Diversity-Oriented Synthesis of Coumarin-Linked Benzimidazoles via a One-Pot, Three-Step, Intramolecular Knoevenagel Cyclization

Article abstract of DOI:10.1021/acscombsci.7b00004

Diversity-oriented synthesis of coumarin-linked benzimidazoles from N-(2-aminophenyl)-2-cyanoacetamide was achieved via a one-pot, three-step sequential reaction in excellent yields. In situ intramolecular cyclization of the cyanoacetamide afforded benzimidazoles which subsequently underwent a Knoevenagel condensation of the 2-cyanomethylbenzimidazoles with salicylaldehydes promoted by triethylamine to reach the target compounds. An important intermediate, 2-(2-imino-2H-chromen-3-yl)-1H-benzimidazole was characterized by X-ray analysis and further hydrolyzed to 2-(coumarin-3-yl)benzimidazole in acidic condition. Among the synthesized compounds, some were found to be promising inhibitors of porcine kidney d-amino acid oxidase (pkDAO).

Full text of DOI:10.1021/acscombsci.7b00004

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Article
Diversity-Oriented Synthesis of Coumarin-Linked Benzimidazoles
via a One-pot, Three-step, Intramolecular Knoevenagel Cyclization
Po-Hsin Eric Yao, Sunil Kumar, Yu-Li Liu, Chiu-Ping Eikon Fang, Chia-Chen Liu, and Chung-Ming Sun
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.7b00004 • Publication Date (Web): 14 Feb 2017
Downloaded from http://pubs.acs.org on February 15, 2017
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Diversity-Oriented Synthesis of Coumarin-Linked Benzimidazoles
via a One-pot, Three-step, Intramolecular Knoevenagel Cyclization
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3
Po-Hsin Eric Yao1, Sunil Kumar1, Yu-Li Liu3, Chiu-Ping Fang3, Chia-Chen Liu and
Chung-Ming Sun *1, 2
1Department of Applied Chemistry, National Chiao-Tung University, Hsinchu 300-10, Taiwan
2Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, 100
Shih-Chuan 1stRoad, Kaohsiung 807-08, Taiwan
3Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan
E-mail: cmsun@mail.nctu.edu.tw
Graphical abstract
H
R3
i. p
-TSA, MeOH
N
CN
ii. Et3
N
N
R2
N,
Salicylaldehyde
R1
R1
iii.
HCl
O
NH
R2
O
-
70 90%
O
Yields; Mild Conditions; Broad Substrate
Inhibitor
Scope; pkDAO
One-pot; High
Abstract
Diversity-oriented
synthesis
of
coumarin-linked
benzimidazoles
from
N-(2-aminophenyl)-2-cyanoacetamide was achieved via a one-pot, three-step sequential reaction
in excellent yields. In situ intramolecular cyclization of the cyanoacetamide afforded
benzimidazoles which subsequently underwent a Knoevenagel condensation of the
2-cyanomethylbenzimidazoles with salicylaldehydes promoted by triethylamine to reach the
target compounds. An important intermediate, 2-(2-imino-2H-chromen-3-yl)-1H-benzimidazole
was characterized by X-ray analysis and further hydrolyzed to 2-(coumarin-3-yl)benzimidazole
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in acidic condition. Among the synthesized compounds, some were found to be promising
inhibitors of porcine kidney D-amino acid oxidase (pkDAO).
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KEYWORDS: Knoevenagel condensation, coumarin, diversity-oriented synthesis, one-pot
synthesis, pkDAO activity.
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INTRODUCTION
Diversity-oriented synthesis (DOS) provides direct access to diverse and complex molecular
scaffolds. Diversified benzimidazoles linked with a classical heterocyclic moieties, such as
pyridine, pyrimidine, thiazole and imidazole have been reported in the literature with significant
biological activities.1,2 For instance, thiabendazole (I) is used as an antifungal and antihelminthic
agent,3 pimobendan (II) is a selective poly(ADP-ribose)polymerase-1 (PARP) inhibitor and
cardiovascular agent,4 Lansoprazole is a proton-pump inhibitor which prevents the stomach's
production of gastric acids5. In addition, coumarin derivatives such as Warfarin and Dicoumarol
are well-known anti-coagulants6 and Novobiocin (III) is used as a potent antibiotic against
Gram-positive bacteria7. Tsay and coworkers8 reported the synthesis of
3-(5-methylbenzimidazol-2-yl)benzocoumarin (IV) with anti-hepatitis C virus (HCV) activity
(Figure 1).
O
O
O
O
CONH2
N
O
N
S
N
H
O
O
OH
N
H
N
N
H
N
O
OH
OH
H
NH2
I
II
III
Antibiotic
PARP inhibitor
Antifungal
O
O
O
O
N
N
N
OH
N
OH
OH
H
IV
V
VI
DAO inhibitor
DAO inhibitor
HCV inhibitor
azole and coumarin
1.
Some bioactive
heterocycles.
Figure
D-Amino acid oxidase (DAO) is a stereospecific degradative enzyme for D-amino acids in
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mammalian tissues. DAO inhibitors help to increase the D-serine levels in the serum and
cerebrospinal fluid of schizophrenic patients.9-10 In the literature, benzopyrrole11 (V, IC50=1.34
µM) and benzoxazole12 (VI, IC50=1.88 µM) derivatives were found as the human DAO
inhibitors. In continuation of our interest to synthesize biologically important heterocycles,13-14
we wish to report herein an efficient method for the synthesis of coumarin linked benzimidazoles
under mild conditions and their evaluation of initial pkDAO activity.
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Romieu et al. reported the synthesis of 3-(2-benzimidazolyl)-7-hydroxycoumarins with only
19-24% yields.15 Very recently, Wet-osot and coworkers demonstrated the use of
N-acylbenzotriazole to synthesize 3-arylcoumarins.16 In 2014, Arora et al. reported the
synthesis of 2-(coumarin-3-yl)benzimidazoles as an anti-inflammatory agent by condensing
o
coumarin-3-carboxylic acid with o-phenylenediamine in the presence of PPA at 175 C.17
Christie and Lui synthesized the same heterocycle from 2-cyanomethyl benzimidazole and
salicylaldehyde in the presence of piperidine (Scheme 1).18
and our
1. Literature
the
synthesis
Scheme
for
of
reports
approach
(coumarin-2-yl)benzimidazoles
Our
Arora et al.
Approach
NH2
R
HOOC
PPA
175 o
+
R
H
C
NH2
O
O
N
One-pot
NC
N
N
R2
O
HN
R2
et al.
Christie
O
N
R
OHC
HO
O
Piperidine
CH2CN
+
N
H
Since the reported syntheses suffers from drawbacks of the multi-step synthesis, use of strong
acidic conditions, high temperature and low yields, we planned to achieve a one-pot, three-step
protocol for the synthesis of 2-(coumarin-3-yl)benzimidazoles under mild conditions in higher
yields.
RESULTS AND DISCUSSION
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As shown in Scheme 2, the substituted diaminobenzene 3 acted as the first point of structural
diversity with various alkyl groups. This diaminobenzene 3 was synthesized from the reaction of
substituted o-nitrofluorobenzene 1 with amines 2 and successive reduction of nitro group by zinc
/ammonium formate in methanol. The regioselective condensation of the primary amine of 3
with cyanoacetic acid was performed in the presence of EDCI and hydroxybenzotriazole (HOBt)
in dichloromethane leading to the formation of N-(2-aminophenyl)-2-cyanoacetamide 4
(procedure in SI).
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2.
N
-(2-aminophenyl)-2-cyanoacetamides (4)
Scheme
of
Preparation
H
NH2
N
NO2
NO2
F
CN
R1
i
ii
iii
R1
R1
R1
O
NH
R2
NH
R2
4
NH
R2
95
%
92-95
%
65-70
%
1
3
R2NH
40 o 6h; ii)
rt,
Zn/HCOONH4 MeOH,
15 min.; iii)
acetic
Cyano
:
Reaction Conditions
2
DCM,
,
C,
rt 12h;
i)
2 ( ),
C,
acid, EDCI, HOBt, CH2Cl2 0 o 30 min,
,
Figure 2 shows the variety of substituted o-nitrofluorobenzenes 1{1-3}, amines 2{1-8} and
salicylaldehydes 5{1-5} used in the synthesis.
NO2
R2
NH2
R1
2
F
1
R2
Compound
R1
Compound
2
1
1
1
1
1
O
{ }
H
4-COOCH3
5-Cl
{ }
2
{ }
2
2
{ }
3
{ }
2
3
{ }
HO
R3
2
2
4
{ }
H
O
5
5
{ }
R3
H
Compound
5
1
{ }
2
6
{ }
5
2
{ }
4-OCH3
2
7
{ }
5
5
5
3
5-
CH3
{ }
O
4
{ }
5-Cl
2
8
HO
{ }
5
{ }
5-NO2
and
5
1-5
{
2.
1
2
Diversity elements, chemsets 1-3
1-8
Figure
{
}, {
}
}
Compounds 4 were treated as the common building block for the synthesis of substituted
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2-(coumarin-3-yl)benzimidazoles. Methyl 3-(2-cyanoacetamido)-4-(propylamino)benzoate
4{2,2} was chosen as the model substrate for the next step. Conventional strong Brønsted acids
viz. TFA, p-TSA, HCl etc. were used for the dehydrative cyclization reactions.19 The dehydrative
intramolecular cyclization reaction of 4 proceeded smoothly in the presence of p-TSA in
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o
methanol at 50 C within 4h and the 2-cyanomethyl benzimidazoles formed in situ were
demonstrated to undergo nucleophilic addition with salicylaldehydes in the presence of
triethylamine to yield intermediate 8 in 5h. Further addition of HCl to the same reaction mixture
and stirring for 2h afforded the final product 6{2,2,1} with 88% yield (Scheme 3). Generally
organic bases20 such as piperidine, triethylamine (TEA), pyridine, etc. are used for the
Knoevenagel condensation, but piperidine and pyridine resulted in lower yields, 76% and 54%,
respectively, as compared to TEA (88%).
Scheme 3.
of
benzimidazoles from N
-cyanoacetamide
Synthesis
2-(coumarin-3-yl)
-(2-aminophenyl)-2
O
O
O
N
H
N
5
Salicylaldehyde ( ),
Et3N
N
CN
O
p-TSA, MeOH
O
50 o 4h
C,
50 o 5h
C,
N
NH
7
4
2,2
{
}
O
O
N
N
N
N
O
O
HCl
(1N)
O
50 o 2h
O
C,
88
HN
O
%
8
6
{
2,2,1
}
This one-pot, three-step process entails the intramolecular cyclization of
N-(2-aminophenyl)-2-cyanoacetamides 4 to give benzimidazole in situ in the presence of p-TSA,
followed by Knoevenagel condensation and acidic hydrolysis. A variety of alkyl and aralkyl
groups viz. propyl, methoxyethyl, cycloalkyl, benzyl, furyl etc. are well tolerated in diversified
positions of benzimidazoles (Table 1). Introduction of both electron-withdrawing (6-NO2 or 6-Cl)
as well as electron-donating group (6-Me or 7-OMe) on coumarin yielded the products with good
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yields (20 examples, 75-96 %). The compound 6{2,9,1} was prepared by the acetylation of
6{2,8,1} in the presence of acetic acid at 80-85 oC for 1h.(Scheme 4)
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of
and
7
{
4.
7
Scheme
Preparation
2,8,1
2,9,1
}.
{
}
O
O
O
N
N
N
O
HCl/H2O
MeOH
CH3COOH
80-85 oC
N
O
6
2,9,1
{
O
}
HN
O
OAc
OH
6
2,8,1
{
8
{
2,9,1
}
}
=
m/z 406.5
[M+1]
O
O
N
N
O
N
H
.
3 X-Ray
structure
8
2,3,1
{
of
crystal
Figure
}.
Table 1. Substrate Scope for the
of
2-(Coumarin-3-yl)benzimidazoles
Synthesis
4h
1. p
2.
-TSA,
R3
H
Et
5h
3N,
Salicylaldehydes,
3. HCl, 2h
N
N
N
R2
CN
R1
R1
O
NH
R2
O
MeOH, 50 oC
One-pot
O
6
4
70-90
%
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O
O
O
N
N
N
N
O
O
N
N
O
O
N
O
N
O
O
O
O
O
O
O
O
6
83
},
%
2,3,1
{
6
{
87%
},
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1,1,1
6
{
88
2,2,1
},
%
6
87
},
%
2,1,1
{
O
O
O
O
N
N
O
N
N
N
N
N
O
O
O
O
N
O
O
O
O
O
O
O
O
6
88
%
2,4,1
6
{
},
90
},
%
6
90
},
2,7,1
%
{
2,6,1
{
6
82
},
%
2,5,1
{
O
O
O
O
N
N
N
N
N
N
N
O
O
O
O
N
O
O
O
O
O
O
O
O
OH
OAc
6
{
78
},
%
6
2,8,1
90
%
2,2,3
6
{
{
},
6
2,6,3
{
72
87
%
%
2,9,1
}*,
},
O
Cl
N
N
O
O
N
O
O
N
N
O
N
N
O
O
Cl
N
O
O
O
O
O
O
O
O
O
6
{
85
},
%
3,1,1
6
70
},
%
2,2,2
{
6
{
86
%
2,7,3
},
6
88
%
2,2,4
{
},
NO2
Cl
NO2
NO2
O
O
O
N
N
N
N
N
N
O
N
O
O
O
O
O
N
O
O
O
O
O
O
O
6
{
82
%
2,2,5
},
6
81
},
%
2,6,5
6
75
%
{
2,7,5
{
},
6
1,1,4
{
80
},
%
6
of
{
* Obtained from
2,8,1
}
acetylation
From the results obtained, a plausible mechanism was proposed for the conversion of 4 to 6
(Scheme 5). Initially, intramolecular dehydrative cyclization reaction of 4 in presence of p-TSA
yielded the benzimidazole intermediate 7. Nucleophilic attack of 7 on the carbonyl carbon of
salicylaldehyde yielded VII, which subsequently converted to the intermediate VIII after
intramolecular proton exchange. Subsequent dehydration of VIII yielded the nitrile intermediate
IX. An intermediate 2-(2-imino-2H-chromen-3-yl)-1H-benzimidazole 8, obtained by the
intramolecular cyclization of IX was isolated and characterized by its mass, NMR (1H and 13C)
and X-ray crystal structure data (Figure 3). Finally, acid-catalyzed hydrolysis of 8 furnished the
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desired 2-coumarinylbenzimidazole 6. It is worthy to mention that the lactone ring remains intact
under acidic condition. The intermediate 7 was isolated and characterized by mass and NMR (1H
and 13C) spectroscopy. (see spectroscopic data in the SI)
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5. A Plausible Mechanism
the Product
Formation
(6)
Scheme
for
H
N
H
CN
H
N
p-TSA,
MeOH
CN
N
R1
CN
R1
R1
O
NH
R2
N
-H
2O
N
OH
R2
R2
7
4
O
H
N
H
R3
R3
HO
O
H
HO
R3
proton
exchange
CN
N
N
R1
R1
H
R1
H
N
N
N
Et3N
CN
CN
OH
OH
R2
R2
R2
VIII
VII
R3
R3
R3
N
N
3O+
N
N
N
R2
H
R1
R1
R1
O
N
O
-H
2O
OH
R2
C
R2
O
HN
N
6
8
IX
Coumarin linked benzimidaole derivatives were screened for their porcine kidney DAO (pkDAO)
inhibitory effects. The cell-based DAO assay was performed at the 20.8 μM drug concentration
and cell-base DAO assay was performed at 100 and 10 μM concentrations for all the compounds.
The half maximal inhibitory concentration (IC50) is a degree of the effectiveness of a substance in
inhibiting a specific biological function. All the compounds were screened for their enzymatic
activities. The synthetic compound 6{2,4,1} was shown to possess the strongest pkDAO effect
with IC50 ranging from 46.70 to 62.79 μM. (See the SI, Table 2 for complete assay)
CONCLUSION
In conclusion, we have developed an efficient and rapid combinatorial synthesis of novel
coumarin linked benzimidazole heterocycles 6 using p-TSA, triethylamine and hydrochloric acid
for the intramolecular cyclization, Knoevenagel condensation and imine hydrolysis, respectively
through a one-pot, three-step sequential reactions. It was found that the scope of the one-pot
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process is broad and this approach did avoid time-consuming and costly purification of each
synthetic intermediates to obtain 2-(coumarin-3-yl)benzimidazoles in excellent yield. Among the
synthesized molecules, the final target compound 6{2,4,1} exhibited strongest porcine kidney
DAO activity (IC50 range = 46.70 to 62.79 μM).
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EXPERIMENTAL PROCEDURES
A
Representative
Procedure for One-pot,
Three-step
Synthesis
of
2-(Coumarin-3-yl)benzimidazoles 6{2,2,1}. To a methanolic (20 mL) solution of 4{2,2} (0.29
g, 1.0 mmol) in a 100 mL round bottom flask was added p-TSA (0.86 g, 5.0 mmol). The reaction
o
mixture was heated at 50 C for 4h. After cooling the reaction mixture to room temperature,
salicylaldehyde (5, 0.18 g, 1.5 mmol) and triethylamine (1.01 g, 10 mmol) were added and the
reaction mixture was stirred at 50 °C for 5h. Subsequently, HCl solution (10 mL, 1N) was added
and the reaction mixture was continuously stirred for 2h at the same temperature until the
reaction was completed (monitored by TLC). The organic solvent was removed by reduced
pressure distillation and the residue obtained was washed with saturated sodium bicarbonate
solution and extracted with CH2Cl2 (2 x 30 mL). The combined organic phase was dried over
MgSO4 and concentrated under vacuum to give the crude product. Further purification was
achieved by column chromatography (EA:Hexane = 1:2) to give 6{2,2,1} (0.32 g, 88 % yield).
1
Methyl 2-(coumarin-3-yl)-1-N-propyl-1H-benzimidazole-5-carboxylate 6{2,2,1}: H NMR
(400 MHz, CDCl3) δ 8.50 (s, 1H), 8.32 (s, 1H), 8.06 (dd, J = 8.6, 1.6 Hz, 1H), 7.66 – 7.61 (m,
2H), 7.46 (t, J = 8.4, 2H), 7.38 (t, J = 7.4, 1H), 4.24 – 4.20 (m, 2H), 3.95 (s, 3H), 1.85 (d, J =
7.4 Hz, 2H), 0.86 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 167.4, 158.9, 154.4, 149.7,
147.3, 142.6, 139.0, 133.3, 128.9, 125.1, 124.7, 124.7, 122.5, 119.3, 118.5, 116.8, 110.1, 52.1,
47.1, 22.9, 11.3. MS (ESI) m/z: 363.2 [M+H]; HRMS (ESI) m/z calcd. for C21H18N2O4:
363.1339 [M+H], found 363.1343.
ASSOCIATED CONTENTS
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Supporting Information
Full characterization and spectroscopic data (1H and 13C NMR, LRMS and HRMS) of
compounds 6 and experimental procedure for intermediates are included in the SI file.
CCDC 1506687 contains the supplementary crystallographic data for 8{2,3,1}.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: cmsun@mail.nctu.edu.tw.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
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.
ABBREVIATIONS
DMSO dimethylsulfoxide
EA
ethyl acetate
HOBt
EDCI
1-hydroxybenzotriazole
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
MeOH methanol
THF
tetrahydrofuran
p-TSA p-toluene sulphonic acid
TEA
h
triethylamine
hour
eq
equivalent
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