Green Synthesis of Chalcone Derivatives Using Chalcones as Precursor

Abstract

Recently, the use of green methodologies like sonication, use of ionic liquids, etc. attracted the attention of researchers in the field of organic synthesis as they have advantages such as mild reaction conditions, environmentally benign procedures, etc. Herein, this chapter highlights some recyclable ionic liquids (ILs) catalyzed ring closure reactions of chalcones to obtain several heterocyclic rings viz.; pyrazoles, pyrans, pyrimidines under ultrasonification. These reactions have very important features i.e., short routine, high yields, being environmentally friendly, high functional group tolerance, formation of a single product, high atom economy, high yielding, no need for column purification, etc. The various synthesized compounds were prepared in optimized reaction conditions in good to efficient yields. Analytical and spectral (FTIR, 1H, and 13C NMR) techniques were employed for the structural elucidation of the synthesized compounds. The ionic liquids used in the synthesis are recycled and reused several times.

1. Introduction

In recent years, the emphasis of science and technology has shifted more toward environmental benign and sustainable resources and progress. Green Chemistry is paramount concept in chemistry for sustainability, which is the implementation of a set of principles that minimize or get rid of the utilization or generation of hazardous substances in the design, manufacture, and applications of chemical products [1]. Presently, Sonochemistry is a simplistic pathway for a huge variety of syntheses in organic chemistry. Hence, significant features of the ultrasound approach compared with traditional methods are in higher yields, milder conditions, lesser reaction times, improved reaction rates, formation of purer products, easier manipulation and a role in waste minimization and energy protection [2, 3, 4, 5].

Multicomponent reactions [6] leading to facinating heterocyclic scaffolds must appear as Potent tools for delivering the molecular diversity required in combinatorial approaches for the synthesis of bioactive compounds and producing varied chemical libraries of drug-like molecules for biological screening [7, 8]. Chalcones, or 1,3-diphenyl-2-propen-1-ones, are commonly occurring heterocyclic ring systems and are important structural motifs found in many natural products and pharmaceuticals. It is also known as benzalacetophenone and benzylidene acetophenone. Chalcones are one of the most important classes of flavonoids [9, 10]. Further ring closure reactions of Chalcones can be used to obtain various heterocyclic rings viz.; Pyrazoles, Pyrans, Cyanopyridines, isoxazoles and pyrimidines having different hetero-cyclic ring systems and multiple derivatives can be synthesized using chalcones [11, 12, 13, 14, 15].

The increased environmental concerns needed the replacement of present methods with new more sustainable processes which used the ionic liquids in place of organic catalysts and solvents [16, 17, 18, 19, 20, 21, 22, 23, 24, 25]. Ionic Liquids (ILs), as a class of molten salts, are composed entirely of ions and their melting point is around or below 100°C [26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36]. Due to short reaction times, mild reaction conditions, better yields, easy recyclability thermally stable, non-flammable character with negligible vapor pressure, adjustable miscibility with organic substrates and tunable solvating ability ionic liquids (ILs) have attracted the attention of organic chemists [37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49]. Furthermore, unique physiochemical properties that make them potential candidates for many applications in pharmaceuticals, industry and academia [50, 51, 52].

There are several varieties of ionic liquids being studied, out of them a few Simple functionalized ILs have created unparalleled fascination as they display some benefits for certain base-catalyzed processes, like easy recycling and better catalytic performance [53]. The environmentally benign basic ionic liquids are used as reaction media as well as catalysts in the development of multicomponent reactions (MCRs). Among all such basic ionic ILs [DBU][OAc] has shown the desired results. Some of the key benefits that can be highlighted for utilization of this IL as catalyst are, the desired product obtained without any further purification and the recyclability of the catalyst was found to be up to 5 cycles. The investigation of alternatives with the help of ionic liquids to conventional organic solvents is a developing research area due to increased environmental concerns.

Herein, we are especially interested in developing the potential use of efficient, simple methodology for the ring closure reactions of chalcones using [DBU][OAc] as ionic liquids as a solvent and catalyst. Chalcones can be used to obtain various heterocyclic rings through ring closure reactions (Figure 1).

Figure 1.

General scheme of ring closure reactions of chalcones.

2. Experimental section

2.1 Materials and methods

Melting points were recorded in open glass capillary tube using Gallenkamp melting point apparatus and are uncorrected. Checked by Thin layer chromatography (TLC) was applied to check the purity of synthesized compounds and Spots were visualized by irradiation with UV lights (254 nm) or by staining with iodine vapors. The Fourier-transform infrared (FT-IR) spectra were recorded on SHIMADZU 8400S FT-IR spectrophotometer and wave number is given in cm⁻¹. The ¹H NMR spectra and ¹³C NMR (by broad band proton decoupling technique) were recorded on JEOL AL spectrometer in CDCl₃/DMSO-d₆ solvents at 400 and 100 MHz and chemical shift were measured in δ ppm relative to TMS as an internal standard. The Mass (HRMS) spectra were recorded on JEOL SX 102/DA-600 using Argon/Xenon gas. The elemental analysis (C, H and N) were performed using vario-III analyzer at CDRI Lucknow.

2.2 General procedure for preparation of DBU based ionic liquid

According to the reported literature [DBUH][OAc] ILs [54] and [DBUH][Cl] ILs [55] were synthesized by the reaction of 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (DBU) and acetic acid or hydrochloric acid, respectively.

2.3 General procedure for preparation of chalcones (3a-c)

Chalcones were synthesized according to the reported procedure with minor modification (Figure 2), the synthesized products were characterized by ¹H NMR, and physical data and compared with those reported in literature [54].

Figure 2.

General procedure of synthesis of chalcones (3a-c).

2.4 Model reaction for preparation of pyrazole derivative (4a)

Chalcone derivative (1 mmol) and methylhydrazine (1 mmol) were ultrasonicated catalyzed by [DBUH][OAc] (5 ml) at 50°C for about 4 h (Figure 3). The crude product was refrigerated overnight. The precipitate formed was filtered off and crystallized from ethanol yielding yellow crystals of the product (4a).

Figure 3.

Model reaction for preparation of pyrazole derivative (4a).

2.4.1 Spectroscopic data of (4a)

¹H NMR (400 MHz, DMSO-d₆) δ 8.81, 7.94, 7.59, 7.47, 7.44, 7.38, 3.96; ¹³C NMR (100.15 MHz, DMSO-d₆) δ 145.51, 133.32, 131.99, 130.37, 129.66, 128.69, 128.34, 126.78, 125.67, 123.12, 122.13, 40.57; HRMS; m/z 312.04 (M+); C₁₆H₁₃BrN₂: calcd. C, 61.36; H, 4.18; N, 8.94; found C, 61.34; H, 4.20; N, 8.97.

2.5 Model reaction for preparation of pyran derivative (5a)

Chalcone derivative (1 mmol) mixed with α,β-diketone (1 mmol) was ultrasonicated in [DBUH][OAc] (5 mL) for about 45 minutes. The mixture was heated to 60°C for 2 h to complete the reaction which was monitored by TLC. The organic layer was extracted with ethyl acetate, washed with water and then dried over Na₂SO₄ which was followed by filtration and concentration. The crude was recrystallized from ethyl acetate and hexane mixture to give pure product (5a). The catalyst remained in the aqueous phase was reused in other reactions (Figure 4).

Figure 4.

Model reaction for preparation of pyran derivative (5a).

2.5.1 Spectroscopic data of (5a)

¹H NMR (400 MHz, DMSO-d₆) δ 7.45, 7.32, 7.28, 7.25, 7.01, 5.27, 3.60, 2.28, 2.21, 2.12, 2.05; ¹³C NMR (100.15 MHz, DMSO-d₆) δ 195.02, 164.92, 142.45, 138.87, 131.92, 129.14, 128.97, 128.27, 128.12, 122.84, 107.13, 76.87, 35.62, 35.14, 27.61, 16.76; HRMS; m/z 370.01 (M+); C₂₀H₁₉BrO₂: calcd. C, 64.72; H, 5.17; found C, 64.75; H, 5.21.

2.6 Model reaction for preparation of cyanopyridine derivative (6a)

A mixture of chalcone derivative (2 mmol) with malononitrile (2 mmol) in 5 mL of [DBUH][OAc] was ultrasonicated at atmospheric pressure at 65°C for 3 h (Figure 5). After completion of the reaction, the mixture was cooled to room temperature and the organic layer was concentrated. The pure product was obtained by column chromatography (n-hexane:ethyl acetate = 80:20) to afford the preferred product (6a).

Figure 5.

Model reaction for preparation of cyanopyridine derivative (6a).

2.6.1 Spectroscopic data of (6a)

¹H NMR (400 MHz, DMSO-d₆) δ 9.21, 8.40, 7.95, 7.62, 7.51, 7.44, 7.46; ¹³C NMR (100.15 MHz, DMSO-d₆) δ 160.21, 152.79, 151.01, 138.51, 138.45, 131.34, 130.03, 129.67, 128.99, 127.91, 121.91, 120.71, 117.22, 110.19; HRMS; m/z 334.06 (M+); C₁₈H₁₁BrN₂: calcd. C, 64.52; H, 3.35; N, 8.37; found C, 64.49; H, 3.33; N, 8.36.

2.7 Model reaction for preparation of isoxazole derivative (7a)

Chalcone derivative (1 mmol) was ultrasonicated with hydroxylamine hydrochloride (1 mmol) in catalytic influence of [DBUH][OAc] ILs (5 mL) at 70°C for 1 h (Figure 6). The formation of product was monitored by TLC. Isoxazole derivative was obtained by keeping the reaction mixture on ice bath, then the desired product was isolated, washed with water, and dried (7a).

Figure 6.

Model reaction for preparation of isoxazole derivative (7a).

2.7.1 Spectroscopic data of (7a)

¹H NMR (400 MHz, DMSO-d₆) δ 8.66, 7.69, 7.57, 7.50, 7.41, 7.32; ¹³C NMR (100.15 MHz, DMSO-d₆) δ 170.26, 154.95, 131.82, 130.67, 128.61, 128.30, 128.07, 127.55, 126.73, 125.41, 116.74; HRMS; m/z 299.04 (M+); C₁₅H₁₀BrNO: calcd. C, 60.01; H, 3.37; N, 4.69; found C, 60.03; H, 3.39; N, 4.71.

2.8 Model reaction for preparation of pyrimidine derivative (8a)

To the mixture of chalcone derivative (1 mmol), guanidine hydrochloride (2 mmol) was added with [DBUH][OAc] ILs was heated under ultrasonication for 2 h at 55°C. The completion of the reaction was checked by TLC (Figure 7). The reaction mixture poured into ice water and formed product was filtered and recrystallized from ethanol (8a).

Figure 7.

Model reaction for preparation of pyrimidine derivative (8a).

2.8.1 Spectroscopic data of (8a)

¹H NMR (400 MHz, DMSO) δ 7.77, 7.64, 7.47, 7.41, 7.15, 2.29; ¹³C NMR (100.15 MHz, DMSO-d₆) δ 160.02, 158.70, 138.09, 136.17, 132.01, 131.05, 130.28, 129.20, 128.35, 125.47, 112.89; HRMS; m/z 325.05 (M+); C₁₆H₁₂BrN₃: calcd. C, 58.93; H, 3.72; N, 12.90; found C, 58.97; H, 3.70; N, 12.91 (see Figure 8).

Figure 8.

General representation of preparation of chalcone derivatives (4-8a-c).

3. Results and discussion

In this chapter, the ring closure reaction of chalcone derivatives in the presence of basic ionic liquid [DBUH]OAc to afford the several derivatives like pyrazoles, pyrans, pyrimidines, isoxazoles, and cyanopyridines. Different catalytic systems were used to optimize the reaction conditions on the set of model reactions.

3.1 Optimization of reaction conditions

The reaction conditions were optimized on the respective model reactions, further these optimized reaction conditions were used to produce corresponding derivatives of chalcones (Table 1).

We have carried out the synthesis of a number of chalcone derivatives (4-8a,b,c) under different reaction conditions. The optimized conditions for all the ring closure reactions of chalcones involved use of [DBUH]OAc ILs as catalyst under sonication for appropriate time at adequate temperature (Table 2, Entry 6).

Table 1.

% yield of desired products (4-8a,b,c).

3.2 Reusability of ionic liquids

The catalytic reusability of ILs was observed during optimized reaction conditions. The ILs were easily recovered as filtration after the completion of reaction. The recovered ILs were used four times without remarkable loss in activity but after that there is sudden decrease (Figure 9) in yield of products.

Figure 9.

Reusability and recyclability of [DBUH]OAc ILs.

S. No.	Catalyst / Solvent	Reaction Condition	Pyrazole Derivative (4a)		Pyran Derivative (5a)		Cyanopyridine Derivative (6a)		Isoxazole Derivative (7a)		Pyrimidine Derivative (8a)
			Temp; (°C)	% Yield	Temp; (°C)	% Yield	Temp; (°C)	% Yield	Temp; (°C)	% Yield	Temp; (°C)	% Yield
1.	No catalyst / DCM	Reflux	120	<5	120	<5	120	<5	120	<5	120	<5
2.	NaOH / DCM	Sonication	100	>15	100	>15	100	>15	100	>15	100	>15
3.	[MIM]BF4 IL	Sonication	100	40	100	35	100	42	100	45	100	38
4.	[MIM]OH IL	Sonication	90	48	90	42	90	51	90	55	90	44
5.	[DBUH]Cl IL	Sonication	90	62	90	65	90	68	90	62	90	60
6.	[DBUH]OAc IL	Sonication	50	97	60	95	65	93	70	94	55	96

Table 2.

Optimization of reaction conditions.

4. Conclusion

In Summary, we developed a simple and efficient catalytic system that can effectively promote the conversion of chalcones into different derivatives viz.; Pyrazoles, Pyrans, Cyanopyridines, isoxazoles and pyrimidines via [DBU][OAc] IL catalyzed ring closure reactions under mild conditions. A series of functional ILs was screened and [DBU][OAc] was determined as the optimal catalyst. This mild and environmental friendly synthetic methodology permitted us to synthesize products in good to excellent yields. There are many merits of the used protocol like, low cost of green catalyst, operational simplicity, obtaining products in high yield, and the catalyst can be reused without any significant loss of catalytic property up to five catalytic cycles.