(Z)-N-Carbamoyl-4-hydroxy-4-(4-methoxyphenyl)-2-oxobut-3-enamide

Abstract

The reaction of 5-(4-methoxyphenyl)furan-2,3-dione with urea in a 1:1 ratio when refluxed in a mixture of 1,2-dichloroethane-DMSO gives (Z)-N-carbamoyl-4-hydroxy-4-(4-methoxyphenyl)-2-oxobut-3-enamide in a good yield. This compound was fully characterized.

1. Introduction

Compounds whose structures are based on an imidazolidinedione fragment (hydantoin) are of particular interest to the pharmaceutical industry as substances with anticancer activity [1,2,3], as kinase [3,4] and COVID-19 [5,6] inhibitors (dantrolene) and anticonvulsant agents [4,7] (Figure 1). Thus, the development of new synthetic approaches to compounds bearing an imidazolidinedione core is in demand.

Currently, our research group is interested in the study of the synthetic potential and other useful properties of enaminones (enaminoketones) fused to a heterocyclic moiety [8,9,10,11]. Eventually, we decided to start an investigation into the imidazolidinedione bearing enaminones, 5-aroylmethylideneimidazolidine-2,4-diones II (Scheme 1) [12]. Earlier, the formation of imidazolidinedione bearing enaminones II was described by fusing 5-arylfuran-2,3-diones I with urea at a temperature of 110–120 °C for 1.5 h (Scheme 1) [12]. Pursuing the development of a synthetic protocol for enaminones II under milder conditions than used in [12], we synthesized an intermediate of the reaction of 5-arylfuran-2,3-diones I and urea, (Z)-N-carbamoyl-4-hydroxy-4-(4-methoxyphenyl)-2-oxobut-3-enamide 1, whose synthesis and characteristics are reported herein.

2. Results and Discussion

The title compound 1 was synthesized in several stages (Scheme 2). Initially, 5-(4- methoxyphenyl)-furan-2,3-dione 2 was obtained in the reaction of 4-(4-methoxyphenyl)-2,4-dioxobutanoic acid with thionyl chloride [8]. Then, as a result of the reaction of compound 2 with urea 3, (Z)-N-carbamoyl-4-hydroxy-4-(4-methoxyphenyl)-2-oxobut-3-enamide 1, the target compound, was obtained for the first time. After three days of exposure in DMSO solution at rt, compound 1 cyclized into 5-hydroxy-5-(2-(4-methoxyphenyl)-2-oxoethyl)imidazolidine-2,4-dione 4. Although compound 4 was observed by NMR, it was not isolated.

The structure of compound 1 was unambiguously confirmed by X-ray diffraction analysis of a single crystal (CCDC 2358753) (Figure 2).

3. Materials and Methods

3.1. General Information

¹H and ¹³C NMR spectra (Supplementary Materials) were obtained on a Bruker Avance III 400 HD spectrometer (Bruker BioSpin AG, Faellanden, Switzerland) (at 400 and 100 MHz, respectively) in DMSO-d₆ using the solvent residual signal (in ¹H NMR, 2.50 ppm; in ¹³C NMR, 39.51 ppm) as an internal standard. The IR spectrum was recorded on a Perkin Elmer Spectrum Two Spectrometer (PerkinElmer Inc., Waltham, MA, USA) as mulls in mineral oil. The melting point was measured on the device of the Khimlabpribor PTP (Khimlabpribor, Klin, Moscow, Russia). HRMS were recorded on Bruker MicroTOF (ESI+) (Bruker Daltonik GmbH, Bremen, Germany). The single-crystal X-ray analysis of compound 1 was performed on an Xcalibur Ruby diffractometer (Agilent Technologies, Wroclaw, Poland). An empirical absorption correction was introduced via the multi-scan method using the SCALE3 ABSPACK algorithm [13]. Using OLEX2 [14], the structure was solved with the SHELXT [15] program and refined by full-matrix least-squares minimization in the anisotropic approximation of all non-hydrogen atoms with the SHELXL [16] program. Hydrogen atoms bound to carbon were positioned geometrically and refined using a riding model. Hydrogen atoms of the OH, NH, and NH₂ groups were refined independently with isotropic displacement parameters. 4-(4-Methoxyphenyl)-2,4-dioxobutanoic acid was obtained according to the reported procedures [17] from commercially available reagents. The starting compound 2 was obtained according to the reported procedures from commercially available reagents [8]. All procedures with compound 2 were performed in oven-dried glassware. All other solvents and reagents were purchased from commercial vendors and used as received.

3.2. (Z)-N-Carbamoyl-4-hydroxy-4-(4-methoxyphenyl)-2-oxobut-3-enamide 1

A solution of 0.423 g (7.05 mmol) of urea 3 in 2 mL of DMSO was added to a solution of 1.44 g (7.05 mmol) of 5-(4-methoxyphenyl)-furan-2,3-dione 2 in 10 mL of anhydrous 1,2-dichloroethane and refluxed for 5 min. Next, the reaction mixture was cooled to room temperature. The formed precipitate was filtered off and recrystallized from chloroform to yield the title compound 1. Yield: 1.14 g (61%); light yellow solid; mp 159–161 °C (decomp.). ¹H NMR (DMSO-d₆, 400 MHz), mixture of tautomers ∼ 5:1 (A:B): A: δ = 3.88 (s, 3H), 7.09 (s, 1H), 7.11 (d, 2H, J = 8.8 Hz), 7.46 (br.s, 1H), 7.53 (br.s, 1H), 8.07 (d, 2H, J = 8.8 Hz), 10.07 (s, 1H), 14.0 (br.s, 1H) ppm; B: δ = 3.86 (s, 3H), 4.50 (s, 2H), 7.06 (d, 2H, J = 8.8 Hz), 7.27 (br.s, 2H), 7.95 (d, 2H, J = 8.8 Hz), 10.13 (s, 1H) ppm. ¹³C NMR (DMSO-d₆, 100 MHz), mixture of tautomers, A: δ = 55.6, 94.3, 114.5 (2C), 125.7, 130.1 (2C), 152.3, 162.2, 164.1, 174.9, 186.2 ppm. IR (mineral oil): 3420, 3343, 3200, 3100, 1721, 1705, 1583 cm⁻¹. HRMS (ESI+): m/z calcd for C₁₂H₁₂N₂O₅: 287.0638 [M + Na]⁺; found: 287.0634. After three days of exposure in DMSO-d₆ solution in an NMR tube, compound 1 cyclized into 5-hydroxy-5-(2-(4-methoxyphenyl)-2-oxoethyl)imidazolidine-2,4-dione 4. ¹H NMR (DMSO-d₆, after three days, 400 MHz): δ = 3.41 (d, 1H, J = 17.6 Hz), 3.63 (d, 1H, J = 17.6 Hz), 3.85 (s, 3H), 6.60 (s, 1H), 7.04 (d, 2H, J = 8.8 Hz), 7.91 (d, 2H, J = 8.8 Hz), 8.10 (s, 1H), 10.51 (s, 1H) ppm. ¹³C NMR (DMSO-d₆, after three days, 100 MHz): δ = 43.6, 55.5, 82.8, 113.9 (2C), 129.1, 130.2 (2C), 156.4, 163.3, 175.0, 194.2 ppm.

Crystal data of compound 1. C₁₂H₁₂N₂O₅, M = 264.24, triclinic, space group P–1, a = 7.8501(11) Å, b = 8.6851(14) Å, c = 9.8080(15) Å, α = 68.302(15)°, β = 86.023(12)°, γ = 77.008(13)°, V = 605.34(17) ų, T = 295(2) K, Z = 2, μ(Mo Kα) = 0.115 mm⁻¹. The final refinement parameters: R₁ = 0.0476 (for observed 2180 reflections with I > 2σ(I)); wR₂ = 0.1377 (for all independent 2801 reflections, R_int = 0.0282), S = 1.058. Largest diff. peak and hole were 0.226 and −0.215 ēÅ⁻³. Crystal structure of compound 1 was deposited at the Cambridge Crystallographic Data Centre with the deposition number CCDC 2358753.