Synthesis and antioxidant properties of novel 2H-chromene-3-carboxylate and 3-acetyl-2H-chromene derivatives

Accepted Manuscript Synthesis and antioxidant properties of novel 2H-chromene-3-carboxylate and 3-acetyl-2H-chromene derivatives Paramasivam Sivaguru, Raman Sandhiya, Mani Adhiyaman, Appaswami Lalitha PII: DOI: Reference:

S0040-4039(16)30471-3 http://dx.doi.org/10.1016/j.tetlet.2016.04.097 TETL 47597

To appear in:

Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

28 January 2016 22 April 2016 26 April 2016

Please cite this article as: Sivaguru, P., Sandhiya, R., Adhiyaman, M., Lalitha, A., Synthesis and antioxidant properties of novel 2H-chromene-3-carboxylate and 3-acetyl-2H-chromene derivatives, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.04.097

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Tetrahedron Letters

Synthesis and antioxidant properties of novel 2H-chromene-3-carboxylate and 3acetyl-2H-chromene derivatives Paramasivam Sivaguru, Raman Sandhiya, Mani Adhiyaman, Appaswami Lalitha* Department of Chemistry, Periyar University, Periyar Palkalai Nagar, Salem – 636 011, Tamil Nadu, India. Corresponding author E-mail: [email protected]

A RT I C L E I N F O

A BS T RA C T

Article history: Received Received in revised form Accepted Available online

In this communication, for the first time we have constructed a series of novel azo group fused 2H-chromene-3-carboxylate and 3-acetyl-2H-chromene derivatives via the Knoevenagal condensation reaction of active methylene compounds with aromatic 5-arylazosalicylaldehydes followed by a nucleophilic addition of the phenolic hydroxyl group to the carbonyl group of one of the ester groups. Shorter reaction times, high yields, simple work-up procedure and mild reaction conditions are the advantages of the present method. In addition, we have also studied the antioxidant activities using DPPH, hydroxyl and ABTS radical scavenging methods.

Keywords: 2H-Chromene-3-carboxylate 3-Acetyl-2H-chromene 5-Arylazosalicylaldehydes Knoevenagal condensation Antioxidant activities

Design and exploration of novel chemical units of medicinal interest is a crucial area in the field of drug discovery. 1,2 Coumarin moiety is a key core structure that occurs in a variety of natural products and biological molecules that are widely used in material chemistry. 3 Coumarins and their derivatives are found to possess a wide range of valuable biological properties including anticancer, 4 anti-HIV, 5 antiacetylcholinesterase, 6 antifungal, 7 antioxidant,8 9 10 antihelmintic, antibacterial and antiviral activities. 11 These heterocyclic motifs are also frequently used as additives in fragrances, agrochemicals, insecticides, food and cosmetics.12 In addition to that, they have found applications as photosensitizers, laser dyes, fluorescent indicators and optical brighteners.13-16 Because of their unique medicinal properties, structural variability, low cost and low toxicity, the coumarin scaffold has been broadly used in the design and development of a number of pharmaceutically important compounds. 17 Depending on the nature as well as pattern of the substitution, coumarins may display a variety of pharmacological, biochemical and therapeutic properties. 18 In general, coumarin and their derivatives have been mainly synthesized from Knoevenagel, Pechmann, Perkin, Reformatsky, and Wittig reactions. 19 To the best of our knowledge, there is no literature available for the synthesis of linear conjugated azo group fused coumarin derivatives. In continuation of our efforts to develop novel heterocyclic compounds, 20 herein we are reporting the synthesis of novel 2H-chromene-3-carboxylate derivatives via piperidine catalyzed Knoevenagel condensation reaction of diethyl malonate with aromatic 5-arylazosalicylaldehydes to

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provide the corresponding products in good to excellent yields (Scheme 1).

Scheme 1. Synthesis of 2H-chromene-3-carboxylate derivatives

In order to optimize the reaction conditions, a model reaction of diethyl malonate (1 equiv) with 5-((4-chlorophenyl)diazenyl)2-hydroxybenzaldehyde (1 equiv) was carried out using 30 mol% of piperidine as the catalyst and ethanol as the solvent at refluxing temperature where, the corresponding product was formed in 90% yield after 1h. Initially this reaction was tried under neat condition but, no significant amount of product was formed even after 24h (Table 1, entry 1). To study the superiority of piperidine as a catalyst, we have compared this reaction with that of some other bases like morpholine, NEt3, pyridine, 2-aminopyridine, DABCO, NaOMe, NaH, NaOH, KOH and arrived to the conclusion that the piperidine is the best choice. The superior activity of piperidine may be attributed to its greater ability to capture the acidic proton thereby facilitating the trouble-free formation of Knoevenagel adduct. While, using 30 mol% of morpholine as a catalyst, the corresponding product was obtained with 76% of yield after 14h. Bases like NEt3, 2aminopyridine, pyridine, DABCO, NaOMe, NaH yielded only trace amounts of product even after 24h. But this condensation reaction did not proceed at all while we carried out this reaction with NaOH and KOH (Table 1).

2

Tetrahedron

Table 1. Impact of various catalyst on the Knoevenagel condensation reaction a Entry

Base (30 mol%)

Reaction time (h)

Yield (%) c

1

-

24

-

2

Piperidine

1

90

3

Morpholine

14

76

4

NEt3

24

Trace

5

2-aminopyridine

24

Trace

6

Pyridine

24

Trace

7

DABCO

24

Trace

8

DBU

48

35b

9

NaOMe

24

Trace

10

NaH

24

Trace

11

NaOH

24

-

12

KOH

24

-

13

L-proline

8

After the selection of suitable catalyst for this condensation reaction, we have also studied the suitable reaction media. For this purpose, we have chosen the reaction of diethyl malonate (1 equiv) with 5-((4-chlorophenyl)diazenyl)-2-hydroxy benzaldehyde (1 equiv) and 30 mol% of piperidine as the catalyst in different solvents like, ethanol, methanol, dioxane, DMF, acetonitrile, toluene, chloroform, dichloromethane and water. All the solvents were explored to promote the reaction, and ethanol was found to be particularly effective for this Knoevenagel condensation reaction (Table 2). But, the reaction does not proceed well with water as a solvent (Table 2, Entry 9). In the case of ethanol also, the yield was better at reflux temperature compared to room temperature.

65

The use of 30 mol% of piperidine and 10 mL of ethanol were crucial for this reaction, and by using this optimized reaction conditions the generality of the reaction was subsequently explored. Different types of substituted 5-arylazosalicylaldehyde derivatives have been prepared and made to react with diethyl malonate to afford the corresponding azo group fused coumarin derivatives in excellent yields (Table 3).

Diethyl malonate (1 equiv) with 5-((4-chlorophenyl)diazenyl)-2hydroxybenzaldehyde (1 equiv) in ethanol using various bases.

Table 3. Synthesis of fused 2H-chromene-3-carboxylate derivativesa

b

Compound 4 as a product.

Entry

R

Isolated Yield.

1

a

c

When the same reaction was carried out with 30 mol% of DBU as a catalyst, unexpectedly the compound 4 was obtained as a sole product (Scheme 2). This might be due to the initially formed expected compound 3d that underwent hydrolysis followed by the decarboxylation. The unexpected compound 4 was confirmed by 1H NMR analysis. In the 1H NMR spectrum, two doublets appeared at δ 8.33-8.32ppm and 8.27-8.25ppm indicating the presence of two benzylidene protons (-CH=CHCO-) and the aromatic protons appeared in the region of δ 8.176.63ppm.

Product (3(a-k))

H

Time (h) 2

Yield (%) b 70

2

2-Cl

3

72

3

3-Cl

2.5

58

4

4-Cl

1

90

5

4-Br

1

85

6

4-Me

3

63

7

4-OMe

3

65

8

3-COCH3

2.5

61

9

4-COCH3

4

68

10

4-COOH

4

63

11

4-SO3 H

4

67

Scheme 2. Formation of the unexpected compound 4

Table 2. Effect of different solvents on the Knoevenagel condensation reactiona Entry

Solvent

Reaction time (h)

Yield (%) c

1

Methanol

6

70

2

Ethanol

1

90

3

Dioxane

10

30

4

DMF

9

20

5

Acetonitrile

6

62

6

Toluene

6

60

7

Chloroform

6

62

8

Dichloromethane

5

67

9

Water

24

-

10

Ethanol b

3

82

a

Diethyl malonate (1 equiv) with 5-((4-chlorophenyl)diazenyl)-2hydroxybenzaldehyde (1 equiv) in different solvents using 30 mol% of piperidine as catalyst. b

Room temperature.

c

Isolated Yield.

a

Diethyl malonate (1 equiv) with 5-((4-chlorophenyl)diazenyl)-2hydroxybenzaldehyde (1 equiv) in ethanol using 30 mol% of piperidine as a catalyst.

b

a

Isolated Yield.

Electron donating as well as electron withdrawing groups present in any of the positions of arylazo ring of salicylaldehyde gave the corresponding products in good to moderate yields and there was no electronic effect observed in the reaction rate as well as in the yield of the product. In the cases of chloro substituted arylazosalicylaldehyde derivatives, lesser yield was observed for chloro group in the 3rd position of the arylazo ring (Table 3, entry 3) than that in 2nd and 4th positions (72 and 90%). This may be due to the limited delocalization of electrons in the aromatic ring. From these emerging results, next we have applied the same protocol for the synthesis of some azo group fused 3-acetyl-2Hchromene derivatives from the condensation reaction of ethyl acetoacetate with 5-arylazosalicylaldehyde using 30 mol% of piperidine as a catalyst where, the corresponding products were obtained in good yields (Scheme 3 and Table 4).

Ethylacetoacetate (1 equiv) with 5-((4-chlorophenyl)diazenyl) -2hydroxybenzaldehyde (1 equiv) in ethanol using 30 mol% of piperidine as a catalyst. b

Isolated Yield.

In addition to that, we have observed a selectivity while conducting the reaction with two equivalents of diethyl malonate and one equivalent of 5-((4-chlorophenyl)diazenyl)-2hydroxybenzaldehyde in the presence of 30 mol% of piperidine by refluxing in ethanol (Scheme 4). It was expected that the initially formed coumarin to undergo Michael addition with another molecule of diethyl malonate to afford the corresponding Michael adduct 7 as a product. But unfortunately, we have observed 83% of compound 3d as a sole product as confirmed by NMR. The 1H NMR spectrum of compound 3d showed a singlet at δ 8.62 ppm which revealed the presence of benzylidene proton and a quartet at δ 4.47-4.42 ppm due to -CH2 protons. One triplet appeared at δ 1.45-1.41 ppm, could be accounted for the presence of -CH3 protons.

Scheme 3. Synthesis of some 3-acetyl-2H-chromene derivatives

Table 4. Synthesis of 3-acetyl-2H-chromene derivatives a Entry

R

1

Product (6(a-k))

H

Time (h) 2

Yield (%) b 68

2

2-Cl

3

73

3

3-Cl

2

53

4

4-Cl

1

85

5

4-Br

1

82

6

4-Me

2

66

Scheme 4. Selective synthesis of 2H-chromene-3-carboxylate derivatives

A plausible mechanism for this reaction is shown in Scheme 5. Initially, the active methylene group activated by piperidine reacts with the carbonyl carbon atom of 5-arylazosalicylaldehyde to yield the corresponding Knoevenagel derivative A. Then, cyclization occurs by the attack of the phenolic hydroxyl group on the carbonyl group of one of the ester groups to give the oxonium ion intermediate B. The unstable oxonium ion B would be readily converted to 2H-chromene derivatives with the elimination of ethanol.

Scheme 5. Possible mechanism for the synthesis of 2H-chromene derivatives 7

4-OMe

2

68

8

3-COCH3

3

61

9

4-COCH3

3

68

10

4-COOH

3

65

11

4-SO3 H

3

69

Antioxidant activity The in-vitro antioxidant activities of all the synthesized compounds were evaluated against 2,2’-diphenyl-1picrylhydrazyl (DPPH), hydroxyl and 2,2’-azinobis-(3ethylbenzthiazoline-6-sulfonate) cation (ABTS+) radicals according to the literature methods with some modifications.21-23 DPPH radical scavenging activity The in-vitro antioxidant activities of the synthesized coumarin-3-carboxylate derivatives (3(a-k)) were evaluated by DPPH radical scavenging method and the results are summarized in table 5. In order to find out the IC50 values, model experiments were carried out with ten different concentrations (20, 40, 60, 80, 100, 200, 400, 600, 800, 1000μg/mL) of 3a in triplicates. The antioxidant activity of the compound 3a increases with increasing the concentration from 20 to 100μg/mL and after remained constant up to 1000μg/mL (Figure 1). But the 50% of activity

4

Tetrahedron

was not observed even with very high concentration (1000μg/mL). So, the antioxidant activity of all other compounds of this series were evaluated in 100μg/mL concentration.

new radical which could react with DPPH radical to form the stable diamagnetic compounds (Scheme 6). The DPPH radical scavenging activities of the 3-acetyl coumarin derivatives are moderate (41-54%) when compared to BHA and ascorbic acid (Table 6). In particular, the compound that contain methoxy group in its structure exhibited the maximum radical scavenging property in this series also (Table 6, entry 7).

Table 6. DPPH radical scavenging compounds 6(a-k) in 100μg/mLa Entry

Figure. 1. DPPH radical scavenging activity of compound 3a

It is seen from the table 5 that, all the synthesized compounds showed the DPPH radical scavenging activity in the range of 3443%. These results revealed that all the compounds exhibited poor radical scavenging activities compared to the standard antioxidants like BHA and ascorbic acid (Table 5). Among the compounds screened, compound 3h having methoxy group in the arylazo ring showed 43% radical scavenging ability, which might be due to the electron donating ability of methoxy group activating the phenyl ring (Table 5, entry 7) and compound 3j exhibited the lowest scavenging ability comparing to the other compounds of this series tested (Table 5, entry 10).

Compound

activities

of

Radical scavenging activity (%) DPPH b

OHc

ABTSb

1

6a

45.48 ± 0.8

87.66 ± 1.2

44.23 ± 0.6

2

6b

46.91 ± 1.1

87.67 ± 0.3

45.79 ± 1.2

3

6c

50.13 ± 0.1

88.12 ± 0.2

49.15 ± 0.4

4

6d

48.07 ± 0.9

89.17 ± 1.9

47.75 ± 0.8

5

6e

47.97 ± 1.0

87.94 ± 0.8

46.98 ± 0.6

6

6f

49.39 ± 1.6

89.02 ± 1.3

48.52 ± 1.2

7

6g

53.67 ± 1.3

87.31 ± 1.5

52.69 ± 0.7

8

6h

49.23 ± 2.7

89.98 ± 1.4

48.56 ± 1.0

9

6i

44.80 ± 2.0

90.33 ± 0.7

43.81 ± 0.9

10

6j

40.73 ± 1.3

90.75 ± 0.3

39.95 ± 2.1

11

6k

40.94 ± 2.1

91.21 ± 0.2

39.82 ± 1.1

a

Results are expressed as mean of triplicates ± standard deviation.

b

1000µl of test sample used for evaluating RSA.

c

Table 5. DPPH radical scavenging activities of compounds 3(a-k) in 100μg/mLa Entry

Compound

Radical scavenging activity (%)

200µl of test sample used for evaluating RSA.

Hydroxyl radical scavenging assay

1

3a

40.46 ± 1.3

91.27 ± 1.0

39.13 ± 1.3

2

3b

36.87 ± 1.2

90.59 ± 0.4

35.84 ± 1.3

3

3c

38.83 ± 1.4

91.24 ± 0.4

37.49 ± 2.9

4

3d

40.09 ± 0.7

91.18 ± 0.3

38.73 ± 1.4

5

3e

39.09 ± 1.1

92.14 ± 0.8

38.15 ± 1.1

6

3f

39.67 ± 0.3

91.40 ± 0.2

38.68 ± 0.9

7

3g

43.09 ± 1.9

91.32 ± 0.3

42.53 ± 1.1

8

3h

42.05 ± 1.0

90.48 ± 0.5

41.54 ± 0.6

9

3i

35.66 ± 1.6

90.91 ± 0.5

35.08 ± 0.7

10

3j

34.34 ± 1.0

91.10 ± 0.4

33.97 ± 0.4

11

3k

40.99 ± 1.2

91.24 ± 0.8

40.19 ± 0.8

Hydroxyl radicals are one of the most reactive oxygen species among the other species and are responsible for the damage of tissues during the inflammation. Hydroxyl radical scavengers could serve as better alternatives for the protection of these tissue damages. The hydroxyl radical scavenging activity of the synthesized compounds were estimated using the 2-deoxy-Dribose oxidation method and the results are given in Table 5 and 6. In this experiment, all the synthesized compounds (3(a-k) and 6(a-k)) exhibited strong hydroxyl radical scavenging activities (87-92%) at 100µg/mL concentration. The hydroxyl radical scavenging activities of the synthesized compounds are slightly lower than that of the standard antioxidant, ascorbic acid (Table 5, entry 13). But, the hydroxyl radical scavenging activities of the compounds 3(a-k) were somewhat slightly higher than that of compounds 6(a-k). Compound 3e (92%) was found to have better hydroxyl scavenging activity than the other compounds studied (Table 5, entry 5).

12

BHA

95.93 ± 0.7

-

-

ABTS radical scavenging activity

13

Ascorbic acid

94.72 ± 0.6

98.23 ± 0.3

93.57 ± 0.5

To confirm the radical scavenging activities of the synthesized compounds, next we have determined their capabilities to reduce the ABTS radical cation. Reduction of ABTS was determined by measuring the absorbance at 734 nm after 10 min incubation with 100µg/mL concentration of each compound. Obtained results were expressed as the percentage of scavenged ABTS+. as shown in Table 5 and 6. All the compounds showed the ABTS radical scavenging activities within the range of 34-53% which is lower than that of the standard antioxidant ascorbic acid (Table 5, entry 13). The results of ABTS radical scavenging activities show almost similar trend that of the DPPH radical scavenging assay. Among the compounds screened, compound 6g (53%) exhibited the higher ABTS radical scavenging activity (Table 6, entry 7).

DPPH b

OHc

ABTSb

a

Results are expressed as mean of triplicates ± standard deviation.

b

1000µl of test sample used for evaluating RSA.

c

200µl of test sample used for evaluating RSA.

Next, we have also checked the DPPH radical scavenging activities of azo group fused 3-acetyl coumarin derivatives (6(ak)) under optimized conditions and their results are illustrated in table 6. These compounds showed better radical scavenging activities than that of azo group fused coumarin-3-carboxylate derivatives which may be attributed to the strong electron withdrawing nature of the acetyl group present in the 3rd position capable of withdrawing the adjacent π electrons to generate the

The antioxidant activities of these coumarins may be explained by the mechanism shown in Scheme 6. By seeing this proposed mechanism, it may be considered that coumarin derivatives would be reduced to give either dimerized biscoumarin 7, dihydrocoumarin24 8 or phenylhydrazo coumarin 9 derivatives.

gratefully acknowledge the Sophisticated Instrumentation Facility (SIF), VIT University, Vellore for providing NMR facilities. References and notes 1. 2. 3.

Scheme 6. Plausible antioxidant mechanism for 2H-chromenes

We have also compared the DPPH radical scavenging activities of the synthesized azo group containing coumarin derivatives 3a and 6a with that of a few already reported coumarins (10 and 11).25 The structures and their percentage inhibition of DPPH radical are shown in Scheme 7.

4.

5.

6.

7. 8.

9. 10.

Scheme 7. Comparison of antioxidant activities of compound 3a and 6a with compound 10 and 11 11.

From the Scheme 7, it is evident that, the azo group containing coumarins (3a and 6a) showed better radical scavenging properties than the corresponding simple coumarins 10 and 11 even at the lower concentration (100µg/mL). The increased antioxidant activities of the compounds 3a and 6a may be attributed to the azo group present in conjugation with the aromatic ring. Due to the enhanced resonance stabilization, they may neutralize the free radicals. It has also been reported in literature that the heterocyclic compounds conjugated with azo groups are having better antioxidant activities.26 In conclusion, we have synthesized some novel azo group containing 2H-chromene-3-carboxylate and 3-acetyl-2Hchromene derivatives via the Knoevenagal condensation reaction of active methylene compounds with 5-arylazosalicylaldehydes catalyzed by piperidine. This protocol aids from the use of cheap starting materials and avoids the use of any toxic substances in the course of the reaction, high yields under mild reaction conditions in very efficient manner. The antioxidant activities of all the synthesized compounds were evaluated by DPPH, hydroxyl and ABTS radical scavenging method and observed that all the synthesized compounds were found to be potent antioxidants towards the hydroxyl radical.

12.

13.

14.

15.

16.

17. 18.

Acknowledgments 19.

We thank Council of Scientific and Industrial Research (CSIR), New Delhi, India for proving financial assistance in the form of major research project (02(0025)/11/EMR-II). We

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6

Tetrahedron 20.

21.

22. 23. 24.

25.

26.

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Supplementary Material Detailed experimental procedure, spectral data and copies of H, 13C NMR and HRMS spectra of the synthesized compounds are presented as a separate supplementary file. 1

Graphical Abstract Synthesis and antioxidant properties of novel 2H-chromene-3-carboxylate and 3-acetyl2H-chromene derivatives

Leave this area blank for abstract info.

Paramasivam Sivaguru, Raman Sandhiya, Mani Adhiyaman, Appaswami Lalitha*

8

Tetrahedron

Highlights  First time we have synthesized the novel 2H-chromene-3-carboxylate and 3-acetyl2H-chromene derivatives in good yields.  Use of cheap starting materials, avoids the toxic substances, high yields, mild reaction conditions are notable advantages.  The

antioxidant

activities

of

all

the

synthesized compounds were determined by DPPH,

hydroxyl

scavenging method.

and

ABTS

radical