(E)-5-(3-Oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)benzo[d]oxazol-2(3H)-one

Abstract

The title compound, (E)-5-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)benzo[d]oxazol-2(3H)-one, was synthesized by the acid- and base-catalyzed aldol condensation of 2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbaldehyde and 3,4,5-trimethoxyacetophenone. The structure of the target compound was confirmed using ¹H NMR, ¹³C NMR, HRMS, and elemental analysis.

1. Introduction

The diverse biological activity and the simple methods for their preparation make chalcones a privileged scaffold in medicinal chemistry [1,2,3]. A large number of natural and synthetic chalcones exhibit anticancer [4,5,6], anti-inflammatory [7], antibacterial [8,9,10], and antioxidant activity [10,11]. An important part in the chalcone molecule is the α,β-unsaturated carbonyl fragment, a Michael acceptor that can covalently interact with the cysteine sulfhydryl groups of protein targets [12,13].

In our previous work, chalcones with a fused oxazole or thiazole motif in ring A showed cytotoxic activity against BV-173, MCF-7, MDA-MB-231, and other cell lines [14,15]. The introduction of the 4-methoxy or 3,4,5-trimetoxy groups in ring B of this series produced chalcones with 4.9–8.3 micromolar range cytotoxicity against BV-173 cells [16]. These results encouraged us to explore placing the azole ring in ring B and the methoxy substituents in ring A of the chalcone scaffold.

The aim of the present work is the synthesis of (E)-5-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)benzo[d]oxazol-2(3H)-one (3). To our knowledge, this is the first example of a heterocyclic chalcone with an oxazole fused to ring B, a prototype for a new series of chalcones with potentially novel biological properties.

2. Results and Discussion

The synthesis of (E)-5-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)benzo[d]oxazol-2(3H)-one (3) was performed by the Claisen–Schmidt condensation of 2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbaldehyde (1) and 3,4,5-trimethoxyacetophenone (2) (Scheme 1). The aldehyde 1 was prepared in three steps, as previously described [17]. Briefly, 4-hydroxy-3-nitrobenzaldehyde protected as the 1,3-propanediol acetal was catalytically reduced to the corresponding aniline, cyclized with 1,1′-carbonyldiimidazole (CDI), and deprotected. The resulting aldehyde 1 was condensed with acetophenone 2 under acid- or base-catalyzed conditions. The acid-catalyzed condensation was performed using SOCl₂/EtOH, as previously described [18]. The base-catalyzed reaction was carried out in ethanol/aqueous NaOH. Both reactions yielded a single product detectable by thin-layer chromatography. The yields were 85% and 89% for the base-catalyzed and acid-catalyzed reactions, respectively.

The structure of compound 3 was confirmed by FTIR, ¹H and ¹³C NMR, HRMS, and elemental analysis, and all the data are in agreement with the assumed structure. The ¹H NMR spectra are consistent with a pure E configuration, as judged by the vinyl proton coupling constant J = 15.5 Hz. The ¹³C NMR spectrum displays 16 signals corresponding to the number of carbon atoms in compound 3. All data are available in the Supplementary Material File (Figures S1–S4).

3. Materials and Methods

3.1. General

All chemicals were purchased from Acros Organics (Geel, Belgium) and Fisher Scientific GmbH (Schwerte, Germany). Reactions and purity of the final compound were monitored by thin-layer chromatography (TLC) on silica gel plates Kieselgel 60 F₂₅₄ (Merck, Darmstadt, Germany), using toluene/chloroform/ethyl acetate (3:1:1 v/v) as eluent.

Melting points were determined on a Boetius hot-stage microscope (Carl Zeiss Jena, Germany). Infrared spectra (FTIR) were acquired on a Shimadzu FTIR 8400S Fourier transform infrared spectrophotometer (Duisburg, Germany) in nujol. NMR spectra were recorded in DMSO-d₆ on a Bruker Avance III HD 500 (Bruker BioSpin GmbH, Rheinstetten, Germany), operating at 500 MHz for ¹H and at 125.8 MHz for ¹³C. Chemical shifts are reported in parts per million (ppm) and were referenced to the residual solvent peaks (DMSO-d₆): 2.50 and 39.52 ppm for ¹H and ¹³C NMR, respectively. Coupling constants (J) were measured in hertz (Hz). High-resolution mass spectra (HRMS) were obtained with an Orbitrap Exploris 120 Mass Spectrometer (Thermo Fisher Scientific GmbH, Bremen, Germany). The elemental analysis was carried out on a VARIO EL III Elemental Analyzer (Elementar Analysensysteme GmbH, Hanau, Germany) and the results for C, H, and N were within ± 0.4% of the theoretical values.

3.2. Synthesis of (E)-5-(3-Oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)benzo[d]oxazol-2(3H)-one (3)

3.2.1. Base-Catalyzed Aldol Condensation

To a suspension of 2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbaldehyde (0.82 g, 5 mmol) and 3,4,5-trimethoxyacetophenone (1.05 g, 5 mmol) in ethanol (25 mL), 30% aq. NaOH (5 mL) was added. The obtained yellow mixture was stirred for 24 h at room temperature to yield a precipitate. The mixture was poured in 30 mL water, warmed, and acidified with 10% HCl. The crystalline product 3 was filtered, washed with cold ethanol and water to neutrality, and dried. Yield: 85% (1.51 g).

3.2.2. Acid-Catalyzed Aldol Condensation

To an ice-cool suspension of 2-oxo-2,3-dihydrobenzo[d]oxazole-5-carbaldehyde (0.82 g, 5 mmol) and 3,4,5-trimethoxyacetophenone (1.05 g, 5 mmol) in absolute ethanol (25 mL), SOCl₂ (3.5 mL) was added slowly. The obtained mixture was stirred for 12 h at room temperature. Water (50 mL) was added and the suspension was heated to boiling. After being cooled to room temperature, the crystalline product 3 was filtered, washed with water, and dried. Yield: 89% (1.58 g).

Light yellow crystals, m.p.: 228–230 °C (ethanol). IR (nujol): 3227 (N-H), 1812 (C=O), 1779 (C=O), 1652 (C=C), 1571 (C=C), 1129 (O-C-O), 902 (C-H) cm⁻¹. ¹H NMR (500 MHz, DMSO-d₆): δ (ppm) 3.76 (s, 3H, OCH₃), 3.90 (s, 6H, OCH₃), 7.37 (d, 1H, arom. H, J = 8.2 Hz), 7.43 (s, 2H, arom. H), 7.66 (m, 2H, arom. H), 7.77 (d, 1H, =CHCO, J = 15.5 Hz), 7.91 (d, 1H, ArCH=, J = 15.5 Hz), 11.89 (br.s., 1H, NH). ¹³C NMR (125.8 MHz, DMSO-d₆): δ (ppm) 56.2, 60.2, 106.2, 109.4, 109.8, 121.3, 124.2, 130.9, 131.2, 133.1, 142.0, 143.8, 145.1, 152.9, 154.5, 187.9. HRMS (ESI): Found 356.1132. Calcd. for C₁₉H₁₇NO₆: 356.1134 [M + H]⁺. Anal. calcd. for C₁₉H₁₇NO₆ (355.35): C, 64.22; H, 4.82; N 3.94. Found: C, 64.39; H, 4.82; N, 3.63.