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(E)-6-Hydroxy-2-Oxo-2H-Chromen-7-Yl 3-(4-Hydroxy-3-Methoxyphenyl)acrylate

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08 May 2023

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09 May 2023

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Abstract
A conjugate compound 5, (E)-6-hydroxy-2-oxo-2H-chromen-7-yl 3-(4-hydroxy-3-methoxyphenyl)acrylate, of 6,7-hydroxycoumarin (esculetin) 3 and (E)-3-(4-hydroxy-3-methoxyphenyl)- acrylic acid (ferulic acid) 1 was prepared in 61% yield by the esterification reaction of a protected ferulic acid 2a with esculetin 3 in the presence of triethylamine in dichloromethane for 3 h, followed by deprotection using 3M HCl. The structure of compound 5 was confirmed by 1H, 13C NMR spectroscopy, mass-spectrometry and elemental analysis.
Keywords: 
Subject: Chemistry and Materials Science  -   Organic Chemistry

1. Introduction

Many coumarin-based derivatives are important structural scaffolds for the synthesis of potential biologically active compounds with different pharmacological applications [1]. They continue to be designed and synthesized [2] because of remarkable biological properties, including anticancer [3], anticonvulsant [4] antimicrobial [5], and antiviral [6] activities. Coumarins having intramolecular charge transfer character have also been investigated for fluorescence sensors [7,8]. Among them, 6,7-dihydroxycoumarin (esculetin) 3 displayed various biological activities such as anticancer [9,10], free radical scavenging [11], anti-inflammatory [12], anti-arthritic [13], and hepatoprotective [14]. And, (E)-3-(4-hydroxy-3-methoxyphenyl)acrylic acid (ferulic acid) 1 is widely present in seeds, nuts, leaves, and fruits. It has many pharmacological effects including antioxidant [15], anticancer [16], neuroprotective [17], and anti-metabolic syndrome [18]. However, there have been no reports on the synthesis of hybrid compounds made of 1 and 3. We report herein the synthesis of a new hybrid compound 5 of potential biological interest, (E)-6-hydroxy-2-oxo-2H-chromen-7-yl 3-(4-hydroxy-3-methoxyphenyl)acrylate.

2. Results

The new compound 5 was prepared as shown in Scheme 1. The hydroxy group of starting material 1 was first protected with acetic anhydride and pyridine according to the previously reported procedure [19] to give 2, (E)-3-(4-acetoxy-3-methoxyphenyl)acrylic acid. After 2 was activated with oxalyl chloride including DMF, the resultant 2a was allowed to react with 3 in dichloromethane at room temperature for 3 h in the presence of triethylamine to afford an esterified product 4, (E)-6-hydroxy-2-oxo-2H-chromen-7-yl 3-(4-acetoxy-3-methoxyphenyl)acrylate in 72% yield. The deprotection of acetyl group of 4 was achieved by use of 3M HCl solution in acetone at room temperature for 24 h to give a conjugate compound 5 in 85% yield.
The 1H NMR spectrum of 4 showed the expected pattern with two sharp singlets at δ 3.82 and 2.24 ppm attributed to methoxy and acetyl protons, respectively, and two doublets at δ 7.81 and 6.93 ppm (J = 16.0 Hz) due to trans vinyl protons in ferulic acid moiety. It also showed two doublets at δ 7.89 and 6.24 ppm (J = 9.5 Hz) due to cis vinyl protons of esculetin moiety, and the aromatic protons were shown as two singlets at δ 7.48, 6.86 and three doublets at δ 7.59 (d, J = 1.7 Hz), 7.36 (dd, J = 8.2, 1.7 Hz) and 7.13 ppm (d, J = 8.2 Hz). A sharp singlet at δ 10.93 of low field was shown for a hydroxy proton of esculetin moiety (Supplementary Materials). In the 13C NMR spectrum, compound 4 displayed three peaks δ 168.8, 165.0, 160.7 ppm for the two carbonyl and newly formed an ester carbon, including sixteen peaks for aromatic and vinyl carbons at δ 153.6, 153.2, 151.7, 146.4, 144.5, 141.9, 136.1, 133.3, 123.8, 122.5 (2C), 117.7, 112.9, 112.8, 111.4, 104.0 ppm, and two peaks for two methyl carbons at δ 56.6, 20.9 ppm. The mass spectrum showed m/z = 395 (M+-1) corresponding the molecular formula, C21H16O8, and elemental analysis also provided satisfactory results.
Compound 5 was confirmed by the absence of signals such as acetyl protons at δ 2.24 ppm in the 1H NMR, and a carbonyl carbon at δ 168.8 ppm in the 13C NMR spectrum, compared to the spectra of compound 4. Two singlets due to two hydroxy groups were shown at δ 10.88 and 9.64 ppm in the 1H NMR spectrum. The mass spectrum provided m/z = 353 (M+-1) corresponding the molecular formula, C19H14O7, and elemental analysis gave satisfactory results. The preliminary biological test of DPPH free radical scavenging activity [20,21] for 4 and 5 as antioxidant exhibited SC50 values of 40.4 and 2.36 μg/mL, respectively, compared to 1 (2.58 μg/mL) and 3 (0.82 μg/mL) with ascorbic acid (1.65 μg/mL) as positive control.
In conclusion, a new compound 5 of biological importance was effectively prepared in 61% yield by the esterification reaction of a protected ferulic acid 2a with esculetin 3 in the presence of triethylamine in dichloromethane for 3 h, followed by deprotection of acetyl group using 3M HCl in acetone.

3. Materials and Methods

3.1. General Information

Ferulic acid, esculetin, oxalic chloride, acetic anhydride, triethylamine, 1,1-diphenyl-2-picryhydrazyl (DPPH), ascorbic acid, and the dry organic solvents were purchased from Sigma-Aldrich (St. Louis, MO, USA) and TCI (Tokyo, Japan). Melting point was determined on Kofler apparatus. Thin-layer chromatography (TLC) was used to monitor reactions and performed using aluminum sheets precoated with silica gel 60 (HF254, Merck, Waltham, MA, USA), and visualized with UV radiation (Fisher Scientific, Waltham, MA, USA). The 1H, and 13C NMR spectrum were recorded in deuterated DMSO with TMS as the standard on a JEOL JNM-ECZ600R 500 FT-NMR (Tokyo, Japan). The mass spectrum was obtained with AGILENT1100 LCMS (Santa Clara, CA, USA) under electrospray ionization (ESI) conditions. Absorbance for the compounds was measured using SpectraMax Paradigm multi-mode microplate reader (San Jose, CA, USA).

3.2. Synthesis of (E)-6-Hydroxy-2-Oxo-2H-Chromen-7-yl 3-(4-Acetoxy-3-Methoxyphenyl)Acrylate (4)

To a stirred solution of 2 (1.0 g, 4.23 mmol) in dry dichloromethane (20 mL) containing few drops of DMF was added oxalyl chloride (1.07 g, 8.45 mmol), and stirred at room temperature for 2 h. After evaporation of the solution, the mixture was diluted with dichloromethane (20 mL), and added 3 (0.75 g, 4.23 mmol) and triethylamine (1.19 mL, 8.50 mmol). The resulting solution was stirred at room temperature for 3 h with monitoring. When the reaction was completed, the mixture was washed with 0.1M HCl solution (10 mL), water (10 mL), and extracted with dichloromethane (2 x 15 mL). The organic extracts were dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by column chromatography (eluent: ethyl acetate/n-hexane = 1/1, v/v) and recrystallized from ethanol to give white solid of 4 in 72% yield (1.20 g). Mp 212–213 °C; TLC Rf = 0.48 (dichloromethane/MeOH = 90/10). 1H NMR (500 MHz, DMSO-d6) (ppm) δ 10.93 (s, 1H), 7.89 (d, J = 9.5 Hz, 1H), 7.81 (d, J = 16.0 Hz, 1H), 7.59 (d, J = 1.7 Hz, 1H), 7.48 (s, 1H), 7.36 (dd, J = 8.2, 1.7 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 16.0 Hz, 1H), 6.86 (s, 1H), 6.24 (d, J = 9.5 Hz, 1H), 3.81 (s, 3H), 2.24 (s, 3H). 13C NMR (126 MHz, DMSO-d6) (ppm) δ 168.8, 165.0, 160.7, 153.6, 153.2, 151.7, 146.4, 144.5, 141.9, 136.1, 133.3, 123.8, 122.5 (2C), 116.1, 113.6, 112.8, 112.1, 111.3, 104.0, 56.3. MS (ESI) m/z = 395 (M+-1). Anal. calcd. for C21H16O8, %: C, 63.64; H, 4.07. Found, %: C, 63.88; H, 4.20.

3.3. Synthesis of (E)-6-Hydroxy-2-Oxo-2H-Chromen-7-yl 3-(4-Hydroxy-3-Methoxyphenyl)Acrylate (5)

A solution of 4 (1.0 g, 2.82 mmol) in acetone (15 mL) containing 3M HCl (1 mL) was heated at 60 °C with stirring for 24 h. After reaction was completed, the mixture was added to saturated aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (2 x 15 mL). The organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: dichloromethane/MeOH = 95/5, v/v) and recrystallized from ethanol to give white solid of 5 in 85% yield (0.84 g). Mp 232–233 °C; TLC Rf = 0.38 (dichloromethane/MeOH = 90/10). 1H NMR (500 MHz, DMSO-d6) (ppm) δ 10.88 (s, 1H), 9.64 (s, 1H), 7.88 (d, J = 9.5 Hz, 1H), 7.71 (d, J = 15.9 Hz, 1H), 7.45 (s, 1H), 7.39 (d, J = 1.6 Hz, 1H), 7.18 (dd, J = 8.2, 1.7 Hz, 1H), 6.85 (s, 1H), 6.79 (d, J = 8.2 Hz, 1H), 6.69 (d, J = 15.9 Hz, 1H), 6.24 (d, J = 9.5 Hz, 1H), 3.80 (s, 3H). 13C NMR (126 MHz, DMSO-d6) (ppm) δ 165.3, 160.7, 153.7, 153.1, 150.3, 148.5, 147.6, 144.5, 136.3, 125.9, 124.1, 122.5, 116.1, 113.6, 112.8, 112.1, 111.3, 104.0, 56.6. MS (ESI) m/z = 353 (M+-1). Anal. calcd. for C19H14O7, %: C, 64.41; H, 3.98. Found, %: C, 64.30; H, 4.09. 3.4. DPPH radical scavenging assay for the compounds.
Each sample was dissolved in methanol at various concentrations ranging from 0 to 100 μg/mL. Then, 50 μL of the sample solution was mixed with 450 μL of a DPPH solution (400 μM) and incubated for 30 minutes at 4 °C. The absorbance was measured at 517 nm using a microplate reader (SpectraMax Paradigm). The SC50, which is the minimum concentration (μg/mL) required to scavenge 50% of the DPPH radicals, was calculated based on the measured absorbance. Ascorbic acid was used as a positive control.

Supplementary Materials

The following supporting information can be downloaded at the website of this paper posted on Preprints.org. Figure S1-S6: 1H NMR, 13C NMR, and Mass spectra of compound 4 and 5.

Author Contributions

Conceptualization, methodology, investigation, writing—original draft preparation, writing—review and editing, Y.-H.S.

Funding

This research received no external funding.

Data Availability Statement

Not applicable.

Acknowledgments

This work was supported by Mokwon University.

Conflicts of Interest

The author declares no conflict of interest.

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Preprints 73018 sch001
Scheme 1. Synthesis of the target compound 5.
Scheme 1. Synthesis of the target compound 5.
Preprints 73018 sch001
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Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
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