Diversity-Oriented Synthesis of Coumarin-Linked Benzimidazoles via

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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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ACS Combinatorial Science

Diversity-Oriented Synthesis of Coumarin-Linked Benzimidazoles via a One-pot, Three-step, Intramolecular Knoevenagel Cyclization Po-Hsin Eric Yao1, Sunil Kumar1, Yu-Li Liu3, Chiu-Ping Fang3, Chia-Chen Liu Chung-Ming Sun *1, 2

3

and

1

Department of Applied Chemistry, National Chiao-Tung University, Hsinchu 300-10, Taiwan

2

Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, 100

Shih-Chuan 1stRoad, Kaohsiung 807-08, Taiwan 3

Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan E-mail: [email protected]

Graphical abstract H N R1

i. p-TSA, MeOH ii. Et3N, Salicylaldehyde iii. HCl

CN

O NH R2

One-pot;

R3 N R1 N R2 O

70 - 90%

High Yields;

Mild Conditions;

Broad Substrate Scope;

O

pkDAO Inhibitor

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

1

ACS Paragon Plus Environment


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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). KEYWORDS: Knoevenagel condensation, coumarin, diversity-oriented synthesis, one-pot synthesis, pkDAO activity.

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).

N H

O

CONH2

N

S

N

N

N H

I Antifungal

O O

N H

OH

O

OH

O

O

N H OH

III Antibiotic

O

O

O N

N OH

N H IV HCV inhibitor

O

O NH2

II PARP inhibitor

N

O

OH

V DAO inhibitor

OH VI DAO inhibitor

Figure 1. Some bioactive azole and coumarin heterocycles.

D-Amino acid oxidase (DAO) is a stereospecific degradative enzyme for D-amino acids in 2


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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. 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 coumarin-3-carboxylic acid with o-phenylenediamine in the presence of PPA at 175 oC.17 Christie and Lui synthesized the same heterocycle from 2-cyanomethyl benzimidazole and salicylaldehyde in the presence of piperidine (Scheme 1).18 Scheme 1. Literature reports and our approach for the synthesis of (coumarin-2-yl)benzimidazoles Arora et al. NH2

R

HOOC +

NH2

O

Our Approach

PPA

R

175 oC

O

One-pot NC

N Christie et al. N CH2CN + N H

OHC

R

N R2 O

Piperidine

O

H N O HN R2

HO

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

3



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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). Scheme 2. Preparation of N-(2-aminophenyl)-2-cyanoacetamides (4) NO2 R1 F

NO2

i

R1 NH R2

92-95 %

1

H N

NH2 R1

ii

iii NH R2

95 %

65-70 %

3

R1

CN

O NH R2 4

Reaction Conditions: i) R2NH2 (2), DCM, 40 oC, 6h; ii) Zn/HCOONH4, MeOH, rt, 15 min.; iii) Cyano acetic acid, EDCI, HOBt, CH2Cl2, 0 oC, 30 min, rt 12h;

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

1{1}

2{1}

H

1{2}

4-COOCH3

1{3}

5-Cl

R2

Compound

R1

Compound

O

2{2} 2{3}

HO 2{4}

R3

H O

5

2{5}

Compound

R3

5{1}

H

5{2}

4-OCH3

5{3}

5-CH3

5{4}

5-Cl

5{5}

5-NO2

2{6} 2{7} O 2{8}

HO

Figure 2. Diversity elements, chemsets 1{1-3}, 2{1-8} and 5{1-5}

Compounds 4 were treated as the common building block for the synthesis of substituted 4


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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 methanol at 50 oC 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. Synthesis of 2-(coumarin-3-yl) benzimidazoles from N-(2-aminophenyl)-2 -cyanoacetamide O

O

H N

O

CN

O

p-TSA, MeOH

O NH

N

50 oC, 4h

50 oC, 5h

N 7

4{2,2}

O O

O N O HN

N

O

HCl (1N) N

N

50 oC, 2h 88 %

one-pot,

three-step

O O

8

This

Salicylaldehyde (5), Et3N

N

6{2,2,1}

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 5



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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)

Scheme 4. Preparation of 7{2,8,1} and 7{2,9,1}. O

O N

O

N

HCl/H2O

O

N

O

N

MeOH

HN

O O

OAc 8{2,9,1}

CH3COOH 80-85 oC

6{2,9,1}

OH 6{2,8,1}

m/z = 406.5 [M+1]

O O

N N O N H

Figure 3. X-Ray crystal structure of 8{2,3,1}.

Table 1. Substrate Scope for the Synthesis of 2-(Coumarin-3-yl)benzimidazoles H N R1

CN

O NH R2 4

1. p-TSA, 4h 2. Salicylaldehydes, Et3N, 5h 3. HCl, 2h

R3 N R1

MeOH, 50 C

N R2 O

One-pot 70-90 %

6

o

6


O

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O

O

N N

O

N

O

N

O

O

N

O

O

N

O

O

N

O

N

O

O

O

6{1,1,1}, 87%

O

O

6{2,3,1}, 83 %

6{2,2,1}, 88 %

6{2,1,1}, 87 %

O O

O N

O

O N

O

N

N

O

6{2,4,1}, 88 %

N

O

N

O

OH

N

O

N

O

N

O

O O

O

OAc

6{2,8,1}, 78 %

6{2,2,3}, 90 %

6{2,9,1}*, 72 % O

N

N

N

O

6{3,1,1}, 85 %

O

O N N

O O

6{2,2,4}, 88 %

NO2 O N

O

N

N N

O

O

N

6{2,6,5}, 81 %

6{2,7,5}, 75 %

O O

O O

6{2,2,5}, 82 %

Cl

NO2

O N

O O

6{2,2,2}, 70 %

O O

N

O

6{2,7,3}, 86 % NO2

N

O

O

O

O

Cl

O

O

N

O

O O

6{2,6,3}, 87 %

O

N

O

O

O

O

O

N

6{2,7,1}, 90 %

O

O

N

O

6{2,6,1}, 90 %

N

O O

O O

O N

Cl

N

6{2,5,1}, 82 %

O O

N

O O

O

N

O

N

O

O

6{1,1,4}, 80 %

* Obtained from acetylation of 6{2,8,1}

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 7



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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) Scheme 5. A Plausible Mechanism for the Product (6) Formation H N R1

H N

p-TSA, MeOH

CN

CN

R1

O NH R2 4

N

CN

N

H

R1 -H2O

N OH

R2

R2

7 O

H N

R1

H

H

R3

CN

R3

O

N R1

HO

N

H N

Et3N

R2

N R1

H N

CN OH

VIII

VII R3

-H2O

H 3O

R1

N R2 IX

OH

C N

R3

R3 N

R1

CN OH

R2

R2

N

R3

HO

proton exchange

N R2 HN

O

8

+

R1

N N R2 O

O

6

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 8


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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). 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 mixture was heated at 50 oC 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). Methyl 2-(coumarin-3-yl)-1-N-propyl-1H-benzimidazole-5-carboxylate 6{2,2,1}: 1H 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 9



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Supporting Information Full characterization and spectroscopic data (1H and

13

C 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}. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. 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 EA HOBt EDCI MeOH THF p-TSA TEA h eq

dimethylsulfoxide ethyl acetate 1-hydroxybenzotriazole 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide methanol tetrahydrofuran p-toluene sulphonic acid triethylamine hour equivalent

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Diversity-Oriented Synthesis of Coumarin-Linked Benzimidazoles via

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