(E)-4-(3-Oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)prop-1-en-1-yl)benzaldehyde

Abstract

In the present study, (E)-4-(3-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)prop-1-en-1-yl)benzaldehyde (2) was synthesized via a base-catalyzed Claisen–Schmidt condensation of 6-acetylbenzo[d]oxazol-2(3H)-one (1) and terephthalaldehyde and characterized by spectroscopic methods.

1. Introduction

Chalcones are α,β-unsaturated carbonyl compounds widely recognized for their diverse biological properties, including antimicrobial, antifungal, anti-inflammatory, and anticancer activities [1,2,3]. In addition to their biological relevance, chalcones serve as important intermediates in organic synthesis and in the preparation of various heterocyclic systems [2,4]. Incorporation of heterocyclic fragments such as benzoxazolone moieties into chalcone frameworks has been reported to enhance their physicochemical and pharmacological properties [4,5]. In this work, we report the synthesis of a benzoxazolone-containing chalcone derivative as a useful intermediate for further functionalization and preparation of hybrid chalcone derivatives, owing to the presence of a free aldehyde group, which provides a reactive site for further structural modification.

2. Results

The target compound (E)-4-(3-oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)prop-1-en-1-yl)benzaldehyde (2) was obtained from 6-acetylbenzo[d]oxazol-2(3H)-one (1) [6] and terephthalaldehyde via a base-catalyzed Claisen–Schmidt condensation (Scheme 1). The reaction was carried out in an ethanolic potassium hydroxide solution at room temperature for 24 h. After completion of the reaction, as monitored by thin-layer chromatography (TLC), the product was isolated and purified by recrystallization.

The reaction was additionally carried out using different molar ratios of terephthalaldehyde to ketone (1:1, 1:2, and 2:1). In all examined cases, the isolated product corresponded to the mono-condensation product, while one aldehyde group remained unreacted. The selective formation of compound 2 was confirmed by the presence of the aldehyde proton signal at δ 10.04 ppm in the ¹H NMR spectrum and the aldehyde carbon resonance at δ 193.1 ppm in the ¹³C NMR spectrum. Furthermore, no signals attributable to a symmetrical bis-chalcone derivative were detected in the isolated product. Although terephthalaldehyde is commonly employed for the synthesis of symmetrical bis-chalcones under Claisen–Schmidt conditions [7,8], preservation of one aldehyde group has also been reported for terephthalaldehyde or phthalaldehyde-derived chalcone intermediates [9,10].

The observed selectivity may be associated with electronic factors that decrease the reactivity of the second aldehyde group after the initial condensation. Initially, terephthalaldehyde is highly reactive because its two aldehyde groups mutually withdraw electron density from each other through strong inductive (–I) and mesomeric (–M) effects. Following the first condensation, the reacted group transforms into an extended conjugated system (chalcone), which stabilizes the benzene ring via resonance and sharply decreases the electrophilicity of the remaining aldehyde carbon atom.

The structure of compound 2 was established by elemental analysis, FTIR spectroscopy, ¹H and ¹³C NMR spectroscopy, and HRMS. In the ¹H NMR spectrum, the two vinyl protons of the α,β-unsaturated carbonyl system appeared at δ 7.77 and 8.13 ppm with a large coupling constant (J = 15.6 Hz), confirming the E-configuration of the double bond. The aldehyde proton was observed as a singlet at δ 10.04 ppm, indicating that one aldehyde group remained unreacted. The aromatic protons resonated in the expected region between δ 7.23 and 8.14 ppm. The ¹³C NMR spectrum further supported the proposed structure, showing characteristic signals for the aldehyde and conjugated carbonyl carbons at δ 193.1 and 187.6 ppm, respectively, together with the expected aromatic and vinylic carbon resonances. The IR spectrum displayed characteristic absorption bands corresponding to carbonyl functional groups. High-resolution mass spectrometric analysis provided additional support for the proposed structure. HPLC analysis indicated the formation of a single major product with high purity.

3. Materials and Methods

3.1. General

All chemicals were purchased from Acros Organics (Geel, Belgium) and Fluorochem (Hadfield, UK). 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/methanol (3.5:1.5:0.5, v/v) as eluent.

Melting points were determined on a Kruss KSN I N melting point apparatus (Hamburg, Germany). NMR spectra were recorded in DMSO-d₆ on a Bruker Avance III HD 500 spectrometer (Billerica, MA, USA) operating at 500 MHz for ¹H and 125.8 MHz for ¹³C. Chemical shifts are reported in parts per million (δ) relative to the solvent peak, and coupling constants (J) are given in hertz (Hz). High-resolution mass spectra (HRMS) were obtained with an Orbitrap Exploris 120 Mass Spectrometer, Thermo Fisher Scientific (Waltham, Massachusetts, USA). Analytical HPLC was carried out on an Agilent 1100 HPLC system (Santa Clara, CA, USA) equipped with a binary pump and diode array detector. The column used is Agilent Eclipse Plus C18 (Santa Clara, CA, USA) (75 mm × 4.6 mm, 3.5 µm). The mobile phase is AcN:H₂O, using a linear gradient of the binary solvent system (AcN:H₂O from 30:70 to 90:10 v/v% for 7.5 min, with a final time of 5 min) with a flow rate of 0.500 mL⁄min.

3.2. Synthesis

(E)-4-(3-Oxo-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)prop-1-en-1-yl)benzaldehyde (2)

To a solution of 6-acetylbenzo[d]oxazol-2(3H)-one (1) (354 mg, 2 mmol) in 10% aqueous KOH (4 mL), a solution of terephthalaldehyde (536 mg, 4 mmol) in ethanol (6 mL) was added. The reaction mixture was stirred at room temperature for 24 h, during which a precipitate formed. The reaction was monitored to completion by thin-layer chromatography (TLC). The mixture was then poured into water (30 mL) and acidified with 10% hydrochloric acid. The resulting crystalline product was filtered, washed with water until neutral, dried, and recrystallized from ethanol to afford compound 2. Yield: 97% (569 mg).

Light yellow crystals; m.p. 276–278 °C (EtOH). IR (nujol): 1574, 1594, 1655, 1770, 3472 cm⁻¹. ¹H NMR (500 MHz, DMSO-d₆): δ 7.24 (d, 1H, ArH, J = 8.2 Hz), 7.77 (d, 1H, CH=, J = 15.6 Hz), 7.97 (d, 1H, ArH, J = 8.2 Hz), 8.08 (dd, 1H, ArH), 8.11 (d, 1H, ArH, J = 8.2 Hz), 8.13 (d, 1H, CH=, J = 15.6 Hz), 10.04 (s, 1H, CHO). ¹³C NMR (126 MHz, DMSO-d₆): δ 193.12, 187.64, 154.92, 143.95, 142.50, 140.82, 137.42, 135.67, 132.02, 130.30, 129.87, 126.39, 125.12, 110.09, 110.05. HRMS (ESI): Found 294.0759. Calcd. for C₁₇H₁₂NO₄: 294.0766 [M + H]⁺.