One-pot synthesis of 4-aryl-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydrocoumarin derivatives in glycerol

ABSTRACT

Glycerol is a new green organic solvent. It not only acts as a phase transfer catalyst but also as a recyclable solvent by significantly enhancing the intramolecular cyclization. A series of 4-aryl-7,7 -dimethyl-5-oxo-3,4,5,6,7,8-hexahydrocoumarin derivatives were synthesized by one-pot multicomponent reaction of Meldrum’s acid with benzaldehyde, and cyclohexanedione in glycerol. Compared to classic methods, this method has the advantages of milder reaction conditions, good yields, easy processing and environmental benignity.

GRAPHICAL ABSTRACT

KEYWORDS:

• One-pot synthesis
• multicomponent reaction
• hexahydrocoumarin derivative
• glycerol

Introduction

As an organic reaction medium, the exploration of glycerol is still very limited, but because of its physical and chemical properties of low toxicity, non-corrosivity, non-combustibility, involatility and wide liquid range, glycerol rightly meets most requirements of ideal green solvents ( 1). It was shown that glycerol, as reaction medium, can not only increase the reaction rate, but also improve the reaction selectivity ( 2, 3). Because of glycerol’s lower solubility in nonpolar organic solvents and miscibility with water, the separation of the products can be realized by an organic solvent extraction method or water washing.

Coumarins are important compounds found in different plant species in nature ( 4). The specialty of coumarins in inhibiting cancer cells, strengthening immunity, inducing apoptosis and nonlinear optics has drawn extra attention in the fields of laser dye and anti-neoplasm ( 5–7). Experimental studies have found that the multi-biological activities of coumarins, such as anti-HIV, anti-tumor, anti-oxidation, anti-inflammatory and other pharmacological activities, are widely applied to anti-coagulation and lymphatic edema in clinic ( 8–11). In addition, coumarins are also widely used in spice, detergent and electroplating ( 12). Thus, the synthesis of various derivatives of coumarin is one of the hotspots in organic synthesis.

There have been a number of reports on the syntheses of 4-aryl-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydrocoumarin derivatives, in either organic solvent or water by catalysis ( 13–15), but these methods present the problem of pollution. Gao et al. ( 16) have have completed the synthesis in ethanol under the microwave-induced condition, but the workup was inconvenient to a certain extent. Du et al. ( 17) and Li et al. ( 18) have completed the synthesis in ionic liquid, but the cost and toxicity of ionic liquids have not been affirmed completely ( 19).

Recently, we have reported the synthesis of hexahydrocoumarin derivatives in PEG-400 media by one-pot reaction, and have got good results ( 20). In this communication, we report a simple and effective method for synthesis of a series of hexahydrocoumarin derivatives by one-pot multicomponent reaction of Meldrum’s acid (1) with benzaldehyde (2), 5,5-dimethyl-1,3-cyclohexanedione (3) in glycerol media. 4-aryl-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydrocoumarin derivatives (4) were obtained in high yields (Scheme 1).

Scheme 1. One-pot synthesis of coumarin derivatives.

4a:Ar=4-ClC₆H₄ 4b:Ar=4-FC₆H₄ 4c:Ar=4-CH₃C₆H₄ 4d:Ar=4-NO₂C₆H₄ 4e:Ar=4-CH₃OC₆H₄ 4f:Ar=2,4-Cl₂C₆H₃ 4g:Ar=3,4-(CH₃)₂C₆H₃ 4h:Ar =3-CH₃O-4-OHC₆H₃ 4i:Ar=4-(CH₃)₂NC₆H₄

Results and discussion

We tried the synthesis of 4a with the reactive substrates 4-chlorobenzaldehyde, Meldrum’s acid and 5,5-dimethyl-1,3-cyclohexanedione at different reaction conditions. It indicated that the yield of 4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydrocoumarin (4a) was affected by the time and temperature of reaction. We concluded that the desired 4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydrocoumarin (4a) can be obtained at 84% yield in glycerol at 100°C for 5 h.

In order to demonstrate the efficiency and applicability of the present method, we performed the reaction of a variety of substituted benzaldehydes in glycerol at 100°C (Table 1). As shown in Table 1, a series of 4-aryl-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydrocoumarin derivatives 4 bearing electron-withdrawing groups (such as halide) or electron-donating groups (such as hydroxyl group and alkoxyl group) were synthesized by reaction of Meldrum’s acid with benzaldehyde and 5,5-dimethyl-1,3-cyclohexanedione to give the corresponding products 4 in good yields under the same reaction conditions. Therefore, we concluded that the electronic nature of the substituents has no significant effect on this reaction.

Table 1. Synthesis of hexahydrocoumarin derivatives 4 in glycerol.

Product	Ar	Temperature (°C)	Time (h)	Yield (%)
4a	4-ClC6H4	100°C	5	84
4b	4-FC6H4	100°C	4	82
4c	4-CH3C6H4	100°C	5	80
4d	4-NO2C6H4	100°C	5	85
4e	4-CH3OC6H4	100°C	5	75
4f	2,4-Cl2C6H3	100°C	4	84
4g	3,4-(CH3)2C6H3	100°C	5	85
4h	3-CH3O-4-OHC6H3	100°C	4	76
4i	4-(CH3)2NC6H4	100°C	4	73

Reaction conditions: 1 (2.0 mmol), 2 (2.0 mmol), 3 (2.0 mmol), glycerol (2 g).

In summary, this work describes an efficient and environmentally friendly approach for the one-pot multicomponent synthesis of 4-aryl-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydrocoumarin derivatives in glycerol. The present method offers very attractive features such as excellent yields, simple reaction conditions, environmental benignity and easy work up. Moreover, glycerol acts not only as a catalyst but also as a clean solvent by significantly enhancing the intramolecular cyclization.

Experimental section

All reagents were obtained commercially and used without further purification. Meldrum’s acid 1 was synthesized according to the literature methods ( 21). Melting points were measured on an XT-4 electrothermal micromelting-point apparatus, and the thermometer was uncorrected. C, H and N analyses were obtained by using an Elemental Vario-EL automatic elemental analysis instrument. FT-IR spectra were recorded using KBr pellets on a Digilab Merlin FT-IR spectrophotometer. ¹H NMR spectra were recorded, on a Varian Mercury plus-400 instrument using dimethyl sulfoxide or CDCl₃ as solvents and tetramethyl silane as internal standard.

A mixture of Meldrum’s acid 1 (2 mmol), benzaldehyde 2 (2 mmol), 5,5-dimethyl-1,3-cyclohexanedione 3 (2 mmol) and in glycerol (2 g) was stirred 4–5 h at 100°C. The progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mixture was filtered and the precipitate was washed with water. The crude products were purified by recrystallization from ethanol (95%) to give products 4a–4i.

4-(4-Chlorophenyl)-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydro coumarin 4a.

Yield 4a (84%), m.p.161–163°C (lit ( 20) m.p.160–162°C); IR (KBr) ν: 1680, 1662, cm⁻¹; ¹H NMR (400 MHz, CDCl₃, δ): 1.09 (s, 3H, CH₃), 1.15 (s, 3H, CH₃), 2.32 (s, 2H, CH₂), 2.53 (s, 2H, COCH₂), 2.87–2.94 (m, 2H, OCOCH₂), 4.26 (t, J = 6.8 Hz, 1H, CH), 7.10 (d, J = 8.0 Hz, 2H, ArH), 7.39 (d, J = 8.0 Hz, 2H).

Anal. calcd for C₁₇H₁₇ClO₃: C 67.00, H 5.62; found C 67.21, H 5.58.

4-(4-Fluorophenyl)-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydro coumarin 4b.

Yield 82%, m.p.166–168°C (lit ( 22) m.p.167–168°C); IR (KBr): 1655, 1601, cm⁻¹; ¹H NMR (400 MHz, CDCl₃, δ): 1.09 (s, 3H, CH₃), 1.15 (s, 3H, CH₃), 2.32 (s, 2H, CH₂), 2153 (s, 2H, CH₂), 2188–2197 (m, 2H, CH₂), 4128–4129 (m, 1H, CH), 6195–7114 (m, 4H, ArH).

Anal. calcd for C₁₇H₁₇FO₃: C 70.82, H 5.94; found C 71.03, H 5.91.

4-(4-Benzyl)-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydro coumarin 4c.

Yield 80%, m.p.105–107°C (lit ( 20) m.p.107–109°C); IR (KBr) ν: 1789, 1680 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, δ): 1.06 (s, 3H, CH₃), 1.16 (s, 3H, CH₃), 2.27 (s, 2H, CH₂), 2.29 (s, 3H, CH₃), 2.51 (s, 2H, COCH₂), 2.83–2.93 (m, 2H, OCOCH₂), 4.20–4.24 (m, 1H, CH), 7.03 (d, J = 8.0 Hz, 2H, ArH), 7.07 (d, J = 8.0 Hz, ArH).

Anal. calcd for C₁₈H₂₀O₃: C 76.03, H 7.09; found C 75.81, H 7.02.

4-(4-Nitrophenyl)-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydro coumarin 4d.

Yield 85%, m.p.133–134°C (lit ( 20) m.p.132–134°C); IR (KBr) ν: 1789, 1655 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, δ): 1.08 (s, 3H, CH₃), 1.16 (s, 3H, CH₃), 2.32 (s, 2H, CH₂), 2.58 (s, 2H, COCH₂), 2.90–3.03 (m, 2H, OCOCH₂), 4.35–4.38 (m, 1H, CH), 7.30 (d, J = 8.0 Hz, 2H, ArH), 8.15 (d, J = 8.0 Hz, 2H, ArH).

Anal. calcd for C₁₇H₁₇NO₅: C 64.75, H 5.43, N 4.44; found C 64.63, H 5.48, N 4.41.

4-(4-Methoxyphenyl)-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydro coumarin 4e.

Yield 75%, m.p.130–131°C (lit (22) m.p. 128–130°C); IR (KBr) ν: 1771, 1650 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, δ):1.13 (s, 3H, CH₃), 1.17 (s, 3H, CH₃), 2.37 (s, 2H, CH₂), 2.56 (s, 2H, COCH₂), 2.89–2.93 (m, 2H, OCOCH₂),3.76 (s, 3H, OCH₃), 4.24–4.28 (m, 1H, CH), 6.69–7.05 (m, 4H, ArH).

Anal. calcd for C₁₈H₂₀O₄: C 71.98, H 6.71; found C 71.73, H 6.75.

4-(2,4-Dichlorophenyl) -7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydro coumarin 4f.

Yield 84%, m.p.172–174°C (lit ( 23) m.p.173–174°C); IR (KBr) ν: 1659, 1472, cm⁻¹; ¹H NMR (400 MHz, CDCl₃, δ): 1.18 (s, 6H, 2CH₃), 2.34 (s, 2H, CH₂), 2.60 (s,2H, CH₂), 2.91–2.93 (m, 2H, CH₂), 4.58–4.68 (m,1H,CH), 6.83–7.43 (m,3H, Ar H).

Anal. calcd for C₁₇H₁₆Cl₂O₃: C 60.19, H 4.75; found C 60.31, H 4.81.

4-(3,4-Dimethylphenyl)-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydro coumarin 4g.

Yield 85%, m.p.121–122°C (lit ( 17) m.p.124–126°C); IR (KBr) ν: 1770, 1659, cm⁻¹; ¹H NMR (400 MHz, CDCl₃, δ): 1.01 (s, 3H, CH₃),1.10 (s, 3H, CH₃), 1.12 (s, 3H, CH₃), 1.16 (s, 3H, CH₃), 2.32 (s, 2H, CH₂), 2.54 (s, 2H, CH₂), 2.90–2.92 (m, 2H, CH₂), 4.24 (m, 1H, CH), 6.85–7.05 (m, 3H, ArH).

Anal. calcd for C₁₉H₂₂O₃: C 76.48, H 7.43; found C 76.29, H 7.48.

4-(3-Methoxy-4-hydroxyphenyl)-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydro coumarin 4h.

Yield 76%, m.p.179–182°C (lit ( 20) m.p.178–180°C); IR (KBr) ν: 1786, 1652, cm⁻¹; ¹H NMR (400 MHz, CDCl₃, δ): 1.14 (s, 3H, CH₃), 1.19 (s, 3H, CH₃), 2.39 (s, 2H, CH₂), 2.54 (s, 2H, COCH₂), 2.90–2.94 (m, 2H, OCOCH₂), 3.87 (s, 3H, OCH₃), 4.22–4.27 (m, 1H, CH), 6.63–6.89 (m, 3H, ArH), 10.90 (s, 1H, OH).

Anal. calcd for C₁₈H₂₀O₅: C 68.34, H 6.37; found C 68.41, H 6.31.

4-(4-(Dimethylamino)phenyl)-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydro coumarin 4i.

Yield 73%, m.p.180–182°C (lit ( 20) m.p. 182–184°C); IR (KBr) ν: 1791, 1703 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, δ): 0.90 (s, 3H, CH₃), 1.15 (s, 3H, CH₃), 2.11 (s, 2H, CH₂), 2.40 (s, 2H, COCH₂), 2.67 (m, 2H, OCOCH₂), 2.89 (s, 6H, 2NCH₃), 4.10–4.35 (m, 1H, CH), 6.51–7.17 (m, 4H, ArH).

Anal. calcd for C₁₉H₂₃NO₃: C 72.82, H 7.40, N 4.47; found C 72.95, H 7.46, N 4.51.

Conclusions

In conclusion, a series of 4-aryl-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydrocoumarin derivatives were synthesized by three-component one-step reaction in glycerol. The dual roles of glycerol were reaction solvent and catalyst, and glycerol can be recycled.

By contrast, the traditional two-component method has the advantages of milder reaction conditions, good yields, easy processing and environmental benignity. Compared with the reaction in organic solvent or in water by noxious catalyzer (such as hexadecyl trimethyl ammonium bromide), glycerol is more environment-friendly. Compared to the reaction in ionic liquids, ionic liquids are expensive and their toxicity needs further confirmation. In contrast to the microwave-induced reaction in ethanol, their yields are not high enough and the work-up is inconvenient to a certain extent. In comparison with the one-pot reaction in PEG-400, this method, which makes the product separation more convenient and the reaction solvent easily accessible, could significantly shorten the reaction time and improve the yield. We wish to report a simple and green but effective synthesis of hexahydrocoumarin derivatives by using glycerol as reaction medium and catalyst.

Disclosure statement

No potential conflict of interest was reported by the authors.

Notes on contributors

Xue-Mei Wang is an associate prof. of organic chemistry, School of Mechanical and Electronical Engineering, Lanzhou University of Technology, People's Republic of China. She has published papers in green organic synthesis fields, focusing on organic chemistry and textile chemistry.

Xi-Cun Wang is a professor of organic chemistry, College of Chemistry and Chemical Engineering, Northwest Normal University, People's Republic of China. He has published papers in fine organic synthesis and green organic synthesis fields, focusing on fine organic synthesis chemistry, green chemistry and heterocyclic chemistry.

Chen-Fei Wang is a postgraduate of textile chemistry and dyeing and finishing engineering, School of Mechanical and Electronical Engineering, Lan Zhou University of Technology, People's Republic of China. He has published papers in modified starch fields.

Liang Yang is an associate prof. of textile chemistry and dyeing and finishing engineering, School of Mechanical and Electronical Engineering, Lan Zhou University of Technology, People's Republic of China. He has published papers in natural biological macromolecule and synthesized polymer fields, focusing on polymer-modified, composite prepare and controlled-release drug delivery.

Additional information

Funding

This work was supported by Science and Technology program of Gansu Province [1606RJZA096].