pyridinones Possessing Anti-influenza Virus - ACS Publications

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“On-water” facile synthesis of novel pyrazolo[3,4b]pyridinones possessing anti-influenza virus activity Li-Yan Zeng, Teng Liu, Jie Yang, Yueli Yang, Chun Cai, and Shu-Wen Liu ACS Comb. Sci., Just Accepted Manuscript • Publication Date (Web): 05 Jun 2017 Downloaded from http://pubs.acs.org on June 8, 2017

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ACS Combinatorial Science

“On-water” facile synthesis of novel pyrazolo[3,4-b]pyridinones possessing anti-influenza virus activity Li-Yan Zeng,† Teng Liu,† Jie Yang,† Yueli Yang,† Chun Cai, # Shuwen Liu*†‡ †

Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of

Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. ‡

State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of

Nephrology, Southern Medical University, Guangzhou 510515, China. #

Chemical Engineering College, Nanjing University of Science and Technology, Nanjing

210094, China. KEYWORDS.

Pyrazolo[3,4-b]pyridinone, One-water reaction, Catalyst-free, Green reaction

and separation, Anti-influenza virus.

ABSTRACT.

A

facile

and

versatile

“on-water”

protocol

for

the

synthesis

of

pyrazolo[3,4-b]pyridinones was developed by the unprecedented construction of two rings and five new bonds in one-pot. It was proved that water was an important promoter of the reaction and PEG2000 was found to improve the reaction in terms of yield. 32 Derivatives were newly

ACS Paragon Plus Environment 1


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synthesized and most of them were prepared in an hour. The scope and limitation indicated that electron withdrawing groups substituted on synthons, substituted benzoyl acetonitriles or aryl aldehydes, were helpful to construct the pyrazolo[3,4-b]pyridinones. The reaction media PEG2000/H2O was successfully recycled and reused at least 5 times without any obvious decrease in yield. The anti-influenza activities of the derivatives were evaluated and the screening results highlighted two derivatives, which exhibited strong inhibitory activity against H5N1 pseudovirus. These positive bioassay results implied that the library of potential anti-influenza virus agent candidates could be rapidly prepared in an eco-friendly manner, and provided a new insight into drug discovery for medicinal chemists.

INTRODUCTION

Proper modification of so-called ‘privileged structures’ allows for a rapid exploration of their functional diversity space. Pyrazolopyridine is one of these privileged structures. When appropriately modified, pyrazolopyridines can exert diverse biological activities1 or present photophysical properties thanks to its D-π-A skeleton.2 The well-known example is Riociguat (BAY-63-2521) (Figure 1) ,3 which was launched in 2013 as an oral soluble guanylate cyclase stimulator for the treatment of cardiopulmonary disease because of its vasodilatatory activity. Other activities were also found in pyrazolopyridine or pyrazolo[3,4-b]pyridinone derivatives, such as antileishmania (Figure 1),4 antitumor, antimicrobial activities1c and so on. Nonetheless, an underwhelming effort has been devoted to the efficient synthesis of the pyrazolopyridine derivatives. To the best of our knowledge, the construction of the pyrazolopyridine skeleton usually started from pyrazoles directly under heating or microwave conditions,1e, 2, 5 and a few reports were involved in reacting the pyridine ring with hydrazine to get the pyrazolopyridines.1b, 1d, 1i, 6

However, existing substituted pyrazoles and pyridines were limited from commercial


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suppliers, and most of them have to be synthesized by chemists themselves. The resulting lengthy syntheses increases the number of laboratory operations, the quantities of agents and solvents used, regardless of the harsh reaction conditions in some cases. Such tedious synthetic procedure thus limits the synthetic extension of the chemical space of pyrazolopyridine.

N

N

N

N F

O N H2N

N

N

O NH2 O O

Riociguat BAY-63-2521

NH

R1 N N R2

R3 R4 Anti-leishmania compounds

Figure 1. Structures of the functional pyrazolopyridines.

We found that, among the existing pyrazolopyridines, the aromatic substitution rarely concurrently emerged at sites 6, 7 and 9 of pyrazolopyridine skeleton together (Figure

2).

However,

compound

3-(4-chlorophenyl)-4,5-dihydro-1,4-diphenyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one, with aromatic groups substituted at positions 6, 7 and 9 (Figure 2), was highlighted when screening the molecular database for the potential anti-influenza virus agents targeting hemagglutinin(HA), the receptor-binding protein that plays an important role in the process of influenza virus entry into host cells. The synthetic scheme for 3-(4-chlorophenyl)-4,5-dihydro-1,4-diphenyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one is not reported. Therefore, we firstly have to synthesize the target compound, and secondly we have

to

develop

an

efficient

protocol

for

the

synthesis

of

3-(4-chlorophenyl)-4,5-dihydro-1,4-diphenyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one

and



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derivatives, so that the diversity of the target compound could be readily expanded to better establish a structure-activity relationship. It is not difficult to construct target molecule

from

3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-5-amine,

however,

limited

diversity of substituted 1,3-diphenyl-1H-pyrazol-5-amines (Figure 2) was available from commercial suppliers, and thus we had to conduct a series of experiments to synthesize them. Fortunately, the preliminary experiments provided a green and facile “on-water” protocol by constructing pyrazole and pyridine directly to synthesize the target compound in one-pot. Compared to traditional methods, our newly developed protocol is much more feasible and flexible, in addition to its eco-friendly methodology. Herein, we would like to disclose our progress for the synthesis of pyrazolo[3,4-b]pyridines in PEG/H2O without any catalyst, and present the preliminary bioassay results. R

Cl

N

8

N

6

7

1

N

N

Ar

Ar

5

N H

O

R'

N N Ar

9

2

N H

4

Substituted 1,3-diphenyl-1H-pyrazol-5-amine Intermediates

Potential anti-virus compound

3

Figure 2. Structure of the target compound.

RESULTS AND DISCUSSION

Preliminary Experiment

We

commenced

with

the

three-component

reaction

(Scheme

1)

of

3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-5-amine 3{1,1}, benzaldehyde 4{1} and Meldrum acid 5

in

refluxing

EtOH,

and

fortunately

got

the

expected

product


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3-(4-chlorophenyl)-4,5-dihydro-1,4-diphenyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one 6{1,1,1} in 49% yield after 2.5 hrs. The intermediate 3{1,1} was also prepared by treatment of 4-chlorobenzoyl acetonitrile 1{1} and 1-phenylhydrazine 2{1} in refluxing EtOH for 8 hrs (Scheme 1). With these preliminary results, we tried to combine the two steps into one. Directly treating four starting materials 1{1}, 2{1}, 4{1} and 5 in refluxing EtOH failed to furnish the expected compound, therefore, we conducted this reaction by adding the starting materials in two batches. 4-chlorobenzoyl acetonitrile 1{1} and 1-phenylhydrazine 2{1} were stirred in refluxing EtOH, and when the intermediate 3{1,1} was formed according to TLC, benzaldehyde 4{1} and Meldrum acid 5 were added. After stirring an additional 2 hrs, the target compound 6{1,1,1} was detected, but failed to be isolated from reaction mixture (Scheme 2). We then replaced 4-chlorobenzoyl acetonitrile 1{1} with benzoyl acetonitrile 1{2} or 4-florobenzoyl acetonitrile 1{4}, and repeated this procedure. Only compound 1{4} successfully provided the corresponding product 3-(4-fluorophenyl)-4,5-dihydro-1,4-diphenyl-1H-pyrazolo[3,4-b]pyridin6(7H)-one 6{1,4,1} based on the analysis of NMR spectrums and HRMS. Scheme 1. Synthesis of target compound in step-wise Cl Cl

O

N N

NH2

+

PhCHO

4{1}

+

O O

reflux

N

O

N

5

N H

O

6{1,1,1}

3{1,1}

Cl O CN

NHNH2

EtOH, reflux

+

Y. 53%

Cl 1{1}

N N

NH2

2{1} Yield in 71% on water Yield in 49% in EtOH

3{1,1}



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Scheme

2.

One-pot

reaction

for

the

synthesis

Page 6 of 29

of

compounds

3-(4-substituted

phenyl)-1-phenyl-1H-pyrazol-5-amine R1

R1

O

H N

CN

NH2

+

R1

PhCHO N

N N

NH2

O

O O

N H

O

6

3 R1 = Cl, H, no products, in EtOH R1 = F, yielded in 19%, in EtOH

N

O

On-water reaction R1 = Cl, yielded in 34% R1 = H, yielded in 29% R1 = F, yielded in 46%

On the other hand, replacement of the hazard solvent with green solvents such as ionic liquids, PEG and water has emerged as a commendable method to gratify the environmental issues.7 Additionally, the “on-water” organic synthesis (a reaction where reactants are insoluble in water), with many theoretical and practical advantages, has gained increasing attention.8 “On-water” synthesis provided not only a better reaction in terms of yield and rate but also a green separation. So water was introduced into this reaction as a solvent. We firstly conducted an “on-water” reaction of intermediate 3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-5-amine 3{1,1}, benzaldehyde 4{1} and Meldrum acid 5. Surprisingly, a higher yield (71%) of target compound was provided than in EtOH (49%) (Scheme 1). We subsequently carried out the one-pot, four-component reactions in refluxing water with the starting materials being added in two batches (Scheme 2). Compared with the same reactions in EtOH, to our delight, all 4-chlorobenzoyl acetonitrile 1{1}, benzoyl acetonitrile 1{2} and 4-florobenzoyl acetonitrile 1{4} were successfully transformed to the corresponding products in 34%, 29% and 46% respectively (Scheme 2). Water proved to be important to promote the one-pot reaction for the synthesis of target compound.


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Encouraged by these results, further optimization was conducted for the synthesis of compound 6{1,1,1}, wherein compounds 4{1} and 5 were added into reaction after 1{1} reacted with 2{1} for 40 minutes. The results were collected in Table 1. To improve the yield, iodine and p-TsOH were tried to promote the reaction, unexpectedly, no product was detected from iodine (Entry 2, Table 1), while TsOH slightly improved the yield of corresponding product 6{1,1,1} to 41% from 34% (Entry 3, Table 1). These two different results alert us that the solubility of the organic compound in water should be considered, since compared to TsOH, iodine is hard to be dissolved in water. Indeed, for many years water was seldom developed as reaction media for organic synthesis because of the poor solubility for most reactants.7b,

8a, 8e, 8g, 9

As mentioned above,

PEG(polyethylene glycol) is also one of the green solvents with reduced flammability, recyclability and a well documented toxicity and environmental burden data.10 With its special properties, PEG/H2O provided a better reaction than water.7b, 11 To address the solubility issue, we added PEGs to the one-pot reaction of 1{1}, 2{1}, 4{1} and Meldrum acid 5. The results collected in Table 1 indicated that 8 mg/mL of PEGs (from PEG200 to PEG2000, Entries 4-8, Table 1) in water made less contribution to improve the yields, and the yield decreased in PEG2000/H2O (8mg/mL). However, when the concentration was increased to 20 mg/mL, the yields were mainly improved. Surprisingly, PEG2000 gave the highest yield up to 76% (Entry 14, Table 1), and the total synthesis was completed in an hour. Further optimization on PEGs (Entries 15-17, Table 1) did not provide better results. Then TsOH, iodine and TfOH were applied to the reaction one by one. Iodine failed to form 6{1,1,1} again (Entry 19, Table 1), while TsOH and TfOH made no improvement for the reaction (Entries 18 and 20, Table 1). We next increased the amount of Meldrum acid 5 aiming to further improve the yield. The results



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collected in table 1 shows that 1.2 equivalent of Meldrum acid gave a slightly higher yield of 79% (Entry 21, Table 1). Therefore, treatment of 4-chlorobenzoyl acenitrile 1{1}, 1-phenylhydrazine 2{1} in refluxing PEG2000/H2O (20mg/mL) for 40 minutes, followed by adding benzaldehyde 4{1} and Meldrum acid 5 (1.2 equiv.) into the mixture will provide the highest yield of product. Table 1. Optimization for reaction of 4-chlorobenzoyl acenitrile 1{1}, 1-phenylhydrazine 2{1}, benzaldehyde 4{1} and Meldrum acid 5.a Entry

PEG/ H2O (mg/mL)

1{1}:2{1}:4{1}:5

Yield (%)b

1

0

1:1:1:1

34%

2

0

1:1:1:1

NRc

3

0

1:1:1:1

41%d

4

PEG200 (8)

1:1:1:1

47%

5

PEG400 (8)

1:1:1:1

44%

6

PEG600 (8)

1:1:1:1

41%

7

PEG1000 (8)

1:1:1:1

37%

8

PEG2000 (8)

1:1:1:1

25%

9

PEG200 (20)

1:1:1:1

44%

10

PEG400 (20)

1:1:1:1

53%

12

PEG600 (20)

1:1:1:1

66%

13

PEG1000 (20)

1:1:1:1

73%

14

PEG2000 (20)

1:1:1:1

76%

15

PEG6000 (20)

1:1:1:1

53%

16

PEG2000 (15)

1:1:1:1

67%

17

PEG2000 (30)

1:1:1:1

68%

18

PEG2000 (20)

1:1:1:1

73%d

19

PEG2000 (20)

1:1:1:1

NRc


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20

PEG2000 (20)

1:1:1:1

75%e

21

PEG2000 (20)

1:1:1:1.2

79%

22

PEG2000 (20)

1:1:1:1.5

75%

a

Reaction conditions: 1{1} (0.5mmol) and 2{1} (0.5mmol), solvent (1.5mL), refluxing for 40 minutes, 4{1} (0.5mmol) and 5 were added, refluxing them for 20 minutes. b Isolated yield. c 20mol% of iodine was added. d 20mol% of p-TsOH was added. e 20mol% of TfOH was added. Substrate Scope

With the optimized conditions in hand, we investigated the scope and limitation of this reaction. Under optimized conditions, a series of pyrazolo[3,4-b]pyridinone derivatives 6 have been obtained from substituted benzoyl acetonitriles 1, hydrazines 2 and aryl aldehydes 4 (Figure 3).

Substituted benzoyl acetonitriles 1 O

O

O CN

O

Cl 1{1}

O

O

CN

CN

F3C

F

1{3}

1{2}

CN

CN

1{4}

1{5}

Hydrazines 2 H N

N

N2H4 H2O

NH2

2{2}

2{1}

H N

NH2

2{3}

Aryl aldehydes 4

3{2}

Cl

3{3}

CHO

CHO

O

Cl

3{1}

CHO

CHO

CHO

3{4}

CHO

HO

OH

3{5}

3{6}



1 2 3 4 5 6 7 8 9 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

CHO

CHO

HO

CHO HO

CHO

O

NC

Br 3{7}

OH

3{8}

Page 10 of 29

O

CHO

O

3{9}

3{10}

3{11}

Figure 3. Building blocks for compound 6.

Several para-substituted benzoyl acetonitriles 1 were initially applied to the reaction. Most of them successfully provided good yields of corresponding products 6{1-5,1,1} in 1 hour. The results collected in Scheme 3 showed that electron-withdraw groups 4-Cl, 4-F, and 4-CF3 on benzoyl acetonitriles made a positive influence on the reaction in terms of yield, while benzoyl acetonitrile 1{2} gave a lower yield of 6{2,1,1} in 63%, and we even failed to get pure compound 6{3,1,1} from electron-donor group 4-MeO substituted benzoyl acetonitrile. Next, a series of substituted benzylaldehydes 4{1-10} were tested, and most of them were smoothly transformed into expected corresponding compounds. Generally, benzylaldehydes with electron-withdrawing groups were more active than those with electron-donated groups. The electron-withdrawing group substituted benzylaldehydes including 2-chlorobenzylaldehyde 4{4} were all completely transformed in 1 h, and provided good yield up to 75% 6{1,8,1}, while we got moderate yields from electron-donated ones with prolonged reaction time up to 8 hrs. We observed that substituent at ortho-position resulted in lower yield because of steric hindrance, but made no difference in reaction time, as product 6{1,4,1} (o-chloro-) was generated after reaction for 1 hour and yielded in 52%, much lower than 6{1,2,1} (p-chloro-, yielded in 72%). However, o-hydroxy benzylaldehyde 4{6} failed to provide the expected product 6{1,6,1}. We also get the products 6{2,2,1} and 6{2,3,1} by reacting benzoyl acetonitrile 1{2} with 1-phenylhydrazine 2{1}, Meldrum acid 5 and 4-chlorobenzylaldehyde 4{1} or 4-methoxylbenzylaldehyde 4{3}, respectively. It is implied that electron-donated groups substituted on synthons 1 and 4 made a


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negative contribution to the reactions in terms of yield and rate. To confirm this result, we then undertook the reaction of 1{1}, 2{1}, 5 and 4-hydroxy-3,5-dimethoxybenzaldehyde 4{9} or 4-hydroxy-3-methoxybenzaldehyde 4{10}, under standard conditions. With both –OH and -OMe groups on synthon 4, although pure product 6{1,1,9} and 6{1,1,10} were successfully obtained in 45% and 47% respectively, but reaction time was extended to 8 hours (overnight). Obviously, 4-CF3 substituted benzoyl acetonitrile 1{5} gave the best yield. We then applied 4-OMe benzylaldehyde 4{3}, 4-CN benzylaldehyde 4{8} and furfural 4{11} to the reactions that 1{5} participated. Likewise, compound 6{5,1,3} was obtained in 66%, higher than 6{1,1,3} (60%), while 6{5,1,8} was yielded in 77%, slightly higher than 6{1,1,8} (75%). With these results, 4-CF3 benzoyl acetonitrile 1{5} was confirmed to be more active than 4-chlorobenzyl acetonitrile 1{1}. Furfural was also transformed into the corresponding compound 6{5,1,11} successfully.

Scheme 3. The synthesis of 4,5-dihydro-1,3,4-triphenyl-1H-pyrazolo[3,4-b]pyridine-6(7H)-ones R1 R1

R3

4

O

R3CHO

CN +

PhNHNH2

N N

R1

1

O NH2

O

2{1}

N N

O

N H

O

O

6{1-5,1,1-11}

5 3{1-5,1}

O

Cl

N

N N

N N H

O

6{1,1,1}, 79%

F

N

N H

O

6{2,1,1}, 63%

N

N

N H

O

6{3,1,1}, 00%a

N

N H

O

6{4,1,1}, 77%



1 2 3 4 5 6 7 8 9 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

Cl

Cl

F3C

Page 12 of 29

O

Cl

Cl

Cl

N

N N

N H

N

O

N H

N

OH

Cl

N H

N

O

6{1,1,3}, 60%b

6{1,1,2}, 72%

6{5,1,1}, 83%

N

N

O

O

6{1,1,4}, 52%

Br

Cl

Cl

N H

CN

Cl

OH

N N

N

O

6{1,1,5}, 51%c

O

N H

N H

O

N

6{1,1,7}, 69%

O

Cl

N N

O

6{1,1,9}, 45%e

N H

N

O

O

F3C

CN

F3C

O

N

N H

N

O

6{2,1,3}, 56%f

6{2,1,2}, 64%

O

OH

Cl

N

N H

N H

6{1,1,8}, 75%

O

N N

N

N

O

6{1,1, 6}, 00%d

OH

Cl

N

N

N H

N H

O

6{1,1,10}, 47%g

F3C O

N

N

N N

N H

O

6{5,1,3}, 66%

N

N H

O

6{5,1,8}, 77%

N

N H

O

6{5,1,11}, 42%

The reaction conditions: Refluxing 1 (0.5mmol) and 2{1} (0.5mmol) in PEG2000/H2O (30mg/1.5mL) for 40 minutes, then compounds 4 (0.6mmol) and 5 (0.5mmol) were added. Reactions were monitored by TLC, completed in 1 hour totally. a Reaction failed to provide pure compound 6{3,1,1}. b Reaction was completed in 2 hours. c Reaction was completed in 7 hours. d Reaction failed to provide comound 6{1,1,6}. e Reaction was completed after stirring overnight. f Reaction was completed in 2 hours. g Reaction was completed after stirring overnight.

Next, we replaced 1-phenylhydrazine 2{1} with hydrazine hydrate 2{2}, and conducted a series of reactions of 1{1}, 2{2}, 5 and various benzyl aldehydes 4 (Scheme 4). Fortunately, a series of bis(substituted phenyl)-4,5-dihydro-1H-pyrazolo[3,4-b]pyridine-6(7H)-ones were smoothly formed in 1 hr under optimized reaction conditions, with moderate to good yields. In general, higher yields were provided compared with 1-phenylhydrazine 2{1}. For example, we


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got compound 6{1,1,1} in 79%, but compound 6{1,2,1} was yielded in 82%. It is implied that hydrazine hydrate 2b is more active than 2a. Consistent with 1-phenylhydrazine 2a, the results collected in scheme 4 also indicated that electron-withdrawing group substituted benzyl aldehydes are more active. As shown in scheme 4, 81% yield of compound 6{1,2,2} was obtained from 4-chlorobenzylaldehyde, while 4-methoxybenzylaldehyde gave compound 6{1,2,3} in 71%, and 4-hydroxybenzaldehyde and 4-hydroxy-3,5-dimethoxybenzaldehyde provided much lower yields of corresponding products 6{1,2,5} and 6{1,2,9}. We also observed that, compared to 4-chlorobenzylaldehyde, 57% yield of expected product 6{1,2,4} was produced from 2-chlorobenzylaldehyde, which implied that steric hindrance affected the reaction in a certain degree. In addition, 4-methoxylbenzoyl acetonitrile 1{3} was tried but provided the expected compound 6{3,2,2} in moderated yield (Scheme 4) this time, since in previous experiment, we failed to get compound 6{3,1,1} (Scheme 3). This result further confirmed that hydrazine hydrate 2{2} was more active. Besides, we also get the compound 6{1,3,2} from 1-(pyridin-2-yl)hydrazine 2{3}, although in low yield 37% with prolonged reaction time (2 hrs). Based on these results, it is apparent that hydrazine hydrate 2{2} is the most active for this reaction among the three hydrazines 2{1}, 2{2} and 2{3}, while 1-(pyridin-2-yl)hydrazine 2{3} is less active than 1-phenylhydrazine 2{1}.

Scheme 4. The synthesis of 4,5-dihydro-3,4-diphenyl-1H-pyrazolo[3,4-b]pyridine-6(7H)-ones R1

R1

4

O +

R2NHNH2

O

N

R1

1

R3

R3CHO

CN

2

N

NH2

R2 3{1-5,1-3}

O O

O

5

N N

R2

N H

O

6{1, 2-3,1-5} 6{1,2,9} and 6{3,2,2}



1 2 3 4 5 6 7 8 9 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

Cl

Cl

Cl

O

Cl

Page 14 of 29

Cl

Cl

N

N

N N H

N

N N O H H 6{1,2,3}, 73%

N N O H H 6{1,2,2}, 81%

N O H 6{1,2,1}, 82%

N N O H H 6{1,2,4}, 57% Cl

Cl

OH

Cl

OH

Cl

O

Cl

O O

N N

N

N

N

N N O H H 6{1,2,5}, 58%

N

N N O H H 6{3,2,2}, 53%

N N O H H 6{1,2,9}, 61%

N H

O

6{1,3,2}, 37%a

The reaction conditions: Refluxing 1 (0.5mmol) and 2{2} (0.5mmol) in PEG2000/H2O (30mg/1.5mL) for 40 minutes, then compounds 4 (0.6mmol) and 5 (0.5mmol) were added. Reactions were monitored by TLC, completed in 1 hour totally. a starting material hydrazine hydrate 2{2} was replaced by 1-(pyridin-2-yl)hydrazine 2{3}, and the reaction was completed in 2 hours. To further broaden the scope of the reaction, we tried to explore more building blocks to replace Meldrum acid 5, and thus carried out another series of reactions. The common used building

blocks

containing

active

methylene,

malononitrile,

ethyl

2-cyanoacetate,

pentane-2,4-dione, ethyl 3-oxobutanoate, 2-oxopropanoic acid were firstly screened, but none of them were transformed into the expected compound, not even ethyl 2-oxobutanoate. We then tried three diones (Entries 1-5, Table 2). To our delight, 5,5-dimethylcyclohexane-1,3-dione 7, structurally similar with Meldrum acid 5, was successfully transformed into the expected compound

in

8{1,1,1}

55%

yield

(Entry

1,

Table

2).

Focusing

on

5,5-dimethylcyclohexane-1,3-dione 7, 4-methoxybenzaldehyde 4{3} was firstly tested and gave corresponding product 8{1,1,3} in 43% yield (Entry 2, Table 2), lower than 8{1,1,1} in reasonable. Next, benzoylacetonitril 1{2} was applied to this reaction instead of 1{1} and produced

8{2,1,2}

in

57%

yield

(Entries

3,

Table

2).

From

these

results,

5,5-dimethylcyclohexane-1,3-dione 7 is less active than Meldrum acid in terms of yield for this protocol. And the synthesis of compound 8{1,2,2} (Entry 4, Table 2) further verified this result,


Page 15 of 29

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wherein hydrazine hydrate 2{2}, presented higher active than 1-phenylhydrazine 2{1}, but gave much lower yield (49%) than 6{1,2,2} (81%, Scheme 4). The last building block we tested is cyclohexane-1,3-dione 9, under optimized conditions, the reaction of 1{2}, 2{1}, 4{1} and 9 provided the anticipated results with expected product 10{2,1,1} and reasonable yield of 55%.

Table 2. The screening of building block 7 and 9.a R1 R1

4

O

R3

R3CHO

O

CN +

R 2NHNH2

O

O

N N

N

R1

1

N

2

R2

R4

NH2

1

2

3

R4 R4

8 or 10{2,1,1}

7, R4 = CH3 9, R4 = H

3

Entry

R2

R4

N H

Building block

Expected product

Yield (%)b

Cl

O CN

1

Cl

NHNH2

55

N

4{1}

2{1}

1{1}

O

CHO N

N H

8{1,1,1} O

Cl

O CN

2

CHO

NHNH2

O

43

O

Cl

4{3}

2{1}

1{1}

N N

O

N H

8{1,1,3}

O

7 Cl

O

CHO

NHNH2

O

CN

3

Cl

1{2}

2{1}

57

N N

4{2}

N H

8{2,1,2}

CN

4

CHO

N2H4H2O

O

49

Cl

Cl

1{1}

2{2}

NHNH2

O

5

Cl

Cl

O

CN

4{2}

N N H

N H

8{1,2,2}

O

CHO

O

O

55

N

1{2}

2{1}

4{1}

9

N

N H

10{2,1,1} a

Reaction conditions: 1 (0.5mmol) and 2 (0.5mmol) , PEG2000 (30mg) and H2O (1.5mL),



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Page 16 of 29

refluxing for 40 minutes, 4 (0.5mmol) and 7 or 9 (0.6mmol) were added, refluxing for 20 minutes. b Isolated yield.

Recyclability of Reaction Media

Finally, the recyclability and reusability were assessed by investigating the reactions starting from Meldrum acid 5 (Figure 4, A). We commenced with the model reaction of 4-chlorobenzoyl acetonitrile 1{1}, 1-phenylhydrazine 2{1}, benzaldehyde 4{1} and Meldrum acid 5 in refluxing PEG2000/H2O (20mg/mL). After cooling the reaction mixture to room temperature, an in-tube extraction with 3 X 1.5 mL of AcOEt was conducted (Figure 4, Ad), followed by the process of purification to provide the product. The water phase (reaction media) was thus simply separated and reused for the next cycle (Figure 4, Aa). With the same procedure, the reaction media was recycled and reused over 8 times for the synthesis of compound 6{1,1,1} (Figure 4, B), and we repeated this recycle experiments for 3 times. It was observed that the yield was always slightly increased when the first recycled reaction media was used, and the substantial decrease in yield occurred when the reaction media has been recycled for 6 or 7 times, and the reaction media looks not clear as seen in Pict. Aa in Figure 4. Thereafter, we carried out the cross-recycling experiment in order to apply the recycled reaction media to different reactions (Figure 4, C). The first recycled reaction media from model reaction was reused for the reaction of benzoyl acetonitrile 1{2}, 1-phenylhydrazine 2{1}, benzaldehyde 4{1} and Meldrum acid 5. To our delight, the starting material not only was transformed into the right compound 6{2,1,1} but also provided a higher yield (68%) than the corresponding yield (63%) obtained in fresh PEG2000/H2O. The second recycled reaction media was subsequently applied to the model reaction again, and gave a 77% yield of compound 6{1,1,1}, then the reaction media was recycled the third time and reused for the synthesis of


Page 17 of 29

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6{2,1,1} the second time. The recycling experiments continued like this, till the yield of 6{1,1,1} decreased to 56% after the reaction media has been recycled for 7 times. In general, the reaction media can be reused at least 5 times not only in the same reaction but also in other reactions in cross-recycling fashion without any obvious change in yields.

Figure 4. The recycle of the reaction media PEG2000/H2O. (A) procedure for the recycle and reuse of reaction media PEG2000/H2O, (B) PEG2000/H2O recyclability study for the synthesis of compound 6{1,1,1}, (C) cross-recyclability of PEG2000/H2O for the synthesis of compound 6{1,1,1} and 6{2,1,1}.

Mechanism Discussion



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Page 18 of 29

With these results, we tried to probe into the reaction mechanism. The synthesis of compound 6{2,1,1} was selected as model reaction. Although the intermediate 3{2,1} was confirmed to be important for the promotion of the reaction, the reaction process after intermediate 3{2,1} formed was unknown. We then isolated the main side product 11{2,1,1} (Figure 5), and the structure was confirmed by 1H NMR and MS. Notably, two molecules of intermediate 3{2,1} instead of Meldrum acid 5 reacted with benzylaldehyde 4{1} to form the structure 11{2,1,1}. Therefore, we can reasonably hypothesize that compared with Meldrum acid, intermediate 3{2,1} is prior to react with aldehyde. From this point of view, the formation of intermediate 3{2,1} is the key of this reaction, and also explained why we were failed to get compound 6{1,1,1} from the reaction that four starting materials added in one batch in the preliminary experiment.

N

N N

NH2

H2N

N

11{2,1,1}

Figure 5. The side product 11{2,1,1} obtained from the reaction for the synthesis of compound 6{2,1,1}

Technically, at a higher temperature 100 ℃ , water can be ionized and provide high concentration of H+. These almost bare protons can penetrate through the water-oil phase boundary as proposed by Marcus and Jung,12 and stay inside of the PEG-water barrier to provide catalytic sites under vigorous agitation, and thus promoted the formation of compounds 6. Based on these knowledge, we proposed the mechanism of this on-water reaction and showed in Scheme 5. The penetration of proton provided catalytic H+, while PEG helped to increase the


Page 19 of 29

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chance of collision for all the reactants as a co-solvent. After the second batch of starting materials (aldehyde and Meldrum acid) were added, the intermediate 3{2,1} attacked to the aldehyde prior than Meldrum acid. Intermediate was supposed to be formed and react to Meldrum acid or another molecule of 3{2,1}. Corresponding compounds 6{2,1,1} and 11{2,1,1} were thus produced. Scheme 5. The proposed mechanism based on the “on-water” synthesis of compound 6{2,1,1} H

H

N

N

H2O

Ph N

Ph

H

H N

N

N

H H

H

O

Ph

PEG

H O

N

H

N

Ph

O

NH Ph

O

H

O

PEG

Ph

O

O

O Ph

Ph

Intermediate

O

5 O

CO2

3{2,1}

H

OH

O

N

Ph

Water

NH Ph

Ph

H2 N N

H

N

O

4{1}

H

H

H

H

Ph

6{2,1,1}

H

1{2}

N

O

O

O

Ph N H

H

O

O N

H

PEG O

Ph

O

N

H

H

Ph

Ph

H

H

N H

H

PEG

N

Ph

O

2{1}

H

Ph N

O

H2N

N N

N N

NH2 H2N

N N

Ph

3{2,1}

11{2,1,1}

N O

O

H2N

N Ph

H

Anti-influenza virus activity

The anti-influenza virus activities of the newly synthesized pyrazolo[3,4-b]pyridinone derivatives

were evaluated by testing the inhibitory activity of 6, 8 and 10 on H5N1

pseudovirus infection. To our delight, 2 derivatives were highlighted with good inhibitory activity against H5N1 pseudovirus and the results shown in Table 3 indicate that 6{5,1,1} and 6{5,1,11} exhibited strong inhibitory activity with IC50 value of 14.022 µM and 2,68 µM



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Page 20 of 29

respectively. Obviously, 6{5,1,11} provided even better result than 6{1,1,1} (IC50 value of 3.50 µM)13 in terms of IC50, and comparable CC50 value. The preliminary pseudovirus neutralization assay results imply this newly developed green synthesis methodology can provide potential anti-influenza virus agents and encourage further investigations.

Table 3. Highlighted results from screening the anti-influenza virus activity of compounds 6,8,10. a IC50 (µM)

CC50 (µM)

Mean ± SD

Mean ± SD

6{5,1,1}

14.02±1.57

153.23±7.31

6{5,1,11}

2.68±0.17

>200

6{1,1,1}c

3.05±0.37

>200

Compounds

a

The screening of the anti-influenza activity for compounds 6,8,10 were done in pseudovirus neutralization assay against Influenza A/Thailand/Kan353/2004 H5N1. b 6{1,1,1} is used as a positive control.

CONCLUSION In summary, we developed a novel protocol for the synthesis of 6,7- aromatic substituted

pyrazolopyridine derivatives 6 from substituted benzoyl acetonitrils 1, 1-phenylhydrazine 2{1} or hydrazine hydrate 2{2}, substituted benzaldehydes 4 and Meldrum acid 5 or 5,5-dimethylcyclohexane-1,3-dione 7 in a simple manner, involving a four-component one-pot reaction without any catalyst in PEG/H2O and the reaction can be completed in an hour. The reaction was extremely expanded by using various benzoyl acetonitrils, benzaldehydes and hydrazines, as well as by screening the building blocks that contained active methylene. It was


Page 21 of 29

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concluded that electron-withdrawing groups on benzoyl acetonitrils 1 and benzaldehydes 4 could lead to better yield, hydrazine hydrate 2{2} was proved to be more active than 1-phenylhydrazine 2{1} by comparing the yields. Above all, the reaction media PEG/H2O not only promoted the reaction but also facilitate the separation. The organic phase can be easily collected by an in-tube extraction. So that the reaction media (water phase) was successfully recycled and reused more than 5 times without an obvious decrease of yield in different reactions in cross-recycling manner. The side product was isolated and the reaction mechanism was discussed. All of these newly prepared derivatives were screened for the anti-influenza activities, 6{5,1,1} and 6{5,1,11} were found to exhibit strong inhibitory activity on H5N1 pseudoviruse. This positive result indicates that a facile and flexible protocol has been developed to synthesize of a library of potential anti-influenza agents rapidly in an eco-friendly manner, and further proved our success of applying green synthesis to drug discovery. The further structure modification and related anti-influenza virus testing are ongoing in our group.

ASSOCIATED CONTENT

Supporting Information The Supporting Information is available free of charge on the ACS Publication website at DOI: Experimental details and spectroscopic characterization of all the compounds, as well as the 1H and 13C NMR spectrums for all products are compiled in Supporting Information.

AUTHOR INFORMATION

Corresponding Author *E-mail: [email protected]



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Page 22 of 29

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding Sources We thank the Natural Science Foundation of China (Nos. U1301224) to Shuwen Liu, and the China Postdoctoral Science Foundation funded project (Nos. 2016M602496) to Liyan Zeng for financial support. Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT

The authors are grateful to the platforms of Guangdong Provincial Key Laboratory of New Drug Screening in Southern Medical University for providing financial and technical support.

ABBREVIATIONS

PEG, polyethylene glycol; NMR, nuclear magnetic resonance; HRMS, high resolution mass spectrometer; TLC, thin layer chromatography.

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One kind of pyrazolopyridine derivatives and their application in

anti-influenza A viruses[P]. CN. Invent. Pat. CN106432230A. 2017, 10.


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“On-water” facile synthesis of novel pyrazolo[3,4-b]pyridinones possessing anti-influenza virus activity Li-Yan Zeng,† Teng Liu,† Jie Yang,† Yueli Yang,† Chun Cai, # Shuwen Liu*†‡


pyridinones Possessing Anti-influenza Virus - ACS Publications

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