4-({4-[(2E)-3-(2,5-Dimethoxyphenyl)prop-2-enoyl]phenyl}amino)-4-oxobutanoic Acid

Abstract

A dimethoxy amide chalcone has been synthesized in a two-step reaction. First, an amine chalcone was synthesized by the reaction of 4′-aminoacetophenone and 2,5-dimethoxybenzaldehyde using 40% NaOH solution as a catalyst in ethanol, and then followed by amidation through the reaction of the formed chalcone and succinic anhydride. The structure of the target compound was established by FTIR, HR-MS, ¹H- and ¹³C-NMR, and 2D-NMR spectral analysis.

1. Introduction

Diaryl-α,β-unsaturated ketones are the biogenic precursor in flavonoid biosynthesis [1] and are known as chalcones. Due to their wide spectrum of pharmacological properties, such as antioxidant [2], antihepatotoxic [3], neuroprotective [4], antibacterial [5,6,7,8], inhibitor of topoisomerase I [9], antimalarial [10,11], and anticancer [12], chalcones attract many researchers to develop efficient synthetic methods and to gain various structural variations of chalcones unavailable in nature. In general, chalcones are synthesized by Claisen-Schmidt condensation.

Previously we have reported the antimicrobial activity of a series of methoxy amino chalcones [13,14]. In order to enhance their efficacy by increasing their solubility and slow release, we converted the basic amino chalcones into amide derivatives through a reaction with succinic anhydride. Herein we report a new amide methoxy chalcone prepared from a methoxy amino chalcone and succinic anhydride.

2. Results

The title compound was synthesized in a two-step reaction. The first step was the synthesis of a methoxy amino chalcone (1) employing the Claisen-Schmidt reaction, then followed by the amidation of (1) through the reaction of (1) with succinic anhydride in ethanol using pyridine as a catalyst, as shown in Scheme 1.

Firstly, the purity of the product was analyzed by determining its melting point and thin layer chromatography. The structure of the product was then characterized based on spectroscopic evidence and the results are displayed below. The product is assumed to exist in the E configuration, since the ¹H-NMR spectrum of the olefinic protons showed a coupling constant of 15.7 Hz indicative of the E configuration. The structure of the title compound and its HMBC correlations is displayed in Figure 1, whereas the chemical shifts and its HMBC correlations is tabulated in

Table 1. ¹H, ¹³C chemical shifts and HMBC correlations of the title compound.

Atom	Chemical Shift (ppm)	HMBC
1 C	153.16
1′ C	56.66
H3	3.80	1
2 C	113.53
H	6.99	1, 6
3 C	118.57
H	6.99	4, 5
4 C	153.77
4′ C	56.22
H3	3.76	4
5 C	112.93
H	7.51	7, 3, 1
6 C	124.08
7 C	138.06
H	7.97	9, 5, 1, 8
8 C	122.36
H	7.86	9, 7, 6
9 C	188.05
10 C	132.64
11 C	130.46
H	8.10	9, 12, 15, 13
12 C	118.73
H	7.73	14, 10, 13
13 C	144.19
14 C	118.73
H	7.73	12, 10, 13
15 C	130.46
H	8.10	9, 14, 11, 13
16 H	10.32	12, 14, 13, 17
17 C	171.35
18 C	29.13
H2	2.50	19, 17, 20
19 C	31.71
H2	2.58	18, 17, 20
20 C	174.33
21 H	12.15

. The complete spectra are attached in supplementary materials.

(E)-4-((3-(3-(2,5-Dimethoxyphenyl)acryloyl)phenyl)amino)-4-oxobutanoic acid (2): orange solid (266 mg; 75%), m.p. 188–190 °C, R_f = 0.61 (ethanol), HR-MS [M + H]⁺ calculated for C₂₁H₂₁NO₆ 384.1447, found 384.1446; IR (KBr, cm⁻¹) 3448 (br, -OH carboxylic), 3340 (str, -NH- amide), 1720 (str, C=O aliphatic carboxylic acid), 1697 (str, C=O amide), 1639 (C=O conjugated), 1593 (str, C=C conjugated), and 1261 (C_alkyl-O-C_aryl); ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm) 12.15 (s, 1H), 10.32 (s, 1H), 8.10 (d, J = 8.7 Hz, 2H), 7.97 (d, J = 15.7 Hz, 1H), 7.86 (d, J = 15.7 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 2.3 Hz, 1H), 7.08–6.92 (m, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 2.58 (t, J = 6.2 Hz, 2H), 2.50 (t, J = 6.0 Hz, 2H). ¹³C-NMR (101 MHz, DMSO-d₆) δ (ppm) 188.05, 174.33, 171.35, 153.77, 153.16, 144.19, 138.06, 132.64, 130.46, 124.08, 122.36, 118.73, 118.57, 113.53, 112.93, 56.66, 56.22, 31.71, 29.13.

The analysis of the correlation spectrum (2D NMR; HMBC) is tabulated in the Table 1 below.

3. Materials and Methods

3.1. General

All reagents and solvents (E.Merck (Darmstadt, Germany) or Sigma Aldrich (St. Louis, MO, USA)) were used without further purification. Reaction progress was monitored by TLC on silica gel GF₂₅₄ aluminum sheets (0.25 mm) using various developing system. Spots were detected under UV light (λ 254 nm). Melting point was measured by Thermo Scientific Fisher-Johns Melting Point Apparatus 220 VAC (Waltham, MA, USA) and uncorrected. FTIR spectrum was recorded in KBr pellet on FTIR spectrophotometer Shimadzu 84005 series (Kyoto, Japan). Mass spectrum was recorded on HR mass spectrometer Waters LCT Premier XE (Santa Clara, CA, USA). NMR spectrum (¹H-, ¹³C-NMR, and HMBC) was recorded using JEOL 400 ECA spectrometer (Tokyo, Japan) with DMSO-d₆ as solvent and internal standard.

3.2. Preparation of the Title Compound (2)

The amino methoxy chalcone (1) was synthesized according to the protocol as described previously [2]. The title compound was synthesized as followed: 1 mmol succinic anhydride was dissolved in 5 mL DCM, then three drops of pyridine was added. The mixture was stirred at 40 °C for 10 min. Then 1 mmol of chalcone (1) in 2 mL DCM was added drop-wise, stirred overnight at room temperature. The precipitate was then filtered off and re-crystallized from ethanol.

4. Conclusions

We have demonstrated the synthesis of a methoxy amide chalcone derivative through the Claisen-Schmidt reaction, followed by amidation.