A concise synthesis of 2-(2-aminothiophene)-benzimidazoles by one-pot multicomponent reaction

Article abstract of DOI:10.1039/c3ra41545g

A one-pot synthesis of 2-aminothiophene linked benzimidazoles was achieved by utilizing 2-cyanomethyl benzimidazoles in a modified Gewald multicomponent reaction. The synthetic strategy of the reaction involved treatment of 2-(cyanomethyl)-benzimdazole wi

Full text of DOI:10.1039/c3ra41545g

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A concise synthesis of 2-(2-aminothiophene)-
benzimidazoles by one-pot multicomponent reaction3
Cite this: DOI: 10.1039/c3ra41545g
Li-Hsun Chen, Ying-Sheng Chuang, Bharat D. Narhe and Chung-Ming Sun*
A one-pot synthesis of 2-aminothiophene linked benzimidazoles was achieved by utilizing 2-cyanomethyl
benzimidazoles in a modified Gewald multicomponent reaction. The synthetic strategy of the reaction
involved treatment of 2-(cyanomethyl)-benzimdazole with aldehydes containing an active methylene
group and sulfur powder under refluxing conditions. The multicomponent reaction proceeded via
Knoevenagel condensation of 2-(cyanomethyl)-benzimdazole with aldehyde to generate an a,b-unsatu-
rated nitrile followed by cyclization with molecular sulfur under basic conditions to give biologically
relevant 2-(2-aminothiophene)-benzimidazoles in good yields.
Received 3rd April 2013,
Accepted 29th May 2013
DOI: 10.1039/c3ra41545g
www.rsc.org/advances
support,9 ionic liquid,10 polymer supported reactions,11 use
of nano-sized catalysts12 are applied advantageously for
synthesis of widely functionalized 2-aminothiophenes using
Gewald reaction in recent years.
Introduction
Despite innumerable discoveries in the field of medicinal
chemistry, various diseases originating from either micro-
organisms or malfunction of body organs post many chal-
lenges. This has caused organic chemists to search for new
biologically active molecules which are more challenging and
interesting. Aminothiophenes are one of the few widely study
molecular architectures for their diverse biological properties.
A few examples of medicinally important 2-aminothiophenes
are shown in Fig. 1.
Olanzapine (I) is a widely used antipsychotic drug for the
treatment of schizophrenia or bipolar disorder.1 Tinoridine (II)
is an anti-inflammatory drug,2 while fully substituted 2-ami-
nothiophene (III) is an agonist of allosteric enhancers at the
adenosine A1 receptor.3 2-Aryl or 2-heteroaryl substituted
benzimidazoles are known for antitumor and anti helminthia-
sis activity. Thiophene linked benzimidazole (IV) is active
against helminthiasis infection in humans and other mam-
mals.4
The synthesis of 2-aryl or 2-heteroaryl benzimidazoles is
mostly limited to use of o-phenylenediamine. The reaction
involves condensation of o-phenylenediamine with a carbonyl
compound or its precursor at elevated temperature or in acidic
catalyst. The reaction is generally associated with harsh
reaction conditions, long reaction time and moderate yields
of product. Recently a few examples of high product yields
under mild reaction conditions have been reported.13 Ellman
and co-workers have employed Rh(I)-catalyzed C–H activation
of benzimidazoles for the synthesis of 2-aryl/heteroaryl
substituted benzimidazoles.14 However most of these reports
are limited to the synthesis of 2-(3-furyl)-benzimidazole.
2-Thiophene linked benzimidazoles with molecular diversity
on both benzimidazole and thiophene rings can serve as
potential candidates for SAR-based drug discovery studies as
they contain two pharmacophores, i.e. benzimidazole and
2-aminothiophene moieties. A straightforward method that
enables synthesis of 2-aminothiophene linked benzimidazoles
with various substituents on both benzimidazole and thio-
phene rings will be of great advantage in the development of
new small chemical entities to explore novel biological
profiles.
The Gewald multicomponent reaction is an elegant and
promising synthetic route for the synthesis of 2-aminothio-
phenes.5 The parent reaction involves Knoevenagel condensa-
tion of cyanoacetate with an aldehyde or ketone having an
a-CH2 group followed by cyclisation with molecular sulfur
under basic conditions.6 Many modified versions of this
reaction have been reported. These include use of various
activated nitriles such as malononitrile, cyanoacetic esters,
and cyanoacetamide. Modern methods such as microwave
We were involved in the diversity-oriented synthesis of
functionalized benzimidazoles and their use in medicinally
important scaffolds.15 In the current study, we disclose a well
planned and executed synthesis of 3-(2-aminothiphene)-
irradiation,7 electrochemical activation,8 use of
a solid
benzimidazoles utilizing
2-cyanomethyl benzimidazoles.
a
multicomponent reaction on
Department of Applied Chemistry, National Chiao-Tung University, Hsinchu 300,
Taiwan E-mail: cmsun@mail.nctu.edu.tw
Electronic supplementary information (ESI) available. CCDC 877845. For ESI
3
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3ra41545g
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Fig. 1 Biologically important aminothiophenes.
poor when the reaction was performed using Et3N, DBU,
Result and discussion
imidazole, or t-BuOK as
a base (entries 5–7 and 11).
The study began with the synthesis of various N-alkylated 2-
(cyanomethyl)-benzimidazoles (Scheme 1). The sulfuric acid
catalyzed methyl esterification of 3-amino-4-flurobenzoic acid
was followed by aromatic nucleophilic substitution of fluorine
with various amines and reduction of the nitro group yielded
corresponding methyl-3,4-diaminobenzoates 1. The condensa-
tion of primary amine of 1 with cyanoacetic acid gave
a-cyanoacetamide 2 that was cyclized under acidic conditions
using TFA to obtain the desired 2-cyanomethyl benzimidazoles
3 in very good yields.15,18
The initial one-pot reaction was performed on benzimda-
zole 3a (R1 = isopropyl) and 3-phenylpropanal using piper-
idine, sulfur powder in refluxing dichloroethane that yielded
benzimidazole linked 2-aminothiophene 4a in 70% yield
(Scheme 2). We quickly screened a few organic solvents such
as toluene, acetonitrile and ethanol to optimize the conver-
sion. This revealed ethanol as a better solvent to give high yield
of product (entries 1–4) probably due to the better solubility of
sulfur in ethanol (Table 1).
Comparable yields of product were obtained when the reaction
was conducted using either piperidine or cesium fluoride as a
base (entries 4 and 12). We preferred piperidine over CsF for
the current studies due to the toxic and corrosive nature of
cesium fluoride.
Under the optimized conditions, various N-alkyl benzimi-
dazoles (3a–f) were treated with a number of a-methylene
aldehydes to demonstrate the scope and generality of this
protocol (Table 2). Various N-alkyl substituent groups on the
benzimidazole nitrogen did not have any significant effect on
reaction output and good yield of products was obtained in all
cases. Benzimidazoles with nitrogen substituents such as
cyclopentyl ring or 4-methoxy benzyl group with an active
methylene group also reacted smoothly. Various aldehydes
reacted smoothly and no change in reactivity was observed.
Our method enables easy manipulation of the C-5 substituent
(R2) in the product thiophene molecule which can be used as a
handle for SAR studies of these molecular frameworks in
medicinal chemistry.
The structure of product 4e (R1 = propyl, R2 = ethyl) was
further confirmed by single crystal X-ray diffraction (Fig. 2).16
The molecule takes a confirmation in which the N-alkyl
substituent on the benzimidazole ring and free C-2 amino
group on the thiophene ring are placed far from each other to
All reactions were then performed in refluxing conditions
for 1.5 h with various bases (1.5 eq). When the reaction was
performed using morpholine, DMAP or K2CO3 as a base, a
moderate yield of the desired 2-aminothiophene 4a was
obtained (entries 8–10). However the yield of product 4a were
Scheme 1 Synthesis of 2-(cyanomethyl)-1-alkyl benzimidazoles.
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Scheme 2 Multicomponent reaction on 2-(cyanomethyl)-N-isopropyl benzimidazole.
avoid possible steric crowding when they are close to each
other.
pyrrole 10 in 76% yield. The reaction proceeded via nucleo-
philic displacement of bromide by nitrogen and subsequent
condensation with the benzoyl carbonyl group and dehydra-
tion to generate the pyrrole moiety in the observed product
(Scheme 4).
The mechanism of product formation is proposed in
Scheme 3. Initially, Knoevenagel condensation between
2-cyanomethylbenzimdazole and an aldehyde yields
Knoevenagel condensation adduct, a,b-unsaturated nitrile 5.
Under basic conditions, a-sulfur generates a sulfide anion
which simultaneously attacks on 5 to generate anion 6 that
reacts with polysulfide to deliver ylidene sulfur adduct 7.
Intramolecular nucleophilic attack of S2 on the nitrile carbon
delivers a cyclic adduct 8 that further tautomerizes to yield
2-aminothiophene benzimidazole 4. We attempted a reaction
between separately prepared Knoevenagel condensation
adduct 5, sulfur and propanal in absence of base and no
product formation was observed. This confirmed the impor-
tant role of a base in formation of adduct 7 and subsequent
cyclization (Scheme 3).
Next, we demonstrated that the free amine group in the
product 2-aminothiophenes can be a handle to increase
molecular diversity. 2-Aminothiphene 4t was mixed with
maleic anhydride in dichloroethane and subjected to micro-
wave irradiation at 100 uC for 5 min. The reaction yielded
pyrrole-2,5-dione substituted thiophene 9 in 74% yield. The
reaction involves nucleophilic attack of the amine nitrogen on
the anhydride carbonyl group to generate intermediate amido
acid which yields the observed pyrrole dione 9 after second
nucleophilic attack and dehydration. Similarly 2-aminothio-
phene 4j on treatment with uracil-derived bromomethyl
pyrimidinonedione in the presence of triethylamine in
refluxing acetonitrile gave highly substituted thiophene linked
In recent years ionic liquids (ILs) have emerged as an eco-
friendly green reaction media.17 Numerous advantages asso-
ciated with IL-supported synthesis encouraged us to apply it
for our current reaction system. In order to test the feasibility
of an IL-supported reaction, we subjected IL-supported
2-cyanomethylbenzimidazole IL-3 to the Gewald multicompo-
nent reaction conditions.18 Treatment of IL-3 with 3-phenyl-
propanal and sulfur powder using piperidine as a base in
acetonitrile resulted in smooth reaction to yield desired
product IL-4 in 76% yield as confirmed by mass analysis
directly with ionic liquid support intact. Removal of the ionic
liquid support using sodium methoxide gave 2-aminothio-
phene 4a in overall 72% yield after precipitation (Scheme 5).
Use of the ionic liquid as a soluble support facilitates
purification by simple precipitation along with advantages
like high loading capacity, homogeneous reaction conditions,
and monitoring of the reaction progress by conventional NMR
spectroscopy.
Conclusions
We report here the first one-pot multicomponent reaction on
2-(cyanomethyl)-benzimdazoles using various aldehydes con-
taining an active methylene group and molecular sulfur under
basic reaction conditions. Our method presents a simple and
efficient route toward the generation of a combined novel
fused, heterocyclic skeleton which is of substantial intellectual
Table 1 Reaction optimization studies of the modified Gewald reactiona
appeal resembling
a drug-like molecule. We have also
achieved a multicomponent condensation reaction on an
ionic liquid support to afford the benzimidazole linked
thiophene. The rapid synthesis and screening of a focused
combinatorial library including the combination of these two
heterocycles will certainly provide ample opportunity to
discover interesting biological activity.
Entry
Base
Solvent
Yield of 4a (%)
1
2
3
4
5
6
7
8
Piperidine
Piperidine
Piperidine
Piperidine
Et3N
DCE
70
65
67
80
43
45
35
61
65
59
23
80
Toluene
CH3CN
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
DBU
Imidazole
Morpholine
DMAP
K2CO3
t-BuOK
9
Experimental section
10
11
12
CsF
General procedure for multicomponent reaction
a
All reactions were performed using 1.0 mmol benzimidazole, 1.2
mmol aldehyde, 1.5 mmol S, and 1.5 mmol of base in 5 mL solvent.
A reaction flask was charged with 2-(cyanomethyl)-benzimida-
zole (1.0 mmol), an aldehyde (1.2 mmol), sulfur powder (48
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Table 2 One-pot multicomponent reaction of various benzimidazoles, aldehydes and molecular sulfur
Entry
R1
R2-CH2CHO
Yield (%)
80
Entry
R1
R2-CH2CHO
Yield (%)
72
4a
4k
4b
4c
4d
4e
82
80
72
69
4l
71
86
81
79
4m
4n
4o
4f
78
76
4p
4q
85
86
4g
4h
82
4r
85
4i
4j
78
85
4s
4t
74
80
mg, 1.5 mmol) and piperidine (148 mL, 1.5 mmol) in ethanol (5
mL). The reaction mixture was heated to reflux for 1.5 h. The
progress of reaction was monitored by TLC. After completion,
the reaction mixture was diluted with water, concentrated on a
rotovap and extracted with dichloromethane. The organic layer
was washed with brine, dried over anhydrous Na2SO4 and
evaporated to obtain crude product that was purified by
column chromatography in reported yields.
Procedure for ionic liquid supported Gewald reaction
A reaction vessel was charged with ionic liquid conjugated 2-
(cyanomethyl)-benzimidazole IL-3 (220 mg, 0.5 mmol), an
aldehyde (80 mg, 0.6 mmol), sulfur powder (24 mg, 0.75 mmol)
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Fig. 2 X-ray crystal structure of 4e.
Hz, 1H), 4.03 (s, 2H), 3.95 (s, 3H), 1.65 (d, J = 7.0 Hz, 6H). 13C
NMR (75 MHz): d 167.8, 155.6, 151.7, 143.5, 139.9, 136.2, 128.6,
128.5, 127.4, 126.7, 123.7, 123.1, 122.2, 121.1, 111.6, 105.3,
52.0, 48.8, 36.1, 21.4. FTIR (KBr): cm21 3444, 3421, 1714. MS
(ESI) m/z: 406 (M + 1)+; Calcd m/z for C23H24N3O2S [M + H]+:
406.1589; Found: 406.1592.
and piperidine (74 mL, 0.75 mmol). Ethanol (5 mL) was added
to the reaction mixture and the mixture was heated to reflux.
The progress of reaction was monitored by NMR directly. After
completion, the reaction mixture was concentrated on a
rotovap. The residue was washed with ether to remove
impurities and then treated with 0.1 M NaOMe in methanol
(5 mL) for 8 h at room temperature. The mixture was filtered to
remove the ionic liquid support and the filtrate was
concentrated, and partitioned between water and diethyl
ether. All the organic layer was washed with brine, dried over
anhydrous Na2SO4 and evaporated to get the product 4a (0.212
g, 72%).
Methyl
2-(2-amino-5-ethylthiophen-3-yl)-1-isopropyl-
1H-benzo[d]imidazole-5-carboxylate, 4b. 1H NMR (300 MHz):
d 8.41 (d, J = 1.5 Hz, 1H), 7.92 (dd, J = 8.6, 1.5 Hz, 1H), 7.57 (d, J
= 8.6 Hz, 1H), 6.51 (s, 1H), 5.32 (bs, 2H), 5.01 (sept, J = 7.0 Hz,
1H), 3.94 (s, 3H), 2.65 (t, J = 7.3 Hz, 2H), 1.67 (d, J = 7.0 Hz, 6H),
0.98 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz): d 168.1, 155.0,
152.1, 143.6, 136.5, 129.5, 124.2, 124.0, 123.5, 121.4, 121.2,
112.0, 105.6, 52.4, 49.2, 32.4, 25.1, 21.8, 14.0. FTIR (KBr): cm21
3442, 3421, 1714. MS (ESI) m/z: 358 (M + 1)+; Calcd m/z for
Methyl
2-(2-amino-5-benzylthiophen-3-yl)-1-isopropyl-
1H-benzo[d]imidazole-5-carboxylate, 4a. 1H NMR (300 MHz):
d 8.42 (s, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H),
7.36–7.22 (m, 5H), 6.56 (s, 1H), 5.66 (bs, 2H), 4.99 (sept, J = 7.0
C
18H22N3O2S [M + H]+: 358.1589; Found: 358.1587.
Scheme 3 A plausible mechanism for the multicomponent coupling reaction.
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Scheme 4 Functionalization of the amino group of 2-aminothophenes.
123.0, 121.7, 121.1, 52.2, 48.7, 21.4, 15.1. FTIR (KBr): cm21
3421, 1714. MS (ESI) m/z: 330 (M + 1)+; Calcd m/z for
C17H20N3O2S [M + H]+: 330.1276; Found: 330.1276.
Methyl
2-(2-amino-5-methylthiophen-3-yl)-1-isopropyl-
1H-benzo[d]imidazole-5-carboxylate, 4c. 1H NMR (300 MHz):
d 8.40 (d, J = 1.0 Hz, 1H), 7.92 (dd, J = 8.6, 1.0 Hz, 1H), 7.55 (d, J
= 8.6 Hz, 1H), 6.49 (s, 1H), 5.61 (bs, 2H), 5.00 (sept, J = 6.9 Hz,
1H), 3.93 (s, 3H), 2.36 (s, 3H), 1.66 (d, J = 6.9 Hz, 6H). 13C NMR
(75 MHz): d 167.8, 154.6, 151.7, 143.5, 136.2, 123.7, 123.1,
Methyl
2-(2-amino-5-methylthiophen-3-yl)-1-propyl-
1H-benzo[d]imidazole-5-carboxylate, 4d. 1H NMR (300 MHz):
d 8.38 (s, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H),
Scheme 5 One-pot, multicomponent reaction on ionic liquid support.
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6.64 (s, 1H), 4.23 (t, J = 7.5 Hz, 2H), 3.95 (s, 3H), 2.38 (s, 3H),
1.92 (sext, J = 7.5 Hz, 2H), 1.02 (t, J = 7.5 Hz, 3H). 13C NMR (75
MHz): d 168.2, 156.5, 152.3, 142.3, 138.6, 124.5, 124.0, 123.0,
121.1, 120.8, 52.4, 46.9, 23.7, 15.7, 11.7. FTIR (KBr): cm21 3417,
1712. MS (ESI) m/z: 330 (M + 1)+; Calcd m/z for C17H20N3O2S [M
+ H]+: 330.1276; Found: 330.1276.
127.2, 127.0, 124.7, 124.2, 122.3, 120.8, 109.7, 104.5, 71.3, 59.6,
52.4, 45.4, 36.5. FTIR (KBr): cm21 3407, 1712. MS (ESI) m/z: 422
(M + 1)+; Calcd m/z for C23H24N3O3S [M + H]+: 422.1538; Found:
422.1536.
Methyl
2-(2-amino-5-methylthiophen-3-yl)-1-(2-methox-
yethyl)-1H-benzo[d]imidazole-5-carboxylate, 4h. 1H NMR (300
MHz): d 8.37 (s, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 8.5 Hz,
1H), 6.77 (s, 1H), 4.46 (t, J = 5.7 Hz, 2H), 3.95 (s, 3H), 3.82 (t, J =
5.7 Hz, 2H), 3.34 (s, 3H), 2.37 (s, 3H). 13C NMR (75 MHz): d
168.2, 156.5, 152.6, 142.5, 138.9, 124.6, 124.1, 122.9, 121.8,
120.8, 109.7, 104.8, 71.4, 59.7, 52.4, 45.3, 15.7. FTIR (KBr):
cm21 3444, 3417, 1714. MS (ESI) m/z: 346 (M + 1)+; Calcd m/z
for C23H20N3O3S [M + H]+: 346.1225; Found: 346.1223.
Methyl
2-(2-amino-5-ethylthiophen-3-yl)-1-propyl-
1H-benzo[d]imidazole-5-carboxylate, 4e. 1H NMR (300 MHz):
d 8.39 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H),
6.68 (s, 1H), 4.25 (t, J = 7.7 Hz, 2H), 3.95 (s, 3H), 2.74 (q, J = 7.5
Hz, 2H), 1.94 (sext, J = 7.7 Hz, 2H), 1.30 (t, J = 7.7 Hz, 3H), 1.00
(t, J = 7.5 Hz, 3H). 13C NMR (75 MHz): d 168.2, 156.5, 152.3,
142.3, 138.6, 124.5, 124.0, 123.0, 121.1, 120.8, 52.4, 46.9, 23.8,
23.7, 15.7, 11.7. FTIR (KBr): cm21 3417, 1712. MS (ESI) m/z: 344
(M + 1)+; Calcd m/z for C18H22N3O2S [M + H]+: 344.1433; Found:
344.1431.
Methyl
2-(2-amino-5-isopropylthiophen-3-yl)-1-(2-methox-
yethyl)-1H-benzo[d]imidazole-5-carboxylate, 4i. 1H NMR (300
MHz): d 8.38 (d, J = 1.5 Hz, 1H), 7.96 (dd, J = 8.6, 1.5 Hz, 1H),
7.39 (d, J = 8.6 Hz, 1H), 6.85 (s, 1H), 6.13 (bs, 2H), 4.46 (t, J = 5.8
Hz, 2H), 3.94 (s, 3H), 3.84 (t. J = 5.8 Hz, 2H), 3.35 (s, 3H), 3.05
(sept, J = 6.8 Hz, 1H), 1.31 (d, J = 6.8 Hz, 6H). 13C NMR (75
MHz): d 167.8, 155.5, 152.5, 142.4, 138.6, 135.8, 124.1, 123.6,
120.5, 118.4, 109.1, 104.1, 71.0, 59.3, 52.0, 45.0, 30.0, 29.7,
24.3. FTIR (KBr): cm21 3421, 3330, 171. MS (ESI) m/z: 374 (M +
1)+; Calcd m/z for C19H24N3O3S [M + H]+: 374.1538; Found:
374.1536.
Methyl
2-(2-amino-5-isopropylthiophen-3-yl)-1-propyl-
1H-benzo[d]imidazole-5-carboxylate, 4f. 1H NMR (300 MHz):
d 8.37 (s, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H),
6.65 (s, 1H), 6.21 (bs, 2H), 4.17 (t, J = 7.8 Hz, 2H), 3.95 (s, 3H),
3.00 (sept, J = 6.8 Hz, 1H), 1.87 (sext, J = 7.3 Hz, 2H), 1.29 (d, J =
6.8 Hz, 6H), 0.99 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz): d 168.2,
156.2, 152.6, 142.6, 138.7, 136.0, 124.2, 123.8, 120.8, 117.8,
109.0, 104.2, 52.4, 46.8, 30.0, 24.7, 23.7, 11.6. FTIR (KBr): cm21
3419, 1712. MS (ESI) m/z: 358 (M + 1)+; Calcd m/z for
C19H24N3O2S [M + H]+: 358.1589; Found: 358.1586.
Methyl
2-(2-amino-5-phenylthiophen-3-yl)-1-(2-methox-
yethyl)-1H-benzo[d]imidazole-5-carboxylate, 4j. 1H NMR (300
MHz): d 8.40 (s, 1H), 8.00 (d, J = 7.0 Hz, 1H), 7.54 (s, 1H), 7.48–
7.33 (m, 5H), 7.23 (t, J = 7.3 Hz, 1H), 4.53 (t, J = 5.6 Hz, 2H),
3.96 (s, 3H), 3.90 (t, J = 5.6 Hz, 2H), 3.38 (s, 3H). 13C NMR (75
MHz): d 168.1, 158.0, 152.3, 142.2, 138.6, 134.6, 129.3, 126.9,
126.7, 125.0, 124.9, 124.3, 120.8, 109.7, 106.1, 71.3, 59.7, 52.4,
Methyl 2-(2-amino-5-benzylthiophen-3-yl) -1-(2-methox-
yethyl)-1H-benzo[d]imidazole-5-carboxylate, 4g. 1H NMR (300
MHz): d 8.39 (s, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 8.5 Hz,
1H), 7.36–7.27 (m, 5H), 6.83 (s, 1H), 4.43 (t, J = 5.7 Hz, 2H), 4.03
(s, 2H), 3.95 (s, 3H), 3.76 (t, J = 5.7 Hz, 2H), 3.29 (s, 3H). 13C
NMR (75 MHz): d 168.1, 157.3, 152.5, 142.3, 140.3, 138.8, 129.0,
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45.7. FTIR (KBr): cm21 3228, 1687. MS (ESI) m/z: 408 (M + 1)+;
Calcd m/z for C22H22N3O3S [M + H]+: 408.1382; Found:
408.1383.
Hz, 2H), 1.66 (sept, J = 7.3 Hz, 2H), 1.01 (t, J = 7.3 Hz, 3H). 13C
NMR (75 MHz): d 168.2, 156.2, 152.4, 142.7, 138.5, 137.7, 129.3,
129.0, 128.9, 127.5, 124.5, 124.0, 121.0, 120.2, 109.1, 104.7,
52.4, 46.8, 36.5, 34.2, 24.9, 14.0. FTIR (KBr): cm21 3421, 1712.
MS (ESI) m/z: 420 (M + 1)+; Calcd m/z for C24H26N3O2S [M + H]+:
420.1746; Found: 420.1749.
Methyl
2-(2-amino-5-benzylthiophen-3-yl)-1-phenethyl-
1H-benzo[d]imidazole-5-carboxylate, 4k. 1H NMR (300 MHz):
d 8.39 (s, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.39–7.21 (m, 9H), 7.02
(dd, J = 7.5, 1.6 Hz, 2H), 6.64 (s, 1H), 4.45 (t, J = 7.7 Hz, 2H),
4.01 (s, 2H), 3.96 (s, 3H), 3.08 (t, J = 7.7 Hz, 2H). 13C NMR (75
MHz): d 168.1, 157.2, 152.2, 142.3, 140.2, 138.3, 137.6, 129.3,
129.1, 129.0, 127.4, 127.1, 124.6, 124.1, 121.4, 120.8, 109.2,
104.5, 52.5, 46.9, 36.5, 36.4. FTIR (KBr): cm21 3421, 3330, 1712.
MS (ESI) m/z: 468 (M + 1)+; Calcd m/z for C28H26N3O2S [M + H]+:
468.1746; Found: 468.1744.
Methyl
2-(2-amino-5-isopropylthiophen-3-yl)-1-phenethyl-
1H-benzo[d]imidazole-5-carboxylate, 4n. 1H NMR (300 MHz):
d 8.40 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.33–7.23 (m, 4H), 7.15
(d, J = 6.6 Hz, 2H), 6.67 (s, 1H), 4.52 (d, J = 7.8 Hz, 2H), 3.96 (s,
3H), 3.17 (d, J = 8.0 Hz, 2H), 3.03 (quint, J = 6.8 Hz, 1H), 1.33 (d,
J = 6.8 Hz, 6H). 13C NMR (75 MHz): d 168.2, 155.8, 152.5, 142.8,
138.5, 137.7, 129.3, 129.0, 127.5, 124.5, 124.0, 121.0, 109.0,
104.5, 52.4, 46.8, 36.5, 30.1, 24.8. FTIR (KBr): cm21 3411, 3275,
1709. MS (ESI) m/z: 420 (M + 1)+; Calcd m/z for C24H26N3O2S [M
+ H]+: 420.1746; Found: 420.1742.
Methyl
2-(2-amino-5-methylthiophen-3-yl)-1-phenethyl-
1
1H-benzo[d]imidazole-5-carboxylate, 4l. H NMR (300 MHz): d
8.39 (d, J = 1.3 Hz, 1H), 7.93 (dd, J = 8.5, 1.3 Hz, 1H), 7.33–7.25
(m, 3H), 7.21 (d, J = 8.5 Hz, 1H), 7.14 (dd, J = 7.0, 1.7 Hz, 2H),
6.63 (d, J = 1.2 Hz, 1H), 6.07 (bs, 2H), 4.52 (t, J = 7.5 Hz, 2H),
3.96 (s, 3H), 3.16 (t, J = 7.5 Hz, 2H), 2.39 (d, J = 1.2 Hz, 3H). 13C
NMR (75 MHz): d 168.0, 155.9, 152.0, 142.3, 138.1, 137.4, 128.9,
128.7, 127.1, 124.1, 123.6, 122.6, 120.8, 52.0, 46.3, 36.1, 15.2.
FTIR (KBr): cm21 3388, 1691. MS (ESI) m/z: 392 (M + 1)+; Calcd
m/z for C21H22N3O2S [M + H]+: 392.1433; Found: 392.1431.
Methyl 2-(2-amino-5-benzylthiophen-3-yl)-1-(4-methoxyben-
zyl)-1H-benzo[d]imidazole-5-carboxylate, 4o. 1H NMR (300
MHz): d 8.44 (d, J = 1.0 Hz, 1H), 7.93 (dd, J = 8.4, 1.0 Hz, 1H),
7.32–7.15 (m, 6H), 6.96 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H),
6.48 (s, 1H), 6.26 (bs, 2H), 5.39 (s, 2H), 3.95 (s, 3H), 3.88 (s, 2H),
3.81 (s, 3H). 13C NMR (75 MHz): d 168.2, 159.5, 137.4, 153.0,
142.9, 140.2, 139.0, 136.0, 128.9, 128.3, 127.1, 127.0, 124.8,
124.3, 121.8, 120.9, 115.0, 109.4, 104.4, 55.7, 52.5, 48.3, 36.4.
FTIR (KBr): cm21 3419, 1712. MS (ESI) m/z: 484 (M + 1)+; Calcd
m/z for C28H26N3O3S [M + H]+: 484.1695; Found: 484.1692.
Methyl
2-(2-amino-5-propylthiophen-3-yl)-1-phenethyl-
1
1H-benzo[d]imidazole-5-carboxylate, 4m. H NMR (300 MHz):
d 8.38 (d, J = 1.3 Hz, 1H), 7.93 (dd, J = 8.5, 1.3 Hz, 1H), 7.32–
7.20 (m, 4H), 7.13 (dd, J = 7.8, 1.3 Hz, 2H), 6.64 (s, 1H), 4.50 (t, J
= 7.6 Hz, 2H), 3.95 (s, 3H), 3.15 (t, J = 7.8 Hz, 2H), 2.33 (t, J = 7.3
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Methyl 2-(2-amino-5-methylthiophen-3-yl)-1-(4-methoxyben-
zyl)-1H-benzo[d]imidazole-5-carboxylate, 4p. 1H NMR (300
MHz): d 8.41 (d, J = 1.4 Hz, 1H), 7.89 (dd, J = 8.5, 1.4 Hz,
1H), 7.14 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 6.88 (d, J =
8.7 Hz, 2H), 6.44 (d, J = 1.2 Hz, 1H), 5.43 (s, 2H), 3.94 (s, 3H),
3.78 (s, 3H), 2.24 (d, J = 1.2 Hz, 3H). 13C NMR (75 MHz): d
168.2, 159.6, 156.6, 153.0, 142.9, 138.9, 128.4, 127.5, 124.7,
124.2, 122.9, 121.4, 114.9, 109.5, 104.6, 55.7, 52.4, 48.3, 15.5.
FTIR (KBr): cm21 3419, 1711. MS (ESI) m/z: 408 (M + 1)+; Calcd
m/z for C22H22N3O3S [M + H]+: 408.1382; Found: 408.1379.
Methyl
2-(2-amino-5-propylthiophen-3-yl)-1-cyclopentyl-
1H-benzo[d]imidazole-5-carboxylate, 4s. 1H NMR (300 MHz):
d 8.39 (s, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H),
6.50 (s, 1H), 5.58 (bs, 2H), 5.08 (quint, J = 7.5 Hz, 2H), 3.90 (s,
3H), 2.60 (t, J = 7.5 Hz, 2H), 2.28–1.99 (m, 7H), 1.74 (t, J = 7.5
Hz, 3H). 13C NMR (75 MHz): d 167.7, 154.7, 152.5, 143.4, 135.8,
128.8, 123.7, 123.0, 121.1, 120.8, 111.1, 57.5, 52.0, 32.0, 30.3,
25.3, 24.6, 13.5. FTIR (KBr): cm21 3421, 3326, 1714. Calcd m/z
for MS (ESI) m/z: 384 (M + 1)+; C21H26N3O2S [M + H]+: 384.1746;
Found: 384.1748.
Methyl 2-(2-amino-5-propylthiophen-3-yl) -1-(4-methoxyben-
zyl)-1H-benzo[d]imidazole-5-carboxylate, 4q. 1H NMR (300
MHz): d 8.42 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 8.4
Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.0 Hz, 2H), 6.46 (s,
1H), 6.22 (s, 2H), 5.42 (s, 2H), 3.94 (s, 3H), 3.78 (s, 3H), 2.52 (t, J
= 7.4 Hz, 2H), 1.54 (sext, J = 6.8 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H).
13C NMR (75 MHz): d 168.2, 156.3, 153.1, 142.9, 139.0, 128.7,
128.4, 124.7, 124.2, 120.9, 114.9, 109.4, 104.5, 55.7, 46.8, 32.2,
24.7, 23.7, 13.9. FTIR (KBr): cm21 3375, 3222, 1693. MS (ESI)
m/z: 436 (M + 1)+; Calcd m/z for C24H26N3O3S [M + H]+:
436.1695; Found: 436.1697.
Methyl
2-(2-amino-5-phenylthiophen-3-yl)-1-cyclopentyl-
1H-benzo[d]imidazole-5-carboxylate, 4t. 1H NMR (300 MHz):
d 8.46 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.49–7.43 (m, 3H), 7.32 (t,
J = 7.4 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 7.13 (s, 1H), 5.90 (bs,
2H), 5.17 (quint, J = 8.7 Hz, 1H), 3.96 (s, 3H), 2.35–2.31 (m, 2H),
2.29–2.07 (m, 4H), 1.81 (t, J = 6.1 Hz, 2H). 13C NMR (75 MHz): d
168.2, 156.9, 152.5, 143.7, 136.3, 134.5, 129.4, 127.1, 127.0,
125.0, 125.0, 124.4, 123.7, 121.7, 120.6, 111.6, 107.2, 58.1, 52.5,
30.9, 25.8. FTIR (KBr): cm21 3421, 1712. MS (ESI) m/z: 418 (M +
1)+; Calcd m/z for C24H24N3O2S [M + H]+: 418.1589; Found:
418.1592.
Preparation of 9: To a dichloroethane solution of 4t (0.15 g,
0.36 mmol) in a microwave absorbance vessel was added
maleic anhydride (24 mL, 0.36 mmol) and the reaction mixture
was irradiated using microwave radiation (150 W) at 100 uC for
5 min. The reaction mixture was concentrated and purified by
column chromatography to get 9 (1.32 g, 74% yield).
Methyl 2-(2-amino-5-isopropylthiophen-3-yl)-1-(4-methoxy-
benzyl)-1H-benzo[d]imidazole-5-carboxylate, 4r. 1H NMR (300
MHz): d 8.43 (s, 1H), 7.90 (dd, J = 8.4, 1.5 Hz, 1H), 7.17 (d, J =
8.5 Hz, 1H), 7.03 (d, J = 8.5 Hz, 2H), 6.85 (dd, J = 8.4, 1.5 Hz,
2H), 6.45 (s, 1H), 6.02 (bs, 2H), 5.38 (s, 2H), 3.94 (s, 3H), 3.75 (s,
3H), 2.86 (sept, J = 6.8 Hz, 1H), 1.16 (d, J = 6.8 Hz, 6H). 13C
NMR (75 MHz): d 168.2, 159.5, 156.3, 153.2, 142.9, 139.1, 136.0,
128.6, 127.4, 124.6, 124.2, 120.8, 118.4, 114.9, 109.3, 104.0,
55.7, 52.4, 48.3, 29.9, 24.5. FTIR (KBr): cm21 3419, 1712. MS
(ESI) m/z: 436 (M + 1)+; Calcd m/z for C24H26N3O3S [M + H]+:
436.1695; Found: 436.1693.
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Methyl 1-cyclopentyl-2-(5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-
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National Chiao Tung University for providing the laboratory
facilities. This study was particularly supported by the ‘‘Centre
for bioinformatics research of aiming for the Top University
Plan’’ of the National Chiao Tung University and Ministry of
Education, Taiwan.
yl)-2-phenylthiophen-3-yl)-1H-benzo[d]imidazole-5-carboxylate,
1
9. H NMR (300 MHz): d 8.43 (d, J = 1.2 Hz, 1H), 7.98 (dd, J =
8.7, 1.2 Hz, 1H), 7.63 (dd, J = 8.5, 1.5 Hz, 2H), 7.53 (s, 1H), 7.48–
7.36 (m, 3H), 6.79 (s, 2H), 5.00 (quint, J = 8.9 Hz, 2H), 3.94 (s,
3H), 2.35–2.25 (m, 4H), 2.18–2.02 (m, 2H), 1.86–1.79 (m, 2H).
13C NMR (75 MHz): d 168.1, 167.6, 149.5, 143.6, 136.1, 134.8,
133.0, 130.7, 129.2, 128.7, 128.1, 126.1, 124.1, 123.8, 122.8,
121.8, 111.5, 58.0, 52.1, 30.5, 25.3. FTIR (KBr): cm21 1728. MS
(ESI) m/z: 498 (M + 1)+; Calcd m/z for C21H26N3O2S [M + H]+:
498.1488; Found: 498.1478.
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Methyl
2-(5-(1,3-dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-
1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)-2-phenylthiophen-3-yl)-1-
(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate, 10. 1H
NMR (300 MHz): d 8.35 (s, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.71
(s, 1H), 7.61 (d, J = 7.7 Hz, 2H), 7.47–7.36 (m, 3H), 7.28–7.15
(m, 2H), 6.96 (t, J = 7.8 Hz, 2H), 6.86 (s, 1H), 6.71 (dd, J = 7.7,
1.0 Hz, 2H), 3.95 (s, 3H), 3.63 (t, J = 5.0 Hz, 2H), 3.47 (s, 3H),
3.44 (t, J = 5.0 Hz, 2H), 3.31 (s, 3H), 3.27 (s, 3H). 13C NMR (75
MHz): d 167.5, 159.6, 151.6, 148.0, 142.7, 141.4, 139.5, 137.7,
135.1, 132.7, 130.2, 130.0, 129.3, 128.8, 128.4, 128.2, 127.3,
126.2, 125.6, 124.7, 124.5, 124.1, 122.5, 109.6, 105.4, 70.2, 59.2,
52.1, 44.1, 31.8, 27.8. FTIR (KBr): cm21 1701, 1659. MS (ESI) m/
z: 646 (M + 1)+; Calcd m/z for C36H32N5O5S [M + H]+: 646.2122;
Found: 646.2112.
16 CCDC 898197 contains the supplementary crystallographic
data for 4e .
3
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Acknowledgements
18 W. S. Hsu, V. Paike and C. M. Sun, Mol. Diversity, 2013, 17,
285.
The authors wish to thank the National Science Council of
Taiwan for financial support and the authorities of the
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