A Green Chemistry Approach towards Synthesis of Bis-coumarins Catalyzed by Different Biocatalysts such as Dragon Fruit Juice, Kiwi Fruit Juice, and Buttermilk Separately by Grind Stone Technique：A Comparative Study

Y. I. Shaikh,^1,* V. S. Shaikh,¹ G. M. Nazeruddin,¹ Zamir Shekh,² G. S. Gugale,³ N. R. Prasad⁴ and Vijay A. Kadnor⁵

¹ Dept. of Chemistry, Abeda Inamdar Senior College, S.P.P.U, Pune, Maharashtra, India.

² Dept. of Chemistry, Shri Shivaji College, Akola, Maharashtra, India.

³ Haribhai V. Desai College, S.P.P.U, Pune, Maharashtra, India.

⁴ School of Nano Science and Technology, Shivaji University, Kolhapur, Maharashtra, India 416004.

⁵ Department of Chemistry, Arts Commerce and Science College Satral. Rahuri, Ahmednagar. Maharashtra

*Email: sheray2k@gmail.com (Y. I. Shaikh)

Abstract

We would like to report the synthesis of derivatives of bis-coumarin. This was accomplished by grinding 20 mmol of 4-hydroxy coumarin with 10 mmol of various aromatic aldehydes in the presence of various biocatalysts such as dragon fruit juice (Hylocereus undatus, the white-fleshed Pitahaya), kiwi fruit juice (Actinidia deliciosa) and buttermilk in aqueous medium for 10 to 15 minutes at ambient conditions. The crude product was obtained by filtration and recrystallized by ethanol. This protocol is a greener approach for organic transformations, thus facilitating the efficient synthesis of bioactive compounds in an environmentally benign way with shorter reaction time, mild reaction conditions, nonhazardous easy workup, and an excellent product yield. This comparative study reveals that rather than fruit juice or buttermilk, the acidic nature of an aqueous medium plays a dominating role in speeding up the reaction. Further, it is also observed that there is not much effect on the yields of the product by using different biocatalysts.

Table of Contents

Keywords: Green chemistry; Dragon fruit (Hylocereus undatus); Kiwi fruit (Actinidia deliciosa); Buttermilk; Grinding; Bis-coumarin.

1. Introduction

The concept of “Green Chemistry”^[1] has been widely adopted to meet the fundamental scientific challenges of protecting human health and the environment while simultaneously achieving commercial viability. One of the thrust areas for achieving this target is to explore an aqueous reaction medium to accomplish the desired chemical transformation and eliminate the use of organic solvents.^[2] Multicomponent reactions (MCRs) can provide products with the diversity needed to discover new compounds using simple and nonhazardous process.^[3-5] Chemists have successfully adopted multicomponent reactions to synthesize an extensive library of biologically active molecules. The multicomponent reactions are among the essential protocols in organic synthesis and medicinal chemistry.^[6] These unique characteristics of the multicomponent reaction have attracted the attention of organic chemists.

The role of naturally available fruit juice in organic synthesis has attracted the interest of chemists, particularly from the view of green chemistry. Several organic reactions using natural catalysts such as clay,^[7-8] natural phosphates,^[9-11] animal bone,^[12] and various fruit juices are reported in the literature. Due to the acidic nature of aqueous fruit juices like lemon,^[13-18] Ananas comosus (pineapple),^[19-20] Cocos nucifera (Coconut),^[21] Acacia concinna,^[22] Sapindus trifolistus,^[23] and Tamarindus indica^[24] fruit are a suitable replacement for various homogeneous acid catalysts. In recent years, research in organic chemistry is mainly focused on developing methods which are greener and eco-friendly to replace toxic and expensive catalysts or hazardous solvents like benzene, toluene, and methanol, which are commonly used in organic synthesis. Nowadays, many organic transformations have been carried out in water.^[25-27] Water is a unique solvent because it is readily available, inexpensive, non-toxic, safer, and environmentally benign. The use of water as a reaction medium is inexpensive and environmentally benign and provides utterly different reactivity.^[28] The applications of an aqueous extract of different fruit juices have witnessed rapid development. This growing interest in fruit juice is mainly because they are biocatalysts, environmentally benign, and cost-effective. In the present work, we have used a simple, efficient, and eco-friendly approach to synthesize bis-coumarin derivatives. Coumarin derivatives have a wide range of therapeutic applications such as photo-chemotherapy, anti-tumor, anti-HIV (Human Immuno-deficiency Virus) therapy, central nervous systems stimulant, antibacterials, anti-inflammatory, anti-coagulants, and dyes.^[29-37] The synthesis of bis-coumarin was accomplished by grinding the aromatic aldehyde and 4-hydroxy coumarin with kiwi/dragon fruit juice and buttermilk as a natural catalyst separately. The reaction is depicted in Scheme I.

Materials and methods

All melting points were measured in open capillary and are uncorrected. IR spectra were recorded using the JASCO FT-IR-4100 instrument. ¹H NMR was recorded on the Bruker MSL-300 instrument using CDCl₃ (deuterated chloroform) as the solvent and TMS (tetramethylsilane) as an internal standard. All reagents were purchased from Merck and Loba and were used without further purification.

2. Experimental

2.1 Preparation of aqueous extract of kiwi/dragon fruit juice and buttermilk

The kiwi/dragon fruits were purchased from the local market. After cutting them into small pieces, 10 g of each fruit was crushed in 50 mL water using a grinder, and was centrifuged using a microcentrifuge (REMI RM-12C). The transparent portion of the aqueous extract of the fruit was used as the catalyst for the reaction separately. The buttermilk was purchased from the local market and was used as the catalyst.

2.2 A general method for the preparation of bis-coumarin derivatives

The mixture of 10 mmol of an aromatic aldehyde, 20 mmol of 4-hydroxy coumarin, 5 mL kiwi/dragon fruit juice, and 2.5 mL buttermilk was grinded mortar pestle separately at the ambient conditions monitoring by thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was poured over about 100 g of crushed ice. The crude solid product was obtained by filtration and purified by crystallization with ethanol. Even though the catalysts were different, the products obtained from the same reaction were mixed, and their identity was confirmed by melting points and spectral data such as IR and ¹HNMR.

3. Results and discussion

The synthesis of bis-coumarin was accomplished by reaction between 4-hydroxy coumarin and substituted benzaldehyde using natural biocatalyst, an efficient and environmentally friendly catalyst. The probable mechanism of the reaction is depicted in Scheme 2. It is observed that there is no remarkable difference on the yield of the product by using different biocatalysts. The results are presented in Table 1. Further, the comparative study reveals that rather than fruit juices or buttermilk, the acidic nature of an aqueous medium plays a dominating role in accelerating the reaction. The reaction was accomplished by the green chemistry approach, shorter reaction time, mild reaction conditions, and easy workup procedure, along with excellent yield. Compared to other catalysts reported in the literature,^[38-39] this is a mild and highly selective transformation and synthesis in a facile and environmentally benign manner. Moreover, the fruit juice/buttermilk are inexpensive and readily available. Furthermore, this protocol is a general methodology because it accommodates comfortably with the electron-withdrawing and electron-donating groups in the substrate.

The reaction is initiated by protonation of an aldehyde followed by reaction of this protonated product with bis-coumarin, which lands up finally to yield the corresponding bis-coumarin.

Scheme 1. Synthesis of bis-coumarins (Fruit juices: dragon fruit, kiwi fruit) (Where R = Phenyl,4-nitro phenyl,4-hydroxy phenyl, 4- chlorophenyl,4-methoxy phenyl).

Scheme 2. A probable reaction mechanism of the synthesis.

Table 1. Data of bis-coumarin derivatives obtained by condensing kiwi/dragon fruit juice/buttermilk catalyzed synthesis of bis-coumarins obtained by condensing 4-hydroxy coumarin and an aromatic aldehyde with 2:1 ratio in aqueous medium at ambient conditions just by grinding.

Entry	R	Yield %			Mixed M.P. (observed) °C	M.P. (reported) °C
		Kiwi fruit	Dragon fruit	Buttermilk
3-a	H	80	80	85	226-227	228-230^[40]
3-b	4-NO2	85	87	90	232-233	232-234^[41]
3-c	4-OH	80	80	82	224-225	222-225^[40]
3-d	4-Cl	82	84	88	253-255	252-254^[42]
3-e	4-MeO	78	80	82	247-248	248-249^[43]

The structures of the products were confirmed by comparing their *mixed M.P. (melting point within a mixed range) of the product obtained from the reaction using different bio-catalyst and spectral data with authentic samples.

4. Spectral data

(3a) 3-((phenyl)(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)-4-hydroxy-2H-chromen-2-one

M.P.: 226-227 °C; IR (KBr) 3057, 1676, 1608, 1568, 1492, 1350, 759 cm^-1; ¹H NMR (CDCl₃): δ (ppm) = 11.53 (s, 1H, OH), 11.32 (s,1H, OH), 8.09-7.24 (m, 13H, 13×CH), 6.11 (s, 1H, CH);

(3b) 3-((4-nitro-phenyl)(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)-4-hydroxy-2H-chromen-2-one). M.P.: 232-233 °C; IR (KBr) 3080, 1660, 1616, 1600, 1566, 1518, 1450, 1348, 765 cm^-1; ¹H NMR (CDCl₃): δ (ppm) = 11.57(s, 1H, OH), 11.37(s, 1H, OH), 8.22-7.26 (m, 12H, 12×CH), 6.13 (s, 1H, CH);

(3c) 3-((4-hydroxy-phenyl)(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)-4-hydroxy-2H-chromen-2-one M.P.: 224-225 °C; IR (KBr) 3452, 3072, 1668, 1608, 1566, 1514, 1433, 1348, 1307, 763 cm^-1; ¹H NMR (CDCl₃): δ (ppm) = 11.49 (s, 1H, OH), 11.29 (s, 1H, OH), 8.05-6.77 (m, 12H, 12×CH), 6.04 (s, 1H, CH), 3.73 (q, 3H, OH);

(3d) 3-((4-chloro-phenyl)(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)-4-hydroxy-2H-chromen-2-one M.P.: 253-255 °C; IR (KBr) 3076, 1668, 1602, 1566, 1491, 1450, 1350, 1270, 1215, 767 cm^-1; ¹H NMR (CDCl₃): δ (ppm) =11.54 (s, 1H, OH), 11.32 (s, 1H, OH), 8.09-7.17 (m, 12H, 12×CH), 6.04 (s, 1H, CH);

(3e) 3-((4-methoxy-phenyl)(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)-4-hydroxy-2H-chromen-2-one M.P.: 247-248 °C; IR (KBr) 3070, 3001, 1668, 1604, 1466, 1510, 1452, 1352, 1309, 1259, 769 cm^-1; ¹H NMR (CDCl₃): δ (ppm) =11.5 (s, 1H, OH), 11.29 (s, 1H, OH), 8.05-6.87 (m, 12H, 12×CH), 6.05 (s, 1H, CH), 3.80 (s, 3H, CH₃O).

5. Conclusion

Coumarin derivatives have many therapeutic applications such as photo-chemotherapy, anti-tumor, anti-HIV therapy, central nervous systems stimulation, antibacterial, anti-inflammatory, anti-coagulation, and dyes. This broad spectrum of applications makes coumarin an essential constituent for pharmaceutical applications. Our green approach of one-pot synthesis of bis-coumarin is a convenient and facile approach for organic transformations, thus facilitating the efficient synthesis of bioactive compounds in an environmentally benign way with shorter reaction time, mild reaction conditions, and easy workup with an excellent yield of the product. However, a comparative study reveals that by using different bio-catalysts, there is not much difference in the yield of the product. Further, it is observed that rather than fruit juices or buttermilk, the acidic nature of the aqueous medium plays a dominating role in speeding up the reaction.

Conflict of interest

There are no conflicts to declare.

Supporting information

Not applicable.

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