INTRODUCTION:

Coumarin is a natural product which was isolated from tonka beans and sweet clover in 1820. The name ‘Coumarin’ comes from Coumarou which is the French term of tonka bean. This moiety is classified as a member of the benzopyrone family which consist of a benzene ring joined to a pyrone ring. Coumarin can also be found in other plants like vanilla grass, sweet grass, sweet woodruff, cassia cinnamon etc.¹The Coumarin smells sweet and bitter in taste. So, it helps to plant from predation. Predator of these plants generally avoids those for the smell. Coumarin firstly synthesized artificially in 1868 and it also have so many application in pharmaceutical, materials and cosmetics. There are so many methods of preparing Coumarin from salicyaldehyde, among them Perkin’s reaction²and Pechmann condensation³ are well known.

Application of Coumarin Derivatives:

a) Application in Medicine:

The coumarins are of great interest due to their pharmacological properties. In particular, their physiological, bacteriostatic and anti-tumour activity makes these compounds attractive. Some coumarin derivatives have anticoagulant activity.⁴ Warfarin drug which is similar to dicoumarol has been synthesized from coumarin. Vitamin-K has important role in blood clotting and dicoumarol reduces the amount of vitamin-K dependent clotting proteins in blood. This is because dicoumarol interferes with vitamin K reductase enzyme in the liver and the liver is unable to reactivate vitamin K, which leads to a decrease in vitamin K dependent clotting proteins.

Figure 1: Coumarin containing drugs in the market.

Besides of this, some derivatives of coumarins can be used as anticancer⁵ or anti tumour activity agents because they have the ability to prevent cell growth. It is also reported that coumarin has favourable effect in the treatment of radiogenic sialadentis and mucositis.⁶

b) Application in Materials:

Though coumarin has significant role in medicinal chemistry, but in past year it is also used in dye sensitized solar cell (DSCs), organic solar cell (OSCs) and dye lasers. The main property of this DSCs and OSCs materials is, they has two part donor and acceptor. Donor part is an electron rich part and acceptor part is electron deficient part and these two parts share electron by conjugation. Coumarin based moieties are used in donor part. These type of coumarin usually have nitrogen containing substitution at 7^th carbon.

Figure.2 Some coumarin derivative used in DSCs materials.

Coumarin derivative also used in perfume and fabric conditioner. It also used as aroma enhancer in tobacco pipe and alcohol, though it is banned in food substances.

EXPERIMENTAL SECTION:

All commercial reagents and solvents were used without additional purification. Analytical thin layer chromatography (TLC) was performed on pre-coated silica gel 60 F₂₅₄ plates. Visualization on TLC was achieved by the use of UV light (254 nm). Column chromatography was undertaken on silica gel (100‒200 mesh) using a proper eluent system. NMR spectra were recorded in chloroform-d and DMSO-d₆at 300 or 400 or 500 MHz for ¹H NMR spectra and 75 MHz or 100 or 125 MHz for ¹³C NMR spectra. Chemical shifts were quoted in parts per million (ppm) referenced to the appropriate solvent peak or 0.0 ppm for tetramethylsilane. The following abbreviations were used to describe peak splitting patterns when appropriate: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, sept = septet, dd = doublet of doublet, td = triplet of doublet, m = multiplet. Coupling constants, J, were reported in hertz unit (Hz). For ¹³C NMR chemical shifts were reported in ppm referenced to the center of a triplet at 77.0 ppm of chloroform-d and 40.0 ppm center for DMSO-d_6.

General procedure for preparation of compounds:

1) General Procedure Synthesis of Salicyldehyde 3 :

Paraformaldehyde (32.37 mmol., 3 equv.), trietylamine (32.37 mmol., 3 equv.) and magnesium chloride (21.58 mmol., 2 equv.) were added in substituted phenol(10.79 mmol., 1 equv.) in a round bottom flask. 30 mL of THF was added in it as solvent and kept the flask at 80°C under N₂atmosphere for 8 hours. After completion of the reaction, some amount of HCl was added in it and washed the reaction mixture with ethyl acetate (2 X 30 mL). The organic portion was dried with sodium sulphate. Then it was concentrated and purified by the column chromatography with silica gel. The desired product was come out with 30% ethyl acetate in hexane.

2) General Procedure for coumarin acetamide derivatives 5:

N-acetyl glycine ( 6.39 mmol., 1 equv.) and sodium acetate (12.78 mmol., 2 equv.) were added in substituted salicyaldehyde (6.39 mmol., 1 equv.) in a one neck round bottom flask. The flask was kept in 120°C under N₂ atmosphere for 5 hours. After completion of the reaction, the reaction mixture was washed with ethyl acetate and dried with sodium sulphate. The organic portion was collected and concentrated. Then it was purified by column chromatography. The product was come out with 40% ethyl acetate in hexane. All the synthesized compound were characterized by NMR and Mass analysis

Spectral Data for all Synthesized Compounds:

1) N-(2-oxo-2H-chromen-3-yl)acetamide (5a)

White solid, Mp 132- 134 °C, Mass : Cal. 203.1, Observe. 203.2

¹H NMR (400 MHz, CDCl₃) δ 8.68 (s, 1H), 8.09 (s, 1H), 7.52 (dd, J = 7.7, 1.5 Hz, 1H), 7.45 (ddd, J = 8.7, 7.3, 1.6 Hz, 1H), 7.31 (ddd, J = 8.6, 6.8, 3.0 Hz, 2H), 2.27 – 2.24 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 169.41, 158.81, 149.90, 129.68, 127.83, 125.21, 123.99, 123.31, 119.86, 116.38, 77.36, 77.05, 76.73, 24.76.

2) N-(6-chloro-2-oxo-2H-chromen-3-yl)acetamide (5b):

Yellow solid, Mp 137- 139 °C, Mass : Cal. 237.1, Observe. 237.3

¹H NMR (400 MHz, CDCl₃) δ 8.68 (s, 1H), 8.09 (s, 1H), 7.52 (dd, J = 7.7, 1.5 Hz, 1H), 7.45 (ddd, J = 8.7, 7.3, 1.6 Hz, 1H), 7.31 (ddd, J = 8.6, 6.8, 3.0 Hz, 1H), 2.27 – 2.24 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 169.43, 158.8, 149.90, 129.68, 127.83, 125.21, 123.99, 123.31, 119.86, 116.38, 77.36, 77.05, 76.73, 24.7.

3) N-(6-methoxy-2-oxo-2H-chromen-3-yl)acetamide (5c):

Brown solid, Mp 166- 168 °C, Mass : Cal. 233.1, Observe. 233.2

¹H NMR (400 MHz, CDCl₃) δ 8.68 (s, 1H), 8.09 (s, 1H), 7.52 (dd, J = 7.7, 1.5 Hz, 1H), 7.45 (ddd, J = 8.7, Hz, 1H), 7.31 (ddd, J = 8.6, 6.8, 3.0 Hz, 1H), 3.35 (s, 3H), 2.27 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 169.43, 158.8, 149.90, 129.68, 127.83, 125.21, 123.99, 123.31, 119.86, 116.38, 77.36, 77.05, 76.73, 40.3, 23.5.

4) N-(6,7-dimethoxy-2-oxo-2H-chromen-3-yl)acetamide (5d):

White solid, Mp 154- 157 °C, Mass : Cal. 263.1, Observe. 263.2

¹H NMR (400 MHz, CDCl₃) δ 8.63 (s, 1H), 7.99 (s, 1H), 7.26 (s, 1H), 6.90 (s, 1H), 6.84 (s, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 2.23 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 169.24, 160.42, 159.07, 152.38, 151.20, 147.35, 146.97, 146.62, 145.32, 124.00, 122.06, 112.22, 108.00, 99.73, 56.37, 56.34, 24.73.

5) N-(2-oxo-6-(trifluoromethyl)-2H-chromen-3-yl)acetamide (5e):

Pale yellow solid, Mp 188- 190 °C, Mass : Cal. 271.1, Observe. 271.3

¹H NMR (400 MHz, CDCl₃) δ 8.68 (s, 1H), 8.09 (s, 1H), 7.52 (dd, J = 7.7, 1.5 Hz, 1H), 7.45 (ddd, J = 8.7, Hz, 1H), 7.31 (ddd, J = 8.6, 6.8, 3.0 Hz, 1H), 2.27 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 169.43, 158.8, 149.90, 129.68, 127.83, 125.21, 123.99, 123.31, 119.86, 116.38, 77.36, 77.05, 76.73, 23.5.

6) N-(6-bromo-2-oxo-2H-chromen-3-yl)acetamide (5f):

Yellow solid, Mp 158- 16 °C, Mass : Cal. 282.1, Observe. 282.3.

¹H NMR (400 MHz, CDCl₃) δ 8.6 (s, 1H), 8.0 (s, 1H), 7.52 (dd, J = 7.7, 1.5 Hz, 1H), 7.45 (ddd, J = 8.7, Hz, 1H), 7.23 (ddd, J = 8.6, 6.8, 3.0 Hz, 1H), 2.23 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 168.4, 158.8, 149.90, 129.6, 127.83, 125.21, 123.99, 123.31, 119.86, 116.37, 77.36, 77.05, 76.73, 23.3.

7) N-(6-acetyl-2-oxo-2H-chromen-3-yl)acetamide (5g):

Green solid, Mp 171- 173°C, Mass : Cal. 245.1, Observe. 245.3.

¹H NMR (400 MHz, CDCl₃) δ 8.6 (s, 1H), 8.0 (s, 1H), 7.52 (dd, J = 7.7, 1.5 Hz, 1H), 7.45 (ddd, J = 8.7, Hz, 1H), 7.23 (ddd, J = 8.6, 6.8, 3.0 Hz, 1H), 2.23 (s, 3H), 2.1 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 168.43, 158.8, 149.90, 129.68, 127.83, 125.21, 123.99, 123.31, 119.8, 116.38, 77.36, 77.05, 76.73, 40.3, 23.4.

8) N-(6-fluoro-2-oxo-2H-chromen-3-yl) acetamide (5h):

Purple solid, Mp 182- 184°C, Mass : Cal. 221.1, Observe. 221.3.

¹H NMR (400 MHz, CDCl₃) δ 8.5 (s, 1H), 8.0 (s, 1H), 7.5 (dd, J = 7.7, 1.5 Hz, 1H), 7.4 (ddd, J = 8.7, Hz, 1H), 7.23(ddd, J = 8.6, 6.8, 3.0 Hz, 1H), 2.4 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 167.4, 158.8, 149.90, 129.6, 127.83, 125.21, 123.99, 123.3, 119.86, 116.37, 77.36, 77.05, 76.73, 23.4.

9) N-(6-methyl-2-oxo-2H-chromen-3-yl)acetamide (5i):

Gummy solid, Mass : Cal. 217.1, Observe. 217.2

¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1H), 8.0 (s, 1H), 7.52 (dd, J = 7.7, 1.5 Hz, 1H), 7.45 (ddd, J = 8.7, Hz, 1H), 7.23 (ddd, J = 8.6, 6.8, 3.0 Hz, 1H), 2.25 (s, 3H), 2.13 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 167.43, 158.8, 149.90, 129.68, 127.83, 125.21, 123.99, 123.31, 119.8, 116.38, 77.36, 77.05, 76.73, 40.3, 23.4.

10) N-acetyl-N-(6,7-dimethoxy-2-oxo-2H-chromen-3-yl)acetamide (5j):

White solid, Mp 182- 184°C, Mass : Cal. 217.1, Observe. 217.2

¹H NMR (400 MHz, CDCl₃) δ 8.41 (s, 1H), 7.17 (s, 1H), 6.66 (s, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 2.40 (s, 3H), 2.39 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 169.45, 167.91, 165.42, 152.37, 147.08, 145.85, 131.29, 123.66, 118.05, 113.12, 105.80, 77.39, 77.07, 76.75, 56.22, 21.03, 15.79

CONCLUSION:

In summary, the ecofriendly protocol was developed and applied for the synthesis of coumarin acetamide derivatives in water. Spectral data of coumarin acetamide derivatives are analysed These analogues are chemically tractable and hence provides ample opportunities for further modification to obtain potent anti-microbial agents. The isolated yield of the coumarin derivatives is excellent, so gram scale synthesis is possible. The scope for various salicyldehyde has shown and it can be extended further for their biological activity programme.

ACKNOWLEDGEMENT:

The authors are thankful to the respective managements and principals for their encouragement and support and supports during the work.

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Received on 10.03.2018 Modified on 11.04.2018

Asian J. Research Chem. 2018; 11(2):441-444.

DOI:10.5958/0974-4150.2018.00080.9