl
O
O
O
H11
C5
7
9
{ }
intramolecular
Cl cyclization
N
N
N
MeO
Base
MeO
CN
MW
Solvent,
CN
H11
N
O
Br
C5
9,1
H11
C5
11
12
{
}
9,1
{
}
Cl
8
1
{ }
base
(equiv)
8
1
12
yield (%)c
{ }
9,1
{
}
entry
solvent
(equiv)
1
2
3
4
5
2
2
2
2
5
5
EDC
EDC
10b
15
5
K
K
K
2CO
3 (2)
2CO
2CO
3 (2)
EDC
3 (5)
3 (0.5)
3 (0.5)
3 (0.5)
(0.5)
K
K
K
2CO
2CO
2CO
EDC
23
75
NR
EDC
6
7
8
toluene
Et N
5
5
EDC
EDC
39
62
3
t-BuOK
(0.5)
(0.5)
5
5
DMAP
EDC
EDC
40
65
9
10
piperidine
(0.5)
aReaction conditions:
7
{9} (1 equiv),
8
{1} (equiv), K2CO3, MW (150 W, 150 °C), 15
b
c
min. Reaction was performed under MW (150 W, 120 °C). Isolated product after
column chromatography; NR- No Reaction.
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under the optimized conditions of thermal heating as well as microwave
irradiation. Moderate to good yields were obtained with a variety of
substitutions.
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11
12
13
14
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Table 3. The substrate scope for the synthesis of 2-aminofuranyl-
benzimidazoles 10 under thermal conditiona
O
H2N
O
R2
N
N
K
e
M
O
2CO3
N
C
N
N
R1
O
e
M
O
r
B
o uene
T l
R1
O
∆
R2
7
1
0
8
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benzimidazoles
Cyanomethyl
2-Bromoacetophenones
4
5
6
7
O
O
O
Cl
N
N
CN
N
N
N
N
CN
CN
MeO
MeO
MeO
Br
Br
O
O
8
9
8 2
{ }
8 1
{ }
7
1
{ }
7
3
{ }
MeO
10
11
12
13
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50
51
52
53
54
55
56
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59
60
7
2
{ }
Br
O
O
O
Br
O
N
N
N
N
N
O
CN
CN
CN
MeO
MeO
MeO
8
8 4
{ }
3
{ }
N
O
S
Br
7
5
O
{ }
7
7
6
{ }
4
{ }
8 5
{ }
O
O
O
N
CN
O
N
N
CN
N
N
CN
MeO
MeO
MeO
N
O
7
8
{ }
7
9
{ }
7
7
{ }
O
N
N
CN
MeO
7
10
{
}
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O
O
O
O
H2N
H2N
H2N
H2N
N
N
N
N
N
N
N
N
MeO
O
MeO
O
MeO
O
MeO
O
6
Cl
Cl
Cl
7
8
9
10
10
3,1
{
67%
72%
H2N
MeO
3,2
{
},
},
10
72%
},
1,1
{
10
70%
2,1
},
{
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
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32
33
34
35
36
37
38
39
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49
50
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60
H2N
O
O
O
O
H2N
H2N
N
N
N
MeO
O
MeO
O
N
N
N
N
MeO
O
MeO
MeO
MeO
O
O
O
N
S
Cl
O
Cl
10
68%
5,1
},
10
65%
},
{
4,2
{
10
63%
6,3
},
10
72%
},
6,1
{
{
O
H2N
O
O
H2N
H2N
H2N
N
N
N
N
MeO
O
N
N
N
MeO
O
MeO
O
N
O
Cl
O
Cl
10
70%
},
9,3
{
10
73%
10
72%
9,1
{ },
8,1
{
},
10
65%
},
7,2
{
H2N
N
N
10
75%
},
6,4
{
aReaction conditions:
tube, 180 oC, 8 h.
7
(1 equiv),
8
(1.2 equiv), K2CO3 (10 equiv), toluene (8 mL), sealed
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Table 4 The substrate scope for the synthesis of 3-cyano-benzopyrrolo-
benzimidazoles 12 under microwave irradiationa
7
8
9
R2
O
R2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
K
2CO3
N
C
N
N
e
M
O
N
N
R1
12
e
M
O
r
B
,
N
C
MW
ED
C
O
R1
7
8
Cl
Cl
Cl
O
O
O
O
N
N
N
N
MeO
MeO
N
N
N
N
MeO
MeO
CN
CN
CN
CN
MeO
12
68%
12
3,2
72%
{
},
12
75%
},
3,1
{
},
1,1
{
12
75%
},
2,1
{
Cl
Cl
O
O
O
N
N
O
MeO
N
N
N
N
CN
MeO
MeO
N
N
MeO
CN
CN
CN
O
S
12
75%
},
4,2
{
12
64%
5,1
{
},
12
12
6,3
{
73%
74%
},
6,1
{
},
Cl
O
O
O
N
N
N
MeO
MeO
N
N
MeO
CN
CN
N
CN
O
O
12
71%
},
12
9,5
{
75%
},
8,1
{
12
67%
7,2
{
},
aReaction conditions:
W, 150 oC), 15 min.
7
(1 equiv),
8
(5 equiv), K2CO3 (0.5 equiv), EDC (4 mL), MW (150
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To investigate a plausible reaction pathway, attempts were made to isolate
5
6
7
C- and N-alkylated intermediates
9{10,1} and 11{10,1}. Subsequently, all
8
9
the attempts made to arrest alkylation reaction of
7
{10} with {1} under
8
10
11
12
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microwave irradiation ended up with the cyclised product 12{10,1}, which
indicated the fast conversion of intermediate 11{10,1} to product 12{10,1}.
O
O
H2N
CN
N
N
MeO
N
N
O
∆
MeO
O
intramolecular
cyclization
4 h
O
Cl
CN
N
N
MeO
9
10
10,1
{ }
10,1
Cl
{
}
Isolated intermediate
7
10
}
{
Cl
O
O
O
O
Br
intramolecular
cyclization
N
N
N
N
MeO
MeO
Cl
MW
CN
Cl
CN
15 min
conversion
Fast
8 1
{ }
11
10,1
12
10,1
{
}
{
}
Isolated
product
Scheme 3 Isolation of the C- and N-alkylated intermediates
11{10,1}
9{10,1} and
However, alkylation reaction of
7
{10} with
8{1} under conventional heating
condition was successfully arrested after 4 h and the intermediate
9
{10,1}
was isolated from the reaction mixture. The obtained reaction intermediate
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9{10,1} was unambiguously studied by X-ray crystallographic study (Figure
5
6
7
4).
8
9
10
11
12
13
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Cl
O
N
N
O
O
CN
Figure 4. ORTEP diagram of intermediate 9{10,1}
The efforts of trapping of the reaction intermediate clearly revealed that the
intramolecular cyclization under conventional thermal condition proceeded
through C-alkylated intermediate 9{10,1}whereas, the intramolecular cyclization
under microwave irradiation progressed through N-alkylated intermediate
11{10,1}.
On the basis of our intermediate isolation study and the obtained results,
the plausible steps involved in the intramolecular ring closure of
intermediate
Scheme 4.
9
and 11 to product 10 and 12 respectively are shown in
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5
O
H
3C
H
C
N
N
R1
O
N
6
7
8
9
7
∆
MW
O
K
2CO3
O
O
H
R2
O
O
R2
H
3C
N
N
R1
H
3C
N
N
R1
O
O
10
11
12
13
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15
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O
N
C
N
N
9
11
R2
H
O
O
O
O
R2
H
3C
N
N
R1
H
H
3C
N
N
R1
H
O
O
O
O
N
C
H
T2
M2
H
O
H
O
R2
H
3C
H
R2
N
N
R1
3C
O
N
N
R1
O
N
C
HN
M3
T3
-
H
2O
O
R2
R2
H
3C
N
N
R1
H
3C
N
N
R1
O
O
N
C
NH2
10
12
Scheme 4 A Plausible mechanism for the formation of compound 10 and 12
The cyclization of intermediate T2 through an attack of the oxygen atom of
the enol on the nearby cyano group afforded T3. Subsequent aromatization
to the furan ring by proton exchange yielded product 10. However, under
microwave irradiation, benzimidazole nitrogen’s lone pair driven cyclization
yielded M2. The proton shift and consequent aromatization to pyrrole ring
by the expulsion of a water molecule from M3 furnished pyrrolo-
benzimidazole product 12
.
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Conclusion
5
6
7
8
9
In conclusion, condition-based scaffold divergence in the condensation
reaction of cyanomethyl benzimidazole with α–bromoketone under classical
heating and microwave irradiation conditions is reported. Under
conventional thermal conditions, cyanomethyl benzimidazole was
regioselectively C-alkylated which on subsequent intramolecular cyclization
furnished 2-aminofuranyl-benzimidazoles. However, under microwave
irradiation conditions, 3-cyano-pyrrolo-benzimidazoles were obtained
through regioselective N-alkylation of 2-cyanomethyl benzimidazole. This
method demonstrated that the competitive reaction pathways or non-
equivalent nucleophilicity could be utilized to achieve skeletal diversity in
the condition-based diversity-oriented synthesis.
10
11
12
13
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Experimental Section
General Methods
13
1H NMR (300 MHz) and C NMR (75 MHz) spectra were recorded on Bruker
DX-300 spectrometer. Chemical shifts are reported in parts per million (ppm) on
the δ scale from an internal standard (TMS). Analytical thin-layer chromatography
(TLC) was performed using 0.25 mm silica gel-coated Kiselgel 60 F254 plates.
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Flash chromatography was performed using the indicated solvent and silica gel 60
(Merck, 230-400 mesh). High-resolution mass spectra (HRMS) were recorded in
ESI mode using TOF mass spectrometer. IR spectra were obtained using FT-IR
spectrometer. Microwave irradiation experiments were performed in a CEM
Discover single-mode microwave reactor equipped with an IR temperature sensor
using standard 10 mL CEM process vial sealed with Teflon® cap. All materials
were purchased from commercial sources and used without further purification.
10
11
12
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A representative procedure for the synthesis of methyl 2-(2-amino-5-(4-
chlorophenyl)furan-3-yl)-1-pentyl-1H-benzo[d]imidazole-5-carboxylate
10{9,1}
To a solution of methyl 2-(cyanomethyl)-1-isopentyl-1H-benzo[d]imidazole-5-
carboxylate 7{9} (0.1 g, 0.3506 mmol) in toluene (5 mL) were added 2-bromo-1-
(4-chlorophenyl)ethanone 8{1} (0.097 g, 0.420 mmol) and potassium carbonate
(0.484 g, 3.506 mmol) at room temperature. The resulting reaction mixture was
heated in sealed tube (180 °C) for 8 hours. The reaction progress was monitored by
TLC. After the reaction was complete, the mixture was cooled to room temperature
and solvent was evaporated under reduced pressure. The crude reaction mixture
was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The
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organic phase was separated, dried over magnesium sulfate and concentrated in
vacuo. The crude product was purified by column chromatography (eluent: 15 %
ethyl acetate in hexanes) to afford the corresponding methyl 2-(2-amino-5-(4-
chlorophenyl)furan-3-yl)-1-pentyl-1H-benzo[d]imidazole-5-carboxylate 10{9,1}.
This procedure was applied for the synthesis of rest of the all derivatives 10.
10
11
12
13
14
15
16
17
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Methyl 2-[2-amino-5-(4-chlorophenyl)furan-3-yl]-1-pentyl-1H-benzimidazole-
5-carboxylate (10{9,1})
1
Pale yellow solid; Yield 109 mg, 72%; m.p. 161-163 °C; H NMR (300 MHz,
CDCl3) δ 8.33 (d, J = 1.4 Hz, 1H), 7.93 (dd, J = 8.4, 1.4 Hz, 1H), 7.45 (d, J = 8.5
Hz, 2H), 7.33-7.24 (m, 3H), 6.79 (s, 1H), 6.57-6.40 (brs, 2H), 4.25 (t, J = 7.5 Hz,
2H), 3.95 (s, 3H), 1.89 (quin, J = 7.1 Hz, 2H), 1.47-1.36 (m, 4H), 0.93 (t, J = 6.9
13
Hz, 3H); C NMR (75 MHz, CDCl3) δ 168.3, 160.2, 151.1, 143.5, 142.7, 138.9,
132.2, 129.3, 129.1, 124.3, 123.9, 123.5, 120.3, 108.6, 103.6, 88.7, 52.4, 44.8, 30.1,
29.5, 22.8, 14.4; IR (cm-1, neat) 3410, 3350, 2954, 2929, 1712, 1618; HRMS m/z
calculated for C24H24ClN3O3: 437.1506; found: 437.1515.
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A representative procedure for the synthesis of methyl 2-(tert-butyl)-3-cyano-
5
6
7
4-pentyl-4H-benzo[d]pyrrolo[1,2-a]imidazole-7-carboxylate (12{9,5})
8
9
A mixture of methyl 2-(cyanomethyl)-1-isopentyl-1H-benzo[d]imidazole-5-
carboxylate 7{9} (0.1 g, 0.3506 mmol), 2-bromo-1-(4-chlorophenyl)ethanone 8{1}
(0.406 g, 1.753 mmol) and potassium carbonate (0.024 g, 0.1753 mmol) in 1,2-
dichloroethane (5 mL) was irradiated in the microwave cavity (150 W, 150 °C) for
15 min. After completion of the reaction, as indicated by TLC, the solvent was
removed under reduced pressure. The crude reaction mixture was diluted with
water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was
separated, dried over magnesium sulfate and concentrated under reduced vacuum.
The crude product was purified by column chromatography (eluent: 30 % ethyl
acetate in hexanes) to furnish methyl 2-(tert-butyl)-3-cyano-4-pentyl-4H-
benzo[d]pyrrolo[1,2-a]imidazole-7-carboxylate 12{9,5} in 75 % yields (0.963 g).
This procedure was applied for the synthesis of rest of the all compound 12.
10
11
12
13
14
15
16
17
18
19
20
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23
24
25
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59
60
Methyl
2-tert-butyl-3-cyano-4-pentyl-4H-pyrrolo[1,2-a]benzimidazole-7-
carboxylate (12{9,5})
1
Off-white solid; Yield 963 mg, 75%; m.p. 142-144 °C; H NMR (300 MHz,
CDCl3) δ 8.23 (s, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.27 (m, 1H), 6.83 (s, 1H), 4.30 (t,
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J = 7.2 Hz, 2H), 3.97 (s, 3H), 1.98-1.94 (m, 2H), 1.47 (s, 9H), 1.44-1.37 (m, 4H),
0.92 (t, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 167.1, 144.7, 142.2, 139.5,
126.1, 125.8, 122.7, 118.3, 112.5, 108.8, 100.9, 63.5, 52.7, 44.8, 32.8, 30.7, 29.4,
29.3, 22.8, 14.3; IR (cm-1, neat): 2958, 2929, 2866, 2200, 1718, 1589; HRMS m/z
calculated for C22H27N3O2: 365.2103; found: 365.2108.
10
11
12
13
14
15
16
17
18
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60
Supporting Information
The Supporting Information is available free of charge on ACS Publications
website. Characterization data of compounds 10 and 12. Full Spectroscopic data
(1H, 13C NMR, HRMS and FT-IR) of compounds 10 and 12. X-ray
crystallographic data of compounds 10{9,1} and 12{9,5}.
Author Information
Corresponding Author
*Email: cmsun@mail.nctu.edu.tw
Acknowledgment: The authors thank Ministry of Science and Technology
(MOST) of Taiwan for financial assistance and the authorities of the National
Chiao Tung University for providing the laboratory facilities.
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6
7
8
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Synthesis as a Tool for the Discovery of Novel Biologically Active Small
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A Boronic Ester Annulation Strategy for Diversity-Oriented Organic Synthesis.
Angew. Chem. Int. Ed. 2002, 41, 152-154. (d) Schreiber, S. L. Target-Oriented and
Diversity-Oriented Organic Synthesis in Drug Discovery. Science 2000, 287,
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Synthesis
of
Aminofuran-linked
Benzimidazoles
and
Cyanopyrrole-fused Benzimidazoles by Condition-Based Skeletal
Divergence
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Wei-Shun Hsu,§ Min-Huan Tsai,§ Indrajeet J. Barve,§ Gorakh S. Yellol§ and
Chung-Ming Sun§,†*
§Department of Applied Chemistry, 1001 Ta-Hseuh Road, National Chiao-Tung University,
Hsinchu 300-10, Taiwan
†Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, 100, Shih-
Chuan 1st Road, Kaohsiung 807-08, Taiwan
*Corresponding author: cmsun@mail.nctu.edu.tw
Graphical Abstract
O
CN
+
N
N
R1
R2
MeO
Br
O
OMe
MeO
O
O
N
N
R1
N
N
R1
NH2
NC
R2
O
∆
MW
R2
A condition-based skeletal divergent synthesis was explored to achieve skeletal diversity in
two component condensation reaction. Cyanomethyl benzimidazole was reacted with α-
bromoketone under thermal conditions to furnish 2-aminofuranyl-benzimidazoles while the
same reaction afforded 3-cyano-benzopyrrolo-imidazoles under microwave irradiation. Two
non-equivalent nucleophilic centers on benzimidazole moiety were manipulated elegantly by
different reaction conditions to achieve the skeletal diversity.
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