Synthesis of benzimidazoles from o-phenylenediamines and DMF derivatives in the presence of PhSiH3

Article abstract of DOI:10.1016/j.tet.2017.05.018

A simple approach to preparation of benzimidazoles from o-phenylenediamines and DMF derivatives, only employing PhSiH₃ as promoter without any other additives, was reported. This route provided moderate to high yields with a broad substrate scope. A plausible mechanism for the reaction is proposed based on the spectroscopic characterization (e.g., HRMS and ¹H NMR) of the reaction mixture.

Full text of DOI:10.1016/j.tet.2017.05.018

Accepted Manuscript
Synthesis of benzimidazoles from o-phenylenediamines and DMF derivatives in the
presence of PhSiH
3
Jianhua Zhu, Zhenbei Zhang, Chengxia Miao, Wei Liu, Wei Sun
PII:
S0040-4020(17)30484-2
10.1016/j.tet.2017.05.018
TET 28684
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 6 March 2017
Revised Date: 27 April 2017
Accepted Date: 4 May 2017
Please cite this article as: Zhu J, Zhang Z, Miao C, Liu W, Sun W, Synthesis of benzimidazoles from o-
phenylenediamines and DMF derivatives in the presence of PhSiH , Tetrahedron (2017), doi: 10.1016/
3
j.tet.2017.05.018.
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Synthesis of benzimidazoles from o-
phenylenediamines and DMF derivatives in
the presence of PhSiH3
Leave this area blank for abstract info.
a,†
b,c,†
b
a,
b,
Jianhua Zhu, Zhenbei Zhang,
Chengxia Miao, Wei Liu ∗ and Wei Sun ∗
a
Department of Pharmacy, Nantong University, Nantong 226000, P.R. China.
b
State Key Laboratory for Oxo Synthesis and Selective Oxidation Suzhou Research Institute of LICP, Lanzhou
Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, China.
c
University of Chinese Academy of Sciences, Beijing 100049, China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of benzimidazoles from o-phenylenediamines and DMF derivatives in the
presence of PhSiH3
a,†
b,c,†
b
a, ∗
b, ∗
Jianhua Zhu, Zhenbei Zhang,
Chengxia Miao, Wei Liu and Wei Sun
a
Department of Pharmacy, Nantong University, Nantong 226000, P.R. China.
State Key Laboratory for Oxo Synthesis and Selective Oxidation Suzhou Research Institute of LICP, Lanzhou Institute of Chemical Physics (LICP), Chinese
b
Academy of Sciences, Lanzhou 730000, China.
c
University of Chinese Academy of Sciences, Beijing 100049, China
†
These authors contributed equally to this work.
ARTICLE INFO
ABSTRACT
Article history:
Received
A simple approach to preparation of benzimidazoles from o-phenylenediamines and DMF
derivatives, only employing PhSiH as promoter without any other additives, was reported. This
3
Received in revised form
Accepted
route provided moderate to high yields with a broad substrate scope. A plausible mechanism for
the reaction is proposed based on the spectroscopic characterization (e.g., HRMS and H NMR)
1
Available online
of the reaction mixture.
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Benzimidazoles
PhSiH
3
o-Phenylenediamines
N,N-Dimethylformamide
Cyclization reaction
1
. Introduction
benzimidazoles from DMF and o-phenylenediamines attracted
our attention because using DMF as C1 source could be
considered as the indirect utilizing of CO2.
Benzimidazoles are ubiquitous motifs, which have found
practical applications in a number of fields such as synthesis of
natural products and biologically active molecules. Also,
1
As one of the most effective polar solvents for various
chemical reactions, N,N-dimethylformamide has been employed
as a widely utilized reactant in organic transformations such as
benzimidazoles are important intermediates in the synthesis of
pharmaceutical compounds such as antimicrobial compounds,
anthelmintic and antipsychotic drugs, antiulcer and anticancer
agents (Fig. 1). Many synthetic procedures for the synthesis of
benzimidazoles from o-phenylenediamines were reported. For
example, a condensation reaction between o-phenylenediamine
and carboxylic acid or their derivatives to form benzimidazoles is
the most popular method. Many kinds of aldehydes, alcohols or
orthoesters are utilized to generate benzimidazoles in the
presence of various catalysts in oxidative conditions. Using
CO as C block for the synthesis of organic compouds is still a
1
5
formylation, amination, and cyanation reactions. A few
approaches have been reported to form benzimidazole from DMF
2
-9
10
1
1
2
1
long-standing
goal,
and
many
cyclization
of
o-
phenylenediamines by CO to construct benzimidazoles was
2
12
reported.
N,N-dimethylformamide (DMF) can be easily
synthesized from CO with dimethylamine in the presence of H
2
2
1
3
and suitable catalyst. Also, DMF or its derivatives are efficient
reagents for the synthesis 1 of benzimidazoles with 1,2-
Fig. 1. Biologically active molecules containing benzimidazole moiety.
4
diaminobenzene (Scheme 1, a). The synthesis of
—
——
∗
Corresponding author. e-mail: weiliu@ntu.edu.cn (W. L.), e-mail: wsun@licp.cas.cn (W. S.)

2
Tetrahedron
ACCEPTED MA
Tab
NU
le
S
2
C
Sc
R
op
I
e of cyclization of o-phenylenediamines with
P
T
a
DMF.
yield
entry
substrate
product
b
(%)
1
2
95
1
a
3a
82
80
58
1
b
3b
3c
3d
3e
3f
3g
3h
3
4
5
6
7
1
c
Scheme 1 Synthesis of benzimidazoles from o-phenylenediamines and DMF.
1
d
and 1,2-dimethylamine. Treatment of o-phenylenediamine with
72
89
88
73
DMF and 2.5 equivalents of SiCl in refluxing CH Cl to provide
4
2
2
benzimidazole was reported by Bourguignon, but there was only
1e
1f
1g
1h
14c
one example in moderate yield (Scheme 1, eq. 1). Kamble and
co-workers reported an flexible method to form benzimidazole
from o-phenylenediamine and DMF, but a large amount of
concentrated hydrochloric acid (70%) was used in this process
14b
(
Scheme 1, eq. 2). Recently, Bhanage and Liu also reported the
preparation of benzimidazole derivatives from DMF and o-
phenylenediamines in the presence of hydrosilicon, but in their
report, metal catalyst Zn(OAc) •2H O or additive B(C F ) and
8
9
2
2
6
5 3
4a,16
1
CO were necessary, respectively (Scheme 1, eq. 3 and 4).
In
2
a continuation of our ongoing research on the synthesis of
12e
valuable benzimidazole compounds, we fortunately found an
61
efficient protocol for the synthesis of benzimidazoles from o-
1
i
3i
phenylenediamines and DMF derivatives employing PhSiH as
3
the only promoter without any other catalysts or additives under
metal-free conditions (Scheme 1, b).
1
1
0
1
50
41
1
j
3j
a
Table 1 Optimization of reaction conditions.
3
k
1k
1
2
31
o
b
entry
hydrosilicon
PhSiH3
equiv T ( C ) time (h) yield(%)
1
l
3
l
1
2
3
4
5
6
7
8
9
4
4
4
4
4
4
3
0
4
4
120
120
120
120
120
120
120
120
100
120
12
12
12
12
12
12
12
12
12
10
95
12
1
1
3
4
46
83
2
Ph SiH2
1m
1n
3
m
Ph SiH
trace
3
3
n
(CH ) PhSiH
trace
3
2
a
The reactions were carried out in a heavy wall pressure tube with 1a (0.4
mmol) and PhSiH (1.6 mmol) in 1 mL DMF at 120 C for 12 h.
Isolated yields.
c
o
(CH CH O) SiH
NR
3
2
3
3
b
d
PMHS
trace
85
2
. Results and discussion
PhSiH3
PhSiH3
PhSiH3
PhSiH3
c
Initially, we began our studies by investigating the
NR
condensation reaction of commercially available o-
phenylenediamines 1a with DMF 2a. To our delight, when
PhSiH3 was employed, the reaction afforded the desired
benzimidazole 3a in 95% yield at 120 °C after 12 h (Table 1,
entry 1). With this preliminary and intriguing result in hand, we
turned to extensively screen a series of hydrosilicons. Various
hydrosilicons were tested under the same conditions such as
Ph SiH , Ph SiH, (CH ) PhSiH, (CH CH O) SiH and PMHS
21
81
1
0
a
The reactions were carried out in a heavy wall pressure tube with 1a (0.4
mmol) and hydrosilicon in 1 mL DMF.
Isolated yields. NR = No reaction. PMHS = Polymethylhydrosiloxane.
b
c
d
2
2
3
3 2
3
2
3
(
Table 1, entries 2−6). The results showed that when the reaction

3
ACCEPTED MANUSCRIPT
Scheme 4 A plausible mechanism for the formation of benzimidazole from o-
phenylenediamine and DMF.
the reaction of different N-substituted formamides including N,N-
diethylformamide and N,N-dimethylacetamide. To our delight,
both of them could serve as good cyclization partners to readily
access the benzimidazole or 2-methyl-benzimidazole in high
yields (Scheme 2).
Scheme 2 The reaction with DMF derivatives.
was promoted by Ph SiH , it afforded the desired product in a
After an exploration of the substrate scope, we focused on
elucidating the mechanism of the synthesis of benzimidazoles
from o-phenylenediamines and DMF derivatives, and some
control experiments were conducted (Scheme 3). At first, we
thought that the reaction should generate acylated intermediate,
and the acylated intermediate dehydrated to form
benzimidazoles. So we performed the reaction of N-(2-
aminophenyl)acetamide with PhSiH3 to test our thought, but
whether in DMF or without solvent, the reaction did not occur
(Scheme 3, a). Then we tried to shorten the reaction time to 6 h
on the standard condition in order to find out what has been
2
2
lower yield along with most of the starting materials recovered
after 12 h (Table 1, entry 2), while Ph SiH, (CH ) PhSiH,
3
3 2
(
CH CH O) SiH and PMHS were ineffective in promoting the
3 2 3
reaction (Table 1, entries 3−6). Further optimization showed that
reducing the amount of PhSiH decreased the yield of compound
3
3
a (Table 1, entry 7). The reaction did not occur at all in the
absence of PhSiH3 (Table 1, entry 8). Lowering reaction
temperature or shortening reaction time led to the decrease in the
yield of benzimidazole 3a (Table 1, entries 9 and 10).
Under the optimized conditions, we proceeded to explore the
scope of o-phenylenediamines, and the results are shown in Table
1
formed during the reaction, and we tested the mixture on H
NMR and HRMS as soon as the reaction was finished. To our
delight, substrate (o-phenylenediamine), product benzimidazole
and the intermediate 4 were found in the mixture (Scheme 3, b,
Fig S1 and S2, Supporting Information). To our knowledge, the
similar compound 5 could cyclize in the presence of silica gel or
acetic acid to form the benzimidazole derivatives 6 (Scheme 3,
2
. The o-phenylenediamines bearing electron-donating and -
withdrawing groups were tolerated well under the reaction
conditions, affording the desired benzimidazoles in moderate to
good yields (Table 2, entries 1−11). It was noteworthy that the
electron properties and steric hindrance of the substituent groups
on the phenyl ring played an important role in the reaction. o-
Phenylenediamines containing electron-withdrawing groups
provided the desired benzimidazoles in better yields than those of
electron-donating groups (Table 2, entries 2, 3, 6 and 7 vs entries
17
c), so we consider that compound 4 might go through a similar
route to transfer into benzimidazole in the presence of PhSiH . At
3
o
last, o-phenylenediamine and DMF were heated at 120 C for 6 h
without PhSiH3 to test whether the intermediate 4 could be
8
and 11). The 4,5-disubstituted-1,2-diamine showed less
formed without PhSiH , and no reaction took place. This
3
reactivity in comparison with that of 4-monosubstituted-1,2-
dimine and gave corresponding products in relative low yields
observation indicated that PhSiH is necessary for construction of
3
intermediate 4.
(
Table 2, entries 4 and 10 vs entries 2 and 8). N-substituted-o-
phenylenediamine could also generate the corresponding product
l, although inferior yield was obtained probably owing to its
On the basis of this finding, a plausible mechanism for the
formation of benzimidazole from o-phenylenediamine and DMF
3
steric hindrance (Table 2, entry 12). In addition, the heterocyclic
compound 1m could tolerate and afford the corresponding
product 3m in 46% yield (Table 2, entry 13). 2-
Aminobenzenethiol was also compatible, efficiently providing 3n
in 83% yield (Table 2, entry 14). Then, we turned to investigate
is depicted in Scheme 4. Firstly, DMF was activated by PhSiH
3
18
to afford I and a Si-O bond was formed. Next, the intermediate
I cooperated with 1,2-diaminobenzene to form the compound II,
1
8, 19
one silanol left and the compound III was formed,
which
1
could be detected by HRMS and H NMR. Afterwards, the
intermediate IV was formed by intermolecular cyclization of the
compound III in the present of PhSiH , and one molecule of
3
HNMe was removed and the product benzimidazole 3a was
2
17
afforded.
3
. Conclusions
In summary,
a simple method for the synthesis of
benzimidazoles from o-phenylenediamines and DMF using
PhSiH3 as the only promotor is reported. Azabenzimidazole,
benzothiazoles and 2-substituted benzimidazoles are also
performed in good yields. This work presents a simple system to
synthesize benzimidazoles under mild condition. This method
has wide substrate scope, providing moderate to high yields.
Besides, NMR characterization and HRMS also gave some hints
for proposed mechanism. Future studies are underway to fully
Scheme 3 Control experiment.

4
Tetrahedron
or MAN
1
acquire the role of PhSiH3 and to build
synthesizing heterocyclic compounds.
A
ne
C
w
CE
sys
P
tem
T
s
E
f
D
Y
U
ell
S
owCRso
I
lid (53.8 mg, 72%); Spectral data of 3e: H NMR
P
T
(400 MHz, DMSO-d ) δ 12.75 (s, 1H), 8.34 (s, 1H), 7.87 (s, 2H).
6
13
C NMR (100 MHz, DMSO-d ) δ 144.8, 124.3. HRMS (ESI)
6
4
. Experimental
+
calcd for C H Cl N [M+H] 186.9824, found: 186.9829.
7
5
2
2
14a
4
.1. General information
4
.8. 6-Nitro-1H-benzo[d]imidazole (3f)
1
All reagents and reactants were obtained from commercial
Yellow solid (58.0 mg, 89%); Spectral data of 3f: H NMR
sources and used without further purification. Anhydrous
solvents were stored in the desiccator. All reactions were
monitored by TLC with GF254 silica gel coated plates. Flash
column chromatography was carried out by using 200-300 mesh
(400 MHz, DMSO-d ) δ 13.14 (s, 1H), 8.58 (s, 1H), 8.53 (s, 1H),
6
13
8.14 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H). C NMR (100
MHz, DMSO-d ) δ 146.8, 142.9, 142.6, 117.6, 115.6, 111.6.
6
+
HRMS (ESI) calcd for C H N O [M+H] 164.0455, found:
7
6
3
2
1
13
silica gel. H NMR and C NMR spectra were recorded on a
164.0457.
.9. 1H-benzo[d]imidazole-6-carbonitrile (3g)
White solid (50.4 mg, 88%); Spectral data of 3g: H NMR
400 MHz, DMSO-d ) δ 12.95 (s, 1H), 8.48 (s, 1H), 8.17 (s, 1H),
Bruker AvanceⅢ NMR spectrometer (400 MHz) in CDCl or
3
20
4
DMSO-d internally referenced to tetramethylsilane (TMS) or
6
CDCl (DMSO-d ) signals. Chemical shifts are reported in ppm
1
3
6
and coupling constants (J) in Hz. All substrates are known
compounds and prepared according to the literature.
(
7
6
13
.76 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H). C NMR (100
MHz, DMSO-d ) δ 145.3, 125.4, 120.1, 103.8. HRMS (ESI)
4
3
.2. General procedure for the synthesis of benzimidazoles (3a-
p) from dimethylamine (1a-1n) and DMF 2a (2b-2c).
6
+
calcd for C
.10. 6-Methyl-1H-benzo[d]imidazole (3h)
Yellow solid (38.5 mg, 73%); Spectral data of 3h: H NMR
400 MHz, Chloroform-d) δ 10.39 (s, 1H), 8.09 (s, 1H), 7.56 (s,
H N [M+H] 144.0556, found: 144.0562.
8 6 3
14a
4
A mixture of 1a (1b-1n, 0.4 mmol) and PhSiH (98 µL, 1.6
3
mmol) in N,N-dimethylformamide 2a (2b-2c, 1 mL) was stirred
at 120 C for 12 h. When the reaction was completed, the
1
o
(
1
resulting mixture was extracted with ethyl acetate three times.
The combined organic layer was washed by NaCl aqueous
solution and dried over anhydrous Na SO , after which the
solvent was removed under reduced pressure. The residue was
purified by column chromatography on silica gel with petroleum
ether and ethyl acetate (6:1-1:2) to give the corresponding
product 3a (3b-3p).
13
H), 7.45 (s, 1H), 7.11 (s, 1H), 2.47 (s, 3H). C NMR (100 MHz,
Chloroform-d) δ 140.6, 137.6, 136.4, 132.9, 124.5, 115.6, 114.9,
+
2
4
2
1
1.8. HRMS (ESI) calcd for C H N [M+H] 133.0760, found:
8 9 2
33.0760.
14a
4.11. 7-Methyl-1H-benzo[d]imidazole (3i)
1
Yellow solid (32.2 mg, 61%); Spectral data of 3i: H NMR
(400 MHz, Chloroform-d) δ 9.69 (s, 1H), 8.13 (s, 1H), 7.49 (d, J
14a
4
.3. 1H-benzo[d]imidazole (3a)
=
8.4 Hz, 1H), 7.20 (t, J = 7.2 Hz, 1H), 7.10 (d, J = 7.2 Hz, 1H),
1
Yellow solid (44.8 mg, 95%); Spectral data of 3a: H NMR
13
2
1
.62 (s, 3H). C NMR (100 MHz, Chloroform-d) δ 140.4, 137.8,
37.0, 126.0, 123.4, 123.1, 112.7, 17.3. HRMS (ESI) calcd for
(
=
400 MHz, Chloroform-d) δ 9.16 (s, 1H), 8.14 (s, 1H), 7.68 (t, J
2.8 Hz, 2H), 7.31 (t, J = 3.2 Hz, 2H). C NMR (100 MHz,
Chloroform-d) δ 140.6, 137.6, 123.2, 115.7. HRMS (ESI) calcd
13
+
C H N [M+H] 133.0760, found: 133.0758.
8
9
2
+
14a
for C H N [M+H] 119.0604, found: 119.0603.
4.12. 5,6-Dimethyl-1H-benzo[d]imidazole (3j)
7
7
2
14a
1
4
.4. 6-Fluoro-1H-benzo[d]imidazole (3b)
Yellow solid (29.2 mg, 50%); Spectral data of 3j: H NMR
(
2
1
400 MHz, Chloroform-d) δ 8.75 (s, 1H), 8.02 (s, 1H), 7.44 (s,
H), 2.36 (s, 6H). C NMR (100 MHz, Chloroform-d). δ 140.0,
1
Yellow solid (44.6 mg, 82%); Spectral data of 3b: H NMR
13
(
=
8
400 MHz, Chloroform-d) δ 9.13 (s, 1H), 8.16 (s, 1H), 7.58 (dd, J
8.8, 4.8 Hz, 1H), 7.32 (dd, J = 8.8, 1.2 Hz, 1H), 7.05 (td, J =
.8, 1.2 Hz, 1H). C NMR (100 MHz, Chloroform-d) δ 159.9 (d,
J = 237.6 Hz), 141.9, 137.7 (d, J = 13.6 Hz), 134.5, 116.4 (d, J =
0.3 Hz), 111.6 (d, J = 25.5 Hz), 101.6 (d, J = 25.8 Hz). HRMS
36.2, 132.1, 115.6, 20.5. HRMS (ESI) calcd for C H N
M+H] 147.0917, found: 147.0919.
9
11
2
+
[
13
14a
4.13. 6-Methoxy-1H-benzo[d]imidazole (3k)
1
(
1
+
Yellow solid (24.3 mg, 41%); Spectral data of 3k: H NMR
400 MHz, Chloroform-d) δ 9.38 (s, 1H), 8.05 (s, 1H), 7.56 (d, J
ESI) calcd for C H FN [M+H] 137.0510, found: 137.0509.
7 6 2
(
14a
4
.5. 6-Bromo-1H-benzo[d]imidazole (3c)
= 8.8 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 6.93 (dd, J =8.8, 1.6 Hz,
1
1
13
H), 3.82 (s, 3H). C NMR (100 MHz, Chloroform-d) δ 157.0,
1
Yellow solid (63.1 mg, 80%); Spectral data of 3c: H NMR
40.2, 137.3, 132.3, 116.5, 113.3, 97.6, 56.0. HRMS (ESI) calcd
(
1
(
1
1
400 MHz, Chloroform-d) δ 8.55 (s, 1H), 8.15 (s, 1H), 7.82 (s,
+
for C H N O [M+H] 149.0709, found: 149.0711.
13
8
9
2
H), 7.53 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H). C NMR
14a
100 MHz, Chloroform-d) δ 141.7, 139.0, 136.7, 126.4, 118.6+,
16.8, 116.2. HRMS (ESI) calcd for C H BrN [M+H]
7 6 2
4.14. 1-Methyl-1H-benzo[d]imidazole (3l)
1
Yellow solid (16.4 mg, 31%); Spectral data of 3l: H NMR
96.9709, found: 196.9714.
(400 MHz, Chloroform-d) δ 10.39 (s, 1H), 8.09 (s, 1H), 7.56 (s,
14a
13
4
.6. 5,6-Difluoro-1H-benzo[d]imidazole (3d)
1H), 7.45 (s, 1H), 7.11 (s, 1H), 2.47 (s, 3H). C NMR (100 MHz,
Chloroform-d) δ 140.6, 137.6, 136.4, 132.9, 124.5, 115.6, 114.9,
1
Yellow solid (34.5 mg, 56%); Spectral data of 3d: H NMR
400 MHz, DMSO-d ) δ 12.67 (s, 1H), 8.29 (s, 1H), 7.65 (t, J =
+
2
1
1.8. HRMS (ESI) calcd for C H N [M+H] 133.0760, found:
33.0761.
8
9
2
(
6
13
8
1
.4 Hz, 2H), C NMR (100 MHz, DMSO-d ) δ 147.9 (d, J =
6.7 Hz), 145.5 (d, J = 16.6 Hz), 144.1, 103.0. HRMS (ESI)
6
14a
4.15. 3H-imidazo[4,5-c]pyridine (3m)
+
calcd for C H F N [M+H] 155.0415, found: 155.0421.
7
5
2
2
1
Yellow solid (21.9 mg, 46%); Spectral data of 3m: H NMR
14a
4
.7. 5,6-Dichloro-1H-benzo[d]imidazole (3e)
(400 MHz, DMSO-d ) δ 8.94 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H),
6
13
7
.59 (s, 1H). C NMR (100 MHz, DMSO-d ) δ 144.3, 141.2,
6

5
+
(
d) Van den Brink PJ, Hattink J, Bransen F, Van Donk E, Brock
1
39.8, 109.4. HRMS (ESI) calcd for C H N [M
A
C
+H
C
]
E
1
P
20
TED
6, MANUSCRIPT
.0
55
6
6
3
TCM. Aquat. Toxicol. 2000; 48: 251-264.
e) Nakai M, Hess RA, Moore BJ, Guttroff RF, Strader LF, Linder
found: 120.0555.
(
14a
RE. J. Androl. 1992; 13: 507-518.
4
.16. Benzo[d]thiazole (3n)
4
.
(a) Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Calvez
GL, Mansourati J, Mottier D, Abgrall JF, Boschat J. J. Am. Coll.
Cardiol. 2008; 51: 256-260.
1
Light yellow liquid (44.8 mg, 83%); Spectral data of 3n: H
NMR (400 MHz, Chloroform-d) δ 8.99 (s, 1H), 8.15 (d, J = 7.6
Hz, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.52 (t, J = 6.8 Hz, 1H), 7.44
(
b) Lindberg P, Nordberg P, Alminger T, Braendstroem A,
Wallmark B. J. Med. Chem. 1986; 29: 1327-1329.
c) Hawkey CJ, Karrasch JA, Szczepanski L, Walker DG, Barkun
13
(
t, J = 7.2 Hz, 1H). C NMR (100 MHz, Chloroform-d) δ 154.0,
(
1
53.3, 133.8, 126.3, 125.6, 123.7, 122.0. HRMS (ESI) calcd for
A, Swannell AJ, Yeomans ND, Omeprazole versus Misoprostol
NIM. N. Engl. J. Med. 1998; 338: 727-734.
+
C H NS [M+H] 136.0215, found: 136.0221.
7
6
(d) Hetzel DJ, Dent J, Reed WD, Narielvala FM, Mackinnon M,
21
4
.17. 2-Methyl-1H-benzo[d]imidazole (3o)
McCarthy JH, Mitchell B, Beveridge BR, Laurence BH, Gibson
GG, Grant AK, Shearman DJC, Whitehead R, Buckle PJ.
Gastroenterology 1988; 95, 903-912.
1
Yellow solid (37.5 mg, 71%); Spectral data of 3o: H NMR
(e) Kuipers EJ, Lundell L, KlinkenbergKnol EC, Havu N, Festen
(400 MHz, Chloroform-d) δ 8.58 (s, 1H), 7.56 (s, 2H), 7.23 (s,
13
HPM, Liedman B, Lamers C, Jansen J, Dalenback J, Snel P, Nelis
GF, Meuwissen S GM. N. Engl. J. Med. 1996; 334: 1018-1022.
(f) Larsson H, Carlsson E, Mattsson H, Lundell L, Sundler F,
Sundell G, Wallmark B, Watanabe T, Hakanson R.
Gastroenterology 1986; 90: 391-399.
2
1
1
H), 2.66 (s, 3H). C NMR (100 MHz, Chloroform-d) δ 151.4,
+
38.4, 122.4, 114.6, 15.0. HRMS (ESI) calcd for C H N [M+H]
8
9
2
33.0760, found: 133.0766.
22
4
.18. 2-Methyl-6-nitro-1H-benzo[d]imidazole (3p)
(
1
(
g) Lind T, Cederberg C, Ekenved G, Haglund U, Olbe L. Gut
983; 24: 270-276.
h) Yeomans ND, Tulassay Z, Juhasz L, Racz I, Howard JM, van
1
Yellow solid (41.1 mg, 58%); Spectral data of 3p: H NMR
400 MHz, Chloroform-d) δ 8.35 (d, J = 2.0 Hz, 1H), 8.05 (dd, J
(
Rensburg CJ, Swannell AJ, Hawkey CJ, Grp AS. N. Engl. J. Med.
1998; 338: 719-726.
(a) Rago R, Mitchen J, Wilding G. Anal. Biochem. 1990; 191: 31-
34.
13
=
8.8, 2.4, Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 2.56 (s, 3H).
C
6
.
NMR (100 MHz, Chloroform-d) δ 156.7, 142.1, 117.2, 113.8,
1
found: 178.0612.
+
11.3, 14.9. HRMS (ESI) calcd for C H N O [M+H] 178.0611,
8 8 3 2
(b) Cesarone CF, Bolognesi C, Santi L. Anal. Biochem. 1979; 100:
1
88-197.
(
c) Chen TR. Exp. Cell Res. 1977; 104: 255-262.
4
.19. Spectral data of the intermediate 4
(d) Kim YJ, Sah RLY, Doong JYH, Grodzinsky AJ. Anal.
1
Biochem. 1988; 174: 168-176.
Spectral data of 4: H NMR (400 MHz, Chloroform-d) δ 7.76
d, J = 7.6 Hz, 1H), 7.54 (s, 1H), 7.44 (d, J = 6.8 Hz, 1H), 7.36 (t,
J = 7.2 Hz, 2H), 6.86 (t, J = 7.2 Hz, 2H), 4.79 (NH , s, 2H), 3.01
(
(
e) Latt SA, Wohlleb JC. Chromosoma 1975; 52: 297-316.
f) Pjura PE, Grzeskowiak K, Dickerson RE. J. Mol. Biol. 1987;
(
2
197: 257-271.
13
(
NCH , s, 6H). C NMR (100 MHz, Chloroform-d) δ 152.9,
40.5, 134.7, 128.0, 123.5, 118.9, 118.1, 77.4. HRMS (ESI)
calcd for C H N [M+H] 164.1182, found: 164.1177.
5. Sharma D, Narasimhan B, Kumar P, Jalbout A. Eur. J. Med.
Chem. 2009; 44: 1119-1127.
6. (a) Farahat AA, Paliakov E, Kumar A, Barghash A-EM, Goda FE,
Eisa HM, Wenzler T, Brun R, Liu W, Wilson WD, Boykin DW.
Bioorg. Med. Chem. 2011; 19: 2156-2167.
3
1
+
9
14
3
Acknowledgements
(b) Valdez-Padilla D, Rodríguez-Morales S, Hernández-Campos
A, Hernández-Luis F, Yépez-Mulia L, Tapia-Contreras A, Castillo
R. Bioorgan. Med. Chem. 2009; 17: 1724-1730.
This work was supported by the National Natural Science
Foundation of China (21402101 to W.L. and 21473226 to W.S.).
(
c) Navarrete-Vázquez G, Yépez L, Hernández-Campos A, Tapia
A, Hernández-Luis F, Cedillo R, González J, Martınez-Fernández
A, Martınez-Grueiro M, Castillo R. Bioorgan. Med. Chem. 2003;
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́
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